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WO2025223561A1 - Composé hétérocyclique à cinq chaînons fusionné à la quinazolinone, composition pharmaceutique associée et utilisation associée - Google Patents

Composé hétérocyclique à cinq chaînons fusionné à la quinazolinone, composition pharmaceutique associée et utilisation associée

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Publication number
WO2025223561A1
WO2025223561A1 PCT/CN2025/091310 CN2025091310W WO2025223561A1 WO 2025223561 A1 WO2025223561 A1 WO 2025223561A1 CN 2025091310 W CN2025091310 W CN 2025091310W WO 2025223561 A1 WO2025223561 A1 WO 2025223561A1
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Prior art keywords
alkyl
group
alkylene
cycloalkyl
alkoxy
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English (en)
Chinese (zh)
Inventor
徐石林
郑明月
施咨含
张素林
孙姚良
林可欣
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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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
    • A61K31/495—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
    • 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
    • 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
    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
    • 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
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This invention relates to the field of medicinal chemistry, specifically to a quinazolinone pentane heterocyclic compound, its pharmaceutical composition, and its uses.
  • Methionine adenosyltransferase 2A is an enzyme that synthesizes S-adenosylmethionine (SAM) from methionine (Met) and adenosine triphosphate (ATP).
  • SAM is the main methyl donor in cellular transmethylation (Physiological Reviews, 2012, 92:1515-1542).
  • RNA, and proteins can be regulated by methylation modification, thereby controlling cell growth, differentiation, and death. Therefore, intracellular SAM levels are tightly regulated.
  • MAT2A has the potential to be a therapeutic target.
  • MAT1A can be reversed to MAT2A during malignant transformation of the liver.
  • MAT2A has also been found to be overexpressed in human epithelial tumors such as gastric, colon, and liver cancer (Acta Histochemica, 2013, 115:48-55).
  • HBx hepatitis B virus
  • the loss of MTAP in chr9p21 typically involves the deletion of the CDKN2A tumor suppressor site. Nearly 15% of human cancers exhibit MTAP gene deletion (Journal of Biological Chemistry, 2024, 300:105492), particularly glioblastoma, melanoma, urothelial carcinoma, pancreatic cancer, and non-small cell lung cancer.
  • MTAP is a key enzyme in the methionine reuptake pathway, degrading MTA, a byproduct of polyamine synthesis, into adenine and 5-methylthioadenosine-1-phosphate (MTR-1p). Since MTAP is the only known enzyme catalyzing MTA degradation, its loss leads to MTA accumulation in cancer cells.
  • MAT2A inhibitors domestically or internationally, with three drugs in clinical trials.
  • the small molecule MAT2A inhibitors under development still face several challenges, such as weak activity, poor selectivity for MTAP-deficient mutant cells, and some off-target toxicities. Therefore, MAT2A inhibitors have attracted considerable research interest from pharmaceutical companies, and the development of specific MAT2A inhibitors could become a new therapeutic approach to improve the treatment outcomes of MTAP-deficient cancers.
  • One object of the present invention is to provide a novel MAT2A inhibitor.
  • a compound of formula IA is provided, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, hydrate, solvate, or prodrug thereof.
  • X, Y1 , and Y2 are each independently selected from C, CH, CR', O, S, N, NH, or NR';
  • R' is selected from: H, deuterium, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy or halogenated C1-6 alkoxy;
  • n is selected from 0, 1, 2, 3;
  • n is selected from 1, 2, 3, 4, 5, 6;
  • L1 is selected from C1-6 alkylene groups, including -O-, -NH-, -NR'-, substituted or unsubstituted groups;
  • R4 and R5 are each independently selected from the following group, either substituted or unsubstituted: H, D, amide, C1-6 alkyl, halo- C1-6 alkyl, deuterated C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-6 alkylene-, C3-10 cycloalkoxy, 5-10 heterocyclic, 5-10 heterocyclic- C1-6 alkylene-, 5-10 heterocyclic oxy ( 5-10 heterocyclic-O-), C3-6 cycloalkyloxy ( C3-6 cycloalkyl-O-), C6-10 aryl, C6-10 aryl-C1-6 alkylene-, 5-10 heteroaryl, 5-10 heteroaryl- C1-6 alkylene-, C 3-10 cycloalkoxy- C1-6 alkylene-;
  • R4 and R5, together with the N atom they are connected to, can form substituted or unsubstituted subgroups: 4-9 membered nitrogen-containing heterocyclic groups or 4-9 membered nitrogen-containing heteroaryl groups;
  • Ring A is selected from the following group of substituted or unsubstituted groups: C6 - C10 aryl, 5-10 membered heteroaryl, 3-10 heterocyclic group;
  • X is selected from CH, CR', O, S, or N.
  • Y1 and Y2 are each independently selected from CH, CH2 , CR', O, S, N, NH or NR'.
  • the compound represented by Formula IA is the compound represented by Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, hydrate, solvate, or prodrug thereof.
  • X is selected from O, S, NH, NR';R' is selected from: H, deuterium, C1-6 alkyl, halo -C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, halo- C1-6 alkoxy;
  • R4 and R5 are each independently selected from the following group, either substituted or unsubstituted: H, D, C1-6 alkyl, halo- C1-6 alkyl, deuterated C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkyl-( C1-6 alkylene)-, C3-10 cycloalkoxy, 5-10 heterocyclic, 5-10 heterocyclic-( C1-6 alkylene)-, 5-10 heterocyclic-oxy( 5-10 heterocyclic-O-), C3-6 cycloalkyloxy(C3-6 cycloalkyl-O-), C6-10 aryl, C6-10 aryl-( C1-6 alkylene)-, 5-10 heteroaryl, 5-10 heteroaryl-( C1-6 alkylene)-, C 3-10 cycloalkoxy-( C1-6 alkylene)-;
  • R4 and R5, together with the N atom they are connected to, can form substituted or unsubstituted subgroups: 4-9 membered nitrogen-containing heterocyclic groups or 4-9 membered nitrogen-containing heteroaryl groups;
  • n, m, L1 , R1 , ring A, R3 , R are as described in the first aspect of the present invention.
