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WO2022188755A1 - 吡啶并嘧啶类化合物及其应用 - Google Patents

吡啶并嘧啶类化合物及其应用 Download PDF

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Publication number
WO2022188755A1
WO2022188755A1 PCT/CN2022/079597 CN2022079597W WO2022188755A1 WO 2022188755 A1 WO2022188755 A1 WO 2022188755A1 CN 2022079597 W CN2022079597 W CN 2022079597W WO 2022188755 A1 WO2022188755 A1 WO 2022188755A1
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Prior art keywords
substituted
alkyl
cycloalkyl
membered heterocycloalkyl
hyt
Prior art date
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PCT/CN2022/079597
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English (en)
French (fr)
Inventor
丁克
张鑫
许芳
任小梅
陆小云
马大为
黄维雪
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Shanghai Institute of Organic Chemistry of CAS
Jinan University
University of Jinan
Original Assignee
Shanghai Institute of Organic Chemistry of CAS
Jinan University
University of Jinan
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Application filed by Shanghai Institute of Organic Chemistry of CAS, Jinan University, University of Jinan filed Critical Shanghai Institute of Organic Chemistry of CAS
Priority to JP2023553413A priority Critical patent/JP7756374B2/ja
Priority to EP22766278.0A priority patent/EP4310084A4/en
Priority to AU2022234998A priority patent/AU2022234998B2/en
Priority to CN202280001130.XA priority patent/CN115348963B/zh
Priority to KR1020237032389A priority patent/KR102912922B1/ko
Publication of WO2022188755A1 publication Critical patent/WO2022188755A1/zh
Priority to US18/462,373 priority patent/US20240132492A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—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
    • 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 invention relates to the field of medicinal chemistry, in particular to a class of pyridopyrimidine compounds and applications thereof.
  • AKT AKmouse plus Transforming or Thymoma
  • protein kinase B protein kinase B
  • PKB protein kinase B
  • AKT1 is widely present in a variety of tissues, including heart, liver, muscle, etc.; AKT2 is mainly distributed in insulin-sensitive tissues, such as skeletal muscle and adipose tissue; AKT3 is mainly distributed in brain, heart, kidney and other tissues.
  • AKT1 is enhanced in approximately 40% of breast and ovarian cancers and more than 50% of prostate cancers; AKT2 is overexpressed in 40% of liver cancers and 57% of colorectal cancers; AKT2 deletion results in hyperglycemia, type 2 Diabetes and impaired glucose uptake; overexpression of AKT1 and AKT2 is also associated with paclitaxel resistance in ovarian cancer; high expression of AKT3 is present in breast, prostate and some osimertinib-resistant non-small cell lung cancers. Therefore, selective regulation of AKT isoforms may play a positive role in the treatment of related diseases.
  • AKT is an important class of tumor therapeutic targets.
  • a number of AKT kinase inhibitors have entered the clinical trial stage, and they have shown good anti-tumor effects.
  • these inhibitors lack selectivity for each subtype of AKT, and indiscriminate inhibition may have certain clinical side effects.
  • prolonged drug treatment may lead to resistance of patients to AKT inhibitors, thereby weakening the efficacy.
  • AKT protein has both kinase function and non-kinase function, and it may be difficult to fully exert the anti-tumor effect by simply inhibiting the kinase function.
  • Targeted degradation of the intact AKT3 protein can not only inhibit its kinase function, but also regulate its non-kinase function, thereby exerting a stronger anti-tumor effect.
  • the present invention provides a new class of pyridopyrimidine compounds, which can selectively degrade AKT3 protein with high activity, can inhibit the proliferation of various tumor cells, and can be used for the treatment of patients with AKT3 protein-related diseases and tumors.
  • the pyridopyrimidine compound having the structure represented by formula (I) or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule:
  • E is selected from: hydrogen, C 1 -C 15 alkyl, substituted C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, substituted C 3 -C 15 cycloalkyl, 3-15 membered heterocycle Alkyl, substituted 3-15 membered heterocycloalkyl;
  • Y is selected from: absent or -O-, -NH-, -NHCO-, -CH2- , -S-, -CO-;
  • Z is selected from: absent or -O-, -NH-, -N(C 1 -C 6 alkyl)-, -NHCO-, -CH 2 -, -S-, -CO-, -SO-;
  • R 1 is selected from: hydrogen, C 1 -C 6 alkyl, halogen or halogen substituted C 1 -C 6 alkyl;
  • R 2 is selected from: C 3 -C 15 cycloalkyl, substituted C 3 -C 15 cycloalkyl, 3-15 membered heterocycloalkyl, substituted 3-15 membered heterocycloalkyl, C 6 -C 10 Aryl, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl;
  • R3 is: Wherein, B is connected to Y through a covalent bond;
  • A is selected from: -NH-, -NHR-;
  • R is selected from: C 6 -C 10 aryl, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl base;
  • B is absent or selected from: C3 - C15cycloalkyl, substituted C3 - C15cycloalkyl, 3-15 membered heterocycloalkyl, substituted 3-15 membered heterocycloalkyl, 3-15 membered heterocycloalkyl membered heterocycloalkanone group, R 8 substituted 3-15 membered heterocycloalkanone group, C 3 -C 12 cycloalkyl substituted amino group, 3-12 membered heterocycloalkyl substituted amino group,
  • E is selected from: hydrogen, C 1 -C 8 alkyl, R 5 substituted C 1 -C 8 alkyl, C 3 -C 12 cycloalkyl, R 6 substituted C 3 -C 12 -membered cycloalkyl, 3-12-membered heterocycloalkyl, 3-12-membered heterocycloalkyl substituted by R 6 ;
  • R 5 is selected from: halogen, C 3 -C 12 cycloalkyl, C 1 -C 3 alkyl substituted C 3 -C 12 cycloalkyl, halogen substituted C 3 -C 12 cycloalkyl;
  • R 6 is selected from: halogen, C 1 -C 6 alkyl, halogen substituted C 1 -C 6 alkyl.
  • E is selected from: hydrogen, C 1 -C 6 alkyl, R 5 substituted C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, R 6 substituted C 3 -C 10 cycloalkyl;
  • R 5 is selected from: halogen, C 6 -C 10 cycloalkyl, methyl substituted C 6 -C 10 cycloalkyl, halogen substituted C 6 -C 10 cycloalkyl;
  • R 6 is selected from: halogen, C 1 -C 3 alkyl.
  • E is selected from: hydrogen, cyclopropyl, where x is an integer from 0-3 and y is an integer from 0-3.
  • L is selected from:
  • n and m are each independently an integer from 0 to 14.
  • L is selected from: Where n is an integer from 0-7 and m is an integer from 0-3.
  • L is selected from: Or L is absent, where n is an integer from 2-7.
  • Y is selected from: -CH2- , -CO-, -O-, or Y is absent;
  • Z is selected from: -NHCO-, -NH-, or Z is absent.
  • R 1 is selected from the group consisting of: hydrogen, halogen, C 1 -C 3 alkyl.
  • R 2 is selected from: C 5 -C 10 cycloalkyl, R 9 substituted C 5 -C 10 cycloalkyl, 5-10 membered heterocycloalkyl, R 9 substituted 5-10 Membered heterocycloalkyl, C 6 -C 10 aryl, R 9 substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, R 9 substituted 5-10 membered heteroaryl, 5-10 membered Heteroaryl ketone group, 5-10-membered heteroaryl ketone group substituted by R 9 ;
  • R 4 is selected from: absent or hydrogen, amino, ester, carboxyl, hydroxyl, mercapto, sulfone, sulfoxide, C 1 -C 15 alkyl, R 10 substituted C 1 -C 15 alkyl, C 3 -C 15 -membered cycloalkyl, 3-15-membered heterocycloalkyl, R 10 -substituted C 3 -C 15 -membered cycloalkyl, R 10 -substituted 3-15-membered heterocycloalkyl, -COR 11 ;
  • R 10 is selected from: C 1 -C 6 alkyl, amino substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, dimethylamino substituted C 1 -C 6 alkyl, 3-6 Membered heterocycloalkyl, dimethylamino, C1 - C3 alkoxy substituted C1 - C6 alkyl, hydroxy substituted C1 - C6 alkyl, C1 - C6 alkyl substituted 3 -6-membered heterocycloalkyl, C 1 -C 6 alkyl acyl, hydroxyl, C 1 -C 6 alkyl substituted C 3 -C 6 cycloalkyl, dimethylaminoethyl substituted 5-6 membered heterocycle Alkyl, C 1 -C 6 alkoxy;
  • R 11 is selected from: vinyl, C 1 -C 6 alkyl, amino substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, amino substituted C 3 -C 6 cycloalkyl, halogen substituted C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1 -C 6 alkyl substituted 3-6 membered heterocycloalkyl, dimethylamino substituted C 1 -C 6 alkyl , 5-6 membered heterocycloalkyl substituted by dimethylaminoethyl.
  • R is selected from:
  • R is selected from:
  • R 2 is selected from: C 5 -C 8 cycloalkyl, R 9 substituted C 5 -C 8 cycloalkyl, 5-8 membered heterocycloalkyl, R 9 substituted 5-8 Membered heterocycloalkyl, phenyl, R 9 substituted phenyl, 5-6 membered heteroaryl, R 9 substituted 5-6 membered heteroaryl;
  • R 4 is selected from: H, C 1 -C 6 alkyl, R 10 substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, R 10 substituted C 3 -C 6 cycloalkyl, 3-6-membered heterocycloalkyl substituted by R 10 , -CH 2 R 11 , -COR 11 ;
  • R 10 is selected from: C 1 -C 3 alkyl, dimethylamino, C 3 -C 6 cycloalkyl, 3-6 membered heterocycloalkyl, C 1 -C 3 alkyl substituted 3-6 membered heterocyclic Cycloalkyl, C 3 -C 6 cycloalkyl substituted by C 1 -C 3 alkyl;
  • R 11 is selected from: vinyl, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, halogen substituted C 3 -C 6 cycloalkyl.
  • R 2 is selected from: C 5 -C 6 cycloalkyl, R 9 substituted C 5 -C 6 cycloalkyl, 5-6 membered heterocycloalkyl, R 9 substituted 5-6 Membered heterocycloalkyl, phenyl, R 9 substituted phenyl;
  • R 4 is selected from: H, C 1 -C 3 alkyl, R 10 substituted C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, 5-6 membered heterocycloalkyl, R 10 substituted C 3 -C 6 cycloalkyl, R 10 substituted 5-6 membered heterocycloalkyl, -CH 2 R 11 , -COR 11 ;
  • R 10 is selected from: C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl;
  • R 11 is selected from: vinyl, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl.
  • R is selected from:
  • R 9 is selected from: H, dimethylamino, C 1 -C 3 alkyl, -NH(R 4 ), -OR 4 , -COR 11 ;
  • R 4 is selected from: H, methylpiperidinyl, -CH 2 R 11 , -COR 11 ;
  • R 11 is selected from: vinyl, C 1 -C 4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl .
  • A is selected from: -NH-, -NHR-;
  • R is selected from: phenyl, R 7 -substituted phenyl, 6-membered heteroaryl, R 7 -substituted 6-membered heteroaryl;
  • R 7 is selected from: C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogen, C 1 -C 6 alkoxy, halogen substituted C 1 -C 6 alkoxy, deuterated C 1 - C 6 alkoxy, halogen substituted C 1 -C 6 alkyl, cyano substituted C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, trifluoromethyl substituted C 3 -C 6 Cycloalkyl, C 1 -C 6 alkyl substituted C 3 -C 6 cycloalkyl, hydroxy, amino, -SO(C 1 -C 6 alkyl), -S(O) 2 (C 1 -C 6 alkyl), C 1 -C 6 alkylthio;
  • B is absent or selected from: C 3 -C 12 cycloalkyl, R 8 substituted C 3 -C 12 cycloalkyl, 3-12 membered heterocycloalkyl, R 8 substituted 3-12 membered heterocycloalkyl , 3-12-membered heterocycloalkanone group, R 8 -substituted 3-12-membered heterocycloalkanone group, C 3 -C 12 -membered cycloalkyl substituted amino group, 3-12-membered heterocycloalkyl substituted amino group ,
  • R 8 is selected from: C 1 -C 6 alkyl, C 3 -C 12 cycloalkyl, 3-12 membered heterocycloalkyl, amino, cyano substituted C 1 -C 6 alkyl, halogen, C 1 -C 6 alkoxy, halogen substituted C 1 -C 6 alkyl, hydroxy, amino.
  • A is selected from:
  • A is selected from: -NH-, -NHR-;
  • R is selected from: phenyl, 6-membered heteroaryl, R 7 -substituted phenyl, R 7 -substituted 6-membered heteroaryl;
  • R 7 is selected from: C 1 -C 3 alkyl, halogen, C 1 -C 3 alkoxy, halogen substituted C 1 -C 3 alkoxy, halogen substituted C 1 -C 3 alkyl, cyano substituted C 1 -C 3 alkyl;
  • B is absent or selected from: C 4 -C 12 cycloalkyl, R 8 substituted C 4 -C 12 cycloalkyl, 4-12 membered heterocycloalkyl, R 8 substituted 4-12 membered heterocycloalkyl ,
  • R 8 is selected from: C 1 -C 3 alkyl, C 4 -C 6 cycloalkyl, 4-6 membered heterocycloalkyl, cyano-substituted C 1 -C 3 alkyl, halogen, C 1 -C 3 Alkoxy, halogen substituted C 1 -C 3 alkyl.
  • A is selected from: -NH-, -NHR-;
  • R is selected from: phenyl, 6-membered nitrogen-containing heteroaryl, R 7 -substituted phenyl, R 7 -substituted 6-membered nitrogen-containing heteroaryl Aryl;
  • R 7 is selected from: C 1 -C 3 alkoxy
  • B is absent or selected from: C 4 -C 8 cycloalkyl, R 8 substituted C 4 -C 10 cycloalkyl, 4-10 membered heterocycloalkyl, R 8 substituted 4-10 membered heterocycloalkyl ,
  • R 8 is selected from: C 1 -C 3 alkyl, C 1 -C 3 alkoxy.
  • R is selected from:
  • the present invention also provides the use of the above-mentioned pyridopyrimidine compounds or their pharmaceutically acceptable salts or their stereoisomers or their prodrug molecules. Including the following technical solutions:
  • the diseases associated with abnormal expression of AKT3 protein include: tumor, cardiovascular disease, diabetes, hypertension, muscular dystrophy, Parkinson's disease, Alzheimer's disease.
  • the tumor is: non-small cell lung cancer, malignant melanoma, prostate cancer, kidney cancer, liver cancer, bladder cancer, ovarian cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, lung cancer, throat cancer carcinoma, nasopharyngeal carcinoma, pancreatic cancer, multiple myeloma, B lymphoma, leukemia, skin squamous cell carcinoma.
  • the present invention also provides an AKT3 protein degrading agent. Including the following technical solutions:
  • An AKT3 protein degrading agent the active ingredient of which contains the above-mentioned pyridopyrimidine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule.
  • the present invention also provides a pharmaceutical composition for treating and/or preventing tumor or preventing tumor recurrence after operation. Including the following technical solutions:
  • a pharmaceutical composition for treating and/or preventing tumor or preventing tumor recurrence after operation prepared from active ingredients and pharmaceutically acceptable carriers or adjuvants, the active ingredients include the above-mentioned pyridopyrimidine compounds or their pharmaceutically acceptable compounds. Acceptable salts or stereoisomers thereof or prodrug molecules thereof.
  • the present invention provides a class of pyridopyrimidine compounds with novel structures or their pharmaceutically acceptable salts or their stereoisomers or their prodrug molecules, which can efficiently and selectively degrade AKT3 protein in cells , but has no effect on AKT1/2, so it can significantly inhibit the proliferation of tumor cells mediated by high expression of AKT3, and can be used to prepare therapeutic drugs for diseases related to abnormal expression of AKT3 protein and various tumors.
  • Figure 1 shows the degradation activity of compound ZX-HYT-11 on AKT1/2/3 in H1975, PC-9, H1299 and A549 cells.
  • any variable eg, R4, R5, etc.
  • the definition of each occurrence is independent of the definition of each other.
  • combinations of substituents and variables are permissible so long as such combinations stabilize the compound.
  • a line drawn into a ring system from a substituent indicates that the indicated bond may be attached to any substitutable ring atom. If the ring system is polycyclic, it means that such bonds are only attached to any suitable carbon atoms adjacent to the ring. It will be appreciated that one of ordinary skill in the art can select substituents and substitution patterns for the compounds of the present invention to provide compounds that are chemically stable and readily synthesized from readily available starting materials by the skill of the art and the methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.
  • alkyl as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • the definition of “ C1 - C6 " in " C1 - C6 alkyl” includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms in a straight or branched chain arrangement.
  • “ C1 - C6 alkyl” specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group whose ring atoms consist of carbon atoms, including spiro, fused and bridged rings.
  • cycloalkyl includes but is not limited to the following groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Wait.
  • alkoxy refers to groups having the structure -O - alkyl, such as -OCH3 , -OCH2CH3 , -OCH2CH2CH3, -O - CH2CH ( CH3 ) 2 , -OCH 2 CH 2 CH 2 CH 3 , -O-CH(CH 3 ) 2 , etc.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic substituent wherein one or more ring atoms are selected from N, O or S(O)m (where m is 0-2 integer) heteroatoms, the remaining ring atoms are carbon, bicyclic or polycyclic rings include spiro rings, fused rings and bridged rings.
  • heteroaryl refers to an aromatic ring containing one or more heteroatoms selected from O, N or S, which may be monocyclic, bicyclic or polycyclic, such as including but not limited to: quinoline base, pyrazolyl, pyrrolyl, thienyl, furanyl, pyridyl, pyrimidinyl, pyrazinyl, triazolyl, imidazolyl, oxazolyl, isoxazolyl, pyridazinyl, etc.; "heteroaryl "Radical” is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl group. The attachment of the heteroaryl group can be through a carbon atom or through a heteroatom.
  • heteroarylketo refers to an aromatic ring containing one or more cyclic carbonyl groups and containing one or more heteroatoms selected from O, N or S, which may be monocyclic, bicyclic or polycyclic. Rings, for example, include but are not limited to: Wait.
  • the attachment of the heteroaromatic keto group can be through a carbon atom or through a heteroatom.
  • heterocycloalkanone refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic substituent containing one or more cyclic carbonyl groups wherein one or more ring atoms are selected from N, O or S(O)m (wherein m is an integer of 0-2) heteroatoms, the remaining ring atoms are carbon, bicyclic or polycyclic rings include spiro rings, fused rings and bridged rings, such as but not limited to: The attachment of the heterocycloalkanone group can be through a carbon atom or through a heteroatom
  • halo means chlorine, fluorine, bromine and iodine.
  • the present invention provides a pyridopyrimidine compound having the structure represented by formula (I):
  • E is selected from: hydrogen, C 1 -C 15 alkyl, substituted C 1 -C 15 alkyl, C 3 -C 15 cycloalkyl, substituted C 3 -C 15 cycloalkyl, 3-15 membered heterocycle Alkyl, substituted 3-15 membered heterocycloalkyl;
  • Y is selected from: absent or -O-, -NH-, -NHCO-, -CH2- , -S-, -CO-;
  • Z is selected from: absent or -O-, -NH-, -N(C 1 -C 6 alkyl)-, -NHCO-, -CH 2 -, -S-, -CO-, -SO-;
  • R 1 is selected from: hydrogen, C 1 -C 6 alkyl, halogen or halogen substituted C 1 -C 6 alkyl;
  • R 2 is selected from: C 3 -C 15 cycloalkyl, substituted C 3 -C 15 cycloalkyl, 3-15 membered heterocycloalkyl, substituted 3-15 membered heterocycloalkyl, C 6 -C 10 Aryl, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl;
  • R3 is: Wherein, B is connected to Y through a covalent bond;
  • A is selected from: -NH-, -NHR-;
  • R is selected from: C 6 -C 10 aryl, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, substituted 5-10 membered heteroaryl base;
  • B is absent or selected from: C3 - C15cycloalkyl, substituted C3 - C15cycloalkyl, 3-15 membered heterocycloalkyl, substituted 3-15 membered heterocycloalkyl, 3-15 membered heterocycloalkyl membered heterocycloalkanone group, R 8 substituted 3-15 membered heterocycloalkanone group, C 3 -C 12 cycloalkyl substituted amino group, 3-12 membered heterocycloalkyl substituted amino group,
  • the present invention includes free forms of compounds of formula I, as well as pharmaceutically acceptable salts and stereoisomers thereof.
  • Some of the specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form" refers to the amine compound in non-salt form.
  • Included pharmaceutically acceptable salts include not only exemplary salts of the particular compounds described herein, but also typical pharmaceutically acceptable salts of all compounds of formula I in free form.
  • the free forms of specific salts of the compounds can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable dilute aqueous base, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate.
  • a suitable dilute aqueous base such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate.
  • the free forms differ somewhat from their respective salt forms in certain physical properties such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention containing a basic or acidic moiety by conventional chemical methods.
  • salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base and a stoichiometric amount or excess of an inorganic or organic acid in the desired salt form in a suitable solvent or combination of solvents.
  • salts of acidic compounds are formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl Salts prepared from oxymonobenzoic acid, fumaric acid, toluenesulfonic acid, methanes
  • salts derived from inorganic bases include aluminum salts, ammonium salts Salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethyl Diamine, N-Ethylmorpholine, N-Ethylpiperidine, Glucosamine, Glucosamine, Histidine, Hydroxocobalamin, Isopropylamine, Lysine, Methylglucamine, Morpholine, Piperazine , Piperidine, quack, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.
  • the present application provides a compound of formula I and a pharmaceutically acceptable salt thereof for the treatment of tumors, cardiovascular diseases, diabetes, hypertension, human or other mammals associated with abnormal expression of AKT3 protein. Muscular dystrophy, Parkinson's, Alzheimer's and other diseases.
  • the compounds of the present application and pharmaceutically acceptable salts thereof can be used for the prevention and/or treatment of non-small cell lung cancer, malignant melanoma, prostate cancer, kidney cancer, bladder cancer, ovarian cancer, colon cancer, Rectal cancer, breast cancer, cervical cancer, lung cancer, laryngeal cancer, nasopharyngeal cancer, pancreatic cancer, multiple myeloma, B lymphoma, leukemia and other tumors, or to prevent tumor recurrence after surgery.
  • the present invention also provides a pharmaceutical composition, which comprises an active ingredient in a safe and effective amount, and a pharmaceutically acceptable carrier or adjuvant.
  • the “active ingredient” in the present invention refers to the compound of formula I or its pharmaceutically acceptable salts or its stereoisomers or its prodrug molecules in the present invention.
  • the "active ingredients" and pharmaceutical compositions of the present invention can be used as AKT3 protein degraders, and can be used for the preparation of prevention and/or treatment of tumors, cardiovascular diseases, diabetes, hypertension, muscular dystrophy, Parkinson's disease, Alzheimer's disease Medications for Zheimer's disease, etc.
  • a “safe and effective amount” refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of active ingredient/dose, more preferably 10-200 mg of active ingredient/dose.
  • the "one dose” is one tablet.
  • “Pharmaceutically acceptable carrier or excipient” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity.
  • composition means that the components of the composition can be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carriers or excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as hard Fatty acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, 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,
  • the compound of formula I of the present invention can form a complex with a macromolecular compound or macromolecule through non-bonding interaction.
  • the compound of formula I of the present invention as a small molecule, can also be linked with a macromolecular compound or a macromolecule through chemical bonds.
  • the macromolecular compounds can be biological macromolecules such as polysaccharides, proteins, nucleic acids, polypeptides, and the like.
  • the mode of administration of the active ingredient or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following:
  • fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and silicic acid;
  • binders such as hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia;
  • humectants for example, glycerin
  • disintegrants for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • absorption accelerators for example, quaternary amine compounds
  • humectants such as cetyl alcohol and glyceryl monostearate
  • adsorbents for example, kaolin
  • Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof.
  • the dosage form may also contain buffering agents.
  • the solid dosage forms can also be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, and the like.
  • the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active ingredient, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • 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.
  • the compounds of the present invention may be administered alone or in combination with other therapeutic agents.
  • a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the compounds of formula I may be used in combination with other drugs known to treat or ameliorate similar conditions.
  • combination administration the mode of administration and dosage of the original drug remains unchanged, while the compound of formula I is administered concurrently or subsequently.
  • the compound of formula I is administered concomitantly with one or more other drugs, it is preferred to use a pharmaceutical composition containing one or more known drugs and the compound of formula I at the same time.
  • Drug combinations also include administration of a compound of formula I with one or more other known drugs at overlapping time periods.
  • the dose of the compound of formula I or known drugs may be lower than when they are administered alone.
  • Drugs or active ingredients that can be used in combination with the compounds of formula I include, but are not limited to:
  • drugs or active ingredients that can be used in combination with the compound of formula I include, but are not limited to: aldesleukin, alendronic acid, interferon, atranoin, allopurinol, allopurinol sodium, palonosetron hydrochloride, hexamethylmelamine, aminoglumitide, amifostine, amrubicin, amidine, anastrozole, dolasetron, aranesp, arglabin, arsenic trioxide, Arnoxin, 5-azacytidine, azathioprine, BCG or tic BCG, betadine, betamethasone acetate, betamethasone sodium phosphate preparation, bexarotene, bleomycin sulfate, bromuridine, bortezomib, busulfan, calcitonin, alezolizumab injection, capecitabine, carboplatin, casodex, cefesone, simoleukin, daunorubicin,
  • a novel pyridopyrimidine compound is provided.
  • the compounds can efficiently and selectively degrade AKT3 protein in cells, but have no effect on AKT1/2, can effectively inhibit the growth of various tumor cells, and can be used for the preparation of anti-tumor drugs.
  • the structures of the compounds were confirmed by nuclear magnetic resonance ( 1 H-NMR) and/or mass spectrometry (MS).
  • the NMR measurement was performed with a Bruker AV-400 nuclear magnetic resonance apparatus, the measurement solvent was deuterated chloroform (CDCl 3 ) or deuterated dimethyl sulfoxide (DMSO-D 6 ), and TMS was the internal standard.
  • the MS measurement was performed with a LCQAD-40000 mass spectrometer. Column chromatography adopts 200-300 mesh silica gel (produced by Qingdao Ocean Chemical Factory).
  • Example 1 N-(3-(2-((4-(4-(2-(2-(2-(2-(2-(2-(2-(((3R,5R,7R)-adamantan-1-yl) )acetamido)ethoxy)ethoxy)ethyl))piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyridine [2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-01)
  • Step 1 Synthesis of tert-butyl (3-((5-bromo-2-chloropyrimidin-4-yl)amino)phenyl)carbamate (3a)
  • Step 3 Synthesis of N-(3-(2-Chloro-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5)
  • Step 4 Synthesis of tert-butyl 4-(4-((8-(3-acrylamidophenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d ]pyrimidin-2-yl)amino)-3-ethoxyphenyl)piperazine-1-carboxylate (7)
  • Step 5 Synthesis of N-(3-(2-((2-methoxy-4-(piperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2, 3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (8)
  • Step 6 Synthesis of N-(3-(2-((4-(4-(2-(2-(2-(2-(2-(2-(2-(2-(((3R,5R,7R)-adamantan-1-yl)) )acetamido)ethoxy)ethoxy)ethyl))piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyridine [2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-01)
  • Example 7 N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)dodecanoyl)piperidine Azin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-07)
  • Example 8 N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperidine Azin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propionamide (ZX-HYT-08)
  • 5-Fluoro-2-nitroanisole 11 (3.00 g, 17.5 mmol), piperazine (7.53 g, 87.5 mmol) and anhydrous potassium carbonate (3.63 g, 26.3 mmol) were successively added to acetonitrile (50 mL), The mixture was stirred at 80°C for 6 hours. TLC monitoring, after the reaction was completed, the organic solvent was evaporated under reduced pressure. The obtained residue was added to 20 mL of distilled water and stirred for 1 hour, filtered under reduced pressure, the obtained filter cake was added to 40 mL of anhydrous ether again, stirred for 1 hour, and then filtered under reduced pressure and filtered with ice in anhydrous ether (3 ⁇ 20 mL).
  • Step 2 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(3-methoxy-4-nitrophenyl)piperazine-1- yl)dodecyl)acetamide (13)
  • the fifth step N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperidine Azin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)propionamide (ZX-HYT-08)
  • Example 10 N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl )piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl) Isobutyramide(ZX-HYT-10)
  • Example 12 N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl )piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl) Pivalamide (ZX-HYT-12)
  • Example 13 N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl )piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl) Cyclohexanecarboxamide (ZX-HYT-13)
  • Example 14 N-(4-(2-((4-(4-(12-(2-(((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl )piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl) Acrylamide (ZX-HYT-14)
  • Example 16 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-ethylphenyl)-5-methyl) yl-7-oxo-7,8-dihydro-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)decyl Dialkyl)acetamide (ZX-HYT-16)
  • the third step 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-ethylphenyl)-5-methyl) yl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl ) acetamide (ZX-HYT-16)
  • Example 17 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-aminophenyl)-5-methyl) -7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)dodecyl) Acetamide (ZX-HYT-17)
  • Example 18 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(3-methoxy-4-((5-methyl-8-( 3-((1-Methylpiperi-4-yl)amino)phenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl )piperazin-1-yl)dodecyl)acetamide (ZX-HYT-18)
  • Example 20 N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido) Dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl ) cyclopentyl) cyclopropanecarboxamide (ZX-HYT-20)
  • the suction-dried filter cake was placed in 15 mL of acetone and stirred at room temperature for 2 hours to be slurried, and filtered under reduced pressure to obtain the filter cake.
  • a white intermediate 26a (0.96 g, yield 67%) was obtained.
