WO2023036252A1 - Pyrrolopyrimidine or pyrrolopyridine derivative and medical use thereof - Google Patents

Pyrrolopyrimidine or pyrrolopyridine derivative and medical use thereof Download PDF

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WO2023036252A1
WO2023036252A1 PCT/CN2022/117868 CN2022117868W WO2023036252A1 WO 2023036252 A1 WO2023036252 A1 WO 2023036252A1 CN 2022117868 W CN2022117868 W CN 2022117868W WO 2023036252 A1 WO2023036252 A1 WO 2023036252A1
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compound
alkyl
methyl
group
cycloalkyl
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PCT/CN2022/117868
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French (fr)
Chinese (zh)
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张海生
卓鉥
代长贵
程辉敏
方磊
牛春意
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希格生科（深圳）有限公司
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Priority to CN202280022476.8A priority Critical patent/CN117043163A/en
Publication of WO2023036252A1 publication Critical patent/WO2023036252A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicines, and in particular relates to a pyrrolopyrimidine or a pyrrolopyridine derivative and its medical use, especially in the preparation of medicines for treating or preventing cancer, pulmonary hypertension, and pathological angiogenesis-related diseases use in .
  • FAM Focal adhesion kinase
  • PTK2 protein tyrosine kinase 2
  • PTK2 protein tyrosine kinase 2
  • integrins growth factor receptors
  • G protein-coupled receptors G protein-coupled receptors
  • cytokine activation integrins
  • FAK has also been shown to play an important role in the nucleus. FAK can promote the degradation of p53 through ubiquitination, which leads to the growth and proliferation of cancer cells. Tang et al. reported that FAK can also regulate the expression of GATA4 and IL-33, thereby reducing the inflammatory response and immune escape. In the tumor microenvironment, nuclear FAK can regulate the formation of new blood vessels and affect the blood supply of tumors.
  • FAK is widely expressed in vivo, plays an important role in cell growth, proliferation, migration, and adhesion, and participates in embryonic development and the occurrence and development of diseases (cancer and cardiovascular diseases, etc.).
  • Overexpression of FAK has been found in many types of cancer, including colon, breast, prostate, thyroid, neuroblastoma, ovary, cervix, brain, head and neck, liver, esophagus, pancreas cancer, lung cancer, gastric cancer and acute leukemia. High expression of FAK often indicates poor prognosis.
  • FAK transmembrane integrin receptors to the extracellular matrix (ECM) recruits FAK to sites of integrin aggregation.
  • ECM extracellular matrix
  • FAK does not directly interact with integrins, but binds to cell membranes and other adhesion proteins through its carboxy-terminal FAT domain. Once recruited, the inactive state of FAK activates its catalytic activity through autophosphorylation of Y397.
  • FAK acts as a molecular scaffold to recruit Src family kinases, and Src can phosphorylate the Y576 and Y577 sites of FAK, further enhancing the activity of FAK, and promoting its recruitment of downstream SH2 domain-containing proteins such as Grb2 and PI3K wait.
  • Grb2 combines with FAK, it can further recruit SOS to form a complex to further activate the downstream Ras-MAPK signaling pathway.
  • FAK and its signaling pathway-related targets are considered as potential targets for the development of anticancer drugs.
  • drugs on the market for FAK inhibitors there are currently no drugs on the market for FAK inhibitors, and only some drugs have entered the clinical stage, such as Defactinib, IN10018, GSK-2256098, etc. Therefore, it is crucial to develop new compounds that modulate the FAK signaling pathway.
  • the purpose of the present invention is to provide a focal adhesion kinase (FAK) inhibitor compound, including its preparation method, a medicament or a composition containing the compound, and use the compound to treat diseases caused by excessive or abnormal cell proliferation, such as cancer
  • the method has a good clinical application prospect.
  • the compound of the invention not only has good inhibitory effect on FAK kinase activity, but also has the effect of reducing activated YAP, and has better pharmacokinetic, drug efficacy and toxicological properties.
  • the first aspect of the present invention provides a compound of formula I, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides substances, metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs,
  • Ring A is independently selected from: C3-C20 heteroaryl and C6-C20 aryl, such as 5-6 membered heteroaryl and phenyl;
  • Ring B is independently selected from: C3-C20 heteroaryl and C6-C20 aryl, such as 5-6 membered heteroaryl and phenyl; preferably, B ring is a six-membered aryl or heteroaryl;
  • L is independently selected from: a bond or CH 2 , preferably, L is CH 2 ;
  • X is independently selected from CH or N, preferably, X is N;
  • Each R 3 is independently selected from: -H, -OH, -halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -NO 2 , -NR 5 R 6 , C1-C6 alkyl, C1 -C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered Heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3 -C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 R9
  • the C5- C7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl can be substituted by 1-3 R9 ;
  • R 5 , R 6 , R' 5 and R' 6 are each independently selected from: H, -OH, halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -NO 2 , -CH 2 CF 3.
  • -NR 7 R 8 -S(O) m R 7 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3 -12-membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group; or in NR 7 R 8 , R 7 and R 8 together form a 3- 10-membered heterocyclic group (including bridged ring and spiro ring); wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group can be substitute
  • R 7 , R 8 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 Alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10
  • the heteroaryl group may be substituted by 1-3 groups selected from the group consisting of -OH, halogen, -CN, -NO 2 , -NH 2
  • n and n' are each independently selected from 0, 1, 2, 3 or 4;
  • n is independently selected from 0, 1 or 2.
  • p is 0, 1 or 2;
  • R 4 is as defined above.
  • the compound has the structure shown in formula II or formula III
  • p 0, 1 or 2;
  • R 1 , R 2 , R 3 , R 4 , B and n' are as defined above.
  • the compound has the structure shown in formula IV or formula V
  • R 1 , R 2 , R 3 , R 4 , B and n' are defined as above, R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3- C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy Base, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 substituents selected from the group: halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkyl, C1-C6 alkoxy.
  • the compounds of formula IV and V have better FAK kinase inhibitory activity relative to similar molecules; in the compound of formula III, the R in the meta-position of the amide bond on the benzene ring in formula IV is an alkane Oxygen (C1-C6 alkoxy, especially methoxy) compounds or compounds of formula V can improve the selectivity relative to other kinases (including but not limited to PYK2) relative to similar molecules.
  • alkane Oxygen C1-C6 alkoxy, especially methoxy
  • the compound has one of the following structures:
  • R 1 , R 2 , R 3 , R 4 are defined as above, and R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group, R' is selected from C1-C6 alkyl group; wherein, the C1-C6 alkyl group, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 substituents selected from the following group: Halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkyl, C1-C
  • ring B is selected from: phenyl, pyridyl or pyrazinyl.
  • each R is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 Aryl, 5-10 membered heteroaryl, -C(O)NR 5 R 6 ; wherein, R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3 -C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkane Oxygen, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 substituents selected from the group:
  • A, B, L, X, R 1 , R 2 , R 3 , R 4 , n and n' are the groups corresponding to each specific compound in the examples.
  • the compound has a structure of one of the following groups or is selected from the following groups:
  • the compound is the compound shown in the examples.
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises the compound as described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers isomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof; and pharmaceutically acceptable carriers, diluents or excipients;
  • the pharmaceutical composition further comprises one or more selected from the group consisting of chemotherapy drugs, PD-1 inhibitors, PD-1 antibodies, PD-L1 inhibitors, PD-L1 antibodies, ALK inhibitors, PI3K inhibitor, BTK inhibitor, EGFR inhibitor, EGFR antibody, VEGFR inhibitor, VEGFR antibody, HDAC inhibitor, CDK inhibitor, MEK inhibitor, Akt inhibitor, mTOR inhibitor, SHP2 inhibitor, KRAS G12C inhibitor , KRAS G12D inhibitor, KRAS G12V inhibitor, c-MET inhibitor, Her2 inhibitor
  • the third aspect of the present invention provides a compound as described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers Conformant, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug, or the pharmaceutical composition as described in the second aspect in the preparation for the prevention or treatment of FAK-related Use in medicine for diseases; preferably, the FAK-related diseases are cancer, pulmonary hypertension, or pathological angiogenesis; more preferably, the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer Cancer of the adrenal gland, bladder, esophagus, head or neck, liver, parathyroid, penis, small intestine, thyroid, urethra, cervix, endometrium, fallopian tube, renal pelvis Cancer, Vaginal Cancer, Vulvar Cancer, Chronic or Acute Leukemia, Colon Cancer, Melanoma, Hematological Malign
  • X' is halogen
  • the method also includes the steps of:
  • X', X" and X"' are each independently halogen (such as Cl, Br, I);
  • a ring, B ring, X, L, R 1 , R 2 , R 3 , R 4 , n and n' are as defined above.
  • a method for treating FAK-related diseases comprising administering a therapeutically effective amount of the compound as described in the first aspect, or its antidote to a subject identified or diagnosed as having a FAK-related disease
  • the sixth aspect of the present invention provides a method for inhibiting FAK kinase activity in a cell or a subject, the method comprising contacting the cell or administering the compound described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof, Hydrate, solvate, isotope or prodrug, or the steps of the pharmaceutical composition as described in the second aspect; preferably, the cell is a mammalian cell; preferably, the subject is a mammal; more preferably human.
  • the seventh aspect of the present invention provides a compound as described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers Conformant, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug, or the pharmaceutical composition as described in the second aspect in the preparation for the prevention or treatment of YAP-related Use in medicine for diseases, especially YAP-positive related diseases; preferably, the YAP-related diseases are cancers; more preferably, the cancers are selected from the group consisting of: skin cancer, bone cancer, glioma, breast cancer, Cancer of the adrenal glands, bladder, esophagus, head or neck, liver, parathyroid, penis, small intestine, thyroid, urethra, cervix, endometrium, fallopian tubes, renal pelvis, Vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma,
  • the eighth aspect of the present invention provides a compound as described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers Conformer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof, or the pharmaceutical composition as described in the second aspect in the preparation for the prevention or treatment of FAK and Use in medicine for YAP-related diseases, especially FAK and YAP-positive related diseases; preferably, the FAK and YAP-related diseases are cancers; more preferably, the cancers are selected from: skin cancer, bone cancer, nerve Glioma, breast cancer, adrenal gland cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small bowel cancer, thyroid cancer, urinary tract cancer, cervical cancer, endometrial cancer , fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia
  • a method for treating YAP (especially YAP-positive)-related diseases comprising administering a therapeutically effective amount of The compound as described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or a pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof, or a pharmaceutical composition as described in the second aspect.
  • a method for reducing activated YAP in a cell or a subject comprising contacting the cell or administering the compound described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof, Hydrate, solvate, isotope or prodrug, or the steps of the pharmaceutical composition as described in the second aspect; preferably, the cell is a mammalian cell; preferably, the subject is a mammal; more preferably human.
  • a method for treating FAK and YAP related diseases comprising administering a therapeutically effective amount of the compound as described in the first aspect to a subject identified or diagnosed as having FAK and YAP related diseases, or Its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or their pharmaceutically acceptable salts, hydrated Compounds, solvates, isotopes or prodrugs, or pharmaceutical compositions as described in the second aspect.
  • a method for inhibiting FAK kinase activity in a cell or a subject, and reducing activated YAP in a cell or a subject comprising contacting or exposing the cell to the subject
  • the subject is administered the compound as described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides , metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, or the steps of the pharmaceutical composition as described in the second aspect;
  • the cells are mammalian cells; preferably , the subject is a mammal; more preferably a human.
  • Figure 1 shows the morphological comparison of normal organoid cells and diffuse gastric cancer organoid cells.
  • Figure 2 shows the effect of compound 4 (2.5 ⁇ M cultured for 48 h) on the proliferation and morphology of diffuse gastric cancer organoid cells.
  • Figure 3 shows the effect of Compound 6 (2.5 ⁇ M cultured for 48 h) on the proliferation and morphology of diffuse gastric cancer organoid cells.
  • Figure 4 shows the effect of Compound 8 (2.5 ⁇ M cultured for 48 h) on the proliferation and morphology of diffuse gastric cancer organoid cells.
  • Figure 5 shows the effect of Compound 9 (2.5 ⁇ M cultured for 48 h) on the proliferation and morphology of diffuse gastric cancer organoid cells.
  • Figure 6 shows the effect of Compound 9 and Defactinib on the proliferation of diffuse gastric cancer organoid cells.
  • Figure 7 shows the effect of Compound 9 on the activity of FAK and YAP proteins in diffuse gastric cancer organoids.
  • Figure 8 shows the effect of Compound 10 on the activity of FAK and YAP proteins in diffuse gastric cancer organoids.
  • Figure 9 shows the effects of compounds 8 and 9 on the activity of FAK and YAP proteins in human diffuse gastric cancer cell lines.
  • Figure 10 shows the effects of Defactinib, IN10018 and compounds 24, 25, 26, 27, and 28 on the activity of FAK and YAP proteins in human diffuse gastric cancer cell lines.
  • Figure 11 shows the effect of Compound 9 and Defactinib on the proliferation of human diffuse gastric cancer tumor cell lines.
  • the present inventors unexpectedly discovered a class of compounds that have good FAK kinase inhibitory activity and simultaneously reduce activated YAP.
  • the compounds also have better pharmacodynamic/pharmacokinetic properties.
  • the present invention has been accomplished.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • alkyl by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the indicated number of carbon atoms (i.e., C1-C6 means 1, 2, 3, 4, 5 or 6 carbon atoms).
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
  • alkyl is also intended to include substituted alkyl, that is, one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position.
  • alkoxy refers to a straight or branched or cyclic alkyl group attached through an ether oxygen from which its free valency is derived.
  • the alkoxy group is preferably a C1-C6 alkoxy group, more preferably a C1-C3 alkoxy group.
  • Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
  • alkenyl denotes a straight or branched chain hydrocarbon group containing one or more double bonds and having the indicated number of carbon atoms.
  • C2-C6 alkenyl means containing 2 to 6 carbon atoms.
  • Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
  • alkynyl denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and having the indicated number of carbon atoms.
  • C2-C6 alkynyl means containing 2 to 6 carbon atoms.
  • Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
  • cycloalkyl refers to a cyclic alkyl group including a saturated monocyclic ring (eg, C3-C8), bicyclic ring (eg, C5-C12 fused bicyclic ring, C5-C12 membered spirobicyclic ring) or polycyclic ring, "C3- "C6 cycloalkyl” means containing 3 to 6 carbon atoms, and "C3-C12 cycloalkyl” means containing 3 to 12 carbon atoms.
  • the cycloalkyl group is preferably a C3-C12 cycloalkyl group, more preferably a C3-C6 cycloalkyl group.
  • cycloalkyl groups of the present invention include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, wait. It is to be understood that substituted or unsubstituted cycloalkyl groups, such as branched cycloalkyl groups (eg, 1-methylcyclopropyl and 2-methylcyclopropyl), are included within the definition of "cycloalkyl”.
  • cycloalkenyl refers to a cycloalkyl group as defined above and further containing 1 or more double bonds, including but not limited to cyclopentenyl, cyclohexenyl.
  • heterocyclyl generally refers to a stable monocyclic ring (such as 3-8 members, that is, 3, 4, 5, 6, 7 or 8 members) or a bicyclic ring (such as 5-12 members, that is, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan or 12 yuan) or yuan polycyclic (such as 7-14 yuan, that is, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan, 12-, 13- or 14-membered) heterocyclic rings, including fused, spiro and/or bridged ring structures, which are saturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S.
  • heterocyclyl may be substituted or unsubstituted. Nitrogen and sulfur heteroatoms as ring atoms may optionally be oxidized. The nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or another substituent if defined).
  • a heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclyl groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocycle can optionally be quaternized.
  • heterocyclic group may be attached to the residue of any heteroatom or carbon atom of a ring or ring system molecule.
  • heterocyclyl groups include, but are not limited to: azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazole Alkyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazine Heptyl, 4-piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl And tetrahydro-1,1-dioxythiophene etc.
  • the spiro ring, fused ring and bridged ring heterocyclic group are optionally connected to other groups through a single bond, or connected to other cycloalkyl, heterocyclic groups through any two or more atoms on the ring.
  • Cyclic, aryl and heteroaryl groups are further linked in rings.
  • aryl alone or as part of a larger moiety such as “aralkyl”, “aralkoxy” or “aryloxyalkyl”, refers to a single ring having a total of 5 to 15 ring members , a bicyclic or tricyclic ring system (preferably a 6-10 membered aromatic ring), wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • “Aryl” can be substituted or unsubstituted.
  • aryl refers to an aromatic ring system including, but not limited to: phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydro naphthyl.
  • the aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring.
  • a fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. Connecting lines drawn from ring systems indicate that bonds may be attached to any suitable ring atom.
  • Aryl groups can be optionally substituted or unsubstituted.
  • heteroaryl refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur.
  • Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazazinyl, triazolyl and tetrazolyl, etc.
  • Heteroaryl can be substituted or unsubstituted.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • substituted means that one or more hydrogen atoms on a specific group are replaced by a specific substituent.
  • the specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment.
  • a certain substituted group can have a substituent selected from a specific group at any substitutable position of the group, and the substituents can be the same or different at each position, namely The individual substitutions are independent of each other.
  • substituents contemplated by this invention are those that are stable or chemically feasible.
  • the typical substituents mentioned above such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, aryl or heteroaryl may be optionally substituted.
  • the substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1 -C6 ureido group, etc.
  • Yes-associated protein is a proto-oncoprotein that exists in the cytoplasm in an inactive form, and when activated, it translocates to the nucleus and activates the transcription of genes involved in cell division and apoptosis.
  • YAP is one of the downstream regulatory proteins in the Hippo signaling pathway, which cooperates with the transcriptional coactivator TAZ to direct gene expression by controlling the TEAD transcription factor family.
  • the Hippo signaling pathway is an evolutionarily conserved signaling pathway that plays key roles in organ development, epithelial homeostasis, tissue regeneration, wound healing and immune regulation. Dysregulation of Hippo pathway and YAP/TAZ-TEAD activity is associated with various diseases, the most important of which is cancer.
  • YAP positive means that the YAP content in the nucleus reaches or exceeds the preset content.
  • FAK positive means that the content of phosphorylated FAK in the cell reaches or exceeds a predetermined level.
  • compound of the present invention or “active ingredient of the present invention” are used interchangeably to refer to a compound of formula I, or its enantiomers, diastereoisomers, racemates, tautomers Isomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, isotopes or prodrugs thereof.
  • the compound of formula I has the following structure:
  • A, B, L, X, R 1 , R 2 , R 3 , R 4 , n and n' are as defined above.
  • the compound has the structure shown in formula II or formula III
  • p, R 1 , R 2 , R 3 , R 4 , B and n' are as defined above.
  • the compound has the structure shown in formula IV or formula V
  • R 1 , R 2 , R 3 , R 4 , B and n' are defined as above, R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3- C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy Base, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 substituents selected from the group: halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkyl, C1-C6 alkoxy.
  • Ring B is a six-membered aryl or heteroaryl group; preferably, ring B is selected from: phenyl, pyridyl or pyrazinyl;
  • R 4 are each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered Heteroaryl, -C(O)NR 5 R 6 ; wherein, R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3 -12 membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group;
  • R 5 , R 6 , R' 5 and R' 6 are each independently selected from: H, OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl;
  • n 1 or 2;
  • salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise stated, the compounds of the present invention are understood to include their salts.
  • the term "salt” as used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base.
  • a compound of the present invention contains a basic moiety, which includes but is not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts”) that may be formed are contained in within the term "salt".
  • Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation.
  • the compound of the present invention may form a salt, for example, compound I reacts with a certain amount, such as an equivalent amount of acid or base, and salts it out in a medium, or freeze-dries it in an aqueous solution.
  • Basic moieties contained in the compounds of the present invention may form salts with organic or inorganic acids.
  • Typical acids from which salts can be formed include acetate (e.g. with acetic acid or a trihaloacetic acid such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate , Benzenesulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphor Salt, Camphorsulfonate, Cyclopentane Propionate, Diglycolate, Lauryl Sulfate, Ethanesulfonate, Fumarate, Glucoheptonate, Glycerophosphate, Hemisulfate, Heptanoate, Hexanoate, Hydrochloride, Hydrobromide, Hydroiodide, Isethionate (eg, 2-hydroxyethanesulfonate), lactate, male
  • Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases.
  • Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine , Hipamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, etc.
  • Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and dipentyl sulfates), long-chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides and iodides), aralkyl halides (such as benzyl and phenyl bromides) and the like.
  • alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, dibutyl, and dipenty
  • Prodrugs and solvates of the compounds of the present invention are also contemplated.
  • the term "prodrug” here refers to a compound that undergoes metabolic or chemical transformation during the treatment of related diseases to produce the compound, salt, or solvate of the present invention.
  • the compounds of the present invention include solvates, such as hydrates.
  • Stereoisomers of all compounds are contemplated by the present invention.
  • the individual stereoisomers of the compounds of the present invention may not exist simultaneously with other isomers (for example, as a pure or substantially pure optical isomer having a specific activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or parts thereof.
  • the chiral center of the present invention has two configurations of S or R, which are defined by the 1974 proposal of the International Union of Theoretical and Applied Chemistry (IUPAC).
  • racemic forms can be resolved by physical methods such as fractional crystallization, or by derivatization into diastereoisomers, or by separation by chiral column chromatography.
  • Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods such as salt formation with optically active acids followed by crystallization.
  • the weight content of the compound obtained by preparation, separation and purification in sequence is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure” compound), described in the main text listed. Such "very pure” compounds of the invention are also included herein as part of the invention.
  • All configurational isomers of the compounds of the invention are contemplated, whether in admixture, pure or very pure form.
  • the definition of the compounds of the present invention includes both cis (Z) and retro (E) olefinic isomers, as well as carbocyclic and heterocyclic cis and trans isomers.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic spin mixtures and other mixtures.
  • an asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers, as well as mixtures thereof, are included in the present invention.
  • the mixture of isomers may contain various ratios of isomers.
  • ratios of isomers For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, readily understood by one of ordinary skill in the art, are also within the scope of the invention.
  • the invention also includes isotopically labeled compounds equivalent to the original compounds disclosed herein. In practice, however, substitution of one or more atoms by an atom with a different atomic mass or mass number usually occurs.
  • isotopes that may be included in compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the compounds of the present invention or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention.
  • Certain isotopically labeled compounds of the present invention such as 3 H and 14 C radioactive isotopes, are useful in tissue distribution assays for drugs and substrates. Tritium, namely 3 H, and carbon-14, namely 14 C, are relatively easy to prepare and detect. is the first choice among isotopes.
  • isotopically-labeled compounds can be prepared in general manner by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent, using the protocols disclosed in the Examples.
  • a specific enantiomer of a compound of the present invention can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture is separated, and the chiral auxiliary is removed to obtain pure enantiomers.
  • the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, and then separated by crystallization or chromatography. Separation by conventional means then gives the pure enantiomers.
  • the compounds of the present invention may be substituted with any number of substituents or functional groups to broaden their scope.
  • substitution appears before or after the term “optional”
  • the general formula including the substituent in the formula of the present invention means that the hydrogen radical is replaced by the specified structural substituent.
  • substituents may be the same or different for each position.
  • substitution includes all permissible organic compound substitutions. Broadly speaking, the permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds.
  • heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to complement its valence.
  • this invention is not intended to be limiting in any way to the organic compounds permissible to be substituted. Combinations of substituents and variables are considered by the present invention to be beneficial in the treatment of diseases in the form of stable compounds.
  • stable herein means having a compound that is stable, detectable for a sufficient period of time to maintain the structural integrity of the compound, preferably active for a sufficient period of time, and is used herein for the above purposes.
  • compositions and methods of administration are provided.
  • the compound of formula (I) described in the present invention or its enantiomer, diastereoisomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, Metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs, and compounds containing formula (I), or their enantiomers, diastereoisomers, racemates, mutual
  • a pharmaceutical composition of variants, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof may be used for the prevention and/or Treatment of the following diseases: cancer, pulmonary hypertension, pathological angiogenesis.
  • the administration mode and dosage of the original drug can remain unchanged, and the compound of formula (I) can be taken simultaneously or first or later; or the compound of formula (I) or its enantiomer, diastereomer Enantiomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof , and other drugs into a single preparation, administered at the same time.
  • pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs When taken together with one or more other drugs, it can be preferably used to contain one or more known drugs and the compound of formula (I) , or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof , hydrate, solvate, isotope or prodrug pharmaceutical composition.
  • the drug combination also includes administration of the compound of formula (I), or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers in overlapping time periods body, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug, and one or several other known drugs.
  • a pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug is used in combination with one or more other drugs
  • the compound of formula (I), or its enantiomer, diastereoisomer isomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs, or Doses of known drugs may be lower than when they are given alone.
  • Compounds described in formula (I), or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolic Products or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs for drug combination drugs or active ingredients include but are not limited to: chemotherapy drugs, PD-1 inhibitors, PD-1 antibodies, PD -L1 inhibitors, PD-L1 antibodies, ALK inhibitors, PI3K inhibitors, BTK inhibitors, EGFR inhibitors, EGFR antibodies, VEGFR inhibitors, VEGFR antibodies, HDAC inhibitors, CDK inhibitors, MEK inhibitors, Akt inhibitors agent, mTOR inhibitor, SHP2 inhibitor, KRAS G12C inhibitor, KRAS G12D inhibitor, KRAS G12V inhibitor, c-MET inhibitor, Her2 inhibitor, Her2 antibody, Claudin18.2 antibody.
  • the compound described in formula (I), or its enantiomer, diastereoisomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or A pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof may also be used in combination with a therapeutic agent for the treatment of pulmonary arterial hypertension (PHA).
  • PHA pulmonary arterial hypertension
  • the PHA therapeutic agent is preferably a vasodilator, such as epoprostenol, tadalafil or ambrisentan and the like.
  • the dosage form of the pharmaceutical composition of the present invention includes (but not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nano-preparation.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • Excipients refer to the additions in pharmaceutical preparations other than the main drug, and can also be called excipients.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 50-1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention compounds are mixed to form a pharmaceutical composition.
  • the preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention.
  • the compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.
  • each reaction is usually carried out in an appropriate solvent under the protection of an inert gas at a temperature of 0 to 90° C., and the reaction time is usually 2-24 hours.
  • the compounds of the present invention are prepared by the following method
  • X', X" and X"' are each independently halogen (such as Cl, Br, I);
  • a ring, B ring, X, L, R 1 , R 2 , R 3 , R 4 , n and n' are as defined above.
  • protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • reagents or materials used in the present invention are all commercially available or obtained in the manner given in literature reports.
  • the compound of the present invention has excellent inhibitory ability to FAK kinase, and/or can significantly reduce/reduce the YAP of activation; Especially when two adjacent R on the A ring 4 and A ring form and ring structure, its The activity is greatly improved; in addition, when R 4 is an alkoxy group or amido group and R 2 is N-methylmethanesulfonamide, its activity can also be significantly improved.
  • the compound of the present invention has relatively low toxic and side effects.
  • the compound of the present invention has better pharmacodynamics and pharmacokinetic properties.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass chromatography (LC-MS).
  • NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic instruments, and the determination solvents included deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol (CD 3 OD), etc., the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in parts per million (ppm).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 COCD 3 deuterated acetone
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • LC-MS Liquid chromatography-mass chromatography
  • Qingdao GF254 silica gel plates were used for thin-layer chromatography, 0.15-0.20mm for TLC, and 0.4mm-0.5mm for preparative thin-layer chromatography.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • the starting materials in the examples of the present invention are all known and commercially available, or can be adopted or synthesized according to literatures reported in the art.
  • PE petroleum ether
  • Pd(PPh 3 ) 4 tetrakistriphenylphosphine palladium
  • Step 1 Synthesis of N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide
  • N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (5.0g, 19.8mmol)
  • 2,4-dichloro-5-iodopyrimidine (5.0 g, 18.2 mmol)
  • DIPEA (12.0 mL, 72.6 mmol) in i-PrOH (100 mL)
  • the reaction mixture was poured into water (150 mL) and extracted twice with ethyl acetate (100 mL).
  • Step 2 Synthesis of 3-(2-chloro-4-((((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)pyrimidin-5-yl)propanoic acid ester
  • Step 3 Synthesis of methyl 2-chloro-7-(2-(N-methylmethylsulfonamido)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate
  • Step 4 Synthesis of 2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl) -7H-Pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester
  • Step 1 Synthesis of 3N-(3-((((2-chloro-5-(propynyl-1))pyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methyl Methanesulfonamide
  • Step 2 Synthesis of N-(3-((2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide
  • Step 3 Synthesis of N-methyl-4-((6-methyl-7-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole and[2,3-d]pyrimidin-2-yl)amino)benzamide
  • Step 1 Synthesis of N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide
  • Step 2 Synthesis of N-(3-(((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazine -2-yl)-N-methylmethanesulfonamide
  • N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide (960mg, 2.11mmol), 3,3-diethoxyprop-1-yne (0.48mL, 2.75mmol), CuI (81mg, 0.42mmol), Pd(PPh) 2Cl2 ( 150mg , 0.21mmol) and DIPEA (10mL) were dissolved in DMF (10mL), react at 65°C for 14h, monitor the completion of the reaction, add water, then add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain N-(3-((((2-chloro-5- (3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide
  • Step 3 Synthesis of N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide
  • Step 4 Synthesis of N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide
  • N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-Methylmethanesulfonamide 200mg, 0.44mmol was dissolved in dioxane (2mL), and concentrated hydrochloric acid (0.5mL) was added under ice-cooling, and reacted at room temperature for 30min.
  • Step 5 Synthesis of N-(3-((2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine- 2-yl)-N-methylmethanesulfonamide
  • Step 6 Synthesis of N-(3-((2-chloro-6-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide
  • N-(3-((2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-Methylmethanesulfonamide (154mg, 0.39mmol) was dissolved in DCE (3mL), under ice-cooling, CDI (316mg, 1.95mmol) was added, and reacted at room temperature for 1.5h.
  • Step 7 Synthesis of 4-((6-cyano-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)-N-methylbenzamide
  • Step 1 Synthesis of 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide
  • Step 2 Synthesis of 4-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)-N-methylbenzamide
  • Step 3 Synthesis of 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide
  • Step 4 Synthesis of 4-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide
  • Step 1 Synthesis of N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-Methylmethanesulfonamide
  • N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylformazine Dissolve sulfonamide (45mg, 0.12mmol) in DCM (1mL), add BAST (24 ⁇ L) under ice bath, react at room temperature for 5h, add water after monitoring the completion of the reaction, then add dichloromethane for extraction, dry and concentrate the extract, column layer Analysis and purification of the concentrate gave N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide 34 mg, MS m/z (ESI): 403.0 [M+H] + .
  • Step 2 Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide
  • Step 3 Synthesis of 4-((6-chloro-7-((2-(N-methylmethylsulfonamido)pyridin-3-yl)methyl)-7H-pyrrolo[2,3-d] Pyrimidin-2-yl)amino)-N-methylbenzamide
  • Step 3 Synthesis of (2-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide
  • Step 4 Synthesis of (2-((((2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl)amino)methyl)phenyl)dimethyl Phosphine oxide
  • Step 5 Synthesis of (2-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)dimethyl Phosphine oxide
  • Step 7 Synthesis of (2-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)dimethylphosphine oxide
  • Step 9 Synthesis of 4-((6-(difluoromethyl)-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl) Amino)-3-methoxy-N-methylbenzamide
  • Step 3 Synthesis of N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide
  • N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (HCl, 5.26g, 20.83mmol)
  • Step 4 Synthesis of N-(3-(((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazine -2-yl)-N-methylmethanesulfonamide
  • reaction solution was stirred in an oil bath at 60°C for 2h.
  • LCMS showed that after the end of the reaction
  • the reaction solution was poured into water (200mL), and extracted twice with ethyl acetate (100mL).
  • the combined organic phase was washed with saturated brine (100mL) three times, and then dried over anhydrous Na 2 SO 4 , Then the dried product was suction filtered and concentrated to obtain the crude product.
  • Step 5 Synthesis of N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide
  • Step 6 Synthesis of N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide
  • Step 7 Synthesis of N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-Methylmethanesulfonamide
  • Step 8 Synthesis of N-(3-((6-(difluoromethyl)-2-((1-isopropyl-3-methyl-1H-pyrazol-5-yl)amino)-7H-pyrrole And[2,3-d]pyrimidine-7-yl)methyl)pyrazine-2-alkyl)-N-methylmethanesulfonamide
  • Pd(OAc) 2 (12 mg, 0.05 mmol
  • BINAP 62 mg, 0.099 mmol
  • Cs 2 CO 3 (242 mg, 0.774 mmol
  • reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), and then dried over anhydrous Na 2 SO 4 , the dried product was suction filtered and concentrated to obtain a crude compound.
  • reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was filtered with suction and concentrated to obtain a crude compound.
  • reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was suction filtered and concentrated to obtain a crude compound.
  • reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was filtered with suction and concentrated to obtain a crude compound.
  • Step 2 Synthesis of 2-chloro-5-(3,3-diethoxy-1-propyl-1-alkyl)-N-(4-methoxybenzyl)pyrimidin-4-amine
  • Step 10 Synthesis of 7-((6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino )-N-methyl-2,3-dihydrobenzofuran-4-carboxamide
  • N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 1 , Pd(OAc) 2 (12 mg, 0.05 mmol), BINAP (62 mg, 0.099 mmol) and Cs 2 CO 3 (242 mg, 0.774 mmol) were added to a solution of 4-dioxane (3 mL), respectively. Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL).
  • Step 2 Synthesis of ethyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate
  • Step 5 Synthesis of 7-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide
  • Step 6 Synthesis of 7-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide
  • Step 1 Synthesis of 4-methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H- Pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylate
  • Step 2 Synthesis of methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole [2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid
  • Step 3 Synthesis of 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-N-ethyl-2,3-dihydrobenzofuran-4-carboxamide
  • Step 2 Synthesis of methyl 3-(N-methylmethylsulfonamido)pyrazine-2-carboxylate
  • the compound 3-(N-methylmethylsulfonamido)pyrazine-2-carboxylic acid methyl ester (1.0g, 4.1mmol) was dissolved in THF (20ml), and NaBH 4 (1.19g, 8.64mmol), the temperature of the reaction solution was raised to 25°C for 1h.
  • the compound N-(3-(hydroxymethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (270mg, 1.23mmol) was dissolved in DCM (5ml), and SOCl was slowly added dropwise 2 (0.26ml, 3.7mmol), the temperature of the reaction solution was raised to 25°C and the reaction was stirred overnight. After the completion of the reaction was monitored by LCMS, the reaction solution was directly rotary evaporated, diluted with DCM (10ml), and then saturated NaHCO 3 (10mL) solution was added to extract and separate The organic phase was then washed with saturated NaCl (10 mL), and then dried with anhydrous sodium sulfate.
  • Step 6 Synthesis of 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2-(trimethyl silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine
  • Step 7 Synthesis of 2-chloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine
  • Step 9 Synthesis of N-(3-((2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-Methylmethanesulfonamide
  • Step 10 Synthesis of N-methyl-4-((7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-6-(trifluoromethyl)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)benzamide
  • reaction solution was stirred at 120° C. for 12 h. After LCMS showed that the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (20 mL), then dried over anhydrous Na 2 SO 4 , and the dried product was suction filtered and concentrated to obtain a crude compound.
  • Step 1 Synthesis of methyl 4-amino-2-fluoro-5-methoxybenzoate
  • Step 2 Synthesis of methyl 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole [2,3-d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoate
  • Step 3 Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid
  • Step 4 Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide
  • Test Example 1 In vitro enzyme inhibitory activity of the compound of the present invention
  • the compound of the present invention has a good inhibitory effect on FAK, and its IC 50 is between 0.001 ⁇ M and 10 ⁇ M, that is, it has good in vitro FAK enzyme inhibitory activity.
  • Test Example 2 Pharmacodynamic evaluation of compounds in diffuse gastric cancer (DGC) organoid model in vitro
  • Organoids were expanded in 6-well plates (7 Matrigel aliquots per well) for 2-3 days prior to evaluation. After passaging, 1000 cells were seeded in 5 ⁇ L Matrigel aliquots into each well of a 96-well plate containing 100 ⁇ L 50% L-WRN medium. After 24 hours of organoid culture, compounds were added. Dissolve the compound in DMSO, prepare the stock solution with a final concentration of 10 ⁇ M, and then dilute the stock solution to 1000 times the used concentration with DMSO, then add the medium to dilute it to the used concentration, and add the diluted solution to the culture well plate, After the compound was added once, the medium was not replaced and the compound was not re-added thereafter. Afterwards, the organoids were cultured for a specified number of days, and then the effects of the compounds were evaluated in the following three ways, all of which used DMSO as a negative control, and Defactinib or IN10018 as a positive control.
  • Cell viability assessment was performed using reagents and protocols from CellTiter-Glo (Promega G7570). Mix 50 ⁇ L of CellTiter-Glo Reagent and 50 ⁇ L of culture medium into each well, shake the plate gently for 30 minutes at room temperature to dissolve the Matrigel, and read the plate on a Tecan plate reader.
  • Test Example 3 Pharmacodynamic evaluation of the compound in vitro in the human diffuse gastric cancer tumor cell line SNU668 model
  • SNU-668 cells grow to 70%-80%, remove the medium supernatant, rinse with PBS once and remove;
  • the administration concentration of each small molecule in each well is 1 ⁇ M or 2.5 ⁇ M, first use 1 mM or 2.5 mM stock, and use medium to dilute each small molecule to 10 ⁇ M or 25 ⁇ M respectively;
  • SDS-PAGE electrophoresis 80v, 30mm, 120v, 60min; transfer membrane: 80v, 60min; blocking: 5% skimmed milk for 1h, primary antibody (non-p-YAP (1:1500, Abcam), p-FAK Y397( 1:1000, CST), actin (1:10000, CST): prepared with 5% BSA ⁇ TBST, incubated overnight at 4°C; secondary antibodies (Goat-anti-mouse-IgG and Goat-anti-rabbit-IgG, 1: 3000, Proteintech): prepared with 5% skimmed milk, incubated at room temperature for 1-2h.
  • the experimental results show that the compound 9 of the present invention can inhibit the cell growth of the human diffuse gastric cancer tumor cell line model. As shown in Figure 11, at 0.5 ⁇ M and 2.5 ⁇ M, Compound 9 can inhibit cell proliferation more significantly than Defactinib.
  • the compound of the present invention can achieve the purpose of treating diseases (especially cancer) by inhibiting FAK kinase activity and/or reducing activated YAP.

Abstract

A pyrrolopyrimidine or a pyrrolopyridine derivative and the medical use thereof. Specifically, the compound has a structure as represented by formula I. The compound has a good inhibitory effect on focal adhesion kinase (FAK) and inhibits a related signaling pathway thereof. The compound can be used in the preparation of a drug for preventing or treating related diseases such as cancers, pulmonary hypertension and pathological angiogenesis, and can especially be used in the preparation of a drug for treating diseases caused by excessive or abnormal cell proliferation, such as tumors or cancers.

Description

吡咯并嘧啶类或吡咯并吡啶类衍生物及其医药用途Pyrrolopyrimidines or pyrrolopyridine derivatives and their medical use 技术领域technical field
本发明属于药物领域，具体地，涉及一种吡咯并嘧啶类或吡咯并吡啶类衍生物及其医药用途，尤其是在制备用于治疗或预防癌症、肺动脉高压、病理性血管生成相关疾病的药物中的用途。The invention belongs to the field of medicines, and in particular relates to a pyrrolopyrimidine or a pyrrolopyridine derivative and its medical use, especially in the preparation of medicines for treating or preventing cancer, pulmonary hypertension, and pathological angiogenesis-related diseases use in .
背景技术Background technique
黏着斑激酶(FAK)，也称为PTK2(蛋白质酪氨酸激酶2)，是一种非受体酪氨酸激酶，位于多条信号传导通路交汇处，可以被整合素、生长因子受体、G蛋白偶联受体、细胞因子激活。FAK除了作为细胞质激酶参与信号传导外，相关研究还显示了FAK在细胞核内也起着重要作用。FAK可以通过泛素化促进p53降解，从而导致癌细胞生长和增殖。唐等人报道了FAK还可以调节GATA4和IL-33的表达，从而减少炎症反应和免疫逃逸。在肿瘤的微环境中，核内FAK可以调节新血管的形成，影响肿瘤的血液供应。Focal adhesion kinase (FAK), also known as PTK2 (protein tyrosine kinase 2), is a non-receptor tyrosine kinase located at the intersection of multiple signal transduction pathways and can be activated by integrins, growth factor receptors, G protein-coupled receptors, cytokine activation. In addition to participating in signal transduction as a cytoplasmic kinase, FAK has also been shown to play an important role in the nucleus. FAK can promote the degradation of p53 through ubiquitination, which leads to the growth and proliferation of cancer cells. Tang et al. reported that FAK can also regulate the expression of GATA4 and IL-33, thereby reducing the inflammatory response and immune escape. In the tumor microenvironment, nuclear FAK can regulate the formation of new blood vessels and affect the blood supply of tumors.
FAK在体内广泛表达，在细胞生长、增殖、迁移、黏附中发挥重要作用，参与胚胎发育及疾病(癌症及心血管疾病等)的发生发展。在许多种类的癌症中发现了FAK的过度表达，包括结肠癌，乳腺癌，***癌，甲状腺癌，神经母细胞瘤，卵巢癌，子***，脑癌，头颈癌，肝癌，食管癌，胰腺癌、肺癌、胃癌和急性白血病。FAK的高表达往往预示着不良的预后。例如有研究发现GTP酶RHOA Y42C突变是弥漫性胃癌当中最常见的功能获得型突变之一，而RHOA Y42C突变的小鼠对FAK抑制剂敏感，这提示抑制FAK的活性可能成为治疗弥漫性胃癌的新策略。 FAK is widely expressed in vivo, plays an important role in cell growth, proliferation, migration, and adhesion, and participates in embryonic development and the occurrence and development of diseases (cancer and cardiovascular diseases, etc.). Overexpression of FAK has been found in many types of cancer, including colon, breast, prostate, thyroid, neuroblastoma, ovary, cervix, brain, head and neck, liver, esophagus, pancreas cancer, lung cancer, gastric cancer and acute leukemia. High expression of FAK often indicates poor prognosis. For example, studies have found that GTPase RHOA Y42C mutation is one of the most common gain-of-function mutations in diffuse gastric cancer, and mice with RHOA Y42C mutation are sensitive to FAK inhibitors, suggesting that inhibiting FAK activity may be a therapeutic strategy for diffuse gastric cancer. new strategy.
在FAK发挥作用的过程中，跨膜整合素受体与细胞外基质(ECM)的结合将FAK招募到整合素聚集的部位。FAK不直接与整合素相互作用，而是通过其羧基末端FAT结构域与细胞膜和其他粘附蛋白结合。一旦被招募，非活化状态的FAK通过Y397的自磷酸化激活其催化活性。磷酸化后，FAK作为分子支架，可以招募Src家族激酶，Src可以磷酸化FAK的Y576和Y577位点，进一步的增强FAK的活性，同时促进其招募下游的含有SH2结构域的蛋白例如Grb2和PI3K等。当Grb2与FAK结合后可以进一步的招募SOS形成复合物从而进一步的激活下游的Ras-MAPK信号通路。During FAK function, the binding of transmembrane integrin receptors to the extracellular matrix (ECM) recruits FAK to sites of integrin aggregation. FAK does not directly interact with integrins, but binds to cell membranes and other adhesion proteins through its carboxy-terminal FAT domain. Once recruited, the inactive state of FAK activates its catalytic activity through autophosphorylation of Y397. After phosphorylation, FAK acts as a molecular scaffold to recruit Src family kinases, and Src can phosphorylate the Y576 and Y577 sites of FAK, further enhancing the activity of FAK, and promoting its recruitment of downstream SH2 domain-containing proteins such as Grb2 and PI3K wait. When Grb2 combines with FAK, it can further recruit SOS to form a complex to further activate the downstream Ras-MAPK signaling pathway.
基于以上，FAK以及其信号通路相关靶点被认为是抗癌药物开发的潜在靶点。而针对FAK的抑制剂目前尚未有药物上市，仅有一些药物进入了临床阶段，例如Defactinib、IN10018、GSK-2256098等。因此，研发新的调节FAK信号通路的化合物至关重要。Based on the above, FAK and its signaling pathway-related targets are considered as potential targets for the development of anticancer drugs. However, there are currently no drugs on the market for FAK inhibitors, and only some drugs have entered the clinical stage, such as Defactinib, IN10018, GSK-2256098, etc. Therefore, it is crucial to develop new compounds that modulate the FAK signaling pathway.
发明内容Contents of the invention
本发明提供了目的是提供一种黏着斑激酶(FAK)抑制剂化合物，包括其制备方法、含有这类化合物的药剂或组合物，使用此类化合物治疗由过度或异常细胞增殖引起的疾病例如癌症的方法，具有较好的临床应用前景。本发明的化合物除了对FAK激酶活性有良好的抑制作用，还兼具有减少活化的YAP的作用，同时有更好的药代、药效以及毒理特性。The purpose of the present invention is to provide a focal adhesion kinase (FAK) inhibitor compound, including its preparation method, a medicament or a composition containing the compound, and use the compound to treat diseases caused by excessive or abnormal cell proliferation, such as cancer The method has a good clinical application prospect. The compound of the invention not only has good inhibitory effect on FAK kinase activity, but also has the effect of reducing activated YAP, and has better pharmacokinetic, drug efficacy and toxicological properties.
本发明第一方面，提供一种式I化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，The first aspect of the present invention provides a compound of formula I, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides substances, metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs,
Figure PCTCN2022117868-appb-000001
Figure PCTCN2022117868-appb-000001
其中，in,
A环独立地选自：C3-C20杂芳基和C6-C20芳基，例如5-6元杂芳基和苯基；Ring A is independently selected from: C3-C20 heteroaryl and C6-C20 aryl, such as 5-6 membered heteroaryl and phenyl;
B环独立地选自：C3-C20杂芳基和C6-C20芳基，例如5-6元杂芳基和苯基；优选地，B环为六元芳基或杂芳基；Ring B is independently selected from: C3-C20 heteroaryl and C6-C20 aryl, such as 5-6 membered heteroaryl and phenyl; preferably, B ring is a six-membered aryl or heteroaryl;
L独立地选自：键或CH 2，优选地，L为CH 2； L is independently selected from: a bond or CH 2 , preferably, L is CH 2 ;
X独立地选自CH或N，优选地，X为N；X is independently selected from CH or N, preferably, X is N;
R 1独立地选自：卤素、-C(＝O)N(CH 3) 2、-C(＝O)NHCH 3、-C(＝O)NH 2、-CH(＝O)、-COOH、CN、C1-C6烷基、-CF 3、-CHF 2、-CH 2F、-CO 2CH 3； R 1 is independently selected from the group consisting of halogen, -C(=O)N(CH 3 ) 2 , -C(=O)NHCH 3 , -C(=O)NH 2 , -CH(=O), -COOH, CN, C1-C6 alkyl, -CF 3 , -CHF 2 , -CH 2 F, -CO 2 CH 3 ;
R 2独立地选自：-N(R 5)S(O) mR 6、-P(＝O)R' 5R' 6、-S(O) mNR 5R 6、-C(＝O)NR 5R 6、-NR 5C(＝O)R 6、-C(＝O)R 5、-C(＝O)OR 5、-OC(＝O)R 5、-S(O) mR 5； R 2 is independently selected from: -N(R 5 )S(O) m R 6 , -P(=O)R' 5 R' 6 , -S(O) m NR 5 R 6 , -C(=O )NR 5 R 6 , -NR 5 C(=O)R 6 , -C(=O)R 5 , -C(=O)OR 5 , -OC(=O)R 5 , -S(O) m R 5 ;
R 3各自独立地选自：-H、-OH、-卤素、-CF 3、-CHF 2、-CH 2F、-CN、-NO 2、-NR 5R 6、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述的C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基可以被1-3个R 9取代； Each R 3 is independently selected from: -H, -OH, -halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -NO 2 , -NR 5 R 6 , C1-C6 alkyl, C1 -C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered Heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3 -C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 R9 ;
R 4各自独立地选自：H、-OR 5、卤素、-CF 3、-CHF 2、-CH 2F、-CN、-NO 2、-NR 5R 6、-C(＝O)NR 5R 6、-C(＝O)NR 5OR 6、-C(R 5)＝NR 6、-NR 5C(＝O)R 6、-C(＝O)R 5、-C(＝O)C(＝O)R 5、-C(＝O)OR 5、-OC(＝O)R 5、-OC(＝O)OR 5、-P(＝O)R' 5R' 6、-S(＝O)(＝NR 5)R 6、-S(O) mR 5、-NR 5S(O) mR 6、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基可以被1-3个R 9取代； Each R 4 is independently selected from: H, -OR 5 , halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -NO 2 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -C(=O)NR 5 OR 6 , -C(R 5 )=NR 6 , -NR 5 C(=O)R 6 , -C(=O)R 5 , -C(=O) C(=O)R 5 , -C(=O)OR 5 , -OC(=O)R 5 , -OC(=O)OR 5 , -P(=O)R' 5 R' 6 , -S (=O)(=NR 5 )R 6 , -S(O) m R 5 , -NR 5 S(O) m R 6 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl , C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 Alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryls can be substituted by 1-3 R9 ;
或者任意相邻的两个R 4和与它们连接的原子共同形成的C5-C7环烷基、5-7元杂环基、苯基、5-6元杂芳基；其中，所述C5-C7环烷基、5-7元杂环基、苯基、5-6元杂芳基可以被1-3个R 9取代； Or any adjacent two R 4 and the C5-C7 cycloalkyl, 5-7 membered heterocyclic group, phenyl, 5-6 membered heteroaryl that are jointly formed with their connected atoms; Wherein, the C5- C7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl can be substituted by 1-3 R9 ;
R 5、R 6、R' 5和R' 6各自独立地选自：H、-OH、卤素、-CF 3、-CHF 2、-CH 2F、-CN、-NO 2、-CH 2CF 3、-NR 7R 8、-S(O) mR 7、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；或者在NR 7R 8中，R 7和R 8与其连接的N原子共同形成3-10元杂环基(包括桥环以及螺环)；其中，所述C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基可以被1-3个R 9取代； R 5 , R 6 , R' 5 and R' 6 are each independently selected from: H, -OH, halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -NO 2 , -CH 2 CF 3. -NR 7 R 8 , -S(O) m R 7 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3 -12-membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group; or in NR 7 R 8 , R 7 and R 8 together form a 3- 10-membered heterocyclic group (including bridged ring and spiro ring); wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group can be substituted by 1-3 R9 ;
R 9各自独立地选自：H、-OH、氧代基(＝O)、卤素、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CN、-NO 2、-OR 10、-C(＝O)R 10、-OC(＝O)R 10、-OC(＝O)R 10、-OC(＝O)OR 10、-C(＝O)NR 10R 11、-NR 10C(＝O)NR 11R 12、-NR 10R 11、-NR 10C(＝O)R 11、-NR 10S(O) mR 11、-S(O) mR 10、-S(O) mNR 10、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述的C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基可以被1-3个选自下组的基团取代：C1-C6烷基、卤素、-OH、-CN、-NO 2、-CHF 2、-CH 2CF 3、-CF 3、-C(O)R 13、-C(O)NR 13R 14、-S(O) mR 13、-S(O) mNR 13R 14取代； Each R 9 is independently selected from: H, -OH, oxo (=O), halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , - OR 10 , -C(=O)R 10 , -OC(=O)R 10 , -OC(=O)R 10 , -OC(=O)OR 10 , -C(=O)NR 10 R 11 , -NR 10 C(=O)NR 11 R 12 , -NR 10 R 11 , -NR 10 C(=O)R 11 , -NR 10 S(O) m R 11 , -S(O) m R 10 , -S(O) m NR 10 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3 -C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 groups selected from the group below: C1-C6 alkyl, halogen, -OH, -CN, -NO 2 , -CHF 2 , -CH 2 CF 3 , -CF 3 , -C(O)R 13 , -C(O)NR 13 R 14 , -S(O) m R 13 , -S(O) m NR 13 R 14 are substituted;
R 7、R 8、R 10、R 11、R 12、R 13和R 14各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述的C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基可以被1-3个选自下组的基团取代：-OH、卤素、-CN、-NO 2、-NH 2、-CHF 2、-CH 2CF 3、-CF 3、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、-C(O)-(C1-C6烷氧基)、C3-C12环烷基、3-12元杂环烷基、C1-C6烷基胺； R 7 , R 8 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 Alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 The heteroaryl group may be substituted by 1-3 groups selected from the group consisting of -OH, halogen, -CN, -NO 2 , -NH 2 , -CHF 2 , -CH 2 CF 3 , -CF 3 , C1 -C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)-(C1-C6 alkoxy), C3-C12 cycloalkyl, 3-12 members Heterocycloalkyl, C1-C6 alkylamine;
n和n'各自独立地选自0、1、2、3或4；n and n' are each independently selected from 0, 1, 2, 3 or 4;
m独立地选自0、1或2。m is independently selected from 0, 1 or 2.
在一些优选实施方式中，
Figure PCTCN2022117868-appb-000002
选自：
Figure PCTCN2022117868-appb-000003
Figure PCTCN2022117868-appb-000004
In some preferred embodiments,
Figure PCTCN2022117868-appb-000002
selected from:
Figure PCTCN2022117868-appb-000003
Figure PCTCN2022117868-appb-000004
其中，p为0、1或2；Wherein, p is 0, 1 or 2;
R 4的定义如上所述。 R 4 is as defined above.
在一些优选实施方式中，所述化合物具有式II或式III所示的结构In some preferred embodiments, the compound has the structure shown in formula II or formula III
Figure PCTCN2022117868-appb-000005
Figure PCTCN2022117868-appb-000005
其中，in,
p为0、1或2；p is 0, 1 or 2;
R 1、R 2、R 3、R 4、B和n'的定义如上所述。 R 1 , R 2 , R 3 , R 4 , B and n' are as defined above.
在一些优选实施方式中，所述化合物具有式IV或式V所示的结构In some preferred embodiments, the compound has the structure shown in formula IV or formula V
Figure PCTCN2022117868-appb-000006
Figure PCTCN2022117868-appb-000006
其中，in,
R 1、R 2、R 3、R 4、B和n'的定义如上所述，R 5和R 6各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述的C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基可以被选自下组的1-3个取代基取代：卤素、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CN、-NO 2、C1-C6烷基、C1-C6烷氧基。 R 1 , R 2 , R 3 , R 4 , B and n' are defined as above, R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3- C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy Base, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 substituents selected from the group: halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkyl, C1-C6 alkoxy.
需要说明的是，本申请化合物中，式IV和V的化合物相对同类分子具有更佳的FAK激酶抑制活性；式III的化合物、式IV中与苯环上的酰胺键间位的R 4为烷氧基(C1-C6烷氧基尤其是甲氧基)时的化合物或式V的化合物相对同类分子可以提高相对其他激酶(包括但不限于PYK2)的选择性。 It should be noted that among the compounds of the present application, the compounds of formula IV and V have better FAK kinase inhibitory activity relative to similar molecules; in the compound of formula III, the R in the meta-position of the amide bond on the benzene ring in formula IV is an alkane Oxygen (C1-C6 alkoxy, especially methoxy) compounds or compounds of formula V can improve the selectivity relative to other kinases (including but not limited to PYK2) relative to similar molecules.
在一些优选实施方式中，所述化合物具有如下结构中的一种：In some preferred embodiments, the compound has one of the following structures:
Figure PCTCN2022117868-appb-000007
Figure PCTCN2022117868-appb-000007
Figure PCTCN2022117868-appb-000008
Figure PCTCN2022117868-appb-000008
其中，in,
R 1、R 2、R 3、R 4的定义如上所述，R 5和R 6各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基，R’选自C1-C6烷基；其中，所述的C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基可以被选自下组的1-3个取代基取代：卤素、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CN、-NO 2、C1-C6烷基、C1-C6烷氧基。 R 1 , R 2 , R 3 , R 4 are defined as above, and R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group, R' is selected from C1-C6 alkyl group; wherein, the C1-C6 alkyl group, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 substituents selected from the following group: Halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkyl, C1-C6 alkoxy.
在一些优选实施方式中，R 1独立地选自：F、Cl、-C(＝O)NH 2、-CH(＝O)、-COOH、-CN、C1-C6烷基、-CF 3、-CHF 2、-CH 2F。 In some preferred embodiments, R 1 is independently selected from: F, Cl, -C(=O)NH 2 , -CH(=O), -COOH, -CN, C1-C6 alkyl, -CF 3 , -CHF 2 , -CH 2 F.
在一些优选实施方式中，B环选自：苯基、吡啶基或吡嗪基。In some preferred embodiments, ring B is selected from: phenyl, pyridyl or pyrazinyl.
在一些优选实施方式中，各R 4独立地选自：H、卤素、C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基、-C(O)NR 5R 6；其中，R 5和R 6各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述的C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基可以被选自下组的1-3个取代基取代：卤素、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CN、-NO 2、C1-C6烷基、C1-C6烷氧基。 In some preferred embodiments, each R is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 Aryl, 5-10 membered heteroaryl, -C(O)NR 5 R 6 ; wherein, R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3 -C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkane Oxygen, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 substituents selected from the group: halogen, -CF 3. -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkyl, C1-C6 alkoxy.
在一些优选实施方式中，R 1独立地选自：F、Cl、-C(＝O)NH 2、-CH(＝O)、-COOH、-CN、甲基、-CF 3、-CHF 2、-CH 2F；和/或 In some preferred embodiments, R 1 is independently selected from: F, Cl, -C(=O)NH 2 , -CH(=O), -COOH, -CN, methyl, -CF 3 , -CHF 2 , -CH 2 F; and/or
各R 4独立地选自：F、Cl、C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、-C(＝O)NH(C1-C6烷基)、-C(＝O)NH(C3-C6环烷基)、-C(＝O)NH(3-6元杂环基)；其中，所述C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、3-6元杂环基可以被选自下组的1-3个取代基取代：卤素、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CN、-NO 2、C1-C6烷基、C1-C6烷氧基；和/或 Each R 4 is independently selected from: F, Cl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, -C (=O) NH (C1-C6 alkyl), - C(=O)NH(C3-C6 cycloalkyl), -C(=O)NH(3-6 membered heterocyclyl); wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered heterocyclic group can be substituted by 1-3 substituents selected from the group: halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , - CN, -NO 2 , C1-C6 alkyl, C1-C6 alkoxy; and/or
R 2独立地选自：-N(R 5)S(O) mR 6、-P(＝O)R' 5R' 6、-S(O) mR 5；其中，R 5、R 6、R' 5和R' 6各自独立地选自：H、-OH、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂 环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，m为1或2；和/或 R 2 is independently selected from: -N(R 5 )S(O) m R 6 , -P(=O)R' 5 R' 6 , -S(O) m R 5 ; wherein, R 5 , R 6 , R'5 and R'6 are each independently selected from: H, -OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl , 3-12 membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group; wherein, m is 1 or 2; and/or
R 3各自独立地选自：-S(O) 2CH 3、-NCH 3S(O) 2CH 3、-NHS(O) 2CH 3、-P(＝O)(CH 3) 2、-P(＝O)(OH) 2；和/或 Each R 3 is independently selected from: -S(O) 2 CH 3 , -NCH 3 S(O) 2 CH 3 , -NHS(O) 2 CH 3 , -P(=O)(CH 3 ) 2 , - P(=O)(OH) 2 ; and/or
Figure PCTCN2022117868-appb-000009
选自：
Figure PCTCN2022117868-appb-000010
Figure PCTCN2022117868-appb-000009
selected from:
Figure PCTCN2022117868-appb-000010
在一些优选实施方式中，A、B、L、X、R 1、R 2、R 3、R 4、n和n'为实施例中各具体化合物所对应基团。 In some preferred embodiments, A, B, L, X, R 1 , R 2 , R 3 , R 4 , n and n' are the groups corresponding to each specific compound in the examples.
在一些优选实施方式中，所述化合物具有下组其中之一的结构或选自下组：In some preferred embodiments, the compound has a structure of one of the following groups or is selected from the following groups:
Figure PCTCN2022117868-appb-000011
Figure PCTCN2022117868-appb-000011
Figure PCTCN2022117868-appb-000012
Figure PCTCN2022117868-appb-000012
在一些优选实施方式中，所述化合物为实施例中所示化合物。In some preferred embodiments, the compound is the compound shown in the examples.
本发明第二方面，提供一种药物组合物，其包含如第一方面所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药；和药学上可接受的载体、稀释剂或赋形剂；优选地，所述药物组合物还包含选自下组的一种或多种：化疗药物、PD-1抑制剂、PD-1抗体、PD-L1抑制剂、PD-L1抗体、ALK抑制剂、PI3K抑制剂、BTK抑制剂、EGFR抑制剂、EGFR抗体、VEGFR抑制剂、VEGFR抗体、HDAC抑制剂、CDK抑制剂、MEK抑制剂、Akt抑制剂、mTOR抑制剂、SHP2抑制剂、KRAS G12C抑制剂、KRAS G12D抑制剂、KRAS G12V抑制剂、c-MET抑制剂、Her2抑制剂、Her2抗体、Claudin18.2抗体。The second aspect of the present invention provides a pharmaceutical composition, which comprises the compound as described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers isomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof; and pharmaceutically acceptable carriers, diluents or excipients; Preferably, the pharmaceutical composition further comprises one or more selected from the group consisting of chemotherapy drugs, PD-1 inhibitors, PD-1 antibodies, PD-L1 inhibitors, PD-L1 antibodies, ALK inhibitors, PI3K inhibitor, BTK inhibitor, EGFR inhibitor, EGFR antibody, VEGFR inhibitor, VEGFR antibody, HDAC inhibitor, CDK inhibitor, MEK inhibitor, Akt inhibitor, mTOR inhibitor, SHP2 inhibitor, KRAS G12C inhibitor , KRAS G12D inhibitor, KRAS G12V inhibitor, c-MET inhibitor, Her2 inhibitor, Her2 antibody, Claudin18.2 antibody.
本发明第三方面，提供一种如第一方面所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如第二方面所述的药物组合物在制备用于预防或治疗与FAK相关疾病的药物中的用途；优选地，所述的FAK相关疾病为癌症、肺动脉高压、或病理性血管生成；更优选地，所述癌症选自：皮肤癌、骨癌、神经胶质瘤、乳腺癌、肾上腺癌、膀胱癌、食道癌、头部或颈部癌症、肝癌、甲状旁腺癌、***癌、小肠癌、甲状腺癌、尿道癌、子***、子宫内膜癌、输卵管癌、肾盂癌、***癌、外阴癌、慢性或急性白血病、结肠癌、黑色素瘤、血液***恶性肿瘤、霍奇金淋巴瘤、肺癌、淋巴细胞性淋巴瘤、中枢神经***肿瘤(CNS)、卵巢癌、胰腺癌、垂体腺瘤、***癌、软组织肉瘤、胃癌、子宫癌。The third aspect of the present invention provides a compound as described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers Conformant, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug, or the pharmaceutical composition as described in the second aspect in the preparation for the prevention or treatment of FAK-related Use in medicine for diseases; preferably, the FAK-related diseases are cancer, pulmonary hypertension, or pathological angiogenesis; more preferably, the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer Cancer of the adrenal gland, bladder, esophagus, head or neck, liver, parathyroid, penis, small intestine, thyroid, urethra, cervix, endometrium, fallopian tube, renal pelvis Cancer, Vaginal Cancer, Vulvar Cancer, Chronic or Acute Leukemia, Colon Cancer, Melanoma, Hematological Malignancies, Hodgkin Lymphoma, Lung Cancer, Lymphocytic Lymphoma, Central Nervous System (CNS), Ovarian Cancer, Pancreas Carcinoma, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, uterine cancer.
本发明第四方面，提供一种制备如第一方面所述的化合物的方法，包括步骤In a fourth aspect of the present invention, there is provided a method for preparing the compound as described in the first aspect, comprising the steps
Figure PCTCN2022117868-appb-000013
Figure PCTCN2022117868-appb-000013
s4)在惰性溶剂中，催化剂存在下，化合物I-1与I-2发生反应，得到式I化合物；s4) In an inert solvent, in the presence of a catalyst, compound I-1 reacts with I-2 to obtain a compound of formula I;
式中，X'为卤素；In the formula, X' is halogen;
优选地，所述方法还包括步骤：Preferably, the method also includes the steps of:
Figure PCTCN2022117868-appb-000014
Figure PCTCN2022117868-appb-000014
s1)在惰性溶剂(如i-PrOH)中，碱(如DIPEA)存在下，化合物I-3与I-4发生反应，得到式I-5化合物；s1) In an inert solvent (such as i-PrOH), in the presence of a base (such as DIPEA), react compound I-3 with I-4 to obtain a compound of formula I-5;
s2)在惰性溶剂(如DMF)中，催化剂(如Pd(PPh 3) 2Cl 2和CuI)存在下和碱性(如DIPEA)条件下，化合物I-5与I-6发生反应，得到式I-7化合物； s2) In an inert solvent (such as DMF), in the presence of a catalyst (such as Pd(PPh 3 ) 2 Cl 2 and CuI) and under basic (such as DIPEA) conditions, compound I-5 reacts with I-6 to obtain the formula I-7 compound;
s3)在惰性溶剂(如NMP)中，碱性(如tBuOK)存在下，化合物I-7发生反应，得到式I-1化合物；s3) In an inert solvent (such as NMP), in the presence of a base (such as tBuOK), compound I-7 is reacted to obtain a compound of formula I-1;
式中，In the formula,
X'、X”和X”'各自独立地为卤素(如Cl、Br、I)；X', X" and X"' are each independently halogen (such as Cl, Br, I);
A环、B环、X、L、R 1、R 2、R 3、R 4、n和n'的定义如上所述。 A ring, B ring, X, L, R 1 , R 2 , R 3 , R 4 , n and n' are as defined above.