  • the compound has the structure shown in formula (II):
  • R1 , R4 , R5 , L1 , R, m and ring A are as described in the first aspect of the present invention.
  • L1 is selected from C1-3 alkylene groups that are bonded, substituted, or unsubstituted.
  • ring A is selected from the following group of substituted or unsubstituted groups: C6 - C10 aryl, 5-10 membered heteroaryl, 4-7 heterocyclic group;
  • substitution refers to substitution by one or more groups selected from the group consisting of: halogen, amino, amine, nitro, hydroxyl, cyano, carboxyl, C1-6 alkyl, halo- C1-6 alkyl, carboxyl-substituted C1-6 alkyl, hydroxyl-substituted C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, halo- C1-6 alkoxy, -NH-C(O) -C1-6 alkyl, -NH-C(O) -C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl.
  • ring A is selected from the following group of substituted or unsubstituted groups: phenyl, pyridinyl, imidazolyl, pyridinyl, pyrimidinyl, thiazolyl, benzopyrazolyl, benzothiazolyl, thiophene; preferably, ring A is selected from substituted or unsubstituted phenyl, pyridinyl, benzopyrazolyl.
  • substitution refers to substitution by one or more groups selected from the group consisting of: halogen, amino, amine, nitro, hydroxyl, cyano, carboxyl, C1-6 alkyl, halo- C1-6 alkyl, carboxyl-substituted C1-6 alkyl, hydroxyl-substituted C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, halo- C1-6 alkoxy, -NH-C(O) -C1-6 alkyl, -NH-C(O) -C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl;
  • ring A is selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, pyridazinyl, pyrimidinyl, ...
  • R4 is selected from the group consisting of: H, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl; and/or
  • R 5 is selected from the following group, substituted or unsubstituted: H, amide, C1-6 alkyl, halo- C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C3-9 cycloalkyl, C3-7 cycloalkoxy, C2-6 alkenyl, C2-6 alkynyl, phenyl, phenyl- C1-6 alkylene-, 5-7 membered heterocyclic, 5-7 membered heterocyclic- C1-6 alkylene-, benzyl, 5-9 membered heteroaryl, 5-9 membered heteroaryl-C1-6 alkylene-, C3-7 cycloalkoxy- C1-6 alkylene-; preferably H, amide, C1-6 alkyl, halo- C1-6 alkyl, C1-6 alkoxy, C3-9 cycloalkyl, C3-7 cycloalkoxy , C2-6 alkenyl, C2-6 alkynyl , phenyl,
  • R4 and R5 are linked to form a ring
  • R4 and R5 along with the N atom they are connected to, together form a substituted or unsubstituted 4-7 membered nitrogen-containing heterocyclic group or a 4-7 membered nitrogen-containing heteroaryl group.
  • R4 is selected from the group consisting of H, C1-6 alkyl, and deuterated C1-6 alkyl; more preferably H and CD3 .
  • R5 is selected from the group consisting of substituted or unsubstituted groups: H, amide, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C1-6 alkoxy, C3-9 cycloalkyl, C3-7 cycloalkoxy, C2-6 alkenyl, C2-6 alkynyl, phenyl, phenyl- C1-6 alkylene-, 5-7 membered heterocyclic, 5-7 membered heterocyclic- C1-6 alkylene-, benzyl, 5-9 membered heteroaryl, 5-9 membered heteroaryl- C1-6 alkylene-, C3-7 cycloalkoxy- C1-6 alkylene-; preferably H, methyl, ethyl, propyl, trifluoroethyl, difluoroethyl, cyclobutoxymethylene, oxodihydropyridylmethylene.
  • R1 is selected from the group consisting of halogens, C1-6 alkyl groups, halogenated C1-6 alkyl groups, C3-6 cycloalkyl groups, 5-7 membered heterocyclic groups, halogenated C3-6 cycloalkyl groups, C1-6 alkoxy groups, and halogenated C1-6 alkoxy groups; more preferably, halogens, C1-6 alkyl groups, halogenated C1-6 alkyl groups, and C1-6 alkoxy groups.
  • R1 is selected from the group consisting of: chlorine, fluorine, trifluoromethyl, methyl, bromine, iodine, cyclopropyl, methoxy, difluoromethyl, trifluoromethoxy, and ethyl; more preferably, R1 is selected from the group consisting of: chlorine, fluorine, trifluoromethyl, bromine, iodine, cyclopropyl, methoxy, difluoromethyl, trifluoromethoxy, and ethyl; more preferably, R1 is selected from the group consisting of: chlorine, bromine, trifluoromethyl, cyclopropyl, methoxy, and methyl; even more preferably, it is chlorine, bromine, trifluoromethyl, and cyclopropyl.
  • R3 is selected from the group consisting of halogen, cyano, nitro, amino, C1-6 alkyl, and halogenated C1-6 alkyl; preferably methyl, chlorine, or fluorine.
  • R is selected from the group consisting of: H, halogen, nitro, amino, amide, hydroxyl, cyano, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, C3-6 cycloalkyl, -NHC(O) OC1-6 alkyl, -C(O)-NH- C1-6 alkyl, C2-6 alkynyl, -OC1-6 alkylene-phenyl, -C1-6 alkylene-COOH; preferably H, halogen, nitro, amino, amide, hydroxyl , cyano, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkyl, -NHC(O) OC1-6 alkyl, C2-6 alkynyl, -OC1-6 alkylene-phenyl, -C1-6 alkylene-COOH.
  • the compound has the structure shown in formula (III):
  • X1 , X2 , X3 , X4 and X5 are each independently CH or N;
  • At most two of X1 , X2 , X3 , X4 and X5 are N; more preferably, one of X1 , X2 , X3 , X4 and X5 is N.