  • the third step N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido) Dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl ) cyclopentyl) cyclopropanecarboxamide (ZX-HYT-20)
  • Example 21 (1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)dodecane yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N- Cyclopropylcyclohexane-1-carboxamide (ZX-HYT-21)
  • Example 23 N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido) Dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl ) cyclohexyl) cyclopropanecarboxamide (ZX-HYT-23)
  • Example 25 N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)piperidine Azin-1-yl)phenyl)amino)-5-methyl-7-oxapyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT -25)
  • Example 27 N-(3-(2-((4-(2-((12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl) oxy)ethoxy)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl) ring Propane carboxamide (ZX-HYT-27)
  • Example 28 N-(3-(2-((4-((12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)dodecyl)oxy) -2-Methoxyphenyl)amino)-5-methyl-7-oxopyrimido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT- 28)
  • Example 29 N-(3-(2-((4-(4-(12-((2-((3R,5R,7R)-adamantan-1-yl)ethyl)amino)dodecane yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrano[2,3-d]pyrimidin-8(7H)-yl)phenyl ) cyclopropanecarboxamide (ZX-HYT-29)
  • the first step N-(3-(2-((4-(4-(12-(1,3-dioxoisoindol-2-yl-yl)dodecyl)piperazine-1- yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrano[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (31 )
  • the third step N-(3-(2-((4-(4-(12-((2-((3R,5R,7R)-adamantan-1-yl)ethyl)amino)dodecane yl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrano[2,3-d]pyrimidin-8(7H)-yl)phenyl ) cyclopropanecarboxamide (ZX-HYT-29)
  • Example 32 (1R,3R,5S,7R)-N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)phenyl)-5-methyl -7-oxo-7,8-dihydropyridyl[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)octyl)-3 ,5-Dimethyladamantane-1-carboxamide (ZX-HYT-32)
  • Example 33 N-(3-(2-((4-(4-(8-(3,3-dimethylsucciamido)octyl)piperazin-1-yl)-2-methoxy ylphenyl)amino)-5-methyl-7-oxopyrano[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-33)
  • Example 34 N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)phenyl)-5-methyl-7-oxo-7,8- Dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)octyl)-4,4-difluorocyclohexane-1 -Carboxamide (ZX-HYT-34)
  • Example 35 (3R,5R,7R)-N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl-7-oxo -7,8-Dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)octyl)adamantane-1-carboxamide (ZX-HYT-35)
  • Example 36 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(3-methoxy-4-((5-methyl-7-oxo) substituted-8-phenyl-7,8))-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)phenyl)piperazin-1-yl)dodecyl)acetamide ( ZX-HYT-36)
  • Example 37 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-((S)-1-(cyclopropanecarbonyl)) Pyrrolidin-3-yl))-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl )piperazin-1-yl)dodecyl)acetamide (ZX-HYT-37)
  • Example 38 N-(3-(2-((4-(2-((12-(2-((3R,5R,7R)-adamantan-1-yl)ethoxy)dodecyl )oxy)ethoxy)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl) Cyclopropanecarboxamide (ZX-HYT-38)
  • Example 39 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-((cyclobutylmethyl)amino)benzene) yl)-5-methyl-7)-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1 -yl)dodecyl)acetamide (ZX-HYT-39)
  • Example 40 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-(cyclopropylmethoxy)benzene) yl)-5-methyl-7-oxo-))7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine- 1-yl)dodecyl)acetamide (ZX-HYT-40)
  • Example 41 N-((1R,3S,5R,7S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl) )acetamido)dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidine-8( 7H)-yl)adamantan-1-yl)cyclopropanecarboxamide (ZX-HYT-41)
  • Example 42 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(8-(cyclopropanecarbonyl)-8-nitrogen) Heterobicyclo[3.2.1]octane))3-yl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)- 3-Methoxyphenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-42)
  • Example 43 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-(dimethylamino)phenyl)) -5-Methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl) Dodecyl)acetamide (ZX-HYT-43)
  • Example 44 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-((azetidine-3 -ylmethyl)amino)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxy Phenyl)piperazin-1-yl)dodecyl)acetamide (ZX-HYT-44)
  • Example 45 2-((3R,5R,7R)-adamantan-1-yl)-N-(12-(4-(4-((8-(3-(azetidine-3- (ylamino)phenyl)-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine -1-yl)dodecyl)acetamide (ZX-HYT-45)
  • Example 46 N-((1S,4S)-4-(2-((4-(4-(12-(2-((3R,5R,7R)-adamantan-1-yl)acetamido) Dodecyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl ) cyclohexyl) cyclopropanecarboxamide (ZX-HYT-46)
  • Example 48 N-(3-(2-((4-(4-(8-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)octyl)piperazine- 1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)pivalamide (ZX-HYT-48)
  • Example 50 N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2 -Methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-50 )
  • Example 51 N-(3-(2-((4-(4-(2-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)ethyl)piperazine- 1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanemethane Amide (ZX-HYT-51)
  • Example 52 N-(3-(2-((4-(4-(4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)butyl)piperazine- 1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanemethane Amide (ZX-HYT-52)
  • Example 53 N-(3-(2-((4-(4-(6-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)hexyl)piperazine-1 -yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-53)
  • Example 54 N-(3-(2-((4-(4-(10-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)decyl)piperazine- 1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanemethane Amide (ZX-HYT-54)
  • Example 55 N-(3-(2-((4-(4-(14-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)tetradecyl)piperidine oxazin-1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl) ring Propane carboxamide (ZX-HYT-55)
  • Example 56 N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2 -Methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (ZX-HYT-56)
  • Example 57 N-(3-(2-((4-(4-(2-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)ethyl)piperazine- 1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide ( ZX-HYT-57)
  • Example 58 N-(3-(2-((4-(4-(4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetamido)butyl)piperazine- 1-yl)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide ( ZX-HYT-58)
  • Example 59 N-(3-(2-((4-(4-(8-(2-((1S,3R,5S,7R)-3,5-dimethyladamantan-1-yl) Acetylamino)octyl)piperazin-1-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidine-8(7H)- yl)phenyl)cyclopropanecarboxamide (ZX-HYT-59)
  • Example 60 (1S,2R,4S)-N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)phenyl)-5-methyl-7 -oxo-7,8-dihydropyridyl[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)octyl)bicyclo[2.2. 1] Hept-5-ene-2-carboxamide (ZX-HYT-60)
  • Example 61 (1R,2R,4S)-N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)phenyl)-5-methyl-7 -oxo-7,8-dihydropyridyl[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)octyl)bicyclo[2.2. 1] Heptane-2-carboxamide (ZX-HYT-61)
  • Example 62 N-(3-(2-((4-(4-(8-(cyclopropanecarboxamido)octyl)piperazin-1-yl)-2-methoxyphenyl)amino) -5-Methyl-7-oxopyrido[2,3-d)]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-62)
  • Example 63 N-(8-(4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl-7-oxo-7,8-dihydropyridine [2,3-d]pyrimidin-2-yl))amino)-3-methoxyphenyl)piperazin-1-yl)octyl)cyclohexanecarboxamide (ZX-HYT-63)
  • Example 64 N-((3S,5S,7S)-adamantan-1-yl)-4-(4-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl -7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)piperazine-1-carboxamide (ZX-HYT- 64)
  • Example 65 N-(3-(2-((4-(4-((3R,5R,7R)-adamantane-1-carbonyl)piperazin-1-yl)-2-methoxyphenyl )amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-65)
  • Example 66 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl )amino)-5-methyl-8-(3-(4-methyl-2-oxopiperazin-1-yl)phenyl)pyrido[2,3-d]pyrimidine-7(8H)- Ketone (ZX-HYT-66)
  • Example 68 N-((3S,5S,7S)-adamantan-1-yl)-4-(5-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl -7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-6-methoxypyridin-2-yl)piperazine-1-carboxamide (ZX -HYT-68)
  • Example 70 N-(3-(2-((6-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-4 -Methoxypyridin-3-yl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX -HYT-70)
  • Example 71 N-((3S,5S,7S)-adamantan-1-yl)-4-(5-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl -7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-4-methoxypyridin-2-yl)piperazine-1-carboxamide (ZX -HYT-71)
  • Example 72 N-(3-(2-((6-(4-((3R,5R,7R)-adamantane-1-carbonyl)piperazin-1-yl)-4-methoxypyridine- 3-yl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-72)
  • Example 73 N-(3-(2-((4-((2-(2-((3R,5R,7R)-adamantan-1-yl)-N-methylacetamido)ethyl) (Methyl)amino)-2-methoxyphenyl))amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl) ring Propane carboxamide (ZX-HYT-73)
  • Example 74 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl )amino)-5-methyl-8-(3-((4-methylpiperazin-1-yl)methyl)phenyl)pyrido[2,3-d]pyrimidin-7(8H)-one (ZX-HYT-74)
  • Example 75 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl )amino)-8-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)-5-methylpyrido[2,3-d]pyrimidine-7( 8H)-ketone (ZX-HYT-75)
  • Example 76 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl )amino)-5-methyl-8-(3-((4-methylpiperazin-1-yl)methyl)-4-(trifluoromethyl)phenyl)pyrido[2,3-d ]pyrimidin-7(8H)-one (ZX-HYT-76)
  • Example 77 3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxy (ylphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-(1-methylazetidine-3- base) benzamide (ZX-HYT-77)
  • Example 78 4-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxy (ylphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-(1-methylazetidine-3- base) pyridine amide (ZX-HYT-106)
  • Example 80 5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxy (ylphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-(1-methylazetidine-3- yl)-2-(trifluoromethyl)benzamide (ZX-HYT-80)
  • Example 81 N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2 -Methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)-1-aminocyclopropane-1-methyl Amide (ZX-HYT-81)
  • Example 82 N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2 -Methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)-2-aminoacetamide (ZX-HYT -82)
  • Example 83 N-(3-(2-((4-(4-(((3R,5R,7R)-adamantan-1-yl)methyl)piperazin-1-yl)-2-methyl Oxyphenyl)amino)-5-methyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-83)
  • Example 84 N-(3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)ethyl)piperazin-1-yl)-2 -Methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-84 )
  • Example 85 N-(3-(2-((4-(((3S,5S,7S)-adamantan-1-yl)amino)-2-methoxyphenyl)amino)-5-methyl yl-7-oxopyrido[2,3-)d]pyrimidin-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-85)
  • Example 86 N-(3-(2-((4-((3R,5R,7R)-adamantan-1-yl)-2-methoxyphenyl)amino)-5-methyl-7 -Oxopyrido[2,3-d]pyrimidin)-8(7H)-yl)phenyl)cyclopropanecarboxamide (ZX-HYT-86)
  • Example 87 N-((3S,5S,7S)-adamantan-1-yl)-1-(4-((8-(3-(cyclopropanecarboxamido)phenyl)-5-methyl -7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)azetidine-3-carboxamide (ZX -HYT-87)
  • Example 88 N-(5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2 -Methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-2-fluorophenyl)-2-aminoacetamide (ZX-HYT-88)
  • Example 90 N-(3-(2-((4-(5-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)-2,5-diazabicyclo )[2.2.2]octan-2-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidine-8(7H)- yl)phenyl)cyclopropanecarboxamide (ZX-HYT-90)
  • Example 91 N-(3-(2-((4-(6-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)-2,6-diazaspiro [3.3]Hept-2-yl))-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)benzene base) cyclopropanecarboxamide (ZX-HYT-91)
  • Example 92 N-(3-(2-((4-(2-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)-2,7-)diazepine Spiro[3.5]non-7-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)benzene base) cyclopropanecarboxamide (ZX-HYT-92)
  • Example 93 N-(3-(2-((4-(5-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)hexahydropyrrolo[3,4- c]pyrrol-2(1H)-yl)-2-methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl) Phenyl)cyclopropanecarboxamide (ZX-HYT-93)
  • Example 96 N-(4-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2 -Methoxyphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)pyridin-2-yl)cyclopropanecarboxamide (ZX- HYT-96)
  • Example 97 2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxyphenyl )amino)-8-(3-((cyclopropylmethyl)amino)phenyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (ZX-HYT-97 )
  • Example 100 5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxy phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-cyclopropyl-2-fluorobenzamide (ZX- HYT-100)
  • Example 101 8-(3-(1H-imidazol-1-yl)phenyl)-2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl) Acetyl)piperazine-1-yl)-2-methoxyphenyl)amino)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (ZX-HYT-101)
  • Example 102 4-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxy (ylphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-cyclopropylpyridineamide (ZX-HYT-102)
  • Example 103 3-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxy (ylphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-cyclopropylbenzamide (ZX-HYT-103)
  • Example 104 5-(2-((4-(4-(2-((3R,5R,7R)-adamantan-1-yl)acetyl)piperazin-1-yl)-2-methoxy (ylphenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)-N-cyclopropyl-2-(trifluoromethyl)benzene Formamide (ZX-HYT-104)
  • Example 105 Effects of compounds on AKT3 protein levels in H1975OR cells
  • Cell line non-small cell lung cancer H1975-OR cell line.
  • the cell line is an Osimertinib-resistant H1975 cell line, which was obtained by a low-dose gradual addition method. Specific method: H1975 cells were plated in a 10cm culture dish at 60-70% confluence, and 50nM Osimertinib was added to the medium. After the cells were stable, the concentration of Osimertinib was gradually doubled to 3 ⁇ M. After gene detection, the obtained drug-resistant cell line (H1975-OR) had significantly higher expression of AKT3 than the original H1975 cell line.
  • Detection was performed using conventional Western Blot (immunoblotting) as follows. H1975-OR cells were seeded in a certain number of 96-well plates, and after adherent culture in an incubator overnight, a certain concentration of compounds was added for 24 hours. Cells were lysed with 1x SDS lysis buffer with protease and phosphatase inhibitors. Cell lysates were separated by SDS-PAGE and transferred to PVDF membranes. Then, the PCDF membrane was removed and immersed in blocking solution (5% BSA TBS containing 0.5% Tween-20) for 1 hour at room temperature, and then incubated with the specific primary antibody at 4°C overnight.
  • blocking solution 5% BSA TBS containing 0.5% Tween-20
  • Dmax the maximum degradation rate
  • Example 106 Effect of compound ZX-HYT-11 on AKT1/2/3 protein in other tumor cells
  • Tumor cells H1975, PC-9, H1299, and A549 were incubated with different given concentrations of compound ZX-HYT-11 for 24 hours, and then analyzed for AKT1/2/3 by immunoblotting as described in Example 105. protein level.
  • the results show (Fig. 1) that the compound ZX-HYT-11 can selectively degrade AKT3 protein in the above cells, but has no effect on AKT1/2, which further shows that the compound is effective and universal in degrading AKT3 protein.
  • Tumor cells (see Table 2-Table 5) were seeded in 96-well plates (2000-3000/well) in complete medium. After overnight incubation, cells were separately treated with compounds at different concentrations (0.000508-10 ⁇ M) for 72 hours. Cell proliferation was assessed with CCK-8 (Cell Counting Kit 8, Dojindo Laboratories, Kumamoto, Japan) assay. Half-maximal inhibitory concentration (IC50 ) values were calculated by concentration-response curve fitting using GraphPad Prism 5.0 software (GraphPad Software, La Jolla, CA). Each IC50 value is expressed as mean ⁇ SD. The results are shown in Table 2-5.

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Abstract

提供了一种具有式(Ⅰ)所示结构的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，及其应用。涉及的化合物可以高效、高选择性地降解细胞中的AKT3蛋白，而对AKT1/2无影响，从而能够显著抑制AKT3高表达介导的肿瘤细胞增殖，可用于制备与AKT3蛋白异常表达相关的癌症和其它相关疾病的治疗药物。

Description

吡啶并嘧啶类化合物及其应用 技术领域
本发明涉及药物化学领域，具体涉及一类吡啶并嘧啶类化合物及其应用。
背景技术
AKT(AKmouse plus Transforming or Thymoma)，又称蛋白激酶B(Protein kinase B,PKB)，是一种分子量约为57kD的丝氨酸/苏氨酸蛋白激酶，该家族包含AKT1、AKT2和AKT3三种亚型。AKT各亚型的功能和组织学分布存在诸多异同，其异常表达与多种疾病的发生、发展密切相关。AKT1广泛存在于多种组织，包括心脏，肝脏，肌肉等；AKT2主要分布于胰岛素敏感的组织中，如骨骼肌和脂肪组织等；AKT3主要分布于大脑、心脏和肾脏等组织。AKT1在大约40％的乳腺癌和卵巢癌以及超过50％的前列腺癌中表达增强；AKT2在40％的肝癌和57％的结直肠癌存在过表达；AKT2缺失会导致高血糖症、2-型糖尿病和葡萄糖摄取障碍；AKT1和AKT2的过表达还与卵巢癌对紫杉醇耐药有关；AKT3的高表达存在于乳腺癌，前列腺癌和部分Osimertinib耐药的非小细胞肺癌中。因此，选择性调控AKT各亚型蛋白可能对相关疾病的治疗起到积极作用。
AKT是一类重要的肿瘤治疗靶点。目前已有多个AKT的激酶抑制剂进入临床试验阶段，且表现出良好的抗肿瘤效果。然而，这些抑制剂对AKT的各个亚型蛋白缺乏选择性，无差别的抑制可能存在一定的临床毒副作用。另外，与传统靶向药物类似，长时间的药物治疗可能导致病人对AKT抑制剂产生耐药，进而减弱疗效。此外，AKT蛋白具有激酶功能和非激酶功能，单纯的抑制激酶功能可能难以彻底发挥抗肿瘤效应。靶向降解完整的AKT3蛋白不仅能够抑制其激酶功能，更能调控其非激酶功能，进而发挥更强的抗肿瘤效果。
因此，开发合成能够选择性降解AKT3蛋白的小分子降解剂对开发AKT3介导的相关疾病的治疗药物具有重要意义。
发明内容
针对上述问题，本发明提供了一类新的吡啶并嘧啶类化合物，这类新的吡啶并嘧啶类化合物能够高活性的选择性降解AKT3蛋白，能够抑制多种肿瘤细胞的增殖，可用于治疗与AKT3蛋白相关的疾病以及肿瘤。
具体技术方案包括如下：
具有式(Ⅰ)所示结构的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子：
Figure PCTCN2022079597-appb-000001
其中：
E选自：氢，C 1-C 15烷基，取代的C 1-C 15烷基，C 3-C 15环烷基，取代的C 3-C 15环烷基，3-15元杂环烷基，取代的3-15元杂环烷基；
L不存在或者为由如下基团中的一个或多个组成的连接单元：亚烷基，醚基，硫醚基，酯基，胺基，酰胺基，杂芳基，环烷基，杂环烷基，-N＝N-；
Y选自：不存在或者-O-，-NH-，-NHCO-，-CH 2-，-S-，-CO-；
Z选自：不存在或者-O-，-NH-，-N(C 1-C 6烷基)-，-NHCO-，-CH 2-，-S-，-CO-，-SO-；
R 1选自：氢，C 1-C 6烷基，卤素或卤素取代的C 1-C 6烷基；
R 2选自：C 3-C 15环烷基，取代的C 3-C 15环烷基，3-15元杂环烷基，取代的3-15元杂环烷基，C 6-C 10芳基，取代的C 6-C 10芳基，5-10元杂芳基，取代的5-10元杂芳基；
R 3为：
Figure PCTCN2022079597-appb-000002
其中，B通过共价键与Y连接；
A选自：-NH-，-NHR-；R选自：C 6-C 10芳基，取代的C 6-C 10芳基，5-10元杂芳基，取代的5-10元杂芳基；
B不存在或者选自：C 3-C 15环烷基，取代的C 3-C 15环烷基，3-15元杂环烷基，取代的3-15元杂环烷基，3-15元杂环烷酮基，R 8取代的3-15元杂环烷酮基，C 3-C 12环烷基取代的胺基，3-12元杂环烷基取代的胺基，
Figure PCTCN2022079597-appb-000003
Figure PCTCN2022079597-appb-000004
在其中一些实施例中，E选自：氢，C 1-C 8烷基，R 5取代的C 1-C 8烷基，C 3-C 12环烷基，R 6取代的C 3-C 12环烷基，3-12元杂环烷基，R 6取代的3-12元杂环烷基；
R 5选自：卤素，C 3-C 12环烷基，C 1-C 3烷基取代的C 3-C 12环烷基，卤素取代的C 3-C 12环烷基；
R 6选自：卤素，C 1-C 6烷基，卤素取代的C 1-C 6烷基。
在其中一些实施例中，E选自：氢，C 1-C 6烷基，R 5取代的C 1-C 6烷基，C 3-C 10环烷基，R 6取代的C 3-C 10环烷基；
R 5选自：卤素，C 6-C 10环烷基，甲基取代的C 6-C 10环烷基，卤素取代的C 6-C 10环烷基；
R 6选自：卤素，C 1-C 3烷基。
在其中一些实施例中，E选自：氢，环丙基，
Figure PCTCN2022079597-appb-000005
Figure PCTCN2022079597-appb-000006
Figure PCTCN2022079597-appb-000007
其中x为0-3的整数，y为0-3的整数。
在其中一些实施例中，L选自：
Figure PCTCN2022079597-appb-000008
Figure PCTCN2022079597-appb-000009
其中n，m分别独立地为0-14的整数。
在其中一些实施例中，L选自：
Figure PCTCN2022079597-appb-000010
Figure PCTCN2022079597-appb-000011
其中n为0-7的整数，m为0-3的整数。
在其中一些实施例中，L选自：
Figure PCTCN2022079597-appb-000012
Figure PCTCN2022079597-appb-000013
或者L不存在，其中n为2-7的整数。
在其中一些实施例中，Y选自：-CH 2-，-CO-，-O-，或者Y不存在；Z选自：-NHCO-，-NH-，或者Z不存在。
在其中一些实施例中，R 1选自：氢，卤素，C 1-C 3烷基。
在其中一些实施例中，R 2选自：C 5-C 10环烷基，R 9取代的C 5-C 10环烷基，5-10元杂环烷基，R 9取代的5-10元杂环烷基，C 6-C 10芳基，R 9取代的C 6-C 10芳基，5-10元杂芳基，R 9取代的5-10元杂芳基，5-10元杂芳酮基，R 9取代的5-10元杂芳酮基；
R 9选自：氨基，-N(C 1-C 6烷基) 2，卤素，C 1-C 6烷基，C 1-C 6烷氧基，卤素取代的C 1-C 6烷基，卤素取代的C 1-C 6烷氧基，-NH(R 4)，-N(R 4) 2，-O(R 4)，-C＝O-NH(R 4)，-C＝O-NH(C 3-C 6环烷基)，R 10取代的C 1-C 6烷基，C 3-C 10环烷基，3-10元杂环烷基，R 10取代的C 3-C 10环烷基，R 10取代的3-10元杂环烷基，-NH(R 4)取代的3-10元杂环烷基，5-10元杂芳基，-COR 11；
R 4选自：不存在或为氢，氨基，酯基，羧基，羟基，巯基，砜基，亚砜基，C 1-C 15烷基，R 10取代的C 1-C 15烷基，C 3-C 15环烷基，3-15元杂环烷基，R 10取代的C 3-C 15环烷基，R 10取代的3-15元杂环烷基，-COR 11；
R 10选自：C 1-C 6烷基，氨基取代的C 1-C 6烷基，C 3-C 6环烷基，二甲胺基取代的C 1-C 6烷基，3-6元杂环烷基，二甲胺基，C 1-C 3烷氧基取代的C 1-C 6烷基，羟基取代的C 1-C 6烷基，C 1-C 6烷基取代的3-6元杂环烷基，C 1-C 6烷基酰基，羟基，C 1-C 6烷基取代的C 3-C 6环烷基，二甲氨乙基取代的5-6元杂环烷基，C 1-C 6烷氧基；
R 11选自：乙烯基，C 1-C 6烷基，氨基取代的C 1-C 6烷基，C 3-C 6环烷基，氨基取代的C 3-C 6环烷基，卤素取代的C 3-C 6环烷基，3-6元杂环烷基，C 1-C 6烷基取代的3-6元杂环烷基，二甲胺基取代的C 1-C 6烷基，二甲胺乙基取代的5-6元杂环烷基。
在其中一些实施例中，R 2选自：
苯基，
Figure PCTCN2022079597-appb-000014
Figure PCTCN2022079597-appb-000015
Figure PCTCN2022079597-appb-000016
其中，R 4选自：
Figure PCTCN2022079597-appb-000017
Figure PCTCN2022079597-appb-000018
在其中一些实施例中，R 2选自：C 5-C 8环烷基，R 9取代的C 5-C 8环烷基，5-8元杂环烷基，R 9取代的5-8元杂环烷基，苯基，R 9取代的苯基，5-6元杂芳基，R 9取代的5-6元杂芳基；
R 9选自：H，二甲胺基，氨基，卤素，C 1-C 3烷基，C 1-C 3烷氧基，卤素取代的C 1-C 3烷基，卤素取代的C 1-C 3烷氧基，-NH(R 4)，-N(R 4) 2，-OR 4，-C＝O-NH(环丙基)，R 10取代的C 1-C 3烷基，C 3-C 6环烷基，3-6元杂环烷基，R 10取代的C 3-C 6环烷基，R 10取代的3-6元杂环烷基，-NH(R 4)取代的3-6元杂环烷基，-COR 11；
R 4选自：H，C 1-C 6烷基，R 10取代的C 1-C 6烷基，C 3-C 6环烷基，3-6元杂环烷基，R 10取代的C 3-C 6环烷基，R 10取代的3-6元杂环烷基，-CH 2R 11，-COR 11；
R 10选自：C 1-C 3烷基，二甲胺基，C 3-C 6环烷基，3-6元杂环烷基，C 1-C 3烷基取代的3-6元杂环烷基，C 1-C 3烷基取代的C 3-C 6环烷基；
R 11选自：乙烯基，C 1-C 4烷基，C 3-C 6环烷基，卤素取代的C 3-C 6环烷基。
在其中一些实施例中，R 2选自：C 5-C 6环烷基，R 9取代的C 5-C 6环烷基，5-6元杂环烷基，R 9取代的5-6元杂环烷基，苯基，R 9取代的苯基；
R 9选自：H、二甲胺基，氨基，C 1-C 3烷基，-NH(R 4)，-OR 4，-C＝O-NH(环丙基)，R 10取代的C 1-C 3烷基，C 3-C 6环烷基，5-6元杂环烷基，R 10取代的C 3-C 6环烷基，R 10取代的5-6元杂环烷基，-COR 11；
R 4选自：H，C 1-C 3烷基，R 10取代的C 1-C 3烷基，C 3-C 6环烷基，5-6元杂环烷基，R 10取 代的C 3-C 6环烷基，R 10取代的5-6元杂环烷基，-CH 2R 11，-COR 11；
R 10选自：C 1-C 3烷基，C 3-C 6环烷基；
R 11选自：乙烯基，C 1-C 4烷基，C 3-C 6环烷基。
在其中一些实施例中，R 2选自：
Figure PCTCN2022079597-appb-000019
其中，R 9选自：H，二甲胺基，C 1-C 3烷基，-NH(R 4)，-OR 4，-COR 11；
R 4选自：H，甲基哌啶基，-CH 2R 11，-COR 11；R 11选自：乙烯基，C 1-C 4烷基，环丙基，环丁基，环戊基。
在其中一些实施例中，A选自：-NH-，-NHR-；R选自：苯基，R 7取代的苯基，6元杂芳基，R 7取代的6元杂芳基；
R 7选自：C 1-C 6烷基，C 3-C 6环烷基，卤素，C 1-C 6烷氧基，卤素取代的C 1-C 6烷氧基，氘代C 1-C 6烷氧基，卤素取代的C 1-C 6烷基，氰基取代的C 1-C 6烷基，氘代C 1-C 6烷基，三氟甲基取代的C 3-C 6环烷基，C 1-C 6烷基取代的C 3-C 6环烷基，羟基，氨基，-SO(C 1-C 6烷基)，-S(O) 2(C 1-C 6烷基)，C 1-C 6烷硫基；
B不存在或者选自：C 3-C 12环烷基，R 8取代的C 3-C 12环烷基，3-12元杂环烷基，R 8取代的3-12元杂环烷基，3-12元杂环烷酮基，R 8取代的3-12元杂环烷酮基，C 3-C 12环烷基取代的胺基，3-12元杂环烷基取代的胺基，
Figure PCTCN2022079597-appb-000020
Figure PCTCN2022079597-appb-000021
R 8选自：C 1-C 6烷基，C 3-C 12环烷基，3-12元杂环烷基，胺基，氰基取代的C 1-C 6烷基，卤素，C 1-C 6烷氧基，卤素取代的C 1-C 6烷基，羟基，氨基。
在其中一些实施例中，A选自：
-NH-，
Figure PCTCN2022079597-appb-000022
Figure PCTCN2022079597-appb-000023
Figure PCTCN2022079597-appb-000024
B不存在或选自：
Figure PCTCN2022079597-appb-000025
Figure PCTCN2022079597-appb-000026
Figure PCTCN2022079597-appb-000027
在其中一些实施例中，A选自：-NH-，-NHR-；R选自：苯基，6元杂芳基，R 7取代的苯基，R 7取代的6元杂芳基；
R 7选自：C 1-C 3烷基，卤素，C 1-C 3烷氧基，卤素取代的C 1-C 3烷氧基，卤素取代的C 1-C 3烷基，氰基取代的C 1-C 3烷基；
B不存在或者选自：C 4-C 12环烷基，R 8取代的C 4-C 12环烷基，4-12元杂环烷基，R 8取代的4-12元杂环烷基，
Figure PCTCN2022079597-appb-000028
R 8选自：C 1-C 3烷基，C 4-C 6环烷基，4-6元杂环烷基，氰基取代的C 1-C 3烷基，卤素，C 1-C 3烷氧基，卤素取代的C 1-C 3烷基。
在其中一些实施例中，A选自：-NH-，-NHR-；R选自：苯基，6元含氮杂芳基，R 7取代的苯基，R 7取代的6元含氮杂芳基；
R 7选自：C 1-C 3烷氧基；
B不存在或者选自：C 4-C 8环烷基，R 8取代的C 4-C 10环烷基，4-10元杂环烷基，R 8取代的4-10元杂环烷基，
Figure PCTCN2022079597-appb-000029
R 8选自：C 1-C 3烷基，C 1-C 3烷氧基。
在其中一些实施例中，R 3选自：
Figure PCTCN2022079597-appb-000030
本发明还提供了上述吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子的应用。包括如下技术方案：
上述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备AKT3蛋白降解剂中的应用。
上述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防和/或治疗与AKT3蛋白异常表达相关的疾病的药物中的应用。
在其中一些实施例中，所述与AKT3蛋白异常表达相关的疾病包括：肿瘤、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症。
上述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防和/或治疗肿瘤或防止肿瘤术后复发的药物中的应用。
在其中一些实施例中，所述肿瘤为：非小细胞肺癌、恶性黑色素瘤、前列腺癌、肾癌、 肝癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、宫颈癌、肺癌、喉癌、鼻咽癌、胰腺癌、多发性骨髓瘤、B淋巴瘤、白血病、皮肤鳞癌。
本发明还提供了一种AKT3蛋白降解剂。包括如下技术方案：
一种AKT3蛋白降解剂，其活性成分含有上所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
本发明还提供了一种治疗和/或预防肿瘤或防止肿瘤术后复发的药物组合物。包括如下技术方案：
一种治疗和/或预防肿瘤或防止肿瘤术后复发的药物组合物，由活性成分和药学上可接受的载体或者辅料制备得到，所述活性成分包括上述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
本发明提供了一类结构新颖的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，该类化合物可以高效、高选择性地降解细胞中的AKT3蛋白，而对AKT1/2无影响，从而能够显著抑制AKT3高表达介导的肿瘤细胞增殖，可用于制备与AKT3蛋白异常表达相关的疾病以及多种肿瘤的治疗药物。
附图说明
图1为化合物ZX-HYT-11对H1975,PC-9,H1299和A549细胞中AKT1/2/3的降解活性。
具体实施方式
本发明所述化合物中，当任何变量(例如R 4、R 5等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上。要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C 1-C 6烷基”中“C 1-C 6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如，“C 1-C 6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。
本文所用术语“环烷基”指环原子由碳原子组成的饱和或部分不饱和的单环、双环或多环环状烃基，双环或多环包括螺环、稠环和桥环。例如：“环烷基”包括但不限于以下基团：环丙基、环丁基、环戊基、环己基、
Figure PCTCN2022079597-appb-000031
Figure PCTCN2022079597-appb-000032
等。
本文所用术语“烷氧基”指具有-O-烷基结构的基团，如-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-O-CH 2CH(CH 3) 2、-OCH 2CH 2CH 2CH 3、-O-CH(CH 3) 2等。
本文所用术语“杂环烷基”指饱和或部分不饱和的单环、双环或多环环状取代基，其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳，双环或多环包括螺环、稠环和桥环。例如：吗啉基、哌啶基、四氢吡咯基、吡咯烷基、二氢咪唑基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、四氢呋喃基、四氢噻吩基、
Figure PCTCN2022079597-appb-000033
Figure PCTCN2022079597-appb-000034
等，及其N-氧化物。杂环取代基的连接可通过碳原子或通过杂原子实现。
本文所用术语“杂芳基”指含有1个或多个选自O、N或S的杂原子的芳香环，该芳香环可以是单环、双环或者多环，例如包括但不限于：喹啉基、吡唑基、吡咯基、噻吩基、呋喃基、吡啶基、嘧啶基、吡嗪基、三氮唑基、咪唑基、噁唑基、异噁唑基、哒嗪基等；“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。杂芳基的连接可通过碳原子或通过杂原子实现。
本文所用术语“杂芳酮基”指含有1个或多个环羰基并且含有1个或多个选自O、N或S的杂原子的芳香环，该芳香环可以是单环、双环或者多环，例如包括但不限于：
Figure PCTCN2022079597-appb-000035
Figure PCTCN2022079597-appb-000036
等。杂芳酮基的连接可通过碳原子或通过杂原子实现。
本文所用术语“杂环烷酮基”指含有一个或多个环羰基的饱和或部分不饱和的单环、双环或多环环状取代基，其中一个或多个环原子选自N、O或S(O)m(其中m是0-2的整数)的杂原子，其余环原子为碳，双环或多环包括螺环、稠环和桥环，例如包括但不限于：
Figure PCTCN2022079597-appb-000037
Figure PCTCN2022079597-appb-000038
杂环烷酮基的连接可通过碳原子或通过杂原子实现
正如本领域技术人员所理解的，本文中所用“卤素”(“halo”)或“卤”意指氯、氟、溴和碘。
本发明提供了一种具有式(Ⅰ)所示结构的吡啶并嘧啶类化合物：
Figure PCTCN2022079597-appb-000039
其中：
E选自：氢，C 1-C 15烷基，取代的C 1-C 15烷基，C 3-C 15环烷基，取代的C 3-C 15环烷基，3-15元杂环烷基，取代的3-15元杂环烷基；
L不存在或者为由如下基团中的一个或多个组成的连接单元：亚烷基，醚基，硫醚基，酯基，胺基，酰胺基，杂芳基，环烷基，杂环烷基，-N＝N-；
Y选自：不存在或者-O-，-NH-，-NHCO-，-CH 2-，-S-，-CO-；
Z选自：不存在或者-O-，-NH-，-N(C 1-C 6烷基)-，-NHCO-，-CH 2-，-S-，-CO-，-SO-；
R 1选自：氢，C 1-C 6烷基，卤素或卤素取代的C 1-C 6烷基；
R 2选自：C 3-C 15环烷基，取代的C 3-C 15环烷基，3-15元杂环烷基，取代的3-15元杂环烷基，C 6-C 10芳基，取代的C 6-C 10芳基，5-10元杂芳基，取代的5-10元杂芳基；
R 3为：
Figure PCTCN2022079597-appb-000040
其中，B通过共价键与Y连接；
A选自：-NH-，-NHR-；R选自：C 6-C 10芳基，取代的C 6-C 10芳基，5-10元杂芳基，取代的5-10元杂芳基；
B不存在或者选自：C 3-C 15环烷基，取代的C 3-C 15环烷基，3-15元杂环烷基，取代的3-15元杂环烷基，3-15元杂环烷酮基，R 8取代的3-15元杂环烷酮基，C 3-C 12环烷基取代的胺基， 3-12元杂环烷基取代的胺基，
Figure PCTCN2022079597-appb-000041
Figure PCTCN2022079597-appb-000042
本发明包括式Ⅰ化合物的游离形式，也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化了的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式Ⅰ化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等，“Pharmaceutical Salts，”J.Pharm.Sci.’1977：66：1－19更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
在一个实施方案中，本申请提供了一种利用具有式Ⅰ的化合物及其药学上可接受的盐治疗人或其它哺乳动物与AKT3蛋白异常表达相关的肿瘤、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症等疾病。
在一个实施方案中，本申请的化合物及其药学上可接受的盐可以用于预防和/或治疗非小细胞肺癌、恶性黑色素瘤、前列腺癌、肾癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、宫颈癌、肺癌、喉癌、鼻咽癌、胰腺癌、多发性骨髓瘤、B淋巴瘤、白血病等肿瘤，或者用于防止肿瘤术后复发。
药物代谢物及前药
本发明所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本发明的权利要求中。
药物组合物
本发明还提供了一种药物组合物，它包含安全有效量范围内的活性成分，以及药学上可接受的载体或者辅料。
本发明所述的“活性成分”是指本发明所述的式I化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
本发明所述的“活性成分”和药物组合物可用作AKT3蛋白降解剂，可用于制备预防和/或治疗肿瘤、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症等的药物。
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片。
“药学上可接受的载体或者辅料”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。
“相容性”在此指的是组合物中各组分能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。
药学上可以接受的载体或者辅料部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022079597-appb-000043
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐 剂、无热原水等。
在另一优选例中，本发明式I化合物可与大分子化合物或高分子通过非键合作用形成复合物。在另一优选例中，本发明式I化合物作为小分子还可通过化学键与大分子化合物或高分子相连接。所述大分子化合物可以是生物大分子如高聚糖、蛋白、核酸、多肽等。
本发明的活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：
(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；
(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；
(c)保湿剂，例如，甘油；
(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；
(e)缓溶剂，例如石蜡；
(f)吸收加速剂，例如，季胺化合物；
(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；
(h)吸附剂，例如，高岭土；和
(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇 和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他治疗药物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
联合用药
式Ⅰ化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时，原来药物的给药方式和剂量保持不变，而同时或随后服用式Ⅰ化合物。当式Ⅰ化合物与其它一种或几种药物同时服用时，优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式Ⅰ化合物与其它一种或几种已知药物。当式Ⅰ化合物与其它一种或几种药物进行药物联用时，式Ⅰ化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式Ⅰ化合物进行药物联用的药物或活性成分包括但不局限为：
雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂，细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体、JAK抑制剂等。
在一个实施方案中，可以与式Ⅰ化合物进行药物联用的药物或活性成分包括但不局限为：阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿 来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他 滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
本发明的有益之处在于：
(1)提供一种结构新颖的吡啶并嘧啶类化合物。
(2)该类化合物可以高效、高选择性地降解细胞中的AKT3蛋白，而对AKT1/2无影响，可以有效抑制多种肿瘤细胞的生长，可用于制备抗肿瘤药物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
以下实施例中的原料可以从商业途径获得，或者通过本领域已知的方法制备，或根据本文所述方法制备。
化合物的结构通过核磁共振( 1H-NMR)和/或质谱(MS)来确定。NMR测定是用Bruker AV-400型核磁共振仪，测定溶剂为氘代氯仿(CDCl 3)或氘代二甲亚砜(DMSO-D 6)，TMS为内标。MS的测定用LCQAD-40000型质谱仪。柱层析采用200-300目硅胶(青岛海洋化工厂生产)。
实施例1：N-(3-(2-((4-(4-(2-(2-(2-(2-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)乙氧基)乙氧基)乙氧基)乙基))哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-01)
Figure PCTCN2022079597-appb-000044
步骤一：合成(3-((5-溴-2-氯嘧啶-4-基)氨基)苯基)氨基甲酸叔丁酯(3a)
Figure PCTCN2022079597-appb-000045
将5-溴-2,4-二氯嘧啶(1)(0.45g,2.0mmol)和(3-氨基苯基)氨基甲酸叔丁酯(2a)(0.42g,2.0mmol)依次溶于N,N-二甲基甲酰胺(DMF)(10mL)溶液中，随后加入碳酸钾(0.55g,4.0mmol)。将悬浮液在室温条件下搅拌过夜。TLC监测反应完全后，向反应液中加入50mL冰水，有大量白色沉淀生成。减压抽滤，分别用冰水和无水乙醚洗涤(3×20mL)滤饼。待滤饼抽干后，将其加入10mL丙酮中打浆，再次减压抽滤，将所得滤饼干燥，得到较纯白色固体化合物3a(0.67g，收率84.2％)。MS(ESI),m/z:399.1[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.29(s,1H),7.78(s,1H),7.45(d,1H,J＝7.2Hz),7.32-7.28(m,2H),7.03(dd,1H,J＝1.2,8.0Hz),6.56(s,1H),1.53(s,9H).
