CN113396147A - Aromatic heterocyclic derivative regulator, preparation method and application thereof - Google Patents

Aromatic heterocyclic derivative regulator, preparation method and application thereof Download PDF

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Publication number
CN113396147A
CN113396147A CN202080012821.0A CN202080012821A CN113396147A CN 113396147 A CN113396147 A CN 113396147A CN 202080012821 A CN202080012821 A CN 202080012821A CN 113396147 A CN113396147 A CN 113396147A
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radical
alkyl
amino
cyano
alkoxy
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Inventor
刘世强
袁逸达
鲍孟
黄胜爱
王婷司
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Priority claimed from CN201910856187.8A external-priority patent/CN112552294B/en
Application filed by Jiangsu Hansoh Pharmaceutical Group Co Ltd, Shanghai Hansoh Biomedical Co Ltd filed Critical Jiangsu Hansoh Pharmaceutical Group Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—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
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—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

Abstract

The invention relates to a heterocyclic aromatic derivative regulator, a preparation method and application thereof. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the compound, and application of the compound as a KRAS G12C mutation inhibitor in treating diseases or symptoms such as leukemia, neuroblastoma, melanoma, breast cancer, lung cancer and colon cancer, wherein each substituent in the general formula (I) is defined as the same as in the specification.

Description

Aromatic heterocyclic derivative regulator, preparation method and application thereof
The application requires the priority of Chinese patent application CN201910471133.X with the application date of 2019, 5 and 31, Chinese patent application CN201910856186.3 with the application date of 2019, 9 and 10, Chinese patent application CN201910856187.8 with the application date of 2019, 9 and 10, Chinese patent application CN201910860731.6 with the application date of 2019, 9 and 11, and Chinese patent application CN 202010014845.1 with the application date of 2020, 1 and 7. The present application refers to the above-mentioned chinese patent application in its entirety.
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to an aromatic heterocyclic derivative inhibitor, and a preparation method and application thereof.
Background
Rat sarcoma (RAS), encoded by protooncogenes HRAS, NRAS and KRAS, is divided into 4 proteins HRAS, NRAS, KRAS4A and KRAS4B, a gtp (guanosine triphosphate) -binding protein. The RAS is located on the inner surface of a cell membrane, the upstream is Receptor Tyrosine Kinase (RTK), and after activation, the RAS regulates and controls downstream signal pathways such as PI3K, RAF and the like, thereby regulating and controlling functions such as growth, survival, migration, differentiation and the like of cells.
RAS has two main states in the body: an inactivated state bound to gdp (guanine diphosphate) and an activated state bound to GTP. The activity of the polypeptide is regulated and controlled by two proteins, and a guanosine nucleotideachange factor (GEF) promotes GDP to be released from RAS protein so that GTP is combined to activate RAS; GTPase Activating Protein (GAP) activates GTPase activating protein (GTPase activating protein) of RAS protein, and hydrolyzes GTP bound on RAS protein into GDP, thereby inactivating RAS. Normally, RAS proteins are in an inactive state, conformationally altered after mutation, RAS is in a continuously activated state, and downstream signaling pathways are also continuously activated, leading to the development of a variety of cancers.
RAS is the first identified oncogene with the highest mutation rate, accounting for an average of 25% of human cancers. The most common oncogenic mutations in the RAS family are KRAS (85%), while NRAS (12%) and HRAS (3%) are less common. KRAS mutations are mainly high in a series of cancers such as pancreatic cancer (95%), colorectal cancer (52%) and lung cancer (31%). The most common mutation mode of KRAS is point mutation, which mostly occurs in the G12, G13 and Q61 of Switch II region (aa59-76) in p-loop (aa 10-17), wherein the G12 mutation is the most common (83%). KRAS G12C is one of the most common mutations in non-small cell lung cancer (NSCLC) and colorectal cancer.
Although there is a great clinical need, to date, no drug targeting KRAS directly is on the market, and patients currently treated clinically for KRAS mutations are generally only able to take chemotherapy. The KRAS inhibitor is difficult to develop mainly by two factors, firstly, the RAS protein has a smooth structure, and small molecules are difficult to combine on the surface of the protein; secondly, the affinity of RAS GTP enzyme to GTP is up to the picomolar (pM) level, the endogenous GTP level is high, and the combination of the two is difficult to block by small-molecule drugs. Recent research shows that KRAS 12 Glycine (Glycine, Gly) is mutated into Cysteine (Cys), and then the conformation is changed to form a new pocket for covalent binding of small molecules, and KRAS G12C is irreversibly locked in a non-activated state of being bound with GDP. Therefore, the KRAS G12C inhibitor is expected to become the first drug directly targeting KRAS.
Many KRAS G12C inhibitors are currently in clinical research, such as AMG 510 developed by Amgen, ARS-3248 developed by Wellspring Biosciences, and MTRX849 developed by Mirati, all of which are currently in phase I clinical research, but no KRAS G12C inhibitor is developed on the market. Among them, AMG 510 showed good therapeutic effect and good safety in early clinical, and is expected to bring more treatment options for KRAS G12C mutant cancer patients in the future.
KRAS G12C currently has no specific targeting drug and has a large clinical demand. The KRAS G12C inhibitor with higher selectivity, better activity and better safety has the potential of treating various cancers and has wide market prospect.
In the inventionContainer
The invention aims to provide a compound shown in a general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
Figure PCTCN2020093731-APPB-000001
wherein:
X 1selected from N or CR1；
X 2Selected from N or CR2；
L is selected from the group consisting of a bond, - (CH)2) n-、-C(R bbR cc) n-、-O(CH 2) n-、-(CH 2) nO-、-S(CH 2) n-、-(CH 2) nS-、-NR bb(CH 2) n-、-NR bb(CH 2) nC(O)-、-CH＝CH(CH 2) n-、-(CH 2) nC(O)NR bb-、-(CH 2) nC(O)-、-CH＝CH(CH 2) nNR bb-、-(CH 2) nS(O) m-、-(CH 2) nNR bb-or- (CH)2) nNR bbS(O) m-；
Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 1selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n-、-NH(CH 2) nC(O)R aa、-O(CH 2) nR aa、-(CH 2) nSR aaOr- (CH)2) nC(O)R aaSaid amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally may be further substituted;
R 2selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
R 3selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O (CH)2) nR bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR cc、-NR bb(CH 2) nNR ccR dd、-CH＝CH(CH 2) nR bb、-CH＝CH(CH 2) nNR bbR cc、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)R cc、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)NR ccR dd、-(CH 2) nR bb、-(CH 2) nSR bb、-(CH 2) nC(O)R bb、-(CH 2) nC(O)OR bb、-(CH 2) nS(O) mR bb、-(CH 2) nNR bbR cc、-(CH 2) nC(O)NR bbR cc、-(CH 2) nNR bbC(O)R ccOr- (CH)2) nNR bbS(O) mR ccOptionally, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, and heterocyclyl may be further substituted;
R 4selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
R 5selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
R aselected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, and alkyl halideA group, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted;
R aaselected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
R bband RccEach independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
or, RbbAnd RccForm, with an adjacent atom, a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally may be further substituted;
R ddselected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, halo-substituted alkyl, alkoxy, haloalkoxy, hydroxyl-substituted alkyl, nitro, alkyl, alkenyl, alkynyl, aryl or heteroaryl,Cycloalkyl, heterocyclyl, aryl and heteroaryl optionally may be further substituted;
or, RccAnd RddForm, with an adjacent atom, a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally may be further substituted;
x is an integer of 0-6;
n is an integer of 0 to 3; and is
m is an integer of 0-2;
wherein, when X1When is N, X2Is N;
or, when X1Is CR1，X 2Is CR2。
In a preferred embodiment of the invention, R1Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, - (CH)2) n-、-NH(CH 2) nC(O)R aa、-O(CH 2) nR aa、-(CH 2) nSR aaOr- (CH)2) nC(O)R aaSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl radical, C2-6Alkenylcarbonyl and 3-12 membered heterocyclyl;
in a further preferred embodiment of the invention, R1Selected from 3-10 membered heterocyclic group or- (CH)2) nC(O)R aaSaid 3-to 10-membered heterocyclic group is optionally substituted by hydrogen, hydroxy, halogen, amino, C1-3Alkyl radical, C2-6Alkenylcarbonyl and 3-10 membered heterocyclyl;
in a preferred embodiment of the invention, RaaSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1- 6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl radical, C2-6Alkenylcarbonyl, 3-12 membered heterocyclyl, -C (O), (CH)2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbIs substituted with one or more substituents of (a).
In a further preferred embodiment of the invention, RaaSelected from 3-10 member heterocyclic radical, the 3-12 member heterocyclic radical is optionally substituted by hydrogen, hydroxyl, halogen, amino, C1-6Alkyl radical, C2-6Alkenylcarbonyl, 3-12 membered heterocyclyl, -C (O), (CH) 2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbIs substituted with one or more substituents of (a).
In a preferred embodiment of the invention, R2Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl.
In a further preferred embodiment of the invention, R2Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-6Alkyl radical, C1-6Haloalkyl and C1-6An alkoxy group.
In a further preferred embodiment of the invention, R2Selected from hydrogen, halogen and C1-3An alkyl group.
In a preferred embodiment of the invention, R3Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, -O (CH)2) nR bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR cc、-NR bb(CH 2) nNR ccR dd、-CH＝CH(CH 2) nR bb、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)R cc、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-CH＝CH(CH 2) nNR bbR ccor-CH ═ CH (CH)2) nNR bb(CH 2) mC(O)NR ccR ddSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1- 6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl and 3-12 membered heterocyclyl.
In a further preferred embodiment of the invention, R3Selected from hydrogen, amino, C3-12Cycloalkyl, 3-12 membered heterocyclyl, -O (CH)2) nR bb、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR ccor-NRbb(CH 2) nNR ccR ddSaid C is3-12Cycloalkyl and 3-12 membered heterocyclyl are optionally substitutedHydrogen, C1-6Alkyl and 3-12 membered heterocyclyl.
In a preferred embodiment of the invention, RbbAnd RccIndependently of one another hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1- 6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl and 3-12 membered heterocyclyl.
In a preferred embodiment of the invention, RddSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6A halogenated alkyl group,C 1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, cyano, C1-6Alkyl and 3-12 membered heterocyclyl.
In a preferred embodiment of the invention, R4Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl.
In a further preferred embodiment of the invention, R4Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-6Alkyl radical, C1-6Haloalkyl and C1-6An alkoxy group.
In a further preferred embodiment of the invention, R4Selected from hydrogen, halogen and C1-3An alkyl group.
In a preferred embodiment of the invention, R5Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, said C1- 6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl radical, C2-6Alkenylcarbonyl, 3-12 membered heterocyclyl, -C (O), (CH)2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbIs substituted with one or more substituents of (a).
In a further preferred embodiment of the invention, R5Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C3-8Cycloalkyl or 3-to 10-membered heterocyclyl, said C1-6Alkyl radical, C3-8Cycloalkyl or 3-to 10-membered heterocyclyl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl radical, C2-6Alkenylcarbonyl, 3-12 membered heterocyclyl, -C (O), (CH)2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbIs substituted with one or more substituents of (a).
In a preferred embodiment of the invention, RaSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl or cyano substituted C1-6Alkyl radical, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl and cyano substituted C1-6Alkyl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl.
In a further preferred embodiment of the invention, RaSelected from hydrogen, halogen, amino, hydroxy, oxo, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano and C1-6Alkyl is substituted by one or more substituents.
In a further preferred embodiment of the present invention, there is provided a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the specific structure:
Figure PCTCN2020093731-APPB-000002
wherein:
M 1selected from the group consisting of CR6R 7Or NR6；
R 6Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, -C (O) (CH)2) nCH＝CHR bbOr-c (o) CH ═ CH (CH)2) nR bbSaid C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
preferably 3-12 membered heterocyclyl, -C (O) (CH)2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbSaid 3-12 membered heterocyclyl is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
R 7selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; preferably hydrogen;
R bselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl or cyano substituted C1-6An alkyl group; preferably hydrogen, halogen or C1-3An alkyl group;
y is an integer of 0 to 6.
In a further preferred embodiment of the present invention, there is provided a compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the specific structure:
Figure PCTCN2020093731-APPB-000003
wherein:
M 2selected from the group consisting of CR8R 9Or NR8；
R 8Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl radicals3-12 membered heterocyclic group, C6-12Aryl, 5-12 membered heteroaryl, -C (O) (CH)2) nCH＝CHR bbOr-c (o) CH ═ CH (CH)2) nR bbSaid C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
preferably 3-12 membered heterocyclyl, -C (O) (CH)2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbSaid 3-12 membered heterocyclyl is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, substituted with one or more substituents;
R 9selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; preferably hydrogen;
R cselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl or cyano substituted C1-6An alkyl group; preferably hydrogen, halogen or C1-3An alkyl group;
z is an integer of 0 to 6.
In a further preferred embodiment of the present invention, there is provided a compound of formula (IV), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the specific structure:
Figure PCTCN2020093731-APPB-000004
in a further preferred embodiment of the present invention, there is provided a compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the specific structure:
Figure PCTCN2020093731-APPB-000005
wherein:
L 2selected from the group consisting of a bond, -O (CH)2) n-、-OC(R bbR cc) n(CH 2) m-、-NR bb(CH 2) n-、-NR bb(CH 2) nNR cc-、-CH＝CH(CH 2) n-or-CH ═ CH (CH)2) nNR bb(CH 2) mC(O)-、-(CH 2) nC(O)NR bb-、-(CH 2) nC(O)-、-CH＝CH(CH 2) nNR bb-or-CH ═ CH (CH)2) nNR bb(CH 2) mC(O)NR cc-；
Ring B is selected from C3-12Cycloalkyl, 3-14 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl; preferably 3-12 membered heterocyclic group, C6-12Aryl and 5-12 membered heteroaryl;
R dselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1- 6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
t is an integer of 0 to 6.
In a further preferred embodiment of the present invention, there is provided a compound of formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having the specific structure:
Figure PCTCN2020093731-APPB-000006
wherein:
R 2selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group;
more preferably fluorine or hydroxyl;
R 3selected from hydrogen, amino, C3-12Cycloalkyl, 3-12 membered heterocyclyl, -O (CH)2) nR bb、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-OC(R bbR cc) n(CH 2) mR dd、-N＝CR bb(CH 2) nNR ccR dd、-NR bbC(O)(CH 2) nR cc、-NR bb(CH 2) nR ccor-NR bb(CH 2) nNR ccR ddSaid C is3-12Cycloalkyl and 3-12 membered heterocyclyl optionally substituted by hydrogen, C1- 6Alkyl and 3-12 membered heterocyclyl;
preferably-N ═ CHNRccR dd、-NR bbC(O)R cc、-NR bb(CH 2) nR ccor-NHb(CH 2) nNR ccR dd；
More preferably
Figure PCTCN2020093731-APPB-000007
Figure PCTCN2020093731-APPB-000008
R 10Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
preferably hydrogen, halogen, hydroxy, C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group;
more preferably hydrogen or methyl;
R 11selected from hydrogen, halogen, amino, hydroxy, oxo, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-10 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano andC 1-6substituted by one or more substituents in the alkyl group;
preferably hydrogen, amino, hydroxy or C1-3An alkoxy group;
more preferably hydrogen, amino, hydroxy or methoxy;
R bband RccEach independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, cyano, C1-6Alkyl amino acyl, and 3-12 member heterocyclic radical;
R ddselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1- 6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, cyano, C1-6Alkyl radical, C1-6Alkyl amino acyl, and 3-12 member heterocyclic radical; and is
m and n are integers of 0 to 3.
In a preferred embodiment of the invention, ring A is selected from C6-10Aryl and 5-12 membered heteroaryl, wherein 5-12 membered heteroaryl preferably contains 1-3 nitrogen atoms, including 5-7 membered nitrogen-containing heteroaryl, benzo 5-7 membered nitrogen-containing heteroaryl or 5-7 membered nitrogen-containing heteroarylacenyl, more preferably the following groups:
Figure PCTCN2020093731-APPB-000009
in a preferred embodiment of the invention, ring B is selected from 5-12 membered heterocyclic groups containing 1-3 nitrogen atoms, more preferably the following groups:
Figure PCTCN2020093731-APPB-000010
the invention provides a compound shown as a general formula (VII), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
Figure PCTCN2020093731-APPB-000011
ring C is selected from phenyl, pyridyl, 5-7 membered nitrogen containing heteroaryl, benzo 5-7 membered nitrogen containing heteroaryl or 5-7 membered nitrogen containing heteroarylacenyl, further preferably from the group consisting of:
Figure PCTCN2020093731-APPB-000012
R 12selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl;
preferably hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy or ethoxy;
R eselected from hydrogen, halogen, hydroxy, amino, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl;
preferably hydrogen, fluorine, chlorine, hydroxyl, amino or methyl;
p is an integer of 0 to 4.
The present invention provides a compound represented by the general formula (VIII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2020093731-APPB-000013
wherein:
X 3is selected from CH2CH, N or NR13；
X 4Is selected from CH2C O, N or CR14；
M is selected from N or CH;
L 3is selected from-O-or-OCH2-；
L 4Is selected from-O-or-CH2-；
R 13Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl;
preferably methyl or cyclopropyl;
R 14selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl;
preferably hydrogen or methyl;
r is selected from 3-8-membered nitrogen-containing heterocyclic group or benzo 3-8-membered nitrogen-containing heterocyclic group, further preferably 5-7-membered nitrogen-containing heterocyclic group or benzo 5-7-membered nitrogen-containing heterocyclic group, wherein the number of nitrogen atoms is 1-2, optionally substituted by halogen or C1-3Substituted by one or more substituents in the alkyl group,
the following substituents are preferred:
Figure PCTCN2020093731-APPB-000014
Figure PCTCN2020093731-APPB-000015
R 15selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl; hydrogen or fluorine are preferred.
The present invention provides a compound represented by the general formula (IX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure PCTCN2020093731-APPB-000016
wherein:
ring D is selected from the following groups:
Figure PCTCN2020093731-APPB-000017
in a most preferred embodiment of the invention, the following specific compounds are included:
Figure PCTCN2020093731-APPB-000018
Figure PCTCN2020093731-APPB-000019
Figure PCTCN2020093731-APPB-000020
Figure PCTCN2020093731-APPB-000021
Figure PCTCN2020093731-APPB-000022
Figure PCTCN2020093731-APPB-000023
the invention also provides a preferable scheme and also relates to a pharmaceutical composition which comprises a therapeutically effective dose of the compound shown in the general formula (I) and a stereoisomer or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to an application of any one of the compounds shown in the general formula (I), stereoisomers or pharmaceutically acceptable salts thereof, or the medicinal composition in preparation of KRAS G12C inhibitor medicines.
The invention also provides a preferable scheme, and also relates to a method for treating, preventing and/or treating diseases mediated by the KRAS G12C inhibitor by using the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, wherein the method comprises the step of administering a therapeutically effective dose of the compound shown in the general formula (I), the stereoisomer thereof or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof to a patient.
In some embodiments, the compounds and compositions of the present invention are useful for the treatment of diseases or disorders that are characterized by noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, gastric cancer, lung cancer, and colon cancer.
The compounds and compositions of the invention are useful in methods of treating diseases or disorders in the preparation of a medicament for the treatment of noonan's syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, lung cancer and colon cancer thereof.