  • At most two of X1 , X2 , X3 , X4 and X5 are N, and the rest are CH; more preferably, one of X1 , X2 , X3 , X4 and X5 is N, and the rest are CH.
  • L1 is a bond
  • X2 is N
  • X1 , X3 , X4 and X5 are each independently CH.
  • R is located between and/or adjacent to the position.
  • the compound forms a dimer structure as shown in formula (IV): Da-W-Db (IV)
  • Da and Db are each independently selected from compounds represented by formula (I'-A):
  • Y1 , Y2 , ring A, n, m, X, L1 , R1 , R, R3 , R4 , and R5 are as described in the first aspect of the present invention
  • W is a divalent linker, having the structure shown below: -Wa-L-Wb-;
  • Wa and Wb are each independently selected from the following group: none, -O-, -S-, -NR a- , -CO-, -COO-, -SO-, -SO 2- , -CO-NR a- , -NR a- CO-, -SO-N( Ra )-, -N( Ra )-SO-, -NR a- COO-, -COO-NR a- , C1-6 alkylene, C2-6 alkenylene, C2-6 ynylene;
  • L is selected from the following group: -O-, -S-, -NR a- , -CO-, -COO-, -SO-, -SO 2- , -CO-NR a- , -NR a- CO-, -SO-N( Ra )-, -N( Ra )-SO-, -NR a- COO-, -COO-NR a- , C 1-6 alkylene, C 2-6 alkenylene, C 6 arylene, 4-7 heterocyclic, C 3-9 cycloalkylene;
  • Ra is independently selected from the group consisting of H, deuterium, cyano, halogen, C1-6 alkyl, C1-6 haloalkyl, or substituted or unsubstituted C3-6 cycloalkyl (preferably substituted by C1-6 alkyl and/or halogen).
  • Da and Db are each independently selected from the compounds represented by formula I': Rings A, n, m, X, L1 , R1 , R, R3 , R4 , and R5 are as described in the first aspect of this invention.
  • Da and Db are each independently the structure shown in Equation I'-B: Preferably, Da and Db are each independently the structure shown in Equation I'. in, Indicates the connection site between Da or Db and W; R1 , R4 , R5 are as described in the first aspect of the present invention.
  • the linking site of the divalent group of the compound of formula (I') is located at the meta, para, or ortho position of the linking site a; preferably at the meta position.
  • Da and Db are the same or different.
  • Da and Db are the same. In another preferred embodiment, Da and Db are not the same.
  • Wa and Wb are each independently selected from the group consisting of: none, -O-, -S-, -NR a- , -CO-, -COO-, -SO-, -SO 2- , -CO-NR a- , -NR a- CO-, -NR a- COO-, -COO-NR a- , C1-6 alkylene.
  • L is selected from the group consisting of: -O-, -S-, -NR a- , -CO-, -COO-, -SO-, -CO-NR a- , -NR a-CO-, -NR a- COO-, -COO- NR a- , C1-6 alkylene, 4-7 heterocyclic, and C3-9 cycloalkylene.
  • W is ethylene, -NH-C(O)-,
  • the compound is selected from the compounds shown in Table 1:
  • the compound is the compound prepared in the examples.
  • each group is the corresponding group in the compound prepared in the examples.
  • a pharmaceutical composition comprising:
  • the dosage form of the pharmaceutical composition is selected from the group consisting of pills, tablets, capsules, powders, and injections.
  • a use is provided for the compound described in the first aspect of the invention for preparing (i) a MAT2A enzyme inhibitor, and/or (ii) a medicament for the prevention and treatment of MAT2A-related cancers.
  • the cancer associated with MAT2A is an MTAP-deficient cancer.
  • the cancer associated with MAT2A is a cancer with an MTAP deletion mutation.
  • the MTAP deficiency refers to a reduction in MTAP protein levels or function.
  • the MTAP deficiency refers to the deletion or mutation of the MTAP gene.
  • the MAT2A-related cancer is caused by enhanced MAT2A function.
  • the cancer is selected from solid tumors and liquid tumors; more preferably, it is selected from the group consisting of glioblastoma, melanoma, urothelial carcinoma, pancreatic cancer, non-small cell lung cancer, colorectal cancer, ovarian cancer, lung cancer, breast cancer, leukemia, liver cancer, thyroid cancer, stomach cancer, bladder cancer, lymphoma, gallbladder cancer, brain cancer, or combinations thereof.
  • a method for treating cancer associated with MAT2A comprising the steps of administering to a subject in need a therapeutically effective amount of the compound of the first aspect of the invention, or the pharmaceutical composition of the second aspect of the invention.
  • the object is MTAP-deficient cancer cells; more preferably, it is MTAP-deleted mutant cancer cells.
  • a method for inhibiting MAT2A enzyme activity wherein a compound described in the first aspect of the invention, or a stereoisomer, tautomer, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition as described in the second aspect of the invention, is contacted with a protein or cell to inhibit MAT2A enzyme activity.
  • the method is non-diagnostic and non-therapeutic.
  • the method is performed in vitro.
  • the object is a mammal, such as a human.
  • the object is a cell.
  • the object is an MTAP-deficient cancer cell.
  • the cells are derived from rodents (such as mice or rats) or primates (such as humans).
  • Figure 1 shows the in vivo antitumor activity of some compounds.
  • alkyl refers to a straight-chain or branched alkane group or a cyclic hydrocarbon group (including hydrocarbon groups connected to other parts via a carbon atom on a ring or a non-cyclic atom), preferably a straight-chain or branched alkane group, containing 1-10 carbon atoms, more preferably 1-10 carbon atoms (C1-C10), and more preferably 1-6 carbon atoms (C1-C6).
  • Typical "alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, etc.
  • alkyl also includes substituted alkyl groups.
  • substituted alkyl means that one or more positions in an alkyl group are substituted, particularly 1-4 substituents, which can be substituted at any position.
  • alkylene refers to a group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, such as methylene (e.g., Or -CH2- ), ethylene (e.g.) ), propylidene (e.g.) ), isopropylidene (e.g.) ), butylide (such as) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as ), Etc.