步骤二：合成(3-(2-氯-5-甲基-7-氧吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)氨基甲酸叔丁酯(4a)
Figure PCTCN2022079597-appb-000046
将化合物3a(2.57g,6.43mmol)和巴豆酸(5.54g,64.3mmol)置于250mL的两口圆底烧瓶中，在氩气保护条件下加入无水四氢呋喃(40mL)和N,N-二异丙基乙胺(11.2mL)。将混合物搅拌均匀后，置换氩气三次。再次加入二(氰基苯)二氯化钯(II)(0.12g,5％)和三(邻甲基苯基)磷(96mg,5％)，并置换氩气三次。然后将混合液缓慢升温至70℃。用TLC检测原料3a反应完全后，加入1.5mL乙酸酐。并将反应液加热至80℃继续搅拌8小时。TLC检测反应完全后，减压蒸除大部分有机溶剂，将残余物用100mL乙酸乙酯稀释。分别用1N HCl(3×100mL)和饱和氯化钠溶液(2×100mL)洗涤有机层，分离出的有机相经无水硫酸钠干燥后，浓缩并通过柱色谱纯化(石油醚/乙酸乙酯＝2:1洗脱)，得到白色固体化合物4a(0.71g，收率30％)。MS(ESI),m/z:387.3[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.61(s,1H),9.10(s,1H),7.51–7.38(m,3H),6.89(dt,J＝7.4,1.7Hz,1H),6.73(d,J＝1.4Hz,1H),2.53(d,J＝1.3Hz,3H),1.47(s,9H).
步骤三：合成N-(3-(2-氯-5-甲基-7-氧吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(5)
Figure PCTCN2022079597-appb-000047
向化合物4a(0.50g,1.29mmol)的DCM(10mL)溶液中加入TFA(2mL)，在室温条件下搅拌0.5小时，待反应完全后，减压蒸除有机溶剂。将所得残余物溶于10mL乙腈，并向该溶液中依次加入无水碳酸钾(0.36g,2.58mmol)和丙烯酰氯(0.17g,1.94mmol)，并在室温条件下继续搅拌0.5小时。待TLC监测反应完全后，蒸干有机溶剂并加入冰水50mL，室温条件下继续搅拌1小时并减压抽滤，滤饼用无水丙酮(2×25mL)洗涤。滤饼干燥后得白色固体中间体5(0.41g，收率93％)。该粗品中间体无需纯化即可用于下一步反应。MS(ESI),m/z:341.0[M+H] +. 1H NMR(400MHz,DMSO-d 6)δppm 10.69(br,1H),9.11(s,1H),7.78(d,J＝8.22Hz,1H),7.71(br,1H),7.49(t,J＝7.92Hz,1H),7.00(d,J＝7.63Hz,1H),6.74(s,1H), 6.56(dd,J＝10.27,16.92Hz,1H),6.26(d,J＝16.82Hz,1H),5.76(d,J＝10.17Hz,1H),2.55(s,3H).
步骤四：合成叔丁基4-(4-((8-(3-丙烯酰胺基苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-乙氧基苯基)哌嗪-1-羧酸酯(7)
Figure PCTCN2022079597-appb-000048
将化合物5(0.68g,2mmol)，化合物6(0.67g,2.2mmol)加入25mL仲丁醇，并往混合液中滴加催化量三氟乙酸。在氩气保护下，将反应液加热至95℃并搅拌过夜。TLC检测反应完全后，将混合物冷却至室温，减压蒸除有机溶剂。将残留物通过柱色谱分离纯化(氯仿/甲醇＝25:1洗脱)，得到黄色固体化合物7(1.11g，收率92％)。MS(ESI),m/z:612.1[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.81(s,1H),8.14(s,1H),7.90(d,J＝8.2Hz,1H),7.56(t,J＝2.0Hz,1H),7.51(t,J＝8.1Hz,1H),7.28(d,J＝8.9Hz,1H),6.98(ddd,J＝7.9,2.0,1.0Hz,1H),6.56(d,J＝2.5Hz,1H),6.50–6.38(m,1H),6.33(d,J＝1.3Hz,1H),6.30–6.21(m,1H),6.03(s,1H),5.77(dd,J＝10.1,2.1Hz,1H),3.78(s,3H),3.51–3.40(m,4H),3.05–2.89(m,4H),2.46(s,3H),1.44(s,9H).
步骤五：合成N-(3-(2-((2-甲氧基-4-(哌嗪-1-基)苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(8)
Figure PCTCN2022079597-appb-000049
向化合物7(1.22g,2mmol)的DCM(20mL)溶液中加入TFA(3mL)，并将所得溶液在室温下搅拌0.5小时。TLC监测反应完全后，蒸除有机溶剂，将所得粗产物经柱色谱纯化(氯仿/甲醇/氨水＝25:1:0.1洗脱)，得到黄色固体产物8(0.91g，收率90％)。MS(ESI), m/z:510.3[M-H] -. 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),8.90(s,1H),8.82(s,1H),8.18(s,1H),7.90(d,J＝8.3Hz,1H),7.56–7.45(m,2H),7.31(d,J＝8.8Hz,1H),7.00(dd,J＝7.9,2.0Hz,1H),6.60(d,J＝2.6Hz,1H),6.45(dd,J＝16.9,10.1Hz,1H),6.35–6.23(m,2H),6.06(s,1H),5.77(dd,J＝10.1,2.1Hz,1H),3.79(s,3H),3.24(s,8H),2.48–2.44(m,3H)
步骤六：合成N-(3-(2-((4-(4-(2-(2-(2-(2-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)乙氧基)乙氧基)乙氧基)乙基))哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-01)
Figure PCTCN2022079597-appb-000050
将化合物8(0.20g,0.39mmol)，2-(2-(2-(2-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)乙氧基)乙氧基)4-甲基苯磺酸乙酯10a(0.23g,0.47mmol)和无水碳酸钾(0.11g,0.8mmol)依次加入DMF(10mL)中，将反应体系升温至90℃搅拌过夜。TLC检测反应完全后，冷却至室温，并向体系中加入饱和氯化钠溶液(50mL)，并用乙酸乙酯(40mL)萃取。用无水硫酸钠干燥并浓缩有机相，将所得粗产物通过柱色谱法纯化(三氯甲烷/甲醇＝30/1洗脱)，得黄色固体目标化合物ZX-HYT-01(0.21g，收率66％)。HRMS(ESI)for C 46H 58N 8O 6Na[M+Na] +:calcd,841.4377；found,841.4372.HPLC analysis:MeOH-H 2O(97:3),RT＝4.747min,98.07％purity. 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H),8.81(s,1H),8.12(s,1H),7.89(d,J＝8.1Hz,1H),7.72(t,J＝5.7Hz,1H),7.57(t,J＝2.1Hz,1H),7.51(t,J＝8.1Hz,1H),7.27(d,J＝8.9Hz,1H),6.98(dd,J＝7.8,2.0Hz,1H),6.56–6.49(m,1H),6.49–6.39(m,1H),6.37–6.21(m,2H),6.00(s,1H),5.77(dd,J＝10.0,2.1Hz,1H),3.78(s,3H),3.60–3.49(m,6H),3.42(t,J＝5.9Hz,2H),3.19(q,J＝5.9Hz,2H),3.02(s,4H),2.63–2.52(m,6H),2.46(s,3H),1.91(s,3H),1.83(s,2H),1.70–1.61(m,3H),1.60–1.50(m,9H). 13C NMR(101MHz,DMSO)δ170.52,163.73,162.63,157.05,156.73,147.43,140.39,137.52,132.15,129.97,127.66,124.52,120.13,119.20,116.98,106.60,100.06,70.15,69.99,69.65,56.15,53.52,50.47,49.12,42.54,38.82,36.93,32.61,28.52,17.48.
实施例2：N-(3-(2-((4-(4-(6-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)己基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-02)
Figure PCTCN2022079597-appb-000051
化合物ZX-HYT-02的合成方法与ZX-HYT-01类似。以化合物8(0.20g,0.39mmol)和6-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)-4-甲基苯磺酸己酯(0.21g,0.47mmol)为原料，经亲核取代反应得到呈黄色固体的化合物ZX-HYT-02(0.18g，收率59％)。HRMS(ESI)for C 46H 58N 8O 4Na[M+Na] +:calcd,809.4479；found,809.4473.HPLC analysis:MeOH-H 2O(97:3),RT＝5.260min,98.05％purity. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.81(s,1H),8.11(s,1H),7.90(d,J＝8.2Hz,1H),7.65(t,J＝5.6Hz,1H),7.59–7.55(m,1H),7.51(t,J＝8.0Hz,1H),7.27(d,J＝8.9Hz,1H),6.98(ddd,J＝7.9,2.1,1.0Hz,1H),6.52(d,J＝2.5Hz,1H),6.49–6.39(m,1H),6.37–6.21(m,2H),6.00(s,1H),5.77(dd,J＝10.1,2.1Hz,1H),3.78(s,3H),3.09–2.95(m,6H),2.48–2.43(m,6H),2.30(t,J＝7.3Hz,2H),1.91(d,J＝5.0Hz,3H),1.81(s,2H),1.69–1.63(m,3H),1.61–1.54(m,9H),1.49–1.43(m,2H),1.42–1.36(m,2H),1.33–1.27(m,4H). 13C NMR(101MHz,DMSO)δ170.22,163.72,162.64,157.06,156.73,147.44,140.39,137.52,132.16,129.98,127.63,124.52,120.12,119.20,116.97,106.60,100.06,58.24,56.14,53.17,50.60,49.14,42.62,38.67,36.94,32.62,29.65,28.52,27.11,26.84,26.70,17.48.
实施例3：N-(3-(2-((4-(4-(8-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)辛基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-03)
Figure PCTCN2022079597-appb-000052
化合物ZX-HYT-03的合成方法与ZX-HYT-01类似。以化合物8(0.20g,0.39mmol)和8-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰氨基)辛基-4-甲基苯磺酸酯(0.20g,0.47mmol)为原料，经亲核取代得到呈黄色固体的化合物ZX-HYT-03(0.17g，收率55％)。HRMS(ESI)for  C 48H 62N 8O 4Na[M+Na] +:calcd,837.4792；found,837.4786.HPLC analysis:MeOH-H 2O(97:3),RT＝5.925min,98.11％purity. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.81(s,1H),8.11(s,1H),7.90(d,J＝8.0Hz,1H),7.63(t,J＝5.6Hz,1H),7.56(t,J＝2.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.27(d,J＝8.9Hz,1H),6.98(dd,J＝8.0,2.0Hz,1H),6.52(d,J＝2.5Hz,1H),6.49–6.39(m,1H),6.36–6.21(m,2H),6.00(s,1H),5.79–5.74(m,1H),3.78(s,3H),3.12–2.94(m,6H),2.49–2.43(m,6H),2.31(q,J＝8.5,7.4Hz,2H),1.91(s,3H),1.81(s,2H),1.71–1.62(m,3H),1.61–1.52(m,9H),1.48–1.42(m,2H),1.41–1.35(m,2H),1.33–1.21(m,11H). 13C NMR(101MHz,DMSO)δ170.15,163.71,162.57,156.97,156.77,147.32,140.41,137.53,132.22,130.11,129.89,127.45,124.48,120.19,119.20,116.99,106.75,106.61,100.08,58.32,56.17,53.20,50.61,49.22,42.64,42.59,38.69,36.98,36.93,32.62,29.64,29.43,29.15,28.57,28.52,27.36,26.87,26.76,17.44.
实施例4：N-(3-(2-((4-(4-(10-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰氨基)癸基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-04)
Figure PCTCN2022079597-appb-000053
化合物ZX-HYT-04的合成方法与ZX-HYT-01类似。以化合物8(0.20g,0.39mmol)和10-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰氨基)4-甲基苯磺酸癸酯(0.24g,0.47mmol)为原料，经亲核取代反应得到呈黄色固体的化合物ZX-HYT-04(0.19g，收率59％)。HRMS(ESI)for C 50H 66N 8O 4Na[M+Na] +:calcd,865.5105；found,865.5099.HPLC analysis:MeOH-H 2O(97:3),RT＝6.906min,97.22％purity. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.81(s,1H),8.11(s,1H),7.96–7.82(m,1H),7.63(t,J＝5.6Hz,1H),7.58–7.54(m,1H),7.51(t,J＝8.0Hz,1H),7.27(d,J＝8.9Hz,1H),6.98(dd,J＝7.7,1.9Hz,1H),6.52(d,J＝2.5Hz,1H),6.44(dd,J＝16.9,10.1Hz,1H),6.35–6.21(m,2H),6.00(s,1H),5.79–5.74(m,1H),3.78(s,3H),3.01(q,J＝6.3Hz,6H),2.46(s,6H),2.35–2.23(m,2H),1.93–1.87(m,3H),1.80(s,2H),1.66(d,J＝12.2Hz,3H),1.61–1.52(m,9H),1.45(d,J＝6.6Hz,2H),1.41–1.35(m,2H),1.32–1.23(m,13H). 13C NMR(101MHz,DMSO)δ170.18,163.71,162.63,157.04,156.73,147.42,140.39,137.52,132.17,129.97,127.61,124.51,120.13,119.20,116.97,106.60,100.06,58.30,56.14,55.37,53.15,50.59,49.13,42.62,38.66,36.94,32.61,29.64,29.48,29.46,29.43,29.17,28.53,27.42,26.87,26.67, 17.48.
实施例5：N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-05)
Figure PCTCN2022079597-appb-000054
化合物ZX-HYT-05的合成方法与ZX-HYT-01类似。以化合物8(0.20g,0.39mmol)和12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基4-甲基苯磺酸酯(0.25g,0.47mmol)为原料，经亲核取代反应得到呈黄色固体的化合物ZX-HYT-05(0.18g，收率54％)。HRMS(ESI)for C 52H 70N 8O 4Na[M+Na] +:calcd,893.5418；found,893.5412.HPLC analysis:MeOH-H 2O(95:5),RT＝9.127min,97.17％purity. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.81(s,1H),8.11(s,1H),7.90(d,J＝8.2Hz,1H),7.62(t,J＝5.7Hz,1H),7.56(t,J＝2.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.27(d,J＝8.9Hz,1H),6.98(ddd,J＝7.9,2.0,1.0Hz,1H),6.52(d,J＝2.5Hz,1H),6.44(dd,J＝16.9,10.1Hz,1H),6.33(d,J＝1.3Hz,1H),6.26(dd,J＝17.0,2.1Hz,1H),6.00(s,1H),5.76(dd,J＝10.1,2.1Hz,1H),3.78(s,3H),3.09–2.94(m,6H),2.49–2.41(m,7H),2.30(t,J＝7.4Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.66(d,J＝12.1Hz,3H),1.58(s,2H),1.56–1.52(m,7H),1.50–1.42(m,2H),1.40–1.33(m,2H),1.31–1.21(m,16H). 13C NMR(101MHz,DMSO)δ170.14,163.69,162.61,157.01,156.73,147.37,140.41,137.52,132.19,129.95,127.55,124.50,120.24,120.14,119.19,116.98,106.65,106.58,100.02,58.36,56.13,53.22,50.59,49.22,42.62,38.66,36.95,32.61,29.64,29.54,29.52,29.48,29.43,29.19,28.54,27.47,26.88,26.77,17.48.
实施例6：N-(3-(2-((4-(4-(14-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十四烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-06)
Figure PCTCN2022079597-appb-000055
化合物ZX-HYT-06的合成方法与ZX-HYT-01类似。以化合物8(0.20g,0.39mmol)和14-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰氨基)4-甲基苯磺酸十四烷基酯(0.26g,0.47mmol)为原料，经亲核取代反应得到呈黄色固体的化合物ZX-HYT-06(0.15g，收率43％)。HRMS(ESI)for C 54H 74N 8O 4Na[M+Na]+:calcd,921.5731；found,921.5725.HPLC analysis:MeOH-H 2O(95:5),RT＝14.347min,98.68％purity. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.80(s,1H),8.11(s,1H),7.90(d,J＝8.1Hz,1H),7.62(t,J＝5.6Hz,1H),7.56(t,J＝2.0Hz,1H),7.51(t,J＝8.1Hz,1H),7.27(d,J＝8.9Hz,1H),6.98(ddd,J＝7.8,2.0,1.0Hz,1H),6.51(d,J＝2.5Hz,1H),6.48–6.39(m,1H),6.36–6.21(m,2H),6.00(s,1H),5.76(dd,J＝10.1,2.1Hz,1H),3.78(s,3H),3.06–2.93(m,6H),2.49–2.40(m,7H),2.30(t,J＝7.4Hz,2H),1.90(s,3H),1.80(s,2H),1.69–1.61(m,3H),1.60–1.53(m,9H),1.50–1.41(m,2H),1.40–1.33(m,2H),1.32–1.20(m,20H). 13C NMR(101MHz,DMSO)δ170.22,163.72,162.64,157.04,156.72,147.44,140.39,137.51,132.15,129.97,127.62,124.51,120.12,119.20,116.96,106.60,100.04,58.29,56.51,56.14,53.15,50.59,49.12,42.60,38.65,36.93,32.61,29.60,29.51,29.48,29.43,29.40,29.15,28.53,27.41,26.84,26.65,18.99,17.47.
实施例7：N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-07)
Figure PCTCN2022079597-appb-000056
向化合物8(0.15g，0.29mmol)的DMF(10mL)溶液中加入12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二酸9(0.12g,0.29mmol)，HATU(0.17g,0.43mmol)和碳酸钾(82mg, 0.58mmol)，并将反应体系在室温下搅拌0.5小时。TLC监测待反应完全后，向反应体系加入乙酸乙酯(20mL)稀释，再分别用饱和氯化钠溶液(1×30mL)和水(3×30mL)洗涤有机层。经无水硫酸钠干燥和浓缩后得到的残余物通过柱色谱纯化(三氯甲烷/甲醇＝30/1洗脱)，得到黄色固体状化合物ZX-HYT-07(0.13g，收率51％)。HRMS(ESI)for C 52H 68N 8O 5Na[M+Na]+:calcd,907.5210；found,907.5205.HPLC analysis:MeOH-H 2O(95:5),RT＝6.582min,100.00％purity. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.81(s,1H),8.11(s,1H),7.90(d,J＝8.2Hz,1H),7.62(t,J＝5.7Hz,1H),7.56(t,J＝2.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.27(d,J＝8.9Hz,1H),6.98(ddd,J＝7.9,2.0,1.0Hz,1H),6.52(d,J＝2.5Hz,1H),6.44(dd,J＝16.9,10.1Hz,1H),6.33(d,J＝1.3Hz,1H),6.26(dd,J＝17.0,2.1Hz,1H),6.00(s,1H),5.76(dd,J＝10.1,2.1Hz,1H),3.78(s,3H),3.09–2.94(m,6H),2.49–2.41(m,7H),2.30(t,J＝7.4Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.66(d,J＝12.1Hz,3H),1.58(s,2H),1.56–1.52(m,7H),1.50–1.42(m,2H),1.40–1.33(m,2H),1.31–1.21(m,16H). 13C NMR(101MHz,DMSO)δ174.77,171.05,170.10,163.66,162.59,157.04,156.70,147.38,140.39,137.52,132.20,129.97,127.61,124.51,120.88,120.15,119.21,117.05,107.22,106.64,100.82,56.15,50.57,50.02,49.59,45.24,42.61,41.25,38.65,36.93,35.58,32.71,32.61,29.65,29.54,29.51,29.45,29.42,29.32,29.21,28.52,26.90,25.60,25.34,17.50.
实施例8：N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙酰胺(ZX-HYT-08)
Figure PCTCN2022079597-appb-000057
第一步：1-(3-甲氧基-4-硝基苯基)哌嗪(12)
Figure PCTCN2022079597-appb-000058
依次将5-氟-2-硝基苯甲醚11(3.00g,17.5mmol)，哌嗪(7.53g，87.5mmol)和无水碳酸钾(3.63g，26.3mmol)加入乙腈(50mL)中，将混合液在80℃的条件下搅拌6小时。TLC监测，待反应完全后，减压蒸除有机溶剂。将所得残余物加入20mL蒸馏水中并搅拌1小时，减压抽滤，将所得滤饼再次加入40mL无水乙醚中，继续搅拌1小时后减压抽滤，用冰的无水乙醚(3×20mL)洗涤滤饼。经干燥后的滤饼即为较纯的化合物12(3.95g，收率95％)。MS(ESI),m/z:238.1[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.21(s,2H),7.97–7.87(m,1H),6.69–6.58(m,2H),3.93(s,3H),3.70–3.63(m,4H),3.28–3.19(m,4H).
第二步：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(3-甲氧基-4-硝基苯基)哌嗪-1-基)十二烷基)乙酰胺(13)
Figure PCTCN2022079597-appb-000059
将化合物12(0.95g，4mmol)，碳酸钾(0.83g，6mmol)和12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基4-甲基苯磺酸酯(2.34g，4.4mmol)依次加入DMF(30mL)中，并将混合液在80℃下加热搅拌过夜。待反应完全后冷却至室温。再将反应液加入50mL饱和氯化钠水溶液中，用乙酸乙酯萃取，分离有机相。有机相经无水硫酸钠干燥后浓缩。剩下的残余物通过柱色谱纯化(三氯甲烷/甲醇＝100/1洗脱)，得到黄色油状的目标化合物13(2.05g，收率86％)。MS(ESI),m/z:619.3[M+Na] +. 1H NMR(400MHz,DMSO-d 6)δ7.88(d,J＝9.4Hz,1H),7.62(t,J＝5.6Hz,1H),6.58(dd,J＝9.5,2.5Hz,1H),6.52(d,J＝2.6Hz,1H),3.91(s,3H),3.42(t,J＝5.1Hz,4H),3.00(q,J＝6.5Hz,2H),2.45(t,J＝5.1Hz,4H),2.33–2.25(m,2H),1.94–1.86(m,3H),1.80(s,2H),1.65(dt,J＝12.2,2.9Hz,3H),1.56(dd,J＝12.7,2.3Hz,9H),1.44(t,J＝7.2Hz,2H),1.36(t,J＝6.5Hz,2H),1.26–1.20(m,16H).