In some embodiments, the invention provides a method of treating a cancer disorder comprising administering a compound or composition of the invention to a patient having a cancer disorder.
In some embodiments, the cancer treated by a compound or composition of the invention is noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, esophageal cancer, head and neck tumors, gastric cancer, lung cancer, and colon cancer thereof; preferably non-small cell lung cancer, colon cancer, esophageal cancer, head and neck tumor.
Detailed description of the invention
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halo, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, preferably methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl.
The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" means-CH2-, "ethylene" means- (CH)2) 2-, "propylene" means- (CH)2) 3-, "butylene" means- (CH)2) 4-and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, e.g., ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
The term "spirocycloalkyl" refers to a5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between monocyclic rings, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/6-membered, 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered, spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2020093731-APPB-000024
etc.;
spirocycloalkyl groups also containing a single spirocycloalkyl group with a heterocycloalkyl group sharing a spiro atom, non-limiting examples include:
Figure PCTCN2020093731-APPB-000025
and the like.
The term "fused cyclic alkyl" refers to a5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of fused ring alkyl groups include:
Figure PCTCN2020093731-APPB-000026
and the like.
The term "bridged cycloalkyl" refers to a5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings have a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. They may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic, depending on the number of constituent rings. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2020093731-APPB-000027
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more of the ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer from 0 to 2) but excludes the ring moiety of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms; further preferred is a 3-8 membered heterocyclic group containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, oxo groups, including a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing spiro heterocyclic group or a nitrogen-containing fused heterocyclic group.
Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepinyl, 1, 4-diazepanyl, pyranyl, and the like, with pyrrolidinyl, morpholinyl, piperidinyl, azepinyl, 1, 4-diazepanyl, and piperazinyl being preferred. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro, fused and bridged rings are optionally linked to other groups by single bonds, or further linked to other cycloalkyl, heterocyclic, aryl and heteroaryl groups by any two or more atoms in the ring.
The term "spiroheterocyclyl" refers to a 5-to 20-membered polycyclic heterocyclic group in which one atom (referred to as the spiro atom) is shared between monocyclic rings, and in which one or more ring atoms is selected from nitrogen, oxygen, or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated pi-electron system. Preferably 6 to 14, more preferably 7 to 10. The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:
Figure PCTCN2020093731-APPB-000028
Figure PCTCN2020093731-APPB-000029
and the like.
The term "fused heterocyclyl" refers to a5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system in which one or more ring atoms is selected from nitrogen, oxygen or S (O)m(it isWherein m is a heteroatom of an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2020093731-APPB-000030
Figure PCTCN2020093731-APPB-000031
and the like.
The term "bridged heterocyclyl" refers to a5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system in which one or more of the ring atoms is selected from nitrogen, oxygen or S (O)m(wherein m is an integer of 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:
Figure PCTCN2020093731-APPB-000032
Figure PCTCN2020093731-APPB-000033
and the like.
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:
Figure PCTCN2020093731-APPB-000034
and the like.
The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate.
The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring can be fused on a heteroaryl, heterocyclic or cycloalkyl ring and comprises benzo 5-10-membered heteroaryl, benzo 3-8-membered cycloalkyl and benzo 3-8-membered heteroalkyl, preferably benzo 5-6-membered heteroaryl, benzo 3-6-membered cycloalkyl and benzo 3-6-membered heteroalkyl, wherein the heterocyclic group is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms and sulfur atoms; or further comprises a three-membered nitrogen-containing fused ring containing a benzene ring.
Wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
Figure PCTCN2020093731-APPB-000035
Figure PCTCN2020093731-APPB-000036
and the like.
The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.
The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 12 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl and the like, preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl; more preferably pyrazolyl, pyrrolyl and oxazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2020093731-APPB-000037
Figure PCTCN2020093731-APPB-000038
and the like.
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl, also known as alkenylene, wherein the alkenyl may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
"alkynyl" refers to (CH ≡ C-), wherein said alkynyl may be further substituted by other related groups, for example: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
The term "alkenylcarbonyl" refers to-C (O) - (alkenyl), wherein alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl groups include: vinylcarbonyl, propenylcarbonyl, butenylcarbonyl. Alkenylcarbonyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH2。
"cyano" means-CN.
"nitro" means-NO2。
"carbonyl" means-C (O) -.
"carboxy" refers to-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et 2O "means diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2(dba) 3"refers to tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bisdiphenylphosphinoferrocene.
"HATU" refers to 2- (7-benzotriazol oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bistrimethylsilyl amide.
"MeLi" refers to methyllithium.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3"refers to sodium triacetoxyborohydride.
Different terms such as "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" and the like all express the same meaning, that is, X can be any one or more of A, B, C.
All hydrogen atoms described in the present invention can be replaced by deuterium, which is an isotope thereof, and any hydrogen atom in the compound of the embodiment related to the present invention can also be replaced by a deuterium atom.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention which are safe and effective for use in the body of a mammal and which possess the requisite biological activity.
Detailed Description
The present invention is further described below with reference to examples, which are not intended to limit the scope of the present invention.
Examples
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated methanol (CD)3OD) and deuterated chloroform (CDCl)3) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 1200Infinity Series Mass spectrometer. HPLC was measured using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C)18150X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees celsius.
Example 1
Preparation of 1- (4- (6-chloro-2, 2' -difluoro-6 ' -hydroxy-3- (methylamino) - [1,1' -biphenyl ] -4-carbonyl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000039
The first step is as follows: preparation of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid
Figure PCTCN2020093731-APPB-000040
2-amino-4-bromo-3-fluorobenzoic acid (10g, 43mmol) was dissolved in DMF (100mL), NCS (5.7g, 43mmol) was added, and the mixture was stirred at 70 ℃ for 15 hours under nitrogen. Cooling, pouring into ice water, precipitating solid, filtering, washing filter cake with water, and drying to obtain the target product 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (9.3g, yield: 82%).
MS m/z(ESI):266.1[M-H] +,268.1[M-H+2] +.
The second step is that: preparation of tert-butyl 4- (2-amino-4-bromo-5-chloro-3-fluorobenzoyl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000041
2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (9.0g, 33.7mmol) was dissolved in DMF (100mL), DIPEA (8.7g, 67.4mmol) and HATU (15.4g, 40.4mmol) were added, and the mixture was stirred at room temperature for 0.5 h. Tert-butylpiperazine-1-carboxylate (12.5g, 67.4mmol) was added and stirring was continued for 5 hours. Water was added, and the mixture was extracted with dichloromethane (3X 50mL), washed with water (20mL), and washed with saturated brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column Chromatography (CH)2Cl 210/MeOH: 1) the objective product, tert-butyl 4- (2-amino-4-bromo-5-chloro-3-fluorobenzoyl) piperazine-1-carboxylate, was purified (11.5g, yield: 78%).
MS m/z(ESI):436.1[M+H] +,438.1[M+H+2] +.
The third step: preparation of (2-amino-4-bromo-5-chloro-3-fluorophenyl) (piperazin-1-yl) methanone
Figure PCTCN2020093731-APPB-000042
Tert-butyl 4- (2-amino-4-bromo-5-chloro-3-fluorobenzoyl) piperazine-1-carboxylate (11.2g, 25.7mmol) was dissolved in dichloromethane (50mL), added TFA (10mL, 136mmol), and stirred at room temperature for 2 hours. Concentrating, adding water and saturated NaHCO3The aqueous solution was adjusted to neutral and extracted with dichloromethane (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give the desired product (2-amino-4-bromo-5-chloro-3-fluorophenyl) (piperazin-1-yl) methanone (8.7g, crude).
MS m/z(ESI):336.1[M+H] +,338.1[M+H+2] +.
The fourth step: preparation of 1- (4- (2-amino-4-bromo-5-chloro-3-fluorobenzoyl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000043
(2-amino-4-bromo-5-chloro-3-fluorophenyl) (piperazin-1-yl) methanone (8.7g, 25.7mmol) was dissolved in dichloromethane (100mL), DIPEA (9.9g, 76.7mmol) was added, acryloyl chloride (2.3g, 25.7mmol) was added dropwise under an ice-water bath, and stirring was continued for 1 hour. Quench with water and extract three times with dichloromethane (30 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the desired product 1- (4- (2-amino-4-bromo-5-chloro-3-fluorobenzoyl) piperazin-1-yl) prop-2-en-1-one (7.3g, two-step yield: 73%).
MS m/z(ESI):390.1[M+H] +,392.1[M+H+2] +.
The fifth step: preparation of 1- (4- (4-bromo-5-chloro-3-fluoro-2- (methylamino) benzoyl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000044
1- (4- (2-amino-4-bromo-5-chloro-3-fluorobenzoyl) piperazin-1-yl) prop-2-en-1-one (1g, 2.6mmol) was dissolved in DMF (30mL), NaH (123mg, 3.1mmol) was added at 0 deg.C, stirring was carried out for 0.5 h, a solution of iodomethane (364mg, 2.6mmol) in DMF (5mL) was added dropwise, warmed to room temperature, and stirred for 1 h. Water and dichloromethane (3 x 30mL) were added for extraction. Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification yielded the target product 1- (4- (4-bromo-5-chloro-3-fluoro-2- (methylamino) benzoyl) piperazin-1-yl) prop-2-en-1-one (230mg, yield: 23%).
MS m/z(ESI):404.1[M+H] +,406.1[M+H+2] +.
And a sixth step: preparation of 1- (4- (6-chloro-2, 2' -difluoro-6 ' -methoxy-3- (methylamino) - [1,1' -biphenyl ] -4-carbonyl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000045
1- (4- (4-bromo-5-chloro-3-fluoro-2- (methylamino) benzoyl) piperazin-1-yl) prop-2-en-1-one (200mg, 0.5mmol) was dissolved in dioxane (20mL), 2-fluoro-6-methoxyphenylboronic acid (127mg, 0.75mmol), tris (dibenzylideneacetone) dipalladium (92mg, 0.1mmol), Xantphos (116mg, 0.2mmol), and Cs were added2CO 3(492mg, 1.5mmol), nitrogen substitution. The reaction was heated to 110 ℃ and reacted overnight. After cooling to room temperature, water and dichloromethane (3 × 20mL) were added for extraction. Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target product 1- (4- (6-chloro-2, 2' -difluoro-6 ' -methoxy-3- (methylamino) - [1,1' -biphenyl)]-4-carbonyl) piperazin-1-yl) prop-2-en-1-one (120mg, yield: 54%).
MS m/z(ESI):450.1[M+H] +,452.1[M+H+2] +.
The seventh step: preparation of 1- (4- (6-chloro-2, 2' -difluoro-6 ' -hydroxy-3- (methylamino) - [1,1' -biphenyl ] -4-carbonyl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000046
1- (4- (6-chloro-2, 2' -difluoro-6 ' -methoxy-3- (methylamino) - [1,1' -biphenyl group)]-4-carbonyl) piperazin-1-yl) prop-2-en-1-one (100mg, 0.22mmol) was dissolved in dichloromethane (10mL), cooled to-40 ℃ and BBr was added dropwise3(550mg, 2.20mmol), warmed to room temperature and stirred for 1 hour. With saturated NaHCO3The aqueous solution was quenched and extracted with dichloromethane (3 × 20 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to obtain a crude product, and purifying by preparative HPLC to obtain the target product 1- (4- (6-chloro-2, 2' -difluoro-6 ' -hydroxy-3- (methylamino) - [1,1' -biphenyl ]]-4-carbonyl) piperazin-1-yl) prop-2-en-1-one (47mg, yield: 48%).
MS m/z(ESI):436.1[M+H] +,438.1[M+H+2] +.
Example 2
Preparation of 1- (4- (6-chloro-3- (dimethylamino) -2,2' -difluoro-6 ' -hydroxy- - [1,1' -biphenyl ] -4-carbonyl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000047
The first step is as follows: preparation of 1- (4- (4-bromo-5-chloro-3-fluoro-2- (dimethylamino) benzoyl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000048
1- (4- (2-amino-4-bromo-5-chloro-3-fluorobenzoyl) piperazin-1-yl) prop-2-en-1-one (1g, 2.6mmol) was dissolved in DMF (30mL) and added at 0 deg.CNaH (123mg, 7.8mmol), stirred for 0.5 h, a solution of iodomethane (364mg, 7.8mmol) in DMF (5mL) was added dropwise, warmed to room temperature, and stirred for 1 h. Water and dichloromethane (3 x 30mL) were added for extraction. Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification yielded the target product 1- (4- (4-bromo-5-chloro-3-fluoro-2- (methylamino) benzoyl) piperazin-1-yl) prop-2-en-1-one (420mg, yield: 13%).
MS m/z(ESI):418.1[M+H] +,419.1[M+H+2] +.
The second step is that: preparation of 1- (4- (6-chloro-3- (dimethylamino) -2,2' -difluoro-6 ' -methoxy- [1,1' -biphenyl ] -4-carbonyl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000049
1- (4- (4-bromo-5-chloro-3-fluoro-2- (dimethylamino) benzoyl) piperazin-1-yl) prop-2-en-1-one (209mg, 0.5mmol) was dissolved in dioxane (20mL), 2-fluoro-6-methoxyphenylboronic acid (127mg, 0.75mmol), tris (dibenzylideneacetone) dipalladium (92mg, 0.1mmol), Xantphos (116mg, 0.2mmol) and Cs were added2CO 3(492mg, 1.5mmol), nitrogen substitution. The reaction was heated to 110 ℃ and reacted overnight. After cooling to room temperature, water and dichloromethane (3 × 20mL) were added for extraction. Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain target product 1- (4- (6-chloro-3- (dimethylamino) -2,2' -difluoro-6 ' -methoxy- [1,1' -biphenyl)]-4-carbonyl) piperazin-1-yl) prop-2-en-1-one (100mg, yield: 43%).
MS m/z(ESI):464.1[M+H] +.
The third step: preparation of 1- (4- (6-chloro-3- (dimethylamino) -2,2' -difluoro-6 ' -hydroxy- - [1,1' -biphenyl ] -4-carbonyl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000050
1- (4- (6-chloro-3- (dimethylamino) -2,2' -difluoro-6 ' -methoxy- [1,1' -biphenyl)]-4-carbonyl) piperazin-1-yl) prop-2-en-1-one (100mg, 0.22mmol) was dissolved in dichloromethane (10mL), cooled to-40 ℃ and BBr was added dropwise3(550mg, 2.20mmol), warmed to room temperature and stirred for 1 hour. With saturated NaHCO3The aqueous solution was quenched and extracted with dichloromethane (3 × 20 mL). Combining organic layers, drying the organic layers by anhydrous sodium sulfate, concentrating the organic layers to obtain a crude product, and purifying the crude product by preparative HPLC to obtain the target product 1- (4- (6-chloro-3- (dimethylamino) -2,2' -difluoro-6 ' -hydroxy- - [1,1' -biphenyl ]]-4-carbonyl) piperazin-1-yl) prop-2-en-1-one (29mg, yield: 29%).
MS m/z(ESI):450.1[M+H] +.
1H NMR(400MHz,Chloroform)δ7.72(s,1H),7.37(s,1H),6.94(s,1H),6.74(s,1H),6.17(s,1H),6.00(s,1H),5.53(s,1H),4.85(s,1H),3.59(s,4H),3.39(s,4H),3.00(s,6H).
Examples 3-10 were prepared according to the scheme of example 1.
Example 11
Preparation of (S) -1- (4- (6- (8-hydroxynaphthalen-2-yl) -5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000051
The first step is as follows: preparation of 4- (2-chloro-5-methylpyrimidin-4-yl) piperazine-1-carboxylic acid tert-butyl ester
Figure PCTCN2020093731-APPB-000052
2, 4-dichloro-5-methylpyrimidine (10g, 61.7mmol) was dissolved in DMF (100mL), and piperazine-1-carboxylic acid tert-butyl ester (13.7g, 74.1mmol), DIPEA (23.9g, 185mmol) and nitrogen were added, and the mixture was heated to 80 ℃ and stirred for 5 hours. Cool, add water and extract with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by column chromatography (EtOAc/petroether ═ 1: 10) to give the desired product tert-butyl 4- (2-chloro-5-methylpyrimidin-4-yl) piperazine-1-carboxylate (15.8g, yield: 82%).
MS m/z(ESI):313.1[M+H] +,315.1[M+H+2] +.
The second step is that: preparation of tert-butyl (S) -4- (5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000053
Tert-butyl 4- (2-chloro-5-methylpyrimidin-4-yl) piperazine-1-carboxylate (5g, 16.0mmol) was dissolved in THF (100mL), and (S) - (1-methylpyrrolidin-2-yl) methanol (3.7g, 32.2mmol) and sodium tert-butoxide (4.6g, 48.0mmol) were added and stirred at room temperature for 5 hours under nitrogen. Quenched with water and extracted three times with ethyl acetate (30 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the target product tert-butyl (S) -4- (5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (4.6g, yield: 73%).
MS m/z(ESI):392.1[M+H] +.
The third step: preparation of tert-butyl (S) -4- (6-bromo-5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000054
Tert-butyl (S) -4- (5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (3.9g, 10mmol) was dissolved in MeOH/H2O(50mL/50mL)In (1), NaHCO is added3(1.2g, 14mmol), liquid bromine (3.0g, 18.7mmol) was added dropwise at room temperature, and the mixture was stirred for 1 hour. Then NaHCO is added3(2.4g, 28mmol) and stirring was continued for 3 hours. Ethyl acetate (3 × 30mL) was extracted, and the organic layers were combined, washed with water, and washed with saturated brine. Drying with anhydrous sodium sulfate, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the target product tert-butyl (S) -4- (6-bromo-5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (1.6g, yield: 34%).
MS m/z(ESI):470.1[M+H] +，472.1[M+H+2] +.
The fourth step: preparation of (S) -4-bromo-5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) -6- (piperazin-1-yl) pyrimidine
Figure PCTCN2020093731-APPB-000055
Tert-butyl (S) -4- (6-bromo-5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (1.5g, 3.2mmol) was dissolved in dichloromethane (50mL), TFA (2mL) was added, and stirring was carried out at room temperature for 2 hours. With saturated NaHCO3The aqueous solution was adjusted to neutral and extracted three times with ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give the desired product (S) -4-bromo-5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) -6- (piperazin-1-yl) pyrimidine (1.2g, crude).
MS m/z(ESI):370.1[M+H] +，372.1[M+H+2] +.
The fifth step: preparation of (S) -1- (4- (6-bromo-5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000056
Reacting (S) -4-bromo-5-methylThe group-2- ((1-methylpyrrolidin-2-yl) methoxy) -6- (piperazin-1-yl) pyrimidine (1.2g, 3.2mmol) was dissolved in dichloromethane (50mL), DIPEA (1.2g, 9.3mmol) was added, acryloyl chloride (345mg, 3.8mmol) was added dropwise at room temperature, and after completion of addition, stirring was carried out at room temperature for 1 hour. Quench with water and extract three times with dichloromethane (20 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification yielded the target product (S) -1- (4- (6-bromo-5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (1.1g, yield: 81%).
MS m/z(ESI):424.1[M+H] +，426.1[M+H+2] +.
