WO2024078555A1 - Composé pyrimidopyridine, composition pharmaceutique et leur utilisation - Google Patents

Composé pyrimidopyridine, composition pharmaceutique et leur utilisation Download PDF

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WO2024078555A1
WO2024078555A1 PCT/CN2023/124140 CN2023124140W WO2024078555A1 WO 2024078555 A1 WO2024078555 A1 WO 2024078555A1 CN 2023124140 W CN2023124140 W CN 2023124140W WO 2024078555 A1 WO2024078555 A1 WO 2024078555A1
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alkyl
butyl
membered
compound
independently
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Chinese (zh)
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谢洪明
刘海望
罗国林
冯锡晖
张英俊
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广东东阳光药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • 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 belongs to the field of medicine. Specifically, the present invention relates to a pyrimidopyridine compound as a KRAS G12D inhibitor, a pharmaceutical composition thereof, and the use of such compound and pharmaceutical composition thereof in the preparation of drugs for preventing or treating KRAS G12D-related diseases.
  • the RAS gene is one of the most commonly mutated genes in cancer (20%-25%).
  • the currently known members of the RAS gene family include KRAS, NRAS and HRAS, among which KRAS mutation is the most common, accounting for about 85%.
  • the mutation rate of KRAS in pancreatic ductal adenocarcinoma (PDAC) is the highest, reaching 97%, followed by colorectal cancer, multiple myeloma and lung cancer, which are 52%, 42% and 32% respectively.
  • PDAC pancreatic ductal adenocarcinoma
  • the most common way for the KRAS gene to mutate is point mutation, and common mutation forms include KRAS G12D mutation (41%), KRAS G12V (28%) and KRAS G12C (14%) mutations.
  • KRAS can be transiently activated by upstream growth factors or tyrosine kinases (such as EGFR).
  • the activated KRAS can activate downstream pathways, including the PI3K-AKT-mTOR signaling pathway that controls cell generation, and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. This also lays a biological foundation for the combination of many targets.
  • KRAS G12C small molecule inhibitors Nature, 2013, 503, 548-551
  • KRAS G12D small molecule inhibitors
  • other mutation types such as KRAS G12D and KRAS G12V have a higher proportion in pancreatic cancer. Therefore, inhibiting KRAS G12D mutations to treat pancreatic cancer is a potentially effective means.
  • Mirati has published a series of KRAS G12D inhibitors in patent application WO20211041671, which show specificity for KRAS G12D mutants and have anti-pancreatic cancer activity.
  • the present invention provides a compound, or a pharmaceutical composition thereof, which can be used as an inhibitor of KRAS, especially as a KRAS 12D inhibitor.
  • the present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a medicament for treating a disease and/or condition, especially cancer, by inhibiting KRAS activity.
  • the compounds of the present invention can effectively bind to KRAS G12D-GTP and inhibit the phosphorylation of ERK downstream of KRAS G12D.
  • the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),
  • Q is O or S
  • Ring A is a C 3-6 carbocyclyl, a C 7-12 carbocyclyl, a 3-6 membered heterocyclyl, a 7-12 membered heterocyclyl, a C 6-12 aryl or a 5-12 membered heteroaryl;
  • Ring B is C 6-12 aryl or 5-12 membered heteroaryl
  • R3 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C1-4 haloalkyl;
  • Y is a bond, O or S
  • L is a C 1-6 alkylene group
  • R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C( ⁇ O)H, -C( ⁇ O)OH, -NR 6g R 7g , C 1-6 alkoxy, C 6-12 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
  • R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-6 alkyl;
  • n are each independently 0, 1, 2, 3, 4, 5, 6 or 7.
  • Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, octahydropentalenyl, bicyclo[3.1.0]cyclohexyl, 2,3-dihydro-1H-indenyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, phenyl, pyridinyl, pyrrolyl, imidazolyl, pyrimidinyl, or benzofuranyl.
  • R 6a , R 6g and R 7g are each independently -H, -D or C 1-4 alkyl.
  • R 6a , R 6g and R 7g are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Ring B is one of the following substructures
  • Each R 6c is independently -H, -D or C 1-4 alkyl
  • R 6b , R 7b and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered hetero
  • Each R 6c is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;
  • R 6b , R 7b together with the N atom to which they are attached form pyrrolidine, piperazine, piperidine, morpholine, oxazolidine or imidazolidine, wherein the pyrrolidine, piperazine, piperidine, morpholine, oxazolidine and imidazolidine are each independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy, isopropoxy, cyanomethyl, hydroxymethyl, hydroxyethyl, tri
  • R 4 is -H, -D, C 1-4 alkyl, 3-6 membered heterocyclyl, 7-10 membered heterocyclyl, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decalinyl, -L-pyridinyl, -L-pyrazolyl, -L-phenyl, -L-NR 6 R 7 , -NR 6 R 7 , -L-NHC( ⁇ NH)NH 2 or -LC( ⁇ O)NR 6 R 7 , wherein the C 1-4
  • L is a C 1-4 alkylene group
  • R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C( ⁇ O)H, -C( ⁇ O)OH, -NR 6g R 7g , C 1-4 alkoxy, C 6-10 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C
  • R 4 is -H, -D, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH 2 -pyrrolidinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl, -CH 2 -oxetanyl, -CH 2 -oxirane, -CH 2 -tetrahydrofuranyl, -CH 2 -octahydroindolizinyl, -CH 2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2 -octahydropentalenyl, -CH 2 -octahydro-1H- indenyl, -CH2 -decalinyl, -CH2 -pyridinyl, -( CH
  • R4 is 4-(6-oxo)-1, 4-oxo-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-oxo-2, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4-pyrrolidino-1, 4 -pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-pyrrolidino- 1 , 4-
  • the invention is substituted with a substituent selected from the group consisting of -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy,
  • the compound described in the present invention has a compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1),
  • R 2a , R 2b and R 2c each have the same definition as described for R 2 in any one of claims 1 to 10.
  • the present invention provides a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.
  • the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof.
  • the pharmaceutical composition can be in liquid, solid, semisolid, gel or spray form.
  • the present invention provides the use of the pharmaceutical composition described in the present invention in the preparation of drugs for preventing, treating or alleviating KRas G12D-related diseases.
  • the KRas G12D-related disease described in the present invention is cancer.
  • the cancer described herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroendocrine cancer. tumor.
  • the present invention also provides a method for preventing or treating KRas G12D-related diseases, which comprises administering a therapeutically effective amount of the compound described in the present invention or a pharmaceutical composition thereof to a patient.
  • the present invention relates to methods for preparing, isolating and purifying the compounds of formula (I) or (I-1).
  • the salts are pharmaceutically acceptable salts.
  • pharmaceutically acceptable includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.
  • the salts of the compounds of the present invention also include intermediates used in the preparation or purification of the compounds of formula (I) or (I-1) or salts of separated enantiomers of the compounds of formula (I) or (I-1), but they are not necessarily pharmaceutically acceptable salts.
  • subject refers to an animal. Typically, the animal is a mammal. Subjects, for example, also refer to primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate. In other embodiments, the subject is a human.
  • patient used in the present invention refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to humans.