第三步：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(14)
Figure PCTCN2022079597-appb-000060
向化合物13(2.98g,5mmol)的甲醇溶液中加入钯碳(0.55g)，用氢气置换3次。将反应液在室温条件下搅拌过夜。待反应完全后，减压抽滤，取滤液并蒸干。所得无色油状液体即为化合物14(2.8g，收率99％)。由于该化合物在空气中极易被氧化，故无需纯化直接用于下一步。MS(ESI),m/z:567.4[M+H] +.
第四步：叔丁基(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)氨基甲酸酯(15a)
Figure PCTCN2022079597-appb-000061
将中间体14(1.13g,2mmol)和化合物4a(0.72g,2mmol)快速加入30mL仲丁醇中，并滴加一滴TFA。用氩气置换3次，并将反应液在95℃的条件下搅拌过夜。TLC监测反应完全后，冷却至室温，减压蒸除反应液中的有机溶剂。将所得残余物通过柱色谱纯化(三氯甲烷/甲醇＝50/1洗脱)，得黄色固体状化合物15a(1.11g，收率61％)。MS(ESI),m/z:917.5[M+H] +. 1H NMR(400MHz,Chloroform-d)δ8.64(s,1H),7.85(s,1H),7.63(s,1H),7.37(t,J＝7.9Hz,1H),6.85(ddd,J＝8.1,2.4,0.9Hz,1H),6.69(ddd,J＝7.8,2.0,0.9Hz,1H),6.61(t,J＝2.1Hz,1H),6.48(d,J＝2.5Hz,1H),6.39(d,J＝1.3Hz,1H),6.21(s,1H),5.36(s,1H),3.85(s,3H),3.81(s,1H),3.25(td,J＝7.2,5.8Hz,2H),3.14(t,J＝5.0Hz,4H),2.64(t,J＝5.0Hz,4H),2.47(d,J＝1.2Hz,3H),2.45–2.39(m,2H),1.99(p,J＝3.1Hz,3H),1.92(s,2H),1.72(dt,J＝12.2,3.1Hz,3H),1.65(dd,J＝10.9,2.5Hz,9H),1.52(dq,J＝20.4,6.8,6.3Hz,4H),1.36–1.26(m,16H).
第五步：N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙酰胺(ZX-HYT-08)
Figure PCTCN2022079597-appb-000062
向装有化合物15a(0.25g,0.27mmol)的圆底烧瓶中加入10mL的DCM和0.50mL的TFA，将该反应体系在室温条件下搅拌0.5小时。待反应完全后，减压蒸除有机溶剂。将所得残余物直接溶于5mL无水乙腈，并向该溶液中依次加入无水碳酸钾(0.14g,1.01mmol)和丙酰氯(0.04g,0.43mmol)，再将反应液于室温条件下搅拌1小时，TLC监测，待反应完全后，蒸干有机溶剂。所得残余物直接拌硅胶并通过柱色谱纯化(三氯甲烷/甲醇＝30/1洗脱)，得到黄色粉末状化合物ZX-HYT-08(0.18g，收率78％)。HRMS(ESI)for C 52H 72N 8O 4Na[M+Na] +:calcd,895.5574；found,895.5569.HPLC analysis:MeOH-H 2O(97:3),RT＝8.712min,95.41％purity. 1H NMR(400MHz,DMSO-d 6)δ10.06(s,1H),8.79(s,1H),8.09(s,1H),7.79(d,J＝8.0Hz,1H),7.62(t,J＝5.8Hz,1H),7.53–7.41(m,2H),7.27(d,J＝8.8Hz,1H),6.92(d,J＝7.8Hz,1H),6.52(s,1H),6.31(s,1H),6.01(s,1H),3.78(s,3H),3.10–2.94(m,6H),2.45(m,5H),2.37–2.25(m,4H),1.90(s,3H),1.80(s,2H),1.68–1.62(m,3H),1.61–1.51(m,9H),1.48–1.41(m,2H),1.41–1.33(m,2H),1.32–1.21(m,18H),1.07(t,J＝7.5Hz,3H). 13C NMR(101MHz,DMSO)δ172.54,170.10,162.60,157.00,156.75,147.32,140.79,137.45,130.11,129.79,123.85,120.27,119.70,118.79,116.98,106.68,106.57,100.04,58.35,56.13,53.25,50.59,49.26,42.62,38.65,36.96,32.61,30.05,29.65,29.57,29.54,29.52,29.48,29.43,29.19,28.54,27.46,26.88,26.77,17.47,10.08.
实施例9：N-(12-(4-(4-((8-(3-乙酰氨基苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)-2-((3R,5R,7R)-金刚烷-1-基)乙酰胺(ZX-HYT-09)
Figure PCTCN2022079597-appb-000063
与ZX-HYT-08的合成方法类似，以化合物15a(0.25g,0.27mmol)和乙酰氯(0.04g,0.51mmol)为原料，经两步反应即可得到黄色粉末状目标化合物ZX-HYT-09(0.11g，收率47％)。HRMS(ESI)for C 51H 71N 8O 4[M+H] +:calcd,859.5598；found,859.5593.HPLC analysis:MeOH-H 2O(97:3),RT＝9.171min,98.91％purity. 1H NMR(400MHz,DMSO-d 6)δ10.17(s,1H),8.80(s,1H),8.13(s,1H),7.76(d,J＝8.0Hz,1H),7.63(t,J＝5.7Hz,1H),7.55–7.42(m,2H),7.27(d,J＝8.8Hz,1H),7.02–6.90(m,1H),6.56(s,1H),6.32(s,1H),6.05(s,1H),3.79(s,3H),3.20–2.93(m,3H),2.49–2.41(m,6H),2.05(s,4H),1.95–1.87(m,3H),1.80(s,2H),1.75–1.61(m,4H),1.61–1.44(m,11H),1.42–1.02(m,22H). 13C NMR(101MHz,DMSO)δ170.14,168.91,162.60,157.00,156.73,147.33,140.74,137.44,129.76,123.96,120.63,119.69,118.81,117.02,106.87,106.62,100.29,57.54,56.18,52.51,50.59,48.30,42.62,38.66,36.95,32.61,29.65,29.53,29.50,29.47,29.44,29.33,29.20,28.69,28.55,27.17,26.90,25.66,24.52,17.47.
实施例10：N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)异丁酰胺(ZX-HYT-10)
Figure PCTCN2022079597-appb-000064
与ZX-HYT-08的合成方法类似，以化合物15a(0.25g,0.27mmol)和异丁酰氯(0.04g,0.37mmol)为原料，经两步反应即可得到黄色粉末状目标化合物ZX-HYT-10(0.16g，收率67％)。HRMS(ESI)for C 53H 74N 8O4Na[M+Na] +:calcd,909.5731；found,909.5725.HPLC analysis:MeOH-H 2O(97:3),RT＝8.363min,98.82％purity. 1H NMR(400MHz,DMSO-d 6)δ10.03(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J＝8.2Hz,1H),7.62(t,J＝5.6Hz,1H),7.56–7.42(m,2H),7.27(d,J＝8.8Hz,1H),6.93(dd,J＝7.8,1.9Hz,1H),6.53(d,J＝2.5Hz,1H),6.32(s,1H),6.02(s,1H),3.78(s,3H),3.14–2.91(m,6H),2.59(p,J＝6.9Hz,2H),2.49–2.23(m,7H),1.91(s,3H),1.80(s,2H),1.68–1.62(m,3H),1.61–1.52(m,9H),1.50–1.41(m,2H),1.40–1.34(m,2H),1.33–1.18(m,17H),1.11–1.05(m,6H). 13C NMR(101MHz,DMSO)δ178.31,175.78,170.12,162.60,157.00,156.75,147.33,140.86,137.45,129.79,123.88,120.31,119.83,118.94,116.98,106.68,106.56,100.04,58.21,56.13,53.14,50.59,49.11,42.62,42.46,38.65,36.96,35.43,33.59,32.61,29.65,29.52,29.45,29.43,29.19,28.54,27.40,26.88,26.61,19.93, 19.90,19.38,17.47.
实施例11：N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-11)
Figure PCTCN2022079597-appb-000065
与ZX-HYT-08的合成方法类似，以化合物15a(0.25g,0.27mmol)和环丙甲酰氯(0.04g,0.38mmol)为原料，经两步反应即可得到黄色粉末状目标化合物ZX-HYT-11(0.15g，收率63％)。HRMS(ESI)for C 53H 72N 8O 4Na[M+Na] +:calcd,907.5574；found,907.5569.HPLC analysis:MeOH-H 2O(95:5),RT＝10.249min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J＝8.0Hz,1H),7.62(t,J＝5.7Hz,1H),7.55–7.41(m,2H),7.28(d,J＝8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J＝2.5Hz,1H),6.32(d,J＝1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.32(q,J＝13.4,7.5Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.69–1.62(m,3H),1.61–1.52(m,9H),1.52–1.44(m,2H),1.42–1.33(m,2H),1.32–1.15(m,18H),0.88–0.75(m,6H). 13C NMR(101MHz,DMSO)δ176.01,172.17,170.08,162.58,157.02,156.73,147.32,140.77,137.47,129.85,123.83,119.68,118.75,116.99,106.72,106.57,100.12,56.15,53.19,50.58,49.20,42.62,38.64,36.95,32.61,29.65,29.51,29.45,29.42,29.18,28.53,27.41,26.87,17.48,15.04,12.87,8.16,7.64.
实施例12：N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)新戊酰胺(ZX-HYT-12)
Figure PCTCN2022079597-appb-000066
与ZX-HYT-08的合成方法类似，以化合物15a(0.25g,0.27mmol)和新戊酰氯(0.04g, 0.33mmol)为原料，经两步反应即可得到黄色粉末状目标化合物ZX-HYT-12(0.18g，收率73％)。HRMS(ESI)for C 54H 76N 8O 4Na[M+Na] +:calcd,923.5887；found,923.5882.HPLC analysis:MeOH-H 2O(97:3),RT＝10.083min,97.50％purity. 1H NMR(400MHz,DMSO-d 6)δ9.37(s,1H),8.81(s,1H),8.10(s,1H),7.91(d,J＝7.8Hz,1H),7.62(t,J＝5.7Hz,1H),7.56(t,J＝2.0Hz,1H),7.46(t,J＝8.0Hz,1H),7.28(d,J＝8.9Hz,1H),6.93(dt,J＝7.9,1.2Hz,1H),6.52(d,J＝2.5Hz,1H),6.40–6.26(m,1H),6.02(s,1H),3.78(s,3H),3.11–2.94(m,6H),2.49–2.42(m,7H),2.36–2.25(m,2H),1.91(t,J＝3.4Hz,3H),1.80(s,2H),1.70–1.62(m,3H),1.61–1.52(m,9H),1.49–1.42(m,2H),1.40–1.33(m,2H),1.33–1.23(m,18H),1.23–1.18(m,9H). 13C NMR(101MHz,DMSO)δ179.87,177.00,170.12,162.63,157.01,156.76,147.34,140.89,137.28,129.57,123.96,120.60,120.24,119.79,116.95,106.73,106.54,99.97,58.31,56.13,53.23,50.59,49.25,42.62,38.65,38.18,36.95,32.61,29.64,29.53,29.51,29.46,29.42,29.18,28.54,27.58,27.48,27.43,26.87,26.74,17.48.
实施例13：N-(3-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环己烷甲酰胺(ZX-HYT-13)
Figure PCTCN2022079597-appb-000067
与ZX-HYT-08的合成方法类似，以化合物15a(0.25g,0.27mmol)和环己甲酰氯(0.05g,0.35mmol)为原料，经两步反应即可得到黄色粉末状目标化合物ZX-HYT-13(0.13g，收率52％)。HRMS(ESI)for C 56H 78N 8O 4Na[M+Na] +:calcd,949.6044；found,949.6038.HPLC analysis:MeOH-H 2O(97:3),RT＝12.082min,96.21％purity. 1H NMR(400MHz,DMSO-d 6)δ10.01(s,1H),8.80(s,1H),8.10(s,1H),7.78(d,J＝8.2Hz,1H),7.62(t,J＝5.7Hz,1H),7.54(t,J＝2.0Hz,1H),7.46(t,J＝8.1Hz,1H),7.27(d,J＝8.9Hz,1H),6.91(ddd,J＝7.8,2.0,1.0Hz,1H),6.52(d,J＝2.5Hz,1H),6.32(d,J＝1.3Hz,1H),6.01(s,1H),3.78(s,3H),3.11–2.95(m,6H),2.50–2.40(m,6H),2.36–2.24(m,3H),1.90(s,3H),1.85–1.70(m,6H),1.68–1.62(m,4H),1.60–1.52(m,8H),1.50–1.44(m,2H),1.41–1.33(m,4H),1.32–1.13(m,21H). 13C NMR(101MHz,DMSO)δ174.86,170.11,162.61,157.02,156.74,147.34,140.92,137.43,130.12,129.78, 123.79,120.27,119.72,118.83,116.99,106.68,106.57,100.04,58.30,56.14,53.25,50.59,49.29,45.34,42.62,38.64,36.95,32.61,29.64,29.60,29.53,29.50,29.48,29.42,29.18,28.54,27.43,26.87,26.77,25.86,25.65,17.47.
实施例14：N-(4-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-14)
Figure PCTCN2022079597-appb-000068
与ZX-HYT-08的合成方法类似，以化合物14(1.13g,2mmol)，化合物4b(0.72g,2mmol)和丙烯酰氯(0.03g,0.38mmol)为原料，经三步反应即可得到黄色粉末状目标化合物ZX-HYT-14(0.21g，收率86％)。HRMS(ESI)for C 52H 70N 8O 4Na[M+Na] +:calcd,893.5418；found,893.5412.HPLC analysis:MeOH-H 2O(97:3),RT＝10.934min,96.59％purity. 1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),8.79(s,1H),8.07(s,1H),7.85(m,2H),7.62(t,J＝5.7Hz,1H),7.26–7.17(m,3H),6.58–6.46(m,2H),6.38–6.28(m,2H),5.96(s,1H),5.81(dd,J＝10.1,2.1Hz,1H),3.78(s,3H),3.04–2.91(m,6H),2.45(s,3H),2.41(s,4H),2.28(t,J＝7.3Hz,2H),1.90(s,3H),1.80(s,2H),1.69–1.62(m,3H),1.59–1.52(m,9H),1.47–1.41(m,2H),1.40–1.33(m,2H),1.32–1.22(m,16H). 13C NMR(101MHz,DMSO)δ170.21,163.68,162.78,157.00,156.90,147.24,139.19,132.48,132.22,129.86,127.38,120.46,120.19,117.00,106.61,99.72,58.30,56.11,53.23,50.60,49.03,42.61,38.67,36.94,32.61,29.63,29.54,29.52,29.49,29.44,29.19,28.54,27.44,26.88,26.77,17.43.
实施例15：N-(4-(2-((4-(4-(12-(2-(((3R,5R,7R)-金刚烷-1-基)乙酰胺基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-15)
Figure PCTCN2022079597-appb-000069
与ZX-HYT-08的合成方法类似，以化合物14(1.13g,2mmol)，化合物4b(0.72g,2mmol)和环丙甲酰氯(0.04g,0.38mmol)为原料，经三步反应即可得到黄色粉末状目标化合物ZX-HYT-15(0.21g，收率86％)。HRMS(ESI)for C 53H 72N 8O 4Na[M+Na] +:calcd,907.5574；found,907.5569.HPLC analysis:MeOH-H 2O(97:3),RT＝9.243min,96.18％purity. 1H NMR(400MHz,DMSO-d 6)δ10.45(s,1H),8.79(s,1H),8.07(s,1H),7.80–7.71(m,2H),7.63(t,J＝5.7Hz,1H),7.27–7.14(m,3H),6.53(d,J＝2.6Hz,1H),6.31(d,J＝1.4Hz,1H),5.99(s,1H),3.79(s,3H),3.16–2.92(m,6H),2.49–2.23(m,6H),1.93–1.83(m,4H),1.80(s,2H),1.69–1.61(m,3H),1.60–1.52(m,9H),1.48(s,2H),1.41–1.19(m,20H),0.92–0.79(m,4H). 13C NMR(101MHz,DMSO)δ172.24,170.20,162.81,157.01,156.93,147.21,139.50,131.85,129.74,120.42,120.04,117.05,106.65,100.03,58.03,56.17,53.03,50.59,48.83,42.61,38.65,36.94,32.61,29.62,29.49,29.41,29.17,28.53,27.32,26.86,26.42,17.44,14.96,7.68.
实施例16：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-乙基苯基)-5-甲基-7-氧代-7,8-二氢-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-16)
Figure PCTCN2022079597-appb-000070
第一步：5-溴-2-氯-N-(3-乙基苯基)嘧啶-4-胺(3c)
Figure PCTCN2022079597-appb-000071
将化合物5-溴-2,4-二氯嘧啶(4.9g,21.5mmol)，3-乙基苯胺(2.6g,21.5mmol)和碳酸钾(5.9g,43mmol)依次加入60mLDMF中，并在室温条件下反应6小时。TLC监测，待 反应完全后，将反应体系加入200mL冰水中，有大量白色固体生成。减压抽滤，并用冰水洗涤滤饼。抽干的滤饼置于50mL丙酮中室温搅拌2小时打浆，减压抽滤，取滤饼。即得白色中间体3c(6.5g，收率92％)。MS(ESI),m/z:312.1[M+H] +. 1H NMR(400MHz,Chloroform-d)δ8.30(s,1H),7.53–7.48(m,1H),7.40(t,J＝2.5Hz,1H),7.33(td,J＝7.8,2.9Hz,1H),7.28(s,1H),7.06(dt,J＝8.2,1.9Hz,1H),2.70(qd,J＝7.7,2.8Hz,2H),1.29(t,J＝7.7,3.0Hz,3H).
第二步：2-氯-8-(3-乙基苯基)-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(3-4c)
Figure PCTCN2022079597-appb-000072
将化合物3c(2.19g,7.01mmol)，巴豆酸(6.04g,70.1mmol)，二(氰基苯)二氯化钯(II)(0.13g,5％)和三(邻甲基苯基)磷(104mg,5％)置于250mL的两口圆底烧瓶中，置换3～5次氩气，用注射器加入无水四氢呋喃(45mL)和N,N-二异丙基乙胺(12mL)后，再次置换氩气三次。然后将反应体系于70℃搅拌6小时。用TLC检测，待原料3c反应完全后，加入5mL乙酸酐，并将反应液加热至80℃继续搅拌8小时。TLC检测反应完全后，减压蒸除大部分有机溶剂，将残余物用100mL乙酸乙酯稀释。分别用1N HCl(3×100mL)和饱和氯化钠溶液(2×100mL)洗涤有机层，分离出的有机相经无水硫酸钠干燥后，浓缩并通过柱色谱纯化(石油醚/乙酸乙酯＝3:1洗脱)，得到白色固体化合物4c(1.66g，收率80％)。MS(ESI),m/z:300.2[M+H] +. 1H NMR(400MHz,Chloroform-d)δ8.83(s,1H),7.49(dd,J＝9.0,7.3Hz,1H),7.38–7.32(m,1H),7.08–7.01(m,2H),6.73–6.67(m,1H),2.76(q,J＝7.6Hz,2H),2.56(s,3H),1.30(t,J＝7.6Hz,3H).
第三步：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-乙基苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-16)
Figure PCTCN2022079597-appb-000073
将化合物4c(0.31g,1mmol)，2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-氨基-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(0.57g,1mmol)和催化量的三氟乙酸依次加入20mL仲丁醇 中，并在90℃的温度下，搅拌反应10小时。TLC监测反应完全后，减压蒸除有机溶剂，所得残余物经柱色谱(三氯甲烷/甲醇＝30:1)分离，得到目标化合物ZX-HYT-16(0.24g，收率29％)。HRMS(ESI)for C 51H 72N 7O 3[M+H] +:calcd,830.5618；found,830.5622.HPLC analysis:MeOH-H 2O(97:3),RT＝13.173min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ8.78(s,1H),8.05(s,1H),7.61(t,J＝5.7Hz,1H),7.46(t,J＝7.7Hz,1H),7.37(d,J＝7.8Hz,1H),7.16(d,J＝8.7Hz,1H),7.10(s,1H),7.06(d,J＝7.8Hz,1H),6.52(s,1H),6.30(s,1H),5.93(s,1H),3.77(s,3H),3.08–2.95(m,6H),2.67(q,J＝7.6Hz,2H),2.49–2.38(m,7H),2.29(t,J＝7.4Hz,2H),1.90(s,3H),1.80(s,2H),1.68–1.62(m,3H),1.60–1.51(m,9H),1.48–1.41(m,2H),1.39–1.34(m,2H),1.30–1.16(m,19H). 13C NMR(101MHz,DMSO)δ170.07,162.72,156.88,147.13,145.34,137.26,129.51,128.68,127.72,126.70,120.39,117.07,106.60,100.19,58.38,56.14,53.27,50.59,49.34,42.63,38.64,36.96,32.61,29.65,29.51,29.47,29.42,29.18,28.55,28.42,27.46,26.88,26.79,17.44,15.88.
实施例17：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-氨基苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-17)
Figure PCTCN2022079597-appb-000074
将中间体14(1.13g,2mmol)，化合物4a(0.72g,2mmol)和催化量的三氟乙酸依次加入30mL的仲丁醇中，并在95℃的温度下搅拌反应10小时。TLC监测反应完全后，减压蒸除有机溶剂。残余物用柱色谱纯化(三氯甲烷/甲醇＝50/1洗脱)。纯化后的中间体再次溶于DCM(8mL)和TFA(0.50mL)中，室温搅拌反应0.5小时，蒸干有机溶剂，残余物经柱色谱分离得黄色粉末状化合物ZX-HYT-17(0.13g，收率54％)。HRMS(ESI)for C 49H 68N 8O 3Na[M+Na] +:calcd,839.5312；found,839.5307.HPLC analysis:MeOH-H 2O(97:3),14.595min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ8.77(s,1H),8.04(s,1H),7.63(t,J＝5.6Hz,1H),7.45(d,J＝8.9Hz,1H),7.17(t,J＝7.9Hz,1H),6.70(dd,J＝8.1,2.3Hz,1H),6.55(d,J＝2.5Hz,1H),6.40(t,J＝2.1Hz,1H),6.38–6.33(m,1H),6.28(d,J＝1.4Hz,1H),6.14(s,1H),5.26(s,2H),3.80(s,3H),3.06(t,J＝5.0Hz,4H),3.00(q,J＝6.5Hz,2H),2.51–2.48(m, 4H),2.43(s,3H),2.38–2.25(m,2H),1.94–1.87(m,3H),1.80(s,2H),1.69–1.62(m,3H),1.60–1.53(m,9H),1.45(q,J＝6.9,6.2Hz,2H),1.36(q,J＝6.5,6.0Hz,2H),1.30–1.23(m,16H). 13C NMR(101MHz,DMSO)δ170.11,162.63,156.84,156.81,150.26,146.96,137.84,130.12,129.81,120.54,117.12,116.29,114.57,113.78,107.13,106.53,100.12,58.32,56.16,53.24,50.59,49.30,46.16,42.62,38.65,36.96,32.61,29.65,29.52,29.47,29.43,29.18,28.54,27.45,26.88,26.71,17.42.
实施例18：2-((3R，5R，7R)-金刚烷-1-基)-N-(12-(4-(3-甲氧基-4-((5-甲基-8-(3-((1-甲基哌-4-基)氨基)苯基)-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-18)
Figure PCTCN2022079597-appb-000075
将化合物ZX-HYT-17(200mg,0.24mmol)，1-甲基哌啶-4-酮(27mg,0.24mmol)，三乙酰氧基硼氢化钠(0.25g,1.2mmol)和催化量的冰乙酸置于20mL超干甲苯中，氩气保护下，将反应体系置于40℃的温度下，搅拌反应2小时。TLC监测，待反应完全后，蒸干有机溶剂，所得残余物直接拌硅胶柱层析(三氯甲烷/甲醇＝25:1洗脱)，纯化后得黄色目标化合物ZX-HYT-18(0.16mg，收率73％)。HRMS(ESI)for C 55H 80N 9O 3[M+H] +:calcd,914.6384；found,914.6379.HPLC analysis:MeOH-H 2O(97:3),RT＝13.264min,99.75％purity. 1H NMR(400MHz,DMSO-d 6)δ8.77(s,1H),8.03(s,1H),7.63(t,J＝5.7Hz,1H),7.42(d,J＝8.9Hz,1H),7.22(t,J＝7.9Hz,1H),6.72(d,J＝7.7Hz,1H),6.54(d,J＝2.5Hz,1H),6.43(t,J＝2.2Hz,1H),6.34(dd,J＝7.4,1.9Hz,1H),6.28(s,1H),6.05(s,1H),5.70(d,J＝7.7Hz,1H),3.79(s,3H),3.05–2.97(m,6H),2.79(s,3H),2.49–2.46(m,4H),2.44(s,3H),2.31(t,J＝7.4Hz,3H),2.23(s,3H),2.16(s,2H),1.96–1.85(m,6H),1.80(s,2H),1.68–1.62(m,3H),1.58–1.51(m,9H),1.46–1.42(m,2H),1.39–1.34(m,2H),1.30–1.21(m,16H). 13C NMR(101MHz,DMSO)δ170.19,162.67,156.83,149.34,147.02,138.08,130.03,117.14,115.99,113.36,111.76,106.92,106.55,100.20,58.30,56.18,55.35,54.28,53.24,50.59,49.39,45.85,42.61,38.65,36.94,32.61,31.73,29.61,29.48,29.39,29.15,28.53,27.42,26.84,26.73,17.40.
实施例19：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-((环丙基甲基)氨基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-19)
Figure PCTCN2022079597-appb-000076
与化合物ZX-HYT-18的合成方法类似，以化合物ZX-HYT-17(0.20g,0.24mmol)和环丙烷甲醛(17mg,0.24mmol)为原料制得黄色固体化合物ZX-HYT-19(0.18g，收率86％)。HRMS(ESI)for C 53H 75N 8O 3[M+H] +:calcd,871.5962；found,871.5957.HPLC analysis:MeOH-H 2O(97:3),RT＝11.992min,97.65％purity. 1HNMR(400MHz,DMSO-d 6)δ8.77(s,1H),8.02(s,1H),7.61(t,J＝5.7Hz,1H),7.43(d,J＝8.8Hz,1H),7.23(t,J＝7.9Hz,1H),6.72(d,J＝8.2Hz,1H),6.54(d,J＝2.5Hz,1H),6.44(d,J＝2.2Hz,1H),6.37(dd,J＝7.4,1.9Hz,1H),6.29(s,1H),6.07(s,1H),5.86(t,J＝5.5Hz,1H),3.80(s,3H),3.08–2.97(m,5H),2.89(d,J＝6.3Hz,2H),2.49–2.40(m,7H),2.35–2.26(m,2H),1.94–1.86(m,3H),1.80(s,2H),1.70–1.62(m,3H),1.60–1.57(m,2H),1.56–1.52(m,7H),1.49–1.43(m,2H),1.39–1.33(m,2H),1.30–1.21(m,16H),1.04(hept,J＝5.8Hz,2H),0.43(dt,J＝8.5,3.0Hz,2H),0.17(t,J＝4.8Hz,2H). 13C NMR(101MHz,DMSO)δ170.09,162.63,156.84,150.61,146.94,137.97,129.89,117.17,116.08,113.05,111.55,106.92,106.56,100.17,56.18,53.23,50.59,49.35,48.11,42.63,38.64,36.96,32.61,29.64,29.50,29.45,29.41,29.17,28.54,27.41,26.87,17.41,11.03,4.02,3.93.
实施例20：N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)环戊基)环丙烷甲酰胺(ZX-HYT-20)
Figure PCTCN2022079597-appb-000077
第一步：N-((1R,3S)-3-((5-溴-2-氯嘧啶-4-基)氨基)环戊基)环丙烷甲酰胺(26a)
Figure PCTCN2022079597-appb-000078
将化合物5-溴-2,4-二氯嘧啶(0.91g,4mmol)，N-((1R,3S)-3-((5-溴-2-氯嘧啶-4-基)氨基)环戊基)环丙烷甲酰胺(0.67g,4mmol)和碳酸钾(0.57g,8mmol)依次加入25mLDMF中，并在室温条件下反应6小时。TLC监测，待反应完全后，将反应体系加入40mL冰水中，有大量白色固体生成。减压抽滤，并用冰水洗涤滤饼。抽干的滤饼置于15mL丙酮中室温搅拌2小时打浆，减压抽滤，取滤饼。即得白色中间体26a(0.96g，收率67％)。MS(ESI),m/z:359.6[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.15(s,1H),8.34(d,J＝7.3Hz,1H),7.23(s,1H),5.67(p,J＝9.4,8.9Hz,1H),4.17–4.04(m,1H),2.31–2.21(m,2H),2.02–1.92(m,2H),1.89–1.79(m,2H),1.63–1.54(m,1H),0.81–0.62(m,4H).
第二步：N-((1R,3S)-3-(2-氯-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)环戊基)环丙烷甲酰胺(27a)
Figure PCTCN2022079597-appb-000079
将化合物26a(1.92g,5.35mmol)，巴豆酸(4.61g,70.1mmol)，二(氰基苯)二氯化钯(II)(0.14g,5％)和三(邻甲基苯基)磷(114mg,5％)置于250mL的两口圆底烧瓶中，置换3～5次氩气，用注射器加入无水四氢呋喃(30mL)和N,N-二异丙基乙胺(5mL)后，再次置换氩气三次。然后将反应体系于70℃搅拌6小时。用TLC检测，待原料26a反应完全后，加入5mL乙酸酐，并将反应液加热至80℃继续搅拌8小时。TLC检测反应完全后，减压蒸除大部分有机溶剂，将残余物用100mL乙酸乙酯稀释。分别用1N HCl(3×100mL)和饱和氯化钠溶液(2×100mL)洗涤有机层，分离出的有机相经无水硫酸钠干燥后，浓缩并通过柱色谱纯化(石油醚/乙酸乙酯＝2:1洗脱)，得到白色固体化合物27a(0.87g，收率47％)。MS(ESI),m/z:347.1[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.05(s,1H),8.24(d,J＝7.4Hz,1H),6.63(d,J＝1.5Hz,1H),5.77(p,J＝9.4,8.9Hz,1H),4.18–4.05(m,1H),2.46(s,3H),2.25–2.15(m,2H),2.07–1.97(m,2H),1.95–1.85(m,2H),1.61–1.52(m,1H),0.69–0.59(m,4H).