本发明第五方面，提供一种治疗FAK相关疾病的方法，所述方法包括给予被鉴定或诊断为具有FAK相关疾病的受试者治疗有效量的如第一方面所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如第二方面所述的药物组合物。In the fifth aspect of the present invention, there is provided a method for treating FAK-related diseases, the method comprising administering a therapeutically effective amount of the compound as described in the first aspect, or its antidote to a subject identified or diagnosed as having a FAK-related disease Enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or their pharmaceutically acceptable salts, hydrates, A solvate, an isotope or a prodrug, or a pharmaceutical composition as described in the second aspect.
本发明第六方面，提供一种用于抑制细胞或受试者中的FAK激酶活性的方法，所述方法包括使所述细胞接触或向所述受试者施用第一方面所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如第二方面所述的药物组合物的步骤；优选地，所述细胞为哺乳动物细胞；优选地，所述受试者为哺乳动物；更优选为人。The sixth aspect of the present invention provides a method for inhibiting FAK kinase activity in a cell or a subject, the method comprising contacting the cell or administering the compound described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof, Hydrate, solvate, isotope or prodrug, or the steps of the pharmaceutical composition as described in the second aspect; preferably, the cell is a mammalian cell; preferably, the subject is a mammal; more preferably human.
本发明第七方面，提供一种如第一方面所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如第二方面所述的药物组合物在制备用于预防或治疗与YAP相关疾病的药物中的用途，尤其是YAP阳性相关的疾病；优选地，所述YAP相关疾病为癌症；更优选地，所述癌症选自：皮肤癌、骨癌、神经胶质瘤、乳腺癌、肾上腺癌、膀胱癌、食道癌、头部或颈部癌症、肝癌、甲状旁腺癌、***癌、小肠癌、甲状腺癌、尿道癌、子***、子宫内膜癌、输卵管癌、肾盂癌、***癌、外阴癌、慢性或急性白血病、结肠癌、黑色素瘤、血液***恶性肿瘤、霍奇金淋巴瘤、肺癌、淋巴细胞性淋巴瘤、中枢神经***肿瘤(CNS)、卵巢癌、胰腺癌、垂体腺瘤、***癌、软组织肉瘤、胃癌、子宫癌。The seventh aspect of the present invention provides a compound as described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers Conformant, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug, or the pharmaceutical composition as described in the second aspect in the preparation for the prevention or treatment of YAP-related Use in medicine for diseases, especially YAP-positive related diseases; preferably, the YAP-related diseases are cancers; more preferably, the cancers are selected from the group consisting of: skin cancer, bone cancer, glioma, breast cancer, Cancer of the adrenal glands, bladder, esophagus, head or neck, liver, parathyroid, penis, small intestine, thyroid, urethra, cervix, endometrium, fallopian tubes, renal pelvis, Vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancy, Hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumor (CNS), ovarian cancer, pancreatic cancer, Pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, uterine cancer.
本发明第八方面，提供一种如第一方面所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如第二方面所述的药物组合物在制备用于预防或治疗与FAK和YAP相关疾病的药物中的用途，尤其是FAK和YAP阳性相关的疾病；优选地，所述的FAK和YAP相关疾病为癌症；更优选地，所述癌症选自：皮肤癌、骨癌、神经胶质瘤、乳腺癌、肾上腺癌、膀胱癌、食道癌、头部或颈部癌症、肝癌、甲状旁腺癌、***癌、小肠癌、甲状腺癌、尿道癌、子***、子宫内膜癌、输卵管癌、肾盂癌、***癌、外阴癌、慢性或急性白血病、结肠癌、黑色素瘤、血液***恶性肿瘤、霍奇金淋巴瘤、肺癌、淋巴细胞性淋巴瘤、中枢神经***肿瘤(CNS)、卵巢癌、胰腺癌、垂体腺瘤、***癌、软组织肉瘤、胃癌、子宫癌。The eighth aspect of the present invention provides a compound as described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers Conformer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof, or the pharmaceutical composition as described in the second aspect in the preparation for the prevention or treatment of FAK and Use in medicine for YAP-related diseases, especially FAK and YAP-positive related diseases; preferably, the FAK and YAP-related diseases are cancers; more preferably, the cancers are selected from: skin cancer, bone cancer, nerve Glioma, breast cancer, adrenal gland cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small bowel cancer, thyroid cancer, urinary tract cancer, cervical cancer, endometrial cancer , fallopian tube cancer, renal pelvis cancer, vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS) , Ovarian cancer, Pancreatic cancer, Pituitary adenoma, Prostate cancer, Soft tissue sarcoma, Gastric cancer, Uterine cancer.
本发明第九方面，提供一种治疗YAP(尤其是YAP阳性)相关疾病的方法，所述方法包括给予被鉴定或诊断为具有YAP(尤其是YAP阳性)相关疾病的受试者治疗有效量的如第一方面所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如第二方面所述的药物组合物。In the ninth aspect of the present invention, there is provided a method for treating YAP (especially YAP-positive)-related diseases, the method comprising administering a therapeutically effective amount of The compound as described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or a pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof, or a pharmaceutical composition as described in the second aspect.
本发明第十方面，提供一种用于减少细胞或受试者中的活化的YAP的方法，所述方法包括使所述细胞接触或向所述受试者施用第一方面所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如第二方面所述的药物组合物的步骤；优选地，所述细胞为哺乳动物细胞；优选地，所述受试者为哺乳动物；更优选为人。In the tenth aspect of the present invention, there is provided a method for reducing activated YAP in a cell or a subject, the method comprising contacting the cell or administering the compound described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof, Hydrate, solvate, isotope or prodrug, or the steps of the pharmaceutical composition as described in the second aspect; preferably, the cell is a mammalian cell; preferably, the subject is a mammal; more preferably human.
另一方面，提供一种治疗FAK和YAP相关疾病的方法，所述方法包括给予被鉴定或诊断为具有FAK和YAP相关疾病的受试者治疗有效量的如第一方面所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如第二方面所述的药物组合物。In another aspect, there is provided a method for treating FAK and YAP related diseases, said method comprising administering a therapeutically effective amount of the compound as described in the first aspect to a subject identified or diagnosed as having FAK and YAP related diseases, or Its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or their pharmaceutically acceptable salts, hydrated Compounds, solvates, isotopes or prodrugs, or pharmaceutical compositions as described in the second aspect.
另一方面，提供一种用于抑制细胞或受试者中的FAK激酶活性，和减少细胞或受试者中的活化的YAP的方法，所述方法包括使所述细胞接触或向所述受试者施用如第一方面所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如第二方面所述的药物组合物的步骤；优选地，所述细胞为哺乳动物细胞；优选地，所述受试者为哺乳动物；更优选为人。In another aspect, there is provided a method for inhibiting FAK kinase activity in a cell or a subject, and reducing activated YAP in a cell or a subject, the method comprising contacting or exposing the cell to the subject The subject is administered the compound as described in the first aspect, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides , metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, or the steps of the pharmaceutical composition as described in the second aspect; preferably, the cells are mammalian cells; preferably , the subject is a mammal; more preferably a human.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.
附图说明Description of drawings
图1示出了正常类器官细胞与弥漫性胃癌类器官细胞的形态对比。Figure 1 shows the morphological comparison of normal organoid cells and diffuse gastric cancer organoid cells.
图2示出了化合物4(2.5μM培养48h)对弥漫性胃癌类器官细胞增殖和形态学的影响。Figure 2 shows the effect of compound 4 (2.5 μM cultured for 48 h) on the proliferation and morphology of diffuse gastric cancer organoid cells.
图3示出了化合物6(2.5μM培养48h)对弥漫性胃癌类器官细胞增殖和形态学的影响。Figure 3 shows the effect of Compound 6 (2.5 μM cultured for 48 h) on the proliferation and morphology of diffuse gastric cancer organoid cells.
图4示出了化合物8(2.5μM培养48h)对弥漫性胃癌类器官细胞增殖和形态学的影响。Figure 4 shows the effect of Compound 8 (2.5 μM cultured for 48 h) on the proliferation and morphology of diffuse gastric cancer organoid cells.
图5示出了化合物9(2.5μM培养48h)对弥漫性胃癌类器官细胞增殖和形态学的影响。Figure 5 shows the effect of Compound 9 (2.5 μM cultured for 48 h) on the proliferation and morphology of diffuse gastric cancer organoid cells.
图6示出了化合物9和Defactinib对弥漫性胃癌类器官细胞增殖的影响。Figure 6 shows the effect of Compound 9 and Defactinib on the proliferation of diffuse gastric cancer organoid cells.
图7示出了化合物9对弥漫性胃癌类器官FAK和YAP蛋白活性的影响。Figure 7 shows the effect of Compound 9 on the activity of FAK and YAP proteins in diffuse gastric cancer organoids.
图8示出了化合物10对弥漫性胃癌类器官FAK和YAP蛋白活性的影响。Figure 8 shows the effect of Compound 10 on the activity of FAK and YAP proteins in diffuse gastric cancer organoids.
图9示出了化合物8和9对人弥漫性胃癌肿瘤细胞系FAK和YAP蛋白活性的影响。Figure 9 shows the effects of compounds 8 and 9 on the activity of FAK and YAP proteins in human diffuse gastric cancer cell lines.
图10示出了Defactinib、IN10018以及化合物24、25、26、27、28对人弥漫性胃癌肿瘤细胞系FAK和YAP蛋白活性的影响。Figure 10 shows the effects of Defactinib, IN10018 and compounds 24, 25, 26, 27, and 28 on the activity of FAK and YAP proteins in human diffuse gastric cancer cell lines.
图11示出了化合物9和Defactinib对人弥漫性胃癌肿瘤细胞系的增殖的影响。Figure 11 shows the effect of Compound 9 and Defactinib on the proliferation of human diffuse gastric cancer tumor cell lines.
具体实施方式Detailed ways
本发明人经过广泛而深入的研究，意外地发现了一类具有较好的FAK激酶抑制活性同时兼具减少活化的YAP的化合物。此外，所述化合物还具有更好药效学/药代动力学性能。在此基础上，完成了本发明。After extensive and in-depth research, the present inventors unexpectedly discovered a class of compounds that have good FAK kinase inhibitory activity and simultaneously reduce activated YAP. In addition, the compounds also have better pharmacodynamic/pharmacokinetic properties. On this basis, the present invention has been accomplished.
术语the term
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。In the present invention, unless otherwise specified, the terms used have the usual meanings known to those skilled in the art.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。 When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
术语“烷基”本身或作为另一取代基的一部分，是指具有指定的碳原子数的直链或支链烃基(即，C1-C6是指包含1、2、3、4、5或6个碳原子)。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。本申请中，烷基还意在包含取代烷基，即烷基中的一个或多个位置被取代，尤其是1-4个取代基，可在任何位置上取代。The term "alkyl" by itself or as part of another substituent refers to a straight or branched chain hydrocarbon group having the indicated number of carbon atoms (i.e., C1-C6 means 1, 2, 3, 4, 5 or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like. In the present application, alkyl is also intended to include substituted alkyl, that is, one or more positions in the alkyl are substituted, especially 1-4 substituents, which can be substituted at any position.
术语“烷氧基”是指通过醚氧连接的直链或支链或环状烷基，其游离价键来自该醚氧。烷氧基优选C1-C6烷氧基，更优选地为C1-C3烷氧基。代表性的例子包括(但并不限于)：甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。The term "alkoxy" refers to a straight or branched or cyclic alkyl group attached through an ether oxygen from which its free valency is derived. The alkoxy group is preferably a C1-C6 alkoxy group, more preferably a C1-C3 alkoxy group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like.
术语“烯基”表示含一个或多个双键且具有指定的碳原子数的直链或支链的烃基。例如，“C2-C6烯基”指含有2至6个碳原子。烯基包括但不限于：乙烯基、丙烯基、丁烯基、1-甲基-2- 丁烯-1-基、庚烯基、辛烯基等。The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more double bonds and having the indicated number of carbon atoms. For example, "C2-C6 alkenyl" means containing 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.
术语“炔基”表示含一个或多个三键且具有指定的碳原子数的直链或支链的烃基。例如，“C2-C6炔基”指含有2至6个碳原子。炔基包括但不限于：乙炔基、丙炔基、丁炔基等。The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more triple bonds and having the indicated number of carbon atoms. For example, "C2-C6 alkynyl" means containing 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
术语“环烷基”是指包括饱和单环(如，C3-C8)、双环(如，C5-C12稠合双环、C5-C12元螺双环)或多环的环状烷基，“C3-C6环烷基”指含有3至6个碳原子，“C3-C12环烷基”指含有3至12个碳原子。环烷基优选C3-C12环烷基，更优选C3-C6环烷基。本发明的代表性的环烷基包括但不限于：环丙基、环丁基、环戊基、环己基、降莰烷基、
Figure PCTCN2022117868-appb-000015
等。应理解，取代或未取代的环烷基，例如支化环烷基(如1-甲基环丙基和2-甲基环丙基)，均包括在“环烷基”的定义中。 The term "cycloalkyl" refers to a cyclic alkyl group including a saturated monocyclic ring (eg, C3-C8), bicyclic ring (eg, C5-C12 fused bicyclic ring, C5-C12 membered spirobicyclic ring) or polycyclic ring, "C3- "C6 cycloalkyl" means containing 3 to 6 carbon atoms, and "C3-C12 cycloalkyl" means containing 3 to 12 carbon atoms. The cycloalkyl group is preferably a C3-C12 cycloalkyl group, more preferably a C3-C6 cycloalkyl group. Representative cycloalkyl groups of the present invention include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl,
Figure PCTCN2022117868-appb-000015
wait. It is to be understood that substituted or unsubstituted cycloalkyl groups, such as branched cycloalkyl groups (eg, 1-methylcyclopropyl and 2-methylcyclopropyl), are included within the definition of "cycloalkyl".
术语“环烯基”是指如上面所定义的、并且进一步含有1或多个双键的环烷基，包括但不限于环戊烯基、环己烯基。The term "cycloalkenyl" refers to a cycloalkyl group as defined above and further containing 1 or more double bonds, including but not limited to cyclopentenyl, cyclohexenyl.
术语“杂环基”通常指稳定的单环(如3-8元，即3元、4元、5元、6元、7元或8元)或二环(如5-12元，即5元、6元、7元、8元、9元、10元、11元或12元)或元多环(如7-14元，即7元、8元、9元、10元、11元、12元、13元或14元)杂环，包括稠环、螺环和/或桥环结构，其为饱和的、部分不饱和的，且其含有碳原子和1个、2个、3个或4个独立地选自N、O和S的杂原子。该术语还包括杂环与芳环(如苯环)稠合所形成的多环基团。“杂环基”可以是取代的或者未取代的。作为环原子的氮和硫杂原子可任选地被氧化。氮原子为取代的或未取代的(即N或NR，其中R为H或如果被定义，则为另一取代基)。杂环可在得到稳定结构的任何杂原子或碳原子处连接至其侧基。如果所得化合物是稳定的，则本文所述的杂环基可在碳或氮原子上被取代。杂环中的氮可任选地被季铵化。优选地，当杂环中S和O原子的总数超过1时，则这些杂原子彼此不相邻。优选地，杂环中S和O原子的总数不大于1。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。杂环基的实施例包括但不限于：氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、***啉基、硫代***啉基、硫代***啉亚砜基、硫代***啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。其中，涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接。The term "heterocyclyl" generally refers to a stable monocyclic ring (such as 3-8 members, that is, 3, 4, 5, 6, 7 or 8 members) or a bicyclic ring (such as 5-12 members, that is, 5 yuan, 6 yuan, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan or 12 yuan) or yuan polycyclic (such as 7-14 yuan, that is, 7 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan, 12-, 13- or 14-membered) heterocyclic rings, including fused, spiro and/or bridged ring structures, which are saturated, partially unsaturated, and which contain carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. The term also includes polycyclic groups formed by the fusion of a heterocyclic ring and an aromatic ring, such as a benzene ring. "Heterocyclyl" may be substituted or unsubstituted. Nitrogen and sulfur heteroatoms as ring atoms may optionally be oxidized. The nitrogen atom is substituted or unsubstituted (ie N or NR, where R is H or another substituent if defined). A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclyl groups described herein may be substituted on carbon or nitrogen atoms if the resulting compound is stable. The nitrogen in the heterocycle can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heterocycle is not greater than one. A heterocyclic group may be attached to the residue of any heteroatom or carbon atom of a ring or ring system molecule. Examples of heterocyclyl groups include, but are not limited to: azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazole Alkyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazine Heptyl, 4-piperidinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl And tetrahydro-1,1-dioxythiophene etc. Among them, the spiro ring, fused ring and bridged ring heterocyclic group are optionally connected to other groups through a single bond, or connected to other cycloalkyl, heterocyclic groups through any two or more atoms on the ring. Cyclic, aryl and heteroaryl groups are further linked in rings.
术语“芳基”，单独或作为较大部分诸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分，是指具有总计5至15个环成员的单环、二环或三环的环***(优选6-10元芳环)，其中所述***中的至少一个环为芳族的且其中所述***中的每个环含有3至7个环成员。“芳基”可以是取代的或者未取代的。在本发明的某些实施方案中，“芳基”是指芳族环***，其包括但不限于：苯基、联苯基、茚满基、1-萘基、2-萘基和四氢萘基。所述芳基可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环。稠合的芳基可在环烷基环或芳族环的合适位置上连接至另一基团。从环***中画出的连接线表明键可连接至任意合适的环原子。芳基可以是任选取代的或未取代的。The term "aryl", alone or as part of a larger moiety such as "aralkyl", "aralkoxy" or "aryloxyalkyl", refers to a single ring having a total of 5 to 15 ring members , a bicyclic or tricyclic ring system (preferably a 6-10 membered aromatic ring), wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. "Aryl" can be substituted or unsubstituted. In certain embodiments of the invention, "aryl" refers to an aromatic ring system including, but not limited to: phenyl, biphenyl, indanyl, 1-naphthyl, 2-naphthyl, and tetrahydro naphthyl. The aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring. A fused aryl group can be attached to another group at a suitable position on the cycloalkyl ring or aromatic ring. Connecting lines drawn from ring systems indicate that bonds may be attached to any suitable ring atom. Aryl groups can be optionally substituted or unsubstituted.
术语“杂芳基”指包含1-4个杂原子、5-14个环原子的杂芳族体系，其中，杂原子选自氧、氮和硫。杂芳基优选5至10元环，更优选为5元或6元，例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者未取代的。The term "heteroaryl" refers to a heteroaromatic system comprising 1-4 heteroatoms, 5-14 ring atoms, wherein the heteroatoms are selected from oxygen, nitrogen and sulfur. Heteroaryl is preferably a 5- to 10-membered ring, more preferably 5- or 6-membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl , furyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazazinyl, triazolyl and tetrazolyl, etc. "Heteroaryl" can be substituted or unsubstituted.
术语“卤素”包括氟、氯、溴和碘。The term "halogen" includes fluorine, chlorine, bromine and iodine.
除非另外说明，假定任何不满价态的杂原子有足够的氢原子补充其价态。Unless otherwise stated, it is assumed that any heteroatom with a dissatisfied valence has sufficient hydrogen atoms to fill its valence.
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的，即各个取代之间是相互独立地。本领域技术人员应理解，本发明 所预期的取代基的组合是那些稳定的或化学上可实现的组合。典型的取代包括但不限于一个或多个以下基团：如氢、氘、卤素(例如，单卤素取代基或多卤素取代基，后者如三氟甲基或包含Cl 3的烷基)、氰基、硝基、氧代(如＝O)、三氟甲基、三氟甲氧基、环烷基、烯基、炔基、杂环基、芳基、杂芳基、OR a、SR a、S(＝O)R e、S(＝O) 2R e、P(＝O) 2R e、S(＝O) 2OR e，P(＝O) 2OR e、NR bR c、NR bS(＝O) 2R e、NR bP(＝O) 2R e、S(＝O) 2NR bR c、P(＝O) 2NR bR c、C(＝O)OR d、C(＝O)R a、C(＝O)NR bR c、OC(＝O)R a、OC(＝O)NR bR c、NR bC(＝O)OR e、NR dC(＝O)NR bR c、NR dS(＝O) 2NR bR c、NR dP(＝O) 2NR bR c、NR bC(＝O)R a、或NR bP(＝O) 2R e，其中，R a可以独立表示氢、氘、烷基、环烷基、烯基、炔基、杂环基、芳基或杂芳基，R b、R c和R d可以独立表示氢、氘、烷基、环烷基、杂环或芳环，或者R b和R c与N原子一起可以形成杂环；R e可以独立表示氢、烷基、环烷基、烯基、炔基、杂环基、芳基或杂芳基。上述典型的取代基，如烷基、环烷基、烯基、环烯基、炔基、杂环基、芳基或杂芳基可以任选取代。所述取代基例如(但并不限于)：卤素、羟基、氰基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、胺基、C1-C6烷氧基、C1-C10磺酰基、及C1-C6脲基等。 In the present invention, the term "substituted" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituents are the corresponding substituents described above, or the substituents appearing in each embodiment. Unless otherwise specified, a certain substituted group can have a substituent selected from a specific group at any substitutable position of the group, and the substituents can be the same or different at each position, namely The individual substitutions are independent of each other. Those skilled in the art will appreciate that combinations of substituents contemplated by this invention are those that are stable or chemically feasible. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (eg, monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl 3 ), Cyano, nitro, oxo (eg =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, OR a , SR a , S(=O)R e , S(=O) 2 R e , P(=O) 2 R e , S(=O) 2 OR e , P(=O) 2 OR e , NR b R c , NR b S(=O) 2 R e , NR b P(=O) 2 R e , S(=O) 2 NR b R c , P(=O) 2 NR b R c , C(=O) OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , NR b C(=O)OR e , NR d C(=O)NR b R c , NR d S(=O) 2 NR b R c , NR d P(=O) 2 NR b R c , NR b C(=O)R a , or NR b P(=O) 2 Re , wherein, R a can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, aryl or heteroaryl, R b , R c and R d can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic or aromatic ring, or R b and R c can form a heterocyclic ring together with N atoms; Re can independently represent hydrogen, alkyl, cycloalkyl , alkenyl, alkynyl, heterocyclyl, aryl or heteroaryl. The typical substituents mentioned above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, aryl or heteroaryl may be optionally substituted. The substituents are for example (but not limited to): halogen, hydroxyl, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-12 membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amine group, C1-C6 alkoxy group, C1-C10 sulfonyl group, and C1 -C6 ureido group, etc.
Yes-associated protein(YAP)是一种原癌蛋白，以非活性形式存在于细胞质中，当被激活时，它会转移到细胞核并激活细胞***和凋亡相关基因的转录。YAP是Hippo信号通路中的下游调节蛋白之一，它与转录共激活因子TAZ协同作用，通过控制TEAD转录因子家族来指导基因表达。Hippo信号通路是一种进化保守的信号传导途径，在器官发育，上皮稳态，组织再生，伤口愈合和免疫调节中起关键作用。Hippo通路以及YAP/TAZ-TEAD活性失调与多种疾病有关，其中最主要的是癌症。Yes-associated protein (YAP) is a proto-oncoprotein that exists in the cytoplasm in an inactive form, and when activated, it translocates to the nucleus and activates the transcription of genes involved in cell division and apoptosis. YAP is one of the downstream regulatory proteins in the Hippo signaling pathway, which cooperates with the transcriptional coactivator TAZ to direct gene expression by controlling the TEAD transcription factor family. The Hippo signaling pathway is an evolutionarily conserved signaling pathway that plays key roles in organ development, epithelial homeostasis, tissue regeneration, wound healing and immune regulation. Dysregulation of Hippo pathway and YAP/TAZ-TEAD activity is associated with various diseases, the most important of which is cancer.
在本发明中，“YAP阳性”是指细胞核内YAP含量达到或超过预设的含量。In the present invention, "YAP positive" means that the YAP content in the nucleus reaches or exceeds the preset content.
在本发明中，“FAK阳性”是指细胞内磷酸化的FAK含量达到或超过预设的含量。In the present invention, "FAK positive" means that the content of phosphorylated FAK in the cell reaches or exceeds a predetermined level.
活性成分active ingredient
如本文所用，术语“本发明的化合物”或“本发明的活性成分”可互换使用，指式I化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、同位素或前药。As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to a compound of formula I, or its enantiomers, diastereoisomers, racemates, tautomers Isomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, isotopes or prodrugs thereof.
本发明中，式I化合物具有如下结构：In the present invention, the compound of formula I has the following structure:
Figure PCTCN2022117868-appb-000016
Figure PCTCN2022117868-appb-000016
其中，A、B、L、X、R 1、R 2、R 3、R 4、n和n'的定义如上所述。 Wherein, A, B, L, X, R 1 , R 2 , R 3 , R 4 , n and n' are as defined above.
优选地，所述化合物具有式II或式III所示的结构Preferably, the compound has the structure shown in formula II or formula III
Figure PCTCN2022117868-appb-000017
Figure PCTCN2022117868-appb-000017
Figure PCTCN2022117868-appb-000018
Figure PCTCN2022117868-appb-000018
其中，p、R 1、R 2、R 3、R 4、B和n'的定义如上所述。 Wherein, p, R 1 , R 2 , R 3 , R 4 , B and n' are as defined above.
优选地，所述化合物具有式IV或式V所示的结构Preferably, the compound has the structure shown in formula IV or formula V
Figure PCTCN2022117868-appb-000019
Figure PCTCN2022117868-appb-000019
其中，in,
R 1、R 2、R 3、R 4、B和n'的定义如上所述，R 5和R 6各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述的C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基可以被选自下组的1-3个取代基取代：卤素、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CN、-NO 2、C1-C6烷基、C1-C6烷氧基。 R 1 , R 2 , R 3 , R 4 , B and n' are defined as above, R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3- C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy Base, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 substituents selected from the group: halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkyl, C1-C6 alkoxy.
优选地，R 1独立地选自：F、Cl、-C(＝O)NH 2、-CH(＝O)、-COOH、CN、甲基、-CF 3、-CHF 2、-CH 2F； Preferably, R 1 is independently selected from: F, Cl, -C(=O)NH 2 , -CH(=O), -COOH, CN, methyl, -CF 3 , -CHF 2 , -CH 2 F ;
B环为六元芳基或杂芳基；优选地，B环选自：苯基、吡啶基或吡嗪基；Ring B is a six-membered aryl or heteroaryl group; preferably, ring B is selected from: phenyl, pyridyl or pyrazinyl;
R 4各自独立地选自：H、卤素、C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基、-C(O)NR 5R 6；其中，R 5和R 6各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基； R 4 are each independently selected from: H, halogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C6-C10 aryl, 5-10 membered Heteroaryl, -C(O)NR 5 R 6 ; wherein, R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3 -12 membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group;
R 2独立地选自：-N(R 5)S(O) mR 6、-P(＝O)R' 5R' 6、-S(O) mR 5； R 2 is independently selected from: -N(R 5 )S(O) m R 6 , -P(=O)R' 5 R' 6 , -S(O) m R 5 ;
其中，R 5、R 6、R' 5和R' 6各自独立地选自：H、OH、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基； Wherein, R 5 , R 6 , R' 5 and R' 6 are each independently selected from: H, OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl;
其中，m为1或2；Wherein, m is 1 or 2;
优选地，R 3各自独立地选自：-S(O) 2CH 3、-NCH 3S(O) 2CH 3、-NHS(O) 2CH 3、-P(＝O)(CH 3) 2、-P(＝O)(OH) 2。 Preferably, each R 3 is independently selected from: -S(O) 2 CH 3 , -NCH 3 S(O) 2 CH 3 , -NHS(O) 2 CH 3 , -P(=O)(CH 3 ) 2 . -P(=O)(OH) 2 .
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明，本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”，指用无机或有机酸和碱形成酸式或碱式的盐。此外，当本发明中的化合物含一个碱性片段时，它包括但不限于吡啶或咪唑，含一个酸性片段时，包括但不限于羧酸，可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒，生理可接受的)盐是首选，虽然其他盐类也有用，例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐，例如，化合物I与一定量如等当量的酸或碱反应，在介质中盐析出来，或在水溶液中冷冻干燥得来。The salts that may be formed by the compounds of the present invention also belong to the scope of the present invention. Unless otherwise stated, the compounds of the present invention are understood to include their salts. The term "salt" as used herein refers to an acidic or basic salt formed with an inorganic or organic acid and a base. In addition, when a compound of the present invention contains a basic moiety, which includes but is not limited to pyridine or imidazole, and an acidic moiety, including but not limited to carboxylic acid, zwitterions ("inner salts") that may be formed are contained in within the term "salt". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during preparation. The compound of the present invention may form a salt, for example, compound I reacts with a certain amount, such as an equivalent amount of acid or base, and salts it out in a medium, or freeze-dries it in an aqueous solution.
本发明中的化合物含有的碱性片段，包括但不限于胺或吡啶或咪唑环，可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸，如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如，2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如，2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐，水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。Basic moieties contained in the compounds of the present invention, including but not limited to amines or pyridine or imidazole rings, may form salts with organic or inorganic acids. Typical acids from which salts can be formed include acetate (e.g. with acetic acid or a trihaloacetic acid such as trifluoroacetic acid), adipate, alginate, ascorbate, aspartate, benzoate , Benzenesulfonate, Bisulfate, Borate, Butyrate, Citrate, Camphor Salt, Camphorsulfonate, Cyclopentane Propionate, Diglycolate, Lauryl Sulfate, Ethanesulfonate, Fumarate, Glucoheptonate, Glycerophosphate, Hemisulfate, Heptanoate, Hexanoate, Hydrochloride, Hydrobromide, Hydroiodide, Isethionate (eg, 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (eg, 2-naphthalenesulfonate), nicotinate, nitrate, oxalate Salt, pectate, persulfate, phenylpropionate (as 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfates (as formed with sulfuric acid), sulfonates, tartrates, thiocyanates, tosylates such as p-toluenesulfonate, dodecanoate, and the like.
本发明的某些化合物可能含有的酸性片段，包括但不限于羧酸，可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐，碱土金属盐如钙、镁盐和有机碱形成的盐(如有机胺)，如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺，以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐，如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物)，二烷基硫酸盐(如，硫酸二甲酯、二乙酯，二丁酯和二戊酯)，长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物)，芳烷基卤化物(如苄基和苯基溴化物)等等。Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical salts formed with bases include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts and salts formed with organic bases (such as organic amines), such as benzathine, dicyclohexylamine , Hipamine (salt with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butyl Amines, and salts with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and dipentyl sulfates), long-chain halides (e.g., decyl, dodecyl, tetradecyl, and tetradecyl chlorides, bromides and iodides), aralkyl halides (such as benzyl and phenyl bromides) and the like.
本发明中化合物的前药及溶剂合物也在涵盖的范围之内。此处术语“前药”是指一种化合物，在治疗相关疾病时，经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂合物。本发明的化合物包括溶剂合物，如水合物。Prodrugs and solvates of the compounds of the present invention are also contemplated. The term "prodrug" here refers to a compound that undergoes metabolic or chemical transformation during the treatment of related diseases to produce the compound, salt, or solvate of the present invention. The compounds of the present invention include solvates, such as hydrates.
本发明中的化合物、盐或溶剂合物，可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。Compounds, salts or solvates of the present invention, possible tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.
所有化合物的立体异构体(例如，那些由于对各种取代可能存在的不对称碳原子)，包括其对映体形式和非对映形式，都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如，作为一个纯的或者实质上是纯的光学异构体具有特殊的活性)，或者也可能是混合物，如消旋体，或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型，由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决，例如分步结晶，或通过衍生为非对映异构体分离结晶，或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到，包括但不限于传统的方法，例如与光学活性酸成盐后再结晶。Stereoisomers of all compounds (for example, those due to possible asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms thereof, are contemplated by the present invention. The individual stereoisomers of the compounds of the present invention may not exist simultaneously with other isomers (for example, as a pure or substantially pure optical isomer having a specific activity), or may be a mixture, such as Racemates, or mixtures with all other stereoisomers or parts thereof. The chiral center of the present invention has two configurations of S or R, which are defined by the 1974 proposal of the International Union of Theoretical and Applied Chemistry (IUPAC). The racemic forms can be resolved by physical methods such as fractional crystallization, or by derivatization into diastereoisomers, or by separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods such as salt formation with optically active acids followed by crystallization.
