WO2021139678A1 - Pyridopyrimidine kras g12c mutant protein inhibitor - Google Patents

Pyridopyrimidine kras g12c mutant protein inhibitor Download PDF

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WO2021139678A1
WO2021139678A1 PCT/CN2021/070462 CN2021070462W WO2021139678A1 WO 2021139678 A1 WO2021139678 A1 WO 2021139678A1 CN 2021070462 W CN2021070462 W CN 2021070462W WO 2021139678 A1 WO2021139678 A1 WO 2021139678A1
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cancer
compound
alkyl
group
kras
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PCT/CN2021/070462
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French (fr)
Chinese (zh)
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徐伟
吴曙光
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广州百霆医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention belongs to the field of medical technology; the present invention relates to new substituted pyridopyrimidine derivatives, specifically to the compound represented by the general formula (I), its isomers or deuterated compounds, and pharmaceutically acceptable salts thereof,
  • the pharmaceutical preparation and the pharmaceutical composition are used in the preparation and treatment of cancer proliferative diseases.
  • RAS protein plays an important role in regulating normal cell growth and proliferation. According to the degree of conservation of RAS amino acid sequence, it can be divided into three types: KRAS, HRAS, and NRAS. RAS is in different "activated” or “inactivated” states by combining with low molecular weight guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP).
  • GTP low molecular weight guanine trinucleotide phosphate
  • GDP guanine dinucleotide phosphate
  • the RAS protein binds to GDP on the plasma membrane of resting cells to form GDP-RAS, which makes RAS in an inactive state; when the cell is stimulated by mitogens and other activating factors, the GDP combined with GDP-RAS and GDP-RAS Free GTP is exchanged, GDP is released, and at the same time, a state where RAS and GTP are combined is formed, that is, activated GTP-RAS. Only activated GTP-RAS can activate the downstream signal pathway of RAS and transmit normal RAS signals. Since the normal RAS protein has GTP hydrolase activity that hydrolyzes GTP into GDP, it can regulate the exchange between activated GTP-RAS and inactivated GDP-RAS, and maintain the balance between RAS activation and inactivation signals.
  • the exchange function between the regulated activated GTP-RAS and the inactivated GDP-RAS is out of control, which keeps the RAS signal in an active state, continuously activates downstream growth signals, stimulates abnormal cell proliferation and induces tumor The occurrence and maintenance of tumor growth (Nature Review cancer 3:11-22, 2003).
  • KRAS Kerat Rev Drug Discov 2014, 13: 828-851
  • HRAS HRAS
  • NRAS NRAS
  • K-RAS Zika virus oncogene
  • G12 glycine at position 12
  • G13 glycine at position 13
  • Q61 glutamine at position 61
  • the G12 mutation has the highest incidence (Nat Rev Drug Discov 2014, 13: 828-851).
  • K-RASRAS G12C mutation refers to the mutation of glycine at position 12 of K-RAS protein to cysteine, which is the most common subtype of K-RAS mutation.
  • the frequency of K-RAS G12C mutation tumors is pancreatic cancer (57%), colorectal cancer (35%), biliary tract cancer (28%), small intestine cancer (17%), lung cancer (16%), endometrial cancer ( 15%) and ovarian cancer (14%) (Seminars in Cancer Biology. 2019 Jun 27.pii: S1044-579X(18)30060-9).
  • Malignant tumors with K-RAS G12C mutations generally do not respond to conventional treatment methods, so patients have a poor clinical prognosis and short survival time.
  • K-RAS G12C mutant protein inhibitor is a new drug target discovered in recent years for anti-RAS targeted therapy (Nature 503:548-551, 2013).
  • K-RAS G12C covalent inhibitor uses the nucleophilic reactivity of the mutated 12th cysteine to design small molecule compounds.
  • K-RAS G12C allosteric pocket It is modified with disulfide bonds to enter the K-RAS G12C allosteric pocket and block K -RAS G12C mutant protein is activated to inhibit tumor growth, but there is still no new K-RAS G12C inhibitor with sufficient high potency and high safety that has been approved by regulatory agencies for marketing. Therefore, in this technical field, there is still an urgent need to discover new selective K-RAS G12C inhibitors for targeted therapy of K-RAS G2C mutant tumors.
  • the present invention provides a compound represented by the general formula (I), its isomer, its pharmaceutically acceptable salt or its deuterated product:
  • X is selected from a 4-8 membered saturated or partially saturated monocyclic ring containing 1 or 2 N atoms, or a 6-12 membered saturated or partially saturated bicyclic ring containing 1 or 2 N atoms, bridged ring, fused ring, spiro
  • the cyclic heterocycloalkyl group may be optionally substituted with 1, 2 or 3 R 6 which are the same or different;
  • R 1 and R 2 are selected from H, halogen, NH 2 , OH, C 1-3 alkyl and C 1-3 heteroalkyl, and the substituents may be optionally substituted by one or more;
  • R 3 is selected from 4-6 membered monocyclic or 6-12 membered bicyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, the aryl, heteroaryl, cycloalkyl, heterocycloalkane
  • the group may be substituted by 1, 2 or 3 R 7 which are the same or different;
  • R 4 is selected from H, alkyl, aminoalkyl, alkylaminoalkyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, -A-NR 8 R 9 , 4-6 membered heterocyclic group, 4-6 Membered heterocyclylalkyl, 5-6 membered aryl, 5-6 membered heteroaryl or heteroarylalkyl, where A, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl or hetero The arylalkyl group may be optionally substituted by one or more R 10 which are the same or different;
  • A is selected from C 1-4 alkylene
  • L is a bond or -NH-
  • R 5 is selected from:
  • R 6 is selected from the group consisting of nitrile group, C 1-3 alkyl group, amino group, halogen, and hydroxyl group;
  • R 7 is selected from halogen, amino, hydroxy, C 1-3 alkyl or halogen substituted C 1-3 alkyl;
  • R 8 is selected from H, or C 1- 3 alkyl
  • R 9 is selected from H, C 1-3 alkyl, heteroalkyl, hydroxyalkyl, acyl;
  • R 10 is selected from H, hydroxyl, halogen,
  • Z is selected from bond, O, S, NR 11 ;
  • R 11 is selected from H or C 1-3 alkylene
  • R 12 is selected from halogen, CF3, and hydroxyalkyl
  • R 13 is selected from H, C 1-3 alkyl, alkylaminoalkyl, alkylaminoalkyl, heterocyclylaminoalkyl, halogen, amido, nitrile, hydroxyalkyl, CF 3 , CF 2 , Methoxy, trifluoromethylamino, alkene;
  • R 14 is selected from H, alkyl, and hydroxyalkyl
  • R 15 is selected from absent, H or C 1-3 alkyl
  • hetero refers to heteroatoms or heteroatoms (atomic groups containing heteroatoms), and heteroatoms refer to atoms other than carbon (C) and hydrogen (H) and atomic groups containing these heteroatoms, such as oxygen ( O), nitrogen (N), sulfur (S), etc.; heteroatom groups refer to C 1-3 heteroalkyl, C 1-6 heteroalkyl, C 1-8 heteroalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heterocyclic aryl, 5-6 membered heterocycloalkenyl, etc;
  • R 5 is selected from:
  • R 3 is selected from:
  • R 4 is selected from:
  • the compound of the present invention isomers, its pharmaceutically acceptable salt or its deuterated compounds are selected from:
  • Certain compounds shown herein may be stereoisomers, including optical isomers and conformational isomers, represented by the general symbol R or S.
  • the present invention also provides the above-mentioned compounds, their pharmaceutically acceptable salts, their isomers, and their deuterated compounds are used in the preparation of cancer drugs.
  • the cancer includes lung cancer, pancreatic cancer, rectal/colon cancer, cholangiocarcinoma, small bowel cancer, endometrial cancer, stomach cancer, ovarian cancer, prostate cancer, cervical cancer, liver cancer, peritoneal cancer, soft tissue cancer, Leukemia, lymphoma, breast cancer, urothelial cancer, testicular cancer, skin cancer, esophageal cancer, thyroid cancer, esophageal cancer, bone cancer and eye cancer.
  • the present invention adopts the electrophoresis gel migration analysis method (gel mobility shift assay) to determine the unique electrophoretic migration change of the covalent binding complex formed by the compound and the cell KRAS G12C mutant protein; the principle is based on the combination of the compound and the K-RAS G12C mutant protein The molecular weight of the formed covalent complex increases. Compared with the free KRAS G12C mutant protein, a corresponding electrophoresis band lag occurs during electrophoresis.
  • Electrophoresis gel migration analysis showed that the compound of the present invention can selectively bind to the KRAS G12C mutant protein in human non-small cell lung cancer NCI-H358 cells containing the KRAS G12C mutation to form a compound-mutant complex, resulting in electrophoretic coagulation.
  • pharmaceutically acceptable salt refers to a salt prepared with a relatively non-toxic acid or base with a compound having a specific substituent discovered in the present invention.
  • an acid addition salt can be obtained by contacting the compound of the present invention in a neutral form with a sufficient amount of acid in a suitable pure solution or an inert solvent.
  • Inorganic acids include hydrochloric acid, sulfuric acid, hydrogen sulfate, carbonic acid, hydrogen carbonate, phosphoric acid, phosphorous acid, monohydrogen phosphate, and dihydrogen phosphate , Hydrobromic acid, hydroiodic acid and nitric acid; organic acids include such as lactic acid, benzenesulfonic acid, acetic acid, propionic acid, malonic acid, isobutyric acid, suberic acid, benzoic acid, phthalic acid, p-toluenesulfonic acid , Citric acid, tartaric acid, maleic acid, amino acids, glucuronic acid.
  • the general formula of the specific compound in the present invention contains acidic or basic groups, and therefore can be converted into acid or base addition salts.
  • stereo or geometric isomers refers to cis and trans isomers, (R)- and (S)-enantiomers, (-)- and (+)-enantiomers, (D)- Isomers, (L)-isomers, diastereomers, and racemic mixtures are all included in the scope of the present invention.
  • cis-trans isomer or "geometric isomer” is due to the fact that double bonds or single bonds of ring-forming carbon atoms cannot rotate freely.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • diastereomer refers to an isomer in which a molecule has more than two chiral centers and has a non-mirror image relationship between the molecules.
  • Dashed key with wedge And a wedge-shaped solid line key ( or ) Refers to the absolute configuration of a steric center in a molecule.
  • tautomers means that the isomers of different functional groups in the molecules of the compound of the present invention are in dynamic equilibrium and can be rapidly transformed into each other.
  • alkyl refers to a linear or branched saturated hydrocarbon group.
  • the alkyl group is a C 1-3 alkyl group; in other embodiments, the alkyl group is a C 1-6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl (including isopropyl and n-propyl), butyl (including n-butyl, isobutyl), pentyl (including n-pentyl, Isopentyl and neopentyl), hexyl.
  • the alkyl group can be monovalent (such as methyl), divalent (such as methylene), multivalent (such as methine), and can be mono-substituted (such as -CH 2 F) or multi-substituted (-CF 3 ).
  • alkenyl refers to a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds.
  • the alkenyl group is C 2-4 alkenyl; in other embodiments, the alkenyl group is C 2-6 alkenyl; in other embodiments, the alkenyl group is C 2-8 alkenyl.
  • ring refers to substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl.
  • the ring includes single ring, double ring and multiple ring. The number of atoms in the ring is defined as the number of ring members.
  • hetero refers to heteroatoms or heteroatom groups (atomic groups containing heteroatoms), that is, atoms other than carbon (C) and hydrogen (H) and atomic groups containing these heteroatoms, such as oxygen (O), nitrogen (N), Sulfur (S) and so on.
  • cycloalkyl refers to a cyclic alkyl group including a monocyclic, bicyclic or tricyclic ring system, wherein the bicyclic or tricyclic ring system includes a spiro ring, a bridged ring, and a fused ring; the alkyl group may be monovalent or divalent , Multivalent, can also be single substitution or multiple substitution.
  • cycloalkenyl refers to a cyclic alkenyl group containing one or more unsaturated carbon-carbon double bonds, wherein the bicyclic or tricyclic ring system includes a spiro ring, a bridged ring, and a fused ring; the alkyl group may be one Valence, divalent, multivalent, and can also be mono- or multi-substitution.
  • cycloalkynyl refers to a cyclic alkyl group containing one or more carbon-carbon triple bonds, including monocyclic, bicyclic, and polycyclic ring systems, wherein the bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
  • the alkyl group can be monovalent, divalent, multivalent, and can also be mono- or multi-substituted.
  • heterocycloalkyl refers to a cyclized heteroalkyl, including monocyclic, bicyclic, and polycyclic ring systems, where bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
  • heterocyclenyl refers to a cyclized heteroalkenyl group, including monocyclic, bicyclic, and polycyclic ring systems, wherein the bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
  • heterocyclic alkynyl refers to a cyclized heterocyclic alkynyl group, including monocyclic, bicyclic, and polycyclic ring systems, wherein the bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
  • aromatic ring refers to a polyunsaturated carbocyclic ring system, including monocyclic, bicyclic, and polycyclic ring systems, in which at least one ring is aromatic and can be monovalent, divalent, multivalent, or Is single substitution or multiple substitution.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art.
  • the specific embodiments and preferred embodiments listed below include but are not limited to the examples of the present invention.
  • the embodiment of the compound of general formula (I) is prepared according to the general reaction scheme (A), wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, L and Z are as defined above.
  • the reactant A1 and concentrated ammonia are heated and reacted in a pressure tube to obtain compound A2
  • the acid chloride obtained by the reaction of A2 and oxalyl chloride directly reacts with liquid ammonia to obtain compound A3, and A3 and oxalyl chloride are heated to form a ring reaction.
  • the embodiment of the compound of general formula (I) is prepared according to the general reaction scheme (B), wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, L and Z are as defined above.
  • the reactant B1 reacts with oxalyl chloride to obtain compound B2
  • B2 reacts with thiourea to obtain compound B3
  • B3 is heated to reflux to form a ring reaction to obtain B4
  • B4 reacts with phosphorus oxychloride to obtain compound B5, B5 and Structural units X and R5 in the compound are reacted in sequence to obtain compound B6,
  • B6 is reacted with different R3 groups to obtain compound B7, and B7 is reacted with structural units substituted with different R4 groups to obtain compound B8.
  • the crude compound B (100.0 mg, 0.5 mmol, 1.00 eq) was dissolved in 0.6 mL of toluene, and N,N-diisopropylethylamine (196.3 mg, 1.5 mmol, 3.00 eq) was added under the protection of nitrogen. The mixture was stirred at 70°C for 30 minutes, phosphorus oxychloride (232.8 mg, 1.5 mmol, 3.00 eq) was added, and the mixture was stirred at reflux at 100°C for 2.5 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure, water (1mL) was added, and the mixture was extracted with ethyl acetate (1mL ⁇ 3).
  • Dissolve compound B (90.6mg, 0.39mmol, 1.00eq) in 3.86mL of dichloromethane under ice bath, add N,N-diisopropylethylamine (49.94mg, 0.39mmol, 1.00eq), add (S) -4N tert-butoxycarbonyl-2 methylpiperazine (77.39 mg, 0.39 mmol, 1.00 eq), stirred at room temperature for 1 hour. After the completion of the reaction, the solvent was spin-dried under reduced pressure, water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL ⁇ 3).
