WO2022127847A1 - Dérivé de pyrimidone et son utilisation dans un médicament - Google Patents

Dérivé de pyrimidone et son utilisation dans un médicament Download PDF

Info

Publication number
WO2022127847A1
WO2022127847A1 PCT/CN2021/138693 CN2021138693W WO2022127847A1 WO 2022127847 A1 WO2022127847 A1 WO 2022127847A1 CN 2021138693 W CN2021138693 W CN 2021138693W WO 2022127847 A1 WO2022127847 A1 WO 2022127847A1
Authority
WO
WIPO (PCT)
Prior art keywords
isopropyl
oxo
mmol
chf
och
Prior art date
Application number
PCT/CN2021/138693
Other languages
English (en)
Chinese (zh)
Inventor
习宁
李敏雄
吴双
席云龙
廖敏
梁恩
冯学金
Original Assignee
广东东阳光药业有限公司
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 广东东阳光药业有限公司 filed Critical 广东东阳光药业有限公司
Publication of WO2022127847A1 publication Critical patent/WO2022127847A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a new class of compounds as KRAS activity inhibitors, a method for preparing them, a pharmaceutical composition comprising the compound, and the application of the compound and the pharmaceutical composition in the treatment of various diseases . More specifically, the compounds described in the present invention can act as inhibitors of the activity or function of KRAS G12C.
  • KRAS is a murine sarcoma virus gene.
  • the KRAS gene encodes a 21kD ras protein, also known as the p21 gene.
  • RAS the ras gene family associated with human tumors
  • KRAS has the greatest impact on human cancers, accounting for 86% of all RAS mutations. It acts like a molecular switch: when normal, it controls the pathway that regulates cell growth; when abnormal, it causes cells to continue growing and stops them self-destruction. It is involved in intracellular signal transmission.
  • the K-ras gene is mutated, the gene is permanently activated and normal ras protein cannot be produced, resulting in disordered intracellular signal transduction, uncontrolled cell proliferation and canceration.
  • KRAS G12C mutation is a relatively common subtype of KRAS gene mutation, which refers to the mutation of glycine No. 12 to cysteine.
  • KRAS G12C mutation is the most common in lung cancer. According to the data reported in the literature (Nat Rev Drug Discov 2014; 13:828-851), KRAS G12C mutation accounts for about 10% of all lung cancer patients.
  • the present invention provides a compound, or a pharmaceutical composition thereof, which acts as an inhibitor of KRAS.
  • the present invention further relates to the use of the compound or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a disease and/or disorder by inhibiting the activity of KRAS by the compound.
  • the present invention further describes the synthesis of said compounds.
  • the compounds of the present invention exhibit excellent biological activity and pharmacokinetic properties.
  • the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide of a compound represented by formula (I) compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • X is -LX 1 -, wherein L is a bond or NH, X 1 is a 4-8-membered monocyclic ring, 5-12-membered condensed ring, 5-12-membered spirocyclic ring or 5-12-membered bridged ring containing nitrogen atoms,
  • the 4-8-membered monocyclic ring, 5-12-membered fused ring, 5-12-membered spiro ring and 5-12-membered bridged ring can be independently optionally substituted with m R x ;
  • Y is N or CH
  • Z is N or CR 2e ;
  • R a and R b are each independently hydrogen, deuterium, halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy groups;
  • R c is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkylamino, 5-6-membered heteroaryl, C 3-6 carbocyclic or 3-6-membered heterocyclic, wherein the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 Carbocyclyl and 3-6 membered heterocyclyl are independently optionally substituted by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C1 -3 alkyl, C 1-3 haloalkyl, C 1-3
  • R 3 is C 6-12 aryl or 5-10-membered heteroaryl, wherein the C 6-12 aryl and 5-10-membered heteroaryl are independently optionally substituted by n R y ;
  • R 2a , R 2b , R 2c , R 2d and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1- 3 alkoxy, C 1-3 haloalkoxy and
  • Each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclic group; wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkoxy Amino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl are independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C
  • n 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • n 1, 2, 3, 4, 5, 6 or 7.
  • X is Wherein, the m and R x have the meanings described in the present invention.
  • R and R are each independently hydrogen, deuterium , halogen, methyl, ethyl, n -propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, Ethoxy or isopropoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl , difluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups;
  • R c is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, - CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclo Butenyl, cyclopentenyl, cyclo
  • R 3 is C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 6-10 aryl and 5-10 membered heteroaryl are independently optionally separated by n R y replaced.
  • R is Among them, the said independently optionally substituted with n R ys .
  • R 2a , R 2b , R 2c , R 2d , and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 Alkylamino is independently optionally 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxy, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 substituted by groups of haloalkyl, C 1-3 alkoxy,
  • R 2a , R 2b , R 2c , R 2d , and R 2e are each independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl radical, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino or ethylamino;
  • each R x is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 membered heterocycle wherein, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy , C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxygen substituted, amino, nitro, cyano, C 1-3 alkyl, C 3-6 cyclo
  • each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, alkene Propyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy , ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino , dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cycl
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention, or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, or solvate thereof , metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles or combinations thereof.
  • the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the manufacture of a medicament for the prevention, treatment or alleviation of KRAS G12C mediated diseases in a patient.
  • the KRAS G12C-mediated disease of the invention is cancer.
  • the cancer of the present invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer , liver, bile duct, breast, colon, appendix, small bowel, leukemia and melanoma.
  • the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).
  • the articles “a”, “an” and “the” are intended to include “at least one” or “one or more” unless stated otherwise or otherwise clearly contradicted by context.
  • these articles refer to one or more than one (ie, at least one) object of the article.
  • a component refers to one or more components, ie, there may be more than one component contemplated for use or use in the implementation of the described embodiments.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to a human.
  • Stereoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans isomers), atropisomers, etc. .
  • Chiral is a molecule that has the property of being non-superimposable with its mirror image; while “achiral” refers to a molecule that is superimposable with its mirror image.
  • Enantiomer refers to two nonsuperimposable, but mirror-image isomers of a compound.
  • Diastereomer refers to a stereoisomer having two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Diastereomeric mixtures can be separated by high resolution analytical procedures such as electrophoresis and chromatography, eg HPLC.
  • any asymmetric atom (eg, carbon, etc.) of the compounds disclosed herein may exist in racemic or enantiomerically enriched forms, such as (R)-, (S)- or (R,S)-configurations exist.
  • each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 70% enantiomeric excess in the (R)- or (S)-configuration 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • the compounds of the present invention may be present as one of the possible isomers or as mixtures thereof, such as racemates and diastereoisomeric mixtures (depending on the number of asymmetric carbon atoms) ) in the form of.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have the cis or trans configuration.
  • any resulting racemate of the final product or intermediate can be resolved into the optical enantiomers by known methods by methods familiar to those skilled in the art, eg, by performing diastereomeric salts thereof obtained. separation. Racemic products can also be separated by chiral chromatography, eg, high performance liquid chromatography (HPLC) using chiral adsorbents.
  • enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Principles of Asymmetric Synthesis (2 nd Ed. Robert E.
  • tautomer or "tautomeric form” refers to structural isomers having different energies that are interconvertible through a low energy barrier.
  • a chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution).
  • protontautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by recombination of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • substituted means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds.
  • substituents such as the compounds of the general formula above, or as in the Examples, subclasses, and subclasses encompassed by the present invention. a class of compounds.
  • optionally substituted by is used interchangeably with the term “unsubstituted or substituted by”, ie the structure is unsubstituted or substituted by one or more of the present invention group substitution; when the number of the substituents is greater than 1, the substituents may be the same or different from each other. For example, “optionally substituted by 1, 2, 3, 4 or 5 groups selected from " described in the present invention, when the number of the substituents is greater than 1, the substituents may
  • C1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl groups .
  • C n1-n2 means that the number of carbon atoms contained in the group is n1-n2, both n1 and n2 are natural numbers other than 0, and n2 is greater than n1, and the "n1-n2" includes n1 , n2, and any natural number in between.
  • C 1-6 alkyl group represents an alkyl group containing 1-6 carbon atoms
  • C 1-6 alkoxy group represents an alkoxy group containing 1-6 carbon atoms
  • C 3-6 carbocyclic group represents an alkoxy group containing 3- Carbocyclyl of 6 carbon atoms.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood to be the linking group.
  • the Markush group definition for that variable recites “alkyl” or “aryl”, it should be understood that the “alkyl” or “aryl” respectively represents the linking An alkylene group or an arylene group.
  • alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally be is substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms.
  • the alkyl group contains 1-12 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms, denoted as C 1-6 alkyl; in yet other implementations In the scheme, the alkyl group contains 1-4 carbon atoms, denoted as C 1-4 alkyl; also in some embodiments, the alkyl group contains 1-3 carbon atoms, denoted as C 1-3 alkane base.
  • alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2CH3 ) ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2CH2CH2CH2CH3), 2 -pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 - pentyl (-CH( CH2CH3 ) 2 ) , 2 -methyl
  • alkenyl refers to a linear or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp 2 double bond, wherein the alkenyl group A group can be optionally substituted with one or more substituents described herein, including the “cis” and “trans” positions, or the “E” and “Z” positions.
  • an alkenyl group contains 2-8 carbon atoms; in another embodiment, an alkenyl group contains 2-6 carbon atoms, denoted as C 2-6 alkenyl; in yet another embodiment In the scheme, alkenyl groups contain 2-4 carbon atoms and are denoted as C 2-4 alkenyl.
  • alkynyl refers to a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, wherein there is at least one site of unsaturation, i.e., a carbon-carbon sp triple bond, wherein the alkynyl group Can be optionally substituted with one or more of the substituents described herein.
  • the alkynyl group contains 2-8 carbon atoms; in other embodiments, the alkynyl group contains 2-6 carbon atoms, denoted as C 2-6 alkynyl; in still other implementations In the scheme, alkynyl groups contain 2-4 carbon atoms and are denoted as C 2-4 alkenyl.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH2C ⁇ CH), 1 -propynyl (propynyl, -C ⁇ C-CH) 3 ) and so on.
  • alkoxy means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In some embodiments, alkoxy groups contain 1-6 carbon atoms, denoted C 1-6 alkoxy; in other embodiments, alkoxy groups contain 1-4 carbon atoms, denoted is C 1-4 alkoxy; in yet other embodiments, the alkoxy group contains 1-3 carbon atoms, denoted as C 1-3 alkoxy.
  • the alkoxy groups may be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butanyl Oxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1 -pentyloxy (n - pentyloxy, -OCH2CH2CH2CH2CH2
  • haloalkyl or “haloalkoxy” denotes an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl group and the alkoxy group are as specifically defined herein. Such examples include, but are not limited to, trifluoromethyl, trifluoromethoxy, and the like.
  • hydroxyalkoxy refers to an alkoxy group substituted with one or more hydroxy groups, examples of which include, but are not limited to, -OCH2OH , -OCH2CH2OH , and the like.
  • Carbocyclyl or “carbocycle” refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms.
  • Carbobicyclyl groups include spirocarbobicyclyl, fused carbobicyclyl, and bridged carbobicyclyl groups, and suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl.
  • carbocyclyl groups further include, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl- 3-alkenyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • cycloalkyl refers to a monovalent or polyvalent non-aromatic saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms; in still other embodiments, the cycloalkyl group contains 3-6 carbon atoms carbon atom. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The cycloalkyl group is optionally substituted with one or more substituents described herein.
  • heterocycle refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing 3 to 14 ring atoms, wherein One or more atoms on the ring are independently replaced by a heteroatom having the meaning as defined in the present invention, the ring may be fully saturated or contain one or more degrees of unsaturation, but an aromatic ring may be not allowed.