本发明中的化合物，依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90％，例如，等于或大于95％，等于或大于99％(“非常纯”的化合物)，在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。The compound in the present invention, the weight content of the compound obtained by preparation, separation and purification in sequence is equal to or greater than 90%, for example, equal to or greater than 95%, equal to or greater than 99% ("very pure" compound), described in the main text listed. Such "very pure" compounds of the invention are also included herein as part of the invention.
本发明的化合物所有的构型异构体都在涵盖的范围之内，无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体，以及碳环和杂环的顺式和反式异构体。All configurational isomers of the compounds of the invention are contemplated, whether in admixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and retro (E) olefinic isomers, as well as carbocyclic and heterocyclic cis and trans isomers.
在整个说明书中，基团和取代基可以被选择以提供稳定的片段和化合物。Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
特定官能团和化学术语定义都详细介绍如下。对本发明来说，化学元素与Periodic Table of the Elements，CAS version，Handbook of Chemistry and Physics，75 th Ed.中定义的一致。特定官能团的定义也在其中描述。此外，有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”，Thomas Sorrell，University Science Books，Sausalito:1999，也有说明，其全部内容纳入参考文献之列。 Definitions of specific functional groups and chemical terms are detailed below. For the purposes of this invention, the chemical elements are as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Definitions of specific functional groups are also described therein. In addition, the basic principles of organic chemistry as well as specific functional groups and reactivity are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated by reference.
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物，包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基，如烷基。所有异构体以及它们的混合物，都包涵在本发明中。Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic spin mixtures and other mixtures. Alternatively an asymmetric carbon atom may represent a substituent, such as an alkyl group. All isomers, as well as mixtures thereof, are included in the present invention.
按照本发明，同分异构体的混合物含有异构体的比率可以是多样的。例如，在只有两个异构体的混合物可以有以下组合：50:50，60:40，70:30，80:20，90:10，95:5，96:4，97:3，98:2，99:1， 或100:0，异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率，及为更复杂的异构体的混合物的比率也在本发明范围之内。According to the present invention, the mixture of isomers may contain various ratios of isomers. For example, in a mixture of only two isomers you can have the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98: 2, 99:1, or 100:0, all ratios of isomers are within the scope of the invention. Similar ratios, as well as ratios that are mixtures of more complex isomers, readily understood by one of ordinary skill in the art, are also within the scope of the invention.
本发明还包括同位素标记的化合物，等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢、碳、氮、氧、磷、硫、氟和氯同位素，分别如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。本发明中的化合物，或对映体，非对映体，异构体，或药学上可接受的盐或溶剂化物，其中含有上述化合物的同位素或其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物，例如 3H和 14C的放射性同位素也在其中，在药物和底物的组织分布实验中是有用的。氚，即 3H和碳-14，即 14C，它们的制备和检测比较容易。是同位素中的首选。此外，较重同位素取代如氘，即 2H，由于其很好的代谢稳定性在某些疗法中有优势，例如在体内增加半衰期或减少用量，因此，在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法，通过用易得的同位素标记试剂替换为非同位素的试剂，用批露在示例中的方案可以制备。 The invention also includes isotopically labeled compounds equivalent to the original compounds disclosed herein. In practice, however, substitution of one or more atoms by an atom with a different atomic mass or mass number usually occurs. Examples of isotopes that may be included in compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, respectively , 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 C radioactive isotopes, are useful in tissue distribution assays for drugs and substrates. Tritium, namely 3 H, and carbon-14, namely 14 C, are relatively easy to prepare and detect. is the first choice among isotopes. In addition, substitution of heavier isotopes such as deuterium, ie 2 H, may be preferred in some cases due to its good metabolic stability, which has advantages in certain therapies, such as increased half-life in vivo or reduced dosage. Isotopically-labeled compounds can be prepared in general manner by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent, using the protocols disclosed in the Examples.
如果要设计一个本发明的化合物特定的对映体的合成，它可以不对称合成制备，或用手性辅剂衍生化，将所产生的非对映混合物分离，再除去手性辅剂而得到纯的对映体。另外，如果分子中含有一个碱性官能团，如氨基酸，或酸性官能团，如羧基，可以用合适的光学活性的酸或碱的与之形成非对映异构体盐，再通过分离结晶或色谱等常规手段分离，然后就得到了纯的对映体。If the synthesis of a specific enantiomer of a compound of the present invention is to be designed, it can be prepared by asymmetric synthesis, or derivatized with a chiral auxiliary, the resulting diastereomeric mixture is separated, and the chiral auxiliary is removed to obtain pure enantiomers. In addition, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, and then separated by crystallization or chromatography. Separation by conventional means then gives the pure enantiomers.
如本文所述，本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常，术语“取代”不论在术语“可选”前面或后面出现，在本发明配方中包括取代基的通式，是指用指定结构取代基，代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时，取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲，允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的，芳环的和非芳环的有机化合物。在本发明中，如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外，本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的。此处术语“稳定”是指具有稳定的化合物，在足够长的时间内检测足以维持化合物结构的完整性，最好是在足够长的时间内都在效，本文在此用于上述目的。As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to broaden their scope. Generally, whether the term "substitution" appears before or after the term "optional", the general formula including the substituent in the formula of the present invention means that the hydrogen radical is replaced by the specified structural substituent. When multiple positions in a specific structure are substituted with multiple specific substituents, the substituents may be the same or different for each position. The term "substitution" as used herein includes all permissible organic compound substitutions. Broadly speaking, the permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds. In the present invention eg heteroatom nitrogen may have hydrogen substituents or any permissible organic compound as described above to complement its valence. Furthermore, this invention is not intended to be limiting in any way to the organic compounds permissible to be substituted. Combinations of substituents and variables are considered by the present invention to be beneficial in the treatment of diseases in the form of stable compounds. The term "stable" herein means having a compound that is stable, detectable for a sufficient period of time to maintain the structural integrity of the compound, preferably active for a sufficient period of time, and is used herein for the above purposes.
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。The metabolites of the compounds involved in the application and their pharmaceutically acceptable salts, and the prodrugs that can be transformed into the structures of the compounds involved in the application and the pharmaceutically acceptable salts thereof in vivo are also included in the claims of the application middle.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
本发明所述的式(I)化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，和含式(I)化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药的药物组合物可用于预防和/或治疗以下疾病：癌症、肺动脉高压、病理性血管生成。The compound of formula (I) described in the present invention, or its enantiomer, diastereoisomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, Metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs, and compounds containing formula (I), or their enantiomers, diastereoisomers, racemates, mutual A pharmaceutical composition of variants, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof may be used for the prevention and/or Treatment of the following diseases: cancer, pulmonary hypertension, pathological angiogenesis.
式(I)所述化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或先或后服用式(I)的化合物；或将式(I)化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，和其他药物制成单一制剂，同时给药。当式(I)化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物，和式(I)化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药的药用组合物。药物联用也包括在重叠的时间段服用式(I)化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，与其它一种或几 种已知药物。当式(I)化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，与其它一种或几种药物进行药物联用时，式(I)化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或已知药物的剂量可能比它们单独用药的剂量低。The compound described in formula (I), or its enantiomer, diastereoisomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or Its pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs can be used in combination with other drugs known to treat or improve similar conditions. During combined administration, the administration mode and dosage of the original drug can remain unchanged, and the compound of formula (I) can be taken simultaneously or first or later; or the compound of formula (I) or its enantiomer, diastereomer Enantiomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof , and other drugs into a single preparation, administered at the same time. When the compound of formula (I), or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or When pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs are taken together with one or more other drugs, it can be preferably used to contain one or more known drugs and the compound of formula (I) , or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof , hydrate, solvate, isotope or prodrug pharmaceutical composition. The drug combination also includes administration of the compound of formula (I), or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers in overlapping time periods body, nitrogen oxide, metabolite or its pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug, and one or several other known drugs. When the compound of formula (I), or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or When a pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug is used in combination with one or more other drugs, the compound of formula (I), or its enantiomer, diastereoisomer isomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs, or Doses of known drugs may be lower than when they are given alone.
可以与式(I)所述化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药进行药物联用的药物或活性成分包括但不局限为：化疗药物、PD-1抑制剂、PD-1抗体、PD-L1抑制剂、PD-L1抗体、ALK抑制剂、PI3K抑制剂、BTK抑制剂、EGFR抑制剂、EGFR抗体、VEGFR抑制剂、VEGFR抗体、HDAC抑制剂、CDK抑制剂、MEK抑制剂、Akt抑制剂、mTOR抑制剂、SHP2抑制剂、KRAS G12C抑制剂、KRAS G12D抑制剂、KRAS G12V抑制剂、c-MET抑制剂、Her2抑制剂、Her2抗体、Claudin18.2抗体。Compounds described in formula (I), or their enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolic Products or their pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs for drug combination drugs or active ingredients include but are not limited to: chemotherapy drugs, PD-1 inhibitors, PD-1 antibodies, PD -L1 inhibitors, PD-L1 antibodies, ALK inhibitors, PI3K inhibitors, BTK inhibitors, EGFR inhibitors, EGFR antibodies, VEGFR inhibitors, VEGFR antibodies, HDAC inhibitors, CDK inhibitors, MEK inhibitors, Akt inhibitors agent, mTOR inhibitor, SHP2 inhibitor, KRAS G12C inhibitor, KRAS G12D inhibitor, KRAS G12V inhibitor, c-MET inhibitor, Her2 inhibitor, Her2 antibody, Claudin18.2 antibody.
式(I)所述化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药还可与用于治疗肺动脉高压(PHA)的治疗剂联用。所述PHA治疗剂优选为血管舒张药，例如依前列醇，他达拉非或安贝生坦等。The compound described in formula (I), or its enantiomer, diastereoisomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or A pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof may also be used in combination with a therapeutic agent for the treatment of pulmonary arterial hypertension (PHA). The PHA therapeutic agent is preferably a vasodilator, such as epoprostenol, tadalafil or ambrisentan and the like.
本发明药物组合物的剂型包括(但并不限于)：注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂、控释型或缓释型或纳米制剂。The dosage form of the pharmaceutical composition of the present invention includes (but not limited to): injection, tablet, capsule, aerosol, suppository, film, drop pill, external liniment, controlled-release or sustained-release or nano-preparation.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药学上可接受的盐及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022117868-appb-000020
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low toxicity. "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween
Figure PCTCN2022117868-appb-000020
), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
“赋形剂”是指在药物制剂中除主药以外的附加物，也可称为辅料。"Excipients" refer to the additions in pharmaceutical preparations other than the main drug, and can also be called excipients.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是 棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
本发明还提供了一种药物组合物的制备方法，包括步骤：将药学上可接受的载体与本发明所述式(I)化合物或其晶型、药学上可接受的盐、水合物或溶剂合物进行混合，从而形成药物组合物。The present invention also provides a preparation method of a pharmaceutical composition, comprising the steps of: mixing a pharmaceutically acceptable carrier with the compound of formula (I) or its crystal form, pharmaceutically acceptable salt, hydrate or solvent of the present invention compounds are mixed to form a pharmaceutical composition.
制备方法Preparation
以下方案和实例中描述了制备式I的化合物的方法。原料和中间体从商业来源购买，由已知步骤制备，或以其他方式说明。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。Methods of preparing compounds of Formula I are described in the following Schemes and Examples. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or otherwise illustrated. In some cases, the order in which the steps of a reaction scheme are performed can be altered to facilitate a reaction or to avoid undesired side reaction products.
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。The preparation method of the compound of formula (I) of the present invention is described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.
通常，在制备流程中，各反应通常惰性气体保护下，适当溶剂中，在0到90℃下进行，反应时间通常为2-24小时。Usually, in the preparation process, each reaction is usually carried out in an appropriate solvent under the protection of an inert gas at a temperature of 0 to 90° C., and the reaction time is usually 2-24 hours.
优选地，本发明化合物采用如下方法制备Preferably, the compounds of the present invention are prepared by the following method
Figure PCTCN2022117868-appb-000021
Figure PCTCN2022117868-appb-000021
s1)在惰性溶剂(如i-PrOH)中，碱(如DIPEA)存在下，化合物I-3与I-4发生反应，得到式I-5化合物；s1) In an inert solvent (such as i-PrOH), in the presence of a base (such as DIPEA), react compound I-3 with I-4 to obtain a compound of formula I-5;
s2)在惰性溶剂(如DMF)中，催化剂(如Pd(PPh 3) 2Cl 2和CuI)存在下和碱性(如DIPEA)条件下，化合物I-5与I-6发生反应，得到式I-7化合物； s2) In an inert solvent (such as DMF), in the presence of a catalyst (such as Pd(PPh 3 ) 2 Cl 2 and CuI) and under basic (such as DIPEA) conditions, compound I-5 reacts with I-6 to obtain the formula I-7 compound;
s3)在惰性溶剂(如NMP)中，碱性(如tBuOK)存在下，化合物I-7发生反应，得到式I-1化合物；s3) In an inert solvent (such as NMP), in the presence of a base (such as tBuOK), compound I-7 is reacted to obtain a compound of formula I-1;
s4)在惰性溶剂(如)中，催化剂存在下，化合物I-1与I-2发生反应，得到式I化合物；s4) In an inert solvent (such as) in the presence of a catalyst, compound I-1 reacts with I-2 to obtain a compound of formula I;
式中，In the formula,
X'、X”和X”'各自独立地为卤素(如Cl、Br、I)；X', X" and X"' are each independently halogen (such as Cl, Br, I);
A环、B环、X、L、R 1、R 2、R 3、R 4、n和n'的定义如上所述。 A ring, B ring, X, L, R 1 , R 2 , R 3 , R 4 , n and n' are as defined above.
本领域技术人员还应当理解，在本文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。Those skilled in the art will also appreciate that in the methods described herein, intermediate compound functional groups may need to be protected by appropriate protecting groups. Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.
本发明所用试剂或材料均可市售或者文献报道中给出的方式获得。The reagents or materials used in the present invention are all commercially available or obtained in the manner given in literature reports.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.
本发明具有以下主要优点：The present invention has the following main advantages:
(1)本发明化合物对FAK激酶具有优良的抑制能力，和/或能显著减少/降低活化的YAP；特别是当A环上两个相邻的R 4与A环形成并环结构时，其活性大大提升；此外，R 4为烷氧基或酰胺基以及R 2为N-甲基甲磺酰胺时，其活性也可以明显改善。 (1) The compound of the present invention has excellent inhibitory ability to FAK kinase, and/or can significantly reduce/reduce the YAP of activation; Especially when two adjacent R on the A ring 4 and A ring form and ring structure, its The activity is greatly improved; in addition, when R 4 is an alkoxy group or amido group and R 2 is N-methylmethanesulfonamide, its activity can also be significantly improved.
(2)本发明化合物具有较低的毒副作用。(2) The compound of the present invention has relatively low toxic and side effects.
(3)本发明化合物具有较好的药效学、药代动力学性能。(3) The compound of the present invention has better pharmacodynamics and pharmacokinetic properties.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental method that does not indicate specific conditions in the following examples, usually according to conventional conditions such as Sambrook et al., molecular cloning: the conditions described in the laboratory manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer suggested conditions. Percentages and parts are by weight unless otherwise indicated.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass chromatography (LC-MS).
NMR是使用Bruker AVANCE-400和Bruker AVANCE-500核磁仪检测的，测定溶剂包含氘代二甲亚砜(DMSO-d 6)、氘代丙酮(CD 3COCD 3)、氘代氯仿(CDCl 3)及氘代甲醇(CD 3OD)等，内标采用四甲基硅烷(TMS)，化学位移以百万分之一(ppm)的单位计量。 NMR was detected using Bruker AVANCE-400 and Bruker AVANCE-500 nuclear magnetic instruments, and the determination solvents included deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated acetone (CD 3 COCD 3 ), deuterated chloroform (CDCl 3 ) and deuterated methanol (CD 3 OD), etc., the internal standard is tetramethylsilane (TMS), and the chemical shift is measured in parts per million (ppm).
液质联用色谱(LC-MS)是使用Agilent 1260质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5 micron C18 100 x 3.0mm色谱柱)。Liquid chromatography-mass chromatography (LC-MS) was detected using an Agilent 1260 mass spectrometer. The determination of HPLC uses Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 100 x 3.0mm chromatographic column).
薄层层析硅胶板使用青岛GF254硅胶板，TLC采用的是0.15-0.20mm，制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。Qingdao GF254 silica gel plates were used for thin-layer chromatography, 0.15-0.20mm for TLC, and 0.4mm-0.5mm for preparative thin-layer chromatography. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
本发明实施例中的起始原料都是已知并有市售的，或者可以采用或按照本领域已报道的文献资料合成的。The starting materials in the examples of the present invention are all known and commercially available, or can be adopted or synthesized according to literatures reported in the art.
除特殊说明外，本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行，反应温度均为摄氏度。Unless otherwise specified, all reactions in the present invention are carried out under the protection of dry inert gas (such as nitrogen or argon) by continuous magnetic stirring, and the reaction temperatures are all in degrees Celsius.
下列简写词的使用贯穿本发明The following abbreviations are used throughout this specification
THF：四氢呋喃THF: Tetrahydrofuran
DCM：二氯甲烷DCM: dichloromethane
PE：石油醚PE: petroleum ether
Na 2CO 3：碳酸钠 Na 2 CO 3 : sodium carbonate
MeOH：甲醇MeOH: Methanol
HCl：盐酸HCl: hydrochloric acid
Pd(PPh 3) 4：四三苯基膦钯 Pd(PPh 3 ) 4 : tetrakistriphenylphosphine palladium
K 2CO 3：碳酸钾 K 2 CO 3 : potassium carbonate
H 2O：水 H2O : water
TEA：三乙胺TEA: Triethylamine
DIEA：N,N-二异丙基乙胺DIEA: N,N-Diisopropylethylamine
DMF：N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide
DMSO：二甲基亚砜DMSO: dimethyl sulfoxide
NaBH 4：硼氢化钠 NaBH 4 : Sodium borohydride
Sn 2(Bu-n) 6：六己基二锡 Sn 2 (Bu-n) 6 : Hexahexyl ditin
CuI：碘化亚铜CuI: cuprous iodide
Cs 2CO 3：碳酸铯 Cs 2 CO 3 : cesium carbonate
K 3PO 4：磷酸钾 K 3 PO 4 : potassium phosphate
Pd 2(dba) 3：三(二亚苄基丙酮)二钯 Pd 2 (dba) 3 : Tris(dibenzylideneacetone)dipalladium
Pd/C：钯碳Pd/C: palladium carbon
Xantphos：2-二环己基磷-2,4,6-三异丙基联苯Xantphos: 2-Dicyclohexylphosphonium-2,4,6-triisopropylbiphenyl
EA：乙酸乙酯EA: ethyl acetate
Boc 2O：二碳酸二叔丁酯 Boc 2 O: di-tert-butyl dicarbonate
Pd(dppf) 2Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯 Pd(dppf) 2 Cl 2 : [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
NaH：氢钠NaH: sodium hydrogen
CH 3I：碘甲烷 CH3I : methyl iodide
L-Proline：L-脯氨酸L-Proline: L-Proline
L-Selectride：三仲丁基硼氢化锂L-Selectride: lithium tri-sec-butyl borohydride
实施例Example
实施例1Example 1
2-((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸甲酯的制备2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole Preparation of methyl[2,3-d]pyrimidine-6-carboxylate
Figure PCTCN2022117868-appb-000022
Figure PCTCN2022117868-appb-000022
步骤1：合成N-(3-((((2-氯-5-碘嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 1: Synthesis of N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide
在0℃下，将N-(3-(氨基甲基)吡嗪-2-基)-N-甲基甲磺酰胺(5.0g,19.8mmol)、2,4-二氯-5-碘嘧啶(5.0g,18.2mmol)和DIPEA(12.0mL,72.6mmol)的i-PrOH(100mL)溶液搅拌3.5h。TLC(石油醚/乙酸乙酯＝5/1)显示反应完成后将反应混合物倒入水(150mL)中，用乙酸乙酯(100mL)萃取2次。合并的有机相用饱和食盐水(100mL)洗涤，用无水Na 2SO 4干燥有机相，然后对干燥产物过滤并旋蒸得到粗品。粗品通过FCC(石油醚/乙酸乙酯＝10/1)纯化，得到N-(3-((((2-氯-5-碘代嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺7.54g。MS m/z(ESI)：455.2[M+H] +。 At 0°C, N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (5.0g, 19.8mmol), 2,4-dichloro-5-iodopyrimidine (5.0 g, 18.2 mmol) and DIPEA (12.0 mL, 72.6 mmol) in i-PrOH (100 mL) was stirred for 3.5 h. TLC (petroleum ether/ethyl acetate=5/1) showed that the reaction was completed. The reaction mixture was poured into water (150 mL) and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was filtered and rotary evaporated to obtain a crude product. The crude product was purified by FCC (petroleum ether/ethyl acetate=10/1) to give N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide 7.54 g. MS m/z (ESI): 455.2 [M+H] + .
步骤2：合成3-(2-氯-4-((((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)氨基)嘧啶-5-基)丙酸酯Step 2: Synthesis of 3-(2-chloro-4-((((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)pyrimidin-5-yl)propanoic acid ester
在氮气保护下，向N-(3-((((2-氯-5-碘嘧啶丁-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(3.0g，6.6mmol)和丙炔酸甲酯(1.6g，19.7mmol)的DMF(30mL)溶液中分别加入Pd(PPh 3) 2Cl 2(70mg)、CuI(126mg,0.661mmol)和DIPEA(3.3mL,20.0mmol)。然后在氮气保护下，将反应 液在70℃油浴中搅拌6h。LCMS显示反应结束后将反应液抽滤，然后将滤液倒入水(200mL)中，并用乙酸乙酯(100mL)萃取2次。合并的有机相用饱和食盐水(100mL)洗涤3次，然后用无水Na 2SO 4干燥有机相，再对干燥产物抽滤并浓缩得到粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到3-(2-氯-4-((((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)氨基)嘧啶-5-基)丙酸酯1.76g。MS m/z(ESI)：411.3[M+H] +。 Under nitrogen protection, to N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide ( 3.0g, 6.6mmol) and methyl propiolate (1.6g, 19.7mmol) in DMF (30mL) solution were added Pd (PPh 3 ) 2 Cl 2 (70mg), CuI (126mg, 0.661mmol) and DIPEA ( 3.3mL, 20.0mmol). Then under the protection of nitrogen, the reaction solution was stirred in a 70°C oil bath for 6h. LCMS showed that the reaction solution was suction filtered after the end of the reaction, and then the filtrate was poured into water (200mL) and washed with ethyl acetate Esters (100mL) were extracted twice. The combined organic phases were washed three times with saturated brine (100mL), then the organic phases were dried with anhydrous Na 2 SO 4 , and the dried product was suction filtered and concentrated to obtain the crude product. The crude product was passed through a flash column Purification by chromatography (petroleum ether/ethyl acetate=10/1) gave 3-(2-chloro-4-((((3-(N-methylmethylsulfonamido)pyrazin-2-yl) Methyl)amino)pyrimidin-5-yl)propionate 1.76 g. MS m/z (ESI): 411.3 [M+H] + .
步骤3：合成2-氯-7-(2-(N-甲基甲基磺酰胺基)苄基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸甲酯Step 3: Synthesis of methyl 2-chloro-7-(2-(N-methylmethylsulfonamido)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate
在0℃下，向3-(2-氯-4-((((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)氨基)嘧啶-5-基)丙酸酯(1.23g，3.04mmol)的NMP(12mL)溶液中加入tBuOK(409mg,3.64mmol)。然后将反应液升温至室温条件下搅拌过夜。TLC(石油醚/乙酸乙酯＝5/1)显示反应结束后将反应液浓缩并用乙酸乙酯(200mL)溶解3次。合并有机相后，有机相用水(100mL)洗涤3次，然后再用饱和食盐水(100mL)洗涤1次。有机相用无水Na 2SO 4干燥，然后对干燥产物过滤并浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到2-氯-7-(2-(N-甲基甲基磺酰胺基)苄基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸甲酯230mg。MS m/z(ESI)：411.3[M+H] +。 At 0°C, to 3-(2-chloro-4-((((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)pyrimidin-5-yl) Propionate (1.23g, 3.04mmol) in NMP (12mL) solution was added tBuOK (409mg, 3.64mmol). Then the reaction solution was warmed up to room temperature and stirred overnight. TLC (petroleum ether/ethyl acetate=5/1 ) shows that after the reaction finishes, the reaction solution is concentrated and dissolved 3 times with ethyl acetate (200mL). After the organic phases are combined, the organic phase is washed 3 times with water (100mL), and then washed 1 time with saturated brine (100mL). The organic phase Dry over anhydrous Na 2 SO 4 , then filter and concentrate the dried product to obtain a crude product. The crude product is purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 2-chloro-7-(2-( Methyl N-methylmethylsulfonamido)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate 230 mg. MS m/z (ESI): 411.3[M+H] + .
步骤4：合成2-((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸甲酯Step 4: Synthesis of 2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl) -7H-Pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester
在室温条件下，向2-氯-7-(2-(N-甲基甲基磺酰胺基)苄基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸甲酯(145mg，0.462mmol)的2-丁醇(14mL)溶液中加入TsOH·H 2O(97mg,0.510mmol)，然后将反应液升温至115℃条件下搅拌8h。TLC(DCM/MeOH＝15:1)显示反应结束后将反应液浓缩并用DCM(10mL)溶解。有机相用水(10mL)洗涤3次，然后再用饱和食盐水(10mL)洗涤1次。有机相用无水Na 2SO 4干燥，然后对干燥产物过滤并浓缩得粗品。粗品通过快速柱层析(DCM/MeOH＝100/1-20/1)纯化，得到2-((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸甲酯43.9mg。 1H NMR(400MHz,DMSO-d 6)δ10.07(s,1H),8.99(s,1H),8.51(d,J＝2.4Hz,1H),8.43(d,J＝2.4Hz,1H),8.26-8.19(m,1H),7.84(d,J＝8.8Hz,2H),7.70(d,J＝8.8Hz,2H),7.34(s,1H),6.05(s,2H),3.70(s,3H),3.37(s,3H),3.22(s,3H),2.75(d,J＝4.4Hz,3H).MS m/z(ESI)：525.5[M+H] +。 At room temperature, methyl 2-chloro-7-(2-(N-methylmethylsulfonamido)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate ( TsOH·H 2 O (97 mg, 0.510 mmol) was added to a solution of 145 mg, 0.462 mmol) in 2-butanol (14 mL), and then the reaction solution was heated to 115° C. and stirred for 8 h. TLC (DCM/MeOH=15:1) showed that after the reaction was completed, the reaction solution was concentrated and dissolved with DCM (10 mL). The organic phase was washed three times with water (10 mL), and then once with saturated brine (10 mL). The organic phase was dried over anhydrous Na2SO4 , then the dry product was filtered and concentrated to give crude product. The crude product was purified by flash column chromatography (DCM/MeOH=100/1-20/1) to give 2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N- Methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester 43.9 mg. 1 H NMR (400MHz,DMSO-d 6 )δ10.07(s,1H),8.99(s,1H),8.51(d,J=2.4Hz,1H),8.43(d,J=2.4Hz,1H) ,8.26-8.19(m,1H),7.84(d,J=8.8Hz,2H),7.70(d,J=8.8Hz,2H),7.34(s,1H),6.05(s,2H),3.70( s, 3H), 3.37 (s, 3H), 3.22 (s, 3H), 2.75 (d, J = 4.4 Hz, 3H). MS m/z (ESI): 525.5 [M+H] + .
实施例2Example 2
2-((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸的制备2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole Preparation of [2,3-d]pyrimidine-6-carboxylic acid
Figure PCTCN2022117868-appb-000023
Figure PCTCN2022117868-appb-000023
在室温条件下，向2-((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸甲酯(130mg，0.248mmol)的甲醇/水(5mL/2.5mL)溶液中加入LiOH·H 2O(104mg,2.48mmol)。然后将反应液升温至50℃条件下搅拌过夜。TLC(DCM/MeOH＝10:1)显示反应结束后将反应液浓缩并用H 2O(20mL)溶解。1M HCl调节溶液pH至2，过滤析出的黄色固体得粗品，通过快速柱层析(DCM/MeOH＝100/1-10/1)纯化粗品，得到2-((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸125mg。 1H NMR(400MHz,DMSO-d 6)δ10.03(s,1H),8.96(s,1H),8.50(d,J＝2.4Hz,1H),8.43(d,J＝2.8Hz,1H),8.23(dd,J＝8.8,4.0Hz,1H),7.85(d,J＝8.8Hz,2H),7.70(d,J＝8.8Hz,2H),7.27(s,1H),6.02(s,2H),3.35(s,3H),3.21(s,3H),2.75(d,J＝4.4Hz,3H)。MS m/z(ESI)：511.5[M+H] +。 At room temperature, to 2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl LiOH·H 2 O (104mg, 2.48 mmol). Then the reaction solution was heated to 50° C. and stirred overnight. TLC (DCM/MeOH=10:1) showed that after the reaction was completed, the reaction solution was concentrated and dissolved with H 2 O (20 mL). 1M HCl adjusted the pH of the solution to 2, filtered the precipitated yellow solid to obtain the crude product, and purified the crude product by flash column chromatography (DCM/MeOH=100/1-10/1) to obtain 2-((4-(methylcarbamoyl )phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-6- Carboxylic acid 125mg. 1 H NMR (400MHz,DMSO-d 6 )δ10.03(s,1H),8.96(s,1H),8.50(d,J=2.4Hz,1H),8.43(d,J=2.8Hz,1H) ,8.23(dd,J=8.8,4.0Hz,1H),7.85(d,J=8.8Hz,2H),7.70(d,J=8.8Hz,2H),7.27(s,1H),6.02(s, 2H), 3.35(s, 3H), 3.21(s, 3H), 2.75(d, J=4.4Hz, 3H). MS m/z (ESI): 511.5 [M+H] + .
实施例3Example 3
N，N-二甲基-2-(((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲 基)-7H-吡咯并[2,3-d]嘧啶-6-羧酰胺的制备N,N-Dimethyl-2-(((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazine-2- Preparation of base)methyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide
Figure PCTCN2022117868-appb-000024
Figure PCTCN2022117868-appb-000024
将2-((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(80mg,0.157mmol)和二甲胺的盐酸盐(20mg,0.245mmol)溶于DMF(1.5mL)溶液中，加入HATU(90mg,0.237mmol)和DIPEA(0.1mL,0.60mmol)，然后在室温下反应2h，LCMS监测反应完全后，用水(10mL)淬灭反应，然后EA(20mL)萃取3次，用饱和食盐水洗有机相，用无水Na 2SO 4干燥有机相，然后对干燥产物进行抽滤并浓缩得到粗品，柱层析(MeOH/DCM＝0-10％)纯化粗品，得到N，N-二甲基-2-(((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酰胺82.0mg。 1H NMR(400MHz,DMSO-d 6)δ9.88(s,1H),8.86(s,1H),8.52(d,J＝2.4Hz,1H),8.48(d,J＝2.4Hz,1H),8.41-8.19(m,1H),7.84(d,J＝8.8Hz,2H),7.72(d,J＝8.8Hz,2H),6.82(s,1H),5.81(s,2H),3.31(s,3H),3.17(s,3H),3.11-3.04(m,3H),2.87-2.79(m,3H),2.76(d,J＝4.4Hz,3H).MS m/z(ESI)：538.5[M+H] +。 2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H- Pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (80mg, 0.157mmol) and dimethylamine hydrochloride (20mg, 0.245mmol) were dissolved in DMF (1.5mL) solution, and HATU (90mg, 0.237mmol) and DIPEA (0.1mL, 0.60mmol), then reacted at room temperature for 2h, after LCMS monitored the reaction was complete, quenched the reaction with water (10mL), then extracted 3 times with EA (20mL), washed the organic phase with saturated brine, Dry the organic phase with anhydrous Na 2 SO 4 , then filter the dry product with suction and concentrate to obtain a crude product, which is purified by column chromatography (MeOH/DCM=0-10%) to obtain N,N-dimethyl-2- (((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo [2,3-d]pyrimidine-6-carboxamide 82.0 mg.1 H NMR (400MHz, DMSO-d 6 )δ9.88(s , 1H),8.86(s,1H),8.52(d,J=2.4 Hz,1H),8.48(d,J=2.4Hz,1H),8.41-8.19(m,1H),7.84(d,J=8.8Hz,2H),7.72(d,J=8.8Hz,2H), 6.82(s,1H),5.81(s,2H),3.31(s,3H),3.17(s,3H),3.11-3.04(m,3H),2.87-2.79(m,3H),2.76(d, J = 4.4 Hz, 3H). MS m/z (ESI): 538.5 [M+H] + .