  • Stereoisomers refer to compounds with the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formula described in the present invention are within the scope of the present invention. In addition, unless otherwise indicated, the structural formula of the compounds described in the present invention includes one or more enriched isotopes of different atoms.
  • Any resulting mixture of stereoisomers can be separated into the pure or substantially pure geometric isomers, enantiomers, diastereomers on the basis of the differences in the constituent physicochemical properties, for example, by chromatography and/or fractional crystallization.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions via reorganization 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-keto tautomerism.
  • a specific example of phenol-keto tautomerism is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • the compounds of the present invention may be independently optionally substituted with one or more substituents, such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • substituents such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • substituents such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • substituents such as the general formula compounds above, or as specific examples in the embodiments, subclasses, and classes of compounds encompassed by the present invention.
  • C 1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • linking substituents are described.
  • the Markush variable listed for that group should be understood as a linking group.
  • the Markush group definition for that variable lists “alkyl” or “aryl”, it should be understood that the "alkyl” or “aryl” represents an alkylene group or an arylene group, respectively, that is connected.
  • alkyl refers to a saturated straight or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally substituted with one or more substituents described herein.
  • the alkyl group contains 1-6 carbon atoms, represented by C 1-6 alkyl; in another embodiment, the alkyl group contains 1-4 carbon atoms, represented by C 1-4 alkyl; in another embodiment, the alkyl group contains 1-3 carbon atoms, represented by C 1-3 alkyl.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), 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 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2-butyl (-C(CH 3 ) 2 ),
  • alkylene refers to a saturated divalent hydrocarbon group derived from a saturated straight or branched hydrocarbon by removing two hydrogen atoms.
  • the alkylene group contains 1-6 carbon atoms, represented by C 1-6 alkylene; in other embodiments, the alkylene group contains 1-4 carbon atoms, represented by C 1-4 alkylene; in other embodiments, the alkylene group contains 1-3 carbon atoms, represented by C 1-3 alkylene; in other embodiments, the alkylene group contains 1-2 carbon atoms, represented by C 1-2 alkylene.
  • alkylene groups include, but are not limited to, methylene (i.e., -CH 2 -), ethylene (i.e., -CH 2 CH 2 -), isopropylene (i.e., -CH(CH 3 )CH 2 -), and the like.
  • alkenyl refers to a straight or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e., one carbon-carbon sp2 double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including “cis” and “trans” orientations, or "E” and “Z” orientations.
  • the alkenyl group contains 2 to 6 carbon atoms, represented by C2-6 alkenyl; in another embodiment, the alkenyl group contains 2 to 4 carbon atoms, represented by C2-4 alkenyl.
  • alkynyl refers to a straight or branched monovalent hydrocarbon group containing 2 to 12 carbon atoms, wherein there is at least one unsaturated site, i.e., one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents described herein.
  • the alkynyl group contains 2 to 6 carbon atoms, represented by C2-6 alkynyl; in another embodiment, the alkynyl group contains 2 to 4 carbon atoms, represented by C2-4 alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl ( -CH2C ⁇ CH ), 1-propynyl (-C ⁇ C- CH3 ), and the like.
  • cyanoalkyl refers to an alkyl group substituted by one or more cyano groups, wherein cyano and alkyl groups have the definitions as described herein.
  • cyanoalkyl refers to an alkyl group substituted by one cyano group.
  • cyanoalkyl is a C 1-6 cyanoalkyl, i.e., a C 1-6 alkyl group substituted by one or more cyano groups.
  • C 1-6 cyanoalkyl is a C 1-6 alkyl group substituted by one cyano group.
  • cyanoalkyl is a C 1-4 cyanoalkyl, i.e., a C 1-4 alkyl group substituted by one or more cyano groups.
  • cyanoalkyl include, but are not limited to, -CH 2 CN, -CH 2 CH 2 CH 2 CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH(CN)CH 2 CH 2 CN, -CH 2 CH(CN)CH 2 CH(CH 3 )CN, and the like.
  • hydroxyalkyl refers to an alkyl group substituted by one or more hydroxyl groups, wherein alkyl and hydroxyl groups have the definitions as described herein. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by 1, 2, 3 or 4 hydroxyl groups. In some embodiments, hydroxyalkyl refers to an alkyl group substituted by one or two hydroxyl groups. In some embodiments, hydroxyalkyl refers to a C 1-6 hydroxyalkyl group, i.e., a C 1-6 alkyl group substituted by one or more hydroxyl groups, preferably, a C 1-6 hydroxyalkyl group refers to an alkyl group substituted by one hydroxyl group.
  • hydroxyalkyl refers to a C 1-4 hydroxyalkyl group. In some embodiments, hydroxyalkyl refers to a C 1-3 hydroxyalkyl group. Examples of hydroxyalkyl groups include, but are not limited to, -CH 2 OH, -CH 2 CH 2 CH 2 CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 CH 2 OH, -CH 2 CH(OH)CH 2 CH( CH 3 ) OH, and the like.
  • haloalkyl means that an alkyl group is substituted with one or more halogen atoms, wherein alkyl and halogen have the definitions as described herein.
  • the haloalkyl is C 1-6 haloalkyl, which means that the C 1-6 alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl is C 1-4 haloalkyl, which means that the C 1-4 alkyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkyl is C 1-3 haloalkyl, which means that the C 1-3 alkyl group is substituted with one or more halogen atoms.
  • Such embodiments include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.
  • haloalkenyl means an alkenyl group substituted with one or more halogen atoms, wherein alkenyl has the definition as described herein.
  • the haloalkenyl is a C2-6 haloalkenyl, which means a C2-6 alkenyl group substituted with one or more halogen atoms; in other embodiments, the haloalkenyl is a C2-4 haloalkenyl, which means a C2-4 alkenyl group substituted with one or more halogen atoms.
  • haloalkynyl means that an alkynyl group is substituted with one or more halogen atoms, wherein alkynyl has the definition as described herein.
  • the haloalkynyl is a C 2-6 haloalkynyl, which means that a C 2-6 alkynyl group is substituted with one or more halogen atoms; in other embodiments, the haloalkynyl is a C 2-4 haloalkynyl, which means that a C 2-4 alkynyl group is substituted with one or more halogen atoms.
  • Such examples include, but are not limited to, 2-chloroethynyl (-C ⁇ CCl), 1-chloropropargyl (-CHClC ⁇ CH), 3-chloropropynyl (-C ⁇ C-CH 2 Cl), and the like.
  • hydroxyalkynyl means an alkynyl group substituted with one or more hydroxyl groups, wherein hydroxyl and alkynyl are defined as described herein.
  • the hydroxyalkynyl group is a C 2-6 hydroxyalkynyl group, which means that the C 2-6 alkynyl group is substituted with one or more hydroxyl groups; in other embodiments, the hydroxyalkynyl group is a C 2-4 hydroxyalkynyl group, which means that the C 2-4 alkynyl group is substituted with one or more hydroxyl groups.
  • Such examples include, but are not limited to, 3-hydroxypropynyl (-C ⁇ C-CH 2 OH), 4-hydroxybutynyl (-C ⁇ C-(CH 2 ) 2 OH), and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, wherein alkoxy and alkyl have the definitions described herein.