  • the alkylene group also includes substituted alkylene groups, and the substituents can be halogenated (e.g., based -CHF- or -CF2- ), hydroxyl, cyano, nitro, etc.
  • C3-10 cycloalkyl ( C1-6 alkylene) refers to a divalent alkylene group with a cycloalkyl group attached to one end. Preferably, it is a C1-C6 alkylene or a C3-C6 cycloalkylene.
  • alkenyl refers to a straight-chain or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 10 carbon atoms.
  • Alkenyl groups are preferably C2-C6 alkenyl groups, more preferably C2-C4 alkenyl groups.
  • Alkenyl groups include, but are not limited to, for example, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, etc.
  • alkenyl groups include substituted alkenyl groups.
  • alkenyl groups also include substituted alkenyl groups, and the substituents can be halogenated, hydroxylated, cyano, nitro, etc.
  • alkynyl refers to a straight-chain or branched hydrocarbon group containing one or more triple bonds and typically having a length of 2 to 10 carbon atoms.
  • the alkynyl group is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl.
  • the alkynyl group includes, but is not limited to, ethynyl, propynyl, or similar groups.
  • the alkynyl group also includes substituted alkynyl groups, which can be halogenated, hydroxyl, cyano, nitro, etc.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group comprising 1-3 rings, each containing 3-8 carbon atoms.
  • C3 - C10 refers to a cycloalkyl compound containing 3, 4, 5, 6, 7, 8, 9 , or 10 carbon atoms.
  • the cycloalkyl is preferably a C3 - C10 cycloalkyl, more preferably a C3 - C6 monocyclic cycloalkyl, C7 -C10 bicyclic or tricyclic cycloalkyl.
  • Substituted cycloalkyl means that one or more positions in the cycloalkyl group are substituted, particularly 1-4 substituents, which can be substituted at any position.
  • Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc.
  • C3 - C9 cycloalkylene refers to a group formed by removing two hydrogen atoms from a cycloalkyl group, such as:
  • heterocyclic group refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic, 4-7 membered monocyclic, or 6-11 membered bicyclic groups), wherein at least one heteroatom is present in a ring with at least one carbon atom.
  • heterocyclic group refers to a heterocyclic group containing 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms.
  • Heterocyclic group is preferably a 4-10 membered heterocyclic group, such as a 4-6 membered monocyclic heterocyclic group or a 7-10 membered bicyclic group, more preferably a 4-8 membered heterocyclic group, and even more preferably a 4-6 membered heterocyclic group.
  • Each heterocyclic group containing a heteroatom may have 1, 2, 3, or 4 heteroatoms, each of which is independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized.
  • Heterocyclic groups can be attached to any heteroatom or carbon atom residue in a ring or cyclic molecule, preferably to an N or C atom in a ring or cyclic molecule.
  • Typical monocyclic heterocycles include, but are not limited to, azazolinyl, pyrrolidinyl, oxazolinyl, imidazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, hexahydroacoxaneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfoxide, thiomorpholinosulfone, 1,3
  • Polycyclic heterocyclic groups refer to heterocyclic groups including spirocyclic, fused-ring, and bridged-ring groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring; the "heterocyclic group” can be substituted or unsubstituted, and when substituted, one or more positions of the heterocyclic group are substituted, especially 1-4 substituents, which can be substituted at any position.
  • 4-7 membered subheterocyclic group refers to a group formed by removing two hydrogen atoms from a heterocyclic group, such as:
  • aryl refers to an aromatic cyclic hydrocarbon group, particularly monocyclic and bicyclic groups.
  • C6 - C10 aryl refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, or 10 ring carbon atoms.
  • Aryl groups include phenyl, biphenyl, or naphthyl.
  • the aryl group may be fused to a heteroaryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring.
  • Examples include phenyl (i.e., a six-membered aromatic ring), naphthyl, etc., wherein a six-membered aryl group is also intended to include a six-membered aryl 5-6-membered cycloalkyl and a six-membered aryl 5-6-membered heterocyclic alkyl.
  • C6 - C12 aryl groups are preferred as C6 - C10 aryl groups.
  • “Substituted aryl" means that one or more positions of the aryl group are substituted, particularly 1-3 substituents, which can be substituted at any position.
  • heteroaryl refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur.
  • heteroatoms are selected from oxygen, nitrogen, and sulfur.
  • 5-10-membered heteroaryl refers to a heteroaromatic system containing 1-4 heteroatoms and 5-10 ring atoms.
  • Heteroaryl groups are preferably 5- to 9-membered rings, more preferably 5, 6, or 7-membered, and non-limiting examples of heteroaryl groups include pyridinyl, pyrazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, terpineyl, phthalazinyl, benzotriazinyl, purine, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoisoxazoleyl, isobenzofuryl, and isoindole.
  • the heteroaryl group includes alkyl, indene, benzotriazinyl, thienopyridyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl, benzofuranyl, benzothiaphenyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazoleyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrroleyl, thiazolyl, furanyl, thiopheneyl, isothiazolyl, furanyl, triazinyl, triazolyl, and tetrazolyl, etc.
  • heteroaryl ring can be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring.
  • "Hyperaryl” can be substituted or unsubstituted; when substituted, one or more positions of the heteroaryl group are substituted, particularly 1-4 substituents, which can be substituted at any position.
  • alkoxy refers to a straight-chain or branched alkoxy group, including alkyl-O- and alkyl-O-alkyl groups.
  • C1 - C10 alkoxy refers to a straight-chain or branched alkoxy group having 1 to 10 carbon atoms, including C1 - C10 alkyl-O- and C1 - C6 alkyl-OC1- C6 alkyl groups, and non-limitingly includes methoxy, ethoxy, propoxy, isopropoxy, and butoxy groups.
  • it is a C1 - C8 alkoxy group, more preferably a C1- C6 alkoxy group.