And a sixth step: preparation of (S) -1- (4- (6- (8-hydroxynaphthalen-2-yl) -5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000057
(S) -1- (4- (6-bromo-5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (100mg, 0.24mmol) was dissolved in dioxane (20mL), 7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-ol (96mg, 0.36mmol), tris (dibenzylideneacetone) dipalladium (46mg, 0.05mmol), Xantphos (58mg, 0.1mmol), and Cs were added2CO 3(236mg, 0.72mmol), nitrogen substitution. The reaction was heated to 110 ℃ and reacted overnight. Concentrate and extract three times with dichloromethane (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by preparative HPLC to give the objective product (S) -1- (4- (6- (8-hydroxynaphthalen-2-yl) -5-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (23mg, yield: 20%).
MS m/z(ESI):488.1[M+H] +.
Examples 12-20 were prepared according to the scheme of example 11.
Example 21
Preparation of N- (4- ((S) -4-acryloyl-2-methylpiperazine-1-carbonyl) -6-chloro-2, 2' -difluoro-6 ' -methoxy- [1,1' -biphenyl ] -3-yl) -4-ethylbenzamide
Figure PCTCN2020093731-APPB-000058
Example 21 was prepared according to example 1.
MS m/z(ESI):582.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ8.03(d,J＝30.4Hz,1H),7.77(d,J＝7.4Hz,2H),7.40(dd, J＝15.1,8.3Hz,1H),7.28(d,J＝8.0Hz,2H),6.86–6.78(m,2H),6.55(s,1H),6.34(d,J＝16.6Hz,1H),5.74(d,J＝10.3Hz,1H),4.56(d,J＝56.7Hz,3H),3.79(s,4H),3.52(s,2H),3.04(s,2H),2.70(q,J＝7.6Hz,2H),1.25(t,J＝7.6Hz,6H).
19F NMR(376MHz,CDCl 3)δ-111.70–-111.81(m),-111.83–-112.11(m).
Example 22
(E) Preparation of (E) -N '- (4- ((S) -4-acryloyl-2-methylpiperazine-1-carbonyl) -6-chloro-2, 2' -difluoro-6 '-methoxy- [1,1' -biphenyl ] -3-yl) -N, N-dimethylformamidine
Figure PCTCN2020093731-APPB-000059
Example 22 was prepared according to example 1.
MS m/z(ESI):505.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ7.67(s,1H),7.37(dd,J＝15.5,7.9Hz,1H),7.21–7.05(m,1H),6.81(t,J＝8.3Hz,2H),6.56(dd,J＝16.6,10.6Hz,1H),6.36(d,J＝16.5Hz,1H),5.76(d,J＝10.4Hz,1H),5.00(s,1H),4.57(d,J＝16.5Hz,2H),3.86–3.76(m,3H),3.48(s,2H),3.27–3.01(m,2H),2.90(dd,J＝51.6,39.6Hz,6H),1.32–1.23(m,3H).
Example 23
Preparation of N- (4- ((S) -4-acryloyl-2-methylpiperazine-1-carbonyl) -6-chloro-2, 2' -difluoro-6 ' -methoxy- [1,1' -biphenyl ] -3-yl) -3-cyanobenzamide
Figure PCTCN2020093731-APPB-000060
Example 23 was prepared according to example 1.
MS m/z(ESI):579.1[M+H] +.
1H NMR(400MHz,CDCl 3)δ12.22(d,J＝31.3Hz,2H),11.91(d,J＝7.7Hz,1H),11.66 (t,J＝7.9Hz,1H),11.43(dt,J＝46.6,23.4Hz,2H),11.00–10.67(m,3H),10.22(d,J＝16.8Hz,1H),9.74(d,J＝10.2Hz,1H),8.48(d,J＝61.2Hz,2H),8.05(d,J＝64.2Hz,1H),7.77(s,3H),7.51(s,2H),7.27(s,3H),7.10(s,1H),5.32–5.01(m,3H).
19F NMR(400MHz,CDCl 3)δ-109.00–-111.89(m),-113.34(d,J＝1.0Hz),-113.37–-114.24(m).
Example 24
Preparation of N1- (4- ((S) -4-acryloyl-2-methylpiperazine-1-carbonyl) -6-chloro-2, 2' -difluoro-6 ' -methoxy- [1,1' -biphenyl ] -3-yl) -N4-methylterephthalamide
Figure PCTCN2020093731-APPB-000061
Example 24 was prepared according to example 1.
MS m/z(ESI):611.1[M+H] +.
19F NMR(400MHz,CDCl 3)δ-111.77(s),-111.94(ddd,J＝18.6,9.3,6.8Hz),-115.73(d,J＝1.5Hz).
1H NMR(400MHz,CDCl 3)δ7.84(d,J＝24.6Hz,4H),7.41(dd,J＝15.4,7.4Hz,1H),7.16(s,1H),6.82(t,J＝10.0Hz,2H),6.35(d,J＝17.0Hz,2H),5.75(d,J＝10.3Hz,1H),4.81–4.23(m,3H),3.79(s,3H),3.53(s,4H),3.03(d,J＝4.4Hz,3H),1.25(s,3H).
Example 25
Preparation of N- (4- ((S) -4-acryloyl-2-methylpiperazine-1-carbonyl) -6-chloro-2, 2' -difluoro-6 ' -methoxy- [1,1' -biphenyl ] -3-yl) isophthalamide
Figure PCTCN2020093731-APPB-000062
Example 25 was prepared according to example 1.
MS m/z(ESI):597.0[M+H] +.
19F NMR(400MHz,CDCl 3)δ-110.92–-111.16(m),-113.21(s),-113.27–-113.42(m).
1H NMR(400MHz,CDCl 3)δ12.41(s,1H),12.04(d,J＝7.6Hz,2H),11.58(t,J＝7.2Hz,1H),11.42(dt,J＝45.9,23.0Hz,2H),10.93(d,J＝8.1Hz,1H),10.87–10.61(m,2H),10.21(d,J＝16.8Hz,1H),9.75(s,1H),8.56(s,1H),8.40–8.20(m,1H),8.12(s,1H),7.77(s,3H),7.48(s,1H),7.27(s,3H),7.09(s,1H),5.25(s,3H).
Example 26
Preparation of 1- ((3S) -4- (5-fluoro-6- (2-fluoro-6-hydroxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinoyl) -3-methylpiperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000063
The first step is as follows: preparation of tert-butyl (S) -4- (2, 6-dichloro-5-fluoronicotinoyl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000064
At 0 deg.C，N 2Oxalyl chloride (2.7mL, 5.3mmol) was added dropwise to a solution of 2, 6-dichloro-5-fluoronicotinic acid (1g, 4.8mmol) in dichloromethane (20mL) with protection, 2 drops of DMF were added dropwise and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ℃, triethylamine (2mL, 9.6mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with water and dichloromethane (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give crude product which was purified by column chromatography (petroether/EtOAc 10: 1 to 5: 1) to give the desired product tert-butyl (S) -4- (2, 6-dichloro-5-fluoronicotinoyl) -3-methylpiperazine-1-carboxylate (1.5g, 79% yield).
MS m/z(ESI):392.1[M+H] +,394.1[M+H+2] +.
The second step is that: preparation of tert-butyl (3S) -4- (2-chloro-5-fluoro-6- (2-fluoro-6-hydroxyphenyl) nicotinoyl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000065
N 2Tert-butyl (S) -4- (2, 6-dichloro-5-fluoronicotinoyl) -3-methylpiperazine-1-carboxylate (950mg, 2.4mmol) was dissolved in 1, 4-dioxane (3mL) under protection, and (2-fluoro-6-hydroxyphenyl) boronic acid (740mg, 4.9mmol), Pd (dppf) Cl was added2.DCM(200mg，0.24mmol)，K 2CO 3(1.0g, 7.2mmol) and reacted at 120 ℃ for 12 hours. The reaction mixture was extracted with water and dichloromethane (3 × 10 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 2200 parts per MeOH: 1 to 80: 1) purification gave the desired product tert-butyl (3S) -4- (2-chloro-5-fluoro-6- (2-fluoro-6-hydroxyphenyl) nicotinoyl) -3-methylpiperazine-1-carboxylate (800mg, 71% yield).
MS m/z(ESI):468.1[M+H] +,470.1[M+H+2] +.
The third step: preparation of tert-butyl (3S) -4- (5-fluoro-6- (2-fluoro-6-hydroxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinoyl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000066
N 2Tert-butyl (3S) -4- (2-chloro-5-fluoro-6- (2-fluoro-6-hydroxyphenyl) nicotinoyl) -3-methylpiperazine-1-carboxylate (300mg, 0.64mmol) was dissolved in 1, 4-dioxane (3mL) under protection, and 2-isopropyl-4-methylpyridin-3-amine (200mg, 1.3mmol), Pd (OAC) was added2(20mg，0.3mmol)，Xantphos(40mg，0.3mmol),K 2CO 3(188mg, 1.3mmol) and reacted at 110 ℃ for 12 hours. The reaction mixture was extracted with water and dichloromethane (3 × 10 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 2100 parts per MeOH: 1 to 80: 1) purification gave the desired product tert-butyl (3S) -4- (5-fluoro-6- (2-fluoro-6-hydroxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinoyl) -3-methylpiperazine-1-carboxylate (60mg, 16% yield).
MS m/z(ESI):582.1[M+H] +.
The fourth step: preparation of (5-fluoro-6- (2-fluoro-6-hydroxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) pyridin-3-yl) ((S) -2-methylpiperazin-1-yl) methanone
Figure PCTCN2020093731-APPB-000067
Tert-butyl (3S) -4- (5-fluoro-6- (2-fluoro-6-hydroxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinoyl) -3-methylpiperazine-1-carboxylate (60mg, 0.1mmol) was dissolved in MeOH (10mL), HCl/1, 4-dioxane solution (1.0mL, 4mmol) was added, and stirring was carried out for 0.5 hour. Concentration gave (5-fluoro-6- (2-fluoro-6-hydroxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) pyridin-3-yl) ((S) -2-methylpiperazin-1-yl) methanone (50mg, 97% yield).
MS m/z(ESI):482.1[M+H] +.
The fifth step: preparation of 1- ((3S) -4- (5-fluoro-6- (2-fluoro-6-hydroxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinoyl) -3-methylpiperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000068
N 2(5-fluoro-6- (2-fluoro-6-hydroxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) pyridin-3-yl) ((S) -2-methylpiperazin-1-yl) methanone (50mg, 0.97mmol) was dissolved in dichloromethane (10mL) with protection, DIEA (5mL, 28mmol) was added, acryloyl chloride (0.02mL,0.97mmol) was added dropwise at 0 ℃, and stirring was completed for 0.5 h. Quench with water and extract with water and ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by acid Prep-HPLC to give the desired product 1- ((3S) -4- (5-fluoro-6- (2-fluoro-6-hydroxyphenyl) -2- ((2-isopropyl-4-methylpyridin-3-yl) amino) nicotinoyl) -3-methylpiperazin-1-yl) prop-2-en-1-one (2mg, 0.04% yield).
1H NMR(400MHz,Methanol-d 4)δ8.39-8.34(m,2H),7.25–7.20(m,2H),6.86-6.80(m,1H),6.67-6.58(m,2H),6.32-6.27(dd,J＝16.6,4.0Hz,1H),5.83-5.79(dd,J＝12.0,4.0Hz,1H),4.65-4.48(m,4H),4.40-4.24(m,1H),3.84-3.72(m,2H),2.82-2.75(m,1H),2.36(s,3H),1.50-1.44(d,J＝6.6Hz,3H),1.20-1.05(m,6H)
MS m/z(ESI):536.1[M+H] +.
Example 27
Preparation of 6- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -N- (4-fluoro-3-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxamide
Figure PCTCN2020093731-APPB-000069
The first step is as follows: preparation of methyl (S) -6- (4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) -2-chloropyrimidine-4-carboxylate
Figure PCTCN2020093731-APPB-000070
Methyl 2, 6-dichloropyrimidine-4-carboxylate (10g,48.3mmol), tert-butyl (S) -3-methylpiperazine-1-carboxylate (9.6g,48mmol) and N, N-diisopropylethylamine (12g,100mmol) were stirred in tetrahydrofuran (150mL) at 50 ℃ for 4 hours. Water (150mL) was added, extraction was performed with ethyl acetate (150 mL. times.2), the organic phase was washed with aqueous ammonium chloride (200mL) and then aqueous sodium chloride (50mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give methyl (S) -6- (4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) -2-chloropyrimidine-4-carboxylate as a yellow solid (17g, 95% yield).
MS m/z(ESI):371.1[M+H] +,373.1[M+H+2] +.
The second step is that: preparation of 6- ((S) -4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxylic acid
Figure PCTCN2020093731-APPB-000071
Methyl (S) -6- (4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) -2-chloropyrimidine-4-carboxylate (2g,5.4mmol), (S) - (1-methylpyrrolidin-2-yl) methanol (3.1g,27mmol), cesium carbonate (5.26g,16.2mmol) and N, N-diisopropylethylamine (6.6g,54mmol) were stirred in dioxane (5mL) at 160 ℃ for 3 hours under microwave agitation. Water (200mL) was added, extraction was performed with ethyl acetate (200mL × 3), the organic phase was washed with aqueous ammonium chloride (200mL) and then aqueous sodium chloride (100mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 6- ((S) -4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxylic acid (2g, yield 85%) as a yellow solid.
MS m/z(ESI):436.3[M+H] +.
The third step: preparation of 6- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxylic acid
Figure PCTCN2020093731-APPB-000072
To a solution of 6- ((S) -4- (tert-butoxycarbonyl) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxylic acid (2g,4.6mmol) in methanol (60mL) was added sulfuric acid (1mL), and the mixture was stirred for 2 hours at 65 ℃. The solution was slowly neutralized with aqueous sodium carbonate and concentrated directly to dryness to give 6- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxylic acid (4g) as a white solid.
MS m/z(ESI):336.2[M+H] +.
The fourth step: preparation of 6- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxylic acid
Figure PCTCN2020093731-APPB-000073
Add N, N-diisopropylethylamine (240mg,2mmol) to a solution of 6- ((S) -2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxylic acid (200mg,0.6mmol) in N, N-dimethylformamide (15mL), and add acryloyl chloride (108mg,1.2mmol) at 0 deg.C, and stir for 1 h. The reaction was quenched with aqueous ammonium chloride (30mL), extracted with ethyl acetate (30mL × 3), and the organic phase was washed with saturated aqueous NaCl (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 6- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxylic acid (200mg) as a yellow solid.
MS m/z(ESI):390.2[M+H] +.
The fifth step: preparation of 6- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -N- (4-fluoro-3-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxamide
Figure PCTCN2020093731-APPB-000074
6- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxylic acid (200mg,0.6mmol), 5-amino-2-fluorophenol (152mg,1.2mmol), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (456mg,1.2mmol) and N, N-diisopropylethylamine (240mg,2mmol) were stirred in N, N-dimethylformamide (6mL) at room temperature for 18 hours. The reaction was filtered, concentrated and purified by preparative HPLC to give 6- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -N- (4-fluoro-3-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxamide (15mg, 10% yield in three steps) as a yellow solid.
MS m/z(ESI):499.2[M+H] +。
1H NMR(400MHz,MeOD-d 4)δ7.56–7.42(m,1H),7.19–7.08(m,2H),7.07–6.97(m,1H),6.92–6.73(m,1H),6.29(d,J＝16Hz,1H),5.89–5.74(m,1H),4.79–4.56(m,1H),4.55–4.29(m,4H),4.24–3.99(m,1H),3.67–3.53(m,1H),3.50–3.37(m,2H),3.24–3.01(m,2H),2.86–2.73(m,1H),2.53(s,3H),2.46–2.33(m,1H),1.93–1.68(m,3H),1.23(d,J＝8Hz,3H).
Example 28
Preparation of 6- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -N- (1H-benzo [ d ] imidazol-4-yl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxamide
Figure PCTCN2020093731-APPB-000075
Example 28 was prepared according to example 27.
1H NMR(400MHz,MeOD-d 4)δ8.18(s,1H),7.56–7.42(m,2H),7.40–7.32(m,2H),6.92–6.73(m,1H),6.28(d,J＝16Hz,1H),5.88–5.75(m,1H),4.77–4.53(m,1H),4.56–4.29(m,4H),4.23–3.99(m,1H),3.68–3.54(m,1H),3.51–3.38(m,2H),3.25–3.00(m,2H),2.87–2.74(m,1H),2.54(s,3H),2.47–2.33(m,1H),1.94–1.69(m,3H),1.24(d,J＝8Hz,3H).
Example 29
Preparation of 6- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -N- (2-fluoro-6-hydroxyphenyl) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) pyrimidine-4-carboxamide
Figure PCTCN2020093731-APPB-000076
Example 28 was prepared according to example 27.
1H NMR(400MHz,MeOD-d 4)δ7.57–7.43(m,1H),7.15–7.08(m,1H),7.03–6.93(m,2H),6.92–6.75(m,1H),6.29(d,J＝16Hz,1H),5.89–5.75(m,1H),4.78–4.54(m,1H),4.54–4.29(m,4H),4.25–3.98(m,1H),3.66–3.53(m,1H),3.51–3.38(m,2H),3.25–3.01(m,2H),2.87–2.74(m,1H),2.53(s,3H),2.47–2.32(m,1H),1.91–1.69(m,3H),1.22(d,J＝8Hz,3H).
Example 30
Preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000077
The first step is as follows: preparation of tert-butyl 4- (5-bromo-2-chloro-6-methylpyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000078
5-bromo-2, 4-dichloro-6-methylpyrimidine (5g, 20.8mmol) was dissolved in ACN (50mL), tert-butylpiperazine-1-carboxylate (5.1g, 27.4mmol), DIPEA (8.1g, 62.7mmol) were added, and the mixture was stirred at room temperature for 15 hours. Water was added and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography (petroether/EtOAc ═ 5: 1) to give the desired product tert-butyl 4- (5-bromo-2-chloro-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (7.9g, yield: 97%).
MS m/z(ESI):391.1[M+H] +,393.1[M+H+2] +.
The second step is that: preparation of tert-butyl 4- (5-bromo-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000079
Tert-butyl 4- (5-bromo-2-chloro-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (5g, 12.8mmol) was dissolved in MeOH (30mL), NaOH (1.5g, 37.5mmol) was added under ice bath, gradually warmed to room temperature and stirred for 5 hours; water and ethyl acetate (50mL) were added and extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography (petroether/EtOAc ═ 5: 1) to give the desired product tert-butyl 4- (5-bromo-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (3.5g, yield: 71%).
MS m/z(ESI):387.1[M+H] +，389.1[M+H+2] +.
The third step: preparation of tert-butyl 4- (5-formyl-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000080
Tert-butyl 4- (5-bromo-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (3.2g, 8.3mmol) was dissolved in anhydrous THF (100mL), cooled to-78 ℃ under nitrogen protection, n-BuLi (9.9mL, 9.9mmol) was added and stirred for 0.5 h. DMF/THF (1mL/5mL) was added, stirred at 78 ℃ for 1 hour, gradually warmed to room temperature. Stirring was continued for 2 hours. Quench with water and extract with water and ethyl acetate (3 × 50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the desired product tert-butyl 4- (5-formyl-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (2.0g, yield: 72%).
MS m/z(ESI):337.1[M+H] +.