  • the purpose of this experiment is to verify the compound of the present invention and human non-small cell lung cancer NCI-H358 cells (KRAS G12C mutation), human non-small cell lung cancer A549 cells (KRAS G12S mutation) and non-small cell lung cancer HCC827 cells (KRAS wild type) KRAS Covalent binding activity of G12C mutant protein.
  • Tumor cell lines Three human non-small cell lung cancer cell lines: NCI-H358 cells (KRAS G12C mutation), A549 cells (KRAS G12S mutation) and HCC827 cells (KRAS wild type).
  • RPMI1640 medium RPMI1640 medium
  • DMEM cell culture medium fetal bovine serum
  • trypsin-0.53mM EDTA digestion solution DMSO
  • penicillin-streptomycin KRAS antibody (Sigma)
  • the secondary antibody is Anti-rabbit IgG -HRP
  • Cell Titer-Gio detection kit Promega microplate detector, cell culture flask, cell culture microplate (96 or 384 well), CO 2 constant temperature incubator, FluorChemR detector (ProteinSimple).
  • the present invention adopts the gel mobility shift assay to measure the unique electrophoretic migration changes of the covalent binding complex formed by the compound and the cell KRAS G12C mutant protein; the principle is based on the combination of the compound and the K-RAS G12C mutant protein. Compared with the free KRAS G12C mutant protein, the molecular weight of the covalent complex increases, and the corresponding electrophoretic band lag occurs during electrophoresis.
  • the tumor cells Resuscitate the tumor cells cryopreserved in liquid nitrogen, culture the cells with a cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin.
  • a cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin.
  • digest and centrifuge to collect the cells and resuspend them in the culture medium ; Inoculate the cells according to the number of 5000-10000 cells per well, and place them in a carbon dioxide incubator at a constant temperature of 37°C, 5% CO 2, and saturated humidity.
  • the cells were washed with phosphate buffered saline (PBS), and then in RIPA buffer (50mm Tris, pH7.5, 150mm NaCl, 1% NP-40, 0.5% deoxycholic acid).
  • PBS phosphate buffered saline
  • RIPA buffer 50mm Tris, pH7.5, 150mm NaCl, 1% NP-40, 0.5% deoxycholic acid.
  • the purpose of this experiment is to verify the compounds of the present invention against human non-small cell lung cancer NCI-H358 cells (KRAS G12C mutation), human non-small cell lung cancer A549 cells (KRAS G12S mutation) and non-small cell lung cancer HCC827 cells (KRAS wild type). Proliferation.
  • Tumor cell lines Three human non-small cell lung cancer cell lines: NCI-H358 cells (KRAS G12C mutation), A549 cells (KRAS G12S mutation) and HCC827 cells (KRAS wild type).
  • Main reagents and instruments RPMI1640 medium, DMEM cell culture medium, fetal bovine serum, 0.25% trypsin-0.53mM EDTA digestion solution, DMSO, penicillin-streptomycin, Cell Titer-Gio detection kit.
  • the tumor cells Resuscitate the tumor cells cryopreserved in liquid nitrogen, culture the cells with a cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin.
  • a cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin.
  • digest and centrifuge to collect the cells and resuspend them in the culture medium ; Inoculate cells according to the number of 5000-10000 cells per well, and place them in a constant temperature 37°C, 5% CO 2 , saturated humidity carbon dioxide incubator for overnight culture.
  • Each test compound of the present invention is diluted into 10 concentration gradients, respectively added to the corresponding wells of the cell plate, and then the cell plate is returned to the carbon dioxide incubator to continue culturing for 72 hours. After incubation, add Promega CellTiter-Glo reagent to each well of the cell plate, incubate at room temperature for 10 minutes, use Promega microplate detector to detect the luminescence signal, and calculate the IC50 value.
  • the compound of the present invention shows a higher anti-proliferative activity inhibitory activity against KRAS G12C mutant human non-small cell lung cancer NCL-H358 cells, but has a higher antiproliferative activity against KRAS G12S mutant human non-small cell lung cancer A549 cells and KRAS wild type HCC827 cells.
  • Weak antiproliferative activity (Table 2). The results of the anti-proliferation experiment are consistent with the results obtained by the aforementioned gel mobility analysis method, indicating the high selectivity of the compound of the present invention on KRAS G12C mutant tumor cells.

Abstract

The present invention belongs to the technical field of medicine, and the specific content of the invention relates to a pyridopyrimidine KRAS G12C mutant protein inhibitor represented by general formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, and a deuterated compound thereof. The present invention further relates to a preparation method for said compound and a preparation method for a pharmaceutically acceptable salt of the compound, a pharmaceutical preparation thereof and a pharmaceutical composition. The present invention further relates to an application of said compound and a pharmaceutically acceptable salt of the compound, a pharmaceutical preparation thereof and a pharmaceutical composition in the treatment of cancer proliferative diseases caused by a KRAS G12C mutant protein.

Description

吡啶并嘧啶类KRAS G12C突变蛋白抑制剂Pyridopyrimidine KRAS G12C mutant protein inhibitor 技术领域Technical field
本发明属于医药技术领域；本发明涉及新的取代的吡啶并嘧啶类衍生物，具体涉及通式(I)所示的化合物，其异构体或其氘代物、其药学上可接受的盐、其药物制剂和药物组合物在制备治疗癌症增殖性疾病中的应用。The present invention belongs to the field of medical technology; the present invention relates to new substituted pyridopyrimidine derivatives, specifically to the compound represented by the general formula (I), its isomers or deuterated compounds, and pharmaceutically acceptable salts thereof, The pharmaceutical preparation and the pharmaceutical composition are used in the preparation and treatment of cancer proliferative diseases.
背景技术Background technique
RAS蛋白在调节正常的细胞生长和增殖中发挥重要作用。根据RAS氨基酸序列保守程度可分为KRAS、HRAS、和NRAS三种。RAS通过与低分子量的鸟嘌呤三核苷酸磷酸(GTP)或鸟嘌呤二核苷酸磷酸(GDP)的结合而处于不同的“活化”或“失活”的状态。正常情况下，RAS蛋白在静止细胞的质膜上与GDP结合，形成GDP-RAS，使RAS处于失活状态；当细胞受到丝裂原等激活因子的刺激时，与GDP-RAS结合的GDP与游离GTP发生交换，释放出GDP，并同时形成RAS与GTP结合的状态，即活化的GTP-RAS。只有活化的GTP-RAS才能激活RAS下游信号通路，传递正常的RAS信号。由于正常的RAS蛋白具有将GTP水解成GDP的GTP水解酶活性，因此可以调控活化型GTP-RAS和失活型GDP-RAS之间的交换，维持RAS活化和失活信号之间的平衡。当RAS蛋白发生突变时，调节活化型GTP-RAS和失活型GDP-RAS之间的交换功能失控，使RAS信号持续处于活化状态，不断地激活下游生长信号，刺激细胞的异常增殖，诱导肿瘤的发生以及维持肿瘤的生长(Nature Review cancer3:11-22,2003)。RAS protein plays an important role in regulating normal cell growth and proliferation. According to the degree of conservation of RAS amino acid sequence, it can be divided into three types: KRAS, HRAS, and NRAS. RAS is in different "activated" or "inactivated" states by combining with low molecular weight guanine trinucleotide phosphate (GTP) or guanine dinucleotide phosphate (GDP). Under normal circumstances, the RAS protein binds to GDP on the plasma membrane of resting cells to form GDP-RAS, which makes RAS in an inactive state; when the cell is stimulated by mitogens and other activating factors, the GDP combined with GDP-RAS and GDP-RAS Free GTP is exchanged, GDP is released, and at the same time, a state where RAS and GTP are combined is formed, that is, activated GTP-RAS. Only activated GTP-RAS can activate the downstream signal pathway of RAS and transmit normal RAS signals. Since the normal RAS protein has GTP hydrolase activity that hydrolyzes GTP into GDP, it can regulate the exchange between activated GTP-RAS and inactivated GDP-RAS, and maintain the balance between RAS activation and inactivation signals. When the RAS protein is mutated, the exchange function between the regulated activated GTP-RAS and the inactivated GDP-RAS is out of control, which keeps the RAS signal in an active state, continuously activates downstream growth signals, stimulates abnormal cell proliferation and induces tumor The occurrence and maintenance of tumor growth (Nature Review cancer 3:11-22, 2003).
人类肿瘤常表达通过点突变激活的RAS蛋白。KRAS、HRAS、和NRAS都能发生突变激活，其中K-RAS(Kirsten rat sarcoma virus oncogene)是在所有RAS驱动的肿瘤中突变率最高的癌基因。大部分K-RAS致癌突变集中在几个热点残基上，最常见的K-RAS突变出现在第12位的甘氨酸(G12)、第13位甘氨酸(G13)、以及第61位的谷氨酰胺(Q61)残疾上，其中G12位的突变发生率最高(Nat Rev Drug Discov 2014,13:828-851)。Human tumors often express RAS proteins that are activated by point mutations. KRAS, HRAS, and NRAS can all be activated by mutation. Among them, K-RAS (Kirsten rat sarcoma virus oncogene) is the oncogene with the highest mutation rate in all RAS-driven tumors. Most of the oncogenic mutations of K-RAS are concentrated in a few hot residues. The most common K-RAS mutations are glycine at position 12 (G12), glycine at position 13 (G13), and glutamine at position 61 (Q61) In terms of disability, the G12 mutation has the highest incidence (Nat Rev Drug Discov 2014, 13: 828-851).
K-RASRAS G12C突变是指K-RAS蛋白的第12位的甘氨酸突变为半胱氨酸，是K-RAS突变最常的见亚型。K-RAS G12C突变肿瘤的发生频率依次为胰腺癌(57％)、大肠癌(35％)、胆道癌(28％)、小肠癌(17％)、肺癌(16％)、子宫内膜癌(15％)和卵巢癌(14％)等(Seminars in Cancer Biology.2019 Jun 27.pii:S1044-579X(18)30060-9)。由于K-RAS G12C突变的恶性肿瘤对常规的治疗方法一般无反应，因此患者临床预后差，存活时间短。K-RASRAS G12C mutation refers to the mutation of glycine at position 12 of K-RAS protein to cysteine, which is the most common subtype of K-RAS mutation. The frequency of K-RAS G12C mutation tumors is pancreatic cancer (57%), colorectal cancer (35%), biliary tract cancer (28%), small intestine cancer (17%), lung cancer (16%), endometrial cancer ( 15%) and ovarian cancer (14%) (Seminars in Cancer Biology. 2019 Jun 27.pii: S1044-579X(18)30060-9). Malignant tumors with K-RAS G12C mutations generally do not respond to conventional treatment methods, so patients have a poor clinical prognosis and short survival time.
虽然大量的研究揭示RAS突变蛋白是治疗人类癌症治疗的重要靶点，但从RAS癌基因发现30多年来以来，抗RAS疗法经历了很多的失败，目前医药界仍然对抗RAS药物，特别是抗K-RAS G12C突变的RAS抑制剂，保持着高度的兴趣和期待。K-RAS G12C突变蛋白抑制剂是近年来发现抗RAS靶向治疗的新型药物靶点(Nature 503:548-551,2013)。K-RAS G12C共价抑制剂是利用突变后的第12位半胱氨酸的亲核反应性来设计小分子化合物，通过用二硫键修饰，进入到K-RAS G12C变构口袋，阻断K-RAS G12C突变蛋白的激活而抑制肿瘤生长，但至今仍没有足够高效能和高安全性的新型K-RAS G12C抑制剂获得监管机构的批准上市。因此，在该技术领域仍然亟待发现新的选择性K-RAS G12C抑制剂用于K-RAS G2C突变肿瘤的靶向治疗。Although a large number of studies have revealed that the RAS mutant protein is an important target for the treatment of human cancer, more than 30 years since the discovery of the RAS oncogene, anti-RAS therapies have experienced many failures. At present, the pharmaceutical industry is still anti-RAS drugs, especially anti-K -RAS Inhibitors of RAS G12C mutations have maintained a high degree of interest and expectations. K-RAS G12C mutant protein inhibitor is a new drug target discovered in recent years for anti-RAS targeted therapy (Nature 503:548-551, 2013). K-RAS G12C covalent inhibitor uses the nucleophilic reactivity of the mutated 12th cysteine to design small molecule compounds. It is modified with disulfide bonds to enter the K-RAS G12C allosteric pocket and block K -RAS G12C mutant protein is activated to inhibit tumor growth, but there is still no new K-RAS G12C inhibitor with sufficient high potency and high safety that has been approved by regulatory agencies for marketing. Therefore, in this technical field, there is still an urgent need to discover new selective K-RAS G12C inhibitors for targeted therapy of K-RAS G2C mutant tumors.