  • cycloalkyloxy refers to cycloalkyl-O-
  • C3 - C10 cycloalkyloxy refers to C3 - C10 cycloalkyl-O-, wherein the definition of C3 - C10 cycloalkyl is as described above.
  • heterocyclic oxy group refers to a heterocyclic group -O-, for example, "5-7-membered heterocyclic oxy group” refers to a 5-7-membered heterocyclic group -O-, wherein the definition of a 5-7-membered heterocyclic group is as described above.
  • halogen refers to chlorine, bromine, fluorine, and iodine.
  • halogenated refers to being replaced by a halogen
  • deuteration refers to being replaced by deuterium.
  • hydroxyl group refers to a group with the structure OH.
  • nitro refers to a group containing the structure NO 2 .
  • cyano refers to a group containing the structure CN.
  • ester group refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic.
  • R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic.
  • the ester group is preferably -COO C1 - C6 alkyl.
  • amino group refers to a group with the structure -NR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic groups, as defined above.
  • R' or R" is each independently selected from the group consisting of: H, deuterium, C1 - C6 alkyl, halogenated C1 - C6 alkyl, C1 - C6 alkoxy, C3 - C6 cycloalkyl, and 4-7 membered heterocyclic groups.
  • R' and R" can be the same or different in the dialkylamine segment.
  • the amino group is preferably NH2 , NHC1 - C6 alkyl, or N( C1 - C6 alkyl) 2 .
  • amide refers to a group with the structure -CONR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic groups, as defined above.
  • R' and R" can be the same or different in the dialkylamine segment.
  • the amide group is preferably -CONH2 , -NHCO ( C1 - C6 alkyl), or -NHCO ( C3 - C6 cycloalkyl).
  • substitution refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent.
  • the specific substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments.
  • a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents at each position may be the same or different.
  • substituents contemplated in this invention are those that are stable or chemically feasible.
  • alkyl corresponds to alkylene
  • cycloalkyl corresponds to cycloalkylene
  • heterocyclic corresponds to heterocyclic
  • alkoxy corresponds to alkoxy
  • multiple refers to 2, 3, 4, and 5.
  • a bond from a substituent (typically an R group) to the center of an aromatic ring will be understood as a bond that provides a connection at any available vertex of the aromatic ring.
  • this description also includes connections on rings fused to the aromatic ring.
  • a bond drawn to the center of a quinazoline would represent a bond connected to any available vertex of the benzene ring or pyrimidine moiety of the quinazoline.
  • the structural formulas described in this invention are intended to include all isomers (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers with double bonds, etc. Therefore, any single stereochemical isomer of the compounds of this invention, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this invention.
  • salts prepared from active compounds with relatively non-toxic acids or bases, depending on the specific substituents on the compounds described herein.
  • base addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired base (solvent-free or in a suitable inert solvent).
  • salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, etc.
  • Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, heparin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, aminobutanetriol, etc.
  • arginine betaine
  • caffeine choline
  • acid addition salts can be obtained by contacting such compounds in neutral form with a sufficient amount of the desired acid (solvent-free or in a suitable inert solvent).
  • Pharmaceutically acceptable examples of acid addition salts include those derived from inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, etc.; and salts derived from relatively non-toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanes
  • inorganic acids such as hydroch
  • salts of amino acids such as arginine salts
  • salts of organic acids such as glucuronic acid or galacturonic acid.
  • Certain specific compounds of the present invention contain both basic and acidic functional groups, thereby enabling the conversion of the compound into a basic addition salt or an acid addition salt.
  • the neutral form of a compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner.
  • the parent form of the compound differs from the various salt forms in some physical properties (e.g., solubility in polar solvents), but otherwise, for the purposes of this invention, those salts are equivalent to the parent form of the compound.
  • the present invention provides compounds in prodrug form.
  • the prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted into the compounds of the present invention in an in vitro environment by chemical or biochemical methods. For example, when placed in a transdermal patch reservoir containing suitable enzymes or chemical reagents, the prodrug can be slowly converted into the compounds of the present invention.
  • Some compounds of the present invention may exist in both solvated and hydrated forms, including hydrated forms.
  • the hydrated forms are generally equivalent to the hydrated forms and should be included within the scope of the present invention.
  • Some compounds of the present invention may exist in polymorphic or amorphous forms. Generally, all physical forms are equivalent for the applications contemplated by the present invention and should be included within the scope of the present invention.
  • Some compounds of this invention possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., isolated enantiomers) should all be included within the scope of this invention.
  • R or S or indicated by dashed or wedge-shaped bonds
  • those compounds are substantially free of other isomers (e.g., at least 80%, 90%, 95%, 98%, 99%, and at most 100% free of other isomers).
  • stereoisomer refers to compounds that have the same chemical structure but differ in the spatial arrangement of their atoms or groups.
  • Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis/trans) isomers, and inhibited isomers. Any mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
  • transisomer refers to a conformational stereoisomer that occurs when rotation around a single bond in a molecule is blocked or significantly slowed due to spatial interactions with other parts of the molecule.
  • the compounds of this invention include all transisomers as a single transisomer, or as a nonspecific mixture of each. If the rotational barrier around the single bond is high enough, and the interconversion between conformations is slow enough, then the separation and differentiation of isomer species as different compounds can be allowed. For example, groups such as, but not limited to, the following groups...
  • compounds S128 and S129 in this invention are trans-restricted isomers, including...
  • tautomer refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer.
  • proton tautomers also called proton transfer tautomers
  • Valence tautomers involve interconversions via the rearrangement of some bonding electrons.
  • the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.
  • isomers e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers,
  • the compounds of the present invention may also contain non-natural proportions of atomic isotopes at one or more isotopic atoms constituting such compounds.
  • a non-natural proportion of an isotope can be defined as ranging from the amount of the atom in question that is naturally found to 100% of that atom.
  • the compounds may be doped with radioactive isotopes, such as tritium ( 3H ), iodine-125 ( 125I ), or carbon-14 ( 14C ), or non-radioactive isotopes, such as deuterium ( 2H ) or carbon-13 ( 13C ).