  • alkoxyalkyl refers to C 1-6 alkoxy C 1-6 alkyl; in other embodiments, alkoxyalkyl refers to C 1-4 alkoxy C 1-4 alkyl; in other embodiments, alkoxyalkyl refers to C 1-4 alkoxy C 1-3 alkyl; in some embodiments, alkoxyalkyl refers to C 1-3 alkoxy C 1-3 alkyl.
  • alkoxy groups include, but are not limited to, methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, methoxyethyl, methoxy-n-propyl, methoxy-isopropyl, ethoxyethyl, ethoxy-n-propyl, ethoxy-isopropyl, n-propoxyethyl, isopropoxyethyl, n-propoxy-n-propyl, n-propoxy-isopropyl, isopropoxy-n-propyl, isopropoxy-isopropyl, and the like.
  • carboxyalkyl refers to an alkyl group substituted by one or more carboxyl groups, wherein the carboxyl group and the alkyl group are specifically defined as described herein.
  • the carboxyalkyl group is a C 1-6 carboxyalkyl group, which refers to a C 1-6 alkyl group substituted by one or more carboxyl groups; in other embodiments, the carboxyalkyl group is a C 1-4 carboxyalkyl group, which refers to a C 1-4 alkyl group substituted by one or more carboxyl groups; in other embodiments, the carboxyalkyl group is a C 1-3 carboxyalkyl group, which refers to a C 1-3 alkyl group substituted by one or more carboxyl groups.
  • carboxyalkyl groups include, but are not limited to, carboxymethyl (-CH 2 COOH), 2-carboxyethyl (-(CH 2 ) 2 COOH), 3-carboxypropyl (-(CH 2 ) 3 COOH), and the like.
  • aminoalkyl refers to an alkyl group substituted by one or more amino groups, wherein alkyl and amino groups have the meanings as described herein.
  • the aminoalkyl group is a C 1-6 aminoalkyl group, which refers to a C 1-6 alkyl group substituted by one or more amino groups; in other embodiments, the aminoalkyl group is a C 1-4 aminoalkyl group, which refers to a C 1-4 alkyl group substituted by one or more amino groups; in other embodiments, the aminoalkyl group is a C 1-3 aminoalkyl group, which refers to a C 1-3 alkyl group substituted by one or more amino groups.
  • aminoalkyl groups include, but are not limited to, aminomethyl (-CH 2 NH 2 ), 2-aminoethyl (-(CH 2 ) 2 NH 2 ), 1-aminoethyl (-CH(NH 2 )CH 3 ), 1,2-diaminoethyl (-CH(NH 2 )CH 2 NH 2 ), and 3-aminopropyl (-(CH 2 ) 3 NH 2 ).
  • alkylamino refers to an amino group substituted by one or two alkyl groups, including “N-alkylamino” and “N,N-dialkylamino", wherein the alkyl and amino groups have the meanings as described in the present invention.
  • alkylamino refers to a C 1-6 alkyl Amino is an alkylamino group containing 1 to 6 carbon atoms; in other embodiments, alkylamino represents C 1-4 alkylamino, which is an alkylamino group containing 1 to 4 carbon atoms; alkylamino represents C 1-3 alkylamino, which is an alkylamino group containing 1 to 3 carbon atoms.
  • Suitable alkylamino groups can be monoalkylamino or dialkylamino groups, such as, but not limited to, N-methylamino (-NHCH 3 ), N-ethylamino (-NHCH 2 CH 3 ), N,N-dimethylamino (-N(CH 3 ) 2 ), N,N-diethylamino (-N(CH 2 CH 3 ) 2 ), and the like.
  • mercaptoalkyl refers to an alkyl group substituted by one or more mercapto groups, wherein the alkyl group has the meaning as described herein.
  • mercaptoalkyl refers to C 1-6 mercaptoalkyl, which is a C 1-6 alkyl group substituted by one or more mercapto groups; preferably, C 1-6 mercaptoalkyl is a C 1-6 alkyl group substituted by one mercapto group.
  • mercaptoalkyl refers to C 1-4 mercaptoalkyl.
  • mercaptoalkyl refers to C 1-3 mercaptoalkyl.
  • mercaptoalkyl examples include, but are not limited to, mercaptomethyl (-CH 2 SH), 2-mercaptoethyl (-(CH 2 ) 2 SH), 3-mercaptopropyl (-(CH 2 ) 3 SH), 2,3-dimercaptopropyl (-CH 2 CH(SH)CH 2 (SH)), and the like.
  • alkoxy means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms, representing a C 1-6 alkoxy group; in another embodiment, the alkoxy group contains 1-4 carbon atoms, representing a C 1-4 alkoxy group; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms, representing a C 1-3 alkoxy group.
  • the alkoxy group may be optionally substituted with one or more substituents as described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3 ), ethoxy (EtO, -OCH2CH3 ) , 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3 ), 2-propoxy (i-PrO, i - propoxy , -OCH( CH3 ) 2 ), 1 -butoxy ( n-BuO, n-butoxy , -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy , -OCH2CH ( CH3 ) 2 ), 2 -butoxy (s-BuO, s-butoxy, -OCH( CH3 ) CH2CH3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC( CH3 ) 3 ), 1-pentoxy (n-pentoxy, -OCH 2 CH 2 CH 2 CH 3 ), 1-
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy and halogen have the same meanings as those defined herein.
  • haloalkoxy refers to a haloalkoxy group containing 1 to 6 carbon atoms, i.e., C 1-6 haloalkoxy; in other embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 4 carbon atoms, i.e., C 1-4 haloalkoxy; in other embodiments, haloalkoxy refers to a haloalkoxy group containing 1 to 3 carbon atoms, i.e., C 1-3 haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy (-OCF 3 ), monofluoromethoxy (-OCH 2 F), 2-fluoroethoxy (-OCH 2 CH 2 F), and the
  • the carbocyclyl contains 3-6 ring carbon atoms, represented by C3-6 carbocyclyl; in other embodiments, the carbocyclyl is a saturated ring containing 3-6 ring carbon atoms, represented by C3-6 cycloalkyl; in other embodiments, the C3-6 cycloalkyl is a saturated monocyclic ring.
  • the carbocyclyl contains 7-12 ring carbon atoms, represented by C7-12 carbocyclyl; in other embodiments, the carbocyclyl is a saturated ring containing 7-12 ring carbon atoms, represented by C7-12 cycloalkyl.
  • carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, octahydro-1H-indenyl, octahydropentalenyl, etc.
  • the cycloalkyl contains 3-10 ring carbon atoms, i.e., C3-10 cycloalkyl; in another embodiment, the cycloalkyl contains 3-6 ring carbon atoms, i.e., C3-6 cycloalkyl; in another embodiment, the cycloalkyl contains 3-5 ring carbon atoms, i.e., C3-5 cycloalkyl.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydro-1H-indenyl, octahydrocyclopentyl, cyclopentyl, cyclohexyl, cyclopent ... Dienyl, etc.
  • heterocycle or “heterocyclyl” means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms; wherein the heterocycle or heterocyclyl is non-aromatic and does not contain any aromatic rings.
  • the heterocycle represents a monovalent heterocyclyl.
  • the sulfur atom of the ring may be optionally oxidized to S-oxide.