The fourth step: preparation of tert-butyl 4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000081
Tert-butyl 4- (5-formyl-2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (1.8g, 5.4mmol) was dissolved in dichloromethane (50mL), methylamine hydrochloride (710mg, 10.6mmol), NaBH (OAc) was added3(1.4g, 6.7mmol) and glacial acetic acid (30mg, 0.5 mmol). Stir at room temperature overnight. Addition of Boc2O (2.3g, 10.6mmol), and stirred at room temperature for 3 hours. Quench with water and extract with water and ethyl acetate (3 × 50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the desired product tert-butyl 4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (1.9g, yield: 79%).
MS m/z(ESI):452.1[M+H] +.
The fifth step: preparation of tert-butyl (E) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (2-fluoro-6-methoxystyryl) -2-methoxypyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000082
Tert-butyl 4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -2-methoxy-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (1.8g, 4.0mmol) was added to an aqueous NaOH solution (5M, 100mL), 2-fluoro-6-methoxybenzaldehyde (730mg, 4.8mmol) and trioctylmethylammonium chloride (220mg, 0.5mmol) were added, and the mixture was heated to reflux and stirred for 5 hours. Cooling, filtering, washing the filter cake with water, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the desired product tert-butyl (E) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (2-fluoro-6-methoxystyryl) -2-methoxypyrimidin-4-yl) piperazine-1-carboxylate (1.7g, yield: 73%).
MS m/z(ESI):588.1[M+H] +.
And a sixth step: preparation of 7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidine
Figure PCTCN2020093731-APPB-000083
Tert-butyl (E) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6- (2-fluoro-6-methoxystyryl) -2-methoxypyrimidin-4-yl) piperazine-1-carboxylate (1.5g, 2.6mmol) was dissolved in ethyl acetate (50mL), a 2M HCl in ethyl acetate solution (6mL) was added, stirred at room temperature for 5 hours, and the solvent was removed by concentration; the crude product was dissolved in water (20mL) and K was added2CO 3(720mg, 5.2mmol) and KI (430mg, 2.6mmol), heated to 100 ℃, stirred for 15 hours, cooled, extracted with water and ethyl acetate (3 x 30 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target product 7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-4- (piperazine-1-yl) -5,6,7, 8-tetrahydropyrido [4,3-d]Pyrimidine (560mg, yield: 57%).
MS m/z(ESI):388.1[M+H] +.
The seventh step: preparation of 1- (4- (7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000084
Mixing 7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-4- (piperazine-1-yl) -5,6,7, 8-tetrahydropyrido [4,3-d]Pyrimidine (500mg, 1.3mmol) was dissolved in dichloromethane (20mL), DIPEA (820mg, 3.9mmol) was added, acryloyl chloride (140mg, 1.6mmol) was added dropwise at room temperature, and stirring was continued for 1 hour. Quench with water and extract three times with dichloromethane (20 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target product 1- (4- (7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-5, 6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (480mg, yield: 84%).
MS m/z(ESI):442.1[M+H] +.
The seventh step: preparation of 1- (4- (7- (2-fluoro-6-hydroxyphenyl) -2-hydroxy-6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000085
1- (4- (7- (2-fluoro-6-methoxyphenyl) -2-methoxy-6-methyl-5, 6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (450mg, 1.0mmol) was dissolved in dichloromethane (50mL), cooled to-40 deg.C, and BBr was added dropwise3(1.3g, 5.2mmol), gradually warmed to room temperature, and stirred for 2 hours. Adding saturated NaHCO3The aqueous solution was stirred for 1 hour, and extracted three times with ethyl acetate (10 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target product 1- (4- (7- (2-fluoro-6-hydroxyphenyl) -2-hydroxyl6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] yl]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (350mg, yield: 85%).
MS m/z(ESI):414.1[M+H] +.
Eighth step: preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000086
4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-6-methylphenyl) -6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-2 (1H) -one (100mg, 0.24mmol) was dissolved in MeOH (20mL), 2-isopropyl-4-methyl-3-pyridineboronic acid (90mg, 0.5mmol), copper acetate (100mg, 0.5mmol), tetramethylethylenediamine (58mg, 0.5mmol) were added, heated to 60 ℃, and stirred for 15 hours. Water and ethyl acetate (10mL) were added and extracted three times. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated to give a crude product, which was purified by preparative HPLC to give the desired product 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-2 (1H) -one (12mg, yield: 9%).
MS m/z(ESI):561.1[M+H] +.
Example 36
Preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-6-methylphenyl) -6-methyl-5, 6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000087
The first step is as follows: preparation of 4, 6-dichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide
Figure PCTCN2020093731-APPB-000088
Oxalyl chloride (501mg,3.95mmol) was added dropwise to a solution of 4, 6-dichloronicotinamide (500mg,2.63mmol) in tetrahydrofuran (30mL) at room temperature, the temperature was raised to 70 ℃ and stirred for 1 hour, the reaction was cooled to room temperature, triethylamine (1063mg,10.5mmol) was added, and a solution of 2-isopropyl-4-methylpyridin-3-amine (1184mg,7.89mmol) in tetrahydrofuran (10mL) was added and stirred for 1 hour. The reaction was quenched with water (50mL) and extracted with ethyl acetate (40 mL. times.3); the ethyl acetate layer was washed with a saturated NaCl solution, dried over anhydrous sodium sulfate, and purified by concentration column chromatography [ eluent: water to acetonitrile/water from 0% to 24% ] to give 4, 6-dichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide (380mg, 39% yield) as a yellow solid.
MS m/z(ESI):367.1[M+H] +,369.1[M+H+2] +。
The second step is that: preparation of 7-chloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000089
To a solution of 4, 6-dichloro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide (343mg,0.937mmol) in tetrahydrofuran (25mL) was added dropwise potassium hexamethyldisilazide (2.5mL,2.5mmol) at 0 deg.C, with stirring for 2 hours. The reaction was quenched with aqueous ammonium chloride (40mL), extracted with ethyl acetate (20 mL. times.3), and the ethyl acetate layer was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated to give 7-chloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (250mg, yield 81%) as a pale yellow solid.
MS m/z(ESI):331.1[M+H] +,369.1[M+H+2] +。
The third step: preparation of 4, 7-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000090
To a solution of 7-chloro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (240mg,0.727mmol) in acetonitrile (20mL) was added N, N-diisopropylethylamine (1.4g,11mmol) and phosphorus oxychloride (671mg,4.36mmol) at room temperature, followed by stirring at 80 ℃ for 1 hour. Cooled to room temperature and used directly in the next reaction.
The fourth step: preparation of tert-butyl (S) -4- (7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydropyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000091
To the reaction mixture in the previous step was added N, N-diisopropylethylamine (938mg,7.27mmol), and the mixture was stirred for 5 minutes, followed by addition of tert-butyl (S) -3-methylpiperazine-1-carboxylate (290mg,1.45mmol), and stirring was continued for 1 hour. Tert-butyl (S) -3-methylpiperazine-1-carboxylate (436mg,2.18mmol) was added thereto, and the mixture was stirred for 1 hour. The reaction was quenched with aqueous ammonium chloride (100mL), extracted with ethyl acetate (30 mL. times.3), and the organic phase was washed with aqueous sodium chloride (30mL) and purified by spin-dry column chromatography [ eluent: dichloromethane to methanol (containing 1% aqueous ammonia)/dichloromethane from 0% to 5% ] to give the product tert-butyl (S) -4- (7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydropyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (730mg, 196% yield over 2 steps) as a yellow solid.
MS m/z(ESI):513.2[M+H] +,515.1[M+H+2] +。
The fifth step: preparation of (S) -7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000092
To a solution of tert-butyl (S) -4- (7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydropyrido [4,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (586mg,1.14mmol) in dichloromethane (30mL) was added 2,6 lutidine (306mg,2.85mmol), trimethylsilyl trifluoromethanesulfonate (762mg,3.43mmol) at room temperature. After completion of the reaction, trimethylsilyl trifluoromethanesulfonate (762mg,3.43mmol) was added and the mixture was stirred for 1 hour. The reaction solution was used directly in the next step.
MS m/z(ESI):413.2[M+H] +,415.1[M+H+2] +。
And a sixth step: preparation of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000093
N, N-diisopropylethylamine (1.2mL) was added to the reaction mixture in the previous step, the mixture was cooled to 0 ℃ and acryloyl chloride (261mg,2.9mmol) was added thereto, and the mixture was stirred for 1 hour. The reaction solution was quenched with aqueous ammonium chloride (30mL), extracted with dichloromethane (20mL × 3), and the dichloromethane layer was purified with saturated aqueous sodium bicarbonate (20mL), saturated aqueous NaCl (20mL), dried over anhydrous sodium sulfate and then subjected to column chromatography [ eluent: dichloromethane to methanol (containing 1% aqueous ammonia)/dichloromethane from 0% to 5% ], to give (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (400mg, 75% yield in 2 steps) as a yellow oily product.
MS m/z(ESI):467.2[M+H] +,469.1[M+H+2] +。
The seventh step: preparation of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000094
(S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (180mg,0.386mmol), (2-fluoro-6-methoxyphenyl) boronic acid (131mg,0.773mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (31mg,0.0386mmol) and cesium carbonate (376mg,1.16mmol) in dioxane (7mL) and water (1mL) were stirred with microwave at 100 ℃ for 1 hour. The reaction solution was spin-dried and purified by column chromatography [ eluent: dichloromethane to methanol (containing 1% aqueous ammonia)/dichloromethane from 0% to 5% ] to give (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (50mg, 23% yield) as a yellow solid.
MS m/z(ESI):557.3[M+H] +。
Eighth step: preparation of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000095
To a solution of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-methoxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one in dichloromethane (10mL) was added boron tribromide (0.45mL,0.45mmol) dropwise at 0 ℃ to slowly turn the solution cloudy, N-diisopropylethylamine (0.1mL) was added to clear the solution, the reaction was stirred at 0 ℃ for 30 minutes, then warmed to room temperature and stirred for 1.5 hours. The reaction solution was poured into aqueous sodium hydrogencarbonate solution, extracted with dichloromethane (20mL × 3), the dichloromethane phase was washed with saturated NaCl solution (20mL), dried over anhydrous sodium sulfate and the organic phase was concentrated, and purified by preparative chromatography to give the product (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one (1.9mg, yield 4%) as a gray solid.
1H NMR(400MHz,Chloroform-d)δ9.32(br,1H),8.64(s,1H),8.26(d,J＝12Hz,1H),7.36-7.30(m,2H),6.88–7.07(m,2H),6.61–6.72(m,2H),6.42(d,J＝16Hz,1H),5.83(d,J＝12Hz,1H),4.53-4.10(m,5H),3.32–3.00(m,3H),1.26(d,J＝4Hz,3H).
MS m/z(ESI):543.2[M+H] +。
Example 37
Preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -8-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000096
Preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -8-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one is according to the route of example 36.
1H NMR(400MHz,Chloroform-d)δ9.99(s,1H),8.86(s,1H),8.68(s,1H),7.74–7.68(m,1H),7.49–7.45(m,1H),7.34–7.32(m,1H),6.86(d,J＝8.0Hz,1H),6.68–6.54(m,1H),6.43(d,J＝16.8Hz,1H),5.84(d,J＝10.0Hz,1H),5.33–5.24(m,1H),4.89–4.70(m,1H),4.61–4.40(m,1H),4.12–3.93(m,1H),3.79–3.53(m,2H),3.18–3.93(m,2H),2.26(s,3H),1.50–1.31(m,3H),1.25(s,6H).
MS m/z(ESI):561.1[M+H] +。
Example 40
Preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -8-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (5-methyl-1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000097
Preparation of 4- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -8-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -7- (5-methyl-1H-indazol-4-yl) pyrido [4,3-d ] pyrimidin-2 (1H) -one is according to the route of example 36.
1H NMR(400MHz,Chloroform-d)δ12.2(s,1H),8.85(s,1H),8.66(s,1H),8.40–8.34(m,1H),8.20(s,1H),7.45–7.43(m,1H),6.86(d,J＝8.0Hz,1H),6.69–6.55(m,1H),6.42(d,J＝16.8Hz,1H),5.84(d,J＝10.0Hz,1H),5.32–5.25(m,1H),4.87–4.66(m,1H),4.65–4.43(m,1H),4.10–3.94(m,1H),3.82–3.52(m,2H),3.17–3.96(m,2H),2.35(s,3H),2.26(s,3H),1.48–1.32(m,3H),1.25(s,6H).
MS m/z(ESI):581.1[M+H] +。
Example 46
Preparation of 1- (4- (7- (2-fluoro-6-hydroxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000098
The first step is as follows: preparation of tert-butyl (S) -4- (5-bromo-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000099
Tert-butyl 4- (5-bromo-2-chloro-6-methylpyrimidin-4-yl) piperazine-1-carboxylate (6g, 15.3mmol) was dissolved in THF (100mL), and (S) - (1-methylpyrrolidin-2-yl) methanol (2.3g, 20.0mmol), NaH (800mg, 20.0mmol) were added under ice bath, gradually warmed to room temperature, stirred for 0.5 hours, heated to 70 ℃, and the reaction was continued for 15 hours; cooled to room temperature, quenched with water, and extracted three times with ethyl acetate (50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH) 2Cl 210/MeOH: 1) purification gave the desired product tert-butyl (S) -4- (5-bromo-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (4.3g, yield: 60%).
MS m/z(ESI):470.1[M+H] +，472.1[M+H+2] +.
The second step is that: preparation of tert-butyl (S) -4- (5-formyl-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000100
Tert-butyl (S) -4- (5-bromo-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (3.5g, 7.4mmol) was dissolved in anhydrous THF (100mL), cooled to-78 ℃ under nitrogen, n-BuLi (8.9mL, 8.9mmol) was added and stirred for 0.5 h. DMF/THF (1mL/5mL) was added, stirred at 78 ℃ for 1 hour, and gradually warmed to room temperature. Stirring was continued for 2 hours. Quench with water and extract with water and ethyl acetate (3 × 50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the desired product tert-butyl (S) -4- (5-formyl-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (2.1g, yield: 68%).
MS m/z(ESI):420.1[M+H] +.
The third step: preparation of tert-butyl (S) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000101
Tert-butyl (S) -4- (5-formyl-6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidinePyridin-4-yl) piperazine-1-carboxylate (2g, 4.8mmol) was dissolved in dichloromethane (50mL), methylamine hydrochloride (640mg, 9.6mmol), NaBH (OAc) was added3(1.2g, 5.7mmol) and glacial acetic acid (30mg, 0.5 mmol). Stir at room temperature overnight. Addition of Boc2O (2.1g, 9.6mmol), and stirred at room temperature for 3 hours. Quench with water and extract with water and ethyl acetate (3 × 50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the desired product tert-butyl (S) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (2.1g, yield: 83%).
MS m/z(ESI):535.1[M+H] +.
The fourth step: preparation of 7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidine
Figure PCTCN2020093731-APPB-000102
Tert-butyl (S) -4- (5- (((tert-butoxycarbonyl) (methyl) amino) methyl) -6-methyl-2- ((1-methylpyrrolidin-2-yl) methoxy) pyrimidin-4-yl) piperazine-1-carboxylate (1.8g, 3.4mmol) was added to an aqueous NaOH solution (5M, 100mL), 2-fluoro-6-methoxybenzaldehyde (630mg, 4.1mmol) and trioctylmethylammonium chloride (220mg, 0.5mmol) were added, heated to reflux, and stirred for 5 hours. Cooling, filtering, washing the filter cake with water, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target product 7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -4- (piperazine-1-yl) -5,6,7, 8-tetrahydropyrido [4,3-d]Pyrimidine (1.5g, yield: 66%).
MS m/z(ESI):671.1[M+H] +.
The fifth step: preparation of 1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000103
Mixing 7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazine-1-yl) -5,6,7, 8-tetrahydropyrido [4,3-d]Pyrimidine (1g, 1.5mmol) was dissolved in ethyl acetate (50mL), 2M HCl in ethyl acetate (6mL) was added, stirred at room temperature for 5 hours, and concentrated to remove the solvent; the crude product was dissolved in water (20mL) and K was added2CO 3(420mg, 3.0mmol) and KI (250mg, 1.5mmol), heated to 100 ℃, stirred for 15 hours, cooled, extracted with water and ethyl acetate (3 x 30 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target product 1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (320mg, yield: 45%).
MS m/z(ESI):471.1[M+H] +.
And a sixth step: preparation of 1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000104
1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (300mg, 0.64mmol) was dissolved in dichloromethane (10mL), DIPEA (400mg, 1.9mmol) was added, acryloyl chloride (69mg, 0.77mmol) was added dropwise at room temperature, and stirring was continued for 1 hour. Quench with water and extract three times with dichloromethane (10 mL). Combining the organic layers, anhydrous sulfurDrying sodium salt, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target product 1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (310mg, yield: 93%).
MS m/z(ESI):525.1[M+H] +.
The seventh step: preparation of 1- (4- (7- (2-fluoro-6-hydroxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4,3-d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000105
1- (4- (7- (2-fluoro-6-methoxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4, 3-d)]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (100mg, 0.19mmol) was dissolved in dichloromethane (20mL), cooled to-40 deg.C, and BBr was added dropwise3(240mg, 0.96mmol), gradually warmed to room temperature, and stirred for 2 hours. Adding saturated NaHCO3The aqueous solution was stirred for 1 hour, and extracted three times with ethyl acetate (10 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to obtain a crude product, and purifying by preparative HPLC to obtain the target product 1- (4- (7- (2-fluoro-6-hydroxyphenyl) -6-methyl-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -5,6,7, 8-tetrahydropyrido [4,3-d]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (23mg, yield: 24%).
MS m/z(ESI):511.1[M+H] +.
Examples 47-52 were prepared according to the scheme of example 46.
Example i-1
Preparation of 1- (4- (7- ((5-chloro-1H-indazol-4-yl) oxo) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000106
The first step is as follows: preparation of tert-butyl 4- (2-chloro-6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000107
2, 4-dichloro-6, 7-dihydro-5H-cyclopenta [ d ] pyrimidine (5g, 26.6mmol) was dissolved in ACN (100mL), tert-butylpiperazine-1-carboxylate (5.9g, 31.7mmol), DIPEA (1.7g, 80.9mmol) and stirred at room temperature for 5 hours. Water was added and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by column chromatography (petroether/EtOAc ═ 5: 1) to give the desired product tert-butyl 4- (2-chloro-6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) piperazine-1-carboxylate (8.4g, yield: 92%).
MS m/z(ESI):339.1[M+H] +,341.1[M+H+2] +.
The second step is that: preparation of tert-butyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000108
Tert-butyl 4- (2-chloro-6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) piperazine-1-carboxylate (7g, 20.7mmol) was dissolved in THF (100mL), and (S) - (1-methylpyrrolidin-2-yl) methanol (3.6g, 31.3mmol) and NaH (1.3g, 32.5mmol) were added under ice bath, gradually warmed to room temperature, stirred for 1 hour, heated to reflux for 13 hours; cooled, quenched with water, and extracted three times with ethyl acetate (50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography (petroether/EtOAc ═ 5: 1) to give the desired product tert-butyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) piperazine-1-carboxylate (4.8g, yield: 55%).
MS m/z(ESI):418.1[M+H] +.