实施例4Example 4
N-甲基-4-((6-甲基-7-(((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯甲酰胺的制备N-methyl-4-((6-methyl-7-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2, Preparation of 3-d]pyrimidin-2-yl)amino)benzamide
Figure PCTCN2022117868-appb-000025
Figure PCTCN2022117868-appb-000025
步骤1：合成3N-(3-((((2-氯-5-(丙炔基-1))嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 1: Synthesis of 3N-(3-((((2-chloro-5-(propynyl-1))pyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methyl Methanesulfonamide
在氮气保护下，向N-(3-((((2-氯-5-碘嘧啶丁-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(586.3mg，1.29mmol)和三丁基(丙-1-炔-1-基)锡烷(850.0mg，2.58mmol)的甲苯(20mL)溶液中分别加入Pd(PPh 3) 4(150.0mg，0.13mmol)和CuI(24.75mg，0.13mmol)，然后在氮气保护下，将反应液在100℃油浴中搅拌2h。LCMS显示反应结束后将反应液抽滤，然后倒入水(10mL)中，并用乙酸乙酯(10mL)萃取2次。合并有机相然后用饱和食盐水(20mL)洗涤，用无水Na 2SO 4干燥有机相，然后对干燥产物进行抽滤并浓缩得到粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到N-(3-((((2-氯-5-(丙炔基-1))嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺230mg。MS m/z(ESI)：367.1[M+H] +。 Under nitrogen protection, to N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide ( 586.3mg, 1.29mmol) and tributyl(prop-1-yn-1-yl) stannane (850.0mg, 2.58mmol) in toluene (20mL) were added Pd(PPh 3 ) 4 (150.0mg, 0.13 mmol) and CuI (24.75mg, 0.13mmol), then under nitrogen protection, the reaction solution was stirred in an oil bath at 100°C for 2h. LCMS showed that the reaction solution was suction filtered after the end of the reaction, and then poured into water (10mL), and extracted twice with ethyl acetate (10mL). The organic phases were combined and then washed with saturated brine (20mL), and the organic phase was dried with anhydrous Na 2 SO 4 , and then the dried product was suction filtered and concentrated to obtain a crude product. The crude product was passed through rapid Purified by column chromatography (petroleum ether/ethyl acetate=10/1) to obtain N-(3-((((2-chloro-5-(propynyl-1))pyrimidin-4-yl)amino)methyl yl)pyrazin-2-yl)-N-methylmethanesulfonamide 230 mg. MS m/z (ESI): 367.1 [M+H] + .
步骤2：合成N-(3-((2-氯-6-甲基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 2: Synthesis of N-(3-((2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide
在0℃条件下，向N-(3-((((2-氯-5-(丙炔基-1))嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(230mg，0.63mmol)的DMF(10mL)溶液中加入DBU(0.85mL，6.3mmol)。然后将反应液升温至60℃条件下搅拌5h。TLC(石油醚/乙酸乙酯＝5/1)显示反应结束后将反应液浓缩并用乙酸乙酯(5mL)溶解。有机相用水(5mL)洗涤3次，然后再用饱和食盐水(10mL)洗涤1次。有机相用无水Na 2SO 4干燥，然后对干燥产物进行过滤并浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝4/1)纯化，得到N-(3-((2-氯-6-甲基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N- 甲基甲磺酰胺80mg。MS m/z(ESI)：367.1[M+H] +。 At 0°C, to N-(3-((((2-chloro-5-(propynyl-1))pyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N - To a solution of methylmethanesulfonamide (230 mg, 0.63 mmol) in DMF (10 mL) was added DBU (0.85 mL, 6.3 mmol). Then the reaction solution was heated to 60° C. and stirred for 5 h. TLC (petroleum ether/ethyl acetate=5/1) showed that after the reaction was completed, the reaction solution was concentrated and dissolved in ethyl acetate (5 mL). The organic phase was washed three times with water (5 mL), and then once with saturated brine (10 mL). The organic phase was dried over anhydrous Na2SO4 , then the dried product was filtered and concentrated to give crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=4/1) to obtain N-(3-((2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 80 mg. MS m/z (ESI): 367.1 [M+H] + .
步骤3：合成N-甲基-4-((6-甲基-7-(((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯甲酰胺Step 3: Synthesis of N-methyl-4-((6-methyl-7-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole and[2,3-d]pyrimidin-2-yl)amino)benzamide
在室温条件下，向N-(3-((2-氯-6-甲基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(50mg，0.14mmol)的2-丁醇(5mL)溶液中加入对氨基苯甲酰胺(22.54mg，0.15mmol)和TsOH·H 2O(26.6mg，0.14mmol)。然后将反应液升温至120℃条件下搅拌8h。TLC(DCM/MeOH＝15:1)显示反应结束后将反应液浓缩并用DCM(5mL)溶解。有机相用水(5mL)洗涤3次，然后再用饱和食盐水(10mL)洗涤1次。有机相用无水Na 2SO 4干燥，然后对干燥产物进行过滤并浓缩得粗品。粗品通过快速柱层析(DCM/MeOH＝100/1-20/1)纯化，得到N-甲基-4-((6-甲基-7-(((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯甲酰胺25mg。 1H NMR(400MHz,DMSO-d 6)δ9.66(s,1H),8.64(s,1H),8.56(d,J＝2.4Hz,1H),8.52(d,J＝2.5Hz,1H),8.18(q,J＝4.1Hz,1H),6.31(d,J＝1.1Hz,1H),5.70(s,2H),3.29(s,3H),3.22(s,3H),2.75(d,J＝4.5Hz,3H),2.24(s,3H).MS m/z(ESI)：481.2[M+H] +。 At room temperature, to N-(3-((2-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)- To a solution of N-methylmethanesulfonamide (50 mg, 0.14 mmol) in 2-butanol (5 mL) was added p-aminobenzamide (22.54 mg, 0.15 mmol) and TsOH·H 2 O (26.6 mg, 0.14 mmol). Then the reaction solution was heated to 120° C. and stirred for 8 h. TLC (DCM/MeOH=15:1) showed that after the reaction was completed, the reaction solution was concentrated and dissolved with DCM (5 mL). The organic phase was washed three times with water (5 mL), and then once with saturated brine (10 mL). The organic phase was dried over anhydrous Na2SO4 , then the dried product was filtered and concentrated to give crude product. The crude product was purified by flash column chromatography (DCM/MeOH=100/1-20/1) to give N-methyl-4-((6-methyl-7-(((3-(N-methylmethyl Sulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)benzamide 25 mg. 1 H NMR (400MHz, DMSO-d 6 ) δ9.66(s,1H),8.64(s,1H),8.56(d,J=2.4Hz,1H),8.52(d,J=2.5Hz,1H),8.18(q,J=4.1Hz,1H ),6.31(d,J=1.1Hz,1H),5.70(s,2H),3.29(s,3H),3.22(s,3H),2.75(d,J=4.5Hz,3H),2.24(s ,3H). MS m/z (ESI): 481.2 [M+H] + .
实施例5Example 5
2-((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酰胺的制备2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole Preparation of [2,3-d]pyrimidine-6-carboxamide
Figure PCTCN2022117868-appb-000026
Figure PCTCN2022117868-appb-000026
将2-((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酸(30mg,0.06mmol)、HATU(33.5mg,0.09mmol)和DIPEA(20μL,0.12mmol)溶于DMF(1mL)中，室温反应1h，加入氨水(20μL,0.12mmol)，室温反应2h，监测反应完全后加水，再加入DCM萃取，干燥浓缩萃取物，并通过柱层析纯化浓缩物，得到2-((4-(甲基氨基甲酰基)苯基)氨基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-羧酰胺10mg。 1H NMR(400MHz,DMSO)δ9.90(s,1H),8.91(s,1H),8.44(d,J＝2.3Hz,1H),8.36(d,J＝2.5Hz,1H),8.18(d,J＝4.8Hz,1H),7.92(s,1H),7.81(d,J＝8.8Hz,2H),7.66(d,J＝8.8Hz,2H),7.23(s,1H),7.19(s,1H),6.00(s,2H),3.33(s,4H),3.16(s,3H),2.71(d,J＝4.5Hz,3H).MS m/z(ESI):510.0[M+H] +。 2-((4-(methylcarbamoyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H- Pyrrolo[2,3-d]pyrimidine-6-carboxylic acid (30mg, 0.06mmol), HATU (33.5mg, 0.09mmol) and DIPEA (20μL, 0.12mmol) were dissolved in DMF (1mL), reacted at room temperature for 1h, Add ammonia (20 μL, 0.12 mmol), react at room temperature for 2 h, add water after monitoring the completion of the reaction, then add DCM for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 2-((4-(methylaminomethyl Acyl)phenyl)amino)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-6 - Carboxamide 10 mg. 1 H NMR (400MHz, DMSO) δ9.90(s, 1H), 8.91(s, 1H), 8.44(d, J=2.3Hz, 1H), 8.36(d, J=2.5Hz, 1H), 8.18( d,J=4.8Hz,1H),7.92(s,1H),7.81(d,J=8.8Hz,2H),7.66(d,J=8.8Hz,2H),7.23(s,1H),7.19( s,1H),6.00(s,2H),3.33(s,4H),3.16(s,3H),2.71(d,J＝4.5Hz,3H).MS m/z(ESI):510.0[M+ H] + .
实施例6Example 6
4-((6-氰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺的制备4-((6-cyano-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 2-yl)amino)-N-methylbenzamide
Figure PCTCN2022117868-appb-000027
Figure PCTCN2022117868-appb-000027
步骤1:合成N-(3-((((2-氯-5-碘嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 1: Synthesis of N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide
将2,4-二氯-5-碘嘧啶(1.2g,4.37mmol)溶于DMF(12mL)中，在0℃下，加入DIPEA(1.3mL,7.94mmol)和N-(3-(氨基甲基)吡嗪-2-基)-N-甲基甲磺酰胺(0.85g,3.97mmol)，0℃反应2h，监测反 应完全后加水，再加入乙酸乙酯萃取，干燥浓缩萃取物，并通过柱层析纯化浓缩物，得到N-(3-((((2-氯-5-碘嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺1.0g，MS m/z(ESI):454.8[M+H] +。 2,4-Dichloro-5-iodopyrimidine (1.2g, 4.37mmol) was dissolved in DMF (12mL), at 0°C, DIPEA (1.3mL, 7.94mmol) and N-(3-(aminomethyl Base) pyrazin-2-yl)-N-methylmethanesulfonamide (0.85g, 3.97mmol), reacted at 0°C for 2h, added water after monitoring the completion of the reaction, added ethyl acetate for extraction, dried and concentrated the extract, and passed The concentrate was purified by column chromatography to give N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 1.0 g, MS m/z (ESI): 454.8 [M+H] + .
步骤2:合成N-(3-(((2-氯-5-(3,3-二乙氧基丙-1-炔-1-基)嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 2: Synthesis of N-(3-(((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazine -2-yl)-N-methylmethanesulfonamide
将N-(3-((((2-氯-5-碘嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(960mg,2.11mmol)、3,3-二乙氧基丙-1-炔(0.48mL,2.75mmol)、CuI(81mg,0.42mmol)、Pd(PPh) 2Cl 2(150mg,0.21mmol)和DIPEA(10mL)溶于DMF(10mL)中，65℃反应14h，监测反应完全后加水，再加入乙酸乙酯萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到N-(3-(((2-氯-5-(3,3-二乙氧基丙-1-炔-1-基)嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺950mg，MS m/z(ESI):455.0[M+H] +。 N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide (960mg, 2.11mmol), 3,3-diethoxyprop-1-yne (0.48mL, 2.75mmol), CuI (81mg, 0.42mmol), Pd(PPh) 2Cl2 ( 150mg , 0.21mmol) and DIPEA (10mL) were dissolved in DMF (10mL), react at 65°C for 14h, monitor the completion of the reaction, add water, then add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain N-(3-((((2-chloro-5- (3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 950mg, MS m/ z(ESI): 455.0[M+H] + .
步骤3:合成N-(3-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 3: Synthesis of N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide
将N-(3-(((2-氯-5-(3,3-二乙氧基丙-1-炔-1-基)嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(950mg,2.09mmol)溶于THF(9.5mL)中，加入TBAF(12.6mL,12.55mmol)，室温反应过夜，监测反应完全后加水，再加入乙酸乙酯萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到N-(3-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺400mg。MS m/z(ESI):454.9[M+H] +。 N-(3-(((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazine-2- Base)-N-methylmethanesulfonamide (950mg, 2.09mmol) was dissolved in THF (9.5mL), added TBAF (12.6mL, 12.55mmol), reacted overnight at room temperature, added water after monitoring the completion of the reaction, and then added ethyl acetate Extract, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 400 mg. MS m/z (ESI): 454.9 [M+H] + .
步骤4:合成N-(3-((2-氯-6-甲酰基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 4: Synthesis of N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide
将N-(3-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(200mg,0.44mmol)溶于二氧六环(2mL)中，冰浴下，加入浓盐酸(0.5mL)，室温反应30min，监测反应完全后加水，再加入饱和碳酸钠溶液将pH调成中性，加入乙酸乙酯萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到N-(3-((2-氯-6-甲酰基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺167mg。MS m/z(ESI):380.9[M+H] +。 N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-Methylmethanesulfonamide (200mg, 0.44mmol) was dissolved in dioxane (2mL), and concentrated hydrochloric acid (0.5mL) was added under ice-cooling, and reacted at room temperature for 30min. After monitoring the completion of the reaction, add water, then add saturated Adjust the pH to neutral with sodium carbonate solution, add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain N-(3-((2-chloro-6-formyl-7H-pyrrolo[ 2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 167 mg. MS m/z (ESI): 380.9 [M+H] + .
步骤5:合成N-(3-((2-氯-6-((羟基亚氨基)甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 5: Synthesis of N-(3-((2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine- 2-yl)-N-methylmethanesulfonamide
将N-(3-((2-氯-6-甲酰基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(167mg,0.44mmol)和盐酸羟胺(80mg,1.15mmol)溶于无水乙醇(4mL)中，50℃反应3h，监测反应完全后浓缩反应液，加水，再加入饱和碳酸氢钠溶液将pH调成中性，过滤，水洗滤饼，得到N-(3-((2-氯-6-((羟基亚氨基)甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺154mg。MS m/z(ESI):395.9[M+H] +。 N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylformazine Dissolve sulfonamide (167mg, 0.44mmol) and hydroxylamine hydrochloride (80mg, 1.15mmol) in absolute ethanol (4mL), react at 50°C for 3h, monitor the completion of the reaction, concentrate the reaction solution, add water, and then add saturated sodium bicarbonate solution to dissolve Adjust the pH to neutral, filter, and wash the filter cake with water to obtain N-(3-((2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 154mg. MS m/z (ESI): 395.9 [M+H] + .
步骤6:合成N-(3-((2-氯-6-氰基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 6: Synthesis of N-(3-((2-chloro-6-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide
将N-(3-((2-氯-6-((羟基亚氨基)甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(154mg,0.39mmol)溶于DCE(3mL)中，冰浴下，加入CDI(316mg,1.95mmol)，室温反应1.5h，监测反应完全后浓缩反应液，然后用柱层析纯化，得到N-(3-((2-氯-6-氰基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺132mg。MS m/z(ESI):377.9[M+H] +。 N-(3-((2-chloro-6-((hydroxyimino)methyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-Methylmethanesulfonamide (154mg, 0.39mmol) was dissolved in DCE (3mL), under ice-cooling, CDI (316mg, 1.95mmol) was added, and reacted at room temperature for 1.5h. After monitoring the completion of the reaction, the reaction solution was concentrated, and then Purification by column chromatography gave N-(3-((2-chloro-6-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-Methylmethanesulfonamide 132mg. MS m/z (ESI): 377.9 [M+H] + .
步骤7:合成4-((6-氰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺Step 7: Synthesis of 4-((6-cyano-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)-N-methylbenzamide
将N-(3-((2-氯-6-氰基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(100mg,0.27mmol)、4-氨基-N-甲基苯甲酰胺(47.8mg,0.32mmol)和TsOH(50.5mg,0.27mmol)溶于仲丁醇(5mL)中，115℃回流反应5h，监测反应完全后冷却至室温，加水，再加入乙酸乙酯萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到4-((6-氰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺33mg。 1H NMR(400MHz,DMSO)δ10.10(s,1H),8.98(s,1H),8.61(d,J＝2.5Hz,1H),8.56(d,J＝2.5Hz,1H),8.23(d,J＝4.5Hz,1H),7.77(d,J＝8.9Hz,2H),7.71(d,J＝8.9Hz,2H),7.54(s,1H),5.80(s,2H),3.30–3.25(m,3H),3.20(s,3H),2.75(d,J＝4.5Hz,3H).MS m/z(ESI):492.1[M+H] +。 N-(3-((2-chloro-6-cyano-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylformazine Sulfonamide (100mg, 0.27mmol), 4-amino-N-methylbenzamide (47.8mg, 0.32mmol) and TsOH (50.5mg, 0.27mmol) were dissolved in sec-butanol (5mL) and refluxed at 115°C 5h, after monitoring that the reaction is complete, cool to room temperature, add water, then add ethyl acetate to extract, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 4-((6-cyano-7-((3-(N- Methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide 33mg. 1 H NMR (400MHz, DMSO) δ10.10(s, 1H), 8.98(s, 1H), 8.61(d, J=2.5Hz, 1H), 8.56(d, J=2.5Hz, 1H), 8.23( d,J=4.5Hz,1H),7.77(d,J=8.9Hz,2H),7.71(d,J=8.9Hz,2H),7.54(s,1H),5.80(s,2H),3.30– 3.25 (m, 3H), 3.20 (s, 3H), 2.75 (d, J=4.5Hz, 3H). MS m/z (ESI): 492.1 [M+H] + .
实施例7Example 7
4-((6-甲酰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺的制备4-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 2-yl)amino)-N-methylbenzamide
Figure PCTCN2022117868-appb-000028
Figure PCTCN2022117868-appb-000028
步骤1:合成4-((6-(二乙氧基甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺Step 1: Synthesis of 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide
将N-(3-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(70mg,0.15mmol)、4-氨基-N-甲基苯甲酰胺(27.8mg,0.19mmol)、BINAP(19mg,0.03mmol)、Pd 2(dba) 3(14mg,0.02mmol)和叔丁醇钠(30mg,0.31mmol)溶于二氧六环(7mL)中，氮气保护，100℃反应4.5h，监测反应完全后加水，再加入乙酸乙酯萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到4-((6-(二乙氧基甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺47mg，MS m/z(ESI):569.1[M+H] +。 N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-methylmethanesulfonamide (70mg, 0.15mmol), 4-amino-N-methylbenzamide (27.8mg, 0.19mmol), BINAP (19mg, 0.03mmol), Pd 2 (dba) 3 (14mg , 0.02mmol) and sodium tert-butoxide (30mg, 0.31mmol) were dissolved in dioxane (7mL), under nitrogen protection, reacted at 100°C for 4.5h, monitored the completion of the reaction, added water, added ethyl acetate to extract, dried and concentrated The extract was purified by column chromatography to obtain 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl) Methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide 47 mg, MS m/z (ESI): 569.1[M+H] + .
步骤2:合成4-((6-甲酰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺Step 2: Synthesis of 4-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)-N-methylbenzamide
将4-((6-(二乙氧基甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺(47mg,0.08mmol)溶于二氧六环(0.7mL)中，冰浴下，加入浓盐酸(0.09mL)，室温反应10min，监测反应完全后加水，再加入饱和碳酸钠溶液将pH调成中性，加入乙酸乙酯萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到4-((6-甲酰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺10mg。 1H NMR(400MHz,DMSO)δ10.20(s,1H),9.63(s,1H),9.08(s,1H),8.50(d,J＝2.5Hz,1H),8.40(d,J＝2.5Hz,1H),8.23(d,J＝5.0Hz,1H),7.84(d,J＝8.9Hz,2H),7.71(d,J＝8.8Hz,2H),7.56(s,1H),5.98(s,2H),3.40(s,4H),3.20(s,3H),2.75(d,J＝4.5Hz,3H).MS m/z(ESI):495.1[M+H] +。 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide (47mg, 0.08mmol) was dissolved in dioxane (0.7mL), under ice-cooling, concentrated hydrochloric acid (0.09mL) was added , react at room temperature for 10min, add water after monitoring the completion of the reaction, then add saturated sodium carbonate solution to adjust the pH to neutral, add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 4-((6-formazan Acyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)- N-Methylbenzamide 10 mg. 1 H NMR(400MHz,DMSO)δ10.20(s,1H),9.63(s,1H),9.08(s,1H),8.50(d,J=2.5Hz,1H),8.40(d,J=2.5 Hz,1H),8.23(d,J=5.0Hz,1H),7.84(d,J=8.9Hz,2H),7.71(d,J=8.8Hz,2H),7.56(s,1H),5.98( s, 2H), 3.40 (s, 4H), 3.20 (s, 3H), 2.75 (d, J = 4.5 Hz, 3H). MS m/z (ESI): 495.1 [M+H] + .
实施例8Example 8
4-((6-甲酰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺的制备4-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 2-yl)amino)-3-methoxy-N-methylbenzamide
Figure PCTCN2022117868-appb-000029
Figure PCTCN2022117868-appb-000029
步骤1：合成3-甲氧基-N-甲基-4-硝基苯甲酰胺Step 1: Synthesis of 3-methoxy-N-methyl-4-nitrobenzamide
将3-甲氧基-4-硝基苯甲酸(600mg,3.04mmol)、HATU(1.73g,4.57mmol)和DIPEA(1mL,6.08mmol)溶于DMF(6mL)中，室温反应1h，加入甲胺盐酸盐(400mg,6.08mmol)，室温反应3h，监测反应完全后加水，再加入乙酸乙酯萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到3-甲氧基-N-甲基-4-硝基苯甲酰胺251mg。MS m/z(ESI):211.0[M+H] +。 Dissolve 3-methoxy-4-nitrobenzoic acid (600mg, 3.04mmol), HATU (1.73g, 4.57mmol) and DIPEA (1mL, 6.08mmol) in DMF (6mL), react at room temperature for 1h, add formaldehyde Amine hydrochloride (400mg, 6.08mmol), react at room temperature for 3h, add water after monitoring the completion of the reaction, then add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 3-methoxy-N-formazan Base-4-nitrobenzamide 251mg. MS m/z (ESI): 211.0 [M+H] + .
步骤2：合成4-氨基-3-甲氧基-N-甲基苯甲酰胺Step 2: Synthesis of 4-amino-3-methoxy-N-methylbenzamide
将3-甲氧基-N-甲基-4-硝基苯甲酰胺(251mg,1.20mmol)、铁粉(167mg,2.99mmol)和氯化铵(160mg,2.99mmol)溶于甲醇(12mL)和水(3mL)中，70℃反应12h，监测反应完全后往反应体系中加入少量水，抽滤，滤液浓缩，柱层析纯化浓缩物，得到4-氨基-3-甲氧基-N-甲基苯甲酰胺193mg。MS m/z(ESI):181.1[M+H] +。 3-Methoxy-N-methyl-4-nitrobenzamide (251 mg, 1.20 mmol), iron powder (167 mg, 2.99 mmol) and ammonium chloride (160 mg, 2.99 mmol) were dissolved in methanol (12 mL) and water (3mL), react at 70°C for 12h, monitor the completion of the reaction, add a small amount of water to the reaction system, filter with suction, concentrate the filtrate, and purify the concentrate by column chromatography to obtain 4-amino-3-methoxy-N- Toluamide 193mg. MS m/z (ESI): 181.1 [M+H] + .
步骤3：合成4-((6-(二乙氧基甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并 [2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺Step 3: Synthesis of 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide
将N-(3-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(57mg,0.13mmol)，4-氨基-3-甲氧基-N-甲基苯甲酰胺(27.2mg,0.15mmol)、BINAP(16mg,0.03mmol)、Pd 2(dba) 3(12mg,0.01mmol)和叔丁醇钠(24mg,0.25mmol)溶于二氧六环(3mL)中，氮气保护，100℃反应4.5h，监测反应完全后加水，再加入乙酸乙酯萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到4-((6-(二乙氧基甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺40mg，MS m/z(ESI):599.1[M+H] +。 N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-methylmethanesulfonamide (57mg, 0.13mmol), 4-amino-3-methoxy-N-methylbenzamide (27.2mg, 0.15mmol), BINAP (16mg, 0.03mmol), Pd 2 (dba) 3 (12mg, 0.01mmol) and sodium tert-butoxide (24mg, 0.25mmol) were dissolved in dioxane (3mL), protected by nitrogen, and reacted at 100°C for 4.5h. After monitoring the completion of the reaction, add water, then add acetic acid Extract with ethyl ester, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyridine Oxyzin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide 40mg, MS m/z ( ESI): 599.1[M+H] + .
步骤4：合成4-((6-甲酰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺Step 4: Synthesis of 4-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide
将4-((6-(二乙氧基甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺(40mg,0.07mmol)溶于二氧六环(0.6mL)中，冰浴下，加入浓盐酸(0.07mL)，室温反应30min，监测反应完全后加水，再加入饱和碳酸钠溶液将pH调成中性，加入乙酸乙酯萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到4-((6-甲酰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺12mg。 1H NMR(400MHz,DMSO)δ9.64(s,1H),9.06(s,1H),8.50(d,J＝2.5Hz,1H),8.44–8.37(m,2H),8.31(dd,J＝11.9,6.5Hz,2H),7.56(s,1H),7.48(d,J＝1.8Hz,1H),7.38(m,1H),5.97(s,2H),3.91(s,3H),3.38(s,3H),3.19(s,3H),2.77(d,J＝4.5Hz,3H).MS m/z(ESI):525.1[M+H] +。 4-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide (40mg, 0.07mmol) was dissolved in dioxane (0.6mL), under ice cooling, added Concentrated hydrochloric acid (0.07mL), react at room temperature for 30min, add water after monitoring the completion of the reaction, then add saturated sodium carbonate solution to adjust the pH to neutral, add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 4 -((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2 -yl)amino)-3-methoxy-N-methylbenzamide 12 mg. 1 H NMR (400MHz, DMSO) δ9.64(s, 1H), 9.06(s, 1H), 8.50(d, J=2.5Hz, 1H), 8.44–8.37(m, 2H), 8.31(dd, J =11.9,6.5Hz,2H),7.56(s,1H),7.48(d,J=1.8Hz,1H),7.38(m,1H),5.97(s,2H),3.91(s,3H),3.38 (s, 3H), 3.19 (s, 3H), 2.77 (d, J = 4.5 Hz, 3H). MS m/z (ESI): 525.1 [M+H] + .
实施例9Example 9
合成4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺的制备Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3 -d] Preparation of pyrimidin-2-yl)amino)-N-methylbenzamide
Figure PCTCN2022117868-appb-000030
Figure PCTCN2022117868-appb-000030
步骤1：合成N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 1: Synthesis of N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-Methylmethanesulfonamide
将N-(3-((2-氯-6-甲酰基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(45mg,0.12mmol)溶于DCM(1mL)中，冰浴下，加入BAST(24μL)，室温反应5h，监测反应完全后加水，再加入二氯甲烷萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺34mg，MS m/z(ESI):403.0[M+H] +。 N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylformazine Dissolve sulfonamide (45mg, 0.12mmol) in DCM (1mL), add BAST (24μL) under ice bath, react at room temperature for 5h, add water after monitoring the completion of the reaction, then add dichloromethane for extraction, dry and concentrate the extract, column layer Analysis and purification of the concentrate gave N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide 34 mg, MS m/z (ESI): 403.0 [M+H] + .
步骤2：合成4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺Step 2: Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide
将N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(28mg,0.07mmol)，4-氨基-N-甲基苯甲酰胺(13mg,0.08mmol)合对甲苯磺酸(13mg,0.07mmol)溶于仲丁醇(3mL)中，115℃反应14h，监测反应完全后体系冷却至室温，加水，再加入乙酸乙酯萃取，干燥浓缩萃取物，柱层析纯化浓缩物，得到4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺17mg。 1H NMR(400MHz,DMSO)δ9.88(s,1H),8.89(s,1H),8.54(d,J＝2.4Hz,1H),8.47(d,J＝2.5Hz,1H),8.19(d,J＝4.5Hz,1H),7.75(d,J＝8.9Hz,2H),7.66(d,J＝8.9Hz,2H),7.19(s,1H),6.94(s,1H),5.81(s,2H),3.29(s,3H),3.20(s,3H),2.74(d,J＝4.5Hz,3H).MS m/z(ESI):517.0[M+H] +。 N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N -Methylmethanesulfonamide (28mg, 0.07mmol), 4-amino-N-methylbenzamide (13mg, 0.08mmol) and p-toluenesulfonic acid (13mg, 0.07mmol) were dissolved in sec-butanol (3mL) , react at 115°C for 14h, monitor the completion of the reaction and cool the system to room temperature, add water, then add ethyl acetate for extraction, dry and concentrate the extract, and purify the concentrate by column chromatography to obtain 4-((6-(difluoromethyl)- 7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N- Toluamide 17mg. 1 H NMR (400MHz, DMSO) δ9.88(s, 1H), 8.89(s, 1H), 8.54(d, J=2.4Hz, 1H), 8.47(d, J=2.5Hz, 1H), 8.19( d,J=4.5Hz,1H),7.75(d,J=8.9Hz,2H),7.66(d,J=8.9Hz,2H),7.19(s,1H),6.94(s,1H),5.81( s, 2H), 3.29 (s, 3H), 3.20 (s, 3H), 2.74 (d, J = 4.5 Hz, 3H). MS m/z (ESI): 517.0 [M+H] + .
实施例10Example 10
4-((6-氯-7-((2-(N-甲基甲基磺酰胺基)吡啶-3-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺的制备4-((6-chloro-7-((2-(N-methylmethylsulfonamido)pyridin-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2- The preparation of base) amino)-N-methylbenzamide
Figure PCTCN2022117868-appb-000031
Figure PCTCN2022117868-appb-000031
步骤1：合成2,6-二氯-7H-吡咯并[2,3-d]嘧啶Step 1: Synthesis of 2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine
在0℃条件下，将2-氯-5,7-二氢-6H-吡咯并[2,3-d]嘧啶-6-酮(1.0g，5.8mmol)溶于POCl 3(10mL)溶液中，缓慢升温至110℃回流搅拌反应1h，TLC检测反应完成后将反应液浓缩旋干，用DCM(20mL)稀释溶解，加饱和NaHCO 3溶液(15mL)萃取，分离合并有机相，加饱和NaCl(20mL)水溶液水洗有机相，旋转浓缩有机相，柱层析(PE/EA＝从0至50％)纯化，得到2,6-二氯-7H-吡咯并[2,3-d]嘧啶600mg。MS m/z(ESI)：188.0[M+H] + Dissolve 2-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (1.0g, 5.8mmol) in POCl 3 (10mL) solution at 0°C , slowly warming up to 110°C under reflux and stirring for 1 h, after TLC detection, the reaction solution was concentrated and spin-dried, diluted and dissolved with DCM (20 mL), extracted with saturated NaHCO 3 solution (15 mL), separated and combined organic phases, added with saturated NaCl ( 20 mL) aqueous solution, washed the organic phase with water, concentrated the organic phase by rotation, and purified by column chromatography (PE/EA=from 0 to 50%) to obtain 600 mg of 2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine. MS m/z(ESI): 188.0[M+H] +
步骤2：合成N-(3-((2,6-二氯-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡啶-2-基)-N-甲基甲磺酰胺Step 2: Synthesis of N-(3-((2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyridin-2-yl)-N-methylformazan Sulfonamide
室温条件下，将2,6-二氯-7H-吡咯并[2,3-d]嘧啶(600mg，3.2mmol)和N-(3-(氯甲基)吡啶-2-基)-N-甲基甲磺酰胺(900mg，3.8mmol)溶于DMF(5mL)溶液中，加入K 2CO 3(880mg，6.4mmol)。然后将混合物升温至45℃条件下搅拌8小时。LCMS显示反应完成后将反应混合物用水(100mL)淬灭，用DCM(80mL)缓慢萃取2次。合并的有机相用盐水(100mL)洗涤，并用无水Na 2SO 4干燥有机相。将干燥产物过滤并蒸发，得到残余物。残余物通过ISCO柱层析纯化(石油醚/乙酸乙酯＝3/1)，得到N-(3-((2,6-二氯-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡啶-2-基)-N-甲基甲磺酰胺200mg，MS m/z(ESI)：386.0[M+H] +。 At room temperature, 2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine (600mg, 3.2mmol) and N-(3-(chloromethyl)pyridin-2-yl)-N- Methylmethanesulfonamide (900 mg, 3.8 mmol) was dissolved in DMF (5 mL) solution, and K 2 CO 3 (880 mg, 6.4 mmol) was added. The mixture was then warmed to 45°C and stirred for 8 hours. After LCMS showed the reaction was complete, the reaction mixture was quenched with water (100 mL) and extracted slowly with DCM (80 mL) twice. The combined organic phases were washed with brine (100 mL), and the organic phase was dried over anhydrous Na2SO4 . The dried product was filtered and evaporated to give a residue. The residue was purified by ISCO column chromatography (petroleum ether/ethyl acetate=3/1) to obtain N-(3-((2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)methyl)pyridin-2-yl)-N-methylmethanesulfonamide 200 mg, MS m/z (ESI): 386.0 [M+H] + .