  • a “heterocycle”, “heterocyclyl” or “heterocyclic” group is a 3-8 membered monocyclic ring (2-6 carbon atoms and selected from N, O, P, S 1-3 heteroatoms, where S or P are optionally substituted with one or more oxygen atoms to give groups like SO, SO2, PO, PO2 ) , or a 7-12 membered bicyclic ring ( 4 - 9 carbon atoms and 1-3 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give like SO, SO 2 , PO, PO 2 groups).
  • a “heterocycle”, “heterocyclyl” or “heterocyclic” group is a 3-6 membered monocyclic ring (2-4 carbon atoms and selected from N, O, P, 1-3 heteroatoms of S, where S or P are optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2 ) .
  • the heterocyclyl group is optionally substituted with one or more substituents described herein.
  • heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl , pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Amyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl , Dioxanyl, Dithianyl, Thioxanyl, Homopiperazinyl, Homopiperi
  • oxidized sulfur atoms in a heterocyclyl group include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like.
  • the heterocyclyl group is optionally substituted with one or more substituents described herein.
  • aryl refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic A family of rings in which each ring system contains a ring of 3-7 atoms with one or more points of attachment to the rest of the molecule.
  • aryl is used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group is optionally substituted with one or more substituents described herein.
  • heteroaryl or “heteroaromatic ring” means a monovalent or polyvalent monocyclic, bicyclic or tricyclic ring containing 5-14 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms A system in which at least one ring is aromatic and at least one ring contains one or more heteroatoms.
  • a heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group.
  • heteroaryl may be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic”.
  • the heteroaryl group is optionally substituted with one or more substituents described herein.
  • heteroaryl groups of 5-10 ring atoms contain 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, 5-6 rings Atomic heteroaryl is a monocyclic ring system and contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • nitrogen-containing monocyclic ring refers to a monocyclic ring of 4-8 ring atoms containing 1 or 2 nitrogen atoms, the ring may be fully saturated or contain one or more degrees of saturation, but not aromatic.
  • monocyclic rings containing nitrogen atoms include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and the like.
  • the nitrogen-containing monocyclic ring is optionally substituted with one or more substituents described herein.
  • fused bicyclic means a monovalent or polyvalent saturated or Partially unsaturated ring system
  • the ring system refers to a non-aromatic bicyclic ring system, the two rings in the ring system share two adjacent carbon atoms.
  • Such systems may contain independent or conjugated unsaturated systems, but whose core structure does not contain aromatic rings or aromatic heterocycles (although aromatic groups may serve as substituents thereon).
  • nitrogen-containing fused ring refers to a fused ring containing 1 or 2 nitrogen atoms, and examples of nitrogen-containing fused rings include, but are not limited to, octahydropyrrolo[3,4-c]pyrrole, and the like .
  • the fused ring is optionally substituted with one or more substituents described herein.
  • spirocyclyl spirocycle
  • spirobicyclyl spirobicyclyl
  • spirobicyclyl spirobicyclyl
  • nitrogen-containing spirocycle refers to a spirocycle containing 1 or 2 nitrogen atoms
  • nitrogen-containing spirocycles include, but are not limited to, 2,7-diazaspiro[3.5]nonane , 2,6-diazaspiro[3.3]heptane and so on.
  • the spiro ring is optionally substituted with one or more substituents described herein.
  • bridged ring or “bridged ring group” refers to a saturated or partially unsaturated bridged ring system, involving a non-aromatic bicyclic ring system, such as shown in formula (b), that is, ring A1 and ring A2 share an alkane chain or A heteroalkane chain wherein each X3 is independently optionally a carbon atom or a heteroatom and j is 1, 2, 3 or 4.
  • Such systems contain 5-12 ring atoms, may contain independent or conjugated unsaturation, but their core structure does not contain aromatic or aromatic rings (although aromatics may be used as substituents thereon).
  • nitrogen-containing bridged ring refers to a bridged ring containing 1 or 2 nitrogen atoms
  • nitrogen-containing bridged rings include, But not limited to, (1R,5S)-3,8-diazabicyclo[3.2.1]octane and the like.
  • the bridged ring is optionally substituted with one or more substituents described herein.
  • j-k ring atoms or "j-k membered” are used interchangeably herein to mean that the cyclic group consists of j-k ring atoms including carbon atoms and/or O, Hetero atoms such as N, S, P, etc.
  • the j and k are each independently any non-zero natural number, and k>j; the "j-k” includes j, k and any natural number in between.
  • 3-8 atoms or 3-8 elements means the cyclic group consists of 3-8 (ie, 3, 4, 5, 6, 7 or 8), 3-6 (ie, 3, 4, 5 or 6), 5-10 (ie, 5, 6, 7, 8, 9 or 10) or 5-6 (ie, 5 or 6) ring atoms including carbon atoms and/or O , N, S, P and other heteroatoms.
  • heteroaryl of 5-10 ring atoms or “heteroaryl of 5-10 members” means that it includes a heteroaryl group of 5, 6, 7, 8, 9, or 10 ring atoms wherein 5, 6, 7, 8, 9 or 10 represent the number of ring atoms, eg pyridyl is a heteroaryl or 6-membered heteroaryl consisting of 6 ring atoms.
  • heteroatom refers to O, S, N, P, and Si, including N, S, and P in any oxidation state; in the form of primary, secondary, tertiary amines, and quaternary ammonium salts; or on a nitrogen atom in a heterocyclic ring.
  • Hydrogen substituted form for example, N (like N in 3,4-dihydro-2H-pyrrolidinyl), NH (like NH in pyrrolidinyl) or NR (like in N-substituted pyrrolidinyl) NR, R are the substituents described in the present invention).
  • halogen or "halogen atom” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkylamino or “alkylamino” includes “N-alkylamino” and "N,N-dialkylamino” wherein the amino group is independently substituted with one or two alkyl groups, respectively.
  • the alkylamino group is an alkylamino group formed by one or two C1-6 alkyl groups attached to a nitrogen atom.
  • the alkylamino group is an amino group substituted with one or two C1-3 alkyl groups.
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino (methylamino), N-ethylamino (ethylamino), N,N -Dimethylamino (dimethylamino), N,N-diethylamino (diethylamino), etc.
  • aminoalkyl includes a C 1-10 straight or branched chain alkyl group substituted with one or more amino groups.
  • the aminoalkyl group is a C 1-6 aminoalkyl group substituted with one or more amino groups, such examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl , aminobutyl and aminohexyl.
  • the ring system formed by the substituent (R x ) m being attached to the central ring by a bond represents m substituents R x can be carried out at any substitutable position or any reasonable position on the present ring. replace.