  • the heterocycle or heterocyclyl consists of 3-10 atoms, represented by a 3-10-membered heterocycle or a 3-10-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-9 atoms, represented by a 3-9-membered heterocycle or a 3-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-9 atoms, represented by a 5-9-membered heterocycle or a 5-9-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 3-6 atoms, represented by a 3-6-membered heterocycle or a 3-6-membered heterocyclyl; in other embodiments, the heterocycle or heterocyclyl consists of 5-6 atoms, represented by a 5-6-membered heterocycle or a 5-6-membere
  • heterocycle examples include, but are not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, pyrazolidine, pyrazoline, oxazolidine, imidazolidine, piperidine, piperazine, morpholine, 3,8-diazabicyclo[3.2.1]octane, 3,6-diazabicyclo[3.1.1]heptane, 2,5-diazabicyclo[2.2.2]octane.
  • the heterocyclic group includes, but is not limited to, oxirane, aziridine, azetidine, oxetane, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophene, thiazolidinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl or morpholinyl, etc.
  • aryl refers to a monovalent, monocyclic, bicyclic and tricyclic carbon ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring consisting of 3-7 atoms.
  • the aryl contains 6-12 ring atoms, represented by C 6-12 aryl or 6-12 membered aryl.
  • the aryl contains 6-10 ring atoms, represented by C 6-10 aryl or 6-10 membered aryl. Examples of aryl groups can include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl and anthracene.
  • heteroaryl or “heteroaromatic ring” refers to a monovalent monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heteroaryl group is usually, but not necessarily, attached to the parent molecule through the aromatic ring of the heteroaryl group.
  • heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the general formula) through any reasonable position (which may be C or N).
  • heteroaryl can be used interchangeably with the term “heteroaromatic ring” or “heteroaromatic compound”.
  • heteroaryl is a heteroaryl containing 5-12 ring atoms, represented by a 5-12 membered heteroaryl; in other embodiments, heteroaryl is a heteroaryl containing 5-10 ring atoms, represented by a 5-10 membered heteroaryl; in other embodiments, heteroaryl is a heteroaryl containing 5-6 ring atoms, represented by a 5-6 membered heteroaryl.
  • heteroaryl examples include, but are not limited to, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, thiazolyl, triazolyl, tetrazolyl, benzopyridinyl, benzimidazolyl, benzopyrrolyl, benzopyrazolyl, benzopyrrolidinyl, and the like.
  • alkylthio means an alkyl group attached to the rest of the molecule through a sulfur atom, wherein alkyl has the definition as described herein.
  • alkylthio is C 1-6 alkylthio, meaning an alkylthio containing 1 to 6 carbon atoms; in other embodiments, alkylthio is C 1-4 alkylthio, meaning an alkylthio containing 1 to 4 carbon atoms; in other embodiments, alkylthio is C 1-3 alkylthio, meaning an alkylthio containing 1 to 3 carbon atoms.
  • alkylthio include, but are not limited to, methylthio (-SCH 3 ), ethylthio (-SCH 2 CH 3 ), and the like.
  • haloalkylthio refers to an alkylthio group substituted by one or more halogen atoms, wherein the alkylthio group has the definition as described herein.
  • the haloalkylthio group is a C 1-6 haloalkylthio group, which refers to a C 1-6 alkylthio group substituted by one or more halogen atoms;
  • haloalkylthio is C 1-4 haloalkylthio, which means C 1-4 alkylthio substituted by one or more halogens; in other embodiments, haloalkylthio is C 1-3 haloalkylthio, which means C 1-3 alkylthio substituted by one or more halogens.
  • haloalkylthio includes, but is not limited to, trifluoromethylthio (-SCF 3 ), 2,2,2-trifluoroethylthio (-SCH 2 CF 3 ), monofluoromethylthio (-SCH 2 F), and the like.
  • arylalkyl refers to an alkyl group substituted with an aryl group, wherein aryl and alkyl have the definitions described herein.
  • arylalkyl is C 6-10 arylC 1-6 alkyl or (6-10 membered aryl)-C 1-6 alkyl; in other embodiments, arylalkyl is C 6-10 arylC 1-4 alkyl or (6-10 membered aryl)-C 1-4 alkyl; in other embodiments, arylalkyl is C 6-10 arylC 1-3 alkyl or (6-10 membered aryl)-C 1-3 alkyl; in other embodiments, arylalkyl is phenylC 1-6 alkyl; in other embodiments, arylalkyl is phenylC 1-4 alkyl; in other embodiments, arylalkyl is phenylC 1-3 alkyl. Examples of arylalkyl include, but are not limited to,
  • heteroarylalkyl refers to an alkyl group substituted with a heteroaryl group, wherein heteroaryl and alkyl are as defined herein.
  • heteroarylalkyl is (5-12 membered heteroaryl)-C 1-6 alkyl; in other embodiments, heteroarylalkyl is 5-12 membered heteroarylC 1-4 alkyl; in other embodiments, heteroarylalkyl is (5-12 membered heteroaryl)-C 1-3 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-6 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-4 alkyl; in other embodiments, heteroarylalkyl is (5-6 membered heteroaryl)-C 1-3 alkyl.
  • heteroarylalkyl include, but are not limited to, pyrimidinylmethyl, pyridinylmethyl, pyridinyle
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocyclyl group, wherein heterocyclyl and alkyl are as specifically defined herein.
  • heterocyclylalkyl is (3-6 membered heterocyclyl)C 1-6 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-4 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-4 alkyl; in other embodiments, heterocyclylalkyl is (3-6 membered heterocyclyl)-C 1-3 alkyl.
  • heterocyclylalkyl include, but are not limited to, piperidinylmethyl, piperidinylethyl, pyrrolidinylmethyl, and the like.
  • cycloalkylalkyl refers to an alkyl group substituted with a cycloalkyl group.
  • the cycloalkylalkyl group is a C 3-6cycloalkylC 1-6alkyl group; in other embodiments, the cycloalkylalkyl group is a C 3-6cycloalkylC 1-4alkyl group; in other embodiments, the cycloalkylalkyl group is a C 3-6cycloalkylC 1-3alkyl group.
  • Examples of cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, and the like.
  • halogen means F (fluorine), Cl (chlorine), Br (bromine) or I (iodine).
  • cyano means -CN or -C ⁇ N.
  • mercapto refers to -SH.
  • hydroxy refers to -OH.
  • amino refers to -NH2 .
  • j-k atoms or "j-k-membered” means that the cyclic group is composed of j-k ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.; j and k are each independently any non-zero natural number, and k>j; "j-k” includes j, k and any natural number in between.
  • “consisting of 3-8 atoms” or “3-8 members”, “consisting of 3-6 atoms” or “3-6 members”, “consisting of 5-10 atoms” or “5-10 members”, or “consisting of 5-6 atoms” or “5-6 members” means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7 or 8), 3-6 (i.e., 3, 4, 5 or 6), 5-10 (i.e., 5, 6, 7, 8, 9 or 10) or 5-6 (i.e., 5 or 6) ring atoms, and the ring atoms include carbon atoms and/or heteroatoms such as O, N, S, P, etc.
  • the ring system formed by substituent (R) q connected to the central ring by a bond represents that q substituents R can be substituted at any substitutable position or any reasonable position on the ring.