步骤3：合成4-((6-氯-7-((2-(N-甲基甲基磺酰胺基)吡啶-3-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺Step 3: Synthesis of 4-((6-chloro-7-((2-(N-methylmethylsulfonamido)pyridin-3-yl)methyl)-7H-pyrrolo[2,3-d] Pyrimidin-2-yl)amino)-N-methylbenzamide
在室温条件下，向N-(3-((2,6-二氯-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡啶-2-基)-N-甲基甲磺酰胺(0.1g,0.26mmol)的2-丁醇(5mL)溶液中加入对氨基苯甲酰胺(46.7mg，0.31mmol)和TsOH·H 2O(49.3mg，0.26mmol)。然后将反应液升温至120℃条件下搅拌8h。TLC(DCM/MeOH＝15:1)显示反应结束后将反应液浓缩并用DCM(5mL)溶解。有机相用水(10mL)和盐水(10mL)依次洗涤。有机相用无水Na 2SO 4干燥，对干燥产物过滤并浓缩得粗品。粗品通过快速柱层析(DCM/MeOH＝从100/1至20/1)纯化，得到4-((6-氯-7-((2-(N-甲基甲基磺酰胺基)吡啶-3-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基苯甲酰胺51mg。 1H NMR(400MHz,DMSO-d 6)δ9.84(s,1H),8.78(s,1H),8.49(dd,J＝4.7,1.7Hz,1H),8.19(d,J＝4.6Hz,1H),7.79(d,J＝8.8Hz,2H),7.69(d,J＝8.8Hz,2H),7.36(dd,J＝7.8,4.7Hz,1H),7.13(dd,J＝7.8,1.6Hz,1H),6.74(s,1H),5.58(s,2H),3.27(s,3H),3.17(s,3H),2.75(d,J＝4.5Hz,3H).MS m/z(ESI)：500.3[M+H] +。 At room temperature, to N-(3-((2,6-dichloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyridin-2-yl)-N-methyl To a solution of methylsulfonamide (0.1 g, 0.26 mmol) in 2-butanol (5 mL) was added p-aminobenzamide (46.7 mg, 0.31 mmol) and TsOH·H 2 O (49.3 mg, 0.26 mmol). Then the reaction solution was heated to 120° C. and stirred for 8 h. TLC (DCM/MeOH=15:1) showed that after the reaction was completed, the reaction solution was concentrated and dissolved with DCM (5 mL). The organic phase was washed successively with water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous Na2SO4 , the dried product was filtered and concentrated to give crude product. The crude product was purified by flash column chromatography (DCM/MeOH = from 100/1 to 20/1) to give 4-((6-chloro-7-((2-(N-methylmethylsulfonamido)pyridine- 3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-methylbenzamide 51 mg. 1 H NMR (400MHz, DMSO-d 6 )δ9.84(s, 1H), 8.78(s, 1H), 8.49(dd, J=4.7, 1.7Hz, 1H), 8.19(d, J=4.6Hz, 1H), 7.79(d, J=8.8Hz, 2H), 7.69(d, J=8.8Hz, 2H), 7.36(dd, J=7.8, 4.7Hz, 1H), 7.13(dd, J=7.8, 1.6 Hz,1H),6.74(s,1H),5.58(s,2H),3.27(s,3H),3.17(s,3H),2.75(d,J=4.5Hz,3H).MS m/z( ESI): 500.3 [M+H] + .
实施例11Example 11
4-((6-(二氟甲基)-7-(2-(二甲基磷酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺的制备4-((6-(Difluoromethyl)-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3 -Preparation of methoxy-N-methylbenzamide
Figure PCTCN2022117868-appb-000032
Figure PCTCN2022117868-appb-000032
步骤1：合成2-(二甲基次膦酰基)苯腈Step 1: Synthesis of 2-(dimethylphosphinoyl)benzonitrile
将2-碘苯氰(6.90g,30.1mmol)和二甲基氧磷(2.50g,45.2mmol)溶于乙腈(150mL)，在氮气保护下，分别依次加入Pd 2(dba) 3(900mg,1.50mmol)、Xant-Phos(1.20g,3.01mmol)、Cs 2CO 3(12.0g,37.0mmol)和三乙胺(21ml,150mmol)，然后恒温到85℃反应19h。TLC检测反应完全后将反应液抽滤，滤饼用乙腈洗涤3次，滤液浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到2-(二甲基次膦酰基)苯腈4.80g，黄色固体。MS m/z(ESI):180.2[M+H] +。 Dissolve 2-iodobenzonitrile (6.90g, 30.1mmol) and dimethyl phosphine (2.50g, 45.2mmol) in acetonitrile (150mL), and add Pd 2 (dba) 3 (900mg, 1.50mmol), Xant-Phos (1.20g, 3.01mmol), Cs 2 CO 3 (12.0g, 37.0mmol) and triethylamine (21ml, 150mmol), then keep the temperature at 85°C for 19h. After the completion of the reaction as detected by TLC, the reaction solution was suction-filtered, the filter cake was washed with acetonitrile for 3 times, and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 4.80 g of 2-(dimethylphosphinoyl)benzonitrile as a yellow solid. MS m/z (ESI): 180.2 [M+H] + .
步骤2：合成(2-(氨基甲基)苯基)二甲基氧膦Step 2: Synthesis of (2-(aminomethyl)phenyl)dimethylphosphine oxide
将2-(二甲基次膦酰基)苯腈(4.80g,28.2mmol)溶于四氢呋喃(60ml)，降温到0℃。在氮气保护下，把硼烷四氢呋喃络合物(84.6ml，1.00mol/L，84.6mmol)缓慢滴加到反应体系，缓慢升温到室温搅拌2h。TLC检测反应完全后反应液用甲醇(100mL)缓慢淬灭，并浓缩。粗品通过快速柱层析(二氯甲烷/甲醇＝10/1)纯化，得到(2-(氨基甲基)苯基)二甲基氧膦1.30g，黄棕色胶状物。MS m/z(ESI):184.1[M+H] + 2-(Dimethylphosphinoyl)benzonitrile (4.80 g, 28.2 mmol) was dissolved in tetrahydrofuran (60 ml), and the temperature was lowered to 0°C. Under nitrogen protection, borane tetrahydrofuran complex (84.6ml, 1.00mol/L, 84.6mmol) was slowly added dropwise to the reaction system, and the temperature was slowly raised to room temperature and stirred for 2h. After the completion of the reaction detected by TLC, the reaction solution was slowly quenched with methanol (100 mL), and concentrated. The crude product was purified by flash column chromatography (dichloromethane/methanol=10/1) to obtain 1.30 g of (2-(aminomethyl)phenyl)dimethylphosphine oxide as a yellow-brown gum. MS m/z(ESI):184.1[M+H] +
步骤3：合成(2-((((2-氯-5-碘嘧啶-4-基)氨基)甲基)苯基)二甲基氧膦Step 3: Synthesis of (2-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide
将2,4-二氯-5-碘嘧啶(1.58g,5.46mmol)和DIPEA(1.80mL,10.9mmol)溶于DMF(10mL)中，降温到-5～0℃后，滴加(2-(氨基甲基)苯基)二甲基氧膦(1.30g,5.46mmol)的DMF(5ml)溶液。滴加完毕后，在0℃下反应2h，监测反应完全后加水，再加入二氯甲烷萃取，干燥浓缩萃取物得粗品，粗品通过快速柱层析(石油醚/乙酸乙酯＝20/1)纯化，得到(2-((((2-氯-5-碘嘧啶-4-基)氨基)甲基)苯基)二甲基氧膦1.35g，白色固体。MS m/z(ESI):422.9[M+H] +。 Dissolve 2,4-dichloro-5-iodopyrimidine (1.58g, 5.46mmol) and DIPEA (1.80mL, 10.9mmol) in DMF (10mL), cool down to -5 ~ 0°C, drop (2- (Aminomethyl)phenyl)dimethylphosphine oxide (1.30 g, 5.46 mmol) in DMF (5 ml). After the dropwise addition was completed, react at 0°C for 2 h, add water after monitoring the completion of the reaction, then add dichloromethane for extraction, dry and concentrate the extract to obtain a crude product, which is subjected to flash column chromatography (petroleum ether/ethyl acetate=20/1) Purification afforded (2-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide 1.35 g as a white solid. MS m/z (ESI): 422.9[M+H] + .
步骤4：合成(2-((((2-氯-5-(3,3-二乙氧基丙-1-炔基)嘧啶-4-基)氨基)甲基)苯基)二甲基氧化膦Step 4: Synthesis of (2-((((2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl)amino)methyl)phenyl)dimethyl Phosphine oxide
将(2-((((2-氯-5-碘嘧啶-4-基)氨基)甲基)苯基)二甲基氧膦(1.35g,3.20mmol)溶于DMF(50mL)中。在氮气保护下，分别加入Pd(PPh 3)Cl 2(225mg,0.32mmol)、PPh 3(42mg，0.16mmol)、碘化亚铜(122mg,0.64mmol)、三乙胺(1.33mL,9.61mmol)和3,3-二乙氧基丙-1-炔(440mg，3.42mmol)。60℃反应4h，TLC监测反应完全后将反应体系抽滤，滤液倒入10％NH 4Cl水溶液(100mL)中，乙酸乙酯萃取，浓缩得粗品。粗品通过快速柱层析(二氯甲烷/甲醇＝10/1)纯化，得到(2-((((2-氯-5-(3,3-二乙氧基丙-1-炔基)嘧啶-4-基)氨基)甲基)苯基)二甲基氧化膦665mg，MS m/z(ESI):422.1[M+H] +。 (2-((((2-Chloro-5-iodopyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide (1.35 g, 3.20 mmol) was dissolved in DMF (50 mL). In Under nitrogen protection, Pd(PPh 3 )Cl 2 (225mg, 0.32mmol), PPh 3 (42mg, 0.16mmol), cuprous iodide (122mg, 0.64mmol), triethylamine (1.33mL, 9.61mmol) were added respectively and 3,3-diethoxyprop-1-yne (440mg, 3.42mmol).React at 60°C for 4h, monitor the reaction by TLC, filter the reaction system with suction, and pour the filtrate into 10% NH 4 Cl aqueous solution (100mL) , extracted with ethyl acetate, and concentrated to give a crude product. The crude product was purified by flash column chromatography (dichloromethane/methanol=10/1) to obtain (2-((((2-chloro-5-(3,3-diethyl Oxyprop-1-ynyl)pyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide 665 mg, MS m/z (ESI): 422.1 [M+H] + .
步骤5：合成(2-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)苯基)二甲基氧膦Step 5: Synthesis of (2-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)dimethyl Phosphine oxide
将(2-((((2-氯-5-(3,3-二乙氧基丙-1-炔基)嘧啶-4-基)氨基)甲基)苯基)二甲基氧化膦(665mg,1.58mmol)溶于四氢呋喃(40mL)中，加入TBAF(9.50mL,9.50mmol,1mol/L)。升温到65℃反应2h。TLC监测反应完全后将反应液浓缩得粗品，粗品通过快速柱层析(二氯甲烷/甲醇＝20/1)纯化，得到(2-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)苯基)二甲基氧膦粗品1.59g，棕 色油状物。MS m/z(ESI):422.1[M+H] +。 (2-((((2-chloro-5-(3,3-diethoxyprop-1-ynyl)pyrimidin-4-yl)amino)methyl)phenyl)dimethylphosphine oxide ( 665mg, 1.58mmol) was dissolved in tetrahydrofuran (40mL), and TBAF (9.50mL, 9.50mmol, 1mol/L) was added. The temperature was raised to 65° C. for 2 h. After the reaction was monitored by TLC, the reaction solution was concentrated to obtain a crude product, which was passed through a flash column Purification by chromatography (dichloromethane/methanol=20/1) gave (2-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-7 -yl)methyl)phenyl)dimethylphosphine oxide crude product 1.59g, brown oil. MS m/z (ESI): 422.1[M+H] + .
步骤6：合成2-氯-7-(2-(二甲基磷酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-6-甲醛Step 6: Synthesis of 2-chloro-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde
将(2-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)苯基)二甲基氧膦(1.59g,粗品)溶于1,4-二氧六环(13mL)中，分批加入浓盐酸(8.00mL,12mol/L)，室温搅拌30min，LCMS监测反应完全后向反应液加水(30mL)稀释，然后用乙酸乙酯萃取(50mL)萃取3次。有机相用饱和食盐水洗涤，然后有机相用无水硫酸钠干燥，过滤干燥产物，浓缩得粗品。粗品通过快速柱层析(二氯甲烷/甲醇＝15/1)纯化，得到2-氯-7-(2-(二甲基磷酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-6-甲醛粗品980mg，棕色油状物。MS m/z(ESI):348.1[M+H] +。 (2-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)dimethylphosphine oxide ( 1.59g, crude product) was dissolved in 1,4-dioxane (13mL), concentrated hydrochloric acid (8.00mL, 12mol/L) was added in batches, stirred at room temperature for 30min, and LCMS was monitored to complete the reaction. Add water (30mL) to the reaction solution Dilute, then extract 3 times with ethyl acetate (50 mL). The organic phase was washed with saturated brine, and then dried over anhydrous sodium sulfate. The dried product was filtered and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (dichloromethane/methanol=15/1) to give 2-chloro-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d ] Pyrimidine-6-carbaldehyde crude product 980mg, brown oil. MS m/z (ESI): 348.1 [M+H] + .
步骤7：合成(2-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)苯基)二甲基氧膦Step 7: Synthesis of (2-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)phenyl)dimethylphosphine oxide
将2-氯-7-(2-(二甲基磷酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-6-甲醛(980mg，粗品)溶于二氯甲烷(20mL)，降温到0℃，然后滴加DAST(750mL)反应液升到室温搅拌2h。LCMS监测反应完全后将反应液缓慢滴加到水中淬灭，再用乙酸乙酯(50mL)萃取3次，有机相用无水硫酸钠干燥，抽滤干燥产物并浓缩得粗品。粗品通过快速柱层析(二氯甲烷/甲醇＝20/1)纯化，得到2-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)苯基)二甲基氧膦128mg，淡黄色固体。MS m/z(ESI):370.1[M+H] +。 2-Chloro-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (980 mg, crude) was dissolved in dichloromethane (20 mL) , cooled to 0° C., then added DAST (750 mL) dropwise to the reaction solution and raised to room temperature and stirred for 2 h. After the completion of the reaction was monitored by LCMS, the reaction solution was slowly added dropwise to water to quench, and then extracted three times with ethyl acetate (50 mL), the organic phase was dried over anhydrous sodium sulfate, and the product was dried by suction filtration and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (dichloromethane/methanol=20/1) to give 2-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine- 7-yl)methyl)phenyl)dimethylphosphine oxide 128 mg, pale yellow solid. MS m/z (ESI): 370.1 [M+H] + .
步骤8：合成4-氨基-3-甲氧基-N-甲基苯甲酰胺Step 8: Synthesis of 4-amino-3-methoxy-N-methylbenzamide
将4-氨基-3-甲氧基苯甲酸(2.00g,11.9mmol)和甲胺盐酸盐(8.08g，119.6mmol)溶于DMF(100mL)，分批加入碳酸钠(12.7g,119.6mmol)之后，再分批加入HATU(9.10g，23.9mmol)，室温反应过夜。TLC监测反应结束后将反应液加到水中，再用乙酸乙酯(50mL)萃取3次，有机相用无水硫酸钠干燥，抽滤干燥产物并浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝1/1)纯化，得到4-氨基-3-甲氧基-N-甲基苯甲酰胺1.42g，白色固体。MS m/z(ESI):181.1[M+H] +。 4-Amino-3-methoxybenzoic acid (2.00g, 11.9mmol) and methylamine hydrochloride (8.08g, 119.6mmol) were dissolved in DMF (100mL), and sodium carbonate (12.7g, 119.6mmol) was added in portions ), then added HATU (9.10 g, 23.9 mmol) in batches, and reacted overnight at room temperature. After the reaction was monitored by TLC, the reaction solution was added to water, extracted three times with ethyl acetate (50 mL), the organic phase was dried over anhydrous sodium sulfate, and the product was dried by suction filtration and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=1/1) to obtain 1.42 g of 4-amino-3-methoxy-N-methylbenzamide as a white solid. MS m/z (ESI): 181.1 [M+H] + .
步骤9：合成4-((6-(二氟甲基)-7-(2-(二甲基磷酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺Step 9: Synthesis of 4-((6-(difluoromethyl)-7-(2-(dimethylphosphoryl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl) Amino)-3-methoxy-N-methylbenzamide
将4-氨基-3-甲氧基-N-甲基苯甲酰胺(50mg，0.28mmol)、2-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)苯基)二甲基氧膦(100mg,0.27mmol)和对甲苯磺酸(55mg,0.32mmol)溶于正丁醇(2.00mL)中。反应液升温到115℃反应过夜。LCMS检测反应完全后将反应液倒入水(10mL)中，乙酸乙酯(20mL)萃取3次。有机相用饱和食盐水洗涤，无水硫酸钠干燥有机相，过滤干燥物，浓缩得粗品。粗品通过快速柱层析(二氯甲烷/甲醇＝20/1)和pre-TLC纯化，得4-((6-(二氟甲基)-7-(2-(二甲基磷酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺3.5mg，黄色固体。MS m/z(ESI):513.2[M+H] +。 4-Amino-3-methoxy-N-methylbenzamide (50 mg, 0.28 mmol), 2-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3 -d] pyrimidin-7-yl)methyl)phenyl)dimethylphosphine oxide (100 mg, 0.27 mmol) and p-toluenesulfonic acid (55 mg, 0.32 mmol) were dissolved in n-butanol (2.00 mL). The temperature of the reaction solution was raised to 115° C. to react overnight. After the completion of the reaction detected by LCMS, the reaction solution was poured into water (10 mL), and extracted three times with ethyl acetate (20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by flash column chromatography (dichloromethane/methanol=20/1) and pre-TLC to give 4-((6-(difluoromethyl)-7-(2-(dimethylphosphoryl)benzyl Base)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide 3.5 mg, yellow solid. MS m/z (ESI): 513.2 [M+H] + .
实施例12Example 12
4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-烷基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-烷基)氨基)-3-甲氧基-N-甲基苯甲酰胺的制备4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazine-2-alkyl)methyl)-7H-pyrrolo[2,3 -d] Preparation of pyrimidine-2-alkyl)amino)-3-methoxy-N-methylbenzamide
Figure PCTCN2022117868-appb-000033
Figure PCTCN2022117868-appb-000033
步骤1：合成N-(3-氰基吡嗪-2-基)-N-甲基甲磺酰胺Step 1: Synthesis of N-(3-cyanopyrazin-2-yl)-N-methylmethanesulfonamide
将3-氯吡嗪-2-腈(8.40g，60.2mmol)、N-甲基甲基-氨基磺酰胺(8.00g，73.3mmol)和K 2CO 3(9.00g，65.1mmol)的乙腈(100mL)混合液在85℃下搅拌12小时。TLC(石油醚/乙酸乙酯＝1/1)显示反应结束后将反应液抽滤，滤饼用ACN(50mL)洗涤3次，滤液浓缩得到粗品。粗品通 过快速色谱柱(FCC，石油醚/乙酸乙酯＝3/1)纯化，得到N-(3-氰基吡嗪-2-基)-N-甲基甲磺酰胺(13.3g，粗品)。MS m/z(ESI)：＝213.04[M+H] +。 3-Chloropyrazine-2-carbonitrile (8.40 g, 60.2 mmol), N-methylmethyl-sulfamate (8.00 g, 73.3 mmol) and K 2 CO 3 (9.00 g, 65.1 mmol) in acetonitrile ( 100 mL) and the mixture was stirred at 85°C for 12 hours. TLC (petroleum ether/ethyl acetate=1/1) showed that after the reaction, the reaction solution was filtered with suction, the filter cake was washed with ACN (50 mL) three times, and the filtrate was concentrated to obtain a crude product. The crude product was purified by flash chromatography column (FCC, petroleum ether/ethyl acetate=3/1) to obtain N-(3-cyanopyrazin-2-yl)-N-methylmethanesulfonamide (13.3 g, crude product) . MS m/z (ESI): = 213.04 [M+H] + .
步骤2：合成N-(3-(氨基甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 2: Synthesis of N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide
室温下，向N-(3-氰基吡嗪-2-基)-N-甲基甲磺酰胺(13.3g)和1M HCl(2.4mL)在MeOH(150mL)中的混合液中加入10％Pd/C(5.50g)。H 2置换3次，然后将反应液在H 2(15psi)环境下搅拌12h。LCMS显示反应结束后将反应液通过硅藻土抽滤，并用MeOH(50mL)洗涤滤饼。滤液浓缩得到粗品。将粗品在DCM(100mL)中打浆，抽滤，干燥，得到N-(3-(氨基甲基)吡嗪-2-基)-N-甲基甲磺酰胺(HCl，5.26g，34.6％)。MS m/z(ESI)：217.04[M+H] +。 To a mixture of N-(3-cyanopyrazin-2-yl)-N-methylmethanesulfonamide (13.3 g) and 1M HCl (2.4 mL) in MeOH (150 mL) was added 10% Pd/C (5.50 g). H 2 was replaced 3 times, and then the reaction solution was stirred for 12 h under H 2 (15 psi) environment. After LCMS showed that the reaction was complete, the reaction solution was suction filtered through celite, and the filter cake was washed with MeOH (50 mL). The filtrate was concentrated to give crude product. The crude product was slurried in DCM (100 mL), filtered with suction and dried to give N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (HCl, 5.26 g, 34.6%) . MS m/z (ESI): 217.04 [M+H] + .
步骤3：合成N-(3-((((2-氯-5-碘嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 3: Synthesis of N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide
在0℃下，将N-(3-(氨基甲基)吡嗪-2-基)-N-甲基甲磺酰胺(HCl，5.26g，20.83mmol)、2,4-二氯-5-碘嘧啶(5.73g，20.84mmol)和DIPEA(6.88mL，41.7mmol)的DMF(60mL)溶液搅拌2h。TLC(石油醚/乙酸乙酯＝5/1)显示反应完成后将反应混合物倒入水(150mL)中，并用乙酸乙酯(100mL)萃取2次。合并的有机相用饱和食盐水(100mL)洗涤3次，然后用无水Na 2SO 4干燥，再对干燥产物过滤并旋蒸得到粗品。粗品通过FCC(石油醚/乙酸乙酯＝10/1)纯化，得到N-(3-((((2-氯-5-碘代嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(5.88g，12.9mmol，62.1％)。MS m/z(ESI)：454.9[M+H] +。 At 0°C, N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (HCl, 5.26g, 20.83mmol), 2,4-dichloro-5- A solution of iodopyrimidine (5.73 g, 20.84 mmol) and DIPEA (6.88 mL, 41.7 mmol) in DMF (60 mL) was stirred for 2 h. TLC (petroleum ether/ethyl acetate=5/1) showed that the reaction was completed, and the reaction mixture was poured into water (150 mL), and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed 3 times with saturated brine (100 mL), then dried over anhydrous Na 2 SO 4 , and the dried product was filtered and rotary evaporated to obtain a crude product. The crude product was purified by FCC (petroleum ether/ethyl acetate=10/1) to give N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide (5.88 g, 12.9 mmol, 62.1%). MS m/z (ESI): 454.9 [M+H] + .
步骤4：合成N-(3-(((2-氯-5-(3,3-二乙氧基丙-1-炔-1-基)嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 4: Synthesis of N-(3-(((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl)pyrazine -2-yl)-N-methylmethanesulfonamide
在氮气保护下，向N-(3-((((2-氯-5-碘嘧啶丁-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(5.88g，12.9mmol)和3,3-二乙氧基丙-1-炔(2.49g，19.4mmol)的DMF(80mL)溶液中分别加入Pd(PPh 3) 2Cl 2(907mg，1.29mmol)、CuI(494mg，2.59mmol)、PPh 3(170mg，0.644mmol)和TEA(5.40mL，38.8mmol)。然后在氮气保护下，将反应液在60℃油浴中搅拌2h。LCMS显示反应结束后将反应液抽滤后，倒入水(200mL)中，并用乙酸乙酯(100mL)萃取2次。合并的有机相用饱和食盐水(100mL)洗涤3次，再用无水Na 2SO 4干燥，然后对干燥产物抽滤并浓缩得到粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到N-(3-(((2-氯-5-(3，3-二乙氧基丙-1-炔-1-基)嘧啶丁-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(8.00g，粗品)。MS m/z(ESI)：455.0[M+H] +。 Under nitrogen protection, to N-(3-((((2-chloro-5-iodopyrimidin-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide ( 5.88g, 12.9mmol) and 3,3-diethoxyprop-1-yne (2.49g, 19.4mmol) in DMF (80mL) were added Pd(PPh 3 ) 2 Cl 2 (907mg, 1.29mmol) , CuI (494mg, 2.59mmol), PPh 3 (170mg, 0.644mmol) and TEA (5.40mL, 38.8mmol). Then, under the protection of nitrogen, the reaction solution was stirred in an oil bath at 60°C for 2h. LCMS showed that after the end of the reaction After the reaction solution was filtered with suction, it was poured into water (200mL), and extracted twice with ethyl acetate (100mL). The combined organic phase was washed with saturated brine (100mL) three times, and then dried over anhydrous Na 2 SO 4 , Then the dried product was suction filtered and concentrated to obtain the crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain N-(3-(((2-chloro-5-(3, 3-diethoxyprop-1-yn-1-yl)pyrimidinbut-4-yl)amino)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide (8.00 g, crude). MS m/z (ESI): 455.0 [M+H] + .
步骤5：合成N-(3-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 5: Synthesis of N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide
在25℃下，向N-(3-(((2-氯-5-(3,3-二乙氧基丙-1-炔-1-基)嘧啶-4-基)氨基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(8.00g，粗品)的THF(40mL)溶液中加入TBAF(1M，78mL，78.0mmol)。然后将反应液在60℃油浴中搅拌1h。TLC(石油醚/乙酸乙酯＝5/1)显示反应结束后将反应液浓缩并用乙酸乙酯(200mL)溶解。有机相用水(100mL)洗涤3次，然后再用饱和食盐水(100mL)洗涤1次。有机相用无水Na 2SO 4干燥，然后对干燥产物过滤并浓缩得粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到N-(3-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(2.53g，5.56mmol，43.0％)。MS m/z(ESI)：455.0[M+H] +。 At 25°C, to N-(3-(((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)methyl) To a solution of pyrazin-2-yl)-N-methylmethanesulfonamide (8.00 g, crude) in THF (40 mL) was added TBAF (1M, 78 mL, 78.0 mmol). Then the reaction solution was stirred in a 60 °C oil bath for 1 h. TLC (petroleum ether/ethyl acetate=5/1) showed that after the reaction was completed, the reaction solution was concentrated and dissolved in ethyl acetate (200 mL). The organic phase was washed three times with water (100 mL), and then once with saturated brine (100 mL). The organic phase was dried over anhydrous Na2SO4 , then the dry product was filtered and concentrated to give crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2, 3-d] Pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide (2.53 g, 5.56 mmol, 43.0%). MS m/z (ESI): 455.0 [M+H] + .
步骤6：合成N-(3-((2-氯-6-甲酰基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 6: Synthesis of N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N- Methylmethanesulfonamide
在25℃下向，向N-(3-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(2.53g，5.56mmol)的1,4-二氧六环(40mL)溶液中加入1M的HCl(1M，16mL)水溶液。然后将反应液在25℃搅拌2h。LCMS显示反应完成后将反应混合物倒入水(80mL)中，并用乙酸乙酯(100mL)萃取2次。合并的有机相用饱和食盐水(100mL)洗涤，并用无水Na 2SO 4干燥。将干燥产物过滤并蒸发，得到N-(3-((2-氯-6-甲酰基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(2.48g，粗品)。MS m/z(ESI)：381.0[M+H] +。 At 25°C, N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrrolo[2,3-d]pyrimidin-7-yl)methyl) To a solution of azin-2-yl)-N-methylmethanesulfonamide (2.53 g, 5.56 mmol) in 1,4-dioxane (40 mL) was added 1M aqueous HCl (1M, 16 mL). The reaction was then stirred at 25 °C for 2 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (80 mL) and extracted 2 times with ethyl acetate (100 mL). The combined organic phases were washed with saturated brine (100 mL), and dried over anhydrous Na 2 SO 4 . The dried product was filtered and evaporated to give N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-Methylmethanesulfonamide (2.48 g, crude). MS m/z (ESI): 381.0 [M+H] + .
步骤7：合成N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 7: Synthesis of N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-Methylmethanesulfonamide
在0℃下，向N-(3-((2-氯-6-甲酰基-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰 胺(2.48g，粗品)的DCM(40mL)溶液中缓慢滴加DAST(2.50mmol，19.3mmol)。然后将反应液在25℃搅拌2h。LCMS显示反应结束后将反应液缓慢滴加到水(100mL)中淬灭，再用DCM(80mL)萃取2次。合并的有机相用盐水(100mL)洗涤，然后用无水Na 2SO 4干燥。将干燥产物抽滤并浓缩得到粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(1.38g，3.43mmol，61.7％，两步收率)。MS m/z(ESI)：403.0[M+H] +。 At 0°C, to N-(3-((2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)- To a solution of N-methylmethanesulfonamide (2.48 g, crude) in DCM (40 mL) was slowly added DAST (2.50 mmol, 19.3 mmol) dropwise. The reaction was then stirred at 25 °C for 2 h. LCMS showed that after the reaction was completed, the reaction solution was slowly dropped into water (100 mL) to quench, and then extracted twice with DCM (80 mL). The combined organic phases were washed with brine (100 mL), then dried over anhydrous Na2SO4 . The dry product was suction filtered and concentrated to give the crude product. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3- d] Pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide (1.38 g, 3.43 mmol, 61.7% over two steps). MS m/z (ESI): 403.0 [M+H] + .
步骤8：合成N-(3-((6-(二氟甲基)-2-((1-异丙基-3-甲基-1H-吡唑-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺Step 8: Synthesis of N-(3-((6-(difluoromethyl)-2-((1-isopropyl-3-methyl-1H-pyrazol-5-yl)amino)-7H-pyrrole And[2,3-d]pyrimidine-7-yl)methyl)pyrazine-2-alkyl)-N-methylmethanesulfonamide
在氮气保护下，向N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺(100mg，0.248mmol)和1-异丙基-3-甲基-1H-吡唑-5-胺(52.0mg，0.372mmol)的1，4-二氧六环(3mL)溶液中分别加入Pd(OAc) 2(12mg，0.05mmol)、BINAP(62mg，0.099mmol)和Cs 2CO 3(242mg，0.774mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，并用乙酸乙酯(30mL)萃取2次。合并的有机相用饱和食盐水(50mL)洗涤，然后用无水Na 2SO 4干燥有机相，对干燥产物进行抽滤并浓缩，得到化合物粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝0/1)纯化，得到N-(3-((6-(二氟甲基)-2-((1-异丙基-3-甲基-1H-吡唑-5-基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺56mg。 1HNMR(400MHz,DMSO-d 6)9.07(s,1H),8.75(s,1H),8.51(d,J＝4.00Hz,1H),8.45(d,J＝4.00Hz,1H),7.16(m,1H),5.73(m,1H),5.62(s,2H),3.15(d,J＝8Hz,6H),1.17(d,J＝8Hz,6H).MS m/z(ESI)：506.1[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (100mg, 0.248mmol) and 1-isopropyl-3-methyl-1H-pyrazol-5-amine (52.0mg, 0.372mmol) of 1,4- To a solution of dioxane (3 mL) were added Pd(OAc) 2 (12 mg, 0.05 mmol), BINAP (62 mg, 0.099 mmol) and Cs 2 CO 3 (242 mg, 0.774 mmol), respectively. Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), and then dried over anhydrous Na 2 SO 4 , the dried product was suction filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to give N-(3-((6-(difluoromethyl)-2-((1-isopropyl-3-methan Base-1H-pyrazol-5-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2-alkyl)-N-methylmethanesulfonamide 56 mg. 1 HNMR (400MHz, DMSO-d 6 ) 9.07(s, 1H), 8.75(s, 1H), 8.51(d, J=4.00Hz, 1H), 8.45(d, J=4.00Hz, 1H), 7.16( m,1H),5.73(m,1H),5.62(s,2H),3.15(d,J=8Hz,6H),1.17(d,J=8Hz,6H).MS m/z(ESI):506.1 [M+H] + .