  • Formula d represents that the G ring may be substituted with m Rx, and when m is greater than 1 , each Rx may be independently selected from the same or different substituent groups.
  • An attachment point can be attached to the rest of the molecule at any linkable position on the loop as described herein.
  • formula e represents that any position on the C-ring or the D-ring that may be attached can serve as a point of attachment.
  • linking sites on the substructure of the group X there are two linking sites on the substructure of the group X that can be connected to the rest of the molecule, and the linking modes of the two linking sites can be interchanged.
  • X is When the general formula (I) of the present invention represents that the N connecting end on X 1 is connected to R 1 , and the other C connecting end is connected to the rest of the general formula (I), as shown in formula f; or that the C connecting end on X is connected R 1 , the other N-connected end connecting the rest of formula (I),
  • protecting group refers to a substituent group that is commonly used to block or protect specific functionality when it reacts with other functional groups.
  • amino protecting group refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC, Boc), benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenemethyleneoxycarbonyl (Fmoc).
  • hydroxyl protecting group refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group
  • suitable protecting groups include acetyl and silyl.
  • Carboxyl protecting group means that the substituent of the carboxyl group is used to block or protect the functionality of the carboxyl group.
  • General carboxyl protecting groups include -CH 2 CH 2 SO 2 Ph, cyanoethyl, 2-(trimethylsilane) yl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl) phosphino)ethyl, nitroethyl, and the like.
  • protecting groups reference can be made to the literature: TW. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable when administered to humans and generally do not produce allergic or similar inappropriate reactions, such as gastrointestinal upset, dizziness, and the like.
  • pharmaceutically acceptable as used herein means approved by a federal regulatory agency or a national government or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, particularly in humans.
  • carrier refers to a diluent, adjuvant, excipient or base with which the compound is administered.
  • These pharmaceutical carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water and Aqueous Solutions Saline solutions and aqueous dextrose and glycerol solutions are preferred for use as carriers, especially for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin.
  • prodrug refers to the conversion of a compound into a compound of formula (I) in vivo. Such conversion is effected by hydrolysis of the prodrug in blood or enzymatic conversion to the parent structure in blood or tissue.
  • the prodrug compounds of the present invention can be esters.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonate esters , carbamates and amino acid esters.
  • a compound that contains a hydroxyl group can be acylated to give the compound in prodrug form.
  • prodrug forms include phosphates, such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • phosphates such as these phosphates are phosphorylated by the hydroxyl group on the parent.
  • a complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008, 51, 2328-2345.
  • Metal refers to a product obtained by metabolism of a specific compound or salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized using assays as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
  • pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: S.M.Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as Acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, etc., or obtain these salts by other methods described in books such as ion exchange.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, inorganic base salts, such as ammonium salts and metal salts of Groups I to XII of the periodic table, and organic base salts, such as those formed with primary, secondary, and tertiary amines. Salt.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association in which the solvent molecule is water.
  • any disease or disorder in some embodiments refers to ameliorating the disease or disorder (ie, slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by a patient. In other embodiments, “treating” refers to modulating a disease or disorder physically (eg, stabilizing an observable symptom) or physiologically (eg, stabilizing a physical parameter), or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to effect the treatment of such disease.
  • a “therapeutically effective amount” can vary depending on the compound, the disease and severity, and the condition, age, weight, sex, etc. of the subject to be treated.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moieties, using conventional chemical methods.
  • such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (eg, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by The preparations are carried out by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a suitable base eg, hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K
  • Such reactions are usually carried out in water or an organic solvent or a mixture of the two.
  • non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required.
  • non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
  • the compounds disclosed herein, including their salts can also be obtained in their hydrate form or in a form containing a solvent (eg, ethanol, DMSO, etc.) for their crystallization.
  • a solvent eg, ethanol, DMSO, etc.
  • Compounds of the present disclosure may form solvates, inherently or by design, with pharmaceutically acceptable solvents, including water; thus, the present invention is intended to include both solvated and unsolvated forms.
  • Isotopically enriched compounds have the structures depicted by the general formulae given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number.
  • Exemplary isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 15N , 17O , 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • Isotopically enriched compounds of the present invention can be prepared by conventional techniques familiar to those skilled in the art or as described in the Examples and Preparations of this invention, using a suitable isotopically labeled reagent in place of the previously used unlabeled reagent.
  • cancer refers to or describes a physiological condition in a patient that is often characterized by uncontrolled cell growth.
  • a “tumor” includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies.
  • cancers include squamous cell carcinoma (eg, epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma), esophageal cancer, Peritoneal cancer, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, appendix cancer, small bowel cancer, endometrial or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, Cancer of the vulva, thyroid, liver, anus, penis, and head and neck.
  • squamous cell carcinoma eg, epithelial squamous cell carcinoma
  • lung cancer including small cell lung cancer, non-small cell lung cancer (NSCLC), lung
  • KRAS G12C inhibitor used in the present invention refers to a substance that can bind to KRAS G12C and inhibit its activity.
  • the present invention provides a compound or a pharmaceutical composition thereof, which can act as an inhibitor of KRAS, especially KRAS G12C.