发明内容Summary of the invention
本发明提供通式(I)所示化合物、其异构体、其药学上可接受的盐或其氘代物：The present invention provides a compound represented by the general formula (I), its isomer, its pharmaceutically acceptable salt or its deuterated product:
Figure PCTCN2021070462-appb-000001
Figure PCTCN2021070462-appb-000001
其中，among them,
X选自含有1或2个N原子的4-8元饱和或部分饱和的单环，或者含有1或2个N原子的6-12元饱和或部分饱和的双环、桥环、融合环、螺环的杂环烷基，可任选被1、2或3个相同或不同的R 6取代； X is selected from a 4-8 membered saturated or partially saturated monocyclic ring containing 1 or 2 N atoms, or a 6-12 membered saturated or partially saturated bicyclic ring containing 1 or 2 N atoms, bridged ring, fused ring, spiro The cyclic heterocycloalkyl group may be optionally substituted with 1, 2 or 3 R 6 which are the same or different;
R 1、R 2选自H、卤素、NH 2、OH、C 1-3烷基和C 1-3杂烷基，所述的取代基可任选1个或多个取代； R 1 and R 2 are selected from H, halogen, NH 2 , OH, C 1-3 alkyl and C 1-3 heteroalkyl, and the substituents may be optionally substituted by one or more;
R 3选自4-6元单环或6-12元双环的芳基、杂芳基，环烷基、杂环烷基，所述的芳基、杂芳基，环烷基、杂环烷基可被1、2或3个相同或不同的R 7取代； R 3 is selected from 4-6 membered monocyclic or 6-12 membered bicyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, the aryl, heteroaryl, cycloalkyl, heterocycloalkane The group may be substituted by 1, 2 or 3 R 7 which are the same or different;
R 4选自H、烷基、氨基烷基、烷基氨基烷基、卤代烷基、羟基烷基、二羟基烷基、-A-NR 8R 9、4-6元杂环基、4-6元杂环基烷基、5-6元芳基、5-6元杂芳基或杂芳基烷基，其中，A、杂环基、杂环基烷基、芳基、杂芳基或杂芳基烷基可任选被1个或多个相同或不同的R 10取代； R 4 is selected from H, alkyl, aminoalkyl, alkylaminoalkyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, -A-NR 8 R 9 , 4-6 membered heterocyclic group, 4-6 Membered heterocyclylalkyl, 5-6 membered aryl, 5-6 membered heteroaryl or heteroarylalkyl, where A, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl or hetero The arylalkyl group may be optionally substituted by one or more R 10 which are the same or different;
A选自C 1-4亚烷基； A is selected from C 1-4 alkylene;
L是键或-NH-；L is a bond or -NH-;
R 5选自： R 5 is selected from:
Figure PCTCN2021070462-appb-000002
Figure PCTCN2021070462-appb-000002
R 6选自腈基、C 1-3烷基、氨基、卤素，羟基； R 6 is selected from the group consisting of nitrile group, C 1-3 alkyl group, amino group, halogen, and hydroxyl group;
R 7选自卤素、氨基、羟基、C 1-3烷基或卤素取代的C 1-3烷基； R 7 is selected from halogen, amino, hydroxy, C 1-3 alkyl or halogen substituted C 1-3 alkyl;
R 8选自H、或C 1-3烷基 R 8 is selected from H, or C 1- 3 alkyl
R 9选自H、C 1-3烷基、杂烷基、羟基烷基、酰基； R 9 is selected from H, C 1-3 alkyl, heteroalkyl, hydroxyalkyl, acyl;
R 10选自H、羟基、卤素、 R 10 is selected from H, hydroxyl, halogen,
Z选自键、O、S、NR 11； Z is selected from bond, O, S, NR 11 ;
R 11选自H、或C 1-3亚烷基； R 11 is selected from H or C 1-3 alkylene;
R 12选自卤素、CF3、羟基烷基； R 12 is selected from halogen, CF3, and hydroxyalkyl;
R 13选自H、C 1-3烷基、烷基氨基烷基、烷基氨基烷基、杂环基氨基烷基、卤素、酰胺基、腈基、羟基烷基、CF 3、CF 2、甲氧基、三氟甲基氨基、烯烃； R 13 is selected from H, C 1-3 alkyl, alkylaminoalkyl, alkylaminoalkyl, heterocyclylaminoalkyl, halogen, amido, nitrile, hydroxyalkyl, CF 3 , CF 2 , Methoxy, trifluoromethylamino, alkene;
R 14选自H、烷基、羟基烷基； R 14 is selected from H, alkyl, and hydroxyalkyl;
R 15选自不存在、H或C 1-3烷基； R 15 is selected from absent, H or C 1-3 alkyl;
在本发明方案中，“杂”指杂原子或杂原子团(含有杂原子的原子团)，杂原子是指碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如氧(O)、氮(N)、硫(S)等；杂原子团指C 1-3杂烷基、C 1-6杂烷基、C 1-8杂烷基、3-8元杂环烷基、5-6元杂环芳基、5-6元杂环烯基等； In the present invention, "hetero" refers to heteroatoms or heteroatoms (atomic groups containing heteroatoms), and heteroatoms refer to atoms other than carbon (C) and hydrogen (H) and atomic groups containing these heteroatoms, such as oxygen ( O), nitrogen (N), sulfur (S), etc.; heteroatom groups refer to C 1-3 heteroalkyl, C 1-6 heteroalkyl, C 1-8 heteroalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heterocyclic aryl, 5-6 membered heterocycloalkenyl, etc;
在本发明的一些方案中，结构单元
Figure PCTCN2021070462-appb-000003
选自： In some aspects of the present invention, the structural unit
Figure PCTCN2021070462-appb-000003
Selected from:
Figure PCTCN2021070462-appb-000004
Figure PCTCN2021070462-appb-000004
在上述结构单元中，R 5选自： In the above structural unit, R 5 is selected from:
Figure PCTCN2021070462-appb-000005
Figure PCTCN2021070462-appb-000005
在本发明的一些方案中，上述R 3选自： In some aspects of the present invention, the above-mentioned R 3 is selected from:
Figure PCTCN2021070462-appb-000006
Figure PCTCN2021070462-appb-000006
Figure PCTCN2021070462-appb-000007
Figure PCTCN2021070462-appb-000007
在本发明的一些方案中，上述R 4选自： In some aspects of the present invention, the above-mentioned R 4 is selected from:
Figure PCTCN2021070462-appb-000008
Figure PCTCN2021070462-appb-000008
Figure PCTCN2021070462-appb-000009
Figure PCTCN2021070462-appb-000009
其他变量的结构单元或基团如本发明所定义。The structural units or groups of other variables are as defined in the present invention.
本发明所示化合物、其异构体、其药学上可接受的盐或其氘代物，选自：The compound of the present invention, its isomers, its pharmaceutically acceptable salt or its deuterated compounds are selected from:
Figure PCTCN2021070462-appb-000010
Figure PCTCN2021070462-appb-000010
Figure PCTCN2021070462-appb-000011
Figure PCTCN2021070462-appb-000011
Figure PCTCN2021070462-appb-000012
Figure PCTCN2021070462-appb-000012
Figure PCTCN2021070462-appb-000013
Figure PCTCN2021070462-appb-000013
Figure PCTCN2021070462-appb-000014
Figure PCTCN2021070462-appb-000014
Figure PCTCN2021070462-appb-000015
Figure PCTCN2021070462-appb-000015
本文所示的某些化合物可以为立体异构体，包括光学异构体和构象异构体，以通用符号R或S表示。Certain compounds shown herein may be stereoisomers, including optical isomers and conformational isomers, represented by the general symbol R or S.
本发明还提供了上述化合物，其药学上可接受的盐、其异构体、其氘代物应用于制备治疗癌症药物。The present invention also provides the above-mentioned compounds, their pharmaceutically acceptable salts, their isomers, and their deuterated compounds are used in the preparation of cancer drugs.
在本发明中，所述癌症包括肺癌、胰腺癌、直/结肠癌、胆管癌、小肠癌、子宫内膜癌、胃癌、卵巢癌、***癌、子***、肝癌、腹膜癌、软组织癌、白血病、淋巴瘤、乳腺癌、尿路上皮癌、睾丸癌、皮肤癌、食道癌、甲状腺癌、食管癌、骨癌和眼癌。In the present invention, the cancer includes lung cancer, pancreatic cancer, rectal/colon cancer, cholangiocarcinoma, small bowel cancer, endometrial cancer, stomach cancer, ovarian cancer, prostate cancer, cervical cancer, liver cancer, peritoneal cancer, soft tissue cancer, Leukemia, lymphoma, breast cancer, urothelial cancer, testicular cancer, skin cancer, esophageal cancer, thyroid cancer, esophageal cancer, bone cancer and eye cancer.
技术效果Technical effect
本发明采用了电泳凝胶迁移分析法(gel mobility shift assay)测定化合物与细胞KRAS G12C突变蛋白形成的共价结合复合物特有的电泳迁移改变；其原理是基于化合物和K-RAS G12C突变蛋白结合形成的共价复合物的分子量增大，与游离的KRAS G12C突变蛋白相比，在电泳时出现相应的电泳带滞后。再用FluorChemR检测仪定量扫描电泳带，计算化合物-G12C突变蛋白的复合物与未结合化合物的G12C突变蛋白的电泳迁移比值，快速和直接测定本发明化合物与KRAS G12C突变蛋白的共价键结合特征。电泳凝胶迁移分析表明，本发明化合物能选择性地与含有KRAS G12C突变的人非小细胞肺癌NCI-H358细胞中的KRAS  G12C突变蛋白结合，形成的化合物-突变蛋白复合物，导致出现电泳凝胶迁滞后，但本发明化合物不能与无KRAS G12C突变的非小细胞肺癌A549细胞的KRAS蛋白结合，也不能与含有野生型KRAS的非小细胞肺癌HCC827细胞的KRAS蛋白结合，不出现上述电泳凝胶迁移的特征性改变。另外，在抗细胞增殖实验中也显示，本发明化合物对KRAS G12C突变的肿瘤细胞具有较强的抗增殖活性，而对无K-RAS G12C突变或野生型肿瘤细胞的抗增殖活性弱，与电泳凝胶迁移分析方法的结果一致。凝胶迁移分析和抗细胞增殖实验均显示本发明化合物选择性地抑制了KRAS G12C突变肿瘤细胞中异常激活的KRAS信号，对K-RAS G12C突变的肿瘤细胞和非突变的肿瘤细胞具有选择性的作用，显示出该类化合物作为KRAS G12C突变抑制剂具有较好的有效性和安全性。The present invention adopts the electrophoresis gel migration analysis method (gel mobility shift assay) to determine the unique electrophoretic migration change of the covalent binding complex formed by the compound and the cell KRAS G12C mutant protein; the principle is based on the combination of the compound and the K-RAS G12C mutant protein The molecular weight of the formed covalent complex increases. Compared with the free KRAS G12C mutant protein, a corresponding electrophoresis band lag occurs during electrophoresis. Then quantitatively scan the electrophoresis band with the FluorChemR detector to calculate the electrophoretic migration ratio between the compound-G12C mutant protein complex and the unbound G12C mutant protein, and quickly and directly determine the covalent bonding characteristics of the compound of the present invention and the KRAS G12C mutant protein . Electrophoresis gel migration analysis showed that the compound of the present invention can selectively bind to the KRAS G12C mutant protein in human non-small cell lung cancer NCI-H358 cells containing the KRAS G12C mutation to form a compound-mutant complex, resulting in electrophoretic coagulation. Gel migration is lagging, but the compound of the present invention cannot bind to the KRAS protein of non-small cell lung cancer A549 cells without KRAS G12C mutation, nor can it bind to the KRAS protein of non-small cell lung cancer HCC827 cells containing wild-type KRAS, and the above electrophoretic gel does not occur. Characteristic changes in glue migration. In addition, the anti-cell proliferation experiments also showed that the compound of the present invention has strong anti-proliferative activity against KRAS G12C mutant tumor cells, but has weak anti-proliferative activity against K-RAS G12C mutant or wild-type tumor cells, which is comparable to electrophoresis. The results of the gel migration analysis method are consistent. Gel migration analysis and anti-cell proliferation experiments show that the compound of the present invention selectively inhibits the abnormally activated KRAS signal in KRAS G12C mutant tumor cells, and is selective for K-RAS G12C mutant tumor cells and non-mutated tumor cells It shows that these compounds have good effectiveness and safety as KRAS G12C mutation inhibitors.
定义和说明Definition and description
本文所用的术语具有以下含义。The terms used herein have the following meanings.
术语“药学上可接受的盐”是指本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备的盐。当本发明化合物中含有碱性官能团时，可以通过在合适的纯溶液或惰性溶剂中用足量的酸与中性形式的本发明化合物接触获得酸加成盐。药学上可接受的酸加成盐，包括无机酸盐和有机酸盐：无机酸包括盐酸、硫酸、硫酸氢根、碳酸、碳酸氢根、磷酸、亚磷酸、磷酸一氢根、磷酸二氢根、氢溴酸、氢碘酸和硝酸；有机酸包括如乳酸、苯磺酸、乙酸、丙酸、丙二酸、异丁酸、辛二酸、苯甲酸、邻苯二甲酸、对甲苯磺酸、柠檬酸、酒石酸、马来酸、氨基酸、葡萄糖醛酸。本发明中的特定化合物通式含有酸性或碱性基团，因此可以被转换成酸或碱加成盐。The term "pharmaceutically acceptable salt" refers to a salt prepared with a relatively non-toxic acid or base with a compound having a specific substituent discovered in the present invention. When the compound of the present invention contains a basic functional group, an acid addition salt can be obtained by contacting the compound of the present invention in a neutral form with a sufficient amount of acid in a suitable pure solution or an inert solvent. Pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts: Inorganic acids include hydrochloric acid, sulfuric acid, hydrogen sulfate, carbonic acid, hydrogen carbonate, phosphoric acid, phosphorous acid, monohydrogen phosphate, and dihydrogen phosphate , Hydrobromic acid, hydroiodic acid and nitric acid; organic acids include such as lactic acid, benzenesulfonic acid, acetic acid, propionic acid, malonic acid, isobutyric acid, suberic acid, benzoic acid, phthalic acid, p-toluenesulfonic acid , Citric acid, tartaric acid, maleic acid, amino acids, glucuronic acid. The general formula of the specific compound in the present invention contains acidic or basic groups, and therefore can be converted into acid or base addition salts.
术语“立体或几何异构体”是指顺式和反式异构体、(R)-和(S)-对映体、(-)-和(+)-对映体、(D)-异构体、(L)-异构体、非对映异构体、以及消旋混合物，都包括在本发明范围内。The term "stereo or geometric isomers" refers to cis and trans isomers, (R)- and (S)-enantiomers, (-)- and (+)-enantiomers, (D)- Isomers, (L)-isomers, diastereomers, and racemic mixtures are all included in the scope of the present invention.
术语“顺反异构体”或“几何异构体”是因双键或成环碳原子单键不能自由旋转所致。The term "cis-trans isomer" or "geometric isomer" is due to the fact that double bonds or single bonds of ring-forming carbon atoms cannot rotate freely.
术语“对映异构体”或“旋光异构体”指互为镜像关系的立体异构体。The term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of each other.
术语“非对映异构体”指分子具有两个以上手性中心，而且分子间有非镜像关系的异构体。The term "diastereomer" refers to an isomer in which a molecule has more than two chiral centers and has a non-mirror image relationship between the molecules.
术语“(D)”或(+)指右旋，“(L”或(-)指左旋，“DL”或“±”指外消旋。The term "(D)" or (+) means dextrorotation, "(L" or (-) means levorotatory, and "DL" or "±" means racemic.
用楔形虚线键
Figure PCTCN2021070462-appb-000016
和楔形实线键(
Figure PCTCN2021070462-appb-000017
或
Figure PCTCN2021070462-appb-000018
)指分子中一个立体中心的绝对构型。 Dashed key with wedge
Figure PCTCN2021070462-appb-000016
And a wedge-shaped solid line key (
Figure PCTCN2021070462-appb-000017
or
Figure PCTCN2021070462-appb-000018
) Refers to the absolute configuration of a steric center in a molecule.
术语“互变异构体”指本发明化合物分子中不同官能团异构体处于动态平衡，并能快速相互转化。The term "tautomers" means that the isomers of different functional groups in the molecules of the compound of the present invention are in dynamic equilibrium and can be rapidly transformed into each other.
术语“烷基”指直链或支链的饱和碳氢基团。在一些实施方案中，所属烷基为C 1-3烷基；在另一些实施方案中，所属烷基为C 1-6烷基。烷基实例包括但不限于甲基、乙基、丙基(包括异丙基和n-丙基)、丁基(包括n-丁基、异丁基)、戊基(包括n-戊基、异戊基和新戊基)、己基。所述的烷基可以是一价(如甲基)、二价(如亚甲基)、多价(如次甲基)，可以是单取代(如-CH 2F)或多取代(-CF 3)。 The term "alkyl" refers to a linear or branched saturated hydrocarbon group. In some embodiments, the alkyl group is a C 1-3 alkyl group; in other embodiments, the alkyl group is a C 1-6 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including isopropyl and n-propyl), butyl (including n-butyl, isobutyl), pentyl (including n-pentyl, Isopentyl and neopentyl), hexyl. The alkyl group can be monovalent (such as methyl), divalent (such as methylene), multivalent (such as methine), and can be mono-substituted (such as -CH 2 F) or multi-substituted (-CF 3 ).
术语“烯基”指直链或支链的含有一个或多个碳-碳双键的碳氢基团。在一些实施方案中，所述烯基为C 2-4烯基；在另一些实施方案中，所述烯基为C 2-6烯基；在另一些实施方案中，所述烯基为C 2-8烯基。 The term "alkenyl" refers to a straight or branched hydrocarbon group containing one or more carbon-carbon double bonds. In some embodiments, the alkenyl group is C 2-4 alkenyl; in other embodiments, the alkenyl group is C 2-6 alkenyl; in other embodiments, the alkenyl group is C 2-8 alkenyl.