实施例13Example 13
N-(3-((6-(二氟甲基)-2-((2-氧代吲哚-6-烷基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺的制备N-(3-((6-(difluoromethyl)-2-((2-oxoindol-6-alkyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-7- Preparation of base) methyl) pyrazin-2-yl)-N-methylmethanesulfonamide
Figure PCTCN2022117868-appb-000034
Figure PCTCN2022117868-appb-000034
在氮气保护下，向N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺(80mg,0.199mmol)和6-氨基吲哚-2-酮(45.0mg，0.298mmol)的1，4-二氧六环(2mL)溶液中分别加入Pd(OAc) 2(9mg,0.04mmol)、BINAP(50mg,0.08mmol)和Cs 2CO 3(195mg,0.579mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，并用乙酸乙酯(30mL)萃取2次。合并的有机相用饱和食盐水(50mL)洗涤，用无水Na 2SO 4干燥有机相，对干燥产物抽滤并浓缩得到化合物粗品。粗品通过快速柱层析纯化(石油醚/乙酸乙酯＝0/1)，得到N-(3-((6-(二氟甲基)-2-((2-氧代吲哚-6-烷基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺12mg。MS m/z(ESI)：515.1[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (80mg, 0.199mmol) and 6-aminoindol-2-one (45.0mg, 0.298mmol) in 1,4-dioxane (2mL) solution respectively Pd(OAc) 2 (9 mg, 0.04 mmol), BINAP (50 mg, 0.08 mmol) and Cs 2 CO 3 (195 mg, 0.579 mmol) were added. Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , the dried product was suction filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to give N-(3-((6-(difluoromethyl)-2-((2-oxoindole-6- Alkyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 12 mg. MS m/z (ESI): 515.1 [M+H] + .
实施例14Example 14
N-(3-((6-(二氟甲基)-2-((2-甲氧基-4-吗啉代苯基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2烷基)-N-甲基甲磺酰胺的制备N-(3-((6-(difluoromethyl)-2-((2-methoxy-4-morpholinophenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 7-yl)methyl)pyrazine-2alkyl)-N-methylmethanesulfonamide
Figure PCTCN2022117868-appb-000035
Figure PCTCN2022117868-appb-000035
在氮气保护下，向N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺(80mg,0.199mmol)和2-甲氧基-4-吗啉代苯胺(62.2mg，0.298mmol)的1，4-二氧六环(2mL)溶液中分别加入Pd(OAc) 2(9mg,0.04mmol)、BINAP(50mg,0.08mmol)和Cs 2CO 3(195mg,0.579mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，并用乙酸乙酯(30mL)萃取2次。合并的有机相用饱和食盐水(50mL)洗涤，再用无水Na 2SO 4干燥有机相，然后对干燥产物抽滤并浓缩得到化合物粗品。粗品通过快速柱层析纯化(石油醚/乙酸乙酯＝0/1)，得到N-(3-((6-(二氟甲基)-2-((2-氧代吲哚-6-烷基)氨基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺45mg。 1HNMR(400MHz,DMSO-d 6)8.74(s,1H),8.54(d,J＝4.00Hz,1H),8.48(d,J＝4.00Hz,1H),7.84(s,1H),7.69(d,J＝8.00Hz,1H),7.17(t,J＝64.0Hz,1H),6.86(s,1H),6.61(s,1H),6.36–6.33(m,1H),5.70(m,2H),3.77(s,3H),3.74(t,J＝4.00Hz,4H),3.24(s,3H),3.18(s,3H),3.05(t,J＝4.00Hz,4H).MS m/z(ESI)：575.1[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (80mg, 0.199mmol) and 2-methoxy-4-morpholinoaniline (62.2mg, 0.298mmol) in 1,4-dioxane (2mL) Pd(OAc) 2 (9 mg, 0.04 mmol), BINAP (50 mg, 0.08 mmol) and Cs 2 CO 3 (195 mg, 0.579 mmol) were added to the solution, respectively. Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was filtered with suction and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to give N-(3-((6-(difluoromethyl)-2-((2-oxoindole-6- Alkyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 45 mg. 1 H NMR (400MHz, DMSO-d 6 ) 8.74(s, 1H), 8.54(d, J=4.00Hz, 1H), 8.48(d, J=4.00Hz, 1H), 7.84(s, 1H), 7.69( d,J=8.00Hz,1H),7.17(t,J=64.0Hz,1H),6.86(s,1H),6.61(s,1H),6.36–6.33(m,1H),5.70(m,2H ),3.77(s,3H),3.74(t,J=4.00Hz,4H),3.24(s,3H),3.18(s,3H),3.05(t,J=4.00Hz,4H).MS m/ z(ESI): 575.1 [M+H] + .
实施例15Example 15
N-(3-((6-(二氟甲基)-2-((2-甲氧基-5-甲基-4-(1-甲基-1,2,3,6-四氢吡啶-4-烷基)苯基]氨基))-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺的制备N-(3-((6-(difluoromethyl)-2-((2-methoxy-5-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridine Preparation of -4-alkyl)phenyl]amino))-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide
Figure PCTCN2022117868-appb-000036
Figure PCTCN2022117868-appb-000036
在氮气保护下，向N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺(80mg,0.199mmol)和2-甲氧基-5-甲基-4-(1-甲基-1,2,3,6-四氢吡啶-4-基)苯胺(69.0mg，0.298mmol)的1，4-二氧六环(2mL)溶液中分别加入Pd(OAc) 2(9mg,0.04mmol)、BINAP(50mg,0.08mmol)和Cs 2CO 3(195mg,0.579mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，并用乙酸乙酯(30mL)萃取2次。合并的有机相用饱和食盐水(50mL)洗涤，再用无水Na 2SO 4干燥有机相，然后对干燥产物抽滤并浓缩得到化合物粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝0/1)纯化，得到N-(3-((6-(二氟甲基)-2-((2-甲氧基-5-甲基-4-(1-甲基-1,2,3,6-四氢吡啶-4-烷基)苯基]氨基))-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺。 1HNMR(400MHz,DMSO-d 6)8.82(s,1H),8.54(d,J＝4Hz,1H),8.48(d,J＝4Hz,1H),7.99(s,1H),7.93(s,1H),8.22(s,1H),7.14(t,J＝64.0Hz,1H),6.90(s,1H),6.68(s,1H),3.78(s,3H),3.25(s,3H),3.17(s,5H),2.75(s,2H),2.42(s,3H),2.36(s,2H),2.07(s,3H),1.90(s,1H)。MS m/z(ESI)：599.2[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (80mg, 0.199mmol) and 2-methoxy-5-methyl-4-(1-methyl-1,2,3,6-tetrahydropyridine- 4-yl)aniline (69.0mg, 0.298mmol) in 1,4-dioxane (2mL) was added Pd(OAc) 2 (9mg, 0.04mmol), BINAP (50mg, 0.08mmol) and Cs 2 CO3 (195 mg, 0.579 mmol). Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was filtered with suction and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to give N-(3-((6-(difluoromethyl)-2-((2-methoxy-5-methoxy Base-4-(1-methyl-1,2,3,6-tetrahydropyridin-4-alkyl)phenyl]amino))-7H-pyrrolo[2,3-d]pyrimidin-7-yl )methyl)pyrazin-2-yl)-N-methylmethanesulfonamide. 1 HNMR (400MHz, DMSO-d 6 ) 8.82(s, 1H), 8.54(d, J=4Hz, 1H), 8.48(d, J=4Hz, 1H), 7.99(s, 1H), 7.93(s, 1H), 8.22(s, 1H), 7.14(t, J=64.0Hz, 1H), 6.90(s, 1H), 6.68(s, 1H), 3.78(s, 3H), 3.25(s, 3H), 3.17(s,5H), 2.75(s,2H), 2.42(s,3H), 2.36(s,2H), 2.07(s,3H), 1.90(s,1H). MS m/z (ESI): 599.2 [M+H] + .
实施例16Example 16
4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-烷基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-烷基)氨基)-3-甲氧基-N-甲基苯甲酰胺的制备4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazine-2-alkyl)methyl)-7H-pyrrolo[2,3 -d] Preparation of pyrimidine-2-alkyl)amino)-3-methoxy-N-methylbenzamide
Figure PCTCN2022117868-appb-000037
Figure PCTCN2022117868-appb-000037
在氮气保护下，向N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺(100mg，0.248mmol)和4-氨基-3-甲氧基-N-甲基苯甲酰胺(67.1mg，0.372mmol)的1，4-二氧六环(3mL)溶液中分别加入Pd(OAc) 2(12mg，0.05mmol)、BINAP(62mg，0.099mmol)和Cs 2CO 3(242mg，0.774mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，并用乙酸乙酯(30mL)萃取 2次。合并的有机相用饱和食盐水(50mL)洗涤，再用无水Na 2SO 4干燥有机相，然后对干燥产物抽滤并浓缩，得到化合物粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝0/1)纯化，得到4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-烷基)氨基)-3-甲氧基-N-甲基苯甲酰胺45mg。 1HNMR(400MHz,DMSO-d 6)8.90(s,1H),8.55(d,J＝2.56Hz,1H),8.47(d,J＝4.00Hz,1H),8.31-8.26(m,1H),8.09(s,1H),7.47(d,J＝2.00Hz,1H),7.37-7.34(m,1H),7.21(d,J＝52Hz,1H),5.96(s,1H),3.92(s,3H),3.30(s,3H),2.78(d,J＝4.00Hz,1H)。MS m/z(ESI)：547.1[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (100mg, 0.248mmol) and 4-amino-3-methoxy-N-methylbenzamide (67.1mg, 0.372mmol) of 1,4-dioxo Pd(OAc) 2 (12 mg, 0.05 mmol), BINAP (62 mg, 0.099 mmol) and Cs 2 CO 3 (242 mg, 0.774 mmol) were added to the hexacyclic (3 mL) solution, respectively. Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was suction filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to give 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido )pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-alkyl)amino)-3-methoxy-N-methylbenzamide 45 mg. 1 HNMR (400MHz, DMSO-d 6 ) 8.90(s, 1H), 8.55(d, J=2.56Hz, 1H), 8.47(d, J=4.00Hz, 1H), 8.31-8.26(m, 1H), 8.09(s,1H),7.47(d,J=2.00Hz,1H),7.37-7.34(m,1H),7.21(d,J=52Hz,1H),5.96(s,1H),3.92(s, 3H), 3.30(s, 3H), 2.78(d, J=4.00Hz, 1H). MS m/z (ESI): 547.1 [M+H] + .
实施例17Example 17
(4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-烷基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-(1-甲基哌啶-4-基)苯甲酰胺的制备(4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazine-2-alkyl)methyl)-7H-pyrrolo[2, Preparation of 3-d]pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide
Figure PCTCN2022117868-appb-000038
Figure PCTCN2022117868-appb-000038
在氮气保护下，向N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺(40mg,0.099mmol)和4-氨基-3-甲氧基-N-(1-甲基-哌啶-4-基)苯甲酰胺(35.0mg，0.149mmol)的1，4-二氧六环(1mL)溶液中分别加入Pd(OAc) 2(5mg,0.02mmol)、BINAP(25mg,0.04mmol)和Cs 2CO 3(97mg,0.298mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，并用乙酸乙酯(30mL)萃取2次。合并的有机相用饱和食盐水(50mL)洗涤，再用无水Na 2SO 4干燥有机相，然后对干燥产物抽滤并浓缩得到化合物粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝0/1)纯化，得到4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-烷基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-(1-甲基哌啶-4-基)苯甲酰胺23mg。 1HNMR(400MHz,DMSO-d 6)8.90(s,1H),8.52(m,1H),8.45(d,J＝4Hz,1H),8.31(d,J＝12Hz,1H),8.22(m,1H),8.09(s,1H),7.45(m,1H),7.39-7.37(m,1H),7.18(t,J＝56Hz,1H),5.79(s,2H),3.90(s,3H),3.27(s,3H),3.18(s,3H),1.94-1.87(m,2H),1.75-1.72(m,2H),1.27(m,1H),1.24-1.20(m,5H),0.85-0.70(m,2H).MS m/z(ESI)：630.2[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (40mg, 0.099mmol) and 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)benzamide (35.0mg , 0.149mmol) in 1,4-dioxane (1mL) were added Pd(OAc) 2 (5mg, 0.02mmol), BINAP (25mg, 0.04mmol) and Cs 2 CO 3 (97mg, 0.298mmol) . Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was filtered with suction and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to give 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido )pyrazine-2-alkyl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-(1-methylpiperidine-4 -yl) benzamide 23mg. 1 HNMR (400MHz, DMSO-d 6 ) 8.90(s, 1H), 8.52(m, 1H), 8.45(d, J=4Hz, 1H), 8.31(d, J=12Hz, 1H), 8.22(m, 1H), 8.09(s, 1H), 7.45(m, 1H), 7.39-7.37(m, 1H), 7.18(t, J=56Hz, 1H), 5.79(s, 2H), 3.90(s, 3H) ,3.27(s,3H),3.18(s,3H),1.94-1.87(m,2H),1.75-1.72(m,2H),1.27(m,1H),1.24-1.20(m,5H),0.85 -0.70 (m,2H). MS m/z (ESI): 630.2 [M+H] + .
实施例18Example 18
7-((6-(二氟甲基)-7-(3-(甲基磺酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺的制备7-((6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N- Preparation of methyl-2,3-dihydrobenzofuran-4-carboxamide
Figure PCTCN2022117868-appb-000039
Figure PCTCN2022117868-appb-000039
步骤1：合成2-氯-5-碘-N-(4-甲氧基苄基)嘧啶-4-胺Step 1: Synthesis of 2-chloro-5-iodo-N-(4-methoxybenzyl)pyrimidin-4-amine
在0℃下，将PMBNH 2(5.00g，36.4mmol)、2,4-二氯-5-碘嘧啶(10.0g，36.4mmol)和DIPEA(9.00mL，54.6mmol)的DMF(100mL)溶液液搅拌2h。TLC(石油醚/乙酸乙酯＝5/1)显示反应结束后将反应混合物倒入水(200mL)中，并用乙酸乙酯(100mL)萃取2次。合并的有机相用饱和食盐水(100mL洗涤3次，再用无水Na 2SO 4干燥有机相，然后对干燥产物过滤并浓缩得化合物粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到2-氯-5-碘-N-(4-甲氧基苄基)嘧啶-4-胺12.0g。MS m/z(ESI)：375.9[M+H] +。 At 0°C, a solution of PMBNH 2 (5.00g, 36.4mmol), 2,4-dichloro-5-iodopyrimidine (10.0g, 36.4mmol) and DIPEA (9.00mL, 54.6mmol) in DMF (100mL) was dissolved Stir for 2h. TLC (petroleum ether/ethyl acetate=5/1) showed that after the reaction was completed, the reaction mixture was poured into water (200 mL), and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed 3 times with saturated brine (100 mL, and then dried with anhydrous Na 2 SO 4 , and then the dried product was filtered and concentrated to obtain a crude product of the compound. The crude product was subjected to flash column chromatography (petroleum ether/ethyl acetate =10/1) purified to obtain 12.0 g of 2-chloro-5-iodo-N-(4-methoxybenzyl)pyrimidin-4-amine. MS m/z (ESI): 375.9[M+H] + .
步骤2：合成2-氯-5-(3,3-二乙氧基-1-丙基-1-烷基)-N-(4-甲氧基苄基)嘧啶-4-胺Step 2: Synthesis of 2-chloro-5-(3,3-diethoxy-1-propyl-1-alkyl)-N-(4-methoxybenzyl)pyrimidin-4-amine
将2-氯-5-碘-N-(4-甲氧基苄基)嘧啶-4-胺(12.0g，31.95mmol)和3,3-二乙氧基丙炔(6.41g，50.0mmol)加入在DMF(120mL)中，在25℃下向混合物中加入Pd(PPh 3)Cl 2(2.34g，3.20mmol)、CuI(1.27g，6.66mmol)、PPh 3(436mg，1.66mmol)和TEA(10mL，100mmol)。然后将反应混合物在氮气气氛下在60℃搅拌2h。LCMS显示反应完成后将反应混合物倒入水(200mL)中，并用乙酸乙酯(100mL)萃取2次。合并的有机相用盐水(100mL)洗涤3次，再用无水Na 2SO 4干燥有机相，然后对干燥产物过滤并蒸发，得到残余物。残余物通过快速柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到2-氯-5-(3,3-二乙氧基-1-丙基-1-基)-N-(4-甲氧基苄基)嘧啶-4-胺13.0g。MS m/z(ESI)：376.0[M+H] +。 2-Chloro-5-iodo-N-(4-methoxybenzyl)pyrimidin-4-amine (12.0 g, 31.95 mmol) and 3,3-diethoxypropyne (6.41 g, 50.0 mmol) In DMF (120 mL), Pd(PPh 3 )Cl 2 (2.34 g, 3.20 mmol), CuI (1.27 g, 6.66 mmol), PPh 3 (436 mg, 1.66 mmol) and TEA were added to the mixture at 25 °C (10 mL, 100 mmol). The reaction mixture was then stirred at 60 °C for 2 h under nitrogen atmosphere. After LCMS showed the reaction was complete, the reaction mixture was poured into water (200 mL) and extracted twice with ethyl acetate (100 mL). The combined organic phases were washed 3 times with brine (100 mL), and the organic phase was dried over anhydrous Na2SO4 , then the dried product was filtered and evaporated to give a residue. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 2-chloro-5-(3,3-diethoxy-1-propyl-1-yl)-N- (4-methoxybenzyl)pyrimidin-4-amine 13.0 g. MS m/z (ESI): 376.0 [M+H] + .
步骤3：合成2-氯-6-(二乙氧基甲基)-7-(4-甲氧基苄基)-7H-吡咯并[2,3-d]嘧啶Step 3: Synthesis of 2-chloro-6-(diethoxymethyl)-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine
在25℃下，向2-氯-5-(3,3-二乙氧基-1-丙基-1-基)-N-(4-甲氧基苄基)嘧啶-4-胺(13.0g，粗品)的THF(50mL)溶液中加入TBAF(1M，105mL，105mmol)。将反应混合物在60℃下搅拌1h。TLC(石油醚/乙酸乙酯＝5/1)显示反应结束后将反应液浓缩后用EtOAc(250mL)溶解。上述溶液用水(100mL)洗涤3次，然后再用饱和食盐盐水(150mL)洗涤1次。有机相用无水Na 2SO 4干燥，然后对干燥产物过滤并蒸发，得到化合物粗品。化合物粗品通过快速柱层析纯化(石油醚/乙酸乙酯＝10/1)，得到2-氯-6-(二乙氧基甲基)-7-(4-甲氧基苄基)-7H-吡咯并[2,3-d]嘧啶7.93g。MS m/z(ESI)：376.0[M+H] +。 At 25°C, to 2-chloro-5-(3,3-diethoxy-1-propyl-1-yl)-N-(4-methoxybenzyl)pyrimidin-4-amine (13.0 g, crude) in THF (50 mL) was added TBAF (1M, 105 mL, 105 mmol). The reaction mixture was stirred at 60 °C for 1 h. TLC (petroleum ether/ethyl acetate=5/1) showed that after the reaction was completed, the reaction solution was concentrated and dissolved with EtOAc (250 mL). The above solution was washed three times with water (100 mL), and then once with saturated brine (150 mL). The organic phase was dried over anhydrous Na2SO4 , then the dried product was filtered and evaporated to give crude compound. The crude compound was purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 2-chloro-6-(diethoxymethyl)-7-(4-methoxybenzyl)-7H - Pyrrolo[2,3-d]pyrimidine 7.93 g. MS m/z (ESI): 376.0 [M+H] + .
步骤4：合成2-氯-7-(4-甲氧基苄基)-7H-吡咯并[2,3-d]嘧啶-6-甲醛Step 4: Synthesis of 2-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde
在25℃下，向2-氯-6-(二乙氧基甲基)-7-(4-甲氧基苄基)-7H-吡咯并[2,3-d]嘧啶(7.93g，21.1mmol)的1,4-六环(80mL)溶液中加入6M的盐酸(36mL)。然后将反应液在25℃下搅拌1h。LCMS显示反应结束后将反应液倒入水(100mL)中，并用EtOAc(150mL)萃取2次。合并的有机相用盐水(200mL)洗涤，再用无水Na 2SO 4干燥有机相。将干燥产物过滤并蒸发，得到2-氯-7-(4-甲氧基苄基)-7H-吡咯并[2,3-d]嘧啶-6-甲醛(5.34g，粗品)。MS M/Z(ESI)：302.0(M+H) +。 At 25°C, 2-chloro-6-(diethoxymethyl)-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine (7.93g, 21.1 mmol) in 1,4-hexacyclo (80 mL) was added 6M hydrochloric acid (36 mL). The reaction was then stirred at 25 °C for 1 h. After LCMS showed that the reaction was complete, the reaction solution was poured into water (100 mL), and extracted twice with EtOAc (150 mL). The combined organic phases were washed with brine (200 mL), and the organic phase was dried over anhydrous Na2SO4 . The dry product was filtered and evaporated to give 2-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (5.34 g, crude). MS M/Z (ESI): 302.0 (M+H) + .
步骤5：合成2-氯-6-(二氟甲基)-7-(4-甲氧基苄基)-7H-吡咯并[2,3-d]嘧啶Step 5: Synthesis of 2-chloro-6-(difluoromethyl)-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine
在0℃下，向2-氯-7-(4-甲氧基苄基)-7H-吡咯并[2,3-d]嘧啶-6-甲醛(5.34g，粗品)的DCM(50mL)溶液中滴加DAST(7.00mL，53.1mmol)。滴加完毕后，将反应液神升温到25℃搅拌2h。LCMS显示反应结束后将反应混合物用水(100mL)缓慢淬灭，再用DCM(80mL)萃取2次。有机相合并后用饱和食盐水(100mL)洗涤，再用无水Na 2SO 4干燥有机相。干燥产物浓缩得化合物粗品。化合物粗品通过快速柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到2-氯-6-(二氟甲基)-7-(4-甲氧基苄基)-7H-吡咯并[2,3-d]嘧啶4.50g。MS m/z(ESI) +：324.0[M+H] +。步骤6：合成2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶 To a solution of 2-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (5.34 g, crude) in DCM (50 mL) at 0 °C DAST (7.00 mL, 53.1 mmol) was added dropwise. After the dropwise addition, the temperature of the reaction solution was raised to 25°C and stirred for 2 h. After LCMS showed the reaction was complete, the reaction mixture was quenched slowly with water (100 mL), and extracted twice with DCM (80 mL). The combined organic phases were washed with saturated brine (100 mL), and dried over anhydrous Na 2 SO 4 . The dried product was concentrated to obtain a crude compound. The crude compound was purified by flash column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 2-chloro-6-(difluoromethyl)-7-(4-methoxybenzyl)-7H-pyrrole And[2,3-d]pyrimidine 4.50g. MS m/z (ESI) + : 324.0 [M+H] + . Step 6: Synthesis of 2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine
在0℃下，向2-氯-7-(4-甲氧基苄基)-7H-吡咯并[2,3-d]嘧啶-6-甲醛(4.50g，13.9mmol)在ACN/H 2O＝5：1(60mL)中的混合物中，加入CAN(56g，992mmol)。然后将混合物在0℃下搅拌12小时。LCMS显示反应完成后将反应混合物用水(100mL)淬灭，用DCM(80mL)缓慢萃取2次。合并的有机相用盐水(100mL)洗涤，再用无水Na 2SO 4干燥有机相。将干燥产物过滤并蒸发，得到残余物。残余物通过FCC(石油醚/乙酸乙酯＝10/1)纯化，得到2-氯-6-二氟甲基-7H-吡咯并[2,3-d]嘧啶2.0g，MS m/z(ESI)：204.02(M+H) +。 To 2-chloro-7-(4-methoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carbaldehyde (4.50g, 13.9mmol) in ACN/H 2 at 0°C To the mixture in O=5:1 (60 mL), CAN (56 g, 992 mmol) was added. The mixture was then stirred at 0 °C for 12 hours. After LCMS showed the reaction was complete, the reaction mixture was quenched with water (100 mL) and extracted slowly with DCM (80 mL) twice. The combined organic phases were washed with brine (100 mL), and the organic phase was dried over anhydrous Na2SO4 . The dried product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate=10/1) to obtain 2.0 g of 2-chloro-6-difluoromethyl-7H-pyrrolo[2,3-d]pyrimidine, MS m/z ( ESI): 204.02 (M+H) + .
步骤7：合成(3-(甲基磺酰基)苯基)甲醇Step 7: Synthesis of (3-(methylsulfonyl)phenyl)methanol
在25℃下，向3-(甲基磺酰基)苯甲酸甲酯(4.0g，18.6mmol)在THF(60mL)中的混合物中加入LAH(780mg，20.5mmol)。然后将混合物在25℃下搅拌12小时。LCMS显示反应完成后将反应混合物用水(100mL)淬灭，用DCM(80mL)缓慢萃取2次。合并的有机相用盐水(100mL)洗涤，再用无水Na 2SO 4干燥有机相。将干燥产物过滤并蒸发，得到残余物。残余物通过FCC(石油醚/乙酸乙酯＝5/1)纯化，得到(3-(甲基磺酰基)苯基)甲醇3.0g，MS m/z(ESI)：186.0[M+H] +。 To a mixture of methyl 3-(methylsulfonyl)benzoate (4.0 g, 18.6 mmol) in THF (60 mL) was added LAH (780 mg, 20.5 mmol) at 25 °C. The mixture was then stirred at 25°C for 12 hours. After LCMS showed the reaction was complete, the reaction mixture was quenched with water (100 mL) and extracted slowly with DCM (80 mL) twice. The combined organic phases were washed with brine (100 mL), and the organic phase was dried over anhydrous Na2SO4 . The dried product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate=5/1) to obtain 3.0 g of (3-(methylsulfonyl)phenyl)methanol, MS m/z (ESI): 186.0[M+H] + .
步骤8：合成1-(氯甲基)-3-(甲基磺酰基)苯Step 8: Synthesis of 1-(chloromethyl)-3-(methylsulfonyl)benzene
在25℃下，向甲基(3-(甲基磺酰基)苯基)甲醇(3.0g 16.1mmol)在CH 2Cl 2(20mL)中的混合物中加入SOCl 2(2.3g，20.5mmol)。然后将混合物在25℃下搅拌12小时。LCMS显示反应完成后将反应混合物用水(100mL)淬灭，再用DCM(80mL2)缓慢萃取2次。合并的有机相用盐水 (100mL)洗涤，再用无水Na 2SO 4干燥有机相。将干燥产物过滤并蒸发，得到残余物。残余物通过FCC纯化(石油醚/乙酸乙酯＝5/1)，得到1-(氯甲基)-3-(甲基磺酰基)苯2.8g，MS m/z(ESI)：186.0[M+H] +。 To a mixture of methyl(3-(methylsulfonyl)phenyl)methanol (3.0 g 16.1 mmol) in CH2Cl2 (20 mL) was added SOCl2 (2.3 g, 20.5 mmol ) at 25 °C. The mixture was then stirred at 25°C for 12 hours. After LCMS showed the reaction was complete, the reaction mixture was quenched with water (100 mL) and slowly extracted 2 times with DCM (80 mL2). The combined organic phases were washed with brine (100 mL), and the organic phase was dried over anhydrous Na2SO4 . The dried product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate=5/1) to obtain 2.8 g of 1-(chloromethyl)-3-(methylsulfonyl)benzene, MS m/z (ESI): 186.0 [M +H] + .
步骤9：合成2-氯-6-(二氟甲基)-7-(3-(甲基磺酰基)苄基)-7H-吡咯并[2,3-d]嘧啶Step 9: Synthesis of 2-chloro-6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine
将2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶(2.0g，9.8mmol)和1-(氯甲基)-3-(甲基磺酰基)苯的混合物(1.98g)，溶于ACN(20mL)，加入K 2CO 3(2.7g，19.6mmol)，然后在45℃下搅拌8小时。LCMS显示反应完成后将反应混合物用水(100mL)淬灭，再用DCM(80mL)缓慢萃取2次。合并的有机相用盐水(100mL)洗涤，再用无水Na 2SO 4干燥有机相。将干燥产物过滤并蒸发，得到残余物。残余物通过FCC(石油醚/乙酸乙酯＝3/1)纯化，得到2-氯-6-(二氟甲基)-7-(3-(甲基磺酰基)苄基)-7H-吡咯并[2,3-d]嘧啶2.8g，MS m/z(ESI)：371.02[M+H] +。 2-Chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 9.8 mmol) and 1-(chloromethyl)-3-(methylsulfonyl) A mixture of benzene (1.98 g), dissolved in ACN (20 mL), added K 2 CO 3 (2.7 g, 19.6 mmol), then stirred at 45° C. for 8 hours. After LCMS showed the reaction was complete, the reaction mixture was quenched with water (100 mL) and slowly extracted with DCM (80 mL) twice. The combined organic phases were washed with brine (100 mL), and the organic phase was dried over anhydrous Na2SO4 . The dried product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate=3/1) to give 2-chloro-6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrole And[2,3-d]pyrimidine 2.8 g, MS m/z (ESI): 371.02 [M+H] + .
步骤10：合成7-((6-(二氟甲基)-7-(3-(甲基磺酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺Step 10: Synthesis of 7-((6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino )-N-methyl-2,3-dihydrobenzofuran-4-carboxamide
在120℃下，向2-氯-6-(二氟甲基)-7-(3-(甲基磺酰基)苄基)-7H-吡咯并[2,3-d]嘧啶(100mg，0.27mmol)和7-氨基-N-的混合物中加入在1,4-二氧六环(3mL)中的甲基2,3,3-二氢苯并呋喃-4-甲酰胺(77.8mg，0.41mmol)中加入Cs 2CO 3(260mg，0.81mmol)、Pd(OAc) 2(12mg，0.054mmol)和BINAP(67mg，0.11mmol)。然后将混合物在120℃下搅拌8小时。LCMS显示反应完成后将反应混合物冷却后用水(100mL)淬灭，再用EA(80mL)缓慢萃取2次。合并有机相后用盐水(100mL)洗涤，再用无水Na 2SO 4干燥有机相。将干燥产物过滤并蒸发，得到残余物。残余物通过FCC(石油醚/乙酸乙酯＝3/1)纯化，得到7-((6-(二氟甲基)-7-(3-(甲基磺酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺30mg。 1HNMR(400MHz,DMSO-d 6)8.91(s,1H),8.32(d,J＝8Hz,1H),8.26-8.23(m,1H),8.14(s,1H),7.83-7.77(m,2H),7.60-7.56(m,1H),7.45-7.38(m,3H),7.31(t,J＝52Hz,1H),7.00(m,1H),5.60(s,2H),3.12(s,3H),2.76(d,J＝8Hz,3H).MS m/z(ESI)：527.02[M+H] +。 At 120°C, 2-chloro-6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine (100mg, 0.27 mmol) and 7-amino-N- was added methyl 2,3,3-dihydrobenzofuran-4-carboxamide (77.8 mg, 0.41 mmol) were added Cs2CO3 (260 mg, 0.81 mmol), Pd(OAc) 2 (12 mg, 0.054 mmol) and BINAP (67 mg, 0.11 mmol). The mixture was then stirred at 120°C for 8 hours. After LCMS showed that the reaction was complete, the reaction mixture was cooled and quenched with water (100 mL), then slowly extracted twice with EA (80 mL). The combined organic phases were washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 . The dried product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate=3/1) to give 7-((6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrole [2,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide 30 mg. 1 HNMR (400MHz, DMSO-d 6 ) 8.91(s, 1H), 8.32(d, J=8Hz, 1H), 8.26-8.23(m, 1H), 8.14(s, 1H), 7.83-7.77(m, 2H),7.60-7.56(m,1H),7.45-7.38(m,3H),7.31(t,J＝52Hz,1H),7.00(m,1H),5.60(s,2H),3.12(s, 3H), 2.76 (d, J = 8 Hz, 3H). MS m/z (ESI): 527.02 [M+H] + .