  • formula a represents that the naphthalene ring can be substituted by n R 2 , and when n is greater than 1, each R 2 can be independently selected from the same or different substituent groups.
  • prodrug used in the present invention refers to a compound that is converted into a compound represented by formula (I) or (I-1) in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug into the parent structure by enzymes in the blood or tissues.
  • the prodrug compound of the present invention can be an ester.
  • the esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.
  • Metal refers to a product obtained by the metabolism of a specific compound or salt thereof in vivo.
  • the metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized by experimental methods as described herein. Such products can be obtained by administering the compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc.
  • the present invention includes metabolites of compounds, including metabolites produced by contacting the compounds of the present invention with mammals for a period of time.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic salt and inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • salts formed by non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods described in books and literature, such as ion exchange methods, to obtain these salts.
  • the present invention also contemplates quaternary ammonium salts formed by any compound containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium and amine cations which counter-form counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 - C8 sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine or a mixture thereof.
  • hydrate refers to an association in which the solvent molecule is water.
  • the term "hydrate” may be used.
  • one molecule of the compound of the present invention may be combined with one water molecule, such as a monohydrate; in another embodiment, one molecule of the compound of the present invention may be combined with more than one water molecule, such as a dihydrate; in yet another embodiment, one molecule of the compound of the present invention may be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the non-hydrated form of the compound.
  • the term “treating" any disease or condition refers to ameliorating the disease or condition (i.e., slowing or preventing 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 physical parameters that may not be perceived by the patient. In other embodiments, “treating” refers to regulating the disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters), or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence, or worsening of a disease or condition.
  • prevent refers to a reduction in the risk of acquiring a disease or disorder (i.e., halting the development of at least one clinical symptom of a disease in a subject who may be exposed or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • terapéuticaally effective amount refers to an amount of a compound that, when administered to a subject to treat a disease, is sufficient to be effective in treating the disease.”
  • Therapeutically effective amount may vary with the compound, the disease and its severity, and the condition, age, weight, sex, etc. of the subject to be treated.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not indicated, all stereoisomers of the structure are contemplated within the present invention and are included as compounds disclosed herein. When stereochemistry is indicated by a solid wedge or dashed line representing a particular configuration, the stereoisomers of the structure are thus unambiguous and defined.
  • Nitrogen oxides of the compounds of the invention are also included within the scope of the invention.
  • Nitrogen oxides of the compounds of the invention can be prepared by oxidation of the corresponding nitrogen-containing basic substance using a conventional oxidizing agent (e.g., hydrogen peroxide) at elevated temperatures in the presence of an acid such as acetic acid, or by reaction with a peracid in a suitable solvent, such as peracetic acid in dichloromethane, ethyl acetate or methyl acetate, or with 3-chloroperoxybenzoic acid in chloroform or dichloromethane.
  • a conventional oxidizing agent e.g., hydrogen peroxide
  • the compound represented by formula (I) or (I-1) may exist in the form of a salt.
  • any structural formula provided by the present invention is also intended to represent the form of these compounds that are not enriched with isotopes and the form of isotopes that are enriched with isotopes.
  • Isotopically enriched compounds have the structure that the general formula provided by the present invention describes, except that one or more atoms are replaced by atoms with selected atomic weight or mass number.
  • Exemplary isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • the present invention provides a compound, or a pharmaceutical composition thereof, which can be used as an inhibitor of KRAS, in particular as a KRAS 12D inhibitor.
  • the present invention further relates to the use of the compound or the pharmaceutical composition thereof for preparing a medicament for treating a disease and/or condition by inhibiting KRAS activity by the compound.
  • the excellent properties of certain parameters of the compounds of the present invention can promote the reduction of side effects, the expansion of therapeutic index or the improvement of tolerance.
  • the compounds of the present invention have better intracellular inhibitory activity and better in vivo performance in rats and dogs. Better pharmacokinetic properties such as reduced exposure.
  • the present invention provides a compound represented by formula (I), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I),
  • Q is O or S
  • Ring A is a C 3-6 carbocyclyl, a C 7-12 carbocyclyl, a 3-6 membered heterocyclyl, a 7-12 membered heterocyclyl, a C 6-12 aryl or a 5-12 membered heteroaryl;
  • Ring B is C 6-12 aryl or 5-12 membered heteroaryl
  • R3 is -H, -D, -OH, -SH, -F, -Cl, -Br, -I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl or C1-4 haloalkyl;
  • Y is a bond, O or S
  • the -L-(3-10 membered heterocyclyl) is substituted with a substituent selected from the group consisting of -D, -OH
  • L is a C 1-6 alkylene group
  • R 6 , R 7 , R 6b , R 7b , R 6d , R 7d , R 6e and R 7e are each independently -H, -D or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -C( ⁇ O)H, -C( ⁇ O)OH, -NR 6g R 7g , C 1-6 alkoxy, C 6-12 aryl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;
  • R 6a , R 6c , R 6g and R 7g are each independently -H, -D or C 1-6 alkyl;
  • n are each independently 0, 1, 2, 3, 4, 5, 6 or 7.
  • Ring A is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, octahydropentalenyl, bicyclo[3.1.0]cyclohexyl, 2,3-dihydro-1H-indenyl, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, piperidinyl, phenyl, pyridinyl, pyrrolyl, imidazolyl, pyrimidinyl, or benzofuranyl.
  • R6 , R7 and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , C1-4 alkyl, C1-4 alkylamino, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-4 alkoxy, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1-4 haloalkoxy and C1-4 haloalkyl.
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2 , C1-4 alkyl, C1-4 alkylamino, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-4 alkoxy, C1-4
  • R 6a , R 6g and R 7g are each independently -H, -D or C 1-4 alkyl.
  • R 6a , R 6g and R 7g are each independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
  • Ring B is one of the following substructures
  • each R 6c is independently -H, -D, or C 1-4 alkyl.
  • R 6b , R 7b and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl , C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered
  • each R 6c is independently -H, -D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.
  • R 4 is -H, -D, C 1-4 alkyl, 3-6 membered heterocyclyl, 7-10 membered heterocyclyl, -L-pyrrolidinyl, -L-morpholinyl, -L-oxetanyl, -L-oxetanyl, -L-tetrahydrofuranyl, -L-octahydroindolizinyl, -L-cyclopropyl, -L-cyclopentyl, -L-octahydropentalenyl, -L-octahydro-1H-indenyl, -L-decahydronaphthyl, -L-pyridyl, -L-pyrazolyl, -L-phenyl, -L-NR 6 R 7 , -NR 6 R 7 , -L-NHC( ⁇ NH)NH 2 or -LC( ⁇ O)NR 6 R 7 , where
  • L is C 1-4 alkylene.
  • R 6d , R 7d and the N atom to which they are attached form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 1-4 alkoxy, C 1-4 cyanoalkyl , C 1-4 hydroxyalkyl, C 1-4 haloalkoxy and C 1-4 haloalkyl.
  • substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , C 1-4 alkyl, C 1-4 alkylamino, C 3-6 cycloalkyl, 3-6 membered
  • the group is preferably substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH2, C1-4 alkyl , C1-4 alkylamino, C3-6 cycloalkyl, 3-6 membered heterocyclyl, C1-4 alkoxy, C1-4 cyanoalkyl, C1-4 hydroxyalkyl, C1-4 haloalkoxy and C1-4 haloalkyl.