The third step: preparation of tert-butyl 4- (7-bromo-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000109
Tert-butyl (S) -4- (2- ((1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-cyclopenta [ d)]Pyrimidin-4-yl) piperazine-1-carboxylate (4g, 9.6mmol) was dissolved in glacial acetic acid (30mL), and liquid bromine (2.3g, 14.3mmol) was added at room temperature and stirred for 15 hours. Saturated aqueous sodium bicarbonate was added to make the mixture basic, and ethyl acetate (3 × 50mL) was extracted. Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target product tert-butyl 4- (7-bromo-2- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -6, 7-dihydro-5H-cyclopenta [ d)]Pyrimidin-4-yl) piperazine-1-carboxylate (2.6g, yield: 54%).
MS m/z(ESI):496.1[M+H] +,498.1[M+H+2] +.
The fourth step: preparation of tert-butyl 4- (7- ((5-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxo) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) piperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000110
Reacting tert-butyl 4- (7-bromo-2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-cyclopenta [ d]Pyrimidin-4-yl) piperazine-1-carboxylic acid ester (200mg, 0.4mmol)) Dissolved in DMF (50mL) and added 5-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-ol (200mg, 0.8mmol) and NaH (35mg, 8.8mmol) under ice bath. Gradually warmed to room temperature and stirred overnight. Quench with water and extract with ethyl acetate (3 × 20 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target product tert-butyl 4- (7- ((5-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxo) -2- (((S) -1-methylpyrrolidin-2-yl) methoxyl) -6, 7-dihydro-5H-cyclopenta [ d]Pyrimidin-4-yl) piperazine-1-carboxylate (160mg, yield: 60%).
MS m/z(ESI):668.1[M+H] +.
The fifth step: preparation of 5-chloro-4- ((2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-yl) oxo) -1H-indazole
Figure PCTCN2020093731-APPB-000111
Tert-butyl 4- (7- ((5-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) oxo) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) piperazine-1-carboxylate (150mg, 0.22mmol) was added to TFA (10mL) and stirred at room temperature for 2 hours. Concentration gave crude desired product 5-chloro-4- ((2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-7-yl) oxo) -1H-indazole (180 mg).
MS m/z(ESI):484.1[M+H] +.
And a sixth step: preparation of 1- (4- (7- ((5-chloro-1H-indazol-4-yl) oxo) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-cyclopenta [ d ] pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000112
Reacting 5-chloro-4- ((2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -4- (piperazin-1-yl) -6, 7-dihydro-5H-cyclopenta [ d [)]Pyrimidin-7-yl) oxo) -1H-indazole (180mg, 0.22mmol) was dissolved in dichloromethane (30mL), DIPEA (140mg, 0.66mmol) was added, acryloyl chloride (30mg, 0.33mmol) was added dropwise at room temperature, and stirring was continued for 1 hour. Adding saturated NaHCO3The aqueous solution was stirred for 1 hour and extracted three times with dichloromethane (10 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to obtain a crude product, and purifying by preparative HPLC to obtain the target product 1- (4- (7- ((5-chloro-1H-indazol-4-yl) oxo) -2- (((S) -1-methylpyrrolidin-2-yl) methoxy) -6, 7-dihydro-5H-cyclopenta [ d]Pyrimidin-4-yl) piperazin-1-yl) prop-2-en-1-one (53mg, yield: 57%).
MS m/z(ESI):538.1[M+H] +,540.1[M+H+2] +.
Examples i-2 to i-6 were prepared according to the route of example i-1.
Example ii-1
Preparation of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -7- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000113
The first step is as follows: preparation of 2, 6-dichloro-5-fluoronicotinamide
Figure PCTCN2020093731-APPB-000114
2, 6-dichloro-5-fluoronicotinic acid (25g, 119mmol) was dissolved in THF (100mL), N' -carbonyldiimidazole (21.2g, 131mmol) was added in portions and stirred at 50 ℃ for 2 hours. The reaction was cooled to 25 ℃, toluene (100mL) was added, and the mixture was concentrated to 80 mL. The concentrate was cooled to 0 ℃ and aqueous ammonia (30mL) was added dropwise, and the reaction solution was gradually warmed to room temperature and stirred for 2 hours. A large amount of water was added and extracted three times with ethyl acetate (100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography (petroether/EtOAc ═ 3: 1) to give the desired product, 2, 6-dichloro-5-fluoronicotinamide (13g, yield: 53%).
The second step is that: preparation of 2, 6-dichloro-5-fluoro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide
Figure PCTCN2020093731-APPB-000115
2, 6-dichloro-5-fluoronicotinamide (3g, 14.4mmol) was dissolved in THF (50mL), oxalyl chloride (1.4mL, 15.9mmol) was added dropwise at room temperature, stirring was carried out at room temperature for 1 hour, stirring was carried out at 60 ℃ for 3 hours, the reaction mixture was cooled to 0 ℃, triethylamine (9mL, 58mmol) was added dropwise, a THF solution of 2-isopropyl-4-methylpyridin-3-amine (2.5g, 15.9mmol) was added dropwise, and stirring was carried out at room temperature for 12 hours. Quench with water and extract with water and ethyl acetate (3 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography (petroether/EtOAc ═ 3: 1) to give the desired product 2, 6-dichloro-5-fluoro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide (1g, yield: 18%).
MS m/z(ESI):385.1[M+H] +，387.1[M+H+2] +.
The third step: preparation of 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione
Figure PCTCN2020093731-APPB-000116
2, 6-dichloro-5-fluoro-N- ((2-isopropyl-4-methylpyridin-3-yl) carbamoyl) nicotinamide (1g, 2.6mmol) was dissolved in anhydrous THF (50mL), cooled to 0 ℃ under nitrogen, KHMDS (5.5mL, 5.5mmol) was added dropwise, and stirred for 0.5 h. Quenched with saturated aqueous ammonium chloride, and extracted with water and ethyl acetate (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by column chromatography (petroether/EtOAc ═ 2: 1) to give the desired product 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione (800mg, yield: 88%).
MS m/z(ESI):349.1[M+H] +,351.1[M+H+2] +.
The fourth step: preparation of 4, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000117
Reacting 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d]Pyrimidine-2, 4(1H,3H) -dione (200mg,0.6mmol) was dissolved in ACN (10mL), DIEA (0.6mL, 3mmol), POCl was added3(0.1mL,0.86mmol) and stirred at 80 ℃ for 0.5 h. Directly used for the next reaction.
MS m/z(ESI):367.1[M+H] +,369.1[M+H+2] +.
The fifth step: preparation of tert-butyl (S) -4- (7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000118
4, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d]To ACN (10mL) containing pyrimidin-2 (1H) -one (200mg,0.6mmol), DIEA (0.6mL, 3mmol) and tert-butyl (S) -3-methylpiperazine-1-carboxylate (170mg, 0.9mmol) were added, and the mixture was stirred at room temperature for 1 hour. Quench with water and extract with water and ethyl acetate (3 × 50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 220/MeOH: 1) purifying to obtain the target product tert-butyl (S) -4- (7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridine)Pyridin-3-yl) -2-carbonyl-1, 2-dihydropyrido [2,3-d]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid ester (160mg, yield: 50%).
MS m/z(ESI):531.1[M+H] +,533.1[M+H+2] +.
And a sixth step: preparation of tert-butyl (S) -4- (6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-7- ((2- (trifluoromethyl) pyridin-3-yl) thio) -1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000119
Reacting tert-butyl (S) -4- (7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydropyrido [2,3-d ]]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (130mg, 0.25mmol) was dissolved in ACN (10mL) and K was added2CO 3(34mg, 0.25mmol), potassium 2- (trifluoromethyl) pyridine-3-thiolate (110mg, 0.5mmol), and stirred at room temperature for 2 hours. Water and ethyl acetate (3 × 30mL) were added for extraction. Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target product tert-butyl (S) -4- (6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-7- ((2- (trifluoromethyl) pyrid-3-yl) sulfo) -1, 2-dihydropyrido [2, 3-d)]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylic acid ester (150mg, yield: 89%).
MS m/z(ESI):674.1[M+H] +.
The seventh step: preparation of (S) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -7- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000120
Tert-butyl (S) -4- (6-fluoro-1- (2-isopropyl-4-methylpyridine)Pyridin-3-yl) -2-carbonyl-7- ((2- (trifluoromethyl) pyridin-3-yl) thio) -1, 2-dihydropyrido [2,3-d]Pyrimidin-4-yl) -3-methylpiperazine-1-carboxylate (150mg, 0.22mmol) was dissolved in dichloromethane (10mL), and TFA (1mL) was added and stirred at room temperature for 2 hours. The reaction solution was poured into saturated NaHCO at 0 deg.C3In the aqueous solution, dichloromethane (20mL) was extracted three times. The organic layers are combined, dried over anhydrous sodium sulfate and concentrated to obtain a crude target product (S) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -7- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrido [2,3-d]Pyrimidin-2 (1H) -one (130mg, yield: 100%).
MS m/z(ESI):574.1[M+H] +.
Eighth step: preparation of (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -7- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000121
Reacting (S) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (2-methylpiperazin-1-yl) -7- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrido [2,3-d]Pyrimidin-2 (1H) -one (130mg, 0.22mmol) was dissolved in dichloromethane (10mL), DIEA (0.2mL, 0.6mmol) was added, acryloyl chloride (40mg, 0.44mmol) was added, and the mixture was stirred at room temperature for 1 hour. Quench with water and extract with water and ethyl acetate (3 × 50 mL). Combining the organic layers, drying over anhydrous sodium sulfate, filtering, concentrating to obtain crude product, and performing column Chromatography (CH)2Cl 220/MeOH: 1) purifying to obtain a target product (S) -4- (4-acryloyl-2-methylpiperazin-1-yl) -6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -7- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrido [2,3-d]Pyrimidin-2 (1H) -one (5mg, yield: 4%).
1H NMR(400MHz,Methanol-d 4)δ8.60(dd,J＝4.8,1.6Hz,1H),8.33(d,J＝5.0Hz,1H),8.12(d,J＝6.8Hz,1H),7.83(dd,J＝8.0,1.6Hz,1H),7.37(dd,J＝8.0,4.8Hz,1H),7.06(d,J＝5.0Hz,1H),6.82(d,J＝12Hz,1H),6.44–6.24(m,1H),5.82(dd,J＝10.6,2.0Hz,1H),4.98(d,J＝59.0Hz,2H),4.40(m,2H),4.11(dd,J＝48.8,13.6Hz,1H),3.93–3.48(m,2H),2.70–2.50(m,1H),1.79(d,J＝3.8Hz,3H),1.52–1.36(m,3H),1.08(d,J＝6.8Hz,3H),0.85(d,J＝6.8Hz,3H).
MS m/z(ESI):628.1[M+H] +.
Examples ii-2 to ii-3 were prepared according to the route of example ii-1.
Examples ii to 8
Preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (1-methyl-3-methylene-2-carbonyl-1, 8-diazaspiro [4.5] decan-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000122
6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (1-methyl-3-methylene-2-carbonyl-1, 8-diazaspiro [4.5] decan-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one.
1H NMR(400MHz,MeOD)δ8.30(d,J＝8Hz,1H),8.20(d,J＝8Hz,1H),7.21–7.08(m,2H),6.61–6.43(m,2H),5.88(s,1H),5.40(s,1H),4.68–4.56(m,2H),4.49(s,2H),3.53–3.34(m,2H),2.85(s,3H),2.79–2.64(m,1H),2.38–2.16(m,2H),1.93(s,3H),1.62–1.42(m,2H),1.10(d,J＝8Hz,3H),0.93(d,J＝8Hz,3H).
MS m/z(ESI):587.3[M+H] +。
Examples ii to 10
Preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (3- (3-methylene-2-carbonylpyrrolidin-1-yl) azetidin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000123
Step 1: preparation of tert-butyl 3- (4-chlorobutyrylamino) azetidine-1-carboxylate
Figure PCTCN2020093731-APPB-000124
To a solution of tert-butyl 3-aminoazetidine-1-carboxylate (2g,11.63mmol) and triethylamine (2.3g,23.26mmol) in dichloromethane (50mL) was added 4-chlorobutyryl chloride (2g,13.95mmol) at 0 deg.C, and the mixture was stirred at room temperature for 2 hours. Water (60mL) was added, dichloromethane (40 mL. times.3) was extracted, the dichloromethane phase was washed with saturated brine, concentrated and purified by column chromatography [ eluent: dichloromethane. about.0% to 3% methanol/dichloromethane ] to give tert-butyl 3- (4-chlorobutyrylamino) azetidine-1-carboxylate (3g, yield 97%) as a colorless oil.
MS m/z(ESI):267.2[M+H] +，269.2[M+H+2] +.
Step 2: preparation of tert-butyl 3- (2-carbonylpyrrolidin-1-yl) azetidine-1-carboxylate
Figure PCTCN2020093731-APPB-000125
To a solution of tert-butyl 3- (4-chlorobutyrylamino) azetidine-1-carboxylate (2.5g,9.36mmol) in tetrahydrofuran (80mL) was added sodium hydride (543mg,13.6mmol) at 0 deg.C, and stirring was completed for 2 hours. The reaction was quenched with aqueous ammonium chloride (60mL), extracted with ethyl acetate (50 mL. times.3), and the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give tert-butyl 3- (2-carbonylpyrrolidin-1-yl) azetidine-1-carboxylate (2.3g, yield 100%) as a colorless oil.
MS m/z(ESI):241.2[M+H] +。
And 3, step 3: preparation of ethyl 1- (1- (tert-butoxycarbonyl) azetidin-3-yl) -2-carbonylpyrrolidine-3-carboxylate
Figure PCTCN2020093731-APPB-000126
To a solution of tert-butyl 3- (2-carbonylpyrrolidin-1-yl) azetidine-1-carboxylate (500mg,2.08mmol) in tetrahydrofuran (12mL) was added dropwise lithium hexamethyldisilazane (4.2mL,4.2mmol) at-78 ℃ with stirring for 1 hour at-78 ℃, a solution of diethyl carbonate (492mg,4.17mmol) in tetrahydrofuran (3mL) at-78 ℃ with stirring for 1 hour at-78 ℃ and then slowly raised to 0 ℃ with stirring for 30 minutes. The reaction was quenched with aqueous ammonium chloride (40mL), extracted with ethyl acetate (40 mL. times.3), and the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give ethyl 1- (1- (tert-butoxycarbonyl) azetidin-3-yl) -2-carbonylpyrrolidine-3-carboxylate (900mg, yield 138%) as a colorless oil.
MS m/z(ESI):313.2[M+H] +。
And 4, step 4: preparation of 1- (1- (tert-butoxycarbonyl) azetidin-3-yl) -2-carbonylpyrrolidine-3-carboxylic acid
Figure PCTCN2020093731-APPB-000127
Crude ethyl 1- (1- (tert-butoxycarbonyl) azetidin-3-yl) -2-carbonylpyrrolidine-3-carboxylate (900mg,2.08mmol) and lithium hydroxide monohydrate (349mg,8.32mmol) were stirred in tetrahydrofuran (15mL) and water (3mL) at room temperature for 1.5 h. Water (50mL) was added, the mixture was washed with ethyl acetate (30 mL. times.2), the aqueous phase was adjusted to pH 3 with hydrochloric acid, extracted with ethyl acetate (30 mL. times.3), and the ethyl acetate phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 1- (1- (tert-butoxycarbonyl) azetidin-3-yl) -2-carbonylpyrrolidine-3-carboxylic acid (360mg, yield 44%) as a yellow oil.
MS m/z(ESI):285.1[M+H] +。
And 5, step 5: preparation of tert-butyl 3- (3-methylene-2-carbonylpyrrolidin-1-yl) azetidine-1-carboxylate
Figure PCTCN2020093731-APPB-000128
To 1- (1- (tert-butoxycarbonyl) azetidin-3-yl) -2-carbonylpyrrolidine-3-carboxylic acid (360mg,1.27mmol) and paraformaldehyde (57mg,1.91mmol) in ethyl acetate (10mL) was added a dimethylamine-tetrahydrofuran solution (0.76mL,1.2mol/L) at 0 deg.C, and the mixture was stirred at 80 deg.C for 2 hours. The reaction solution was concentrated and purified by column chromatography [ eluent: petroleum ether-ethyl acetate/petroleum ether from 0% to 50% to dichloromethane/ethyl acetate-1/1 ] to give tert-butyl 3- (3-methylene-2-carbonylpyrrolidin-1-yl) azetidine-1-carboxylate (250mg, yield 78%) as a white solid.
MS m/z(ESI):253.2[M+H] +。
And 6, step 6: preparation of 7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000129
To a solution of tert-butyl 3- (3-methylene-2-carbonylpyrrolidin-1-yl) azetidine-1-carboxylate (100mg,0.4mmol) in methanol (1mL) was added dioxane hydrochloride solution (5mL,4mol/L) at room temperature, and after completion of stirring at room temperature for 1 hour, the reaction mixture was concentrated to give 7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one hydrochloride (100mg, yield 133%) as a colorless oil.
MS m/z(ESI):153.1[M+H] +.
And 7, step 7: preparation of 4, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000130
To a solution of 7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (100mg,0.287mmol) in acetonitrile (8mL) was added N, N-diisopropylethylamine (370mg,2.87mmol), followed by phosphorus oxychloride (133mg,0.862mmol) at room temperature and stirred for 1H at 80 ℃. Cooled to room temperature and used directly in the next reaction.
And 8, step 8: preparation of 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (3- (3-methylene-2-carbonylpyrrolidin-1-yl) azetidin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000131
The reaction solution of the previous step was added to a solution of crude 7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one hydrochloride (100mg,0.4mmol) and N, N-diisopropylethylamine (370mg,2.87mmol) in acetonitrile (5mL) and stirred at room temperature for 1 hour. Water (60mL) was added, extraction was performed with ethyl acetate (40 mL. times.3), and the organic phase was washed with aqueous ammonium chloride (40mL) and then with aqueous sodium chloride (30mL), and purification was performed by preparative chromatography [ eluent: ethyl acetate ] after concentration to give 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (3- (3-methylene-2-carbonylpyrrolidin-1-yl) azetidin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (70mg, yield 50%) as a yellow oil.
MS m/z(ESI):482.2[M+H] +，484.2[M+H+2] +
Step 9: preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (3- (3-methylene-2-carbonylpyrrolidin-1-yl) azetidin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000132
7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (3- (3-methylene-2-carbonylpyrrolidin-1-yl) azetidin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (35mg,0.073mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (23mg,0.145mmol), (1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (6mg,0.0073mmol) and cesium carbonate (71mg,0.219mmol) were stirred in dioxane (2mL) and water (4 drops) in a microwave at 100 ℃ for 1 hour. The reaction solution was filtered, the filtrate was concentrated, and preparative chromatography [ eluent: dichloromethane/methanol ═ 12/1] was purified to give 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (3- (3-methylene-2-carbonylpyrrolidin-1-yl) azetidin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (13mg, yield 32%) as a yellow solid.
1H NMR(400MHz,CDCl 3)δ9.20(s,1H),8.61(d,J＝4Hz,1H),7.92(d,J＝12Hz,1H),7.33–7.27(m,2H),6.77–6.60(m,2H),6.08(s,1H),5.46(s,1H),5.34–5.19(m,1H),4.92(s,4H),3.77–3.57(m,2H),2.99–2.88(m,2H),2.87–2.64(m,1H),2.12(s,3H),1.29(d,J＝4Hz,3H),1.12(d,J＝4Hz,3H).