术语“环”指被取代或未被取代的环烷基、环烯基、环炔基、芳基、杂环烷基、杂环烯基、杂环炔基、芳基。所述的环包括单环、双环、多环。环上原子的数目定义为环的元数。The term "ring" refers to substituted or unsubstituted cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl. The ring includes single ring, double ring and multiple ring. The number of atoms in the ring is defined as the number of ring members.
术语“杂”指杂原子或杂原子团(含有杂原子的原子团)，即碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如氧(O)、氮(N)、硫(S)等。The term "hetero" refers to heteroatoms or heteroatom groups (atomic groups containing heteroatoms), that is, atoms other than carbon (C) and hydrogen (H) and atomic groups containing these heteroatoms, such as oxygen (O), nitrogen (N), Sulfur (S) and so on.
术语“环烷基”指包括单环，双环或三环体系的环状烷基，其中双环或三环体系包括螺环、桥环、并环；所述的烷基可以是一价、二价、多价，也可以是单取代或多取代。The term "cycloalkyl" refers to a cyclic alkyl group including a monocyclic, bicyclic or tricyclic ring system, wherein the bicyclic or tricyclic ring system includes a spiro ring, a bridged ring, and a fused ring; the alkyl group may be monovalent or divalent , Multivalent, can also be single substitution or multiple substitution.
术语“环烯基”指含有一个或多个不饱和的碳-碳双键的环状烯基，其中双环或三环体系包 括螺环、桥环、并环；所述的烷基可以是一价、二价、多价，也可以是单取代或多取代。The term "cycloalkenyl" refers to a cyclic alkenyl group containing one or more unsaturated carbon-carbon double bonds, wherein the bicyclic or tricyclic ring system includes a spiro ring, a bridged ring, and a fused ring; the alkyl group may be one Valence, divalent, multivalent, and can also be mono- or multi-substitution.
术语“环炔基”指含有一个或多个碳-碳三键的环状烷基，包括单环，双环、多环体系，其中双环或三环体系包括螺环、并环和桥环。所述的烷基可以是一价、二价、多价，也可以是单取代或多取代。The term "cycloalkynyl" refers to a cyclic alkyl group containing one or more carbon-carbon triple bonds, including monocyclic, bicyclic, and polycyclic ring systems, wherein the bicyclic or tricyclic ring systems include spiro, fused, and bridged rings. The alkyl group can be monovalent, divalent, multivalent, and can also be mono- or multi-substituted.
术语“杂环烷基”指环化的杂烷基，包括单环，双环、多环体系，其中双环或三环体系包括螺环、并环和桥环。The term "heterocycloalkyl" refers to a cyclized heteroalkyl, including monocyclic, bicyclic, and polycyclic ring systems, where bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
术语“杂环烯基”指环化的杂烯基，包括单环，双环、多环体系，其中双环或三环体系包括螺环、并环和桥环。The term "heterocyclenyl" refers to a cyclized heteroalkenyl group, including monocyclic, bicyclic, and polycyclic ring systems, wherein the bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
术语“杂环炔基”指环化的杂环炔基，包括单环，双环、多环体系，其中双环或三环体系包括螺环、并环和桥环。The term "heterocyclic alkynyl" refers to a cyclized heterocyclic alkynyl group, including monocyclic, bicyclic, and polycyclic ring systems, wherein the bicyclic or tricyclic ring systems include spiro, fused, and bridged rings.
术语“芳环”或“芳基”指多不饱和的碳环体系，包括单环，双环、多环体系，其中至少一个环具有芳香性，可以是一价、二价、多价，也可以是单取代或多取代。The term "aromatic ring" or "aryl" refers to a polyunsaturated carbocyclic ring system, including monocyclic, bicyclic, and polycyclic ring systems, in which at least one ring is aromatic and can be monovalent, divalent, multivalent, or Is single substitution or multiple substitution.
本发明化合物可通过本领域技术人员熟知的多种合成方法合制备，以下列举的具体实施方式以及优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art. The specific embodiments and preferred embodiments listed below include but are not limited to the examples of the present invention.
具体实施方式Detailed ways
以下通过一般反应流程和具体的实施例对本发明进行详细的描述，但所述内容并不包含对本发明的任何限制。The following describes the present invention in detail through the general reaction process and specific examples, but the content does not contain any limitation to the present invention.
一般反应流程(A)General reaction process (A)
Figure PCTCN2021070462-appb-000019
Figure PCTCN2021070462-appb-000019
通式(I)化合物的实施方式根据一般反应流程(A)制备，其中R 1、R 2、R 3、R 4、R 5、X、L以及Z的定义如上文。根据一般反应流程所示，反应物A1与浓氨水在耐压管中加热反应得到化合物A2，A2与草酰氯反应得到的酰氯直接与液氨反应得到化合物A3，A3与草酰氯加热发生成环反应得到A4，A4与二异丙基乙胺，三氯氧磷反应得到化合物A5，A5与结构单元
Figure PCTCN2021070462-appb-000020
中的X、R5依次反应得到化合物A6，A6与不同的R3基团反应得到化合物A7，A7与包含不同的R4基团取代的结构单元-Z-R 5反应得到化合物A8。 The embodiment of the compound of general formula (I) is prepared according to the general reaction scheme (A), wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, L and Z are as defined above. According to the general reaction process, the reactant A1 and concentrated ammonia are heated and reacted in a pressure tube to obtain compound A2, the acid chloride obtained by the reaction of A2 and oxalyl chloride directly reacts with liquid ammonia to obtain compound A3, and A3 and oxalyl chloride are heated to form a ring reaction. Obtain A4, A4, diisopropylethylamine, and phosphorus oxychloride to obtain compound A5, A5 and structural unit
Figure PCTCN2021070462-appb-000020
The X, R5 successively to give compound A6, A6 R3 group is reacted with different compounds to obtain A7, A7 and R4 groups comprise different structural units substituted with -ZR 5 to give compound A8.
一般反应流程(B)General reaction process (B)
Figure PCTCN2021070462-appb-000021
Figure PCTCN2021070462-appb-000021
通式(I)化合物的实施方式根据一般反应流程(B)制备，其中R 1、R 2、R 3、R 4、R 5、X、L以及Z的定义如上文。根据一般反应流程所示，反应物B1与草酰氯反应得到化合物B2，B2与硫脲反应得到化合物B3,B3加热回流发生成环反应得到B4，B4与三氯氧磷反应得到化合物B5，B5与结构单元
Figure PCTCN2021070462-appb-000022
中的X、R5依次反应得到化合物B6，B6与不同的R3基团反应得到化合物B7,B7与包含不同的R4基团取代的结构单元反应得到化合物B8。 The embodiment of the compound of general formula (I) is prepared according to the general reaction scheme (B), wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, L and Z are as defined above. According to the general reaction process, the reactant B1 reacts with oxalyl chloride to obtain compound B2, B2 reacts with thiourea to obtain compound B3, and B3 is heated to reflux to form a ring reaction to obtain B4, and B4 reacts with phosphorus oxychloride to obtain compound B5, B5 and Structural units
Figure PCTCN2021070462-appb-000022
X and R5 in the compound are reacted in sequence to obtain compound B6, B6 is reacted with different R3 groups to obtain compound B7, and B7 is reacted with structural units substituted with different R4 groups to obtain compound B8.
实施例1：Example 1:
Figure PCTCN2021070462-appb-000023
Figure PCTCN2021070462-appb-000023
化合物(S)-1-(4-(7-(萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 509.26[M+H] +。 Compound (S)-1-(4-(7-(naphthalen-1-yl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrido[2,3-d]pyrimidine The synthesis of -4-yl)piperazin-1-yl)prop-2-en-1-one refers to the general reaction schemes (A) and (B); MS (ESI) m/z 509.26 [M+H] + .
合成路线和具体方法如下：The synthetic route and specific method are as follows:
Figure PCTCN2021070462-appb-000024
Figure PCTCN2021070462-appb-000024
第一步first step
将化合物A(500.0mg，2.9mmol，1.00eq)溶解于5mL甲苯中，于氮气保护下加入草酰氯(443.8mg，3.5mmol，1.20eq)。混合物在110℃下搅拌15小时。冷却至室温，过滤，滤渣用甲苯洗涤(5mL×2)，干燥。得到粗品化合物B(528mg，浅黄色固体)，产物不经纯化直接进行下步反应。Compound A (500.0 mg, 2.9 mmol, 1.00 eq) was dissolved in 5 mL of toluene, and oxalyl chloride (443.8 mg, 3.5 mmol, 1.20 eq) was added under nitrogen protection. The mixture was stirred at 110°C for 15 hours. It was cooled to room temperature, filtered, and the filter residue was washed with toluene (5 mL×2) and dried. The crude compound B (528 mg, light yellow solid) was obtained, and the product was directly subjected to the next reaction without purification.
第二步Second step
将粗品化合物B(100.0mg，0.5mmol，1.00eq)溶解于0.6mL甲苯中，于氮气保护下加入N,N-二异丙基乙胺(196.3mg，1.5mmol，3.00eq)。混合物在70℃下搅拌30分钟，加入三氯氧磷(232.8mg，1.5mmol，3.00eq)，在100℃下回流搅拌2.5小时。反应完成后，溶剂减压旋干，加水(1mL)，乙酸乙酯萃取(1mL×3)，合并的有机相用饱和氯化钠溶液洗涤(1mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用快速液相色谱***纯化所得残余物，得到化合物C(37.5mg，白色固体)，产率：31.6％。The crude compound B (100.0 mg, 0.5 mmol, 1.00 eq) was dissolved in 0.6 mL of toluene, and N,N-diisopropylethylamine (196.3 mg, 1.5 mmol, 3.00 eq) was added under the protection of nitrogen. The mixture was stirred at 70°C for 30 minutes, phosphorus oxychloride (232.8 mg, 1.5 mmol, 3.00 eq) was added, and the mixture was stirred at reflux at 100°C for 2.5 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure, water (1mL) was added, and the mixture was extracted with ethyl acetate (1mL×3). The combined organic phase was washed with saturated sodium chloride solution (1mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced. It was concentrated under pressure, and the obtained residue was purified with a flash liquid chromatography system to obtain compound C (37.5 mg, white solid), yield: 31.6%.
第三步third step
冰浴下将化合物C(300.0mg，1.28mmol，1.00eq)溶解于12.8mL二氯甲烷，加入N,N-二异丙基乙胺(165.3mg，1.28mmol，1.00eq)，加入1-叔丁氧羰基哌嗪(238.3mg，1.28mmol，1.00eq)，在室温下搅拌1小时。反应完成后，溶剂减压旋干，加水(12.8mL)，乙酸乙酯萃取(12.8mL×3)，合并的有机相用饱和氯化钠溶液洗涤(12.8mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用快速液相色谱***纯化所得残余物，得到化合物D(362.0mg，淡黄色固体)，产率：73.6％。Dissolve compound C (300.0mg, 1.28mmol, 1.00eq) in 12.8mL dichloromethane under ice bath, add N,N-diisopropylethylamine (165.3mg, 1.28mmol, 1.00eq), add 1-tert Butoxycarbonylpiperazine (238.3 mg, 1.28 mmol, 1.00 eq) was stirred at room temperature for 1 hour. After the reaction was completed, the solvent was spin-dried under reduced pressure, water (12.8 mL) was added, and the mixture was extracted with ethyl acetate (12.8 mL×3). The combined organic phase was washed with saturated sodium chloride solution (12.8 mL), dried over anhydrous sodium sulfate, and filtered The filtrate was concentrated under reduced pressure, and the resulting residue was purified with a flash liquid chromatography system to obtain compound D (362.0 mg, pale yellow solid), yield: 73.6%.
第四步the fourth step
将化合物D(50.0mg，0.13mmol，1.00eq)、碳酸钠(41.4mg，0.39mmol)和1-萘硼酸(24.6mg，0.14mmol，1.10eq)溶解于乙腈(0.65mL)和水(0.65mL)，氮气鼓泡10分钟，加入四(三苯基磷)钯(7.5mg，0.006mmol，0.05eq)，氮气鼓泡5分钟。混合物在80℃下回流搅拌3小时。反应完成后，溶剂减压旋干，加水(1.3mL)，乙酸乙酯萃取(1.3mL×3)，合并的有机相用饱和氯化钠溶液洗涤(1.3mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用快速液相色谱***纯化所得残余物，得到化合物E(50.9mg，淡黄色固体)，产率：82.2％。Compound D (50.0mg, 0.13mmol, 1.00eq), sodium carbonate (41.4mg, 0.39mmol) and 1-naphthaleneboronic acid (24.6mg, 0.14mmol, 1.10eq) were dissolved in acetonitrile (0.65mL) and water (0.65mL) ), bubbling with nitrogen for 10 minutes, adding tetrakis(triphenylphosphorus) palladium (7.5 mg, 0.006 mmol, 0.05 eq), bubbling with nitrogen for 5 minutes. The mixture was stirred under reflux at 80°C for 3 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure, water (1.3 mL) was added, and the mixture was extracted with ethyl acetate (1.3 mL×3). The combined organic phase was washed with saturated sodium chloride solution (1.3 mL), dried over anhydrous sodium sulfate, and filtered The filtrate was concentrated under reduced pressure, and the resulting residue was purified with a flash liquid chromatography system to obtain compound E (50.9 mg, pale yellow solid), yield: 82.2%.
第五步the fifth step
将化合物E(50.9mg，0.11mmol，1.00eq)溶解于1,4-二氧六环(0.27mL)，加入N-甲基-L脯氨醇(61.6mg，0.54mmol，5.00eq)、碳酸铯(69.7mg，0.21mmol，2.00eq)，将混合物置于密封管中90℃搅拌24小时。反应完成后，溶剂减压旋干，加水(1.5mL)，乙酸乙酯萃取(1.5mL×3)，合并的有机相用饱和氯化钠溶液洗涤(1.5mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用快速液相色谱***纯化所得残余物，得到化合物F(20.3mg，淡黄色固体)，产率：34.2％。Compound E (50.9mg, 0.11mmol, 1.00eq) was dissolved in 1,4-dioxane (0.27mL), and N-methyl-L prolinol (61.6mg, 0.54mmol, 5.00eq), carbonic acid were added Cesium (69.7mg, 0.21mmol, 2.00eq), the mixture was placed in a sealed tube at 90°C and stirred for 24 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure, water (1.5 mL) was added, and the mixture was extracted with ethyl acetate (1.5 mL×3). The combined organic phase was washed with saturated sodium chloride solution (1.5 mL), dried over anhydrous sodium sulfate, and filtered The filtrate was concentrated under reduced pressure, and the resulting residue was purified with a flash liquid chromatography system to obtain compound F (20.3 mg, pale yellow solid), yield: 34.2%.