第三步：N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)环戊基)环丙烷甲酰胺(ZX-HYT-20)
Figure PCTCN2022079597-appb-000080
将化合物27a(0.17g,0.5mmol)，化合物14(0.28g,0.5mmol)和催化量的三氟乙酸依次加入10mL仲丁醇中，并在90℃的温度下，搅拌反应10小时。TLC监测反应完全后，减压蒸除有机溶剂，残余物经柱色谱(三氯甲烷/甲醇＝35:1)分离，得到目标化合物ZX-HYT-20(0.13g，收率30％)。HRMS(ESI)for C 52H 77N 8O 4[M+H] +:calcd,877.6068；found,877.6062.HPLC analysis:MeOH-H 2O(95:5),13.792min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ8.72(s,1H),8.62(s,1H),8.16(s,1H),7.62(t,J＝5.6Hz,1H),7.51(d,J＝8.6Hz,1H),6.63(d,J＝2.5Hz,1H),6.51(dd,J＝8.8,2.5Hz,1H),6.16(d,J＝1.3Hz,1H),5.84(s,1H),4.08(q,J＝7.8Hz,1H),3.79(s,3H),3.14(t,J＝4.8Hz,4H),3.00(q,J＝6.5Hz,2H),2.51–2.45(m,6H),2.35(s,3H),2.33–2.19(m,4H),2.04–1.87(m,4H),1.86–1.72(m,4H),1.69–1.61(m,3H),1.60–1.52(m,9H),1.50–1.41(m,2H),1.40–1.32(m,2H),1.32–1.17(m,16H),0.75–0.53(m,4H). 13C NMR(101MHz,DMSO)δ172.23,170.08,163.06,160.29,157.37,155.88,153.16,149.92,146.19,119.63,117.24,107.10,106.87,100.36,58.38,55.93,53.27,50.57,50.14,49.89,49.18, 42.60,38.62,36.94,34.09,32.60,31.65,29.65,29.53,29.49,29.43,29.19,28.51,27.46,26.88,26.78,25.90,17.19,14.15,12.89,8.19,6.67,6.62.
实施例21：(1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡啶并[2,3-d]嘧啶-8(7H)-基)-N-环丙基环己烷-1-羧酰胺(ZX-HYT-21)
Figure PCTCN2022079597-appb-000081
与化合物ZX-HYT-20的合成方法类似，以化合物14(0.28g,0.5mmol)和N-(((1R,3S)-3-氨基环己基)环丙烷甲酰胺(0.18g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-21(0.13g，收率29％)。HRMS(ESI)for C 53H 79N 8O 4[M+H] +:calcd,891.6224；found,891.6219.HPLC analysis:MeOH-H 2O(95:5),RT＝11.542min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ8.82–8.44(m,2H),7.82–7.08(m,3H),6.65(s,1H),6.52(d,J＝8.7Hz,1H),6.12(s,1H),5.41–4.88(m,1H),3.78(s,3H),3.16(s,4H),3.00(q,J＝6.4Hz,2H),2.71–2.53(m,4H),2.44–2.21(m,7H),2.17–1.94(m,2H),1.90(s,3H),1.80(s,2H),1.71–1.61(m,4H),1.59–1.51(m,10H),1.50–1.42(m,3H),1.39–1.33(m,2H),1.30–1.18(m,19H),0.60–0.51(m,2H),0.38–0.28(m,2H). 13C NMR(101MHz,DMSO)δ175.49,170.09,157.15,128.32,128.23,115.89,107.36,106.56,100.65,100.56,100.49,58.25,55.50,53.17,52.03,50.58,48.92,44.47,42.62,38.64,36.95,32.61,29.64,29.49,29.42,29.17,28.54,27.75,27.38,26.87,25.49,22.67,17.13,6.16,6.05.
实施例22：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-((S)-1-(环丙烷羰基)哌啶-3-基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-22)
Figure PCTCN2022079597-appb-000082
与化合物ZX-HYT-20的合成方法类似，以化合物14(0.28g,0.5mmol)和(S)-(3-氨基哌 啶-1-基)(环丙基)甲酮(0.15g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-22(0.13g，收率29％)。HRMS(ESI)for C 52H 77N 8O 4[M+H] +:calcd,877.6068；found,877.6067.HPLC analysis:MeOH-H 2O(97:3),11.956min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ8.96(s,1H),8.70(s,1H),7.61(t,J＝5.6Hz,1H),7.09(s,1H),6.61(s,1H),6.48(s,1H),6.14(s,1H),5.35–4.74(m,1H),4.50–3.76(m,4H),3.73(s,3H),3.14(s,4H),3.00(q,J＝6.4Hz,2H),2.50–2.39(m,4H),2.38–2.29(m,5H),2.00–1.86(m,4H),1.80(s,3H),1.69–1.61(m,4H),1.59–1.52(m,10H),1.48–1.42(m,3H),1.39–1.34(m,2H),1.29–1.21(m,16H),0.77–0.55(m,4H). 13C NMR(101MHz,DMSO)δ171.40,171.11,170.08,157.36,155.90,146.49,119.19,115.82,107.01,106.57,100.16,58.34,55.75,53.27,50.58,48.98,47.11,43.60,42.62,38.65,36.95,32.60,29.65,29.51,29.47,29.42,29.18,28.55,27.45,26.88,26.73,25.48,17.16,10.89,7.28,7.15.
实施例23：N-((1R,3S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)环己基)环丙烷甲酰胺(ZX-HYT-23)
Figure PCTCN2022079597-appb-000083
与化合物ZX-HYT-20的合成方法类似，以化合物14(0.28g,0.5mmol)和(1R,3S)-3-氨基-N-环丙基环己烷-1-羧酰胺(0.18g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-23(0.26g，收率58％)。HRMS(ESI)for C 53H 79N 8O 4[M+H] +:calcd,891.6224；found,891.6219.HPLC analysis:MeOH-H 2O(95:5),RT＝11.070min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ8.69(s,1H),8.63(s,1H),8.09(s,1H),7.62(t,J＝5.6Hz,1H),6.66(d,J＝2.5Hz,1H),6.55(d,J＝8.8Hz,1H),6.10(s,1H),5.33(s,1H),3.79(s,3H),3.67(s,1H),3.17(s,4H),3.00(q,J＝6.5Hz,2H),2.68–2.51(m,4H),2.43–2.24(m,6H),1.90(s,3H),1.83–1.71(m,4H),1.69–1.61(m,4H),1.61–1.52(m,10H),1.51–1.41(m,4H),1.40–1.32(m,3H),1.31–1.17(m,18H),0.68–0.54(m,4H). 13C NMR(101MHz,DMSO)δ171.87,170.09,157.18,145.86,120.00,117.81,116.08,107.22,106.72,100.51,58.20,55.90,52.99,50.58,48.86,48.13,42.62,38.64,36.95,34.95,32.60,32.41,29.64,29.49,29.41,29.17,28.54,27.38,27.31,26.87,24.13,17.12,14.03,6.57.
实施例24：2-(((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶基[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-24)
Figure PCTCN2022079597-appb-000084
与化合物ZX-HYT-20的合成方法类似，以化合物14(0.28g,0.5mmol)和环戊胺(0.13g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-24(0.21g，收率53％)。HRMS(ESI)for C 48H 72N 7O 3[M+H] +:calcd,794.5697；found,794.5699.HPLC analysis:MeOH-H 2O(97:3),14.410min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ8.73–8.63(m,2H),7.61(t,J＝5.6Hz,1H),7.31(d,J＝8.7Hz,1H),6.62(d,J＝2.5Hz,1H),6.49(dd,J＝8.7,2.5Hz,1H),6.12(s,1H),5.60(s,1H),3.74(s,3H),3.18–3.09(m,4H),3.00(q,J＝6.4Hz,2H),2.51–2.42(m,4H),2.36–2.26(m,5H),2.19–2.08(m,2H),1.90(s,3H),1.80(s,2H),1.69–1.61(m,4H),1.60–1.52(m,12H),1.48–1.42(m,3H),1.40–1.32(m,3H),1.29–1.22(m,16H). 13C NMR(101MHz,DMSO)δ170.08,163.14,160.65,157.19,155.91,154.16,150.52,145.91,126.66,119.56,116.67,107.18,106.80,100.38,58.38,55.82,53.24,52.51,50.58,49.27,42.62,38.64,36.96,32.61,29.64,29.49,29.45,29.40,29.17,28.54,27.66,27.45,26.87,26.75,25.07,17.14.
实施例25：N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)苯基)氨基)-5-甲基-7-氧杂吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-25)
Figure PCTCN2022079597-appb-000085
将化合物28a(0.27g,0.5mmol)，化合物21(0.18g,0.5mmol)和催化量的三氟乙酸依次加入10mL仲丁醇中，并在95℃的温度下，搅拌反应10小时。TLC监测反应完全后，减压蒸除有机溶剂，残余物经柱色谱(三氯甲烷/甲醇＝45:1)分离，得到目标化合物ZX-HYT-25(0.25g，收率52％)。HRMS(ESI)for C 52H 71N 8O 3[M+H] +:calcd,855.5649；found,855.5644. 1H NMR(400MHz,DMSO-d 6)δ10.40(s,1H),9.83(s,1H),8.82(s,1H),7.86(d,J＝8.3Hz,1H),7.61(t,J＝5.7Hz,1H),7.52–7.43(m,2H),7.19(d,J＝8.4Hz,2H),6.93(d,J＝7.8Hz,1H),6.55(d,J＝8.3Hz,2H),6.30(s,1H),3.05–2.93(m,6H),2.49–2.39(m,7H),2.30(t,J＝7.3Hz,2H), 1.90(s,3H),1.82–1.74(m,3H),1.68–1.63(m,3H),1.59–1.52(m,9H),1.47–1.41(m,2H),1.39–1.34(m,2H),1.30–1.22(m,16H),0.83–0.74(m,4H). 13C NMR(101MHz,DMSO)δ172.18,170.09,162.61,158.77,156.91,156.73,147.36,146.73,140.86,137.68,132.24,129.93,123.84,119.72,118.75,116.73,115.74,106.23,58.35,53.27,50.59,49.31,42.63,38.65,36.96,32.61,29.65,29.52,29.48,29.43,29.19,28.54,27.45,26.88,26.78,17.46,15.03,7.72,7.60.
实施例26：N-(3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-26)
Figure PCTCN2022079597-appb-000086
与化合物ZX-HYT-25的合成方法类似，以化合物21(0.18g,0.5mmol)和化合物28b(0.28g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-26(0.14g，收率33％)。HRMS(ESI)for C 53H 73N 8O 3[M+H] +:calcd,869.5806；found,869.5800.HPLC analysis:MeOH-H 2O(95:5),RT＝6.397min,96.91％purity. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.84(s,1H),8.76(s,1H),7.65(dd,J＝11.6,7.0Hz,2H),7.49(s,1H),7.38(t,J＝8.1Hz,1H),7.15–7.03(m,1H),6.86(d,J＝7.8Hz,1H),6.64(s,1H),6.42(s,1H),6.26(s,1H),3.00(q,J＝6.3Hz,6H),2.51–2.39(m,7H),2.30(t,J＝7.3Hz,2H),2.10(s,3H),1.91(s,3H),1.85–1.75(m,3H),1.71–1.62(m,3H),1.61–1.51(m,9H),1.50–1.42(m,2H),1.40–1.34(m,2H),1.32–1.21(m,16H),0.89–0.69(m,4H). 13C NMR(101MHz,DMSO)δ172.15,170.08,162.70,157.06,156.72,147.27,140.56,137.23,129.56,129.20,123.92,119.68,118.52,117.42,116.50,112.99,106.37,58.40,53.27,50.59,49.14,42.62,38.64,36.96,32.61,29.65,29.52,29.48,29.43,29.18,28.54,27.46,26.88,26.79,18.84,17.48,15.04,7.67.
实施例27：N-(3-(2-((4-(2-((12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)氧基)乙氧基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-27)
Figure PCTCN2022079597-appb-000087
与化合物ZX-HYT-25的合成方法类似，以化合物21(0.18g,0.5mmol)和化合物28c(0.27g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-27(0.22g，收率51％)。HRMS(ESI)for C 51H 69N 6O 6[M+H] +:calcd,861.5279；found,861.5273.HPLC analysis:MeOH-H 2O(90:10),RT＝7.673min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),8.82(s,1H),8.19(s,1H),7.74(d,J＝8.2Hz,1H),7.64(t,J＝5.7Hz,1H),7.53(t,J＝2.0Hz,1H),7.47(t,J＝8.0Hz,1H),7.31(d,J＝8.9Hz,1H),6.93(dd,J＝7.8,2.0Hz,1H),6.55(d,J＝2.6Hz,1H),6.33(s,1H),6.03(s,1H),4.01(t,J＝4.6Hz,2H),3.78(s,3H),3.70–3.63(m,2H),3.44(t,J＝6.6Hz,2H),2.99(q,J＝6.4Hz,2H),2.46(s,3H),1.94–1.86(m,3H),1.83–1.74(m,3H),1.68–1.61(m,3H),1.58–1.47(m,11H),1.38–1.19(m,18H),0.85–0.71(m,4H). 13C NMR(101MHz,DMSO)δ172.20,170.09,162.56,157.06,156.72,147.31,140.75,137.47,129.80,123.87,121.49,119.76,118.81,117.13,106.70,104.65,99.36,70.87,69.09,67.72,56.29,50.58,42.62,38.65,36.94,32.60,29.68,29.64,29.53,29.51,29.44,29.38,29.18,28.53,26.88,26.14,17.47,15.03,7.69,7.63.
实施例28：N-(3-(2-((4-((12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)氧基)-2-甲氧基苯基)氨基)-5-甲基-7-氧嘧啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-28)
Figure PCTCN2022079597-appb-000088
与化合物ZX-HYT-25的合成方法类似，以化合物21(0.18g,0.5mmol)和化合物28d(0.25g,0.5mmol)为原料制得黄色固体化合物ZX-HYT-28(0.24g，收率59％)。HRMS(ESI)for C 49H 65N 6O 5[M+H] +:calcd,817.5016；found,817.5011.HPLC analysis:MeOH-H 2O(95:5),RT＝9.932min,95.18％purity. 1H NMR(400MHz,DMSO-d 6)δ10.43–10.34(m,1H),8.86–8.75(m,1H),8.14(s,1H),7.76(d,J＝8.2Hz,1H),7.60(d,J＝6.2Hz,1H),7.51(d,J＝2.6Hz,1H),7.46(td,J＝8.1,2.5Hz,1H),7.31(dd,J＝8.8,2.5Hz,1H),6.93(d,J＝7.8Hz,1H),6.51(s,1H), 6.32(s,1H),6.04(s,1H),3.87(q,J＝5.7Hz,2H),3.78(s,3H),2.99(td,J＝7.1,3.3Hz,2H),2.45(s,3H),1.90(s,3H),1.83–1.75(m,3H),1.71–1.61(m,5H),1.60–1.51(m,9H),1.43–1.32(m,5H),1.31–1.21(m,13H),0.84–0.72(m,4H). 13C NMR(101MHz,DMSO)δ172.18,170.10,162.57,157.06,156.72,147.31,140.75,137.47,129.80,123.87,121.31,119.74,118.82,117.11,106.68,104.55,99.29,67.98,56.27,50.59,42.62,38.65,36.94,32.61,29.65,29.51,29.45,29.29,29.23,29.19,28.54,26.89,26.05,17.46,15.01,7.64.
实施例29：N-(3-(2-((4-(4-(12-((2-((3R,5R,7R)-金刚烷-1-基)乙基)氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡喃并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-29)
Figure PCTCN2022079597-appb-000089
第一步：N-(3-(2-((4-(4-(12-(1,3-二氧代异吲哚-2-基-基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡喃并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(31)
Figure PCTCN2022079597-appb-000090
将化合物29(0.26mg,0.5mmol)，化合物30a(0.20g,0.5mmol)和无水碳酸钾(0.14g,1mmol)置于DMF(8mL)中，并在70℃的温度下搅拌反应7小时，TLC检测，待反应完全后，加入100mL乙酸乙酯中。相继用饱和食盐水(2×40mL)，蒸馏水(3×40mL)洗涤有机层，分离、干燥并蒸干有机层，所得残余物经柱色谱纯化(三氯甲烷/甲醇＝45:1洗脱)， 得黄色粉末状化合物31(0.31g，收率76％)。HRMS(ESI)for C 49H 59N 8O 5[M+H] +:calcd,
839.4608；found,839.4602.HPLC analysis:MeOH-H 2O(95:5),RT＝9.870min,100％purity. 1H
NMR(400MHz,DMSO-d 6)δ10.37(s,1H),8.78(s,1H),8.07(s,1H),7.83(s,5H),7.56–7.40(m,2H),7.26(d,J＝8.9Hz,1H),6.91(s,1H),6.51(s,1H),6.30(s,1H),6.01(s,1H),3.77(s,3H),
3.58–3.51(m,2H),3.02(s,4H),2.48–2.36(m,7H),2.28(s,2H),1.81–1.69(m,2H),1.60–
1.53(m,2H),1.46–1.40(m,2H),1.32–1.17(m,15H),0.83–0.71(m,4H).
第二步：N-(3-(2-((4-(4-(12-氨基十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(32)
Figure PCTCN2022079597-appb-000091
将化合物31(0.84mg,1mmol)和80％的水合肼(2mL)置于40mL无水乙醇中，并在70℃的温度下搅拌反应3小时，TLC检测，待反应完全后，减压蒸干有机溶剂，残余物置于50mLDCM中，充分搅拌后抽滤，滤液蒸干后柱层析(三氯甲烷/甲醇＝10:1洗脱)，得黄色固体状化合物32(0.67g，收率94％)。HRMS(ESI)for C 41H 57N 8O 3[M+H] +:calcd,709.4554；found,709.4548.HPLC analysis:MeOH-H 2O(95:5),RT＝7.589min,97.81％purity. 1H NMR(400MHz,DMSO-d 6)δ10.40(s,1H),8.78(s,1H),8.08(s,1H),7.81(s,1H),7.56–7.38(m,2H),7.27(d,J＝8.9Hz,1H),6.91(d,J＝7.8Hz,1H),6.52(s,1H),6.31(s,1H),6.01(s,1H),3.78(s,3H),3.03(s,6H),2.49–2.38(m,7H),2.29(t,J＝7.4Hz,2H),1.78(d,J＝9.6Hz,1H),1.45(s,3H),1.31–1.20(m,17H),0.85–0.70(m,4H).
第三步：N-(3-(2-((4-(4-(12-((2-((3R,5R,7R)-金刚烷-1-基)乙基)氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡喃并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-29)
Figure PCTCN2022079597-appb-000092
将化合物32(177mg,0.25mmol)，金刚烷乙醛(45mg,0.25mmol)，三乙酰氧基硼氢化钠(0.27g,1.25mmol)和催化量的冰乙酸置于20mL超干甲苯中，氩气保护下，将反应体系置于40℃的温度下，搅拌反应2小时。TLC监测，待反应完全后，蒸干有机溶剂，所得残余物直接拌硅胶柱层析(三氯甲烷/甲醇＝15:1洗脱)，得黄色固体目标化合物ZX-HYT-29(0.12mg，收率55％)。HRMS(ESI)for C 52H 73N 8O 3[M+H] +:calcd,857.5806；found,857.5801.HPLC analysis:MeOH-H 2O(97:3),RT＝6.096min,99.17％purity. 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),8.80(s,1H),8.09(s,1H),7.81(d,J＝8.2Hz,1H),7.51–7.42(m,2H),7.27(d,J＝8.9Hz,1H),6.92(dd,J＝7.7,2.0Hz,1H),6.53(d,J＝2.5Hz,1H),6.32(s,1H),6.02(s,1H),3.78(s,3H),3.03(t,J＝4.8Hz,4H),2.50–2.42(m,11H),2.30(t,J＝7.4Hz,2H),1.93–1.86(m,3H),1.81–1.73(m,1H),1.70–1.62(m,3H),1.62–1.55(m,3H),1.45(s,8H),1.38(t,J＝6.9Hz,2H),1.33–1.22(m,17H),1.21–1.16(m,2H),0.82–0.74(m,4H). 13C NMR(101MHz,DMSO)δ172.17,162.58,157.00,156.75,147.31,140.79,137.47,129.84,123.82,119.69,118.74,116.99,106.70,106.56,100.07,58.34,56.15,53.28,50.01,49.29,44.49,44.15,42.62,37.12,31.86,29.87,29.80,29.47,28.52,27.43,27.32,26.79,17.47,15.03,7.70,7.62.
实施例30：N-(3-(2-((2-甲氧基-4-(4-辛基哌嗪-1-基)苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-30)
Figure PCTCN2022079597-appb-000093
将化合物29(0.13mg,0.25mmol)，化合物30b(48mg,0.25mmol)和无水碳酸钾(69mg,0.5mmol)置于DMF(5mL)中，并在70℃的温度下搅拌反应7小时，TLC检测，待反应完全后，加入30mL乙酸乙酯中。相继用饱和食盐水(2×20mL)，蒸馏水(3×20mL)洗涤有机层，分离、干燥并蒸干有机层，所得残余物经柱色谱纯化(三氯甲烷/甲醇＝50:1洗脱)，得黄色粉末状目标化合物ZX-HYT-30(0.11g，收率69％)。HRMS(ESI)for C 37H 48N 7O 3[M+H] +:calcd,638.3819；found,638.3813.HPLC analysis:MeOH-H 2O(95:5),RT＝6.803min,98.91％purity. 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),8.80(s,1H),8.10(s,1H),7.80(d,J＝8.0Hz,1H),7.51–7.42(m,2H),7.27(d,J＝8.9Hz,1H),6.92(d,J＝8.2Hz,1H),6.53(d,J＝ 2.5Hz,1H),6.31(s,1H),6.02(s,1H),3.78(s,3H),3.03(t,J＝4.8Hz,4H),2.50–2.43(m,7H),2.31(t,J＝7.4Hz,2H),1.82–1.73(m,1H),1.46(s,2H),1.30–1.23(m,10H),0.90–0.85(m,3H),0.82–0.74(m,4H). 13C NMR(101MHz,DMSO)δ172.19,162.60,157.02,156.75,147.33,140.79,137.48,129.86,123.83,120.30,119.68,118.73,116.99,106.70,106.57,100.08,58.35,56.15,53.27,49.28,31.76,29.44,29.20,27.46,26.79,22.57,17.46,15.03,14.44,7.69,7.62.
实施例31：N-(3-(2-((2-甲氧基-4-(4-辛基哌嗪-1-基)苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-31)
Figure PCTCN2022079597-appb-000094
将化合物29(0.53mg,1mmol)，化合物30c(0.34g,1mmol)和无水碳酸钾(0.28g,2mmol)置于DMF(10mL)中，并在70℃的温度下搅拌反应7小时，TLC检测，待反应完全后，加入50mL乙酸乙酯中。相继用饱和食盐水(2×50mL)，蒸馏水(3×50mL)洗涤有机层，分离、干燥并蒸干有机层，残余物经柱色谱纯化(三氯甲烷/甲醇＝50:1洗脱)后，直接溶于30mL无水乙醇并滴加1mL的80％水合肼。将反应体系于40℃的温度下，搅拌反应2小时，待反应完全后，蒸干有机溶剂。残余物与50mLDCM充分搅拌后，减压抽滤，滤液蒸干后经柱层析纯化(三氯甲烷/甲醇＝10:1洗脱)，得黄色固体状化合物ZX-HYT-31(0.57g，收率88％)。HRMS(ESI)for C 37H 49N 8O 3[M+H] +:calcd,653.3928；found,653.3934.HPLC analysis:MeOH-H 2O(95:5),RT＝7.852min,97.44％purity. 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),8.79(s,1H),8.10(s,1H),7.80(d,J＝8.1Hz,1H),7.53–7.41(m,2H),7.27(d,J＝8.9Hz,1H),6.95–6.87(m,1H),6.52(d,J＝2.5Hz,1H),6.31(s,1H),6.02(s,1H),3.78(s,3H),3.03(d,J＝5.4Hz,4H),2.56–2.52(m,1H),2.50–2.46(m,5H),2.45(s,3H),2.30(t,J＝7.4Hz,2H),1.78(qd,J＝7.0,5.2Hz,1H),1.45(t,J＝7.3Hz,2H),1.36(t,J＝6.8Hz,2H),1.32–1.24(m,10H),0.83–0.74(m,4H). 13C NMR(101MHz,DMSO)δ172.24,162.63,157.02,156.73,147.39,140.77,137.46,129.88,123.83,120.25,119.66,118.75,116.97,106.69,106.57,100.06,58.36,56.15,53.26,49.25,41.77,33.00,29.48,29.44,27.42,26.83,26.77,17.46,15.03,7.72,7.62.
实施例32：(1R,3R,5S,7R)-N-(8-(4-(4-((8-(3-(环丙烷甲酰氨基)苯基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶基[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)-3,5-二甲基金刚烷-1-羧酰胺(ZX-HYT-32)
Figure PCTCN2022079597-appb-000095
将化合物ZX-HYT-31(0.13mg,0.2mmol)，(1R,3R,5S,7R)-3,5-二甲基金刚烷-1-羧酸(42mg,0.2mmol)，HATU(91mg,0.24mmol)和DIPEA(52mg,0.4mmol)置于乙腈(6mL)中，并在室温条件下搅拌反应1小时，TLC检测，待反应完全后，蒸干有机溶剂，残余物拌硅胶蒸干直接柱色谱分离(三氯甲烷/甲醇＝50:1洗脱)得黄色粉末状目标化合物ZX-HYT-32(93mg，收率55％)。HRMS(ESI)for C 50H 67N 8O 4[M+H] +:calcd,843.5285；found,843.5280.HPLC analysis:MeOH-H 2O(95:5),6.693min,99.44％purity. 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.79(s,1H),8.09(s,1H),7.80(d,J＝8.2Hz,1H),7.50–7.42(m,2H),7.31(t,J＝5.6Hz,1H),7.27(d,J＝8.9Hz,1H),6.91(d,J＝7.9Hz,1H),6.52(d,J＝2.6Hz,1H),6.31(s,1H),6.01(s,1H),3.78(s,3H),3.09–2.97(m,6H),2.50–2.46(m,4H),2.45(s,3H),2.30(t,J＝7.5Hz,2H),2.03(p,J＝3.2Hz,1H),1.77(td,J＝7.2,3.7Hz,1H),1.60–1.53(m,2H),1.51–1.41(m,3H),1.40–1.34(m,5H),1.33(s,1H),1.30–1.22(m,11H),1.14–1.05(m,2H),0.82–0.75(m,10H). 13C NMR(101MHz,DMSO)δ176.90,172.21,162.61,157.00,156.73,147.36,140.77,137.46,129.86,123.83,120.29,119.67,118.75,116.97,106.72,106.57,100.07,58.35,56.15,53.23,50.80,49.21,45.51,42.89,42.17,38.93,37.91,31.17,30.92,29.53,29.37,29.34,29.18,27.35,26.70,17.46,15.03,7.72,7.63.
实施例33：N-(3-(2-((4-(4-(8-(3,3-二甲基丁二酰胺基)辛基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧吡喃并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-33)
Figure PCTCN2022079597-appb-000096
与化合物ZX-HYT-32的合成方法类似，以化合物ZX-HYT-31(0.13mg,0.2mmol)和3,3-二甲基丁酸(23mg,0.2mmol)为原料，经过酰胺缩合即得化合物ZX-HYT-33(60mg，收率40％)。HRMS(ESI)for C 43H 59N 8O 4[M+H] +:calcd,751.4659；found,751.4654.HPLC analysis:MeOH-H 2O(90:10),6.793min,98.37％purity. 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),8.79(s,1H),8.09(s,1H),7.80(d,J＝7.6Hz,1H),7.67(t,J＝5.5Hz,1H),7.52–7.42(m,2H),7.27(d,J＝8.8Hz,1H),6.92(d,J＝7.9Hz,1H),6.52(d,J＝2.5Hz,1H),6.36–6.28(m,1H),6.02(s,1H),3.78(s,3H),3.08–2.98(m,6H),2.50–2.46(m,4H),2.45(s,3H),2.30(t,J＝7.4Hz,2H),1.93(s,2H),1.82–1.73(m,1H),1.45(t,J＝7.2Hz,2H),1.38(q,J＝6.6Hz,2H),1.32–1.21(m,8H),0.95(s,9H),0.83–0.73(m,4H). 13C NMR(101MHz,DMSO)δ172.18,170.98,162.58,157.00,156.74,147.31,140.78,137.48,129.85,123.83,120.27,119.68,118.74,116.99,106.71,106.56,100.07,58.36,56.15,53.28,49.37,49.28,38.70,30.82,30.16,29.67,29.44,29.21,27.39,26.89,26.78,17.46,15.04,7.71,7.62.
实施例34：N-(8-(4-(4-((8-(3-(环丙烷甲酰胺基)苯基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)-4,4-二氟环己烷-1-羧酰胺(ZX-HYT-34)
Figure PCTCN2022079597-appb-000097
与化合物ZX-HYT-32的合成方法类似，以化合物ZX-HYT-31(0.13mg,0.2mmol)和4,4-二氟环己烷-1-羧酸(33mg,0.2mmol)为原料，经过酰胺缩合即得化合物ZX-HYT-34(73mg，收率46％)。HRMS(ESI)for C 44H 57F 2N 8O 4[M+H] +:calcd,799.4471；found,799.4465.HPLC  analysis:MeOH-H 2O(97:3),RT＝4.194min,99.49％purity. 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),8.80(s,1H),8.10(s,1H),7.86–7.74(m,2H),7.50–7.43(m,2H),7.27(d,J＝8.9Hz,1H),6.92(d,J＝7.8Hz,1H),6.53(d,J＝2.5Hz,1H),6.31(s,1H),6.02(s,1H),3.78(s,3H),3.08–2.98(m,6H),2.49–2.46(m,4H),2.45(s,3H),2.30(t,J＝7.4Hz,2H),2.21(t,J＝11.8Hz,1H),2.08–1.98(m,2H),1.86–1.71(m,5H),1.61(t,J＝11.9Hz,2H),1.49–1.42(m,2H),1.41–1.35(m,2H),1.31–1.23(m,8H),0.82–0.75(m,4H). 13C NMR(101MHz,DMSO)δ173.95,172.18,162.58,156.99,156.74,147.32,140.77,137.47,129.84,124.20,123.82,120.26,119.67,118.73,116.98,106.70,106.56,100.07,58.36,56.14,53.27,49.27,41.49,38.79,32.97,32.73,32.50,29.53,29.42,29.19,27.39,26.78,26.17,26.08,17.46,15.04,7.69,7.63.
实施例35：(3R,5R,7R)-N-(8-(4-(4-((8-(3-(环丙烷甲酰氨基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)金刚烷-1-羧酰胺(ZX-HYT-35)
Figure PCTCN2022079597-appb-000098
与化合物ZX-HYT-32的合成方法类似，以化合物ZX-HYT-31(0.13mg,0.2mmol)和(3R,5R,7R)-金刚烷-1-羧酸(36mg,0.2mmol)为原料，经过酰胺缩合即得化合物ZX-HYT-35(74mg，收率45％)。HRMS(ESI)for C 48H 63N 8O 4[M+H] +:calcd,815.4972；found,815.4967.HPLC analysis:MeOH-H 2O(95:5),5.824min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),8.79(s,1H),8.09(s,1H),7.80(s,1H),7.53–7.41(m,2H),7.28(dd,J＝12.6,7.2Hz,2H),6.91(d,J＝7.9Hz,1H),6.58–6.48(m,1H),6.31(s,1H),6.02(s,1H),3.78(s,3H),3.09–2.97(m,6H),2.47(d,J＝19.2Hz,7H),2.34–2.26(m,2H),1.95(s,3H),1.75(t,J＝6.2Hz,7H),1.70–1.58(m,6H),1.45(s,2H),1.38(t,J＝6.6Hz,2H),1.33–1.20(m,8H),0.89–0.70(m,4H). 13C NMR(101MHz,DMSO)δ177.08,172.16,162.57,157.00,156.73,147.31,140.76,137.46,129.83,129.76,123.81,119.66,118.72,116.97,116.84,106.69,106.55,100.13,100.06,58.38,56.14,53.28,49.28,38.90,36.65,29.59,29.41,29.21,28.15,27.39,26.78,26.72,17.46,15.07,15.03,7.71,7.70.