MS m/z(ESI):559.2[M+H] +。
Examples ii to 11
Preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (1-carbonyl-8-azaspiro [4.5] dec-2-en-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000133
The first step is as follows: preparation of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylic ester
Figure PCTCN2020093731-APPB-000134
To tert-butyl 4-formylpiperidine-1-carboxylate (30g,14.1mmol) in N, N-dimethylformamide (300mL) was added lithium tert-butoxide (13.5g,16.9mmol) at 0 ℃ and stirred for 30 minutes, followed by addition of allyl bromide (19g,16.2mmol) and stirring at 0 ℃ for 2 hours. The reaction solution was poured into an aqueous ammonium chloride solution (1L), extracted with ethyl acetate (1L. times.2), and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (500mL), dried over anhydrous sodium sulfate and purified by column chromatography [ eluent: petroleum ether-ethyl acetate/petroleum ether from 0% to 2% ] to give tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (15g, yield 42%) as a colorless oily product.
The second step is that: preparation of tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylic acid ester
Figure PCTCN2020093731-APPB-000135
To a solution of tert-butyl 4-allyl-4-formylpiperidine-1-carboxylate (25g,99mmol) in tetrahydrofuran (300mL) was added dropwise vinylmagnesium chloride (65mL,123.5mmol) at-78 deg.C, and the mixture was stirred slowly at room temperature for 30 minutes. The reaction solution was poured into an aqueous ammonium chloride solution (1L), extracted with ethyl acetate (1L. times.2), the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (500mL), dried over anhydrous sodium sulfate and purified by column chromatography [ eluent: petroleum ether-ethyl acetate/petroleum ether from 0% to 5% ] to give tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (25g, yield 90%) as a colorless oily product.
The third step: preparation of tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylic acid ester
Figure PCTCN2020093731-APPB-000136
To a solution of tert-butyl 4-allyl-4- (1-hydroxyallyl) piperidine-1-carboxylate (25g,89mmol) in dichloromethane (400mL) at 0 deg.C was added a Starm's reagent (41.5g,98mmol), and the mixture was stirred at 40 deg.C for 1 hour. The reaction mixture was slowly poured into an aqueous sodium hydrogencarbonate/sodium sulfite solution (1/1,1L), extracted with dichloromethane (1L. times.2), the dichloromethane layer was washed with a saturated aqueous sodium chloride solution (500mL), dried over anhydrous sodium sulfate and then spin-dried, followed by addition of n-heptane (200mL), stirring for 5 minutes, filtration of insoluble matter, and concentration of the filtrate gave t-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate (24.8g, yield 100%) as a colorless oily product, which was quickly fed to the next step.
The fourth step: preparation of tert-butyl 1-carbonyl-8-azaspiro [4.5] dec-2-ene-8-carboxylic acid esters
Figure PCTCN2020093731-APPB-000137
Tert-butyl 4-acryloyl-4-allylpiperidine-1-carboxylate (24.8g,89mmol) and dichloro (o-isopropoxyphenylmethylene) (tricyclohexylphosphine) ruthenium (II) (1.2g,1.4mmol) were stirred in toluene (700mL) at 90 ℃ for 2 h. After the reaction liquid is cooled, the reaction liquid is concentrated and purified by column chromatography (eluent: petroleum ether-ethyl acetate/petroleum ether from 0% to 20%) to obtain a red-black solid product, namely tert-butyl 1-carbonyl-8-azaspiro [4.5] dec-2-ene-8-carboxylic ester (13g, yield 58%).
MS m/z(ESI):252.1[M+H] +。
The fifth step: preparation of 8-azaspiro [4.5] dec-2-en-1-one
Figure PCTCN2020093731-APPB-000138
To a solution of tert-butyl 1-carbonyl-8-azaspiro [4.5] dec-2-ene-8-carboxylate (100mg,0.4mmol) in methanol (1mL) was added dioxane hydrochloride solution (5mL,4mol/L) at room temperature, and after completion of the addition, the mixture was stirred at room temperature for 1 hour, and the reaction mixture was concentrated to give 8-azaspiro [4.5] dec-2-ene-1-one (80mg, yield 133%) as a colorless oil.
MS m/z(ESI):152.1[M+H] +.
And a sixth step: preparation of 4, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000139
To a solution of 7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (100mg,0.287mmol) in acetonitrile (8mL) was added N, N-diisopropylethylamine (370mg,2.87mmol), followed by phosphorus oxychloride (133mg,0.862mmol) at room temperature and stirred for 1H at 80 ℃. Cooled to room temperature and used directly in the next reaction.
The seventh step: preparation of 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (1-carbonyl-8-azaspiro [4.5] dec-2-en-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000140
The reaction solution of the previous step was added to a solution of crude 8-azaspiro [4.5] dec-2-en-1-one hydrochloride (100mg,0.4mmol) and N, N-diisopropylethylamine (370mg,2.87mmol) in acetonitrile (5mL), and stirred at room temperature for 1 hour. Water (60mL) was added, extraction was performed with ethyl acetate (40 mL. times.3), the organic phase was washed with aqueous ammonium chloride (40mL) and aqueous sodium chloride (30mL), and after concentration, thin layer chromatography [ eluent: ethyl acetate ] was performed to purify the desired product, 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (1-carbonyl-8-azaspiro [4.5] dec-2-en-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (43mg, 31% yield in two steps).
MS m/z(ESI):482.2[M+H] +，484.2[M+H+2] +.
Eighth step: preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (1-carbonyl-8-azaspiro [4.5] dec-2-en-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000141
7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (1-carbonyl-8-azaspiro [4.5] dec-2-en-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (43mg,0.088mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (27mg,0.18mmol), (1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (7mg,0.0088mmol) and cesium carbonate (86mg,0.26mmol) were stirred in dioxane (2mL) and water (0.5mL) with microwave at 100 ℃ for 1 hour. The reaction solution was filtered, the filtrate was spin-dried, and purified by thin layer chromatography [ eluent: dichloromethane/methanol ═ 12/1] to give 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (1-carbonyl-8-azaspiro [4.5] dec-2-en-8-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (13mg, yield 26%) as a yellow solid.
1H NMR(400MHz,CDCl 3)δ9.32(s,1H),8.58(d,J＝4Hz,1H),7.89(d,J＝8Hz,1H),7.74–7.63(m,1H),7.24–7.21(m,2H),6.69–6.56(m,2H),6.19(d,J＝4Hz,1H),4.50–4.45(m,2H),3.58–3.55(m,2H),3.39–3.35(m,2H),2.79–2.64(m,1H),2.38–2.16(m,2H),2.03(s,3H),1.62–1.42(m,2H),1.22(d,J＝4Hz,3H),1.06(d,J＝4Hz,3H).
MS m/z(ESI):558.2[M+H] +。
Examples ii to 15
Preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (7-methylene-6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazin-2-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000142
The first step is as follows: preparation of tert-butyl 6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazine-2-carboxylic acid esters
Figure PCTCN2020093731-APPB-000143
To a solution of octahydro-6H-pyrido [1,2-a ] pyrazin-6-one (500mg,2.6mmol) and triethylamine (800mg,7.8mmol) in dichloromethane (50mL) at 0 ℃ was added di-tert-butyl dicarbonate (1.1g,5.2mmol), and the mixture was stirred at room temperature for 2 hours. Water (60mL) was added, dichloromethane (40 mL. times.3) was extracted, the dichloromethane layer was washed with saturated brine, and after concentration, column chromatography [ eluent: Petroleum ether-Ethyl acetate/Petroleum ether from 0% to 50% ] was performed to obtain tert-butyl 6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazine-2-carboxylate (700mg, yield 93%) as a yellow oil.
MS m/z(ESI):255.1[M+H] +.
The second step is that: preparation of 2- (tert-butyl) 7-ethyl 6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazine-2, 7-dicarboxylate
Figure PCTCN2020093731-APPB-000144
To a solution of tert-butyl 3- (2-carbonylpyrrolidin-1-yl) azetidine-1-carboxylate (700mg,2.4mmol) in tetrahydrofuran (12mL) was added dropwise lithium hexamethyldisilazane (4.8mL,4.8mmol) at-78 ℃ with stirring for 1 hour at-78 ℃ and a solution of diethyl carbonate (570mg,4.8mmol) in tetrahydrofuran (3mL) at-78 ℃ with stirring for 1 hour at-78 ℃ and slowly raised to 0 ℃ with stirring for 30 minutes. The reaction was quenched with aqueous ammonium chloride (40mL), extracted with ethyl acetate (40mL × 3), and the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2- (tert-butyl) 7-ethyl 6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazine-2, 7-dicarboxylate (800mg, yield 100%) as a yellow oil.
MS m/z(ESI):327.2[M+H] +。
The third step: preparation of 2- (tert-butoxycarbonyl) -6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazine-7-carboxylic acid
Figure PCTCN2020093731-APPB-000145
Crude 2- (tert-butyl) 7-ethyl 6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazine-2, 7-dicarboxylate (800mg,2.45mmol) and lithium hydroxide monohydrate (500mg,9.8mmol) were stirred in tetrahydrofuran (10mL) and water (2mL) at room temperature for 2 hours. Water (50mL) was added, the mixture was washed with ethyl acetate (30 mL. times.2), the aqueous phase was adjusted to pH 3 with 2N diluted hydrochloric acid, ethyl acetate (30 mL. times.3) was extracted, the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 2- (tert-butoxycarbonyl) -6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazine-7-carboxylic acid (650mg, yield 89%) as a yellow oil.
MS m/z(ESI):299.1[M+H] +。
The fourth step: preparation of tert-butyl 7-methylene-6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazine-2-carboxylic acid ester
Figure PCTCN2020093731-APPB-000146
To a solution of 2- (tert-butoxycarbonyl) -6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazine-7-carboxylic acid (650mg,2.2mmol) and paraformaldehyde (100mg,3.3mmol) in ethyl acetate (10mL) was added a dimethylamine-tetrahydrofuran solution (1.3mL, 2.6mol/L) at 0 ℃ and stirred at 80 ℃ for 2 hours. The reaction solution was concentrated and purified by column chromatography [ eluent: petroleum ether-ethyl acetate/petroleum ether from 0% to 100% ] to give t-butyl 7-methylene-6-carbonyl octahydro-2H-pyrido [1,2-a ] pyrazine-2-carboxylate (280mg, yield 48%) as a white solid.
MS m/z(ESI):267.2[M+H] +。
The fifth step: preparation of 7-methyleneoctahydro-6H-pyrido [1,2-a ] pyrazin-6-one
Figure PCTCN2020093731-APPB-000147
To a solution of tert-butyl 7-methylene-6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazine-2-carboxylate (130mg,0.5mmol) in methanol (2mL) was added dioxane hydrochloride solution (5mL,4mol/L) at room temperature, and after stirring at room temperature for 1 hour, the reaction mixture was concentrated to give 7-methyleneoctahydro-6H-pyrido [1,2-a ] pyrazine-6-one hydrochloride (150mg, yield 150%) as a colorless oil.
MS m/z(ESI):167.1[M+H] +.
And a sixth step: preparation of 4, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000148
To a solution of 7-chloro-6-fluoro-4-hydroxy-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (100mg,0.287mmol) in acetonitrile (8mL) was added N, N-diisopropylethylamine (370mg,2.87mmol), followed by phosphorus oxychloride (133mg,0.862mmol) at room temperature and stirred for 1H at 80 ℃. Cooled to room temperature and used directly in the next reaction.
The seventh step: preparation of 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (7-methylene-6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazin-2-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000149
The reaction solution of the previous step was added to a solution of crude 7-methyleneoctahydro-6H-pyrido [1,2-a ] pyrazin-6-one hydrochloride (150mg,0.5mmol) and N, N-diisopropylethylamine (0.6mL,2.5mmol) in acetonitrile (10mL) and stirred at room temperature for 1 hour. Water (60mL) was added, extraction was performed with ethyl acetate (40mL × 3), the organic phase was washed with aqueous ammonium chloride (40mL), aqueous sodium chloride (30mL), and after concentration, thin layer chromatography [ eluent: dichloromethane/methanol ═ 20/1] was purified to give 7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (7-methylene-6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazin-2-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (150mg, yield 60%) as a yellow oil.
MS m/z(ESI):497.1[M+H] +.
Eighth step: preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (7-methylene-6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazin-2-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000150
7-chloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -4- (7-methylene-6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazin-2-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (80mg,0.16mmol), ((2-fluoro-6-hydroxyphenyl) boronic acid (50mg,0.32mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (10mg,0.02mmol) and potassium acetate (80mg,0.8mmol) were stirred in dioxane (3mL) and water (0.5mL) at 90 ℃ for 1 hour, the reaction was filtered, the filtrate was spin-dried, purified by thin layer chromatography [ eluent dichloromethane/methanol ═ 20/1] to give 6-fluoro- 7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (7-methylene-6-carbonyloctahydro-2H-pyrido [1,2-a ] pyrazin-2-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one (30mg, 32% yield) as a yellow solid.
1H NMR(400MHz,CDCl 3)δ9.20(s,1H),8.61(d,J＝4Hz,1H),7.92(d,J＝12Hz,1H),7.33–7.27(m,2H),6.77–6.60(m,2H),6.08(s,1H),5.46(s,1H),5.34–5.19(m,2H),4.92(s,4H),3.77–3.57(m,2H),1.99–1.88(m,2H),1.87–1.64(m,2H),2.12(s,3H),1.29(d,J＝4Hz,3H),1.12(d,J＝4Hz,3H).
MS m/z(ESI):573.2[M+H] +。
Examples ii to 22
Preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (4- (2-carbonyl-2, 5-dihydro-1H-pyrrol-1-yl) piperidin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000151
Preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (4- (3-methylene-2-carbonylpyrrolidin-1-yl) piperidin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one reference examples ii-10.
1H NMR(400MHz,CD 3OD)δ8.64(d,J＝7.9Hz,1H),8.30(s,1H),8.24(d,J＝7.5Hz,1H),7.32(td,J＝7.4,5.0Hz,1H),7.22(td,J＝7.7,1.5Hz,1H),7.11(dq,J＝7.5,0.8Hz,1H),6.78(dd,J＝7.5,1.7Hz,1H),6.43(dt,J＝10.8,6.2Hz,1H),6.03(dt,J＝11.0,0.9Hz,1H),4.65(p,J＝7.1Hz,1H),3.80(dd,J＝6.2,1.1Hz,2H),3.63–3.49(m,4H),3.13(hept,J＝6.8Hz,1H),2.34(s,2H),2.07–1.92(m,4H),1.46(d,J＝6.8Hz,6H).
MS m/z(ESI):573.1[M+H] +。
Examples ii to 23
Preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (4- (3-methylene-2-carbonylpyrrolidin-1-yl) piperidin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one
Figure PCTCN2020093731-APPB-000152
Preparation of 6-fluoro-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-methylpyridin-3-yl) -4- (4- (3-methylene-2-carbonylpyrrolidin-1-yl) piperidin-1-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one reference examples ii-10.
1H NMR(400MHz,CD 3OD)δ9.39(s,1H),8.65(s,1H),7.96(d,J＝9.0Hz,1H),7.30(s,2H),6.82–6.57(m,2H),6.04(s,1H),5.39(s,1H),4.75(s,2H),4.50(s,1H),3.45(s,4H),2.83(s,2H),2.06(d,J＝29.5Hz,7H),1.29(s,3H),1.12(s,3H).
MS m/z(ESI):587.1[M+H] +。
Example iii-1
Preparation of 1- ((3S) -4- (7-fluoro-6- (2-fluoro-6-hydroxyphenyl) -4- (2-isopropyl-4-methylpyridin-3-yl) -4H-imidazo [4,5-b ] quinolin-9-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000153
The first step is as follows: preparation of tert-butyl (S) -4- (4-bromo-2, 5-difluorobenzoyl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000154
4-bromo-2, 5-difluorobenzoic acid (5g,21.2mmol) was dissolved in DMF (100mL), DIPEA (5.47g, 42.4mmol) and HATU (9.7g, 25.4mmol) were added, and the mixture was stirred at room temperature for 0.5 h. Tert-butyl (S) -3-methylpiperazine-1-carboxylate (8.48g, 42.4mmol) was added and stirring was continued for 6 hours. Water was added, extracted with dichloromethane (3X 50mL), and the organic phase was washed with water (20mL) and then with saturated brine (20 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the title compound tert-butyl (S) -4- (4-bromo-2, 5-difluorobenzoyl) -3-methylpiperazine-1-carboxylate (8.2g, 92% yield).
MS m/z(ESI):419.1[M+H] +，421.1[M+H+2] +.
The second step is that: preparation of tert-butyl (S) -4- (4-bromo-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) benzoyl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000155
Tert-butyl (S) -4- (4-bromo-2, 5-difluorobenzoyl) -3-methylpiperazine-1-carboxylate (8.0g,19.1mmol), 2-isopropyl-4-methylpyridin-3-amine (2.86g,19.1mmol) were added to DMF (100mL), sodium tert-butoxide (2.38g,24.8mmol) was added, reaction was carried out at room temperature overnight, water was added, extraction was performed with ethyl acetate (3 × 50mL), and the organic phase was washed with water (20mL) and then with saturated brine (20 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification yielded the title compound tert-butyl (S) -4- (4-bromo-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) benzoyl) -3-methylpiperazine-1-carboxylate (8.5g, 81% yield).
MS m/z(ESI):549.1[M+H] +，551.1[M+H+2] +.
The third step: preparation of tert-butyl (S) -4- (4-bromo-5-fluoro-2- (N- (2-isopropyl-4-methylpyridin-3-yl) -2-nitroacetylamino) benzoyl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000156
Tert-butyl (S) -4- (4-bromo-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) benzoyl) -3-methylpiperazine-1-carboxylate (8.1g,14.7mmol), 2-nitroacetic acid (1.86g,17.7mmol) were added to DMF (100mL), and triethylamine (7.4g,73.7mmol) and T were added at 0 deg.C3P (14.1g,44.3mmol, 50% in EtOAc), gradually warmed to room temperature for reaction overnight, added water, extracted with dichloromethane (3 × 50mL), washed the organic phase with water (20mL) and then with saturated brine (20 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification yielded the title compound tert-butyl (S) -4- (4-bromo-5-fluoro-2- (N- (2-isopropyl-4-methylpyridin-3-yl) -2-nitroacetoamino) benzoyl) -3-methylpiperazine-1-carboxylate (6.3g, 68% yield).
MS m/z(ESI):636.1[M+H] +，638.1[M+H+2] +.
The fourth step: preparation of tert-butyl (S) -4- (7-bromo-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-carbonyl-1, 2-dihydroquinolin-4-yl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000157
Tert-butyl (S) -4- (4-bromo-5-fluoro-2- (N- (2-isopropyl-4-methylpyridin-3-yl) -2-nitroacetylamino) benzoyl) -3-methylpiperazine-1-carboxylate (5.8g,9.1mmol) was added to DMF (50mL), NaH (437mg,10.9mmol) was added at 0 ℃, the reaction was allowed to react at room temperature for 3 hours, the reaction was continued to 70 ℃ for 15 hours, quenched with water and extracted with dichloromethane (3 × 50 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target compound tert-butyl (S) -4- (7-bromo-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-carbonyl-1, 2-dihydroquinolin-4-yl) -3-methylpiperazine-1-carboxylate (2.7g, 48% yield).
MS m/z(ESI):618.1[M+H] +，620.1[M+H+2] +.