  • radioactive isotopes such as tritium ( 3H ), iodine-125 ( 125I ), or carbon-14 ( 14C )
  • non-radioactive isotopes such as deuterium ( 2H ) or carbon-13 ( 13C ).
  • such isotopic variants may provide additional uses.
  • isotopic variants of the compounds of the present invention may have additional uses, including but not limited to, as diagnostic and/or imaging agents, or as cytotoxic/radiotoxic therapeutic agents.
  • isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics, thereby contributing to increased safety, tolerability, or efficacy during treatment. All isotopic variants of the compounds of the present invention, regardless of radioactivity, should be included within the scope of the present invention.
  • the term "compound of the invention” refers to a compound as defined in the first aspect (e.g., a compound represented by formula I, II, III or IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, deuterated derivative, hydrate, solvate or prodrug thereof.
  • the term also includes various crystal forms of compounds of formula I, or pharmaceutically acceptable salts thereof.
  • the present invention also provides a method for preparing compounds of formula (I) of the present invention.
  • the preparation of compounds of general formula (I) of the present invention can be accomplished by the following exemplary methods and examples, but these methods and examples should not be considered in any way as limiting the scope of the invention.
  • the compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of synthetic methods known in the art and the methods described herein.
  • the products obtained from each reaction step are obtained using separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc.
  • the starting materials and chemical reagents required for synthesis can be conventionally synthesized according to literature (such as those provided by Scifinder) or purchased.
  • Step 1 Compound 1 reacts with iodomethane to produce compound 2;
  • the organic solvent used in the reaction is not particularly limited, but it is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from amide solvents, nitrile solvents, ether solvents, etc.; preferably selected from DMF, acetonitrile, tetrahydrofuran, etc., and more preferably from DMF.
  • the reaction is carried out under alkaline conditions, and the base used is not particularly limited, but it is preferably carried out under suitable alkaline conditions.
  • the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, TEA, DIPEA, or cesium carbonate; preferably, the base is selected from cesium carbonate.
  • the reaction temperature is not particularly limited, but room temperature is preferred.
  • the reaction time is not particularly limited, for example, 1-24 hours.
  • Step 2 Compound 2 and 2,2-ethoxyethanol are nucleophilically substituted to give compound 3;
  • the organic solvent used in the reaction is not particularly limited, but is preferably carried out in a suitable organic solvent.
  • the organic solvent is preferably an anhydrous solvent, such as an ether solvent (e.g., tetrahydrofuran).
  • the reaction is carried out under alkaline conditions, and the base used is not particularly limited, but is preferably selected from sodium hydroxide.
  • the reaction temperature is not particularly limited, but is preferably cooled to room temperature in an ice bath.
  • the reaction time is not particularly limited, for example, 1-24 hours.
  • Step 3 Compound 3 undergoes a ring-closing reaction to give compound 4;
  • the organic solvent used in the reaction is not particularly limited, but is preferably carried out in a suitable organic solvent.
  • the organic solvent is preferably an aromatic solvent, such as toluene.
  • the reaction is preferably carried out under acidic conditions, and the acid is not particularly limited, but preferably selected from polyphosphoric acid.
  • the reaction temperature is not particularly limited, but is preferably 50-80°C, more preferably 60-65°C.
  • the reaction time is not particularly limited, for example, 1-24 hours.
  • Step 4 Compound 4 undergoes ammonolysis with ammonia-methanol to produce compound 5;
  • the preferred reagent is 7M ammonia-methanol.
  • the reaction temperature is not particularly limited, but is preferably 80-100°C, more preferably 60-65°C.
  • the reaction time is not particularly limited, for example, 12-24 hours.
  • Step 5 In the presence of oxalyl chloride, compound 5 is treated with an amine of formula R 2 NH 2 to obtain acylurea compound 6;
  • the organic solvent used in the reaction is not particularly limited, but it is preferably carried out in a suitable organic solvent.
  • the organic solvent is preferably an anhydrous solvent, such as 1,2-dichloroethane.
  • the reaction temperature is not particularly limited, but is preferably 50-85°C, more preferably 80-85°C.
  • the reaction time is not particularly limited, for example, 1-3 hours.
  • Step 6 Compound 6 is cyclized by dehydrogenation in the presence of a base to obtain compound 7;
  • the organic solvent used in the reaction is not particularly limited, but is preferably carried out in a suitable organic solvent.
  • the organic solvent is preferably an anhydrous solvent, such as tetrahydrofuran.
  • the reaction is carried out under alkaline conditions, and the base used is not particularly limited, but is preferably selected from KHMDS.
  • the reaction temperature is not particularly limited, but is preferably -78 to 0°C, more preferably -78°C.
  • the reaction time is not particularly limited, for example, 4 to 24 hours.
  • Step 7 Under the action of a base such as triethylamine, the lactam is chlorinated with phosphorus oxychloride to obtain compound 8;
  • the organic solvent used in the reaction is not particularly limited, but it is preferably carried out in a suitable organic solvent.
  • the organic solvent is preferably an anhydrous solvent, such as acetonitrile.
  • the reaction is carried out under alkaline conditions, and the base used is not particularly limited, but preferably selected from TEA.
  • the reaction temperature is not particularly limited, but it is preferably 70-80°C, more preferably 80°C.
  • the reaction time is not particularly limited, for example, 1-4 hours.
  • Step 8 Compound 5 was nucleophilically substituted with NHR 4R 5 to obtain compound 9.
  • the organic solvent used in the reaction is not particularly limited, but is preferably carried out in a suitable organic solvent.
  • the organic solvent is preferably an anhydrous solvent, such as acetonitrile.
  • the reaction is carried out under alkaline conditions, and the base used is not particularly limited, but is preferably selected from DIPEA.
  • the reaction temperature is not particularly limited, but is preferably 50-70°C, more preferably 60°C.
  • the reaction time is not particularly limited, for example, 0.5-4 hours.