  • the present invention further relates to the use of the compound or a pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a disease and/or disorder by inhibiting the activity of KRAS G12C with the compound.
  • the present invention further describes methods of synthesizing the compounds.
  • the compounds of the present invention exhibit improved biological activity and pharmacokinetic properties.
  • the present invention relates to a compound, which is a compound represented by formula (I), or a stereoisomer, geometric isomer, tautomer, nitroxide of a compound represented by formula (I) compounds, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,
  • each of X, Y, Z, R 1 , R 2a , R 2b , R 2c , R 2d and R 3 has the meaning described in the present invention.
  • X is -LX 1 -, wherein L is a bond or NH, and X 1 is a nitrogen-containing 4-8 membered monocyclic, 5-12 membered fused ring, 5-12 membered spirocyclic ring, or 5-membered -12-membered bridged rings, the 4-8-membered monocycles, 5-12-membered fused rings, 5-12-membered spiro rings, and 5-12-membered bridged rings can be independently optionally substituted with m Rx ; wherein Rx and m have the meaning described in the present invention.
  • the 4-8-membered monocyclic ring, 5-12-membered fused ring, 5-12-membered spirocyclic ring or 5-12-membered bridged ring containing nitrogen atoms in the present invention refers to the single ring, fused ring, spiro ring Rings and bridged rings each independently contain 1 or 2 nitrogen atoms.
  • X is wherein Rx and m have the meanings described in the present invention.
  • Y is N or CH.
  • Z is N or CR 2e ; wherein R 2e has the meaning described herein.
  • R a is hydrogen, deuterium, halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
  • Ra is hydrogen, deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropyl Propoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently optionally substituted by 1, 2, 3 , 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.
  • R b is hydrogen, deuterium, halogen atom, C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkoxy, wherein the C 1-3 alkyl, C 1-3 haloalkyl and C 1-3 alkoxy independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano , C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy and C 1-3 hydroxyalkoxy.
  • R is hydrogen, deuterium , halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl, methoxy, ethoxy, or isopropyl Propoxy, wherein said methyl, ethyl, n-propyl, isopropyl, difluoromethyl, methoxy, ethoxy and isopropoxy are independently optionally substituted by 1, 2, 3 , 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, difluoromethyl , methoxy, ethoxy, isopropoxy, trifluoromethoxy, -OCH 2 OH and -OCH 2 CH 2 OH groups.
  • R c is hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl, C 3-6 carbocyclic or 3-6 membered heterocyclic, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, 5-6 membered heteroaryl group, C 3-6 carbocyclyl and 3-6 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro , cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy
  • Rc is hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF2 , -CF3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl, cyclo Hexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, methylamino
  • R 3 is C 6-12 aryl or 5-10 membered heteroaryl, wherein said C 6-12 aryl and 5-10 membered heteroaryl are independently optionally separated by n R y is substituted; wherein n is 1, 2, 3, 4, 5, 6 or 7, and R y has the meaning described herein.
  • R 3 is C 6-10 aryl or 5-10 membered heteroaryl, wherein said C 6-10 aryl and 5-10 membered heteroaryl are independently optionally surrounded by n Ry is substituted; n is 1, 2, 3, 4, 5, 6 or 7, wherein Ry has the meaning described herein.
  • R3 is Among them, the said independently optionally substituted with n R y ; wherein n is 1, 2, 3, 4, 5, 6 or 7 and R y has the meaning described herein.
  • R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 2-4 alkene group, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 haloalkoxy and C 1-3 hydroxyalkoxy groups are substituted.
  • R 2a is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropy
  • R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 2-4 alkene group, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 haloalkoxy and C 1-3 hydroxyalkoxy groups are substituted.
  • R 2b is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropy
  • R 2c is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 2c is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 2-4 alkene group, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 haloalkoxy and C 1-3 hydroxyalkoxy groups are substituted.
  • R 2c is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropy
  • R 2d is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 2d is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 2-4 alkene group, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 haloalkoxy and C 1-3 hydroxyalkoxy groups are substituted.
  • R 2d is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropy
  • R 2e is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkyne group, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 1-6 alkylamino; wherein, the C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy and C 1-6 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1-3 substituted with haloalkoxy and C 1-3 hydroxyalkoxy groups.
  • R 2e is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy or C 1-4 alkylamino; wherein, the C 1-4 alkyl, C 2-4 alkene group, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy and C 1-4 alkylamino are independently optionally replaced by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxo, amino, nitro, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 1- 3 haloalkoxy and C 1-3 hydroxyalkoxy groups are substituted.
  • R 2e is hydrogen, deuterium, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy, ethoxy radical, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methylamino, dimethyl Amino or ethylamino; wherein, the methyl, ethyl, n-propyl, isopropy
  • each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocycle wherein, the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 alkylamino, C 3-8 cycloalkyl and 3-8 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, oxygen substituted, amino, nitro, cyano, C 1-3 alkyl, C 1-3
  • each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, C1-4 alkyl, C2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl or 3-6 membered hetero Cyclic group; wherein, the C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy group, C 1-4 alkylamino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl independently optionally by 1, 2, 3, 4 or 5 independently selected from deuterium, halogen, hydroxyl, of oxo, amino, nitro, cyano, C 1-3 alkyl
  • each Rx is independently deuterium, fluorine, chlorine, bromine, iodine, hydroxy, oxo, amino, nitro, cyano, methyl, ethyl, n-propyl, isopropyl, Allyl, propenyl, propargyl, propynyl, -CHF 2 , -CF 3 , -CHFCH 2 F, -CF 2 CHF 2 , -CH 2 CF 3 , -CH 2 CF 2 CHF 2 , methoxy group, ethoxy, n-propoxy, isopropoxy, -OCHF 2 , -OCF 3 , -OCHFCH 2 F, -OCF 2 CHF 2 , -OCH 2 CF 3 , -OCH 2 CF 2 CHF 2 , methyl Amino, dimethylamino, ethylamino, cyclopropyl, cyclobutyl, cyclopentyl