第六步Sixth step
将化合物F(20.3mg，0.036mmol，1.00eq)溶解于二氯甲烷(0.12mL)中，于氮气保护下加入三氟乙酸(125.2mg，1.10mmol，30.00eq)，混合物在室温下搅拌1小时。反应完成后，溶剂减压旋干，加入饱和碳酸氢钠溶液(1.5mL)，乙酸乙酯萃取(1.5mL×3)，合并的有机相用饱和氯化钠溶液洗涤(1.5mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得到化合物G(16.6mg，淡黄色固体)，产率：99.9％。Compound F (20.3mg, 0.036mmol, 1.00eq) was dissolved in dichloromethane (0.12mL), trifluoroacetic acid (125.2mg, 1.10mmol, 30.00eq) was added under nitrogen protection, and the mixture was stirred at room temperature for 1 hour . After the reaction was completed, the solvent was spin-dried under reduced pressure, saturated sodium bicarbonate solution (1.5 mL) was added, and ethyl acetate extraction (1.5 mL×3) was added. The combined organic phase was washed with saturated sodium chloride solution (1.5 mL), anhydrous It was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound G (16.6 mg, pale yellow solid), yield: 99.9%.
第七步Seventh step
冰浴下将化合物G(16.6mg，0.036mmol，1.00eq)溶解于二氯甲烷(0.12mL)中，于氮气保护下加入N,N-二异丙基乙胺(18.9mg，0.146mmol，4.00eq)、丙烯酰氯(3.3mg，0.036mmol，1.00eq)，混合物在冰浴下反应10分钟。反应完成后，溶剂减压旋干，加入饱和碳酸氢钠溶液(1.5mL)，乙酸乙酯萃取(1.5mL×3)，合并的有机相用饱和氯化钠溶液洗涤(1.5mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用快速液相色谱***纯化所得残 余物，得到化合物1(8.5mg，淡黄色固体)，产率：45.7％。Compound G (16.6mg, 0.036mmol, 1.00eq) was dissolved in dichloromethane (0.12mL) under ice bath, and N,N-diisopropylethylamine (18.9mg, 0.146mmol, 4.00 eq), acryloyl chloride (3.3 mg, 0.036 mmol, 1.00 eq), and the mixture was reacted for 10 minutes in an ice bath. After the reaction was completed, the solvent was spin-dried under reduced pressure, saturated sodium bicarbonate solution (1.5 mL) was added, and ethyl acetate extraction (1.5 mL×3) was added. The combined organic phase was washed with saturated sodium chloride solution (1.5 mL), anhydrous It was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a flash liquid chromatography system to obtain compound 1 (8.5 mg, pale yellow solid), yield: 45.7%.
实施例2Example 2
Figure PCTCN2021070462-appb-000025
Figure PCTCN2021070462-appb-000025
化合物1-((S)-3-甲基-4-(7-(萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 523.28[M+H] +。 Compound 1-((S)-3-methyl-4-(7-(naphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyridine The synthesis of and [2,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one refers to the general reaction schemes (A) and (B); MS (ESI) m/z 523.28 [M+H] + .
合成路线和具体方法如下：The synthetic route and specific method are as follows:
Figure PCTCN2021070462-appb-000026
Figure PCTCN2021070462-appb-000026
第一步first step
将化合物A(100.0mg，0.5mmol，1.00eq)溶解于0.6mL甲苯中，于氮气保护下加入N,N-二异丙基乙胺(196.3mg，1.5mmol，3.00eq)。混合物在70℃下搅拌30分钟，加入三氯氧磷(232.8mg，1.5mmol，3.00eq)，在100℃下回流搅拌2.5小时。反应完成后，溶剂减压旋干，加水(1mL)，乙酸乙酯萃取(1mL×3)，合并的有机相用饱和氯化钠溶液洗涤(1mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用快速液相色谱***纯化所得残余物，得到化合物B(37.5mg，白色固体)，产率：31.6％。Compound A (100.0 mg, 0.5 mmol, 1.00 eq) was dissolved in 0.6 mL of toluene, and N,N-diisopropylethylamine (196.3 mg, 1.5 mmol, 3.00 eq) was added under nitrogen protection. The mixture was stirred at 70°C for 30 minutes, phosphorus oxychloride (232.8 mg, 1.5 mmol, 3.00 eq) was added, and the mixture was stirred at reflux at 100°C for 2.5 hours. After the reaction was completed, the solvent was spin-dried under reduced pressure, water (1mL) was added, and the mixture was extracted with ethyl acetate (1mL×3). The combined organic phase was washed with saturated sodium chloride solution (1mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced. It was concentrated under pressure, and the obtained residue was purified with a flash liquid chromatography system to obtain compound B (37.5 mg, white solid), yield: 31.6%.
第二步Second step
冰浴下将化合物B(90.6mg，0.39mmol，1.00eq)溶解于3.86mL二氯甲烷，加入N,N-二异丙基乙胺(49.94mg，0.39mmol，1.00eq)，加入(S)-4N叔丁氧羰基-2甲基哌嗪(77.39mg，0.39mmol，1.00eq)，在室温下搅拌1小时。反应完成后，溶剂减压旋干，加水(10.0mL)，乙酸乙酯萃取(10.0mL×3)，合并的有机相用饱和氯化钠溶液洗涤(10.0mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用快速液相色谱***纯化所得残余物，得到化合物D(121.8 mg，淡黄色固体)，产率：79.1％。Dissolve compound B (90.6mg, 0.39mmol, 1.00eq) in 3.86mL of dichloromethane under ice bath, add N,N-diisopropylethylamine (49.94mg, 0.39mmol, 1.00eq), add (S) -4N tert-butoxycarbonyl-2 methylpiperazine (77.39 mg, 0.39 mmol, 1.00 eq), stirred at room temperature for 1 hour. After the completion of the reaction, the solvent was spin-dried under reduced pressure, water (10.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL×3). The combined organic phase was washed with saturated sodium chloride solution (10.0 mL), dried over anhydrous sodium sulfate, and filtered The filtrate was concentrated under reduced pressure, and the obtained residue was purified with a flash liquid chromatography system to obtain compound D (121.8 mg, pale yellow solid), yield: 79.1%.
第三步third step
将化合物D(121.8mg，0.39mmol，1.00eq)、碳酸钠(97.24mg，0.92mmol，3.00eq)和1-萘硼酸(57.9mg，0.34mmol，1.10eq)溶解于乙腈(1.66mL)和水(1.66mL)，氮气鼓泡10分钟，加入四(三苯基磷)钯(17.67mg，0.015mmol，0.05eq)，氮气鼓泡5分钟。混合物在80℃下回流搅拌3小时。反应完成后，溶剂减压旋干，加水(5mL)，乙酸乙酯萃取(5mL×3)，合并的有机相用饱和氯化钠溶液洗涤(5mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用快速液相色谱***纯化所得残余物，得到化合物F(143.3mg，淡黄色固体)，产率：95.63％。Compound D (121.8mg, 0.39mmol, 1.00eq), sodium carbonate (97.24mg, 0.92mmol, 3.00eq) and 1-naphthaleneboronic acid (57.9mg, 0.34mmol, 1.10eq) were dissolved in acetonitrile (1.66mL) and water (1.66 mL), bubbling with nitrogen for 10 minutes, adding tetrakis(triphenylphosphorus) palladium (17.67 mg, 0.015 mmol, 0.05 eq), bubbling with nitrogen for 5 minutes. The mixture was stirred under reflux at 80°C for 3 hours. After the completion of the reaction, the solvent was spin-dried under reduced pressure, water (5mL) was added, and the mixture was extracted with ethyl acetate (5mL×3). The combined organic phase was washed with saturated sodium chloride solution (5mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced. It was concentrated under pressure, and the obtained residue was purified with a flash liquid chromatography system to obtain compound F (143.3 mg, pale yellow solid), yield: 95.63%.
第四步the fourth step
将化合物F(143.3mg，0.29mmol，1.00eq)加入密闭管，溶解于1，4-二氧六环(0.25mL)，再加入碳酸铯(190.6mg，0.58mmol，2eq)、N-甲基-L脯氨醇(168.41mg，0.19mL，1.46mmol，5eq)，90℃高压反应搅拌24h，反应结束后，冷却到室温，加水(5.0mL)，乙酸乙酯萃取(5.0mL×3)，合并的有机相用饱和氯化钠溶液洗涤(5.0mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用快速液相色谱***纯化所得残余物，得到化合物H(57.8mg，浅灰色固体)产率：34.75％。Compound F (143.3mg, 0.29mmol, 1.00eq) was added to a closed tube, dissolved in 1,4-dioxane (0.25mL), then cesium carbonate (190.6mg, 0.58mmol, 2eq), N-methyl -L prolinol (168.41mg, 0.19mL, 1.46mmol, 5eq), 90°C high pressure reaction and stirring for 24h, after the reaction is over, cool to room temperature, add water (5.0mL), ethyl acetate extraction (5.0mL×3), The combined organic phase was washed with saturated sodium chloride solution (5.0 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by a flash liquid chromatography system to obtain compound H (57.8 mg, light gray solid ) Yield: 34.75%.
第五步the fifth step
将化合物H(57.8mg，0.1mmol，1eq)溶解于二氯甲烷(0.3mL)，于氮气保护下加入三氟乙酸(0.23mL，3.05mmol，30eq)，室温搅拌1小时，溶剂减压旋干，冰浴下将混合物溶解于二氯甲烷(0.3mL)，氮气保护下加入N,N-二异丙基乙胺(0.06mL，0.4mmol，4.00eq)，丙烯酰氯的二氯甲烷溶液(8.085mmL，0.1mmol，1.00eq，0.03mL二氯甲烷)，在0℃搅拌10分钟，反应结束后用饱和碳酸氢钠(5mL)淬灭，加入乙酸乙酯(5.0mL×3)，水(5.0mL)萃取，合并的有机相用饱和氯化钠溶液洗涤(5.0mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，用快速液相色谱***纯化所得残余物，得到化合物2(29.2mg，淡黄色固体)，产率55％。Compound H (57.8mg, 0.1mmol, 1eq) was dissolved in dichloromethane (0.3mL), trifluoroacetic acid (0.23mL, 3.05mmol, 30eq) was added under nitrogen protection, stirred at room temperature for 1 hour, and the solvent was spin-dried under reduced pressure , The mixture was dissolved in dichloromethane (0.3mL) under ice bath, N,N-diisopropylethylamine (0.06mL, 0.4mmol, 4.00eq), acryloyl chloride in dichloromethane (8.085 mmL, 0.1mmol, 1.00eq, 0.03mL dichloromethane), stirred at 0°C for 10 minutes, after the reaction was quenched with saturated sodium bicarbonate (5mL), added ethyl acetate (5.0mL×3), water (5.0 mL), the combined organic phase was washed with saturated sodium chloride solution (5.0 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue obtained was purified by a flash liquid chromatography system to obtain compound 2 (29.2 mg , Pale yellow solid), the yield is 55%.
实施例3Example 3
Figure PCTCN2021070462-appb-000027
Figure PCTCN2021070462-appb-000027
化合物1-(4-(2-(2-(二甲基氨基)乙氧基)-7-(3-羟基萘-1-基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 499.24[M+H] +。 Compound 1-(4-(2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalene-1-yl)pyrido[2,3-d]pyrimidin-4-yl) The synthesis of piperazin-1-yl)prop-2-en-1-one refers to general reaction schemes (A) and (B); MS (ESI) m/z 499.24 [M+H] + .
实施例4Example 4
Figure PCTCN2021070462-appb-000028
Figure PCTCN2021070462-appb-000028
化合物1-(4-(6-氯-2-(2-(二甲基氨基)乙氧基)-7-(3-羟基萘-1-基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 533.20[M+H]+。Compound 1-(4-(6-chloro-2-(2-(dimethylamino)ethoxy)-7-(3-hydroxynaphthalene-1-yl)pyrido[2,3-d]pyrimidine- The synthesis of 4-yl)piperazin-1-yl)prop-2-en-1-one refers to the general reaction schemes (A) and (B); MS (ESI) m/z 533.20[M+H]+.
实施例5Example 5
Figure PCTCN2021070462-appb-000029
Figure PCTCN2021070462-appb-000029
化合物1-((S)-4-(7-(3-羟基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 539.27[M+H] +。 Compound 1-((S)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[ The synthesis of 2,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one refers to the general reaction schemes (A) and (B); MS (ESI ) m/z 539.27 [M+H] + .
实施例6Example 6
Figure PCTCN2021070462-appb-000030
Figure PCTCN2021070462-appb-000030
化合物1-((S)-4-(7-(3-羟基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)吡啶并[2,3-d]嘧啶-4-基)-2,5-二甲基哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z553.29[M+H] +。 Compound 1-((S)-4-(7-(3-hydroxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)pyrido[ The synthesis of 2,3-d]pyrimidin-4-yl)-2,5-dimethylpiperazin-1-yl)prop-2-en-1-one refers to the general reaction schemes (A) and (B); MS (ESI) m/z 553.29 [M+H] + .
实施例7Example 7
Figure PCTCN2021070462-appb-000031
Figure PCTCN2021070462-appb-000031
化合物(S)-7-(2,3-二甲基苯)-2-((1-甲基吡咯烷-2-基)甲氧基)-4-(4-乙烯磺酰基)哌嗪-1-基)吡啶并[2,3-d]嘧啶的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 523.24[M+H] +。 Compound (S)-7-(2,3-dimethylbenzene)-2-((1-methylpyrrolidin-2-yl)methoxy)-4-(4-vinylsulfonyl)piperazine- The synthesis of 1-yl)pyrido[2,3-d]pyrimidine refers to the general reaction schemes (A) and (B); MS(ESI) m/z 523.24[M+H] + .
实施例8Example 8
Figure PCTCN2021070462-appb-000032
Figure PCTCN2021070462-appb-000032
化合物2-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(丙炔酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 580.22[M+H] +。 Compound 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-pyrido The synthesis of [2,3-d]pyrimidin-4-yl)-1-(propioyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS (ESI) m/z 580.22[M+H] + .
实施例9Example 9
Figure PCTCN2021070462-appb-000033
Figure PCTCN2021070462-appb-000033
化合物2-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z582.23[M+H] +。 Compound 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-pyrido The synthesis of [2,3-d]pyrimidin-4-yl)-1-(acryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI)m/z582. 23[M+H] + .
实施例10Example 10
Figure PCTCN2021070462-appb-000034
Figure PCTCN2021070462-appb-000034
化合物2-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 600.22[M+H] +。 Compound 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-pyrido The synthesis of [2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI)m /z 600.22[M+H] + .
实施例11Example 11
Figure PCTCN2021070462-appb-000035
Figure PCTCN2021070462-appb-000035
化合物2-((S)-4-(7-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z562.29[M+H] +。 Compound 2-((S)-4-(7-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-pyridine The synthesis of and [2,3-d]pyrimidin-4-yl)-1-(acryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI)m/z562 .29[M+H] + .
实施例12Example 12
Figure PCTCN2021070462-appb-000036
Figure PCTCN2021070462-appb-000036
化合物2-((S)-4-(7-(8-甲基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z580.28[M+H] +。 Compound 2-((S)-4-(7-(8-methylnaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-pyridine The synthesis of and [2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI) m/z580.28[M+H] + .
实施例13Example 13
Figure PCTCN2021070462-appb-000037
Figure PCTCN2021070462-appb-000037
化合物2-((S)-4-(7-(3-羟基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z564.27[M+H] +。 Compound 2-((S)-4-(7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-pyrido The synthesis of [2,3-d]pyrimidin-4-yl)-1-(acryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI)m/z564. 27[M+H] + .