实施例36：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(3-甲氧基-4-((5-甲基-7-氧代-8-苯基-7,8))-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-36)
Figure PCTCN2022079597-appb-000099
化合物ZX-HYT-36的合成方法参照实施例16。HRMS(ESI)for C 49H 68N 7O 3[M+H] +:calcd,803.5384；found,803.5379.HPLC analysis:MeOH-H 2O(95:5),RT＝11.983min,99.29％purity. 1H NMR(400MHz,DMSO-d 6)δ8.79(s,1H),8.07(s,1H),7.61(t,J＝5.6Hz,1H),7.53(dq,J＝14.0,7.3Hz,3H),7.27(d,J＝7.3Hz,2H),7.17(d,J＝8.8Hz,1H),6.52(s,1H),6.31(s,1H),5.97(s,1H),3.77(s,3H),3.08–2.94(m,6H),2.50–2.37(m,7H),2.31(t,J＝7.8Hz,2H),1.90(s,3H),1.80(s,2H),1.69–1.62(m,3H),1.60–1.52(m,9H),1.45(t,J＝7.2Hz,2H),1.37(t,J＝6.7Hz,2H),1.29–1.22(m,16H). 13C NMR(101MHz,DMSO)δ170.08,162.70,156.92,156.85,147.20,137.25,129.55,129.52,128.33,120.30,117.02,106.75,106.60,100.14,79.66,58.33,56.12,53.24,50.59,49.28,42.63,38.65,36.96,32.61,29.65,29.51,29.48,29.43,29.18,28.55,27.45,26.88,26.74,17.46.
实施例37：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-((S)-1-(环丙烷羰基)吡咯烷-3-基))-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-37)
Figure PCTCN2022079597-appb-000100
化合物ZX-HYT-37的合成方法参照实施例20。HRMS(ESI)for C 51H 75N 8O 4[M+H] +:calcd,863.5911；found,863.5906.HPLC analysis:MeOH-H 2O(97:3),9.734min,100％purity. 1H NMR(400MHz,Methanol-d 4)δ8.70(s,1H),7.24(s,1H),6.67(s,1H),6.58(d,J＝6.0Hz,1H),6.19(s,1H),5.75(s,1H),5.39(s,1H),3.80(s,3H),3.27–3.20(m,4H),3.14(t,J＝6.9Hz,2H),2.81(d,J ＝30.8Hz,1H),2.66(t,J＝5.0Hz,4H),2.52(s,1H),2.46–2.35(m,5H),2.23–2.11(m,1H),1.95(s,3H),1.91(s,2H),1.74(d,J＝12.3Hz,3H),1.67(s,2H),1.63(d,J＝2.9Hz,7H),1.59–1.54(m,2H),1.51–1.45(m,2H),1.38–1.25(m,16H),0.90–0.78(m,1H),0.55–0.44(m,2H),0.18–0.03(m,2H). 13C NMR(101MHz,DMSO)δ171.17,170.09,163.11,157.46,155.88,150.21,150.05,146.67,131.96,125.70,125.40,119.48,116.53,107.01,100.18,58.39,55.92,53.31,50.58,50.31,49.18,48.95,42.61,38.65,36.95,32.59,29.63,29.49,29.17,28.54,27.45,26.86,17.19,14.00,12.41,11.86,7.64,7.41.
实施例38：N-(3-(2-((4-(2-((12-(2-((3R,5R,7R)-金刚烷-1-基)乙氧基)十二烷基)氧基)乙氧基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-38)
Figure PCTCN2022079597-appb-000101
化合物ZX-HYT-38的合成方法参照实施例27。HRMS(ESI)for C 51H 75N 8O 4[M+H] +:calcd,847.5248；found,847.5351.HPLC analysis:MeOH-H 2O(97:3),4.685min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ10.42(s,1H),8.81(s,1H),8.18(s,1H),7.80–7.66(m,1H),7.54(t,J＝2.1Hz,1H),7.47(t,J＝8.0Hz,1H),7.32(d,J＝8.9Hz,1H),6.93(d,J＝7.8Hz,1H),6.55(d,J＝2.5Hz,1H),6.33(s,1H),6.03(s,1H),4.07–3.95(m,2H),3.78(s,3H),3.71–3.63(m,2H),3.45–3.42(m,2H),3.36–3.32(m,2H),3.27(t,J＝6.4Hz,2H),2.45(s,3H),1.88(s,2H),1.77(p,J＝6.4Hz,1H),1.61(q,J＝12.0Hz,4H),1.54–1.37(m,8H),1.31–1.17(m,23H),0.87–0.81(m,2H),0.79–0.77(m,4H). 13C NMR(101MHz,DMSO)δ172.22,162.59,157.09,156.69,147.36,140.74,137.46,130.12,129.84,123.86,121.43,119.71,118.78,117.10,106.68,104.53,99.27,70.83,70.36,69.07,67.66,66.26,56.26,43.73,42.59,37.04,31.79,31.74,29.68,29.56,29.52,29.48,29.45,29.37,29.33,29.26,29.22,28.48,26.19,26.13,22.59,17.49,15.03,14.45,7.74,7.66.
实施例39：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-((环丁基甲基)氨基)苯基)-5-甲基-7)-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-39)
Figure PCTCN2022079597-appb-000102
化合物ZX-HYT-39的合成方法参照实施例19。HRMS(ESI)for C 54H 77N 8O 3[M+H] +:calcd,885.6119；found,885.6114.HPLC analysis:MeOH-H 2O(97:3),13.507min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ8.77(s,1H),8.01(s,1H),7.61(t,J＝5.9Hz,1H),7.43(d,J＝8.8Hz,1H),7.22(t,J＝8.0Hz,1H),6.69(d,J＝8.2Hz,1H),6.54(s,1H),6.42(s,1H),6.35(d,J＝7.7Hz,1H),6.28(s,1H),6.05(s,1H),5.72(t,J＝5.7Hz,1H),3.79(s,3H),3.09–2.95(m,8H),2.60–2.52(m,2H),2.50–2.45(m,4H),2.43(s,3H),2.29(t,J＝7.4Hz,2H),2.00(q,J＝8.0Hz,2H),1.90(s,3H),1.85–1.77(m,4H),1.73–1.65(m,3H),1.65–1.61(m,2H),1.59–1.56(m,2H),1.56–1.52(m,6H),1.47–1.41(m,2H),1.39–1.34(m,2H),1.30–1.21(m,16H). 13C NMR(101MHz,DMSO)δ170.12,162.63,156.82,150.68,146.95,137.95,129.90,120.56,117.16,115.92,113.01,111.30,106.86,106.55,100.17,58.32,56.17,53.27,50.59,49.42,49.25,42.62,38.64,36.95,34.72,32.61,29.63,29.49,29.45,29.40,29.16,28.54,27.42,26.86,26.76,26.17,18.42,17.41.
实施例40：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-(环丙基甲氧基)苯基)-5-甲基-7-氧代-))7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-40)
Figure PCTCN2022079597-appb-000103
化合物ZX-HYT-40的合成方法参照实施例16。HRMS(ESI)for C 53H 73N 7O 4[M+H] +:calcd,872.5797；found,872.5789. 1H NMR(400MHz,DMSO-d 6)δ8.78(s,1H),8.08(s,1H),7.61(t,J＝5.7Hz,1H),7.44(t,J＝8.1Hz,1H),7.28(d,J＝8.8Hz,1H),7.08(dd,J＝8.4,2.6Hz,1H),6.86(t,J＝2.2Hz,1H),6.81(dd,J＝7.6,1.9Hz,1H),6.54(d,J＝2.5Hz,1H),6.30(d,J＝1.4Hz,1H),6.00(s,1H),3.86–3.73(m,5H),3.10–2.94(m,6H),2.50–2.40(m,7H),2.30(s,2H),1.95– 1.85(m,3H),1.80(s,2H),1.69–1.62(m,3H),1.60–1.52(m,9H),1.49–1.42(m,2H),1.37(t,J＝6.7Hz,2H),1.30–1.23(m,17H),0.53(dt,J＝10.2,3.0Hz,2H),0.28(dt,J＝6.1,3.0Hz,2H). 13C NMR(101MHz,DMSO)δ170.08,162.59,159.85,156.88,156.81,147.13,138.33,130.22,121.48,117.06,115.85,114.49,106.60,100.18,72.76,58.34,56.13,53.25,50.59,49.32,42.63,38.64,36.96,32.61,29.65,29.51,29.47,29.42,29.18,28.54,27.44,26.87,17.44,10.57,3.54.
实施例41：N-((1R,3S,5R,7S)-3-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)金刚烷-1-基)环丙烷甲酰胺(ZX-HYT-41)
Figure PCTCN2022079597-appb-000104
化合物ZX-HYT-41的合成方法参照实施例16。HRMS(ESI)for C 57H 82N 8O 4[M+H] +:calcd,943.6532；found,943.6541. 1H NMR(400MHz,DMSO-d 6)δ10.55(s,1H),9.15(s,1H),8.79(s,1H),8.08(s,1H),7.64(t,J＝5.7Hz,1H),6.53(d,J＝2.6Hz,1H),6.31(d,J＝1.4Hz,1H),5.99(s,1H),3.79(s,3H),3.16–2.92(m,6H),2.49–2.23(m,6H),1.93–1.83(m,4H),1.80(s,2H),1.69–1.61(m,6H),1.60–1.52(m,9H),1.48(s,2H),1.41–1.19(m,32H),1.02–0.79(m,4H).
实施例42：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(8-(环丙烷羰基)-8-氮杂双环[3.2.1]辛烷))3-基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-42)
Figure PCTCN2022079597-appb-000105
化合物ZX-HYT-42的合成方法参照实施例16。HRMS(ESI)for C 54H 78N 8O 4[M+H] +:calcd,903.6224；found,903.6231.HPLC analysis:MeOH-H 2O(97:3),12.782min,100％purity. 1H NMR(400MHz,DMSO-d 6)δ8.73(s,1H),8.37(s,1H),7.61(t,J＝5.7Hz,2H),6.65(d,J＝2.5 Hz,1H),6.57(d,J＝8.9Hz,1H),6.15(s,1H),5.31(s,1H),4.65–4.47(m,2H),3.81(s,3H),3.23–3.07(m,4H),3.00(q,J＝6.5Hz,2H),2.69–2.52(m,4H),2.38–2.26(m,5H),2.22–2.13(m,2H),1.90(s,4H),1.80(s,2H),1.68–1.62(m,3H),1.59–1.52(m,8H),1.50–1.44(m,2H),1.39–1.33(m,2H),1.30–1.21(m,22H),0.84–0.74(m,2H),0.71–0.60(m,2H). 13C NMR(101MHz,DMSO)δ170.36,170.09,162.97,157.33,146.18,107.72,106.90,100.54,58.19,56.09,53.19,51.44,50.58,48.96,42.62,38.64,36.95,33.32,32.60,32.35,31.76,31.13,30.93,29.64,29.48,29.41,29.17,28.54,27.37,26.87,23.32,22.57,18.30,17.19,14.42,11.72,7.21,7.15,6.53.
实施例43：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4–((8-(3-(二甲基氨基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-43)
Figure PCTCN2022079597-appb-000106
化合物ZX-HYT-43的合成方法参照实施例16。HRMS(ESI)for C 51H 72N 8O 3[M+H] +:calcd,845.5806；found,845.5797.HPLC analysis:MeOH-H 2O(95:5),RT＝12.901min,99.52％purity. 1H NMR(400MHz,DMSO-d 6)δ8.78(s,1H),8.03(s,1H),7.61(t,J＝5.7Hz,1H),7.40–7.30(m,2H),6.85(dd,J＝8.4,2.5Hz,1H),6.62(t,J＝2.2Hz,1H),6.54(d,J＝2.5Hz,1H),6.50(dd,J＝7.5,1.8Hz,1H),6.29(s,1H),5.98(s,1H),3.79(s,3H),3.09–2.97(m,6H),2.90(s,6H),2.50–2.46(m,4H),2.44(s,3H),2.32(d,J＝8.7Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.65(d,J＝12.2Hz,3H),1.58(s,2H),1.56–1.54(m,6H),1.45(t,J＝7.1Hz,2H),1.36(q,J＝6.5,5.9Hz,2H),1.32–1.23(m,17H). 13C NMR(101MHz,DMSO)δ170.07,162.68,156.91,156.77,151.82,146.91,138.12,129.87,120.57,117.20,116.85,113.36,112.11,106.62,100.22,58.33,56.16,55.38,53.24,50.59,49.32,42.63,38.65,36.96,32.61,29.65,29.51,29.46,29.43,29.19,28.55,27.44,26.88,26.72,17.41.
实施例44：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-((氮杂环丁烷-3-基甲基)氨基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-44)
Figure PCTCN2022079597-appb-000107
化合物ZX-HYT-44的合成方法参照实施例17。HRMS(ESI)for C 53H 75N 9O 3[M+H] +:calcd,886.6071；found,886.6066.HPLC analysis:MeOH-H 2O(95:5),RT＝8.652min,98.25％purity. 1H NMR(400MHz,DMSO-d 6)δ9.95(s,1H),8.79(s,1H),8.69(s,1H),8.13(s,1H),7.64(t,J＝5.7Hz,1H),7.45(d,J＝8.8Hz,1H),7.25(t,J＝8.0Hz,1H),6.72(d,J＝8.3Hz,1H),6.64(d,J＝2.5Hz,1H),6.50–6.39(m,2H),6.30(s,1H),6.06(s,1H),3.95(s,2H),3.81(s,3H),3.76–3.64(m,4H),3.57(s,2H),3.30–3.23(m,4H),3.13(s,4H),3.04–2.89(m,5H),2.45(s,3H),1.90(s,3H),1.80(s,2H),1.70–1.61(m,4H),1.60–1.51(m,8H),1.40–1.34(m,2H),1.33–1.19(m,16H). 13C NMR(101MHz,DMSO)δ170.15,162.64,158.69,158.40,156.89,156.81,150.09,147.02,138.15,129.96,121.57,119.19,117.24,116.80,116.21,112.57,112.28,107.27,106.71,100.91,56.31,55.97,51.27,50.58,49.41,46.70,45.42,42.61,38.65,36.94,32.61,31.46,29.64,29.49,29.41,29.27,29.16,28.97,28.52,26.88,26.49,23.66,17.42.
实施例45：2-((3R,5R,7R)-金刚烷-1-基)-N-(12-(4-(4-((8-(3-(氮杂环丁烷-3-基氨基)苯基)-5-甲基-7-氧-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)十二烷基)乙酰胺(ZX-HYT-45)
Figure PCTCN2022079597-appb-000108
化合物ZX-HYT-45的合成方法参照实施例17。HRMS(ESI)for C 52H 73N 9O 3[M+H] +:calcd,872.5915；found,872.5926.HPLC analysis:MeOH-H 2O(95:5),RT＝4.763min,98.21％purity. 1H NMR(400MHz,DMSO-d 6)δ8.76(s,1H),8.01(s,1H),7.61(s,1H),7.43–7.32(m,1H),7.23(s,1H),6.67–6.57(m,1H),6.53(s,1H),6.46–6.22(m,4H),6.03(s,1H),4.18(s,1H),3.94–3.64(m,7H),3.06–2.96(m,6H),2.48–2.35(m,7H),2.29(s,2H),1.89(s,3H),1.79(s,2H),1.67– 1.61(m,3H),1.59–1.50(m,9H),1.47–1.41(m,2H),1.38–1.34(m,2H),1.29–1.17(m,16H). 13C NMR(101MHz,DMSO)δ170.11,162.61,156.82,148.94,147.00,138.05,130.10,120.51,117.14,113.44,111.57,106.87,106.55,100.11,58.40,56.16,54.58,54.44,53.29,50.59,49.35,47.79,42.62,38.65,36.95,32.60,29.64,29.51,29.42,29.18,28.54,27.48,26.88,26.80,17.41.
实施例46：N-((1S,4S)-4-(2-((4-(4-(12-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十二烷基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)环己基)环丙烷甲酰胺(ZX-HYT-46)
Figure PCTCN2022079597-appb-000109
化合物ZX-HYT-46的合成方法参照实施例20。HRMS(ESI)for C 53H 78N 8O 4[M+H] +:calcd,891.6219；found,891.6223. 1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.51(s,1H),7.48(t,J＝5.9Hz,1H),7.07(d,J＝7.5Hz,1H),6.91(d,J＝11.5Hz,1H),6.76(dd,J＝7.5,1.5Hz,1H),6.45(q,J＝1.1Hz,1H),6.31(d,J＝1.6Hz,1H),4.11(p,J＝7.0Hz,1H),3.86(s,3H),3.59(dp,J＝11.4,7.0Hz,1H),3.27(t,J＝7.1Hz,4H),3.07(td,J＝7.1,5.9Hz,2H),2.63(t,J＝7.1Hz,4H),2.50–2.41(m,4H),2.38(t,J＝7.1Hz,2H),2.28(s,2H),2.10(s,3H),1.78–1.70(m,2H),1.70–1.54(m,15H),1.54–1.48(m,5H),1.41–1.38(m,4H),1.34–1.18(m,14H),1.00–0.86(m,4H).
实施例47：N-(3-(2-((4-(4-(8-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)辛基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-47)
Figure PCTCN2022079597-appb-000110
化合物ZX-HYT-47的合成方法参照实施例8。HRMS(ESI)for C 49H 64N 8O 4[M+H] +:calcd, 829.5123；found,829.5135. 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J＝8.0Hz,1H),7.62(t,J＝5.7Hz,1H),7.55–7.41(m,2H),7.28(d,J＝8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J＝2.5Hz,1H),6.32(d,J＝1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.32(q,J＝13.4,7.5Hz,2H),1.94–1.87(m,3H),1.80(s,3H),1.69–1.62(m,4H),1.61–1.52(m,9H),1.52–1.44(m,2H),1.42–1.33(m,2H),1.32–1.15(m,10H),0.88–0.75(m,4H).
实施例48：N-(3-(2-((4-(4-(8-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)辛基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)新戊酰胺(ZX-HYT-48)
Figure PCTCN2022079597-appb-000111
化合物ZX-HYT-48的合成方法参照实施例8。HRMS(ESI)for C 50H 68N 8O 4[M+H] +:calcd,845.5436；found,845.5441. 1H NMR(400MHz,DMSO-d 6)δ9.38(s,1H),8.80(s,1H),8.11(s,1H),7.91(d,J＝8.2Hz,1H),7.64(t,J＝5.6Hz,1H),7.55(t,J＝2.1Hz,1H),7.46(t,J＝8.1Hz,1H),7.28(d,J＝8.9Hz,1H),6.93(dd,J＝7.7,2.0Hz,1H),6.52(d,J＝2.5Hz,1H),6.32(s,1H),6.03(s,1H),3.78(s,3H),3.15–3.04(m,4H),3.01(q,J＝6.5Hz,2H),2.71–2.52(m,4H),2.48–2.38(m,5H),1.90(s,3H),1.80(s,2H),1.68–1.62(m,3H),1.58–1.53(m,9H),1.51–1.43(m,2H),1.41–1.35(m,2H),1.30–1.25(m,8H),1.21(s,9H).
实施例49：N-(3-(2-((4-(4-(8-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)辛基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙酰胺(ZX-HYT-49)
Figure PCTCN2022079597-appb-000112
化合物ZX-HYT-49的合成方法参照实施例8。HRMS(ESI)for C 48H 64N 8O 4[M+H] +:calcd, 817.5123；found,817.5134. 1H NMR(400MHz,DMSO-d 6)δ10.05(s,1H),8.80(s,1H),8.10(s,1H),7.82–7.75(m,1H),7.63(t,J＝5.7Hz,1H),7.51–7.43(m,2H),7.26(d,J＝8.9Hz,1H),6.96–6.89(m,1H),6.53(d,J＝2.6Hz,1H),6.35–6.29(m,1H),6.01(s,1H),3.78(s,3H),3.10–2.96(m,6H),2.49–2.41(m,7H),2.36–2.25(m,4H),1.91(s,3H),1.80(s,2H),1.70–1.62(m,3H),1.60–1.52(m,9H),1.49–1.43(m,2H),1.40–1.35(m,2H),1.31–1.23(m,8H),1.07(t,J＝7.5Hz,3H).
实施例50：N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-50)
Figure PCTCN2022079597-appb-000113
化合物ZX-HYT-50的合成方法参照实施例8。HRMS(ESI)for C 41H 47N 7O 4[M+H] +:calcd,702.3702；found,702.3713. 1H NMR(600MHz,DMSO-d 6)δ10.39(s,1H),8.81(s,1H),8.14(s,1H),7.80(s,1H),7.54–7.41(m,2H),7.29(d,J＝8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.70–3.57(m,4H),3.09–2.94(m,4H),2.46(s,3H),2.16(s,2H),1.94(s,3H),1.78(p,J＝6.3Hz,1H),1.69–1.60(m,12H),0.82–0.73(m,4H).
实施例51：N-(3-(2-((4-(4-(2-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)乙基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-51)
Figure PCTCN2022079597-appb-000114
化合物ZX-HYT-51的合成方法参照实施例8。HRMS(ESI)for C 43H 52N 8O 4[M+H] +:calcd,745.4184；found,745.4191. 1H NMR(600MHz,DMSO-d 6)δ10.40(s,1H),8.80(s,1H),8.11(s,1H),7.79(s,1H),7.61(t,J＝5.7Hz,1H),7.54–7.42(m,2H),7.28(d,J＝8.9Hz,1H),6.93(dt,J＝8.1,1.6Hz,1H),6.53(d,J＝2.5Hz,1H),6.32(s,1H),6.00(s,1H),3.79(s,3H),3.20(q,J＝6.4Hz,2H),3.09–2.98(m,4H),2.57–2.52(m,4H),2.46(s,3H),2.40(t,J＝6.6Hz,2H),1.91(s,3H),1.86–1.82(m,2H),1.78(tt,J＝7.3,3.7Hz,1H),1.69–1.64(m,3H),1.60–1.56(m,9H),0.80–0.74(m,4H).
实施例52：N-(3-(2-((4-(4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)丁基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-52)
Figure PCTCN2022079597-appb-000115
化合物ZX-HYT-52的合成方法参照实施例8。HRMS(ESI)for C 45H 56N 8O 4[M+H] +:calcd,773.4497；found,773.4485. 1H NMR(600MHz,DMSO-d 6)δ10.39(s,1H),8.81(s,1H),8.14(s,1H),7.81(s,1H),7.71(s,1H),7.50–7.43(m,2H),7.29(d,J＝8.8Hz,1H),6.95–6.91(m,1H),6.56(s,1H),6.33(s,1H),6.02(s,1H),3.79(s,3H),3.18–2.86(m,8H),2.64–2.51(m,6H),2.46(s,3H),1.95–1.90(m,3H),1.83(s,2H),1.80–1.76(m,1H),1.69–1.63(m,3H),1.61–1.52(m,9H),1.46–1.40(m,2H),0.83–0.75(m,4H).
实施例53：N-(3-(2-((4-(4-(6-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)己基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-53)
Figure PCTCN2022079597-appb-000116
化合物ZX-HYT-53的合成方法参照实施例8。HRMS(ESI)for C 47H 60N 8O 4[M+H] +:calcd,801.4810；found,801.4823. 1H NMR(600MHz,DMSO-d 6)δ10.40(s,1H),8.81(s,1H),8.17(s,1H),7.91(s,1H),7.76(s,1H),7.50–7.45(m,2H),7.19(d,J＝8.8Hz,1H),6.95–6.93(m,1H),6.57(s,1H),6.34(s,1H),6.12(s,1H),3.79(s,3H),3.18–2.86(m,8H),2.64–2.51(m,8H),2.46(s,3H),1.95–1.90(m,3H),1.83(s,2H),1.80–1.76(m,1H),1.69–1.63(m,3H),1.61–1.52(m,9H),1.48–1.37(m,4H),0.83–0.75(m,4H).
实施例54：N-(3-(2-((4-(4-(10-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)癸基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-54)
Figure PCTCN2022079597-appb-000117
化合物ZX-HYT-54的合成方法参照实施例8。HRMS(ESI)for C 51H 68N8O 4[M+H] +:calcd,857.5436；found,857.5441. 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J＝8.0Hz,1H),7.62(t,J＝5.7Hz,1H),7.57–7.41(m,2H),7.28(d,J＝8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J＝2.5Hz,1H),6.32(d,J＝1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.32(q,J＝13.4,7.5Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.69–1.62(m,3H),1.61–1.52(m,9H),1.52–1.44(m,2H),1.42–1.33(m,2H),1.31–1.11(m,14H),0.88–0.75(m,6H).
实施例55：N-(3-(2-((4-(4-(14-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)十四烷基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-55)
Figure PCTCN2022079597-appb-000118
化合物ZX-HYT-55的合成方法参照实施例8。HRMS(ESI)for C 55H 76N 8O 4[M+H] +:calcd,913.6062；found,913.6062. 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J＝8.0Hz,1H),7.62(t,J＝5.7Hz,1H),7.55–7.41(m,2H),7.28(d,J＝8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J＝2.5Hz,1H),6.32(d,J＝1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.32(q,J＝13.4,7.5Hz,2H),1.94–1.87(m,3H),1.80(s,2H),1.69–1.62(m,3H),1.61–1.52(m,9H),1.52–1.44(m,2H),1.42–1.33(m,2H),1.32–1.12(m,22H),0.88–0.75(m,6H).
实施例56：N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-56)
Figure PCTCN2022079597-appb-000119
化合物ZX-HYT-56的合成方法参照实施例8。HRMS(ESI)for C 40H 45N 7O 4[M+H] +:calcd,688.3606；found,688.3673.. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.80(s,1H),8.11(s,1H),7.90(d,J＝8.1Hz,1H),7.62(t,J＝5.6Hz,1H),7.56(t,J＝2.0Hz,1H),7.51(t,J＝8.1Hz,1H),7.27(d,J＝8.9Hz,1H),6.98(ddd,J＝7.8,2.0,1.0Hz,1H),6.51(d,J＝2.5Hz,1H),6.48–6.39(m,1H),6.36–6.21(m,2H),6.00(s,1H),5.76(dd,J＝10.1,2.1Hz,1H),3.78(s,3H),3.06– 2.93(m,4H),2.49–2.40(m,4H),2.41(s,3H),2.30-2.12(m,2H),1.79–1.61(m,3H),1.42–1.20(m,12H).
实施例57：N-(3-(2-((4-(4-(2-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)乙基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-57)
Figure PCTCN2022079597-appb-000120
化合物ZX-HYT-57的合成方法参照实施例8。HRMS(ESI)for C 42H 50N 8O 4[M+H] +:calcd,731.4028；found,731.4031. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.80(s,1H),8.11(s,1H),7.90(d,J＝8.1Hz,1H),7.62(t,J＝5.6Hz,1H),7.56(t,J＝2.0Hz,1H),7.51(t,J＝8.1Hz,1H),7.27(d,J＝8.9Hz,1H),6.98(ddd,J＝7.8,2.0,1.0Hz,1H),6.51(d,J＝2.5Hz,1H),6.48–6.39(m,1H),6.36–6.21(m,2H),6.00(s,1H),5.76(dd,J＝10.1,2.1Hz,1H),3.78(s,3H),3.06–2.93(m,4H),2.49–2.40(m,4H),2.41(s,3H),2.30-2.12(m,4H),1.69–1.61(m,3H),1.60–1.53(m,4H),1.32–1.20(m,10H).
实施例58：N-(3-(2-((4-(4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰氨基)丁基)哌嗪-1-基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)丙烯酰胺(ZX-HYT-58)
Figure PCTCN2022079597-appb-000121
化合物ZX-HYT-58的合成方法参照实施例8。HRMS(ESI)for C 44H 54N 8O 4[M+H] +:calcd,759.4341；found,759.4356.
1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.80(s,1H),8.11(s,1H),7.90(d,J＝8.1Hz, 1H),7.62(t,J＝5.6Hz,1H),7.56(t,J＝2.0Hz,1H),7.51(t,J＝8.1Hz,1H),7.27(d,J＝8.9Hz,1H),6.98(ddd,J＝7.8,2.0,1.0Hz,1H),6.51(d,J＝2.5Hz,1H),6.48–6.39(m,1H),6.36–6.21(m,2H),6.00(s,1H),5.76(dd,J＝10.1,2.1Hz,1H),3.78(s,3H),3.06–2.93(m,6H),2.49–2.40(m,7H),2.30(t,J＝7.4Hz,2H),1.90(s,3H),1.69–1.61(m,3H),1.60–1.53(m,3H),1.50–1.41(m,2H),1.32–1.20(m,10H).
实施例59：N-(3-(2-((4-(4-(8-(2-((1S,3R,5S,7R)-3,5-二甲基金刚烷-1-基)乙酰氨基)辛基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-59)
Figure PCTCN2022079597-appb-000122
化合物ZX-HYT-59的合成方法参照实施例32。HRMS(ESI)for C 51H 68N 8O 4[M+H] +:calcd,857.5442；found,857.5436.HPLC analysis:MeOH-H 2O(85:15),RT＝13.264min,96.02％purity. 1H NMR(400MHz,DMSO-d 6)δ10.41(s,1H),8.79(s,1H),8.14(s,1H),7.81(d,J＝7.9Hz,1H),7.66(t,J＝5.7Hz,1H),7.50–7.43(m,2H),7.29(d,J＝8.8Hz,1H),6.92(dd,J＝7.9,2.0Hz,1H),6.55(d,J＝2.5Hz,1H),6.32(s,1H),6.04(s,1H),3.78(s,3H),3.12(q,J＝7.4Hz,4H),3.01(q,J＝6.4Hz,2H),2.82(s,2H),2.52–2.37(m,7H),2.02–1.95(m,1H),1.83(s,1H),1.77(p,J＝6.2Hz,1H),1.54(s,1H),1.41–1.34(m,3H),1.28–1.26(m,7H),1.25–1.23(m,8H),1.20–1.16(m,3H),1.13–1.07(m,2H),1.03–0.98(m,1H),0.86–0.62(m,10H). 13C NMR(101MHz,DMSO)δ172.23,170.21,162.60,157.03,156.74,147.36,140.72,137.48,129.84,123.89,119.74,118.84,117.04,106.89,106.63,100.37,56.22,54.03,52.51,51.10,49.88,48.94,43.18,42.29,41.21,38.62,34.20,31.32,31.01,29.63,29.58,29.32,29.13,27.05,26.87,18.53,17.46,17.23,15.05,12.99,7.73,7.63.