  • the present invention relates to one of the following compounds or stereoisomers, geometric isomers, tautomers, nitrogen oxides, solvates, hydrates, metabolites, Esters, pharmaceutically acceptable salts or prodrugs thereof, but in no way limited to:
  • the present invention relates to pharmaceutical compositions comprising stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites of the aforementioned compounds Products, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable carriers, excipients, diluents, adjuvants, vehicles, or any combination thereof.
  • the present invention relates to the use of the aforementioned compound or a pharmaceutical composition thereof in the manufacture of a medicament for preventing, treating or alleviating a KRAS G12C mediated disease in a patient.
  • the KRAS G12C mediated disease is cancer.
  • the cancer of the present invention is lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer , liver, bile duct, breast, colon, appendix, small bowel, leukemia and melanoma.
  • the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I).
  • the pharmaceutical composition of the present invention features a compound represented by formula (I), a compound listed in the present invention, or a compound of the examples, and a pharmaceutically acceptable carrier.
  • the amount of the compound in the pharmaceutical composition of the present invention is effective to treat or alleviate a KRAS G12C mediated disease in a patient.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other that can be administered directly or indirectly according to the needs of the patient Adducts or derivatives, compounds described in other aspects of the invention, metabolites thereof or residues thereof.
  • compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the particular target dosage form.
  • a pharmaceutically acceptable carrier including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, preservatives, solid binders or lubricants, etc.
  • Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, sorbitan Potassium acid, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidones, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl Sodium cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; talc; adjuvants such as
  • the compound is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (referred to herein as a pharmaceutical carrier) selected according to the form of administration and conventional pharmaceutical practice, which may be an oral tablet, Capsules, elixirs, syrups, and more.
  • a suitable pharmaceutical diluent, excipient, or carrier referred to herein as a pharmaceutical carrier
  • a pharmaceutical carrier selected according to the form of administration and conventional pharmaceutical practice, which may be an oral tablet, Capsules, elixirs, syrups, and more.
  • the active pharmaceutical ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methylcellulose , magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier Combined, such as ethanol, glycerol, water, etc.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be added to the mixture.
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene Ethylene Glycol, Wax, etc.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrating agents include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds of this invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups , and emulsifiers. They may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all using dosage forms well known to those of ordinary skill in the art of pharmacy. They may be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the chosen mode of administration and standard pharmaceutical practice.
  • oral dosage forms such as tablets, capsules (each of which includes sustained or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups , and emulsifiers. They may also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all using dosage forms well known to those of ordinary skill in the art
  • the compounds of the present invention can be administered in intranasal form via topical use of a suitable intranasal vehicle, or transdermally via the use of transdermal patches.
  • a suitable intranasal vehicle or transdermally via the use of transdermal patches.
  • the dose administered is continuous rather than intermittent throughout the period of administration.
  • the compounds of the present invention can also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine.
  • the compounds of the present invention are also conjugated to soluble polymers that serve as targeted drug carriers.
  • soluble polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylate amine-phenol, polyhydroxyethyl aspartamide phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues amino acid.
  • the compounds of the present invention can be coupled with a class of biodegradable polymers for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly ⁇ caprolactone Crosslinked or amphiphilic blocking copolymers of esters, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.
  • biodegradable polymers for achieving controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly ⁇ caprolactone Crosslinked or amphiphilic blocking copolymers of esters, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels.
  • Dosage regimens for compounds of the present invention will vary with known factors such as the pharmacokinetic profile of the particular agent and its mode of administration and route of administration; the race, age, sex, health, medical condition and weight of the recipient; Nature and extent of symptoms; type of concurrent therapy; frequency of therapy; route of administration, patient's renal and hepatic function, and desired effect.
  • a physician or veterinarian can make a decision and prescribe an effective amount of the drug to prevent, offset, or stop the development of cancer.
  • the daily oral dose of each active ingredient employed is in the range of between about 0.001 to 1000 mg/kg of body weight.
  • the most preferred dosage range is from about 1 to about 10 mg/kg body weight/minute during conventional rate infusion.
  • the compounds of the present invention may be administered once a day, or may be administered in two, three or four times a day.
  • Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain from about 1 mg to about 1000 mg of active ingredient.
  • the weight of the active ingredient will generally be about 0.5-95% by weight of the total weight of the pharmaceutical composition.
  • a compound of the present invention When a compound of the present invention is administered with other therapeutic agents, generally, the amounts of each component in a typical daily dose and in a typical dosage form, relative to the additive or synergistic effects of the therapeutic agents when administered in combination, are The usual dose when administered alone may be reduced.
  • the compounds involved in the present invention or their pharmaceutically acceptable salts or their hydrates can be effectively used for preventing, treating or alleviating diseases mediated by KRAS G12C in patients, in particular, they can effectively treat lung cancer, lymphoma, esophageal cancer, ovarian cancer and pancreatic cancer. , rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, appendix cancer, small bowel cancer, leukemia and melanoma, etc.
  • the compounds of the present invention can be prepared by the methods described herein, unless otherwise specified, wherein the substituents are as defined herein.