  • R 4 is -H, -D, -CH 3 , -CH 2 CH 3 , -(CH 2 ) 2 CH 3 , piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, -CH 2 -pyrrolidinyl, -CH 2 -morpholinyl, -(CH 2 ) 2 -morpholinyl, -CH 2 -oxetanyl, -CH 2 -oxiranyl, -CH 2 -tetrahydrofuranyl, -CH 2 -octahydroindolizinyl, -CH 2 -cyclopropyl, -CH 2 -cyclopentyl, -CH 2 -octahydropentalenyl, -CH 2 -octahydro-1H-indenyl, -CH 2 -decalinyl, -CH 2 -pyridinyl , -
  • R 6d , R 7d , R 6e and R 7e are each as defined in the present invention.
  • R4 is
  • R4 is
  • R 6d , R 7d and the N atom to which they are attached are taken together to form azetidine, pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine or imidazolidine, wherein each of the azetidine, pyrrolidine, piperazine, piperidine, morpholinyl, oxazolidine and imidazolidine is independently optionally substituted with 1, 2, 3 or 4 substituents selected from -D, -OH, -F, -Cl, -Br, -I, -CN, -NH 2 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, cyclopropyl, cyclopentyl, pyrrolidinyl, methoxy, ethoxy,
  • the compound described in the present invention has a compound represented by formula (I-1), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-1),
  • R 2a , R 2b and R 2c each have the same definition as described for R 2 in the present invention.
  • R 2a , R 2b and R 2c are each independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C( ⁇ O)NR 6b R 7b , -C( ⁇ O)R 6c , -C( ⁇ O)OR 6c , -C( ⁇ O)NR 6b R 7b , -NR 6b C( ⁇ O)R 7b , -NR 6b R 7b , C 1-6 alkyl, C 1-6 alkylthio, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 hydroxyalkynyl, C 1-6 alkoxy, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 1-6 haloalkyl, C 2-6 haloalkenyl, C 2-6 haloalkynyl, C 1-6 haloalkoxy, C 1-6 C1-6 alky
  • R 2a , R 2b and R 2c are each independently -D, -OH, -F, -Cl, -Br, -I, -CN, -SH, -CH 2 C( ⁇ O)NR 6b R 7b , -C( ⁇ O)R 6c , -C( ⁇ O)OR 6c , -C( ⁇ O)NR 6b R 7b , -NR 6b C( ⁇ O)R 7b , -NR 6b R 7b , C 1-4 alkyl, C 1-4 alkylthio, C 2-4 alkenyl, C 2-4 alkynyl, C 2-4 hydroxyalkynyl, C 1-4 alkoxy, C 1-4 cyanoalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkyl, C 2-4 haloalkenyl, C 2-4 haloalkynyl, C 1-4 haloalkoxy, C 1-4 C 1-4 alkyl, C
  • the compound described in the present invention has a compound represented by formula (I-2), or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by formula (I-2),
  • the compound described in the present invention is a compound of the following structure, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug of the structure,
  • the present invention provides a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention further comprises a pharmaceutically acceptable adjuvant.
  • the adjuvants described in the present invention include, but are not limited to, carriers, excipients, diluents, solvents, or combinations thereof.
  • the pharmaceutical composition can be in liquid, solid, semisolid, gel or spray form.
  • the present invention provides the use of the pharmaceutical composition described in the present invention in the preparation of drugs for preventing, treating or alleviating KRas G12D-related diseases.
  • the KRas G12D-related disease described in the present invention is cancer.
  • the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate the symptoms of cancer in patients, including, but not limited to: cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma hamartoma, mesothelioma; Gastrointestinal cancers: Esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lympho
  • the cancer described herein is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroma.
  • the present invention also provides a method for preventing or treating KRas G12D-related diseases, which comprises administering a therapeutically effective amount of the compound described in the present invention or a pharmaceutical composition thereof to a patient.
  • the present invention relates to methods for preparing, isolating and purifying compounds of formula (I), (I-1) or (I-2).
  • the salts are pharmaceutically acceptable salts.
  • pharmaceutically acceptable includes that the substance or composition must be suitable chemically and toxicologically with respect to the other ingredients that make up the formulation and with the mammal to be treated.
  • the salts of the compounds of the present invention also include intermediates used to prepare or purify the compounds represented by formula (I), (I-1) or (I-2) or salts of separated enantiomers of the compounds represented by formula (I), (I-1) or (I-2), but are not necessarily pharmaceutically acceptable salts.
  • the pharmaceutical composition of the present invention is characterized by comprising a compound represented by formula (I), (I-1) or (I-2), a compound listed in the present invention, or
  • the amount of the compound in the pharmaceutical composition of the present invention is effective to treat or alleviate KRAS G12D-mediated diseases in patients.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other adducts or derivatives that can be directly or indirectly administered according to the needs of the patient, the compounds described in other aspects of the present invention, their metabolites or their residues.
  • the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable adjuvant, which, as used in the present invention, includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form.
  • a pharmaceutically acceptable adjuvant includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, 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, potassium sorbate, partial glyceride mixtures 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, polyvinyl pyrrolidone, 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 cellulose sodium cellulose, ethylcellulose and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa
  • active ingredient is usually mixed with excipient, diluted by excipient or encapsulated in such carrier in the form of capsule, pouch, paper or other container, for example.
  • excipient can be solid, semisolid or liquid material, which is used as carrier, carrier or medium of active ingredient.
  • Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talcum powder, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, etc.
  • the composition can be tablets, pills, powders, lozenges, capsules, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid form or in liquid medium), for example, ointments containing up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions and aseptically packaged powders.
  • the composition is formulated for oral administration.
  • the composition is formulated into tablets or capsules.
  • the compounds or pharmaceutical compositions of the present invention can be administered in the form of oral dosage forms, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, and all dosage forms used are well known to those of ordinary skill in the pharmaceutical field. They can be administered alone, but will generally be administered together with a pharmaceutical carrier selected based on the selected mode of administration and standard pharmaceutical practice.
  • oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, and all dosage forms used are well known to
  • the compounds or pharmaceutical compositions of the invention can be administered in intranasal form via topical use of a suitable intranasal vehicle, or via the use of an intranasal Patches are administered transdermally.
  • the dosage is administered continuously rather than intermittently throughout the duration of administration.
  • the compounds or pharmaceutical compositions of the present invention can also be administered in the form of liposome 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 invention or pharmaceutical compositions are also coupled with soluble polymers, which serve as targeted drug carriers.
  • soluble polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues.
  • the compounds of the invention can be coupled with a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly- ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.
  • biodegradable polymers for controlled drug release for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly- ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic blocking copolymers of hydrogels.
  • the dosage regimen of the compounds or pharmaceutical compositions of the present invention will vary with known factors, such as the pharmacokinetic characteristics of the specific agent and its mode and route of administration; the race, age, sex, health status, medical condition and weight of the recipient; the nature and extent of the symptoms; the type of concurrent treatment; the frequency of treatment; the route of administration, the patient's renal and liver function, and the 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 dosage of each active ingredient used is between about 0.001 and 1000 mg/kg body weight per day, preferably, between about 0.01 and 100 mg/kg body weight.