实施例60：(1S,2R,4S)-N-(8-(4-(4-((8-(3-(环丙烷甲酰氨基)苯基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶基[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)双环[2.2.1]庚-5-烯-2-羧酰胺(ZX-HYT-60)
Figure PCTCN2022079597-appb-000123
化合物ZX-HYT-60的合成方法参照实施例32。HRMS(ESI)for C 45H 56N 8O 4[M+H] +:calcd,773.4503；found,773.4497.HPLC analysis:MeOH-H 2O(97:3),RT＝4.703min,98.47％purity. 1H NMR(400MHz,DMSO-d 6)δ10.43(s,1H),9.87(s,1H),9.27(s,1H),8.81(s,1H),8.17(s,1H),7.78(d,J＝8.0Hz,1H),7.56(t,J＝5.7Hz,1H),7.48–7.44(m,1H),7.32(d,J＝8.8Hz,1H),6.93(d,J＝7.8Hz,1H),6.61(s,1H),6.33(s,1H),6.10(dd,J＝5.7,3.0Hz,1H),5.82–5.76(m,1H),3.80(s,3H),3.76–3.70(m,1H),3.60–3.55(m,1H),3.14–3.08(m,8H),3.04–3.00(m,1H),2.98–2.92(m,2H),2.82–2.74(m,2H),2.45(s,3H),1.79(t,J＝6.1Hz,1H),1.73–1.67(m,2H),1.38–1.35(m,1H),1.32–1.29(m,3H),1.27–1.24(m,3H),1.20–1.16(m,7H),0.83–0.74(m,4H). 13C NMR(101MHz,DMSO)δ173.07,172.27,162.57,157.06,156.73,147.34,140.71,137.48,137.28,132.58,129.81,123.93,119.82,118.92,117.12,107.10,106.70,100.79,56.30,51.27,49.85,46.67,46.15,46.11,43.77,42.56,38.91,29.68,28.93,28.84,26.73,26.46,17.47,15.03,9.04,7.65.
实施例61：(1R,2R,4S)-N-(8-(4-(4-((8-(3-(环丙烷甲酰氨基)苯基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶基[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)双环[2.2.1]庚烷-2-羧酰胺(ZX-HYT-61)
Figure PCTCN2022079597-appb-000124
化合物ZX-HYT-61的合成方法参照实施例32。HRMS(ESI)for C 45H 58N 8O 4[M+H] +: calcd,775.4659；found,775.4654.HPLC analysis:MeOH-H 2O(95:5),4.929min,96.20％purity. 1H NMR(400MHz,DMSO-d 6)δ10.40(s,1H),8.78(s,1H),8.08(s,1H),7.81(d,J＝7.9Hz,1H),7.70–7.58(m,1H),7.53–7.42(m,2H),7.27(d,J＝8.9Hz,1H),6.91(d,J＝7.9Hz,1H),6.52(s,1H),6.30(s,1H),6.02(s,1H),3.78(s,3H),3.11–2.93(m,7H),2.59–2.53(m,1H),2.49–2.45(m,4H),2.44–2.40(m,4H),2.29(t,J＝7.4Hz,2H),2.22–2.09(m,2H),1.85–1.68(m,2H),1.60–1.53(m,1H),1.49–1.42(m,4H),1.40–1.35(m,3H),1.29–1.24(m,9H),0.82–0.75(m,4H). 13C NMR(101MHz,DMSO)δ175.06,173.17,172.21,162.60,156.97,156.73,147.32,140.79,137.47,130.11,129.85,123.82,120.28,119.68,118.75,116.98,106.72,106.56,100.04,58.37,56.14,53.27,49.27,46.87,46.33,41.94,41.04,38.98,38.95,37.06,36.29,35.86,33.79,31.13,29.81,29.73,29.65,29.44,29.31,29.21,28.86,27.39,27.03,26.82,26.78,24.32,17.45,15.04,7.71,7.63.
实施例62：N-(3-(2-((4-(4-(8-(环丙烷甲酰胺基)辛基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d)]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-62)
Figure PCTCN2022079597-appb-000125
化合物ZX-HYT-62的合成方法参照实施例32。HRMS(ESI)for C 41H 52N 8O 4[M+H] +:calcd,721.4184；found,721.4192. 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J＝8.0Hz,1H),7.62(t,J＝5.7Hz,1H),7.55–7.41(m,2H),7.28(d,J＝8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J＝2.5Hz,1H),6.32(d,J＝1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.33(s,3H),1.94–1.87(m,3H),1.69–1.62(m,2H),1.61–1.52(m,9H),1.52–1.44(m,2H),0.88–0.75(m,8H).
实施例63：N-(8-(4-(4-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基))氨基)-3-甲氧基苯基)哌嗪-1-基)辛基)环己烷甲酰胺(ZX-HYT-63)
Figure PCTCN2022079597-appb-000126
化合物ZX-HYT-63的合成方法参照实施例32。HRMS(ESI)for C 44H 58N 8O 4[M+H] +:calcd,763.4654；found,763.4661. 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.80(s,1H),8.11(s,1H),7.81(d,J＝8.0Hz,1H),7.62(t,J＝5.7Hz,1H),7.55–7.41(m,2H),7.28(d,J＝8.9Hz,1H),6.99–6.88(m,1H),6.53(d,J＝2.5Hz,1H),6.32(d,J＝1.4Hz,1H),6.02(s,1H),3.79(s,3H),3.12–2.94(m,6H),2.49–2.41(m,4H),2.33(s,3H),1.94–1.87(m,3H),1.69–1.62(m,2H),1.61–1.52(m,11H),1.52–1.44(m,4H),0.88–0.75(m,10H).
实施例64：N-((3S,5S,7S)-金刚烷-1-基)-4-(4-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌嗪-1-甲酰胺(ZX-HYT-64)
Figure PCTCN2022079597-appb-000127
将化合物29(0.13mg,0.25mmol)，1-异氰基金刚烷(44mg,0.25mmol)和三乙胺(38mg,0.38mmol)置于无水乙醇(5mL)中，并在25℃的温度下搅拌反应1小时，TLC检测，待反应完全后，蒸干反应液，所得残余物经柱色谱纯化(三氯甲烷/甲醇＝40:1洗脱)，得黄色粉末状目标化合物ZX-HYT-64(0.17g，收率97％)。HRMS(ESI)for C 40H 46N 8O 4[M+H] +:calcd,703.3715；found,703.3721. 1H NMR(400MHz,DMSO-d 6)δ10.38(s,1H),8.80(s,1H),8.11(s,1H),7.87–7.76(m,1H),7.52–7.42(m,2H),7.28(d,J＝8.9Hz,1H),6.98–6.85(m,1H),6.61–6.52(m,1H),6.32(s,1H),6.04(s,1H),5.77(s,1H),3.80(s,3H),3.45–3.36(m,4H),3.02–2.93(m,4H),2.46(s,3H),2.05–1.98(m,3H),1.98–1.91(m,6H),1.82–1.74(m,1H),1.67– 1.57(m,6H),0.82–0.75(m,4H).
实施例65：N-(3-(2-((4-(4-((3R,5R,7R)-金刚烷-1-羰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-65)
Figure PCTCN2022079597-appb-000128
化合物ZX-HYT-65的合成方法参照实施例32。HRMS(ESI)for C 40H 45N 7O 4[M+H] +:calcd,688.3606；found,688.3611.HRMS(ESI)for C 40H 46N 8O 4[M+H] +:calcd,703.3715；found,703.3723. 1H NMR(600MHz,DMSO-d 6)δ10.39(s,1H),8.81(s,1H),8.13(s,1H),7.81(s,1H),7.53–7.43(m,2H),7.29(d,J＝8.8Hz,1H),6.98–6.89(m,1H),6.62–6.52(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.77–3.69(m,4H),3.08–2.96(m,4H),2.46(s,3H),2.01(s,3H),1.98–1.90(m,6H),1.78(p,J＝6.2,5.4Hz,1H),1.76–1.67(m,6H),0.84–0.75(m,4H).
实施例66：2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-8-(3-(4-甲基-2-氧代哌嗪-1-基)苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-66)
Figure PCTCN2022079597-appb-000129
化合物ZX-HYT-66的合成方法参照实施例18。MS(ESI),m/z:731.6[M+H] +. 1H NMR(400MHz,Chloroform-d)δ9.07(s,1H),8.48(s,1H),7.87(t,J＝1.5Hz,1H),7.53(d,J＝7.5Hz,1H),7.26(t,J＝7.5Hz,1H),7.09(dd,J＝24.7,7.5Hz,2H),6.74(dd,J＝7.5,1.5Hz,1H),6.58(q,J＝0.9Hz,1H),6.30(d,J＝1.5Hz,1H),3.94–3.85(m,5H),3.68(t,J＝7.0Hz,4H),3.51(s,2H), 3.32(t,J＝7.1Hz,4H),2.69(t,J＝7.1Hz,2H),2.47(d,J＝1.1Hz,3H),2.39(s,3H),2.34(s,2H),2.00(p,J＝7.0Hz,3H),1.69–1.58(m,12H).
实施例67：N-(3-(2-((6-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基吡啶-3-基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-67)
Figure PCTCN2022079597-appb-000130
化合物ZX-HYT-67的合成方法参照实施例32。HRMS(ESI)for C 40H 46N 8O 4[M+H] +:calcd,703.3715；found,703.3723. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.79(s,1H),8.34(s,1H),7.77–7.66(m,1H),7.50–7.40(m,3H),6.90(d,J＝7.8Hz,1H),6.30(s,1H),5.86(s,1H),3.80(s,3H),3.66–3.53(m,4H),3.42–3.36(m,4H),2.45(s,3H),2.16(s,2H),1.97–1.89(m,3H),1.82–1.73(m,1H),1.70–1.57(m,12H),0.83–0.70(m,4H).
实施例68：N-((3S,5S,7S)-金刚烷-1-基)-4-(5-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-6-甲氧基吡啶-2-基)哌嗪-1-甲酰胺(ZX-HYT-68)
Figure PCTCN2022079597-appb-000131
化合物ZX-HYT-68的合成方法参照实施例65。HRMS(ESI)for C 39H 45N 9O 4[M+H] +:calcd,704.3667；found,704.3653. 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H),8.79(s,1H),8.32(s,1H),7.78–7.70(m,1H),7.50–7.40(m,3H),6.90(d,J＝7.8Hz,1H),6.30(s,1H),5.83(s,1H),5.76(s,1H),3.80(s,3H),3.45–3.35(m,8H),2.45(s,3H),2.05–1.98(m,3H),1.98– 1.90(m,6H),1.82–1.74(m,1H),1.68–1.56(m,6H),0.83–0.73(m,4H).
实施例69：N-(3-(2-((6-(4-((3R,5R,7R)-金刚烷-1-羰基)哌嗪-1-基)-2-甲氧基吡啶-3-基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-69)
Figure PCTCN2022079597-appb-000132
化合物ZX-HYT-69的合成方法参照实施例32。HRMS(ESI)for C 39H 44N 8O 4[M+H] +:calcd,689.3558；found,689.3562. 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H),8.79(s,1H),8.33(s,1H),7.81–7.66(m,1H),7.50–7.40(m,3H),6.91(d,J＝7.8Hz,1H),6.31(s,1H),5.86(s,1H),3.81(s,3H),3.75–3.65(m,4H),3.33–3.33(m,4H),2.45(s,3H),2.05–1.98(m,3H),1.98–1.91(m,6H),1.81–1.63(m,7H),0.84–0.71(m,4H).
实施例70：N-(3-(2-((6-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-4-甲氧基吡啶-3-基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-70)
Figure PCTCN2022079597-appb-000133
化合物ZX-HYT-70的合成方法参照实施例32。HRMS(ESI)for C 40H 46N 8O 4[M+H] +:calcd,703.3715；found,703.3723. 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),8.72(s,1H),8.52(s,1H),7.83(s,1H),7.66–7.56(m,1H),7.46(s,1H),7.36(s,1H),6.91–6.74(m,1H),6.40–6.20(m,2H),3.73(s,3H),3.64–3.55(m,4H),3.51–3.39(m,4H),2.42(s,3H),2.21–2.12(m,2H),1.93(s,3H),1.81–1.73(m,1H),1.72–1.54(m,12H),0.83–0.72(m,4H).
实施例71：N-((3S,5S,7S)-金刚烷-1-基)-4-(5-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-4-甲氧基吡啶-2-基)哌嗪-1-甲酰胺(ZX-HYT-71)
Figure PCTCN2022079597-appb-000134
化合物ZX-HYT-71的合成方法参照实施例65。HRMS(ESI)for C 39H 45N 9O 4[M+H] +:calcd,704.3667；found,704.3653. 1H NMR(400MHz,DMSO-d 6)δ10.30(s,1H),8.72(s,1H),8.50(s,1H),7.82(s,1H),7.63–7.55(m,1H),7.47(s,1H),7.37(s,1H),6.85(s,1H),6.30(s,1H),6.27(s,1H),5.74(s,1H),3.73(s,3H),3.45–3.35(m,8H),2.42(s,3H),2.06–1.99(m,3H),1.99–1.93(m,6H),1.82–1.74(m,1H),1.65–1.58(m,6H),0.84–0.74(m,4H).
实施例72：N-(3-(2-((6-(4-((3R,5R,7R)-金刚烷-1-羰基)哌嗪-1-基)-4-甲氧基吡啶-3-基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-72)
Figure PCTCN2022079597-appb-000135
化合物ZX-HYT-72的合成方法参照实施例32。HRMS(ESI)for C 39H 44N 8O 4[M+H] +:calcd,689.3558；found,689.3562. 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),8.72(s,1H),8.52(s,1H),7.84(s,1H),7.66–7.54(m,1H),7.46(s,1H),7.37(s,1H),6.84(s,1H),6.34–6.24(m,2H),3.78–3.65(m,7H),3.49–3.39(m,4H),2.42(s,3H),2.05–1.88(m,9H),1.80–1.63(m,7H),0.82–0.73(m,4H).
实施例73：N-(3-(2-((4-((2-(2-((3R,5R,7R)-金刚烷-1-基)-N-甲基乙酰氨基)乙基)(甲基)氨基)-2-甲氧基苯基))氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-73)
Figure PCTCN2022079597-appb-000136
化合物ZX-HYT-73的合成方法参照实施例32。HRMS(ESI)for C 41H 49N 7O 4[M+H] +:calcd,704.3919；found,704.3923. 1H NMR(400MHz,DMSO-d 6)δ10.35(s,1H),8.79(s,1H),8.34(s,1H),7.77–7.66(m,1H),7.50–7.40(m,3H),6.90(d,J＝7.8Hz,1H),6.30(s,1H),5.86(s,1H),3.80(s,3H),3.67(s,3H),3.42–3.36(m,4H),3.16(s,3H),2.45(s,3H),2.16(s,2H),1.97–1.89(m,3H),1.82–1.72(m,1H),1.71–1.58(m,12H),0.85–0.73(m,4H).
实施例74：2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-8-(3-((4-甲基哌嗪-1-基)甲基)苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-74)
Figure PCTCN2022079597-appb-000137
化合物ZX-HYT-74的合成方法参照实施例18。MS(ESI),m/z:730.9[M+H] +. 1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.49(s,1H),7.81(p,J＝1.3Hz,1H),7.42(dt,J＝7.5,1.5Hz,1H),7.34(t,J＝7.5Hz,1H),7.13(dddd,J＝7.5,2.6,1.7,1.1Hz,1H),7.07(d,J＝7.5Hz,1H),6.74(dd,J＝7.5,1.5Hz,1H),6.58(q,J＝0.9Hz,1H),6.30(d,J＝1.5Hz,1H),3.87(s,3H),3.68(t,J＝7.0Hz,4H),3.54(t,J＝1.0Hz,2H),3.32(t,J＝7.1Hz,4H),3.02(t,J＝7.1Hz,4H),2.49– 2.43(m,7H),2.33(d,J＝8.8Hz,5H),2.00(s,3H),1.67–1.57(m,12H).
实施例75：2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-8-(4-氟-3-((4-甲基哌嗪-1-基)甲基)苯基)-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-75)
Figure PCTCN2022079597-appb-000138
化合物ZX-HYT-75的合成方法参照实施例18。MS(ESI),m/z:748.9[M+H] +. 1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.78(s,1H),7.85(dq,J＝4.9,1.1Hz,1H),7.41(ddd,J＝7.5,4.9,1.5Hz,1H),7.27–7.18(m,1H),7.07(d,J＝7.5Hz,1H),6.74(dd,J＝7.5,1.5Hz,1H),6.58(q,J＝0.9Hz,1H),6.30(d,J＝1.5Hz,1H),3.89(s,3H),3.67(t,J＝7.0Hz,4H),3.61(d,J＝1.1Hz,2H),3.31(t,J＝7.1Hz,4H),2.59(td,J＝6.9,0.8Hz,4H),2.48–2.42(m,7H),2.33(d,J＝9.0Hz,5H),2.10(s,3H),1.69–1.51(m,12H).
实施例76：2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-8-(3-((4-甲基哌嗪-1-基)甲基)-4-(三氟甲基)苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-76)
Figure PCTCN2022079597-appb-000139
化合物ZX-HYT-76的合成方法参照实施例18。MS(ESI),m/z:798.9[M+H] +. 1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.49(s,1H),7.60–7.54(m,2H),7.42(dd,J＝7.4,1.5Hz, 1H),7.07(d,J＝7.5Hz,1H),6.74(dd,J＝7.5,1.5Hz,1H),6.58(q,J＝0.9Hz,1H),6.30(d,J＝1.5Hz,1H),3.89(s,2H),3.81–3.64(m,6H),3.31(t,J＝7.1Hz,4H),2.67(td,J＝7.0,0.8Hz,4H),2.49–2.42(m,7H),2.34(d,J＝10.2Hz,4H),2.16(s,3H),1.67–1.57(m,12H).
实施例77：3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-(1-甲基氮杂环丁烷-3-基)苯甲酰胺(ZX-HYT-77)
Figure PCTCN2022079597-appb-000140
化合物ZX-HYT-77的合成方法参照实施例18。MS(ESI),m/z:730.9[M+H] +. 1H NMR(500MHz,Chloroform-d)δ9.09(s,1H),8.68(s,1H),8.29(t,J＝1.5Hz,1H),7.79(d,J＝9.5Hz,1H),7.71(dt,J＝7.3,1.5Hz,1H),7.52(dt,J＝7.5,1.5Hz,1H),7.41(t,J＝7.5Hz,1H),7.07(d,J＝7.5Hz,1H),6.74(dd,J＝7.5,1.5Hz,1H),6.59(q,J＝1.0Hz,1H),6.30(d,J＝1.5Hz,1H),4.14(dp,J＝9.5,7.0Hz,1H),3.87(s,3H),3.68(t,J＝7.0Hz,4H),3.32(t,J＝7.1Hz,4H),3.16(dd,J＝12.4,7.0Hz,2H),2.94(dd,J＝12.4,7.1Hz,2H),2.47(d,J＝1.1Hz,3H),2.34(s,2H),2.24(s,3H),1.98(s,3H),1.69–1.50(m,12H).
实施例78：4-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-(1-甲基氮杂环丁烷-3-基)吡啶酰胺(ZX-HYT-106)
Figure PCTCN2022079597-appb-000141
化合物ZX-HYT-78的合成方法参照实施例18。MS(ESI),m/z:732.3[M+H] +. 1H NMR(500MHz,Chloroform-d)δ9.07(s,1H),8.75(d,J＝1.5Hz,1H),8.48(s,1H),8.43(d,J＝7.5Hz,1H),8.33(dd,J＝7.4,1.5Hz,1H),7.99(d,J＝10.3Hz,1H),7.07(d,J＝7.5Hz,1H),6.74(dd,J＝7.5,1.5Hz,1H),6.58(q,J＝1.0Hz,1H),6.30(d,J＝1.5Hz,1H),4.14(dp,J＝9.5,7.0Hz,1H),3.87(s,3H),3.68(t,J＝7.0Hz,4H),3.32(t,J＝7.1Hz,4H),3.16(dd,J＝12.4,7.0Hz,2H),2.94(dd,J＝12.4,7.1Hz,2H),2.47(d,J＝1.1Hz,3H),2.34(s,2H),2.24(s,3H),1.98(s,3H),1.69–1.50(m,12H).
实施例79：5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-2-氟-N-(1-甲基氮杂环丁烷-3-基)苯甲酰胺(ZX-HYT-79)
Figure PCTCN2022079597-appb-000142
化合物ZX-HYT-79的合成方法参照实施例18。MS(ESI),m/z:749.3[M+H] +. 1H NMR(600MHz,Chloroform-d)δ8.65(s,1H),8.01(dd,J＝6.9,2.7Hz,1H),7.76(s,1H),7.45–7.27(m,3H),6.81(dd,J＝12.2,3.2Hz,1H),6.44(s,1H),6.37(s,1H),6.05(s,1H),3.84(s,3H),3.82–3.78(m,4H),3.72–3.67(m,4H),3.51-3.16(m,4H),2.93(tq,J＝7.2,3.6Hz,1H),2.62(s,3H),2.46(s,3H),2.20(s,2H),2.00–1.97(m,3H),1.72–1.65(m,12H).
实施例80：5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-(1-甲基氮杂环丁烷-3-基)-2-(三氟甲基)苯甲酰胺(ZX-HYT-80)
Figure PCTCN2022079597-appb-000143
化合物ZX-HYT-80的合成方法参照实施例18。MS(ESI),m/z:799.3[M+H] +. 1H NMR(400MHz,Chloroform-d)δ9.07(s,1H),8.48(s,1H),8.02(d,J＝1.5Hz,1H),7.67(d,J＝7.4Hz,1H),7.56(dd,J＝7.5,1.6Hz,1H),7.32(d,J＝9.7Hz,1H),7.07(d,J＝7.5Hz,1H),6.74(dd,J＝7.5,1.5Hz,1H),6.57(q,J＝0.9Hz,1H),6.30(d,J＝1.5Hz,1H),4.31-4.14(m,1H),3.86(s,2H),3.68(t,J＝7.0Hz,4H),3.32(t,J＝7.1Hz,4H),3.17(dd,J＝12.5,7.0Hz,2H),2.95(dd,J＝12.4,7.0Hz,2H),2.47(d,J＝1.1Hz,3H),2.34-2.25(m,4H),2.12(s,3H),1.7–1.57(m,12H).
实施例81：N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)-1-氨基环丙烷-1-甲酰胺(ZX-HYT-81)
Figure PCTCN2022079597-appb-000144
化合物ZX-HYT-81的合成方法参照实施例18。MS(ESI),m/z:717.3[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),8.80(s,1H),8.13(s,1H),7.87(s,1H),7.60(s,1H),7.48(t,J＝8.1Hz,1H),7.28(d,J＝8.8Hz,1H),6.95(d,J＝7.8Hz,1H),6.57(s,1H),6.32(s,1H),6.06(s,1H),3.79(s,3H),3.70–3.55(m,4H),3.11–2.92(m,4H),2.46(s,3H),2.16(s,2H),1.93(s,3H),1.74–1.50(m,12H),1.21–1.09(m,2H),0.93–0.80(m,2H).
实施例82：N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)-2-氨基乙酰胺(ZX-HYT-82)
Figure PCTCN2022079597-appb-000145
化合物ZX-HYT-82的合成方法参照实施例18。MS(ESI),m/z:691.3[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),8.81(s,1H),8.11(s,1H),7.87(s,1H),7.60(s,1H),7.48(t,J＝8.1Hz,1H),7.28(d,J＝8.8Hz,1H),6.95(d,J＝7.8Hz,1H),6.57(s,1H),6.32(s,1H),6.06(s,1H),4.12(s,2H),3.79(s,3H),3.70–3.55(m,4H),3.11–2.92(m,4H),2.46(s,3H),2.16(s,2H),1.93(s,3H),1.74–1.50(m,12H).
实施例83：N-(3-(2-((4-(4-(((3R,5R,7R)-金刚烷-1-基)甲基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基)-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-83)
Figure PCTCN2022079597-appb-000146
将化合物29(0.13g，0.25mmol)，1-金刚烷甲醛(0.041g，0.025mmol)和氰基硼氢化钠(0.032g，0.5mmol)依次加入10mL二氯甲烷中。室温条件下搅拌2h。TLC检测，反应完全后蒸干反应液。剩下的固体残余物经柱层析纯化(三氯甲烷/甲醇＝40:1洗脱)，得黄色粉末状目标化合物ZX-HYT-83(0.11g，收率65％)。HRMS(ESI)for C 40H 47N 7O 3[M+H] +:calcd,674.3813；found,674.3824. 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),8.82(s,1H),8.24(s,1H),7.81(s,1H),7.64–7.43(m,2H),7.29(d,J＝8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.70–3.57(m,4H),3.09–2.94(m,4H),2.46 (s,3H),2.16(s,2H),1.94(s,3H),1.79(p,J＝6.3Hz,1H),1.72–1.61(m,12H),0.87–0.71(m,4H).
实施例84：N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-84)
Figure PCTCN2022079597-appb-000147
化合物ZX-HYT-84的合成方法参照实施例83。HRMS(ESI)for C 41H 49N 7O 3[M+H] +:calcd,688.3970；found,688.3981. 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),8.82(s,1H),8.24(s,1H),7.81(s,1H),7.64–7.43(m,2H),7.29(d,J＝8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.70–3.57(m,4H),3.09–2.94(m,4H),2.46(s,3H),2.26(s,2H),1.95(s,3H),1.79(p,J＝6.4Hz,1H),1.72–1.63(m,14H),0.88–0.70(m,4H).
实施例85：N-(3-(2-((4-(((3S,5S,7S)-金刚烷-1-基)氨基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-)d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-85)
Figure PCTCN2022079597-appb-000148
化合物ZX-HYT-85的合成方法参照实施例25。HRMS(ESI)for C 35H 38N 6O 3[M+H] +:calcd,591.7355；found,591.9362. 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),8.82(s,1H),8.24(s,1H),7.81(s,1H),7.64–7.43(m,2H),7.29(d,J＝8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),5.83(s,1H),3.80(s,3H),2.46(s,3H),1.95(s,3H),1.79 (p,J＝6.4Hz,1H),1.74–1.63(m,12H),0.88–0.71(m,4H).
实施例86：N-(3-(2-((4-((3R,5R,7R)-金刚烷-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶)-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-86)
Figure PCTCN2022079597-appb-000149
化合物ZX-HYT-86的合成方法参照实施例25。HRMS(ESI)for C 35H 37N 5O 3[M+H] +:calcd,576.2969；found,576.2971. 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),8.82(s,1H),8.24(s,1H),7.81(s,1H),7.64–7.43(m,2H),7.29(d,J＝8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),2.46(s,3H),1.95(s,3H),1.79(p,J＝6.4Hz,1H),1.74–1.63(m,12H),0.88–0.71(m,4H).
实施例87：N-((3S,5S,7S)-金刚烷-1-基)-1-(4-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)氮杂环丁烷-3-甲酰胺(ZX-HYT-87)
Figure PCTCN2022079597-appb-000150
化合物ZX-HYT-87的合成方法参照实施例25。HRMS(ESI)for C 39H 43N 7O 4[M+H] +:calcd,674.3449；found,674.3452. 1H NMR(400MHz,DMSO-d 6)δ10.37(s,1H),8.77(s,1H),8.02(s,1H),7.79–7.65(m,1H),7.53–7.47(m,1H),7.44(t,J＝8.0Hz,1H),7.16(d,J＝8.7Hz,1H),6.93(d,J＝7.8Hz,1H),6.31–6.26(m,2H),5.93(s,1H),5.62(s,1H),3.97(s,3H),3.77–3.59(m,4H),2.44(s,3H),1.93–1.86(m,3H),1.81–1.73(m,2H),1.68–1.49(m,12H),0.83–0.70(m,4H).
实施例88：N-(5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-2-氟苯基)-2-氨基乙酰胺(ZX-HYT-88)
Figure PCTCN2022079597-appb-000151
化合物ZX-HYT-88的合成方法参照实施例18。MS(ESI),m/z:709.8[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),8.91(s,1H),8.18(s,1H),7.87(s,1H),7.60(s,1H),7.4(d,J＝7.8Hz,1H),6.98(d,J＝7.8Hz,1H),6.57(s,1H),6.32(s,1H),6.06(s,1H),4.12(s,2H),3.79(s,3H),3.70–3.55(m,4H),3.11–2.92(m,4H),2.46(s,3H),2.16(s,2H),1.93(s,3H),1.74–1.50(m,12H).
实施例89：N-(((3R,5R,7R)-金刚烷-1-基)甲基)-1-(4-((8-(3-(环丙烷甲酰胺基)苯基)-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基苯基)哌啶-4-甲酰胺(ZX-HYT-89)
Figure PCTCN2022079597-appb-000152
化合物ZX-HYT-89的合成方法参照实施例25。HRMS(ESI)for C 42H 49N 7O 4[M+H] +:calcd,716.3919；found,716.3921. 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.80(s,1H),8.10(s,1H),7.84–7.75(m,1H),7.70–7.63(m,1H),7.51–7.42(m,2H),7.26(d,J＝8.8Hz,1H),6.92(d,J＝7.9Hz,1H),6.53(s,1H),6.31(s,1H),6.03(s,1H),3.78(s,3H),3.67–3.56(m,2H),2.81–2.75(m,2H),2.64–2.54(m,2H),2.45(s,3H),2.37–2.28(m,1H),1.97–1.87(m,3H),1.82–1.53(m,11H),1.49–1.37(m,6H),0.83–0.71(m,4H).
实施例90：N-(3-(2-((4-(5-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)-2,5-二氮杂双环)[2.2.2]辛烷-2-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-90)
Figure PCTCN2022079597-appb-000153
化合物ZX-HYT-90的合成方法参照实施例25。HRMS(ESI)for C 43H 49N 7O 4[M+H] +:calcd,728.9175；found,728.9182. 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H),8.76(s,1H),8.02(s,1H),7.79–7.65(m,1H),7.53–7.47(m,1H),7.44(t,J＝8.0Hz,1H),7.16(d,J＝8.7Hz,1H),6.93(d,J＝7.8Hz,1H),6.32–6.22(m,2H),5.62(s,1H),3.98–3.87(m,4H),3.77–3.59(m,5H),3.29–3.22(m,2H),2.44(s,3H),1.93–1.86(m,3H),1.85–1.73(m,5H),1.68–1.49(m,12H),0.83–0.70(m,4H).
实施例91：N-(3-(2-((4-(6-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)-2,6-二氮杂螺[3.3]庚-2-基))-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-91)
Figure PCTCN2022079597-appb-000154
化合物ZX-HYT-91的合成方法参照实施例25。HRMS(ESI)for C 42H 47N 7O 4[M+H] +:calcd,714.3762；found,714.3774. 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H),8.76(s,1H),8.02(s,1H),7.79–7.65(m,1H),7.53–7.47(m,1H),7.44(t,J＝8.0Hz,1H),7.16(d,J＝8.7Hz, 1H),6.93(d,J＝7.8Hz,1H),6.32–6.22(m,2H),5.62(s,1H),3.98–3.87(m,4H),3.77–3.59(m,5H),3.29–3.22(m,2H),2.44(s,3H),1.93–1.86(m,3H),1.85–1.73(m,3H),1.68–1.49(m,12H),0.83–0.70(m,4H).