实施例14Example 14
Figure PCTCN2021070462-appb-000038
Figure PCTCN2021070462-appb-000038
化合物2-((S)-4-(7-(3-羟基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z582.26[M+H] +。 Compound 2-((S)-4-(7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-pyrido The synthesis of [2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI)m /z582.26[M+H] + .
实施例15Example 15
Figure PCTCN2021070462-appb-000039
Figure PCTCN2021070462-appb-000039
化合物2-((S)-4-(7-(3-羟基萘-1-基)-2-(((S)-1-甲基哌啶-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 596.27[M+H] +。 Compound 2-((S)-4-(7-(3-hydroxynaphthalene-1-yl)-2-(((S)-1-methylpiperidin-2-yl)methoxy)-pyrido The synthesis of [2,3-d]pyrimidin-4-yl)-1-(acryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS (ESI) m/z 596.27 [M+H] + .
实施例17Example 17
Figure PCTCN2021070462-appb-000040
Figure PCTCN2021070462-appb-000040
化合物2-((S)-4-(7-(3-甲氧基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z596.27[M+H] +。 Compound 2-((S)-4-(7-(3-methoxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)- The synthesis of pyrido[2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI ) m/z596.27[M+H] + .
实施例18Example 18
Figure PCTCN2021070462-appb-000041
Figure PCTCN2021070462-appb-000041
化合物2-((S)-4-(7-(2,3-二甲基苯)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z544.28[M+H] +。 Compound 2-((S)-4-(7-(2,3-dimethylbenzene)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-pyrido The synthesis of [2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI)m /z544.28[M+H] + .
实施例19Example 19
Figure PCTCN2021070462-appb-000042
Figure PCTCN2021070462-appb-000042
化合物2-((S)-4-(7-(2-氟-6-羟基苯)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z550.23[M+H] +。 Compound 2-((S)-4-(7-(2-fluoro-6-hydroxybenzene)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-pyrido The synthesis of [2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI)m /z550.23[M+H] + .
实施例20Example 20
Figure PCTCN2021070462-appb-000043
Figure PCTCN2021070462-appb-000043
化合物2-((S)-4-(7-(8-氯萘-1-基)-2-(((R)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 600.22[M+H] +。 Compound 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((R)-1-methylpyrrolidin-2-yl)methoxy)-pyrido The synthesis of [2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI)m /z 600.22[M+H] + .
实施例21Example 21
Figure PCTCN2021070462-appb-000044
Figure PCTCN2021070462-appb-000044
化合物2-((S)-4-(7-(5,6-二甲基1H-吲哚-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 583.29[M+H] +。 Compound 2-((S)-4-(7-(5,6-dimethyl 1H-indol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl) The synthesis of methoxy)-pyrido[2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B) ); MS (ESI) m/z 583.29 [M+H] + .
实施例22Example 22
Figure PCTCN2021070462-appb-000045
Figure PCTCN2021070462-appb-000045
化合物2-((S)-4-(7-(5,6-二甲基1H-吲哚-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 565.30[M+H] +。 Compound 2-((S)-4-(7-(5,6-dimethyl 1H-indol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl) The synthesis of methoxy)-pyrido[2,3-d]pyrimidin-4-yl)-1-(acryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS (ESI) m/z 565.30 [M+H] + .
实施例23Example 23
Figure PCTCN2021070462-appb-000046
Figure PCTCN2021070462-appb-000046
化合物2-((S)-4-(7-(5,6-二甲基1H-吲唑-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 566.29[M+H] +。 Compound 2-((S)-4-(7-(5,6-dimethyl 1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl) The synthesis of methoxy)-pyrido[2,3-d]pyrimidin-4-yl)-1-(acryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS (ESI) m/z 566.29 [M+H] + .
实施例24Example 24
Figure PCTCN2021070462-appb-000047
Figure PCTCN2021070462-appb-000047
化合物2-((S)-4-(7-(5,6-二甲基1H-吲唑-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 584.29[M+H] +。 Compound 2-((S)-4-(7-(5,6-dimethyl 1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl) The synthesis of methoxy)-pyrido[2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B) ); MS (ESI) m/z 584.29 [M+H] + .
实施例25Example 25
Figure PCTCN2021070462-appb-000048
Figure PCTCN2021070462-appb-000048
化合物2-((S)-4-(7-(5-甲基1H-吲唑-4-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z570.27[M+H] +。 Compound 2-((S)-4-(7-(5-methyl1H-indazol-4-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy The synthesis of )-pyrido[2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS (ESI) m/z570.27[M+H] + .
实施例26Example 26
Figure PCTCN2021070462-appb-000049
Figure PCTCN2021070462-appb-000049
化合物2-((S)-4-(7-(5-甲基1H-吲唑-4-基)-2-(((S)4,4-二氟-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 606.25[M+H]。Compound 2-((S)-4-(7-(5-methyl1H-indazol-4-yl)-2-(((S)4,4-difluoro-1-methylpyrrolidine-2 -Yl)methoxy)-pyrido[2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refer to the general reaction scheme (A)和(B); MS(ESI)m/z 606.25[M+H].
实施例27Example 27
Figure PCTCN2021070462-appb-000050
Figure PCTCN2021070462-appb-000050
化合物2-((S)-4-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-3-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z600.22[M+H] +。 Compound 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-3-yl)methoxy)-pyrido The synthesis of [2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI)m /z600.22[M+H] + .
实施例28Example 28
Figure PCTCN2021070462-appb-000051
Figure PCTCN2021070462-appb-000051
化合物2-((S)-1-(2-氟丙烯酰基)-4-(7-(2-甲基-3-甲氧基苯基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z560.27[M+H] +。 Compound 2-((S)-1-(2-fluoroacryloyl)-4-(7-(2-methyl-3-methoxyphenyl)-2-(((S)-1-methyl The synthesis of pyrrolidin-2-yl)methoxy)-pyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS (ESI) m/z560.27[M+H] + .
实施例29Example 29
Figure PCTCN2021070462-appb-000052
Figure PCTCN2021070462-appb-000052
化合物2-((S)-4-(7-(8-氯萘-1-基)-2-(((2S,4R)-4-氟-1-甲基吡咯烷-2-基)甲氧基)吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z618.22[M+H] +。 Compound 2-((S)-4-(7-(8-chloronaphthalene-1-yl)-2-(((2S,4R)-4-fluoro-1-methylpyrrolidin-2-yl)methyl The synthesis of oxy)pyrido[2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS (ESI) m/z 618.22 [M+H] + .
实施例30Example 30
Figure PCTCN2021070462-appb-000053
Figure PCTCN2021070462-appb-000053
化合物2-((S)-4-(7-(5-氯异喹啉-4-基)-2-(((2S)-1-甲基吡咯烷-2-基)甲氧基)吡啶并[2,3-d]嘧啶-4-基)-1-(2-氟丙烯酰基)哌嗪-2-基)乙腈的合成参考一般反应流程(A)和(B)；MS(ESI)m/z601.22[M+H] +。 Compound 2-((S)-4-(7-(5-chloroisoquinolin-4-yl)-2-(((2S)-1-methylpyrrolidin-2-yl)methoxy)pyridine The synthesis of and [2,3-d]pyrimidin-4-yl)-1-(2-fluoroacryloyl)piperazin-2-yl)acetonitrile refers to the general reaction schemes (A) and (B); MS(ESI) m/z601.22[M+H] + .
实施例31Example 31
Figure PCTCN2021070462-appb-000054
Figure PCTCN2021070462-appb-000054
化合物1-(4-(6-氯-7-(5-氯-6-氟1H-吲唑-4-基)-2-(((3R,4R)-4-甲氧基-1-甲基吡咯烷-3-基)甲氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 615.18[M+H] +。 Compound 1-(4-(6-chloro-7-(5-chloro-6-fluoro 1H-indazol-4-yl)-2-(((3R,4R)-4-methoxy-1-methyl (Pyrrolidin-3-yl) methoxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one. Refer to the general reaction scheme for the synthesis of ( A) and (B); MS (ESI) m/z 615.18 [M+H] + .
实施例32Example 32
Figure PCTCN2021070462-appb-000055
Figure PCTCN2021070462-appb-000055
化合物1-(4-(6-氯-7-(5-氯-6-氟1H-吲唑-4-基)-2-(((3R,4R)-4-甲氧基-1-甲基吡咯烷-3-基)甲氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-氟丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 633.17[M+H] +。 Compound 1-(4-(6-chloro-7-(5-chloro-6-fluoro 1H-indazol-4-yl)-2-(((3R,4R)-4-methoxy-1-methyl Reference for the synthesis of pyrrolidin-3-yl)methoxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one General reaction schemes (A) and (B); MS (ESI) m/z 633.17 [M+H] + .
实施例35Example 35
Figure PCTCN2021070462-appb-000056
Figure PCTCN2021070462-appb-000056
化合物1-(4-(6-氯-7-(5-氯-6-氟1H-吲唑-4-基)-2-(((3R,4R)-4-乙氧基-1-甲基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 615.18[M+H] +。 Compound 1-(4-(6-chloro-7-(5-chloro-6-fluoro 1H-indazol-4-yl)-2-(((3R,4R)-4-ethoxy-1-methyl Pyrrolidin-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one. Refer to the general reaction scheme (A ) And (B); MS (ESI) m/z 615.18 [M+H] + .
实施例36Example 36
Figure PCTCN2021070462-appb-000057
Figure PCTCN2021070462-appb-000057
化合物1-(4-(6-氯-7-(5-氯-6-氟1H-吲唑-4-基)-2-(((3S,4R)-4-乙基-1-甲基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 599.18[M+H] +。 Compound 1-(4-(6-chloro-7-(5-chloro-6-fluoro 1H-indazol-4-yl)-2-(((3S,4R)-4-ethyl-1-methyl The synthesis of pyrrolidin-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refers to the general reaction scheme (A) And (B); MS (ESI) m/z 599.18 [M+H] + .
实施例37Example 37
Figure PCTCN2021070462-appb-000058
Figure PCTCN2021070462-appb-000058
化合物1-(4-(6-氯-7-(5,6-二氯-1H-吲唑-4-基)-2-(((3R,4R)-4-甲氧基-1-甲基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 617.92[M+H] +。 Compound 1-(4-(6-chloro-7-(5,6-dichloro-1H-indazol-4-yl)-2-(((3R,4R)-4-methoxy-1-methyl Pyrrolidin-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one. Refer to the general reaction scheme (A ) And (B); MS (ESI) m/z 617.92 [M+H] + .
实施例38Example 38
Figure PCTCN2021070462-appb-000059
Figure PCTCN2021070462-appb-000059
化合物1-(4-(6-氯-7-(5-氯-6-氟1H-吲唑-4-基)-2-(((3S,4R)-1,4-二甲基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z585.17[M+H] +。 Compound 1-(4-(6-chloro-7-(5-chloro-6-fluoro 1H-indazol-4-yl)-2-(((3S,4R)-1,4-dimethylpyrrolidine -3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refer to general reaction schemes (A) and ( B); MS (ESI) m/z 585.17 [M+H] + .
实施例39Example 39
Figure PCTCN2021070462-appb-000060
Figure PCTCN2021070462-appb-000060
化合物1-(4-(6-氯-7-(5-甲基-1H-吲唑-4-基)-2-(((3R,4R)-4-甲氧基-1-甲基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 563.22[M+H] +。 Compound 1-(4-(6-chloro-7-(5-methyl-1H-indazol-4-yl)-2-(((3R,4R)-4-methoxy-1-methylpyrrole (Alk-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refers to the general reaction scheme (A) and (B); MS (ESI) m/z 563.22 [M+H] + .
实施例40Example 40
Figure PCTCN2021070462-appb-000061
Figure PCTCN2021070462-appb-000061
化合物1-(4-(6-氯-7-(5-氯-1H-吲唑-4-基)-2-(((3R,4R)-4-甲氧基-1-甲基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 583.47[M+H] +。 Compound 1-(4-(6-chloro-7-(5-chloro-1H-indazol-4-yl)-2-(((3R,4R)-4-methoxy-1-methylpyrrolidine -3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refer to general reaction schemes (A) and ( B); MS (ESI) m/z 583.47 [M+H] + .
实施例41Example 41
Figure PCTCN2021070462-appb-000062
Figure PCTCN2021070462-appb-000062
化合物1-(4-(6-氯-7-(5-氯-6-氟1H-吲唑-4-基)-2-(((3R,4R)-4-甲氧基-丙-2-炔-1-基)吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 625.49[M+H] +。 Compound 1-(4-(6-chloro-7-(5-chloro-6-fluoro 1H-indazol-4-yl)-2-(((3R,4R)-4-methoxy-prop-2 -Yn-1-yl)pyrrolidin-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one Refer to general reaction schemes (A) and (B); MS (ESI) m/z 625.49[M+H] + .
实施例42Example 42
Figure PCTCN2021070462-appb-000063
Figure PCTCN2021070462-appb-000063
化合物1-(4-(7-(5-氯-6-氟1H-吲唑-4-基)-2-(((3R,4R)-1-乙基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z581.05[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro 1H-indazol-4-yl)-2-(((3R,4R)-1-ethyl-4-methoxypyrrolidine- The synthesis of 3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refers to the general reaction schemes (A) and (B) ); MS(ESI) m/z581.05[M+H] + .
实施例43Example 43
Figure PCTCN2021070462-appb-000064
Figure PCTCN2021070462-appb-000064
化合物1-(4-(7-(5-氯-6-氟1H-吲唑-4-基)-2-(((3R,4R)-1-乙基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-氟丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 599.04[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro 1H-indazol-4-yl)-2-(((3R,4R)-1-ethyl-4-methoxypyrrolidine- 3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one refer to the general reaction scheme (A ) And (B); MS (ESI) m/z 599.04 [M+H] + .
实施例44Example 44
Figure PCTCN2021070462-appb-000065
Figure PCTCN2021070462-appb-000065
化合物1-(4-(7-(5,6-二氯-1H-吲唑-4-基)-2-(((3R,4R)-1-甲基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z583.17[M+H] +。 Compound 1-(4-(7-(5,6-Dichloro-1H-indazol-4-yl)-2-(((3R,4R)-1-methyl-4-methoxypyrrolidine- The synthesis of 3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refers to the general reaction schemes (A) and (B) ); MS(ESI) m/z583.17[M+H] + .
实施例45Example 45
Figure PCTCN2021070462-appb-000066
Figure PCTCN2021070462-appb-000066
化合物1-(4-(7-(5,6-二氯-1H-吲唑-4-基)-2-(((3R,4R)-1-甲基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-氟丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 601.46[M+H] +。 Compound 1-(4-(7-(5,6-Dichloro-1H-indazol-4-yl)-2-(((3R,4R)-1-methyl-4-methoxypyrrolidine- 3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one refer to the general reaction scheme (A ) And (B); MS (ESI) m/z 601.46 [M+H] + .
实施例46Example 46
Figure PCTCN2021070462-appb-000067
Figure PCTCN2021070462-appb-000067
化合物1-(4-(7-(5-氯-6-氟-1H-吲唑-4-基)-2-(((3R,4R)-1-甲基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 567.20[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-(((3R,4R)-1-methyl-4-methoxypyrrolidine -3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refer to general reaction schemes (A) and ( B); MS (ESI) m/z 567.20 [M+H] + .