  • the compound of the present invention can be administered once a day, or can be administered twice, three times or four times a day.
  • Each unit dose of a dosage form (pharmaceutical composition) suitable for administration may contain about 1 mg to about 100 mg of active ingredient.
  • the weight of the active ingredient will generally account for about 0.5-95% of the total weight of the composition.
  • the compounds and compositions described herein can be administered alone or in combination with other compounds or other therapeutic agents.
  • the compounds or compositions of the present invention can be administered simultaneously or sequentially with other therapeutic agents by the same or different routes of administration.
  • the compounds of the present invention can be included in a single formulation or in a separate formulation with other therapeutic agents.
  • the amount of each component in a typical daily dose and typical dosage form may be reduced relative to the usual dose when administered alone, taking into account the additive or synergistic effects of the therapeutic agents when administered in combination.
  • the compounds or pharmaceutically acceptable salts or hydrates thereof or pharmaceutical compositions thereof involved in the present invention can be effectively used to prevent, treat or alleviate KRAS-mediated diseases, especially KRAS G12D-mediated diseases, especially cancer, in patients.
  • the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate the symptoms of cancer in patients, including, but not limited to: cardiac cancer: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung cancer: bronchial cancer (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), non-small cell lung cancer, small cell lung cancer, alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma hamartoma Cancers of the gastrointestinal tract: esophageal (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcino
  • the compounds of the present invention or their pharmaceutical compositions can be effectively used to prevent, treat or alleviate cancer symptoms in patients including non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, colon cancer, small intestine cancer, pancreatic cancer, uterine cancer, gastric cancer, esophageal cancer, prostate cancer, ovarian cancer, breast cancer, leukemia, melanoma, lymphoma or neuroma.
  • the present invention will further illustrate the technical scheme of the present invention with the following examples.
  • the following examples are only used to illustrate the specific implementation method of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the scope of protection of the present invention.
  • the technical means or methods not specifically described are conventional technical means or methods in the art.
  • Room temperature in the embodiments means 15°C–30°C; in some embodiments, room temperature is 20°C–30°C.
  • Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, etc. None of them were further purified when used.
  • Anhydrous tetrahydrofuran, dioxane, toluene, and ether were obtained by drying under reflux with sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by drying under reflux 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 bottles were plugged with appropriate rubber stoppers, and substrates were injected via syringe. All glassware was dried.
  • the chromatographic column used was a silica gel column, and the silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.
  • the low-resolution mass spectrometry (MS) data were measured using an Agilent 6120 quadrupole HPLC-MS (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min.
  • Mobile phase 5%-95% (CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid), electrospray ionization (ESI), at 210 nm/254 nm, with UV detection.
  • Compound (IA) can be synthesized by referring to the method of Synthesis Scheme 1.
  • R 1 , R 2 , R 3 , R 5 , ring A, m and n have the same definitions as those described in the present invention
  • Hal is a halogen, preferably Cl or Br
  • Ra is a C 1-4 alkyl, preferably a methyl or ethyl group
  • q is a natural number of 1-6, preferably 1 or 2
  • the 3-10 membered heterocyclic group has the same definitions as those described in the present invention, and may be optionally substituted by the substituents described in the present invention.
  • Compound (IA-01) reacts with compound (IA-02) under appropriate conditions (such as in the presence of cesium carbonate, t-BuBrettPhos G3 Pd and t-BuBrettPhos) to obtain compound (IA-0); compound (IA-0) is deprotected from the amino group under acidic conditions to obtain compound (IA-1); compound (IA-1) is reacted with NIS or I2 under appropriate acidic conditions (such as periodic acid or p-toluenesulfonic acid) and in a suitable solvent (such as ethanol or acetonitrile) to obtain compound (IA-2); compound (IA-2) is reacted with CO and alcohol R a under the action of a palladium catalyst (such as Pd(PPh 3 ) 2 Cl 2 ) and appropriate conditions (such as the action of a base TEA); OH (such as ethanol or methanol) to obtain compound (IA-3); compound (IA-3) reacts with 2,2,2-
  • Compound (IB) can be synthesized by referring to the method of Synthesis Scheme 2.
  • R 1 , R 2 , R 3 , R 5 , Ring A and m have the definitions described in the present invention
  • n1 is a natural number of 1-6
  • q is a natural number of 1-6, preferably 1 or 2
  • 3-10 membered heterocyclic group has the definitions described in the present invention, and can be optionally substituted by the substituents described in the present invention.
  • Compound (IA-10) is reacted with compound (IB-1) in the presence of a suitable catalyst (such as XPhos Pd G2) to obtain compound (IB-2); compound (IB-2) is reacted under acidic conditions (such as HCl) to obtain compound (IB).
  • a suitable catalyst such as XPhos Pd G2
  • compound (IB-2) is reacted under acidic conditions (such as HCl) to obtain compound (IB).
  • Compound (IC) can be synthesized by referring to the method of Synthesis Scheme 3.
  • R 1 , R 2 , R 3 , R 5 , Ring A and m are as defined in the present invention;
  • n2 is a natural number of 1-5;
  • q is a natural number of 1-6, preferably 1 or 2;
  • 3-10 membered heterocyclic group is as defined in the present invention, and can be optionally substituted by a substituent as described in the present invention.
  • Compound (IA-10) reacts with compound (IC-1) under the action of a suitable catalyst (such as XPhos Pd G2 or XPhos Pd G3) to obtain compound (IC-2); compound (IC-2) reacts under acidic conditions (such as HCl) to obtain compound (IC-3) or an acid addition salt of compound (IC-3); compound (IC-3) or an acid addition salt of compound (IC-3) removes the TIPS group under suitable conditions (such as CsF in DMF solvent) to obtain compound (IC).
  • a suitable catalyst such as XPhos Pd G2 or XPhos Pd G3
  • compound M1-2 (2.40 g, 7.14 mmol), Pd 2 (dba) 3 (0.13 g, 0.14 mmol), XantPhos (0.21 g, 0.36 mmol), tert-butyl carbamate (1.00 g, 8.57 mmol) and cesium carbonate (5.82 g, 17.85 mmol) were added, and the atmosphere was replaced with nitrogen three times.
  • Anhydrous 1,4-dioxane (40 mL) was added, and the atmosphere was replaced with nitrogen three times. The temperature was raised to 80°C and stirred for reaction for 2 h.
  • compound 1-8 (256 mg, 0.48 mmol), 1,4-dioxane (5 mL), ((2R,7aS)-2-fluoro-hexahydro-1H-pyrrolizine-7a-yl)methanol (110 mg, 0.72 mmol) and DIPEA (0.24 mL, 1.44 mmol) were added, the temperature was raised to 90 ° C and stirred for 24 h, the stirring was stopped, the mixture was concentrated, ethyl acetate (40 mL) was added, and saturated ammonium chloride solution (20 mL) and saturated sodium chloride solution (20 mL) were used in sequence.
  • Example 6 The synthesis of Example 6 was performed with reference to Example 2, and cyclopentanol was used instead of 3-fluorocyclobutane-1-ol to obtain 47 mg of yellow solid compound 6, LC-MS (ESI, pos.ion) m/z: 685.6 [M+H] + ; HRMS (ESI): 685.3156 [M+H] + .