  • R2 is L1 -ring A
  • R1 , R4 , R5 , L1 , and ring A are as defined in the first aspect of this invention.
  • the compounds of this invention possess excellent MAT2A enzyme inhibitory activity
  • the compounds of this invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of this invention as the main active ingredient can be used to treat and prevent diseases related to MAT2A expression or MTAP deletion-mutant cancers.
  • the compounds of this invention can be used to treat the following diseases: cancer, etc.
  • compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier.
  • Safe and effective range refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects.
  • “Pharmaceutically acceptable carriers” refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl
  • Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol
  • composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.
  • auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.
  • the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.
  • suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.
  • the compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the pharmaceutical composition When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is the pharmaceutically considered effective dose. Because the compound of the present invention has excellent inhibitory effects on MAT2A enzyme activity, only low doses are needed to achieve therapeutic or preventative effects against MAT2A-related tumors. Generally, for a person weighing 60 kg, the daily dose is typically 0.01–10 mg/kg (based on the portion of the compound of the present invention in the compound, pharmaceutical composition, or prodrug), preferably 0.05–5 mg/kg, more preferably 0.1–1 mg/kg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.
  • the main advantages of the present invention include:
  • the compounds of the present invention have novel structures and good MAT2A inhibitory activity.
  • the compounds of the present invention have good pharmacokinetic properties and bioavailability.
  • the compounds of the present invention have good in vivo antitumor activity.
  • the compounds of the present invention can be prepared, isolated, or obtained by any method obvious to those skilled in the art.
  • the compounds of the present invention can also be prepared according to the exemplary preparation methods provided below (such as the methods in the examples). Reaction conditions, steps, and reactants not provided in the exemplary preparation methods are obvious and known to those skilled in the art.
  • the symbols and conventions used in these processes, methods, and examples, whether or not specific abbreviations are specifically defined, have meanings well known to those skilled in the art.
  • the raw materials used in the examples may be obtained commercially available or synthesized in a manner known to those skilled in the art or by similar methods described in the examples.
  • Synthesis of S1-4 A suspension of polyphosphoric acid (2.6 g, 7.67 mmol) in toluene (18 mL) was stirred at 60 °C for 30 min. Then, a toluene solution (4.5 mL) of intermediate S1-3 (815 mg, 2.54 mmol) was added to the above suspension. The reaction system was stirred at 60 °C for 2 hours and concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic phase was washed with water and saturated sodium bicarbonate aqueous solution, respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Synthesis of S18-3 Compound S18-2 (150 mg, 0.672 mmol) and THF (2.5 mL) were placed in a vial under nitrogen atmosphere. LAH (38.27 mg, 1.01 mmol) was added, and the reaction mixture was stirred at 70 °C for 2 hours. The reaction mixture was cooled to 0 °C and quenched with wet Na2SO4 . The reaction mixture was filtered through a diatomaceous earth mat after washing with EtOAc. The filtrate was dried over Na2SO4 , filtered, and concentrated to give S18-3 (70 mg).
  • Synthesis of S18-4 Refer to the preparation method in Example 1, except that aniline is replaced with (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methylamine;
  • Synthesis of S18-5 Refer to the preparation method of Example 1, except that S1-6 is replaced with S18-4;
  • Synthesis of S21-3 Refer to the synthesis of S1-4.
  • Synthesis of S26-2 Compound S26-1 (250 mg, 1.53 mmol) was dissolved in ultra-dry tetrahydrofuran (15 mL). NaH (67.3 mg, 1.68 mmol) was added in portions under ice bath conditions, and the mixture was stirred for 30 minutes under ice bath conditions. Subsequently, SEMCl (280.5 mg, 1.68 mmol) was slowly added dropwise, and the reaction was carried out at room temperature for 2 hours. The reaction solution was extracted with water and EtOAc, and the organic phase was dried over anhydrous sodium sulfate. The intermediate S26-2 (199 mg) was purified by Flash column chromatography.
  • Synthesis of S26-3 Compound S26-2 (199 mg, 0.678 mmol) was dissolved in 15 mL of ethanol, and 20 mg of Pd/C was added. The reaction was carried out overnight under a hydrogen atmosphere. The reaction solution was then filtered under reduced pressure, and the filtrate was concentrated under reduced pressure to obtain compound S26-3 (197 mg).
  • Synthesis of S26-5 Refer to the synthesis of compound S1-7.
  • S40 was prepared according to the method described in Example 1, replacing S1-4 with S40-2 to obtain compound S40.
  • ESI-MS (m/z): 332.2 [M+H] + .
  • Example 83 Synthesis of 3-(4-chloro-9-(methylamino)-7-oxofurano[2,3-f]quinazolin-6(7H)-yl)-N-(3-(4-chloro-9-(methylamino)-7-oxofurano[2,3-f]quinazolin-6(7H)-yl)phenyl)benzamide (S127)
  • Example 84 Synthesis of compounds S128 and S129.
  • the compound was prepared according to the method described in Example 1 and purified using a chiral SFC column (column: AD-H/SFC 20mm ID ⁇ 250mmL, 5 ⁇ M; mobile phase: mobile phase A was CO2 , mobile phase B was isopropanol; isocratic elution conditions: 5% B (v/v), 12min; flow rate: 50g/min; detector: PDA; column temperature: 35°C; back pressure: 100Bar).
  • the first peak obtained was compound S128 (retention time: 5.97min), and the second peak obtained was S129 (retention time: 7.63min).
  • the absolute configuration of compound S129 was confirmed by single-crystal diffraction experiments.
  • Test Example 1 Inhibitory Activity Test of Quinazolinone Five-Membered Heterocyclic Derivatives Against MAT2A
  • a method for detecting MAT2A enzyme activity was established.
  • the reaction conditions were as follows: the protein was diluted to 200 nM in enzyme activity reaction buffer (50 mM Tris, pH 8.0, 50 mM KCl , 15 mM MgCl2, 0.3 mM EDTA, 0.005% [w/v] bovine serum albumin [BSA]), and the compound was diluted to a final concentration of 20 ⁇ with DMSO.