The fifth step: preparation of tert-butyl (S) -4- (3-amino-7-bromo-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydroquinolin-4-yl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000158
Tert-butyl (S) -4- (7-bromo-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-carbonyl-1, 2-dihydroquinolin-4-yl) -3-methylpiperazine-1-carboxylate (2.5g,4.1mmol) was added to a solvent (ethanol: water ═ 5: 1) (60mL), iron powder (1.15g,20.5mmol) and NH were added4Cl (220mg,4.1mmol), heated under reflux for 3 hours, cooled, filtered, and the filtrate was extracted with dichloromethane (3 × 50 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the title compound tert-butyl (S) -4- (3-amino-7-bromo-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydroquinolin-4-yl) -3-methylpiperazine-1-carboxylate (2.1g, 88% yield).
MS m/z(ESI):588.1[M+H] +，590.1[M+H+2] +.
And a sixth step: preparation of tert-butyl (S) -4- (6-bromo-7-fluoro-4- (2-isopropyl-4-methylpyridin-3-yl) -4H-imidazo [4,5-b ] quinolin-9-yl) -3-methylpiperazine-1-carboxylate
Figure PCTCN2020093731-APPB-000159
Tert-butyl (S) -4- (3-amino-7-bromo-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-carbonyl-1, 2-dihydroquinolin-4-yl) -3-methylPiperazine-1-carboxylate (1.5g,2.55mmol) was added to formamide (30mL), heated to 180 ℃ for 5 hours, cooled, concentrated, added water, and extracted with dichloromethane (3 x 30 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target compound tert-butyl (S) -4- (6-bromo-7-fluoro-4- (2-isopropyl-4-methylpyridine-3-yl) -4H-imidazo [4, 5-b)]Quinolin-9-yl) -3-methylpiperazine-1-carboxylic acid ester (350mg, 23% yield).
MS m/z(ESI):597.1[M+H] +，599.1[M+H+2] +.
The seventh step: preparation of (S) -1- (4- (6-bromo-7-fluoro-4- (2-isopropyl-4-methylpyridin-3-yl) -4H-imidazo [4,5-b ] quinolin-9-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000160
Reacting tert-butyl (S) -4- (6-bromo-7-fluoro-4- (2-isopropyl-4-methylpyridin-3-yl) -4H-imidazo [4, 5-b)]Quinolin-9-yl) -3-methylpiperazine-1-carboxylate (300mg,0.5mmol) was dissolved in dichloromethane (10mL), TFA (2mL) was added, and the mixture was stirred at room temperature for 2 hours. Concentrating, adding water and saturated NaHCO3The aqueous solution was adjusted to neutral and extracted with dichloromethane (3 × 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Dissolve in dichloromethane (10mL), add DIPEA (195mg, 1.5mmol), add acryloyl chloride (49mg, 0.55mmol) dropwise over an ice-water bath, and continue stirring for 1 hour. Quench with water and extract three times with dichloromethane (20 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target compound (S) -1- (4- (6-bromo-7-fluoro-4- (2-isopropyl-4-methylpyridine-3-yl) -4H-imidazo [4, 5-b)]Quinolin-9-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one (235mg, 85% yield).
MS m/z(ESI):551.1[M+H] +，553.1[M+H+2] +.
Eighth step: preparation of 1- ((3S) -4- (7-fluoro-6- (2-fluoro-6-hydroxyphenyl) -4- (2-isopropyl-4-methylpyridin-3-yl) -4H-imidazo [4,5-b ] quinolin-9-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one
Figure PCTCN2020093731-APPB-000161
Mixing (S) -1- (4- (6-bromo-7-fluoro-4- (2-isopropyl-4-methylpyridin-3-yl) -4H-imidazo [4, 5-b)]Quinolin-9-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one (30mg,0.05mmol) was dissolved in dioxane (3mL), 2-fluoro-6-hydroxyphenylboronic acid (13mg, 0.08mmol), tris (dibenzylideneacetone) dipalladium (18mg, 0.02mmol), Xantphos (23mg, 0.04mmol) and Cs were added2CO 3(49mg, 0.15mmol), nitrogen substitution. The reaction is carried out for 1 hour by microwave heating to 110 ℃. After cooling to room temperature, water and dichloromethane (3 × 20mL) were added for extraction. Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to obtain a crude product, and purifying by preparative HPLC to obtain the target compound 1- ((3S) -4- (7-fluoro-6- (2-fluoro-6-hydroxyphenyl) -4- (2-isopropyl-4-methylpyridin-3-yl) -4H-imidazo [4, 5-b)]Quinolin-9-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one (11mg, 34% yield).
MS m/z(ESI):583.1[M+H] +.
Examples iii to 12
Preparation of (2R) -3-acryloyl-11-fluoro-10- (2-fluoro-6-hydroxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-2, 3,4,4a,6, 8-hexahydro-1H-pyrandino [1',2':4,5] pyrandino [2,3-c ] quinoline-5, 7-dione
Figure PCTCN2020093731-APPB-000162
The first step is as follows: preparation of 1- (tert-butyl) 3-methyl (6R) -4- (4-bromo-2, 5-difluorobenzoyl) -6-methylpiperazine-1, 3-dicarboxylate
Figure PCTCN2020093731-APPB-000163
4-bromo-2, 5-difluorobenzoic acid (10g,42.4mmol) was dissolved in DMF (100mL), DIPEA (16.4g, 127.2mmol) and HATU (19.3g, 50.9mmol) were added, and the mixture was stirred at room temperature for 0.5 h. 1- (tert-butyl) 3-methyl (6R) -6-methylpiperazine-1, 3-dicarboxylate (13.1g, 50.9mmol) was added and stirring was continued for 13 hours. Water was added and extracted with dichloromethane (3 x 50 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the title compound, 1- (tert-butyl) 3-methyl (6R) -4- (4-bromo-2, 5-difluorobenzoyl) -6-methylpiperazine-1, 3-dicarboxylate (17.6g, 87% yield).
MS m/z(ESI):477.1[M+H] +，479.1[M+H+2] +.
The second step is that: preparation of 1- (tert-butyl) 3-methyl (6R) -4- (4-bromo-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) benzoyl) -6-methylpiperazine-1, 3-dicarboxylate
Figure PCTCN2020093731-APPB-000164
1- (tert-butyl) 3-methyl (6R) -4- (4-bromo-2, 5-difluorobenzoyl) -6-methylpiperazine-1, 3-dicarboxylate (10g,21.0mmol), 2-isopropyl-4-methylpyridin-3-amine (3.8g,25.2mmol) were added to DMF (100mL), sodium hydride (1.0g,25.2mmol) was added at 0 ℃ and the mixture was reacted at room temperature overnight; quenched with water, extracted with ethyl acetate (3 × 50mL), and the organic phase washed with water (20mL) and then with saturated brine (20 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the title compound, 1- (tert-butyl) 3-methyl (6R) -4- (4-bromo-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) benzoyl) -6-methylpiperazine-1, 3-dicarboxylate (11.8g, 77% yield).
MS m/z(ESI):607.1[M+H] +，609.1[M+H+2] +.
The third step: preparation of 1- (tert-butyl) 3-methyl (6R) -4- (4-bromo-5-fluoro-2- (N- (2-isopropyl-4-methylpyridin-3-yl) -2-nitroacetamido) benzoyl) -6-methylpiperazine-1, 3-dicarboxylate
Figure PCTCN2020093731-APPB-000165
1- (tert-butyl) 3-methyl (6R) -4- (4-bromo-5-fluoro-2- ((2-isopropyl-4-methylpyridin-3-yl) amino) benzoyl) -6-methylpiperazine-1, 3-dicarboxylate (5g,8.2mmol), 2-nitroacetic acid (1.04g,9.9mmol) were added to DMF (60mL), and triethylamine (4.1g,41mmol) and T were added at 0 deg.C3P (7.8g,24.6mmol, 50% in EtOAc), gradually warmed to room temperature for reaction overnight, added water, extracted with dichloromethane (3 × 50mL), washed the organic phase with water (20mL) and then with saturated brine (20 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification yielded the objective compound 1- (tert-butyl) 3-methyl (6R) -4- (4-bromo-5-fluoro-2- (N- (2-isopropyl-4-methylpyridin-3-yl) -2-nitroacetamido) benzoyl) -6-methylpiperazine-1, 3-dicarboxylate (3.1g, 54% yield).
MS m/z(ESI):694.1[M+H] +，696.1[M+H+2] +.
The fourth step: preparation of 1- (tert-butyl) 3-methyl (6R) -4- (7-bromo-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-carbonyl-1, 2-dihydroquinolin-4-yl) -6-methylpiperazine-1, 3-dicarboxylate
Figure PCTCN2020093731-APPB-000166
1- (tert-butyl) 3-methyl (6R) -4- (4-bromo-5-fluoro-2- (N- (2-isopropyl-4-methylpyridin-3-yl) -2-nitroacetamido) benzoyl) -6-methylpiperazine-1, 3-dicarboxylate (2.8g,4.0mmol) was added to DMF (50mL), NaH (192mg,4.8mmol) was added at 0 ℃ to react at room temperature for 1 hour, and heating was continued to 70 ℃ to continue the reactionAfter 15 hours of reaction, water was added to quench and extracted with dichloromethane (3 × 50 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purification gave the title compound 1- (tert-butyl) 3-methyl (6R) -4- (7-bromo-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-carbonyl-1, 2-dihydroquinolin-4-yl) -6-methylpiperazine-1, 3-dicarboxylate (0.8g, 30% yield).
MS m/z(ESI):676.1[M+H] +，678.1[M+H+2] +.
The fifth step: preparation of tert-butyl (2R) -10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-5, 7-dicarbonyl-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrandino [1',2':4,5] pyrandino [2,3-c ] quinoline-3-carboxylic acid ester
Figure PCTCN2020093731-APPB-000167
1- (tert-butyl) 3-methyl (6R) -4- (7-bromo-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -3-nitro-2-carbonyl-1, 2-dihydroquinolin-4-yl) -6-methylpiperazine-1, 3-dicarboxylate (700mg,1.0mmol) was added to a solvent (ethanol: water ═ 5: 1) (50mL), iron powder (280mg,5mmol) and NH were added4Cl (110mg,2.1mmol), heated under reflux for 3 hours, cooled, filtered, and the filtrate was added with saturated brine and extracted with dichloromethane (3 × 30 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target compound tert-butyl (2R) -10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-5, 7-dicarbonyl-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrandinitrogen group [1',2':4,5]Pyrane diazenyl [2,3-c ]]Quinoline-3-carboxylic acid ester (420mg, 66% yield).
MS m/z(ESI):614.1[M+H] +，616.1[M+H+2] +.
And a sixth step: preparation of tert-butyl (2R) -10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dicarbonyl-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrandino [1',2':4,5] pyrandino [2,3-c ] quinoline-3-carboxylic acid ester
Figure PCTCN2020093731-APPB-000168
Tert-butyl (2R) -10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2-methyl-5, 7-dicarbonyl-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrandino [1',2':4, 5)]Pyrane diazenyl [2,3-c ]]Quinoline-3-carboxylic acid ester (400mg,0.65mmol) was added to DMF (20mL), NaH (31mg,0.78mmol), methyl iodide (101mg,0.72mmol) were added at 0 deg.C, stirred for 1 hour, allowed to warm to room temperature and allowed to react for 2 hours, quenched with water, added with water, and extracted with dichloromethane (3X 30 mL). Drying the organic layer with anhydrous sodium sulfate, filtering, concentrating, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target compound tert-butyl (2R) -10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dicarbonyl-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrane diazanyl [1',2':4,5]Pyrane diazenyl [2,3-c ]]Quinoline-3-carboxylic acid ester (330mg, yield 80%).
MS m/z(ESI):628.1[M+H] +，630.1[M+H+2] +.
The seventh step: preparation of (2R) -3-acryloyl-10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-2, 3,4,4a,6, 8-hexahydro-1H-pyrandino [1',2':4,5] pyrandino [2,3-c ] quinoline-5, 7-dione
Figure PCTCN2020093731-APPB-000169
Tert-butyl (2R) -10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-5, 7-dicarbonyl-1, 2,4,4a,5,6,7, 8-octahydro-3H-pyrandino [1',2':4,5]Pyrane diazenyl [2,3-c ]]Quinoline-3-carboxylic acid ester (300mg,0.48mmol) was dissolved in dichloromethane (10mL), and TFA (2mL) was added and stirred at room temperature for 2 hours. Concentrating, adding water and saturated NaHCO3The aqueous solution is adjusted to neutral, dichloroMethane (3 × 50mL) was extracted. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give the crude product. Dissolved in dichloromethane (10mL), DIPEA (195mg, 1.5mmol) was added, acryloyl chloride (47mg, 0.53mmol) was added dropwise under an ice-water bath, and stirring was continued for 1 hour. Quench with water and extract three times with dichloromethane (20 mL). Combining the organic layers, drying over anhydrous sodium sulfate, concentrating to give crude product, and performing column Chromatography (CH)2Cl 210/MeOH: 1) purifying to obtain the target compound (2R) -3-acryloyl-10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridine-3-yl) -2, 6-dimethyl-2, 3,4,4a,6, 8-hexahydro-1H-pyrandinyl [1',2':4, 5)]Pyrane diazenyl [2,3-c ]]Quinoline-5, 7-dione (210mg, 76% yield).
MS m/z(ESI):582.1[M+H] +，584.1[M+H+2] +.
Eighth step: preparation of (2R) -3-acryloyl-11-fluoro-10- (2-fluoro-6-hydroxyphenyl) -8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-2, 3,4,4a,6, 8-hexahydro-1H-pyrandino [1',2':4,5] pyrandino [2,3-c ] quinoline-5, 7-dione
Figure PCTCN2020093731-APPB-000170
The (2R) -3-acryloyl-10-bromo-11-fluoro-8- (2-isopropyl-4-methylpyridin-3-yl) -2, 6-dimethyl-2, 3,4,4a,6, 8-hexahydro-1H-pyrandinyl [1',2':4,5]Pyrane diazenyl [2,3-c ]]Quinoline-5, 7-dione (20mg,0.03mmol) was dissolved in dioxane (3mL), and 2-fluoro-6-hydroxyphenylboronic acid (7mg, 0.04mmol), tris (dibenzylideneacetone) dipalladium (18mg, 0.02mmol), Xantphos (23mg, 0.04mmol), and Cs were added2CO 3(33mg, 0.1mmol), nitrogen substitution. The reaction is carried out for 1 hour by microwave heating to 110 ℃. After cooling to room temperature, water and dichloromethane (3 × 20mL) were added for extraction. Combining organic layers, drying by anhydrous sodium sulfate, concentrating to obtain a crude product, and purifying by preparative HPLC to obtain a target compound (2R) -3-acryloyl-11-fluoro-10- (2-fluoro-6-hydroxyphenyl) -8- (2-isopropyl-4-methylpyridine-3-yl) -2, 6-dimethyl-2, 3,4,4a,6, 8-hexahydro-1H-pyranyl [1',2':4,5]Pyrane diazenyl [2,3-c ]]Quinolines-5, 7-dione (6mg, yield 29%).
MS m/z(ESI):614.1[M+H] +.
Biological test evaluation
The present invention is further described and explained below in conjunction with test examples, which are not intended to limit the scope of the present invention.
Test example 1 assay for the inhibitory Effect of the Compound of the present invention on the proliferative Activity of H358/Mia PaCa-2 cells
1.1 purpose of experiment:
the purpose of this test example was to measure the inhibitory effect of compounds on the proliferative activity of H358 and Mia PaCa-2 cells.
1.2 laboratory instruments and reagents:
1.2.1 Instrument:
microplate reader (BioTek Synergy H1);
pipettor (Eppendorf & Rainin).
1.2.2 reagents:
NCI-H358 was purchased from Nanjing Kebai Biotech Ltd;
mia PaCa-2 was purchased from ATCC;
cell Titer-Glo cells were purchased from Promega under the product number G7573;
RPMI 1640 was purchased from Gibco under cat # 22400089;
DMEM available from Gibco under the cat number 11995065;
FBS is available from Gibco under the cat # 10091148;
PBS from Gibco, cat # 10010023;
pancreatin was purchased from Gibco under the cat number 25200056;
cell culture plates were purchased from Corning under the accession number 3610.
1.3 Experimental methods:
culturing H358 or Mia PaCa-2 cells to an appropriate confluency, collecting H358 or Mia PaCa-2 cells, adjusting the cells to an appropriate cell concentration using complete medium, plating the cell suspension in a 96-well plate at 90. mu.L/well, placing at 37 ℃ and 5% CO2Incubators attached overnight, with DMSO and incubationsPreparing compound solutions with different concentrations, setting solvent control, adding the compound solution into 96-well plate, placing 10 μ L per well, placing at 37 deg.C and 5% CO2And (3) continuously culturing for 72-144H in the incubator, adding CellTiter-Glo solution, shaking and mixing uniformly, incubating for 10 minutes in a dark place, and reading by using a BioTek Synergy H1 enzyme-labeling instrument.
1.4 Experimental data processing method:
calculating the inhibition rate by using the luminescence signal value, and fitting the concentration and the inhibition rate by using Graphpad Prism software to obtain IC50The value is obtained.
1.5 Experimental results:
the results of the experiments are shown in Table 1, IC of the example compounds on NCI-H358 and Mia PaCa-2 cell proliferation inhibitory Activity50The value is obtained.
TABLE 1
Figure PCTCN2020093731-APPB-000171
Figure PCTCN2020093731-APPB-000172
1.6. And (4) experimental conclusion:
according to the data, the compounds of the examples of the invention have good proliferation inhibition effect on NCI-H358 and Mia PaCa-2 cells.
Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative and that various changes or modifications may be made without departing from the principles and spirit of the invention. The scope of the invention is therefore defined by the appended claims.