实施例47Example 47
Figure PCTCN2021070462-appb-000068
Figure PCTCN2021070462-appb-000068
化合物1-(4-(7-(5-氯-6-氟-1H-吲唑-4-基)-2-(((3R,4R)-1-甲基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-氟丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 585.01[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-(((3R,4R)-1-methyl-4-methoxypyrrolidine -3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one refer to the general reaction scheme ( A) and (B); MS (ESI) m/z 585.01 [M+H] + .
实施例48Example 48
Figure PCTCN2021070462-appb-000069
Figure PCTCN2021070462-appb-000069
化合物1-(4-(7-(5-氯-6-氟-1H-吲唑-4-基)-2-(((3R,4R)-1-异丙基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 595.08[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-(((3R,4R)-1-isopropyl-4-methoxypyrrole (Alk-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refers to the general reaction scheme (A) and (B); MS (ESI) m/z 595.08 [M+H] + .
实施例49Example 49
Figure PCTCN2021070462-appb-000070
Figure PCTCN2021070462-appb-000070
化合物1-(4-(7-(5-氯-6-氟-1H-吲唑-4-基)-2-(((3R,4R)-1-异丙基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-氟丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 613.07[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-(((3R,4R)-1-isopropyl-4-methoxypyrrole (Alk-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one refer to the general reaction scheme (A) and (B); MS (ESI) m/z 613.07 [M+H] + .
实施例50Example 50
Figure PCTCN2021070462-appb-000071
Figure PCTCN2021070462-appb-000071
化合物1-(4-(7-(5-氯-6-氟-1H-吲唑-4-基)-2-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z599.20[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinoline -5-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refer to general reaction schemes (A) and ( B); MS (ESI) m/z 599.20 [M+H] + .
实施例51Example 51
Figure PCTCN2021070462-appb-000072
Figure PCTCN2021070462-appb-000072
化合物1-(4-(7-(5-氯-6-氟-1H-吲唑-4-基)-2-(((3R,4R)-1-甲基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 581.05[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-(((3R,4R)-1-methyl-4-methoxypyrrolidine -3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)prop-2-en-1-one. Refer to the general reaction scheme for the synthesis (A) and (B); MS (ESI) m/z 581.05 [M+H] + .
实施例52Example 52
Figure PCTCN2021070462-appb-000073
Figure PCTCN2021070462-appb-000073
化合物1-(4-(7-(5-氯-6-氟-1H-吲唑-4-基)-2-(((3R,4R)-1-甲基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)-3-甲基哌嗪-1-基)-2-氟丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 599.04[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-(((3R,4R)-1-methyl-4-methoxypyrrolidine -3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)-2-fluoroprop-2-en-1-one Refer to general reaction schemes (A) and (B); MS (ESI) m/z 599.04 [M+H] + .
实施例53Example 53
Figure PCTCN2021070462-appb-000074
Figure PCTCN2021070462-appb-000074
化合物1-(4-(7-(5-甲基-6-氯-1H-吲唑-4-基)-2-(((3R,4R)-1-甲基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 563.06[M+H] +。 Compound 1-(4-(7-(5-methyl-6-chloro-1H-indazol-4-yl)-2-(((3R,4R)-1-methyl-4-methoxypyrrole (Alk-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refers to the general reaction scheme (A) and (B); MS (ESI) m/z 563.06 [M+H] + .
实施例54Example 54
Figure PCTCN2021070462-appb-000075
Figure PCTCN2021070462-appb-000075
化合物1-(4-(7-(5-甲基-6-氯-1H-吲唑-4-基)-2-(((3R,4R)-1-甲基-4-甲氧基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-氟丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 581.05[M+H] +。 Compound 1-(4-(7-(5-methyl-6-chloro-1H-indazol-4-yl)-2-(((3R,4R)-1-methyl-4-methoxypyrrole (Alk-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one refer to the general reaction scheme (A) and (B); MS (ESI) m/z 581.05 [M+H] + .
实施例55Example 55
Figure PCTCN2021070462-appb-000076
Figure PCTCN2021070462-appb-000076
化合物1-(4-(7-(5-氯-6-氟-1H-吲唑-4-基)-2-((2-甲基异吲哚啉-4-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)-2-氟丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z603.03[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-((2-methylisoindolin-4-yl)oxy)pyrido The synthesis of [2,3-d]pyrimidin-4-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one refers to the general reaction schemes (A) and (B); MS (ESI ) m/z603.03[M+H] + .
实施例56Example 56
Figure PCTCN2021070462-appb-000077
Figure PCTCN2021070462-appb-000077
化合物1-(4-(7-(5-氯-1H-吲唑-4-基)-2-((2-甲基-1,2,3,4-四氢异喹啉-5-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z599.07[M+H] +。 Compound 1-(4-(7-(5-chloro-1H-indazol-4-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl )Oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refer to general reaction schemes (A) and (B); MS (ESI) m/z599.07[M+H] + .
实施例57Example 57
Figure PCTCN2021070462-appb-000078
Figure PCTCN2021070462-appb-000078
化合物1-(4-(2-(((3R,4R)-1-(叔丁基)-4-甲氧基吡咯烷-3-基)氧基)-7-(5-氯-6-氟-1H-吲唑-4-基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 609.25[M+H] +。 Compound 1-(4-(2-(((3R,4R)-1-(tert-butyl)-4-methoxypyrrolidin-3-yl)oxy)-7-(5-chloro-6- The synthesis of fluoro-1H-indazol-4-yl)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one refers to the general reaction scheme (A ) And (B); MS (ESI) m/z 609.25 [M+H] + .
实施例58Example 58
Figure PCTCN2021070462-appb-000079
Figure PCTCN2021070462-appb-000079
化合物1-(4-(7-(5-氯-6-氟-1H-吲唑-4-基)-2-(((3R,4R)-4-(二氟甲基)-1-甲基吡咯烷-3-基)氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-1-基)丙-2-烯-1-酮的合成参考一般反应流程(A)和(B)；MS(ESI)m/z 587.19[M+H] +。 Compound 1-(4-(7-(5-chloro-6-fluoro-1H-indazol-4-yl)-2-(((3R,4R)-4-(difluoromethyl)-1-methyl Pyrrolidin-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one. Refer to the general reaction scheme (A ) And (B); MS (ESI) m/z 587.19 [M+H] + .
实施例59Example 59
Figure PCTCN2021070462-appb-000080
Figure PCTCN2021070462-appb-000080
化合物2-((S)-4-(7-(3-甲氧基萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-吡啶并[2,3-d]嘧啶-4-基)-1-(丙烯酰基)哌嗪-2-基)乙腈，其合成在一般反应流程(A)和(B)；MS M/Z 677.69。Compound 2-((S)-4-(7-(3-methoxynaphthalen-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)- Pyrido[2,3-d]pyrimidin-4-yl)-1-(acryloyl)piperazin-2-yl)acetonitrile, its synthesis is in the general reaction schemes (A) and (B); MS M/Z 677.69 .
实施例60Example 60
Figure PCTCN2021070462-appb-000081
Figure PCTCN2021070462-appb-000081
化合物2-(((S)-1-(2-氟丙烯酰基)-4-(7-(2-甲基-1,2,3,4-四氢异喹啉-8-基)-2-(1-甲基吡咯烷-2-基)甲氧基)吡啶并[2,3-d]嘧啶-4-基)哌嗪-2-基)乙腈，其合成参考一般反应流程(A)和(B)；MS M/Z 584.70。Compound 2-(((S)-1-(2-fluoroacryloyl)-4-(7-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-2 -(1-Methylpyrrolidin-2-yl)methoxy)pyrido[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile, its synthesis refers to the general reaction scheme (A) And (B); MS M/Z 584.70.
实验例1Experimental example 1
本实验目的是验证本发明化合物与人非小细胞肺癌NCI-H358细胞(KRAS G12C突变)、 人非小细胞肺癌A549细胞(KRAS G12S突变)和非小细胞肺癌HCC827细胞(KRAS野生型)的KRAS G12C突变蛋白的共价结合活性。The purpose of this experiment is to verify the compound of the present invention and human non-small cell lung cancer NCI-H358 cells (KRAS G12C mutation), human non-small cell lung cancer A549 cells (KRAS G12S mutation) and non-small cell lung cancer HCC827 cells (KRAS wild type) KRAS Covalent binding activity of G12C mutant protein.
肿瘤细胞株：三种人非小细胞肺癌细胞株：NCI-H358细胞(KRAS G12C突变)、A549细胞(KRAS G12S突变)和HCC827细胞(KRAS野生型)。Tumor cell lines: Three human non-small cell lung cancer cell lines: NCI-H358 cells (KRAS G12C mutation), A549 cells (KRAS G12S mutation) and HCC827 cells (KRAS wild type).
主要试剂和仪器：RPMI1640培养基、DMEM细胞培养基、胎牛血清、0.25％胰蛋白酶-0.53mM EDTA消化液、DMSO、青霉素-链霉素、KRAS抗体(Sigma)，二抗为Anti-rabbit IgG-HRP、Cell Titer-Gio检测试剂盒。Promega微孔板检测仪、细胞培养瓶、细胞培养微孔板(96或384孔)、CO 2恒温培养箱，FluorChemR检测仪(ProteinSimple)。 Main reagents and instruments: RPMI1640 medium, DMEM cell culture medium, fetal bovine serum, 0.25% trypsin-0.53mM EDTA digestion solution, DMSO, penicillin-streptomycin, KRAS antibody (Sigma), the secondary antibody is Anti-rabbit IgG -HRP, Cell Titer-Gio detection kit. Promega microplate detector, cell culture flask, cell culture microplate (96 or 384 well), CO 2 constant temperature incubator, FluorChemR detector (ProteinSimple).
实验方法：experimental method:
本发明采用了凝胶迁移分析法(gel mobility shift assay)测定化合物与细胞KRAS G12C突变蛋白形成的共价结合复合物特有的电泳迁移改变；其原理是基于化合物和K-RAS G12C突变蛋白结合形成的共价复合物的分子量增大，与游离的KRAS G12C突变蛋白相比，在电泳时出现相应的电泳带滞后。再用FluorChemR检测仪定量扫描电泳带，计算化合物-G12C突变蛋白的复合物与未结合化合物的G12C突变蛋白的电泳迁移比值，快速和直接测定本发明化合物与KRAS G12C突变蛋白的共价键结合特征；化合物与KRAS G12C突变蛋白结合结合越多，其计算的比值就也大。The present invention adopts the gel mobility shift assay to measure the unique electrophoretic migration changes of the covalent binding complex formed by the compound and the cell KRAS G12C mutant protein; the principle is based on the combination of the compound and the K-RAS G12C mutant protein. Compared with the free KRAS G12C mutant protein, the molecular weight of the covalent complex increases, and the corresponding electrophoretic band lag occurs during electrophoresis. Then quantitatively scan the electrophoresis band with the FluorChemR detector to calculate the electrophoretic migration ratio between the compound-G12C mutant protein complex and the unbound G12C mutant protein, and quickly and directly determine the covalent bonding characteristics of the compound of the present invention and the KRAS G12C mutant protein ; The more the compound binds to the KRAS G12C mutant protein, the larger the calculated ratio.
将液氮冻存的肿瘤细胞复苏，用含10％胎牛血清,10％青霉素-链霉素的细胞培养液培养细胞，待细胞生长至指数增长期，消化离心收集细胞重悬于培养液中；按每孔5000-10000个细胞数接种细胞，置于恒温37℃、5％CO 2、饱和湿度的二氧化碳培养箱中培养。 Resuscitate the tumor cells cryopreserved in liquid nitrogen, culture the cells with a cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin. When the cells grow to the exponential growth phase, digest and centrifuge to collect the cells and resuspend them in the culture medium ; Inoculate the cells according to the number of 5000-10000 cells per well, and place them in a carbon dioxide incubator at a constant temperature of 37°C, 5% CO 2, and saturated humidity.
化合物以不同浓度和不同的时间处理细胞后，用磷酸盐缓冲液(PBS)洗涤细胞，然后在RIPA缓冲液(50mm Tris，pH7.5，150mm NaCl，1％NP-40，0.5％脱氧胆酸钠,0.1％SDS，含蛋白酶和磷酸酶抑制剂)中裂解细胞，提取细胞总蛋白，用BCA蛋白检测试剂盒测定蛋白质浓度；取等量蛋白质进行SDS-PAGE电泳，电泳结束后，将电泳凝胶转移至硝化纤维素膜上；转膜后在TBS-0.1％吐温-20中用5％脱脂牛奶阻断膜，然后加入一抗，并在4 0C轻微震摇，孵育过夜。过夜孵育后的膜经洗涤后，在室温下与荧光结合的二抗孵育1小时，用FluorChemR检测仪(ProteinSimple)扫描电泳带。 After the compounds were treated with different concentrations and different times, the cells were washed with phosphate buffered saline (PBS), and then in RIPA buffer (50mm Tris, pH7.5, 150mm NaCl, 1% NP-40, 0.5% deoxycholic acid). Sodium, 0.1% SDS, containing protease and phosphatase inhibitors) lyse the cells, extract the total cell protein, use the BCA protein detection kit to determine the protein concentration; take the same amount of protein for SDS-PAGE electrophoresis, after the electrophoresis is over, the electrophoresis is coagulated gel was transferred to a nitrocellulose membrane; Tween film after transfection, the TBS-0.1% -20 with 5% skim milk blocking film, followed by addition of primary antibody overnight at 4 0 C and mild shaking and incubated. The membrane after overnight incubation was washed, and incubated with the fluorescent-bound secondary antibody for 1 hour at room temperature, and the electrophoretic band was scanned with a FluorChemR detector (ProteinSimple).
实验结果Experimental results
在凝胶迁移率分析中，本发明中的大部分化合物能选择性地与含有KRAS G12C突变的人非小细胞肺癌NCI-H358细胞中的KRAS G12C突变蛋白结合，形成的化合物-突变蛋白复合物出现凝胶迁移率阻滞，但化合物不能与KRAS G12S突变的非小细胞肺癌A549细胞的KRAS G12S突变蛋白结合，也不能和含有野生型KRAS的非小细胞肺癌HCC827细胞的野生型KRAS蛋白结合，不出现凝胶迁移率阻滞现象(表1)。实验结果表示如下：“A”≤25％比值；25％<“B”≤50％；“C”≥50％。In gel mobility analysis, most of the compounds of the present invention can selectively bind to the KRAS G12C mutant protein in human non-small cell lung cancer NCI-H358 cells containing the KRAS G12C mutation to form a compound-mutant complex Gel mobility is blocked, but the compound cannot bind to the KRAS G12S mutant protein of KRAS G12S mutant non-small cell lung cancer A549 cells, nor can it bind to the wild-type KRAS protein of non-small cell lung cancer HCC827 cells containing wild-type KRAS. There is no gel mobility blocking phenomenon (Table 1). The experimental results are expressed as follows: "A"≤25% ratio; 25%<"B"≤50%; "C"≥50%.