  • enzyme activity reaction buffer 50 mM Tris, pH 8.0, 50 mM KCl , 15 mM MgCl2, 0.3 mM EDTA, 0.005% [w/v] bovine serum albumin [BSA]
  • MAT2A protein dilution 20 ⁇ L was added to 2 ⁇ L of the test compound, followed by 20 ⁇ L of substrate mix (500 ⁇ M ATP, 400 ⁇ M L-methionine) to initiate the enzyme activity reaction, and the mixture was incubated at 25 °C for 60 minutes. After the reaction was terminated, the amount of phosphate generated in the enzymatic reaction was measured using a PiColorLock TM (Abcam), and the amount of phosphate generated was used to determine the formation of SAM in the reaction.
  • substrate mix 500 ⁇ M ATP, 400 ⁇ M L-methionine
  • Inhibition rate % (1 - (Abs test sample - Abs average of negative control samples ) / (Abs average of positive control samples - Abs average of negative control samples )) ⁇ 100%.
  • the IC50 value was determined by fitting the data to a standard four-parameter dose-response equation using GraphPad Prism software.
  • Test Example 2 Antiproliferative Activity Test of Quinazolinone Five-Membered Heterocyclic Derivatives against HCT116 MTAP -/- and HCT116 MTAP +/+ Cells
  • Cells were seeded at a density of 400 cells per well in 384-well cell culture plates and cultured overnight at 37°C and 5% CO2 to allow for cell adhesion.
  • the highest concentration of the compound was 10 ⁇ M, which was serially diluted at a 1:2 ratio before being added to the cell culture plates.
  • cell viability was assessed using the CellTiter-Meiluncell cell viability assay kit (Meilun, PWL214).
  • the GI50 value was calculated using a variable slope (four-parameter) nonlinear regression (curve fitting) with GraphPad Prism software.
  • the compounds of the present invention have good oral exposure and oral bioavailability in mice.
  • Test Example 4 Mouse Tumor Pharmacodynamic Model of Quinazolinone Five-Membered Heterocyclic Derivative
  • mice Female BALB/c nude mice were inoculated under the armpit with 1 ⁇ 107 HCT116 MTAP -/- cells to construct a mouse xenograft tumor model.
  • the solvent used in the experiment was physiological saline containing 5% DMSO, 5% PEG400, and 90% saline containing 10% hydroxypropyl- ⁇ -cyclodextrin.
  • Compound S49 was administered at two doses of 10 mg/kg and 30 mg/kg, and the positive control compound AG-270 was administered at a single dose of 50 mg/kg, all orally once daily. Changes in tumor volume and body weight were observed and recorded daily. After the last administration, the mice were euthanized, and subcutaneous tumors were isolated for biochemical analysis. The tumor volume was calculated using the following formula: (tumor length ⁇ tumor width2 )/2.
  • the compound of the present invention has good in vivo efficacy in mice.

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Abstract

La présente invention concerne un dérivé hétérocyclique à cinq chaînons fusionné à la quinazolinone ayant une structure représentée par la formule (I-A). Les résultats expérimentaux montrent que le composé fourni par la présente invention présente une bonne activité inhibitrice contre MAT2A, présente une activité inhibitrice contre la prolifération de cellules cancéreuses avec une mutation de délétion MTAP, et peut être utilisé pour traiter et/ou prévenir des maladies cancéreuses associées à MAT2A.
PCT/CN2025/091310 2024-04-26 2025-04-25 Composé hétérocyclique à cinq chaînons fusionné à la quinazolinone, composition pharmaceutique associée et utilisation associée Pending WO2025223561A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112574224A (zh) * 2019-09-30 2021-03-30 上海迪诺医药科技有限公司 Kras g12c抑制剂及其应用
CN113166078A (zh) * 2018-12-10 2021-07-23 伊迪亚生物科学有限公司 2-氧代喹唑啉衍生物作为甲硫氨酸腺苷转移酶2a抑制剂
WO2022143864A1 (fr) * 2020-12-31 2022-07-07 江苏先声药业有限公司 Composé tricyclique et son utilisation
WO2023116390A1 (fr) * 2021-12-24 2023-06-29 上海海和药物研究开发股份有限公司 Composé bicyclique fusionné à une pyrimidine-2(1h)-one, doté d'une activité inhibitrice vis-à-vis de mat2a, et son utilisation
CN116903613A (zh) * 2022-04-20 2023-10-20 深圳微芯生物科技股份有限公司 2-氧代喹唑啉并五元杂环衍生物、其制备方法及其应用
WO2024002024A1 (fr) * 2022-06-27 2024-01-04 石药集团中奇制药技术（石家庄）有限公司 Composés tricycliques et leurs utilisations

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113166078A (zh) * 2018-12-10 2021-07-23 伊迪亚生物科学有限公司 2-氧代喹唑啉衍生物作为甲硫氨酸腺苷转移酶2a抑制剂
CN112574224A (zh) * 2019-09-30 2021-03-30 上海迪诺医药科技有限公司 Kras g12c抑制剂及其应用
WO2022143864A1 (fr) * 2020-12-31 2022-07-07 江苏先声药业有限公司 Composé tricyclique et son utilisation
WO2023116390A1 (fr) * 2021-12-24 2023-06-29 上海海和药物研究开发股份有限公司 Composé bicyclique fusionné à une pyrimidine-2(1h)-one, doté d'une activité inhibitrice vis-à-vis de mat2a, et son utilisation
CN116903613A (zh) * 2022-04-20 2023-10-20 深圳微芯生物科技股份有限公司 2-氧代喹唑啉并五元杂环衍生物、其制备方法及其应用
WO2024002024A1 (fr) * 2022-06-27 2024-01-04 石药集团中奇制药技术（石家庄）有限公司 Composés tricycliques et leurs utilisations

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