实施例92：N-(3-(2-((4-(2-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)-2,7-)二氮杂螺[3.5]壬-7-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-92)
Figure PCTCN2022079597-appb-000155
化合物ZX-HYT-92的合成方法参照实施例25。HRMS(ESI)for C 44H 51N 7O 4[M+H] +:calcd,742.4075；found,742.4082. 1H NMR(400MHz,DMSO-d 6)δ10.36(s,1H),8.76(s,1H),8.02(s,1H),7.79–7.65(m,1H),7.53–7.47(m,1H),7.44(t,J＝8.0Hz,1H),7.16(d,J＝8.7Hz,1H),6.93(d,J＝7.8Hz,1H),6.32–6.22(m,2H),5.62(s,1H),3.98–3.87(m,7H),3.77–3.59(m,4H),3.29–3.22(m,2H),2.44(s,3H),1.93–1.86(m,3H),1.85–1.73(m,5H),1.68–1.49(m,12H),0.83–0.70(m,4H).
实施例93：N-(3-(2-((4-(5-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)苯基)环丙烷甲酰胺(ZX-HYT-93)
Figure PCTCN2022079597-appb-000156
化合物ZX-HYT-93的合成方法参照实施例25。HRMS(ESI)for C 43H 49N 7O 4[M+H] +:calcd,728.3919；found,728.3919. 1H NMR(400MHz,DMSO-d 6)δ10.37(s,1H),8.81(s,1H),8.14(s,1H),7.80(s,1H),7.54–7.41(m,2H),7.29(d,J＝8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.70–3.57(m,4H),3.09–2.94(m,4H),2.46(s,3H),2.16(s,2H),1.94(s,3H),1.81-1.74(m,1H),1.69–1.53(m,14H),0.82–0.73(m,4H).
实施例94：N-(5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-2-氟苯基)环丙烷甲酰胺(ZX-HYT-94)
Figure PCTCN2022079597-appb-000157
化合物ZX-HYT-94的合成方法参照实施例20。HRMS(ESI)for C 41H 46FN 7O 4[M+H] +:calcd,720.3668；found,720.3673. 1H NMR(400MHz,DMSO-d 6)δ10.49(s,1H),8.82(s,1H),8.51(s,1H),7.83(s,1H),7.67–7.56(m,1H),7.42(s,1H),7.31(s,1H),6.91–6.74(m,1H),6.40–6.20(m,2H),3.73(s,3H),3.64–3.55(m,4H),3.51–3.39(m,4H),2.42(s,3H),2.21–2.12(m,2H),1.93(s,3H),1.81–1.73(m,1H),1.72–1.54(m,12H),0.83–0.72(m,4H).
实施例95：N-(5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-2-(三氟甲基)苯基)环丙烷甲酰胺(ZX-HYT-95)
Figure PCTCN2022079597-appb-000158
化合物ZX-HYT-95的合成方法参照实施例20。HRMS(ESI)for C 42H 46F 3N 7O 4[M+H] +:calcd,770.3636；found,770.3641. 1H NMR(600MHz,DMSO-d 6)δ10.19(s,1H),8.77(s,1H),8.51(s,1H),7.88(s,1H),7.68–7.55(m,1H),7.41(s,1H),7.30(s,1H),6.91–6.74(m,1H),6.40–6.20(m,2H),3.73(s,3H),3.64–3.55(m,4H),3.51–3.39(m,4H),2.42(s,3H),2.21–2.12(m,2H),1.93(s,3H),1.81–1.73(m,1H),1.72–1.54(m,12H),0.83–0.72(m,4H).
实施例96：N-(4-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)吡啶-2-基)环丙烷甲酰胺(ZX-HYT-96)
Figure PCTCN2022079597-appb-000159
化合物ZX-HYT-96的合成方法参照实施例20。HRMS(ESI)for C 40H 46N 8O 4[M+H] +:calcd,703.3715；found,703.3723. 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),8.77(s,1H),8.51(s,1H),7.88(s,1H),7.68–7.59(m,1H),7.31(s,1H),7.21(s,1H),6.91–6.74(m,1H),6.40–6.20(m,2H),3.73(s,3H),3.64–3.55(m,4H),3.51–3.39(m,4H),2.42(s,3H),2.21–2.12(m,2H),1.93(s,3H),1.81–1.73(m,1H),1.72–1.54(m,12H),0.83–0.72(m,4H).
实施例97：2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-8-(3-((环丙基甲基)氨基)苯基)-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-97)
Figure PCTCN2022079597-appb-000160
化合物ZX-HYT-97的合成方法参照实施例18。HRMS(ESI)for C 41H 49N 7O 3[M+H] +: calcd,688.3970；found,688.3965. 1H NMR(400MHz,DMSO-d 6)δ10.39(s,1H),8.81(s,1H),8.14(s,1H),7.80(s,1H),7.54–7.41(m,2H),7.29(d,J＝8.8Hz,1H),6.98–6.87(m,1H),6.66–6.50(m,1H),6.33(s,1H),6.03(s,1H),3.80(s,3H),3.70–3.57(m,4H),3.24(dd,J＝7.0,5.9Hz,2H),3.09–2.94(m,4H),2.46(s,3H),2.16(s,2H),1.94(s,3H),1.71–1.60(m,1H),1.69–1.60(m,12H),0.82–0.73(m,4H).
实施例98：2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-8-(3-吗啉代苯基)吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-98)
Figure PCTCN2022079597-appb-000161
化合物ZX-HYT-98的合成方法参照实施例18。HRMS(ESI)for C 43H 54N 8O 3[M+H] +:calcd,731.4392；found,731.4395. 1H NMR(500MHz,DMSO-d 6)δ8.77(s,1H),8.09(s,1H),7.37(t,J＝8.0Hz,1H),7.29(d,J＝8.8Hz,1H),7.07(d,J＝8.5Hz,1H),6.85(d,J＝2.3Hz,1H),6.69–6.63(m,1H),6.57(d,J＝2.5Hz,1H),6.29(s,1H),5.99(s,1H),3.77(s,3H),3.68(t,J＝4.9Hz,4H),3.62(dq,J＝11.0,5.4,5.0Hz,4H),3.10(q,J＝5.0Hz,4H),3.04–2.94(m,4H),2.43(s,3H),2.14(t,J＝4.5Hz,2H),1.91(s,3H),1.67–1.54(m,12H).
实施例99：N-(3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-5-(三氟甲基)苯基)-2-氨基乙酰胺(ZX-HYT-99)
Figure PCTCN2022079597-appb-000162
化合物ZX-HYT-99的合成方法参照实施例18。MS(ESI),m/z:759.8[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ10.19(s,1H),8.91(s,1H),8.18(s,1H),7.90(s,1H),7.78(s,1H),7.4(d,J＝7.8Hz,1H),6.98(d,J＝7.8Hz,1H),6.57(s,1H),6.32(s,1H),6.06(s,1H),4.12(s,2H),3.79(s,3H),3.70–3.55(m,4H),3.11–2.92(m,4H),2.46(s,3H),2.16(s,2H),1.93(s,3H),1.74–1.50(m,12H).
实施例100：5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-环丙基-2-氟苯甲酰胺(ZX-HYT-100)
Figure PCTCN2022079597-appb-000163
化合物ZX-HYT-100的合成方法参照实施例18。MS(ESI),m/z:720.4[M+H] +. 1H NMR(600MHz,Chloroform-d)δ8.65(s,1H),8.01(dd,J＝6.9,2.7Hz,1H),7.76(s,1H),7.45–7.27(m,3H),6.81(dd,J＝12.2,3.2Hz,1H),6.44(s,1H),6.37(s,1H),6.05(s,1H),3.84(s,3H),3.82–3.78(m,2H),3.72–3.67(m,2H),3.06(dt,J＝14.9,4.9Hz,4H),2.93(tq,J＝7.2,3.6Hz,1H),2.46(s,3H),2.20(s,2H),2.00–1.97(m,3H),1.72–1.65(m,12H),0.91–0.86(m,2H),0.65–0.61(m,2H).
实施例101：8-(3-(1H-咪唑-1-基)苯基)-2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-yl)-2-甲氧基苯基)氨基)-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(ZX-HYT-101)
Figure PCTCN2022079597-appb-000164
化合物ZX-HYT-101的合成方法参照实施例18。MS(ESI),m/z:685.1[M+H] +. 1H NMR (400MHz,DMSO-d 6)δ10.19(s,1H),8.91(s,1H),8.18(s,1H),7.87(s,1H),7.72(s,1H),7.46–7.59(m,2H),7.4(d,J＝7.8Hz,1H),7.18(s,1H),6.98(d,J＝7.8Hz,1H),6.57(s,1H),6.32(s,1H),6.06(s,1H),3.79(s,3H),3.70–3.55(m,4H),3.11–2.92(m,4H),2.46(s,3H),2.16(s,2H),1.93(s,3H),1.74–1.50(m,12H).
实施例102：4-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-环丙基吡啶酰胺(ZX-HYT-102)
Figure PCTCN2022079597-appb-000165
化合物ZX-HYT-102的合成方法参照实施例18。MS(ESI),m/z:703.3[M+H] +. 1H NMR(600MHz,Chloroform-d)δ8.72(d,J＝5.1Hz,1H),8.68(s,1H),8.20(s,1H),8.11(d,J＝3.9Hz,1H),7.42(dd,J＝6.1,4.3Hz,1H),7.26(s,1H),6.43(s,1H),6.37(s,1H),3.84(s,3H),3.81(t,J＝5.2Hz,2H),3.68(t,J＝5.1Hz,2H),3.05(s,4H),2.98(dq,J＝7.2,3.6Hz,1H),2.48(s,3H),2.20(s,2H),1.99(s,3H),1.73–1.65(m,12H),0.94–0.89(m,2H),0.72–0.67(m,2H).
实施例103：3-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-环丙基苯甲酰胺(ZX-HYT-103)
Figure PCTCN2022079597-appb-000166
化合物ZX-HYT-103的合成方法参照实施例18。MS(ESI),m/z:702.4[M+H] +. 1H NMR(500MHz,Chloroform-d)δ8.63(s,1H),8.10–7.97(m,1H),7.83(s,1H),7.64(t,J＝7.8Hz,1H), 7.58(t,J＝1.9Hz,1H),7.40(d,J＝7.8Hz,1H),7.26(s,1H),6.50(d,J＝3.2Hz,1H),6.41(d,J＝2.6Hz,1H),6.35(d,J＝1.4Hz,1H),6.02(s,1H),3.83(s,3H),3.82–3.76(m,2H),3.73–3.64(m,2H),3.12–2.99(m,4H),2.84(tq,J＝7.2,3.7Hz,1H),2.45(s,3H),2.21(s,2H),2.03–1.90(m,3H),1.77–1.54(m,12H),0.85–0.74(m,2H),0.59–0.45(m,2H).
实施例104：5-(2-((4-(4-(2-((3R,5R,7R)-金刚烷-1-基)乙酰基)哌嗪-1-基)-2-甲氧基苯基)氨基)-5-甲基-7-氧代吡啶并[2,3-d]嘧啶-8(7H)-基)-N-环丙基-2-(三氟甲基)苯甲酰胺(ZX-HYT-104)
Figure PCTCN2022079597-appb-000167
化合物ZX-HYT-104的合成方法参照实施例18。MS(ESI),m/z:770.2[M+H] +. 1H NMR(600MHz,Chloroform-d)δ8.66(s,1H),7.90(d,J＝8.2Hz,1H),7.80(s,1H),7.52–7.45(m,2H),7.21(s,1H),6.49–6.40(m,1H),6.37(s,1H),6.15(s,1H),5.90(s,1H),3.85(s,3H),3.83–3.74(m,2H),3.71–3.64(m,2H),3.13–3.04(m,4H),2.83(q,J＝3.6Hz,1H),2.48(s,3H),2.24–2.19(m,2H),1.99(s,3H),1.75–1.63(m,12H),0.84–0.78(m,2H),0.56–0.47(m,2H).
实施例105：化合物对H1975OR细胞中AKT3蛋白水平的影响
细胞株：非小细胞肺癌H1975-OR细胞株。该细胞株为Osimertinib耐药H1975细胞株，通过低剂量逐渐递加法培养获得。具体方法：将H1975细胞以60-70％汇合度铺于10cm培养皿中，添加50nM的Osimertinib于培养基中，待细胞状态稳定后，逐渐将Osimertinib浓度加倍培养至3μM。经基因检测，获得的耐药细胞株(H1975-OR)相对于原H1975细胞株存在AKT3显著高表达。
使用常规Western Blot(免疫印迹法)进行检测，具体如下。将H1975-OR细胞按一定数量种于96孔板，培养箱内贴壁培养过夜后，加入一定浓度的化合物作用24小时。用带有蛋白酶和磷酸酶抑制剂的1×SDS裂解缓冲液裂解细胞。通过SDS-PAGE分离细胞裂解物，并转移至PVDF膜上。然后，在室温下，将PCDF膜取出浸于封闭液(含0.5％Tween-20的5％BSA TBS溶液)中封闭处理1小时，然后在4℃下与对特定的一抗孵育过夜。用TBST洗涤印迹， 并在室温下与辣根过氧化物酶(HRP)标记的二抗孵育2小时。最后用ECLplus荧光检测试剂(Thermo Scientific,Waltham,MA)进行蛋白显影，并使用Amersham Imager 600系统(GE,America)进行拍照。检测结果使用ImageJ软件分别进行灰度处理，得到灰度值G(Density)，使用以下公式计算蛋白最大降解率(Maximal degradation rate，Dmax)：Dmax＝1-(Gmax-Gmin)/Gmax×100％，其中，Gmax＝空白对照组Density (目的蛋白条带)/Density (对应GAPDH)；Gmin为化合物处理组观察到目标蛋白降解最大值时的Density (目的蛋白条带)/Density (对应GAPDH)。所得结果以Dmax(％)呈现，如表1所示。
表1化合物诱导H1975-OR细胞中AKT1、AKT2和AKT3蛋白降解的能力
Figure PCTCN2022079597-appb-000168
实施例106：化合物ZX-HYT-11对其他肿瘤细胞中AKT1/2/3蛋白的影响
将肿瘤细胞(H1975,PC-9,H1299和A549)分别与不同给定浓度的化合物ZX-HYT-11一起孵育24小时，然后使用实施例105所述的免疫印迹法分析AKT1/2/3的蛋白水平。结果显示(图1)，化合物ZX-HYT-11能选择性地降解上述细胞中的AKT3蛋白，而对AKT1/2 无影响，进一步表明：该化合物降解AKT3蛋白的有效性和普适性。
实施例107：化合物对肿瘤细胞的增殖抑制活性
将肿瘤细胞(见表2-表5)接种于完全培养基中的96孔板中(2000-3000个/孔)。孵育过夜后，用不同浓度(0.000508～10μM)的化合物分别处理细胞72小时。用CCK-8(Cell Counting Kit 8,Dojindo Laboratories,Kumamoto,Japan)实验评估细胞增殖情况。使用GraphPad Prism 5.0软件(GraphPad Software，La Jolla，CA)通过浓度响应曲线拟合计算半数最大抑制浓度(IC 50)值。每个IC 50值均表示为平均值±SD。结果如表2-5所示。
表2化合物对多种肿瘤细胞的增殖抑制活性
Figure PCTCN2022079597-appb-000169
Figure PCTCN2022079597-appb-000170
表3化合物对PC-9等肿瘤细胞的增殖抑制活性
Figure PCTCN2022079597-appb-000171
表4化合物对MDA-MB-231等肿瘤细胞的增殖抑制活性
Figure PCTCN2022079597-appb-000172
Figure PCTCN2022079597-appb-000173
表5化合物对A549等肿瘤细胞的增殖抑制活性
Figure PCTCN2022079597-appb-000174
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对以下实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (27)

  1. 具有式(Ⅰ)所示结构的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子：
    Figure PCTCN2022079597-appb-100001
    其中：
    E选自：氢，C 1-C 15烷基，取代的C 1-C 15烷基，C 3-C 15环烷基，取代的C 3-C 15环烷基，3-15元杂环烷基，取代的3-15元杂环烷基；
    L不存在或者为由如下基团中的一个或多个组成的连接单元：亚烷基，醚基，硫醚基，酯基，胺基，酰胺基，杂芳基，环烷基，杂环烷基，-N＝N-；
    Y选自：不存在或者-O-，-NH-，-NHCO-，-CH 2-，-S-，-CO-；
    Z选自：不存在或者-O-，-NH-，-N(C 1-C 6烷基)-，-NHCO-，-CH 2-，-S-，-CO-，-SO-；
    R 1选自：氢，C 1-C 6烷基，卤素或卤素取代的C 1-C 6烷基；
    R 2选自：C 3-C 15环烷基，取代的C 3-C 15环烷基，3-15元杂环烷基，取代的3-15元杂环烷基，C 6-C 10芳基，取代的C 6-C 10芳基，5-10元杂芳基，取代的5-10元杂芳基；
    R 3为：
    Figure PCTCN2022079597-appb-100002
    其中，B通过共价键与Y连接；
    A选自：-NH-，-NHR-；R选自：C 6-C 10芳基，取代的C 6-C 10芳基，5-10元杂芳基，取代的5-10元杂芳基；
    B不存在或者选自：C 3-C 15环烷基，取代的C 3-C 15环烷基，3-15元杂环烷基，取代的3-15元杂环烷基，3-15元杂环烷酮基，R 8取代的3-15元杂环烷酮基，C 3-C 12环烷基取代的胺基，3-12元杂环烷基取代的胺基，
    Figure PCTCN2022079597-appb-100003
    Figure PCTCN2022079597-appb-100004
  2. 根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，E选自：氢，C 1-C 8烷基，R 5取代的C 1-C 8烷基，C 3-C 12环烷基，R 6取代的C 3-C 12环烷基，3-12元杂环烷基，R 6取代的3-12元杂环烷基；
    R 5选自：卤素，C 3-C 12环烷基，C 1-C 3烷基取代的C 3-C 12环烷基，卤素取代的C 3-C 12环烷基；
    R 6选自：卤素，C 1-C 6烷基，卤素取代的C 1-C 6烷基。
  3. 根据权利要求2所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，E选自：氢，C 1-C 6烷基，R 5取代的C 1-C 6烷基，C 3-C 10环烷基，R 6取代的C 3-C 10环烷基；
    R 5选自：卤素，C 6-C 10环烷基，甲基取代的C 6-C 10环烷基，卤素取代的C 6-C 10环烷基；
    R 6选自：卤素，C 1-C 3烷基。
  4. 根据权利要求2所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，E选自：氢，环丙基，
    Figure PCTCN2022079597-appb-100005
    Figure PCTCN2022079597-appb-100006
    其中x为0-3的整数，y为0-3的整数。
  5. 根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，L选自：
    Figure PCTCN2022079597-appb-100007
    Figure PCTCN2022079597-appb-100008
    Figure PCTCN2022079597-appb-100009
    其中n，m分别独立地为0-14的整数。
  6. 根据权利要求5所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，L选自：
    Figure PCTCN2022079597-appb-100010
    Figure PCTCN2022079597-appb-100011
    其中n为0-7的整数，m为0-3的整数。
  7. 根据权利要求6所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，L选自：
    Figure PCTCN2022079597-appb-100012
    Figure PCTCN2022079597-appb-100013
    或者L不存在，其中n为2-7的整数。
  8. 根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，Y选自：-CH 2-，-CO-，-O-，或者Y不存在；Z选自：-NHCO-，-NH-，或者Z不存在。
  9. 根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 1选自：氢，卤素，C 1-C 3烷基。
  10. 根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 2选自：C 5-C 10环烷基，R 9取代的C 5-C 10环烷基，5-10元杂环烷基，R 9取代的5-10元杂环烷基，C 6-C 10芳基，R 9取代的C 6-C 10芳基，5-10元杂芳基，R 9取代的5-10元杂芳基，5-10元杂芳酮基，R 9取代的5-10元杂芳酮基；
    R 9选自：氨基，-N(C 1-C 6烷基) 2，卤素，C 1-C 6烷基，C 1-C 6烷氧基，卤素取代的C 1-C 6烷基，卤素取代的C 1-C 6烷氧基，-NH(R 4)，-N(R 4) 2，-O(R 4)，-C＝O-NH(R 4)，-C＝O-NH(C 3-C 6环烷基)，R 10取代的C 1-C 6烷基，C 3-C 10环烷基，3-10元杂环烷基，R 10取代的C 3-C 10环烷基，R 10取代的3-10元杂环烷基，-NH(R 4)取代的3-10元杂环烷基，5-10元杂芳基，-COR 11；
    R 4选自：不存在或为氢，氨基，酯基，羧基，羟基，巯基，砜基，亚砜基，C 1-C 15烷基，R 10取代的C 1-C 15烷基，C 3-C 15环烷基，3-15元杂环烷基，R 10取代的C 3-C 15环烷基，R 10取代 的3-15元杂环烷基，-COR 11；
    R 10选自：C 1-C 6烷基，氨基取代的C 1-C 6烷基，C 3-C 6环烷基，二甲胺基取代的C 1-C 6烷基，3-6元杂环烷基，二甲胺基，C 1-C 3烷氧基取代的C 1-C 6烷基，羟基取代的C 1-C 6烷基，C 1-C 6烷基取代的3-6元杂环烷基，C 1-C 6烷基酰基，羟基，C 1-C 6烷基取代的C 3-C 6环烷基，二甲氨乙基取代的5-6元杂环烷基，C 1-C 6烷氧基；
    R 11选自：乙烯基，C 1-C 6烷基，氨基取代的C 1-C 6烷基，C 3-C 6环烷基，氨基取代的C 3-C 6环烷基，卤素取代的C 3-C 6环烷基，3-6元杂环烷基，C 1-C 6烷基取代的3-6元杂环烷基，二甲胺基取代的C 1-C 6烷基，二甲胺乙基取代的5-6元杂环烷基。
  11. 根据权利要求10所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 2选自：
    苯基，
    Figure PCTCN2022079597-appb-100014
    Figure PCTCN2022079597-appb-100015
    Figure PCTCN2022079597-appb-100016
    其中，R 4选自：
    H，
    Figure PCTCN2022079597-appb-100017
    Figure PCTCN2022079597-appb-100018
  12. 根据权利要求10所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 2选自：C 5-C 8环烷基，R 9取代的C 5-C 8环烷基，5-8元杂环烷基，R 9取代的5-8元杂环烷基，苯基，R 9取代的苯基，5-6元杂芳基，R 9取代的5-6元杂芳基；
    R 9选自：H，二甲胺基，氨基，卤素，C 1-C 3烷基，C 1-C 3烷氧基，卤素取代的C 1-C 3烷基，卤素取代的C 1-C 3烷氧基，-NH(R 4)，-N(R 4) 2，-OR 4，-C＝O-NH(环丙基)，R 10取代的C 1-C 3烷基，C 3-C 6环烷基，3-6元杂环烷基，R 10取代的C 3-C 6环烷基，R 10取代的3-6元杂环烷基，-NH(R 4) 取代的3-6元杂环烷基，-COR 11；
    R 4选自：H，C 1-C 6烷基，R 10取代的C 1-C 6烷基，C 3-C 6环烷基，3-6元杂环烷基，R 10取代的C 3-C 6环烷基，R 10取代的3-6元杂环烷基，-CH 2R 11，-COR 11；
    R 10选自：C 1-C 3烷基，二甲胺基，C 3-C 6环烷基，3-6元杂环烷基，C 1-C 3烷基取代的3-6元杂环烷基，C 1-C 3烷基取代的C 3-C 6环烷基；
    R 11选自：乙烯基，C 1-C 4烷基，C 3-C 6环烷基，卤素取代的C 3-C 6环烷基。
  13. 根据权利要求12所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 2选自：C 5-C 6环烷基，R 9取代的C 5-C 6环烷基，5-6元杂环烷基，R 9取代的5-6元杂环烷基，苯基，R 9取代的苯基；
    R 9选自：H、二甲胺基，氨基，C 1-C 3烷基，-NH(R 4)，-OR 4，-C＝O-NH(环丙基)，R 10取代的C 1-C 3烷基，C 3-C 6环烷基，5-6元杂环烷基，R 10取代的C 3-C 6环烷基，R 10取代的5-6元杂环烷基，-COR 11；
    R 4选自：H，C 1-C 3烷基，R 10取代的C 1-C 3烷基，C 3-C 6环烷基，5-6元杂环烷基，R 10取代的C 3-C 6环烷基，R 10取代的5-6元杂环烷基，-CH 2R 11，-COR 11；
    R 10选自：C 1-C 3烷基，C 3-C 6环烷基；
    R 11选自：乙烯基，C 1-C 4烷基，C 3-C 6环烷基。
  14. 根据权利要求12所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 2选自：
    Figure PCTCN2022079597-appb-100019
    其中，R 9选自：H，二甲胺基，C 1-C 3烷基，-NH(R 4)，-OR 4，-COR 11；
    R 4选自：H，甲基哌啶基，-CH 2R 11，-COR 11；R 11选自：乙烯基，C 1-C 4烷基，环丙基，环丁基，环戊基。
  15. 根据权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，
    A选自：-NH-，-NHR-；R选自：苯基，R 7取代的苯基，6元杂芳基，R 7取代的6元杂芳基；
    R 7选自：C 1-C 6烷基，C 3-C 6环烷基，卤素，C 1-C 6烷氧基，卤素取代的C 1-C 6烷氧基，氘代C 1-C 6烷氧基，卤素取代的C 1-C 6烷基，氰基取代的C 1-C 6烷基，氘代C 1-C 6烷基，三氟甲基取代的C 3-C 6环烷基，C 1-C 6烷基取代的C 3-C 6环烷基，羟基，氨基，-SO(C 1-C 6烷基)， -S(O) 2(C 1-C 6烷基)，C 1-C 6烷硫基；
    B不存在或者选自：C 3-C 12环烷基，R 8取代的C 3-C 12环烷基，3-12元杂环烷基，R 8取代的3-12元杂环烷基，3-12元杂环烷酮基，R 8取代的3-12元杂环烷酮基，C 3-C 12环烷基取代的胺基，3-12元杂环烷基取代的胺基，
    Figure PCTCN2022079597-appb-100020
    Figure PCTCN2022079597-appb-100021
    R 8选自：C 1-C 6烷基，C 3-C 12环烷基，3-12元杂环烷基，胺基，氰基取代的C 1-C 6烷基，卤素，C 1-C 6烷氧基，卤素取代的C 1-C 6烷基，羟基，氨基。
  16. 根据权利要求15所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，A选自：
    -NH-，
    Figure PCTCN2022079597-appb-100022
    Figure PCTCN2022079597-appb-100023
    Figure PCTCN2022079597-appb-100024
    B不存在或选自：
    Figure PCTCN2022079597-appb-100025
    Figure PCTCN2022079597-appb-100026
    Figure PCTCN2022079597-appb-100027
  17. 根据权利要求15所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，A选自：-NH-，-NHR-；R选自：苯基，6元杂芳基，R 7取代的苯基，R 7取代的6元杂芳基；
    R 7选自：C 1-C 3烷基，卤素，C 1-C 3烷氧基，卤素取代的C 1-C 3烷氧基，卤素取代的C 1-C 3烷基，氰基取代的C 1-C 3烷基；
    B不存在或者选自：C 4-C 12环烷基，R 8取代的C 4-C 12环烷基，4-12元杂环烷基，R 8取代的4-12元杂环烷基，
    Figure PCTCN2022079597-appb-100028
    R 8选自：C 1-C 3烷基，C 4-C 6环烷基，4-6元杂环烷基，氰基取代的C 1-C 3烷基，卤素，C 1-C 3烷氧基，卤素取代的C 1-C 3烷基。
  18. 根据权利要求17所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，A选自：-NH-，-NHR-；R选自：苯基，6元含氮杂芳基，R 7取代的苯基，R 7取代的6元含氮杂芳基；
    R 7选自：C 1-C 3烷氧基；
    B不存在或者选自：C 4-C 8环烷基，R 8取代的C 4-C 10环烷基，4-10元杂环烷基，R 8取代的4-10元杂环烷基，
    Figure PCTCN2022079597-appb-100029
    R 8选自：C 1-C 3烷基，C 1-C 3烷氧基。
  19. 根据权利要求18所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，R 3选自：
    Figure PCTCN2022079597-appb-100030
  20. 权利要求1所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子，其特征在于，所述化合物选自：
    Figure PCTCN2022079597-appb-100031
    Figure PCTCN2022079597-appb-100032
    Figure PCTCN2022079597-appb-100033
    Figure PCTCN2022079597-appb-100034
    Figure PCTCN2022079597-appb-100035
    Figure PCTCN2022079597-appb-100036
    Figure PCTCN2022079597-appb-100037
    Figure PCTCN2022079597-appb-100038
    Figure PCTCN2022079597-appb-100039
    Figure PCTCN2022079597-appb-100040
    Figure PCTCN2022079597-appb-100041
    Figure PCTCN2022079597-appb-100042
    Figure PCTCN2022079597-appb-100043
    Figure PCTCN2022079597-appb-100044
    Figure PCTCN2022079597-appb-100045
  21. 权利要求1-20任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备AKT3蛋白降解剂中的应用。
  22. 权利要求1-20任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防和/或治疗与AKT3蛋白异常表达相关的疾病的药物中的应用。
  23. 根据权利要求22所述的应用，其特征在于，所述与AKT3蛋白异常表达相关的疾病包括：肿瘤、心血管疾病、糖尿病、高血压、肌营养不良症、帕金森症、阿尔茨海默症。
  24. 权利要求1-20任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子在制备预防和/或治疗肿瘤或防止肿瘤术后复发的药物中的应用。
  25. 根据权利要求24所述的应用，其特征在于，所述肿瘤为：非小细胞肺癌、恶性黑色素瘤、前列腺癌、肾癌、肝癌、膀胱癌、卵巢癌、结肠癌、直肠癌、乳腺癌、宫颈癌、肺癌、喉癌、鼻咽癌、胰腺癌、多发性骨髓瘤、B淋巴瘤、白血病、皮肤鳞癌。
  26. 一种AKT3蛋白降解剂，其特征在于，其活性成分含有权利要求1-20任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
  27. 一种治疗和/或预防肿瘤或防止肿瘤术后复发的药物组合物，其特征在于，由活性成分和药学上可接受的载体或者辅料制备得到，所述活性成分包括权利要求1-20任一项所述的吡啶并嘧啶类化合物或者其药学上可接受的盐或者其立体异构体或者其前药分子。
PCT/CN2022/079597 2021-03-08 2022-03-07 吡啶并嘧啶类化合物及其应用 Ceased WO2022188755A1 (zh)

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