  • Example 9 The synthesis of Example 9 was performed by referring to Example 2, and 3-hydroxycyclopentanone was used instead of 3-fluorocyclobutane-1-ol to obtain 21 mg of yellow solid compound 9, LC-MS (ESI, pos.ion) m/z: 699.5 [M+H] + ; HRMS (ESI): 699.2935 [M+H] + .
  • Example 10 The synthesis of Example 10 was performed by referring to Example 2, and 1-methylcyclopentanol was used instead of 3-fluorocyclobutane-1-ol to obtain 32 mg of yellow solid compound 10.
  • Example 11 The synthesis of Example 11 was carried out with reference to Example 2, and bicyclo[3.1.0]hexan-3-ol was substituted for 3-fluorocyclobutane-1-ol to obtain 45 mg of yellow solid compound 11, LC-MS (ESI, pos.ion) m/z: 697.5 [M+H] + ; HRMS (ESI): 697.3124 [M+H] + .
  • Example 12 The synthesis of Example 12 was carried out in accordance with Example 2, with 2-indanol replacing 3-fluorocyclobutane-1-ol, and finally 30 mg of yellow solid compound 12 was obtained, LC-MS (ESI, pos.ion) m/z: 733.5 [M+H] + ; HRMS (ESI): 733.3136 [M+H] + .
  • Example 13 The synthesis of Example 13 was carried out in accordance with Example 2, with cyclohexanol replacing 3-fluorocyclobutane-1-ol, and finally 40 mg of yellow solid compound 13 was obtained, LC-MS (ESI, pos.ion) m/z: 699.5 [M+H] + ; HRMS (ESI): 699.3246 [M+H] + .
  • Example 14 The synthesis of Example 14 was carried out in accordance with Example 2, with phenol replacing 3-fluorocyclobutane-1-ol, and finally 20 mg of yellow solid compound 14 was obtained, LC-MS (ESI, pos.ion) m/z: 693.0 [M+H] + ; HRMS (ESI): 693.2788 [M+H] + .
  • Example 15 The synthesis of Example 15 was carried out in accordance with Example 2, with 3-hydroxypyridine replacing 3-fluorocyclobutane-1-ol, and finally 10 mg of yellow solid compound 15 was obtained, LC-MS (ESI, pos.ion) m/z: 694.2 [M+H] + ; HRMS (ESI): 694.2732 [M+H] + .
  • Example 19 Referring to Example 16, tert-butyl (3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzo[b]thiophene-2-yl)carbamate was used to replace 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane for synthesis, and finally 12 mg of yellow solid compound 19 was obtained, LC-MS (ESI, pos.ion) m/z: 713.4 [M+H] + ; HRMS (ESI): 713.2424 [M+H] + .
  • Example 20 Referring to the steps in Example 16, 2-(tert-butoxycarbonylamino)-7-fluoro-1,3-benzothiazol-4-yl]boric acid was used instead of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane to synthesize, and finally 15 mg of yellow solid compound 20 was obtained, LC-MS (ESI, pos.ion) m/z: 689.2 [M+H] + ; HRMS (ESI): 689.2468 [M+H] + .
  • compound 1-8 200 mg, 0.37 mmol
  • 1,4-dioxane 4 mL
  • (hexahydro-1H-pyrrolidine-7a-yl)methanol 78 mg, 0.55 mmol
  • DIPEA 0.18 mL, 1.11 mmol
  • Example 22 The synthesis of Example 22 was performed with reference to Example 21, and N-methyl-L-prolinol was used instead of (hexahydro-1H-pyrroline-7a-yl)methanol to obtain 18 mg of yellow solid compound 22.
  • Example 23 The synthesis of Example 23 was performed with reference to Example 21, and N-methyl-D-prolinol was used instead of (hexahydro-1H-pyrroline-7a-yl)methanol to obtain 10 mg of yellow solid compound 23.
  • Example 24 The synthesis of Example 24 was performed with reference to Example 21, and (hexahydro-1H-pyrrolidine-7a-yl)methanol was substituted with ⁇ 1-[(dimethylamino)methyl]cyclopropyl ⁇ methanol to obtain 9 mg of yellow solid compound 23.
  • Example 25 [1-(morpholin-4-ylmethyl)cyclopropyl]methanol was substituted for (hexahydro-1H-pyrrolidine-7a-yl)methanol to obtain 16 mg of yellow solid compound 25, LC-MS (ESI, pos.ion) m/z: 719.5 [M+H] + ; HRMS (ESI): 719.2985 [M+H] + .
  • Example 26 The synthesis of Example 26 was performed with reference to Example 21, and (2,6-dimethyltetrahydro-1H-pyrroline-7a(5H)-yl)methanol was substituted for (hexahydro-1H-pyrroline-7a-yl)methanol to obtain 8 mg of yellow solid compound 26.
  • AGS cells were revived using 1640 medium containing 10% fetal bovine serum;
  • Relative signal value (signal value of the channel corresponding to the target protein/signal value of the channel corresponding to the internal reference protein) ⁇ 10000
  • the compounds of the present invention can effectively bind to KRAS G12D-GTP, inhibiting the binding of KRAS to cRAF and SOS1 proteins.
  • the compounds of the present invention can effectively inhibit pERK downstream of KRAS.
  • the inventors conducted a pharmacokinetic evaluation of the compound of the present invention in rats.
  • the animal information is shown in Table 3.
  • the compound of the present invention was diluted with 5% DMSO + 30% PEG400 + 65% saline, 10% DMSO + 10% Kolliphor HS15 +
  • the animals were administered with 80% Saline, 10% DMSO + 89% (25% SBE-B-CD) + (2% HCl), 20% PEG400 + 80% sterile water for injection or 10% DMA + 10% HS15 + 30% PEG400 + 50% sterile aqueous solution for injection.
  • the animals were fasted for 12 hours before administration and had free access to water.
  • the rats were administered a dose of 1 mg/kg.
  • blood was collected venously at the following time points (blood volume of about 0.15 mL): 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24 hours (rats).
  • EDTA-K 2 was added to the blood collection tube as an anticoagulant in advance.
  • the blood samples were centrifuged at 12,000 rpm for 2 minutes, and the plasma was collected and stored at -20°C or -70°C.

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Abstract

La présente invention relève du domaine des médicaments, et concerne en particulier un composé pyrimidopyridine, une composition pharmaceutique et leur utilisation. Plus particulièrement, la présente invention concerne un composé de formule (I), ou un stéréoisomère, un tautomère, un oxyde d'azote, un solvate, un métabolite, un sel pharmaceutiquement acceptable ou un promédicament du composé représenté par la formule (I). Le composé et la composition pharmaceutique de celui-ci, impliqués dans la présente invention, en tant qu'inhibiteur de KRAS G12D peuvent être utilisés pour préparer des médicaments pour prévenir ou traiter des maladies associées à KRAS G12D, et peuvent en particulier être utilisés pour préparer des médicaments pour prévenir ou traiter des cancers.
PCT/CN2023/124140 2022-10-13 2023-10-12 Composé pyrimidopyridine, composition pharmaceutique et leur utilisation WO2024078555A1 (fr)

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