  • the following reaction schemes and examples serve to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium.
  • Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
  • reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Factory.
  • the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 ⁇ 30 mm, 3.5 ⁇ m, 6 min, flow rate 0.6 mL/min.
  • Mobile phase 5 %-95% ( CH3CN with 0.1% formic acid) in ( H2O with 0.1% formic acid) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.
  • ESI electrospray ionization
  • the compound represented by formula ( 15 ) can be prepared by reaction scheme 1: the compound represented by formula ( 1 ) reacts with oxalyl chloride and ammonia water to obtain the compound represented by formula ( 2 ).
  • the compound represented by the formula ( 2 ), the compound represented by the formula ( 3 ) and the compound represented by the formula ( 4 ) are reacted to obtain the compound represented by the formula ( 5 ).
  • the compound represented by the formula ( 5 ) is reacted under the action of potassium bis(trimethylsilyl)amide to obtain the compound represented by the formula ( 6 ).
  • the compound represented by the formula ( 6 ) is reacted under the action of phosphorus oxychloride to obtain the compound represented by the formula ( 7 ).
  • the compound represented by the formula ( 7 ) and the compound represented by the formula ( 8 ) are reacted under the action of N,N-diisopropylethylamine to obtain the compound represented by the formula ( 9 ).
  • the compound represented by formula ( 11 ) is obtained by reacting with potassium acetate (or cesium carbonate) under the action.
  • the compound represented by formula ( 11 ) is in zinc cyanide, bis(tri-tert-butylphosphine) palladium and tri-tert-butylphosphine (or zinc cyanide and chloro(2-dicyclohexylphosphino-2',4', Under the action of 6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)), the reaction obtained by formula ( 12 ) compounds shown.
  • the compound represented by the formula ( 12 ) is de-Boc removed under the action of trifluoroacetic acid to obtain the compound represented by the formula ( 13 ).
  • the compound represented by the formula ( 13 ) and the compound represented by the formula ( 14 ) can obtain the compound represented by the formula ( 15 ) under the action of N,N-diisopropylethylamine.
  • 2,5,6-Trichloropyridine-3-carboxylic acid (5.0g, 22mmol), dichloromethane (60.0mL) and N,N-dimethylformamide (0.05mL, 0.6mmol) were added to the reaction flask, Cool to 0°C, add oxalyl chloride (2.4mL, 28mmol) dropwise, stir at 0°C for 24h, add ammonia solution in isopropanol (17.0mL, 2.0mol/L, 34mmol), continue stirring for 4h, suction filter, filter cake Washed with dichloromethane (50 mL ⁇ 2), and dried to obtain the title compound as a white solid (1.6 g, yield 32.0%).
  • the second step Synthesis of 2,5,6-trichloro-N-((2-isopropyl-4-methylpyridin-3-yl)carbamoyl)nicotinamide
  • 2,5,6-Trichloronicotinamide (1.46g, 6.48mmol) and tetrahydrofuran (10mL) were added to the reaction flask, the temperature was raised to 75°C, oxalyl chloride (1.0g, 7.9mmol) was added dropwise, and the reaction was stirred at 75°C for 1 h, Cooled to room temperature, concentrated to remove the solvent, cooled to 0 °C, added tetrahydrofuran (5 mL) to dissolve, and then added dropwise a solution of 2-isopropyl-4-methyl-pyridin-3-amine (1.0 g, 6.7 mmol) in tetrahydrofuran (5 mL).
  • the fourth step is the synthesis of 4,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one
  • the eighth step 7 (2-Fluoro-6-methoxyphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-4-((S)-2-methyl Synthesis of piperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the first step Synthesis of 5-bromo-1,3-lutidine-2(1H)-one
  • the fourth step 1- (2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,7-diazepine Synthesis of Spiro[4.4]nonan-2-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the fifth step 4-(7-Acryloyl-2,7-diazaspiro[4.4]nonan-2-yl)-1-(2-isopropyl-4-methylpyridin-3-yl)- 7-(2-Methoxyphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the fourth step 1- (2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,7-diazepine Synthesis of Spiro[3.5]nonan-7-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the first step 5-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate tert-butyl ester
  • the first step the synthesis of methyl 4-amino-5-bromo-2-fluorobenzoate
  • the aqueous phase was extracted with ethyl acetate (50.0 mL).
  • the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure.
  • the filter cake was dried under vacuum at 60° C. for 12 h to obtain the title compound as an off-white solid (7.30 g, yield 81.3%).
  • the seventh step The synthesis of 6-bromo-4-chloro-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazolin-2(1H)-one
  • 6-Bromo-4-chloro-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazolin-2(1H)-one (2.07g) was successively added to the reaction flask , 3.99mmol), acetonitrile (30mL), N,N-diisopropylethylamine (1.03g, 7.97mmol) and (S)-3-methylpiperazine-1-carboxylate tert-butyl ester (0.80g, 3.99 mmol).
  • the reaction system was heated to 80°C for 2h.
  • the fourth step 1- (2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxyphenyl)-2-oxo-4-(2,6-diazepine Synthesis of Spiro[3.3]heptan-2-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the first step 7 (2-Fluoro-6-methoxyphenyl)-4-((S)-4-(2-fluoroacryloyl)-2-methylpiperazin-1-yl)-1- Synthesis of (2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the first step 5-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester
  • the third step 5-(6-cyano-7-(2-fluoro-5-methylphenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo Synthesis of -1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester
  • the second step 4-(6-Chloro-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-di Synthesis of Hydropyrido[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester
  • the third step 4-(6-cyano-7-(2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-di Synthesis of Hydropyrido[2,3-d]pyrimidin-4-yl)-4,7-diazaspiro[2.5]octane-7-carboxylic acid tert-butyl ester
  • the fourth step 7 (2-fluorophenyl)-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-4-(4,7-diazaspiro[ Synthesis of 2.5]octan-4-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the fifth step 4-(7-acryloyl-4,7-diazaspiro[2.5]octan-4-yl)-7-(2-fluorophenyl)-1-(2-isopropyl-4 Synthesis of -methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the third step 1- (2-isopropyl-4-methylpyridin-3-yl)-7-(5-methyl-1H-indazol-4-yl)-4-((S)-2- Synthesis of Methylpiperazin-1-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • the fourth step 1- (2-isopropyl-4-methylpyridin-3-yl)-7-(2-methoxy-3-methylphenyl)-2-oxo-4-(4, Synthesis of 7-diazaspiro[2.5]octan-4-yl)-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrile
  • 6-Bromo-7-iodo-1-(2-isopropyl-4-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione (1.00 g, 2.00 mmol), (2-fluoro-5-methylphenyl)boronic acid (0.37 g, 2.40 mmol), sodium carbonate (0.64 g, 6.00 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.10 g mmol), 1,4-dioxane (15.0 mL) and water (3.5 mL).
  • the reaction system was heated to 100°C under nitrogen protection for overnight reaction. After the reaction was completed, it was cooled to room temperature and filtered.
  • the first step 4-(6,7-dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3 Synthesis of -d]pyrimidin-4-yl)-3,5-dimethylpiperazine-1-carboxylate tert-butyl ester