Claims (21)

  1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2020093731-APPB-100001
    wherein:
    X 1selected from N or CR1；
    X 2Selected from N or CR2；
    L is selected from the group consisting of a bond, - (CH)2) n-、-C(R bbR cc) n-、-O(CH 2) n-、-(CH 2) nO-、-S(CH 2) n-、-(CH 2) nS-、-NR bb(CH 2) n-、-NR bb(CH 2) nC(O)-、-CH＝CH(CH 2) n-、-(CH 2) nC(O)NR bb-、-(CH 2) nC(O)-、-CH＝CH(CH 2) nNR bb-、-(CH 2) nS(O) m-、-(CH 2) nNR bb-or- (CH)2) nNR bbS(O) m-；
    Ring a is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl;
    R 1selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH)2) n-、-NH(CH 2) nC(O)R aa、-O(CH 2) nR aa、-(CH 2) nSR aaOr- (CH)2) nC(O)R aaSaid amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally may be further substituted;
    R 2selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
    R 3selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thio, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -O (CH)2) nR bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR cc、-NR bb(CH 2) nNR ccR dd、-CH＝CH(CH 2) nR bb、-CH＝CH(CH 2) nNR bbR cc、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)R cc、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)NR ccR dd、-(CH 2) nR bb、-(CH 2) nSR bb、-(CH 2) nC(O)R bb、-(CH 2) nC(O)OR bb、-(CH 2) nS(O) mR bb、-(CH 2) nNR bbR cc、-(CH 2) nC(O)NR bbR cc、-(CH 2) nNR bbC(O)R ccOr- (CH)2) nNR bbS(O) mR ccOptionally, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, and heterocyclyl may be further substituted;
    R 4selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
    R 5selected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
    R aselected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, alkyl, alkenyl, alkynyl, oxo, thioxo,Deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally being further substituted;
    R aaselected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
    R bband RccEach independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally being further substituted;
    or, RbbAnd RccForm, with an adjacent atom, a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally may be further substituted;
    R ddselected from the group consisting of hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, said amino, alkyl, alkenyl, alkynyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, and mixtures thereofAlkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl optionally may be further substituted;
    or, RccAnd RddForm, with an adjacent atom, a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which cycloalkyl, heterocyclyl, aryl and heteroaryl groups optionally may be further substituted;
    x is an integer of 0-6;
    n is an integer of 0 to 3; and is
    m is an integer of 0-2;
    wherein, when X1When is N, X2Is N;
    or, when X1Is CR1，X 2Is CR2。
  2. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is1Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, - (CH)2) n-、-NH(CH 2) nC(O)R aa、-O(CH 2) nR aa、-(CH 2) nSR aaOr- (CH)2) nC(O)R aaSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl radical, C2-6Alkenylcarbonyl and 3-12 membered heterocyclyl;
    preferably 3-to 10-membered heterocyclyl or- (CH)2) nC(O)R aaSaid 3-to 10-membered heterocyclic group is optionally substituted by hydrogen, hydroxy, halogen, amino, C1-3Alkyl radical, C2-6Alkenylcarbonyl and 3-10 membered heterocyclyl;
    R aaselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl radical, C2-6Alkenylcarbonyl, 3-12 membered heterocyclyl, -C (O), (CH)2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbSubstituted with one or more substituents of (a);
    preferably 3-10 membered heterocyclic group, said 3-12 membered heterocyclic group being optionally substituted by hydrogen, hydroxy, halogen,Amino group, C1-6Alkyl radical, C2-6Alkenylcarbonyl, 3-12 membered heterocyclyl, -C (O), (CH)2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbSubstituted with one or more substituents of (a);
    R bband n is as defined in claim 1.
  3. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is2Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl;
    preferably hydrogen, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
    more preferably hydrogen, halogen or C1-3An alkyl group.
  4. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is3Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl,C 6-12Aryl, 5-12 membered heteroaryl, -O (CH)2) nR bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR cc、-NR bb(CH 2) nNR ccR dd、-CH＝CH(CH 2) nR bb、-CH＝CH(CH 2) nNR bb(CH 2) mC(O)R cc、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-CH＝CH(CH 2) nNR bbR ccor-CH ═ CH (CH)2) nNR bb(CH 2) mC(O)NR ccR ddSaid amino group, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl and 3-12 membered heterocyclyl;
    preferably hydrogen, amino, C3-12Cycloalkyl, 3-12 membered heterocyclyl, -O (CH)2) nR bb、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-OC(R bbR cc) n(CH 2) mR dd、-NR bb(CH 2) nR ccor-NRbb(CH 2) nNR ccR ddSaid C is3-12Cycloalkyl and 3-12 membered heterocyclyl optionally substituted by hydrogen, C1-6Alkyl and 3-12 membered heterocyclyl;
    R bband RccIndependently of one another hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl and 3-12 membered heterocyclyl;
    R ddselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1- 6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, cyano, C1-6Alkyl and 3-12 membered heterocyclyl;
    m and n are as defined in claim 1.
  5. The compound, its stereoisomers, or its pharmaceutically acceptable salts according to claim 1, wherein R is4Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl;
    preferably hydrogen, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
    more preferably hydrogen, halogen or C1-3An alkyl group.
  6. A compound according to claim 1, a stereoisomer thereof or a pharmaceutical thereofA pharmaceutically acceptable salt, wherein R is5Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl radical, C2-6Alkenylcarbonyl, 3-12 membered heterocyclyl, -C (O), (CH)2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbSubstituted with one or more substituents of (a);
    preferably hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C3-8Cycloalkyl or 3-to 10-membered heterocyclyl, said C1-6Alkyl radical, C3-8Cycloalkyl and 3-10 membered heterocyclyl, optionally substituted by hydrogen, hydroxy, halogen, amino, C1-6Alkyl radical, C2-6Alkenylcarbonyl, 3-12 membered heterocyclyl, -C (O), (CH)2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbSubstituted with one or more substituents of (a);
    R bband n is as defined in claim 1.
  7. According toThe compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R isaSelected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl or cyano substituted C1-6Alkyl radical, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl and cyano substituted C1-6Alkyl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1- 6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
    preferably hydrogen, halogen, amino, hydroxy, oxo, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano and C1-6Alkyl is substituted by one or more substituents.
  8. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein formula (I) is further represented by formula (II):
    Figure PCTCN2020093731-APPB-100002
    wherein:
    M 1selected from the group consisting of CR6R 7Or NR6；
    R 6Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, -C (O) (CH)2) nCH＝CHR bbOr-c (o) CH ═ CH (CH)2) nR bbSaid C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
    preferably 3-12 membered heterocyclyl, -C (O) (CH)2) nCH＝CHR bbOr-c (o) CH ═ CH (CH)2) nR bbSaid 3-12 membered heterocyclyl is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
    R 7selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; preferably hydrogen;
    R bselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl or cyano substituted C1-6An alkyl group; preferably hydrogen, halogen or C1-3An alkyl group;
    y is an integer of 0 to 6.
  9. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein formula (I) is further represented by formula (III):
    Figure PCTCN2020093731-APPB-100003
    wherein:
    M 2selected from the group consisting of CR8R 9Or NR8；
    R 8Selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl, 5-12 membered heteroaryl, -C (O) (CH)2) nCH＝CHR bbOr-c (o) CH ═ CH (CH)2) nR bbSaid C is1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
    preferably 3-12 membered heterocyclyl, -C (O) (CH)2) nCH＝CHR bbAnd-c (o) CH ═ CH (CH)2) nR bbSaid 3-12 membered heterocyclyl is optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
    R 9selected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl; preferably hydrogen;
    R cselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Hydroxyalkyl or cyano radicalsSubstituted C1-6An alkyl group; preferably hydrogen, halogen or C1-3An alkyl group;
    z is an integer of 0 to 6.
  10. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 8, wherein formula (II) is further represented by formula (IV):
    Figure PCTCN2020093731-APPB-100004
  11. the compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 9, wherein formula (III) is further represented by formula (V):
    Figure PCTCN2020093731-APPB-100005
    wherein:
    L 2selected from the group consisting of a bond, -O (CH)2) n-、-OC(R bbR cc) n(CH 2) m-、-NR bb(CH 2) n-、-NR bb(CH 2) nNR cc-、-CH＝CH(CH 2) n-or-CH ═ CH (CH)2) nNR bb(CH 2) mC(O)-、-(CH 2) nC(O)NR bb-、-(CH 2) nC(O)-、-CH＝CH(CH 2) nNR bb-or-CH ═ CH (CH)2) nNR bb(CH 2) mC(O)NR cc-；
    Ring B is selected from C3-12Cycloalkyl, 3-14 membered heterocyclyl, C6-14Aryl or 5-14 membered heteroaryl;
    preferably 3-12 membered heterocyclic group, C6-12Aryl or 5-12 membered heteroaryl;
    R dselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1- 6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, oxo, thioxo, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl;
    t is an integer of 0 to 6.
  12. The compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 10, wherein formula (IV) is further represented by formula (VI):
    Figure PCTCN2020093731-APPB-100006
    wherein:
    R 2selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
    preferably hydrogen, fluorine, chlorine, bromine, hydroxyl, C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group;
    more preferably fluorine or hydroxyl;
    R 3selected from hydrogen, amino, C3-12Cycloalkyl, 3-12 membered heterocyclyl, -O (CH)2) nR bb、-(CH 2) nC(O)NR bbR cc、-(CH 2) nC(O)R bb、-OC(R bbR cc) n(CH 2) mR dd、-N＝CR bb(CH 2) nNR ccR dd、-NR bbC(O)(CH 2) nR cc、-NR bb(CH 2) nR ccor-NRbb(CH 2) nNR ccR ddSaid C is3-12Cycloalkyl and 3-12 membered heterocyclyl, optionally substituted by hydrogen, C1-6Alkyl and 3-12 membered heterocyclyl;
    preferably-N ═ CHNRccR dd、-NR bbC(O)R cc、-NR bb(CH 2) nR ccor-NHb(CH 2) nNR ccR dd；
    More preferably
    Figure PCTCN2020093731-APPB-100007
    Figure PCTCN2020093731-APPB-100008
    R 10Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-6Alkyl radical, C1-6Haloalkyl or C1-6An alkoxy group;
    preferably hydrogen, halogen, hydroxy, C1-3Alkyl radical, C1-3Haloalkyl or C1-3An alkoxy group;
    more preferably hydrogen or methyl;
    R 11selected from hydrogen, halogen, amino, hydroxy, oxo, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl or 5-to 10-membered heteroaryl, said amino, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Hydroxyalkyl radical, C3-8Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl, optionally substituted with hydrogen, deuterium, halogen, amino, hydroxy, cyano and C1-6Substituted by one or more substituents in the alkyl group;
    preferably hydrogen, amino, hydroxy or C1-3An alkoxy group;
    more preferably hydrogen, amino, hydroxy or methoxy;
    R bband RccEach independently selected from hydrogen, deuterium, halogen, amino, hydroxyl, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, cyano, C1-6Alkyl amino acyl, amino acyl and 3-12 member heterocyclic radical one or more substituents substituted;
    R ddselected from hydrogen, deuterium, halogen, amino, hydroxy, cyano, nitro, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1- 6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl or 5-12 membered heteroaryl, said amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Deuterated alkyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, C1-6Hydroxyalkyl, cyano-substituted C1-6Alkyl radical, C3-12Cycloalkyl, 3-12 membered heterocyclyl, C6-12Aryl and 5-12 membered heteroaryl, optionally substituted by hydrogen, hydroxy, halogen, amino, cyano, C1-6Alkyl radical, C1-6Alkyl amino acyl, amino acyl and 3-12 member heterocyclic radical one or more substituents substituted; and is
    m and n are integers of 0 to 3.
  13. The compound of any one of claims 1 or 8 to 11, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
    ring A is selected from C6-10Aryl or 5-12 membered heteroaryl, said 5-12 membered heteroaryl preferably containing 1-3 nitrogen atoms, including 5-7 membered nitrogen-containing heteroaryl, benzo 5-7 membered nitrogen-containing heteroaryl or 5-7 membered nitrogen-containing heteroarylacenyl, more preferably the following groups:
    Figure PCTCN2020093731-APPB-100009
  14. the compound of each formula, its stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 9,
    ring B is selected from 5-12 membered heterocyclic group containing 1-3 nitrogen atoms, more preferably the following groups:
    Figure PCTCN2020093731-APPB-100010
    Figure PCTCN2020093731-APPB-100011
  15. a compound of formula (VII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2020093731-APPB-100012
    ring C is selected from phenyl, pyridyl, 5-7 membered nitrogen containing heteroaryl, benzo 5-7 membered nitrogen containing heteroaryl or 5-7 membered nitrogen containing heteroarylacenyl, further preferably from the group consisting of:
    Figure PCTCN2020093731-APPB-100013
    R 12selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl;
    hydrogen, fluorine, chlorine, methyl, ethyl, propyl, methoxy or ethoxy are preferred.
    R eSelected from hydrogen, halogen, hydroxy, amino, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C1-3Hydroxyalkyl radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl;
    preferably hydrogen, fluorine, chlorine, hydroxyl, amino or methyl;
    p is an integer of 0 to 4.
  16. A compound of formula (VIII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2020093731-APPB-100014
    wherein:
    X 3is selected from CH2CH, N orNR 13；
    X 4Is selected from CH2C O, N or CR14；
    M is selected from N or CH;
    L 3is selected from-O-or-OCH2-；
    L 4Is selected from-O-or-CH2-；
    R 13Selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl;
    preferably methyl or cyclopropyl;
    R 14selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl;
    preferably hydrogen or methyl;
    r is selected from 3-8-membered nitrogen-containing heterocyclic group or benzo 3-8-membered nitrogen-containing heterocyclic group, further preferably 5-7-membered nitrogen-containing heterocyclic group or benzo 5-7-membered nitrogen-containing heterocyclic group, wherein the number of nitrogen atoms is 1-2, optionally substituted by halogen or C1-3Substituted by one or more substituents in the alkyl group,
    the following substituents are preferred:
    Figure PCTCN2020093731-APPB-100015
    R 15selected from hydrogen, halogen, amino, hydroxyl, cyano, nitro, C1-3Alkyl radical, C1-3Haloalkyl, C1-3Alkoxy radical, C3-8Cycloalkyl or 3-8 membered heterocyclyl; hydrogen or fluorine are preferred.
  17. A compound of formula (IX), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2020093731-APPB-100016
    wherein:
    ring D is selected from the following groups:
    Figure PCTCN2020093731-APPB-100017
  18. a compound, stereoisomer or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 17, which is selected from the following compounds:
    Figure PCTCN2020093731-APPB-100018
    Figure PCTCN2020093731-APPB-100019
    Figure PCTCN2020093731-APPB-100020
    Figure PCTCN2020093731-APPB-100021
    Figure PCTCN2020093731-APPB-100022
    Figure PCTCN2020093731-APPB-100023
  19. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1 to 18, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  20. Use of a compound according to any one of claims 1 to 18, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, in the manufacture of a medicament for the treatment of a KRAS G12C inhibitor.
  21. Use of a compound according to any one of claims 1 to 18, a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, for the manufacture of a medicament for the treatment of diseases or disorders of noonan's syndrome, leopard syndrome, leukemia, neuroblastoma, melanoma, esophageal cancer, head and neck tumors, breast cancer, lung cancer, and colon cancer; non-small cell lung cancer, colon cancer, esophageal cancer and head and neck tumors are preferred.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113853373A (en) * 2019-10-30 2021-12-28 劲方医药科技(上海)有限公司 Substituted heterocyclic ring compound, preparation method and medical application thereof
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

Families Citing this family (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112300194B (en) * 2019-07-30 2022-01-14 上海凌达生物医药有限公司 Condensed ring pyridone compounds, preparation method and application
AU2020372881A1 (en) 2019-10-28 2022-06-09 Merck Sharp & Dohme Llc Small molecule inhibitors of KRAS G12C mutant
WO2021127404A1 (en) * 2019-12-20 2021-06-24 Erasca, Inc. Tricyclic pyridones and pyrimidones
GB202001344D0 (en) * 2020-01-31 2020-03-18 Redx Pharma Plc Ras Inhibitors
MX2022011283A (en) * 2020-03-12 2022-11-16 D3 Bio Wuxi Co Ltd Pyrimidoheterocyclic compounds and application thereof.
AU2021248363B2 (en) 2020-04-03 2024-02-15 Medshine Discovery Inc. Octahydropyrazinodiazanaphthyridine dione compounds
US20230023009A1 (en) * 2020-06-05 2023-01-26 Sparcbio Llc Heterocyclic compounds and methods of use thereof
US20230107642A1 (en) 2020-12-18 2023-04-06 Erasca, Inc. Tricyclic pyridones and pyrimidones
AU2022212151A1 (en) * 2021-02-01 2023-08-17 Medshine Discovery Inc. Pyrimidopyran compound
CA3211725A1 (en) * 2021-03-17 2022-09-22 Tao Jiang Pyrimidine-fused cyclic compound, preparation method therefor and use thereof
TW202246267A (en) * 2021-03-25 2022-12-01 大陸商上海濟煜醫藥科技有限公司 Fused pyridone compound salt form and crystal form, and application thereof
CN115124533A (en) * 2021-03-26 2022-09-30 浙江海正药业股份有限公司 Tetracyclic derivative, preparation method and medical application thereof
WO2022223037A1 (en) * 2021-04-22 2022-10-27 劲方医药科技(上海)有限公司 Salt or polymorph of kras inhibitor
WO2022266167A1 (en) * 2021-06-16 2022-12-22 Erasca, Inc. Amide and urea-containing tricyclic kras inhibitors
WO2022265974A1 (en) * 2021-06-16 2022-12-22 Erasca, Inc. Aminoheterocycle-substituted tricyclic kras inhibitors
WO2022266206A1 (en) 2021-06-16 2022-12-22 Erasca, Inc. Kras inhibitor conjugates
WO2022266069A1 (en) * 2021-06-16 2022-12-22 Erasca, Inc. Tricyclic kras g12d inhibitors
WO2022271658A1 (en) * 2021-06-23 2022-12-29 Erasca, Inc. Tricyclic kras inhibitors
WO2023283933A1 (en) * 2021-07-16 2023-01-19 Silexon Biotech Co., Ltd. Compounds useful as kras g12d inhibitors
CN117677624A (en) * 2021-07-19 2024-03-08 上海艾力斯医药科技股份有限公司 Novel pyridopyrimidine derivatives
CA3226720A1 (en) * 2021-07-23 2023-01-26 Suzhou Zanrong Pharma Limited Kras g12d inhibitors and uses thereof
TW202327569A (en) 2021-09-01 2023-07-16 瑞士商諾華公司 Pharmaceutical combinations comprising a tead inhibitor and uses thereof for the treatment of cancers
WO2023041059A1 (en) * 2021-09-18 2023-03-23 南京明德新药研发有限公司 Octahydropyrazinodiazanaphthyridine dione compound and crystal form thereof
WO2023183755A1 (en) * 2022-03-21 2023-09-28 Erasca, Inc. Tricyclic pyrimidones
WO2023212549A1 (en) * 2022-04-26 2023-11-02 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2023212548A1 (en) * 2022-04-26 2023-11-02 Erasca, Inc. Tricyclic pyridones and pyrimidones
WO2024076674A1 (en) * 2022-10-05 2024-04-11 Amgen Inc. Heterocyclic inhibitors of kras g12c mutant proteins and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104844573A (en) * 2015-04-17 2015-08-19 中国药科大学 Miazines BTK inhibitor, preparation method and medical application thereof
CN105189456A (en) * 2013-03-15 2015-12-23 亚瑞克西斯制药公司 Covalent inhibitors of KRAS G12C
WO2016044772A1 (en) * 2014-09-18 2016-03-24 Araxes Pharma Llc Combination therapies for treatment of cancer

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JOP20190272A1 (en) * 2017-05-22 2019-11-21 Amgen Inc Kras g12c inhibitors and methods of using the same
AU2019262589B2 (en) * 2018-05-04 2022-07-07 Amgen Inc. KRAS G12C inhibitors and methods of using the same
MX2020012261A (en) * 2018-06-12 2021-03-31 Amgen Inc Kras g12c inhibitors encompassing a piperazine ring and use thereof in the treatment of cancer.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105189456A (en) * 2013-03-15 2015-12-23 亚瑞克西斯制药公司 Covalent inhibitors of KRAS G12C
WO2016044772A1 (en) * 2014-09-18 2016-03-24 Araxes Pharma Llc Combination therapies for treatment of cancer
CN104844573A (en) * 2015-04-17 2015-08-19 中国药科大学 Miazines BTK inhibitor, preparation method and medical application thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113853373A (en) * 2019-10-30 2021-12-28 劲方医药科技(上海)有限公司 Substituted heterocyclic ring compound, preparation method and medical application thereof
CN115057872A (en) * 2019-10-30 2022-09-16 劲方医药科技(上海)有限公司 Substituted heterocyclic ring compound, preparation method and medical application thereof
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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