表1本发明实例化合物对KRAS G12C活性的抑制作用Table 1 The inhibitory effect of the example compounds of the present invention on the activity of KRAS G12C
Figure PCTCN2021070462-appb-000082
Figure PCTCN2021070462-appb-000082
Figure PCTCN2021070462-appb-000083
Figure PCTCN2021070462-appb-000083
Figure PCTCN2021070462-appb-000084
Figure PCTCN2021070462-appb-000084
实验例2Experimental example 2
本实验目的是验证本发明化合物对人非小细胞肺癌NCI-H358细胞(KRAS G12C突变)、人非小细胞肺癌A549细胞(KRAS G12S突变)和非小细胞肺癌HCC827细胞(KRAS野生型)的抗增殖作用。The purpose of this experiment is to verify the compounds of the present invention against human non-small cell lung cancer NCI-H358 cells (KRAS G12C mutation), human non-small cell lung cancer A549 cells (KRAS G12S mutation) and non-small cell lung cancer HCC827 cells (KRAS wild type). Proliferation.
肿瘤细胞株：三种人非小细胞肺癌细胞株：NCI-H358细胞(KRAS G12C突变)、A549细胞(KRAS G12S突变)和HCC827细胞(KRAS野生型)。Tumor cell lines: Three human non-small cell lung cancer cell lines: NCI-H358 cells (KRAS G12C mutation), A549 cells (KRAS G12S mutation) and HCC827 cells (KRAS wild type).
主要试剂和仪器：RPMI1640培养基、DMEM细胞培养基、胎牛血清、0.25％胰蛋白酶-0.53mM EDTA消化液、DMSO、青霉素-链霉素、Cell Titer-Gio检测试剂盒。Promega微孔板检测仪、细胞培养瓶、细胞培养微孔板(96或384孔)、CO 2恒温培养箱。 Main reagents and instruments: RPMI1640 medium, DMEM cell culture medium, fetal bovine serum, 0.25% trypsin-0.53mM EDTA digestion solution, DMSO, penicillin-streptomycin, Cell Titer-Gio detection kit. Promega microplate detector, cell culture flask, cell culture microplate (96 or 384 well), CO 2 constant temperature incubator.
实验方法：experimental method:
将液氮冻存的肿瘤细胞复苏，用含10％胎牛血清,10％青霉素-链霉素的细胞培养液培养细胞，待细胞生长至指数增长期，消化离心收集细胞重悬于培养液中；按每孔5000-10000个细胞数接种细胞，置于恒温37℃、5％CO 2、饱和湿度二氧化碳培养箱中过夜培养。 Resuscitate the tumor cells cryopreserved in liquid nitrogen, culture the cells with a cell culture medium containing 10% fetal bovine serum and 10% penicillin-streptomycin. When the cells grow to the exponential growth phase, digest and centrifuge to collect the cells and resuspend them in the culture medium ; Inoculate cells according to the number of 5000-10000 cells per well, and place them in a constant temperature 37°C, 5% CO 2 , saturated humidity carbon dioxide incubator for overnight culture.
药物作用72h后，从37℃孵箱中取出96孔板室温下放置30min以进行CTG检测，实验过程中不要晃动板。加入100μl CTG试剂，混匀2min，然后再室温下孵育10min，GloMax 96微孔板发光仪检测记录发光值(CellTiter-Glo Luminescent Cell Viability Assay，Promega)，观察细胞活力。After 72 hours of drug action, remove the 96-well plate from the 37°C incubator and place it at room temperature for 30 minutes for CTG detection. Do not shake the plate during the experiment. Add 100μl CTG reagent, mix well for 2min, and then incubate at room temperature for 10min. GloMax 96 microplate luminometer detects and records the luminescence value (CellTiter-Glo Luminescent Cell Viability Assay, Promega), and observe cell viability.
将本发明的每个待测化合物稀释成10个浓度梯度，分别加入细胞板的相应孔中，然后将细胞板放回二氧化碳培养箱中继续培养72小时。培养结束后，向细胞板中每孔加入Promega CellTiter-Glo试剂，室温下孵育10min，采用Promega微孔板检测仪检测发光信号，并计算IC50值。本发明化合物抗增殖活性的结果以A、B、ND表示：0.001μM≤“A”≤1μM；“B”>1μM；ND＝未测定。Each test compound of the present invention is diluted into 10 concentration gradients, respectively added to the corresponding wells of the cell plate, and then the cell plate is returned to the carbon dioxide incubator to continue culturing for 72 hours. After incubation, add Promega CellTiter-Glo reagent to each well of the cell plate, incubate at room temperature for 10 minutes, use Promega microplate detector to detect the luminescence signal, and calculate the IC50 value. The results of the antiproliferative activity of the compound of the present invention are expressed as A, B, ND: 0.001 μM≤"A"≤1μM; "B">1μM; ND=not determined.
实验结果：Experimental results:
本发明化合物对KRAS G12C突变的人非小细胞肺癌NCL-H358细胞显示出较高的抗增殖活性抑制活性，但对KRAS G12S突变的人非小细胞肺癌A549细胞以及KRAS野生型HCC827细胞显示出较弱的抗增殖活性(表2)。抗增殖实验结果与上述凝胶迁移率分析法得出的结果一致，表明了本发明化合物对KRAS G12C突变肿瘤细胞作用的高选择性。The compound of the present invention shows a higher anti-proliferative activity inhibitory activity against KRAS G12C mutant human non-small cell lung cancer NCL-H358 cells, but has a higher antiproliferative activity against KRAS G12S mutant human non-small cell lung cancer A549 cells and KRAS wild type HCC827 cells. Weak antiproliferative activity (Table 2). The results of the anti-proliferation experiment are consistent with the results obtained by the aforementioned gel mobility analysis method, indicating the high selectivity of the compound of the present invention on KRAS G12C mutant tumor cells.
表2典型化合物对KRAS-G12C介导的细胞增殖的抑制作用Table 2 Inhibitory effects of typical compounds on KRAS-G12C-mediated cell proliferation
编号Numbering H358 IC 50 H358 IC 50 A549 IC 50 A549 IC 50 HCC IC 50 HCC IC 50
11 BB BB BB
22 BB BB BB
33 BB BB BB
44 AA BB BB
55 BB BB BB
66 BB BB NDND
77 BB BB BB
88 AA BB BB
99 AA BB BB
1010 AA BB BB
1111 AA BB BB
1212 AA BB BB
1313 AA BB BB
1414 AA BB BB
1515 BB BB BB
1717 BB NDND BB
1818 BB BB BB
1919 BB BB NDND
2020 AA BB BB
21twenty one BB BB BB
22twenty two BB BB BB
23twenty three AA BB BB
24twenty four AA BB BB
2525 BB BB BB
2626 NDND NDND BB
2727 BB BB BB
2828 AA BB BB
2929 NDND BB BB
3030 BB BB NDND
3131 AA BB BB
3232 AA NDND NDND
3535 BB BB BB
3636 BB BB BB
3737 NDND BB BB
3838 BB BB BB
3939 BB BB BB
4040 BB BB BB
4141 BB BB BB
4242 BB BB BB
4343 BB BB BB
4444 AA BB BB
4545 AA BB BB
4646 AA BB NDND
4747 AA BB BB
4848 NDND NDND NDND
4949 AA BB BB
5050 BB BB BB
5151 BB BB BB
5252 NDND NDND NDND
5353 BB BB BB
5454 BB BB BB
5555 AA BB BB
5656 AA BB BB
5757 BB BB BB
5858 AA BB BB
5959 AA BB BB
6060 NDND NDND NDND

Claims (9)

  1. 通式(I)所示化合物、其异构体、其药学上可接受的盐或其氘代物：The compound represented by the general formula (I), its isomer, its pharmaceutically acceptable salt or its deuterated substance:
    Figure PCTCN2021070462-appb-100001
    Figure PCTCN2021070462-appb-100001
    其中，among them,
    X选自含有1或2个N原子的4-8元饱和或部分饱和的单环，或者含有1或2个N原子的6-12元饱和或部分饱和的双环、桥环、融合环、螺环的杂环烷基，可任选被1、2或3个相同或不同的R 6取代； X is selected from a 4-8 membered saturated or partially saturated monocyclic ring containing 1 or 2 N atoms, or a 6-12 membered saturated or partially saturated bicyclic ring containing 1 or 2 N atoms, bridged ring, fused ring, spiro The cyclic heterocycloalkyl group may be optionally substituted with 1, 2 or 3 R 6 which are the same or different;
    R 1、R 2选自H、卤素、NH 2、OH、C 1-3烷基和C 1-3杂烷基，所述的取代基可任选1个或多个取代； R 1 and R 2 are selected from H, halogen, NH 2 , OH, C 1-3 alkyl and C 1-3 heteroalkyl, and the substituents may be optionally substituted by one or more;
    R 3选自4-6元单环或6-12元双环的芳基、杂芳基，环烷基、杂环烷基，所述的芳基、杂芳基，环烷基、杂环烷基可被1、2或3个相同或不同的R 7取代； R 3 is selected from 4-6 membered monocyclic or 6-12 membered bicyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, the aryl, heteroaryl, cycloalkyl, heterocycloalkane The group may be substituted by 1, 2 or 3 R 7 which are the same or different;
    R 4选自H、烷基、氨基烷基、烷基氨基烷基、卤代烷基、羟基烷基、二羟基烷基、-A-NR 8R 9、4-6元杂环基、4-6元杂环基烷基、5-6元芳基、5-6元杂芳基或杂芳基烷基，其中，A、杂环基、杂环基烷基、芳基、杂芳基或杂芳基烷基可任选被1个或多个相同或不同的R 10取代； R 4 is selected from H, alkyl, aminoalkyl, alkylaminoalkyl, haloalkyl, hydroxyalkyl, dihydroxyalkyl, -A-NR 8 R 9 , 4-6 membered heterocyclic group, 4-6 Membered heterocyclylalkyl, 5-6 membered aryl, 5-6 membered heteroaryl or heteroarylalkyl, where A, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl or hetero The arylalkyl group may be optionally substituted by one or more R 10 which are the same or different;
    A选自C 1-4亚烷基； A is selected from C 1-4 alkylene;
    L是键或-NH-；L is a bond or -NH-;
    R 5选自 R 5 is selected from
    Figure PCTCN2021070462-appb-100002
    Figure PCTCN2021070462-appb-100002
    R 6选自腈基、C 1-3烷基、氨基、卤素，羟基； R 6 is selected from the group consisting of nitrile group, C 1-3 alkyl group, amino group, halogen, and hydroxyl group;
    R 7选自卤素、氨基、羟基、C 1-3烷基或卤素取代的C 1-3烷基； R 7 is selected from halogen, amino, hydroxy, C 1-3 alkyl or halogen substituted C 1-3 alkyl;
    R 8选自H、或C 1-3烷基 R 8 is selected from H, or C 1- 3 alkyl
    R 9选自H、C 1-3烷基、杂烷基、羟基烷基、酰基； R 9 is selected from H, C 1-3 alkyl, heteroalkyl, hydroxyalkyl, acyl;
    R 10选自H、羟基、卤素、 R 10 is selected from H, hydroxyl, halogen,
    Z选自键、氧(O)、硫(S)、NR 11； Z is selected from bond, oxygen (O), sulfur (S), NR 11 ;
    R 11选自H、或C 1-3亚烷基； R 11 is selected from H or C 1-3 alkylene;
    R 12选自卤素、CF3、羟基烷基； R 12 is selected from halogen, CF3, and hydroxyalkyl;
    R 13选自H、C 1-3烷基、烷基氨基烷基、烷基氨基烷基、杂环基氨基烷基、卤素、酰胺基、腈基、羟基烷基、CF 3、CF 2、甲氧基、三氟甲基氨基、烯烃； R 13 is selected from H, C 1-3 alkyl, alkylaminoalkyl, alkylaminoalkyl, heterocyclylaminoalkyl, halogen, amido, nitrile, hydroxyalkyl, CF 3 , CF 2 , Methoxy, trifluoromethylamino, alkene;
    R 14选自H、烷基、羟基烷基； R 14 is selected from H, alkyl, and hydroxyalkyl;
    R 15为不存在、H或C 1-3烷基。 R 15 is absent, H or C 1-3 alkyl.
  2. 根据权利要求1所述化合物、其异构体、其药学上可接受的盐或其氘代物的异构体、药学上可接受的盐或氘代物。The compound, its isomer, its pharmaceutically acceptable salt, or its deuterated isomer, pharmaceutically acceptable salt or deuterated compound according to claim 1.
  3. 根据权利要求1或2所述的化合物，结构单元
    Figure PCTCN2021070462-appb-100003
    选自：     The compound according to claim 1 or 2, the structural unit
    Figure PCTCN2021070462-appb-100003
    Selected from:
    Figure PCTCN2021070462-appb-100004
    Figure PCTCN2021070462-appb-100004
  4. 根据权利要求1、2或3所述的化合物，结构单元
    Figure PCTCN2021070462-appb-100005
    中的R 5选自：     The compound of claim 1, 2 or 3, the structural unit
    Figure PCTCN2021070462-appb-100005
    R 5 in is selected from:
    Figure PCTCN2021070462-appb-100006
    Figure PCTCN2021070462-appb-100006
  5. 根据权利要求1～4任意一项所述的化合物，R 3选自： The compound according to any one of claims 1 to 4, R 3 is selected from:
    Figure PCTCN2021070462-appb-100007
    Figure PCTCN2021070462-appb-100007
    Figure PCTCN2021070462-appb-100008
    Figure PCTCN2021070462-appb-100008
  6. 根据权利要求1～5任意一项所述的化合物，R 4选自： The compound according to any one of claims 1 to 5, R 4 is selected from:
    Figure PCTCN2021070462-appb-100009
    Figure PCTCN2021070462-appb-100009
    Figure PCTCN2021070462-appb-100010
    Figure PCTCN2021070462-appb-100010
  7. 根据权利要求1～6任意一项所述的化合物，选自：The compound according to any one of claims 1 to 6, selected from:
    Figure PCTCN2021070462-appb-100011
    Figure PCTCN2021070462-appb-100011
    Figure PCTCN2021070462-appb-100012
    Figure PCTCN2021070462-appb-100012
    Figure PCTCN2021070462-appb-100013
    Figure PCTCN2021070462-appb-100013
    Figure PCTCN2021070462-appb-100014
    Figure PCTCN2021070462-appb-100014
    Figure PCTCN2021070462-appb-100015
    Figure PCTCN2021070462-appb-100015
    Figure PCTCN2021070462-appb-100016
    Figure PCTCN2021070462-appb-100016
  8. 权利要求1～7任意一项所述的化合物、其异构体、其药学上可接受的盐或其氘代物在制备治疗癌症药物中的应用。The use of the compound, its isomer, its pharmaceutically acceptable salt, or its deuterated substance according to any one of claims 1 to 7, in the preparation of a medicine for treating cancer.
  9. 根据权利要求8所述的应用，所述的癌症选自：肺癌、胰腺癌、直/结肠癌、胆管癌、小肠癌、子宫内膜癌、胃癌、卵巢癌、***癌、子***、肝癌、腹膜癌、软组织癌、白血病、淋巴瘤、乳腺癌、尿路上皮癌、睾丸癌、皮肤癌、食道癌、甲状腺癌、食管癌、骨癌和眼癌。The application according to claim 8, wherein the cancer is selected from: lung cancer, pancreatic cancer, rectal/colon cancer, cholangiocarcinoma, small intestine cancer, endometrial cancer, gastric cancer, ovarian cancer, prostate cancer, cervical cancer, liver cancer , Peritoneal cancer, soft tissue cancer, leukemia, lymphoma, breast cancer, urothelial cancer, testicular cancer, skin cancer, esophageal cancer, thyroid cancer, esophageal cancer, bone cancer and eye cancer.
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