Abstract

L'invention concerne un dérivé de pyrimidone et son utilisation dans un médicament. Plus particulièrement, la présente invention concerne un nouveau dérivé de pyrimidone et une composition pharmaceutique contenant un tel composé. La présente invention concerne en outre un procédé de préparation du composé et de la composition pharmaceutique, une utilisation dans la préparation d'un médicament pour traiter des maladies et/ou des symptômes à médiation par KRAS G12C, et en particulier une utilisation dans la préparation d'un médicament pour traiter le cancer.
PCT/CN2021/138693 2020-12-17 2021-12-16 Dérivé de pyrimidone et son utilisation dans un médicament WO2022127847A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011501090.4 2020-12-17
CN202011501090 2020-12-17

Publications (1)

Publication Number Publication Date
WO2022127847A1 true WO2022127847A1 (fr) 2022-06-23

Family

ID=81991997

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/138693 WO2022127847A1 (fr) 2020-12-17 2021-12-16 Dérivé de pyrimidone et son utilisation dans un médicament

Country Status (2)

Country Link
CN (1) CN114644628A (fr)
WO (1) WO2022127847A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106488910A (zh) * 2013-10-10 2017-03-08 亚瑞克西斯制药公司 Kras g12c的抑制剂
CN107849022A (zh) * 2015-04-10 2018-03-27 亚瑞克西斯制药公司 取代的喹唑啉化合物和其使用方法
WO2018119183A2 (fr) * 2016-12-22 2018-06-28 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2018217651A1 (fr) * 2017-05-22 2018-11-29 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019051291A1 (fr) * 2017-09-08 2019-03-14 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2020239077A1 (fr) * 2019-05-29 2020-12-03 上海翰森生物医药科技有限公司 Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son application

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106488910A (zh) * 2013-10-10 2017-03-08 亚瑞克西斯制药公司 Kras g12c的抑制剂
CN107849022A (zh) * 2015-04-10 2018-03-27 亚瑞克西斯制药公司 取代的喹唑啉化合物和其使用方法
WO2018119183A2 (fr) * 2016-12-22 2018-06-28 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2018217651A1 (fr) * 2017-05-22 2018-11-29 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2019051291A1 (fr) * 2017-09-08 2019-03-14 Amgen Inc. Inhibiteurs de kras g12c et leurs procédés d'utilisation
WO2020239077A1 (fr) * 2019-05-29 2020-12-03 上海翰森生物医药科技有限公司 Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son application

Also Published As

Publication number Publication date
CN114644628A (zh) 2022-06-21

Similar Documents

Publication Publication Date Title
CN105732636B (zh) 杂芳化合物及其在药物中的应用
CN107011348B (zh) 作为btk活性的抑制剂的杂芳基吡啶酮和氮杂-吡啶酮化合物
CN113135924B (zh) 嘧啶衍生物及其在药物中的应用
TW202140450A (zh) 用於癌症治療的ｋｒａｓ抑制劑
WO2022037560A1 (fr) Dérivé de pyrimidone et son utilisation dans un médicament
CN106749233B (zh) 一类磺酰胺衍生物及其应用
CN105732637B (zh) 杂芳化合物及其在药物中的应用
WO2021143680A1 (fr) Dérivé hétéroaryle, son procédé de préparation et son utilisation
WO2012058193A1 (fr) Activité de l'enzyme kinase à répétition riche en leucine
CN107344940B (zh) Btk抑制剂及其用途
WO2015158310A1 (fr) Inhibiteur de tyrosine kinase et ses utilisations
TWI683811B (zh) 二氫噠嗪-３,５-二酮衍生物
JP2014506930A (ja) セリン／トレオニンキナーゼインヒビター
WO2017071516A1 (fr) Inhibiteur de kinase et procédé pour sa préparation et utilisation pharmaceutique correspondante
KR20230035036A (ko) 이중 키나제-브로모도메인 억제제
WO2021057970A1 (fr) Inhibiteur de ret, composition pharmaceutique associée et utilisation associée
WO2022033544A1 (fr) Composé hétéroaryle substitué, composition et utilisation associées
WO2021057963A1 (fr) Inhibiteur de ret, composition pharmaceutique comprenant celui-ci et utilisation associée
WO2021043209A1 (fr) Inhibiteur de ret, composition pharmaceutique et utilisation associée
CN108948019B (zh) 黏着斑激酶抑制剂及其用途
TWI692358B (zh) 含有鈉依賴性磷酸輸送蛋白抑制劑之醫藥
WO2022127847A1 (fr) Dérivé de pyrimidone et son utilisation dans un médicament
CN113620944A (zh) 新型的ret抑制剂、其药物组合物及其用途
CN108299436B (zh) 黄嘌呤类化合物及其药物组合物和应用
CN113620945A (zh) Ret抑制剂、其药物组合物及其在药物中的应用

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: 21905773

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: 21905773

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 21905773

Country of ref document: EP

Kind code of ref document: A1