实施例19Example 19
4-((6-(二氟甲基)-7-(3-(甲基磺酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺的制备4-((6-(Difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3- Preparation of Methoxy-N-Methylbenzamide
Figure PCTCN2022117868-appb-000040
Figure PCTCN2022117868-appb-000040
在氮气保护条件下，将2-氯-6-(二氟甲基)-7-(3-(甲基磺酰基)苄基)-7H-吡咯并[2,3-d]嘧啶(100mg，0.27mmol)和4-氨基-3-甲氧基-N-甲基苯甲酰胺(69mg，0.41mmol)溶于1,4-二氧六环(3mL)，加入Cs 2CO 3(260mg，0.81mmol)、Pd(OAc) 2(12m，0.054mmol)和BINAP(67mg，0.11mmol)，然后将反应体系缓慢升温至120℃，搅拌8小时。LCMS显示反应完成后将反应混合物冷却至室温后用水(100mL)淬灭，用乙酸乙酯(80mL)缓慢萃取2次。合并有机相后用盐水(100mL)洗涤，再用无水Na 2SO 4干燥有机相。将干燥产物过滤并蒸发，得到残余物。残余物经过FCC(石油醚/乙酸乙酯＝1/1)纯化，得到4-((6-(二氟甲基)-7-(3-(甲基磺酰基)苄基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-3-甲氧基-N-甲基苯甲酰胺75mg。 1HNMR(400MHz,DMSO-d 6)8.85(s,1H),8.33(s,1H),8.05-8.01(m,1H),7.83-7.74(m,3H),7.60(t,J＝8Hz,1H),7.41-7.38(m,3H),7.28(t,J＝56Hz,1H),7.10(d,J＝8Hz,1H),6.97-6.96(m,1H),4.49(t,J＝8Hz,1H),3.40(t,J＝8Hz,2H),2.72(d,J＝8Hz,3H).MS m/z(ESI)：515.02[M+H] +。 Under the condition of nitrogen protection, 2-chloro-6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrolo[2,3-d]pyrimidine (100mg, 0.27mmol) and 4-amino-3-methoxy-N-methylbenzamide (69mg, 0.41mmol) were dissolved in 1,4-dioxane (3mL), added Cs 2 CO 3 (260mg, 0.81 mmol), Pd(OAc) 2 (12m, 0.054mmol) and BINAP (67mg, 0.11mmol), then the reaction system was slowly heated to 120°C and stirred for 8 hours. After LCMS showed that the reaction was complete, the reaction mixture was cooled to room temperature, quenched with water (100 mL), and slowly extracted twice with ethyl acetate (80 mL). The combined organic phases were washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 . The dried product was filtered and evaporated to give a residue. The residue was purified by FCC (petroleum ether/ethyl acetate=1/1) to give 4-((6-(difluoromethyl)-7-(3-(methylsulfonyl)benzyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-methylbenzamide 75mg. 1 HNMR (400MHz, DMSO-d 6 ) 8.85(s, 1H), 8.33(s, 1H), 8.05-8.01(m, 1H), 7.83-7.74(m, 3H), 7.60(t, J=8Hz, 1H), 7.41-7.38(m, 3H), 7.28(t, J=56Hz, 1H), 7.10(d, J=8Hz, 1H), 6.97-6.96(m, 1H), 4.49(t, J=8Hz , 1H), 3.40 (t, J = 8Hz, 2H), 2.72 (d, J = 8Hz, 3H). MS m/z (ESI): 515.02 [M+H] + .
实施例20Example 20
7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺法的制备7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] Preparation of pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide
Figure PCTCN2022117868-appb-000041
Figure PCTCN2022117868-appb-000041
在氮气保护下，向N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺(100mg，0.248mmol)和7-氨基-N-甲基-2,3-二氢苯并呋喃-4羧酰胺(71.5mg，0.372mmol)的1，4-二氧六环(3mL)溶液中分别加入Pd(OAc) 2(12mg，0.05mmol)、BINAP(62mg，0.099mmol)和Cs 2CO 3(242mg，0.774mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，并用乙酸乙酯(30mL)萃取2次。合并的有机相用饱和食盐水(50mL)洗涤，再用无水Na 2SO 4干燥有机相，然后对干燥产物抽滤并浓缩得到化合物粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝0/1)纯化，得到7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺76mg。 1HNMR(400MHz,DMSO-d 6)8.90(s,1H),8.55(d,J＝2.56Hz,1H),8.84(s,1H),8.55-8.48(m,2H),8.22(s,1H),8.10(m,1H),7.76(d,J＝8.00Hz,1H),7.32(d,J＝52Hz,1H),7.08(d,J＝8Hz,1H),6.92(s,1H),5.76(s,2H),4.53(t,J＝12.0Hz,2H),3.42(t,J＝8.00Hz,2H),3.33(s,3H),3.25(s,3H),2.74(d,J＝4.00Hz,3H)。MS m/z(ESI)：559.1[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 1 , Pd(OAc) 2 (12 mg, 0.05 mmol), BINAP (62 mg, 0.099 mmol) and Cs 2 CO 3 (242 mg, 0.774 mmol) were added to a solution of 4-dioxane (3 mL), respectively. Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was filtered with suction and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to give 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonylamino) )pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxy Amide 76mg. 1 HNMR (400MHz, DMSO-d 6 ) 8.90(s, 1H), 8.55(d, J=2.56Hz, 1H), 8.84(s, 1H), 8.55-8.48(m, 2H), 8.22(s, 1H ),8.10(m,1H),7.76(d,J=8.00Hz,1H),7.32(d,J=52Hz,1H),7.08(d,J=8Hz,1H),6.92(s,1H), 5.76(s,2H),4.53(t,J=12.0Hz,2H),3.42(t,J=8.00Hz,2H),3.33(s,3H),3.25(s,3H),2.74(d,J = 4.00Hz, 3H). MS m/z (ESI): 559.1 [M+H] + .
实施例21Example 21
4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰氨基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟-5-甲氧基-N-(1-甲基哌啶-4-基)苯甲酰胺的制备4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonylamino)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] Preparation of pyrimidin-2-yl)amino)-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide
Figure PCTCN2022117868-appb-000042
Figure PCTCN2022117868-appb-000042
在氮气保护下，向N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺(100mg，0.25mmol)和4-氨基-2-氟-5-甲氧基-N-(1-甲基哌啶-4-基)苯甲酰胺(88.6mg，0.3mmol)的1，4-二氧六环(10mL)溶液中分别加入Pd 2(dba) 3(23.8mg，0.025mmol)、BINAP(31.2mg，0.05mmol)和tBuONa(48.0mg，0.5mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，并用乙酸乙酯(20mL)萃取2次。合并的有机相用饱和食盐水(20mL)洗涤，再用无水Na 2SO 4干燥有机相，然后对干燥产物抽滤并浓缩得到化合物粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝0/100)纯化，得到4-氨基-2-氟-5-甲氧基-N-(1-甲基哌啶-4-基)苯甲酰胺56mg。 1HNMR(400MHz,DMSO-d 6)δ8.95(s,1H),8.55(d,J＝2.4Hz,1H),8.47(d,J＝2.4Hz,1H),8.24(d,J＝13.1Hz,1H),8.19(s,1H),7.94(d,J＝5.1Hz,1H),7.33–7.07(m,2H),6.99(s,1H),5.83(s,2H),3.90(s,3H),3.78(s,1H),3.30(s,5H),3.19(s,4H),2.91(s,2H),2.33(s,5H),1.83(d,J＝10.6Hz,2H),1.62(dd,J＝21.2,10.8Hz,2H)。MS m/z(ESI)：648.2[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -Alkyl)-N-methylmethanesulfonamide (100mg, 0.25mmol) and 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzamide Pd 2 (dba) 3 (23.8 mg, 0.025 mmol), BINAP (31.2 mg, 0.05 mmol) and tBuONa (48.0 mg , 0.5mmol). Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was filtered with suction and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/100) to give 4-amino-2-fluoro-5-methoxy-N-(1-methylpiperidin-4-yl)benzene Formamide 56 mg. 1 HNMR (400MHz, DMSO-d 6 ) δ8.95(s, 1H), 8.55(d, J=2.4Hz, 1H), 8.47(d, J=2.4Hz, 1H), 8.24(d, J=13.1 Hz, 1H), 8.19(s, 1H), 7.94(d, J=5.1Hz, 1H), 7.33–7.07(m, 2H), 6.99(s, 1H), 5.83(s, 2H), 3.90(s ,3H),3.78(s,1H),3.30(s,5H),3.19(s,4H),2.91(s,2H),2.33(s,5H),1.83(d,J=10.6Hz,2H) , 1.62 (dd, J = 21.2, 10.8 Hz, 2H). MS m/z (ESI): 648.2 [M+H] + .
实施例22Example 22
7-((6-甲酰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺的制备7-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine- Preparation of 2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide
Figure PCTCN2022117868-appb-000043
Figure PCTCN2022117868-appb-000043
步骤1：合成4-溴-2,3-二氢苯并呋喃-7-胺Step 1: Synthesis of 4-bromo-2,3-dihydrobenzofuran-7-amine
将2,3-二氢苯并呋喃-7-胺(5g,40.0mmol)溶于DMF(60mL)中，分批加入NBS(7.2g,40.7mmol)，室温反应3h，监测反应完全后加水，再加入二氯甲烷萃取，干燥浓缩萃取物，再通过柱层析得到4-溴-2,3-二氢苯并呋喃-7-胺7.2g，MS m/z(ESI):214.0[M+H] +。 Dissolve 2,3-dihydrobenzofuran-7-amine (5g, 40.0mmol) in DMF (60mL), add NBS (7.2g, 40.7mmol) in batches, react at room temperature for 3h, and add water after monitoring the completion of the reaction. Then dichloromethane was added for extraction, the extract was dried and concentrated, and 7.2 g of 4-bromo-2,3-dihydrobenzofuran-7-amine was obtained by column chromatography, MS m/z (ESI): 214.0 [M+ H] + .
步骤2：合成7-氨基-2,3-二氢苯并呋喃-4-羧酸乙酯Step 2: Synthesis of ethyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate
将4-溴-2,3-二氢苯并呋喃-7-胺(3.5g,16.28mmol)、八羰基二钴(5.5g,16.28mmol)、醋酸钯(0.18g,0.81mmol)、XantPhos(0.94g,1.63mmol)和DMAP(7.9g,65.12mmol)溶于甲苯(26mL)和乙醇(9mL)中，氮气保护，105℃反应12h，监测反应完全后加水，再加入乙酸乙酯萃取，干燥浓缩萃取物，再通过柱层析纯化，得到7-氨基-2,3-二氢苯并呋喃-4-羧酸乙酯1.84g，MS m/z(ESI):208.1[M+H] +。 4-Bromo-2,3-dihydrobenzofuran-7-amine (3.5g, 16.28mmol), dicobalt octacarbonyl (5.5g, 16.28mmol), palladium acetate (0.18g, 0.81mmol), XantPhos ( 0.94g, 1.63mmol) and DMAP (7.9g, 65.12mmol) were dissolved in toluene (26mL) and ethanol (9mL), under nitrogen protection, reacted at 105°C for 12h, after monitoring the completion of the reaction, add water, then add ethyl acetate to extract, dry The extract was concentrated and purified by column chromatography to obtain 1.84 g of ethyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate, MS m/z (ESI): 208.1[M+H] + .
步骤3：合成7-氨基-2,3-二氢苯并呋喃-4-羧酸Step 3: Synthesis of 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid
将7-氨基-2,3-二氢苯并呋喃-4-羧酸乙酯(500mg,2.42mmol)溶于THF(10mL)和水(10mL)中，加入NaOH(290mg,7.25mmol)，60℃反应过夜，监测反应完全后浓缩反应液，加入2M盐酸溶液调节pH至弱酸性，然后抽滤，得到7-氨基-2,3-二氢苯并呋喃-4-羧酸340mg。MS m/z(ESI):180.0[M+H] +。 Dissolve ethyl 7-amino-2,3-dihydrobenzofuran-4-carboxylate (500mg, 2.42mmol) in THF (10mL) and water (10mL), add NaOH (290mg, 7.25mmol), 60 The reaction was carried out overnight at ℃, and the reaction solution was concentrated after monitoring the completion of the reaction. 2M hydrochloric acid solution was added to adjust the pH to weak acidity, and then filtered with suction to obtain 340 mg of 7-amino-2,3-dihydrobenzofuran-4-carboxylic acid. MS m/z (ESI): 180.0 [M+H] + .
步骤4：合成7-氨基-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺Step 4: Synthesis of 7-amino-N-methyl-2,3-dihydrobenzofuran-4-carboxamide
将7-氨基-2,3-二氢苯并呋喃-4-羧酸(340mg,1.90mmol)、HATU(866mg,2.28mmol)和甲胺盐酸盐(256mg,3.80mmol)溶于DMF(5mL)中，加入DIPEA(1.26mL,7.60mmol)，室温反应12h，监测反应完全后加水，再加入二氯甲烷萃取，干燥浓缩萃取物，再通过柱层析得到3-甲氧基-N-甲基-4-硝基苯甲酰胺300mg，MS m/z(ESI):193.1[M+H] +。 7-Amino-2,3-dihydrobenzofuran-4-carboxylic acid (340mg, 1.90mmol), HATU (866mg, 2.28mmol) and methylamine hydrochloride (256mg, 3.80mmol) were dissolved in DMF (5mL ), add DIPEA (1.26mL, 7.60mmol), react at room temperature for 12h, add water after monitoring the completion of the reaction, then add dichloromethane for extraction, dry and concentrate the extract, and then obtain 3-methoxy-N-formaldehyde by column chromatography Nyl-4-nitrobenzamide 300 mg, MS m/z (ESI): 193.1 [M+H] + .
步骤5：合成7-((6-(二乙氧基甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺Step 5: Synthesis of 7-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole And[2,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide
将N-(3-((2-氯-6-(二乙氧基甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(220mg,0.48mmol)、3-甲氧基-N-甲基-4-硝基苯甲酰胺(140mg,0.73mmol)、BINAP(60mg,0.10mmol)、Pd 2(dba) 3(45mg,0.05mmol)和叔丁醇钠(94mg,0.97mmol)溶于二氧六环(22mL)中，氮气保护，100℃反应4.5h，监测反应完全后加水，再加入乙酸乙酯萃取，干燥浓缩萃取物，再通过柱层析纯化，得到7-((6-(二乙氧基甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺210mg，MS m/z(ESI):611.2[M+H] +。 N-(3-((2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl) -N-methylmethanesulfonamide (220mg, 0.48mmol), 3-methoxy-N-methyl-4-nitrobenzamide (140mg, 0.73mmol), BINAP (60mg, 0.10mmol), Pd 2 (dba) 3 (45mg, 0.05mmol) and sodium tert-butoxide (94mg, 0.97mmol) were dissolved in dioxane (22mL), under nitrogen protection, reacted at 100°C for 4.5h, after monitoring the completion of the reaction, add water, then add acetic acid Ethyl ester extraction, drying and concentrating the extract, and purification by column chromatography afforded 7-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyridine Azin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide 210mg , MS m/z (ESI): 611.2 [M+H] + .
步骤6：合成7-((6-甲酰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺Step 6: Synthesis of 7-((6-formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide
将7-((6-(二乙氧基甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺(210mg,0.34mmol)溶于二氧六环(2mL)和水(2mL)中，冰浴下，加入TFA(1mL)，室温反应1h，监测反应完全后加水，再加入二氯甲烷萃取，干燥浓缩萃取物，再通过柱层析纯化，得到7-((6-甲酰基-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲基-2,3-二氢苯并呋喃-4-羧酰胺27mg。 1H NMR(500MHz,DMSO)δ9.58(s,1H),8.98(s,1H),8.75(s,1H),8.47(d,J＝2.2Hz,1H),8.39(d,J＝2.3Hz,1H),8.12(d,J＝4.6Hz,1H),7.66(d,J＝8.3Hz,1H),7.51(s,1H),7.08(d,J＝8.3Hz,1H),5.87(s,2H),4.48(t,J＝8.7Hz,2H),3.39(t,J＝8.6Hz,2H),3.32(s,3H),3.15(s,3H),2.71(d,J＝4.5Hz,3H).MS m/z(ESI):537.1[M+H] +。 7-((6-(diethoxymethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-2-yl)amino)-N-methyl-2,3-dihydrobenzofuran-4-carboxamide (210mg, 0.34mmol) was dissolved in dioxane (2mL) and water (2mL), under ice bath, add TFA (1mL), react at room temperature for 1h, add water after monitoring the completion of the reaction, then add dichloromethane for extraction, dry and concentrate the extract, and then purify by column chromatography to obtain 7-((6 -Formyl-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino )-N-methyl-2,3-dihydrobenzofuran-4-carboxamide 27 mg. 1 H NMR (500MHz, DMSO) δ9.58(s, 1H), 8.98(s, 1H), 8.75(s, 1H), 8.47(d, J=2.2Hz, 1H), 8.39(d, J=2.3 Hz,1H),8.12(d,J=4.6Hz,1H),7.66(d,J=8.3Hz,1H),7.51(s,1H),7.08(d,J=8.3Hz,1H),5.87( s,2H),4.48(t,J=8.7Hz,2H),3.39(t,J=8.6Hz,2H),3.32(s,3H),3.15(s,3H),2.71(d,J=4.5 Hz, 3H). MS m/z (ESI): 537.1 [M+H] + .
实施例23Example 23
7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-乙基-2,3-二氢苯并呋喃-4-羧酰胺的制备7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] Preparation of pyrimidin-2-yl)amino)-N-ethyl-2,3-dihydrobenzofuran-4-carboxamide
Figure PCTCN2022117868-appb-000044
Figure PCTCN2022117868-appb-000044
步骤1：合成4甲基7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酸酯Step 1: Synthesis of 4-methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H- Pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylate
在氮气保护下，向N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-酰基)甲基)吡嗪-2-烷基)-N-甲基甲磺酰胺(540mg，1.35mmol)和7-氨基-2,3-二氢苯并呋喃-4-羧酸乙酯(335.3mg，1.62mmol)的1，4-二氧六环(30mL)溶液中分别加入Pd 2(dba) 3(128.2mg，0.14mmol)、BINAP(168.0mg，0.27mmol)和tBuONa(259.5mg，2.74mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，并用乙酸乙酯(30mL)萃取2次。合并的有机相用饱和食盐水(50mL)洗涤，再用无水Na 2SO 4干燥有机相，然后对干燥产物抽滤并浓缩，得到化合物粗品。快速柱层析(DCM/MeOH＝0-10％)纯化，得到甲基7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酸酯320mg，MS m/z(ESI)：560.1[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 1,4 - Pd 2 (dba) 3 (128.2 mg, 0.14 mmol), BINAP (168.0 mg, 0.27 mmol) and tBuONa (259.5 mg, 2.74 mmol) were added to dioxane (30 mL) solution, respectively. Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was suction filtered and concentrated to obtain a crude compound. Purification by flash column chromatography (DCM/MeOH=0-10%) gave methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyridine Azin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylate 320mg, MS m/ z(ESI): 560.1 [M+H] + .
步骤2：合成甲基7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酸Step 2: Synthesis of methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole [2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid
在室温条件下，向甲基7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酸酯(320mg，0.56mmol)的甲醇/水(10mL/20mL)溶液中加入LiOH·H 2O(40.1mg,1.68mmol)。然后将反应液升温至50℃条件下搅拌过夜。TLC(DCM/MeOH＝10:1)显示反应结束后将反应液浓缩并用H 2O(20mL)溶解。1M HCl调节溶液Ph至2，有黄色固体析出，粗品过滤，通过快速柱层析(DCM/MeOH＝从100/1至10/1)纯化，得到甲基7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酸280mg，MS m/z(ESI)：546.1[M+H] +。 At room temperature, methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H -Pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylate (320mg, 0.56mmol) in methanol/water (10mL/20mL) LiOH·H 2 O (40.1 mg, 1.68 mmol) was added to it. Then the reaction solution was heated to 50° C. and stirred overnight. TLC (DCM/MeOH=10:1) showed that after the reaction was completed, the reaction solution was concentrated and dissolved with H 2 O (20 mL). 1M HCl adjusted the pH of the solution to 2, a yellow solid precipitated out, the crude product was filtered, and purified by flash column chromatography (DCM/MeOH=from 100/1 to 10/1) to obtain methyl 7-((6-(difluoromethane Base)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino) -2,3-Dihydrobenzofuran-4-carboxylic acid 280 mg, MS m/z (ESI): 546.1 [M+H] + .
步骤3：合成7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-乙基-2,3-二氢苯并呋喃-4-羧酰胺Step 3: Synthesis of 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-N-ethyl-2,3-dihydrobenzofuran-4-carboxamide
将化合物甲基7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酸(60.0mg,0.12mmol)和乙胺盐酸盐(30.1mg,0.37mmol)溶于DMF(10mL)溶液中，将HATU(91.3mg,0.24mmol)和DIPEA(0.12mL,0.72mmol)加入到反应体系中，然后在室温下反应2h，LCMS监测反应完全后，用水(10mL)淬灭反应，然后用EA(10mL)萃取3次，合并的有机相用饱和NaCl水洗1次，用无水Na 2SO 4干燥有机相，然后过滤浓缩干燥产物，再通过对浓缩物柱层析(MeOH/DCM＝从0至10％)纯化，得到7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-乙基-2,3-二氢苯并呋喃-4-羧酰胺32.0mg。 1H NMR(400MHz,DMSO-d 6)δ8.84(s,1H),8.55(d,J＝2.4Hz,1H),8.48(d,J＝2.4Hz,1H),8.23(s,1H),8.13(t,J＝5.6Hz,1H),7.75(d,J＝8.4Hz,1H),7.31–7.05(m,2H),6.92(s,1H),5.75(s,2H),4.52(t,J＝8.8Hz,2H),3.42(t,J＝8.8Hz,2H),3.26–3.21(m,5H),3.19(s,3H),1.10(t,J＝7.2Hz,3H).MS m/z(ESI)：573.2[M+H] +。 The compound methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (60.0mg, 0.12mmol) and ethylamine hydrochloride (30.1mg, 0.37mmol) In DMF (10mL) solution, HATU (91.3mg, 0.24mmol) and DIPEA (0.12mL, 0.72mmol) were added to the reaction system, then reacted at room temperature for 2h, after LCMS monitored the reaction was complete, quenched with water (10mL) The reaction was quenched, then extracted 3 times with EA (10 mL), the combined organic phase was washed once with saturated NaCl water, and the organic phase was dried with anhydrous Na 2 SO 4 , then the product was concentrated and dried by filtration, and then passed through the column chromatography of the concentrate ( MeOH/DCM = from 0 to 10%) purification to give 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl) Methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-ethyl-2,3-dihydrobenzofuran-4-carboxamide 32.0 mg. 1 H NMR (400MHz,DMSO-d 6 )δ8.84(s,1H),8.55(d,J=2.4Hz,1H),8.48(d,J=2.4Hz,1H),8.23(s,1H) ,8.13(t,J=5.6Hz,1H),7.75(d,J=8.4Hz,1H),7.31–7.05(m,2H),6.92(s,1H),5.75(s,2H),4.52( t,J=8.8Hz,2H),3.42(t,J=8.8Hz,2H),3.26–3.21(m,5H),3.19(s,3H),1.10(t,J=7.2Hz,3H). MS m/z (ESI): 573.2 [M+H] + .
实施例24Example 24
7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲氧基-2,3-二氢苯并呋喃-4-羧酰胺的制备7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] Preparation of pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide
Figure PCTCN2022117868-appb-000045
Figure PCTCN2022117868-appb-000045
将化合物甲基7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酸(50mg,0.09mmol)、O-甲基羟胺盐酸盐(23.4mg,0.28mmol)、HATU(68.5mg,0.18mmol)、DMAP(1.0mg,0.01mmol)和DIPEA(0.1mL,0.54mmol)加入到DMF(6mL)中，然后在室温下反应2h，LCMS监测反应完全后，用水(10mL)淬灭反应，然后用EA(20mL)萃取2次，用饱和NaCl水溶液洗有机相1次，然后用无水Na 2SO 4干燥，再过滤浓缩干燥产物，最后通过对浓缩物柱层析得到7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-甲氧基-2,3-二氢苯并呋喃-4-羧酰胺25mg。 1H NMR(400MHz,DMSO-d 6)δ11.39(s,1H),8.84(s,1H),8.55(d,J＝2.3Hz,1H),8.48(d,J＝2.4Hz,1H),8.27(s,1H),7.77(d,J＝8.4Hz,1H),7.19(t,J＝53.3Hz,1H),6.98(d,J＝8.5Hz,1H),6.93(s,1H),5.76(s,2H),4.54(t,J＝8.8Hz,2H),3.68(s,3H),3.41(t,J＝8.6Hz,2H),3.26(s,3H),3.19(s,3H).MS m/z(ESI)：575.2[M+H] +。 The compound methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (50mg, 0.09mmol), O-methylhydroxylamine hydrochloride (23.4mg, 0.28mmol ), HATU (68.5mg, 0.18mmol), DMAP (1.0mg, 0.01mmol) and DIPEA (0.1mL, 0.54mmol) were added to DMF (6mL), and then reacted at room temperature for 2h. (10mL) to quench the reaction, then extracted twice with EA ( 20mL ), washed the organic phase once with saturated NaCl aqueous solution, then dried with anhydrous Na2SO4 , then filtered and concentrated the dry product, and finally passed the concentrated column layer 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2, 3-d] pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4-carboxamide 25 mg. 1 H NMR (400MHz,DMSO-d 6 )δ11.39(s,1H),8.84(s,1H),8.55(d,J=2.3Hz,1H),8.48(d,J=2.4Hz,1H) ,8.27(s,1H),7.77(d,J=8.4Hz,1H),7.19(t,J=53.3Hz,1H),6.98(d,J=8.5Hz,1H),6.93(s,1H) ,5.76(s,2H),4.54(t,J=8.8Hz,2H),3.68(s,3H),3.41(t,J=8.6Hz,2H),3.26(s,3H),3.19(s, 3H). MS m/z (ESI): 575.2 [M+H] + .
实施例25Example 25
7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-异丁基-2,3-二氢苯并呋喃-4-羧酰胺的制备7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] Preparation of pyrimidin-2-yl)amino)-N-isobutyl-2,3-dihydrobenzofuran-4-carboxamide
Figure PCTCN2022117868-appb-000046
Figure PCTCN2022117868-appb-000046
将化合物甲基7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酸(60.0mg,0.11mmol)、异丁胺(24.1mg,0.33mmol)、HATU(83.7mg,0.22mmol)、DMAP(1.5mg,0.011mmol)和DIPEA(0.12mL,0.66mmol)加入到DMF(6mL)中，然后在室温下反应2h，LCMS监测反应完全后，用水(10mL)淬灭反应，再用EA(10mL)萃取3次，用饱和NaCl水溶液洗有机相，然后用无水Na 2SO 4干燥，再过滤浓缩干燥产物，最后通过对浓缩物柱层析(MeOH/DCM＝0-10％)纯化，得到7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-异丁基-2,3-二氢苯并呋喃-4-羧酰胺35.1mg。 1H NMR(400MHz,DMSO-d 6)δ8.83(s,1H),8.54(d,J＝2.3Hz,1H),8.48(d,J＝2.4Hz,1H),8.26(s,1H),8.14(t,J＝5.8Hz,1H),7.74(d,J＝8.4Hz,1H),7.25(t,J＝53.3Hz,53.3Hz,1H),7.08(d,J＝8.4Hz,1H),6.92(s,1H),5.75(s,2H),4.52(t,J＝8.7Hz,2H),3.41(t,J＝8.7Hz,2H),3.24(s,3H),3.18(s,3H),3.03(t,J＝6.4Hz,2H),1.81(dp,J＝13.7,6.9Hz,1H),0.88(d,J＝6.7Hz,6H).MS m/z(ESI)：601.2[M+H] +。 The compound methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (60.0mg, 0.11mmol), isobutylamine (24.1mg, 0.33mmol), HATU ( 83.7mg, 0.22mmol), DMAP (1.5mg, 0.011mmol) and DIPEA (0.12mL, 0.66mmol) were added to DMF (6mL), then reacted at room temperature for 2h, after LCMS monitoring the reaction was complete, quenched with water (10mL) The reaction was quenched, and then extracted 3 times with EA (10mL), the organic phase was washed with saturated NaCl aqueous solution, then dried with anhydrous Na 2 SO 4 , and the product was concentrated and dried by filtration, and finally the concentrated product was purified by column chromatography (MeOH/DCM= 0-10%) purification to give 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H - 35.1 mg of pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-isobutyl-2,3-dihydrobenzofuran-4-carboxamide. 1 H NMR (400MHz,DMSO-d 6 )δ8.83(s,1H),8.54(d,J=2.3Hz,1H),8.48(d,J=2.4Hz,1H),8.26(s,1H) ,8.14(t,J=5.8Hz,1H),7.74(d,J=8.4Hz,1H),7.25(t,J=53.3Hz,53.3Hz,1H),7.08(d,J=8.4Hz,1H ),6.92(s,1H),5.75(s,2H),4.52(t,J=8.7Hz,2H),3.41(t,J=8.7Hz,2H),3.24(s,3H),3.18(s ,3H),3.03(t,J=6.4Hz,2H),1.81(dp,J=13.7,6.9Hz,1H),0.88(d,J=6.7Hz,6H).MS m/z(ESI): 601.2[M+H] + .
实施例26Example 26
7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-(1-甲基哌啶-4-基)-2,3-二氢苯并呋喃-4-羧酰胺的制备7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] Preparation of pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)-2,3-dihydrobenzofuran-4-carboxamide
Figure PCTCN2022117868-appb-000047
Figure PCTCN2022117868-appb-000047
将化合物甲基7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酸(100mg,0.18mmol)、N-甲基哌啶-4-胺(62.8mg,0.55mmol)、HATU (137.0mg,0.36mmol)、DMAP(2.4mg,0.018mmol)和DIPEA(0.17mL,1.08mmol)加入到DMF(10mL)中，然后在室温下反应2h，LCMS监测反应完全后，用水(10mL)淬灭反应，再用EA(20mL)萃取3次，饱和食盐水洗有机相，然后用无水Na 2SO 4干燥有机相，将干燥产物过滤浓缩，再通过对浓缩物柱层析(MeOH/DCM＝从0至10％)纯化，得到7-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-N-(1-甲基哌啶-4-基)-2,3-二氢苯并呋喃-4-羧酰胺64.0mg。 1H NMR(400MHz,DMSO-d 6)δ8.83(s,1H),8.54(d,J＝2.4Hz,1H),8.48(d,J＝2.4Hz,1H),8.26(s,1H),8.01(d,J＝7.6Hz,1H),7.76(d,J＝8.4Hz,1H),7.30–7.05(m,2H),6.92(s,1H),5.75(s,2H),4.52(t,J＝8.8Hz,2H),3.75(s,1H),3.40(t,J＝8.8Hz,3H),3.24(s,3H),3.18(s,3H),2.93–2.83(m,2H),2.33–2.13(m,5H),1.78(d,J＝10.8Hz,2H),1.61(d,J＝9.9Hz,2H)。MS m/z(ESI)：642.2[M+H] +。 The compound methyl 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid (100mg, 0.18mmol), N-methylpiperidin-4-amine (62.8mg, 0.55mmol), HATU (137.0mg, 0.36mmol), DMAP (2.4mg, 0.018mmol) and DIPEA (0.17mL, 1.08mmol) were added to DMF (10mL), then reacted at room temperature for 2h, LCMS monitoring after the reaction was complete , Quenched the reaction with water (10mL), extracted 3 times with EA (20mL), washed the organic phase with saturated brine, then dried the organic phase with anhydrous Na 2 SO 4 , filtered and concentrated the dried product, and passed through the column layer of the concentrate Purification by chromatography (MeOH/DCM = from 0 to 10%) afforded 7-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazine-2- Base)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)-2,3-dihydrobenzofuran - 4-carboxamide 64.0 mg. 1 H NMR (400MHz,DMSO-d 6 )δ8.83(s,1H),8.54(d,J=2.4Hz,1H),8.48(d,J=2.4Hz,1H),8.26(s,1H) ,8.01(d,J=7.6Hz,1H),7.76(d,J=8.4Hz,1H),7.30–7.05(m,2H),6.92(s,1H),5.75(s,2H),4.52( t,J=8.8Hz,2H),3.75(s,1H),3.40(t,J=8.8Hz,3H),3.24(s,3H),3.18(s,3H),2.93–2.83(m,2H ), 2.33–2.13 (m, 5H), 1.78 (d, J=10.8Hz, 2H), 1.61 (d, J=9.9Hz, 2H). MS m/z (ESI): 642.2 [M+H] + .
实施例27Example 27
N-甲基-4-((7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯甲酰胺的制备N-methyl-4-((7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-6-(trifluoromethyl)-7H-pyrrolo Preparation of [2,3-d]pyrimidin-2-yl)amino)benzamide
Figure PCTCN2022117868-appb-000048
Figure PCTCN2022117868-appb-000048
步骤1：合成3-(N-甲基甲磺酰胺基)吡嗪-2-羧酸Step 1: Synthesis of 3-(N-methylmethylsulfonamido)pyrazine-2-carboxylic acid
将化合物N-(3-氰基吡嗪-2-基)-N-甲基甲磺酰胺(3g,14.15mmol)溶于EtOH(30ml)，再加入10％NaOH(60ml)，反应液100℃冷凝回流反应16h，LCMS监测反应完全后旋干反应液，再加浓盐酸调pH至5，DCM(100ml)萃取6次，有机相用饱和NaCl洗，再用无水硫酸钠干燥有机相，过滤浓缩干燥产物，得淡黄色油固状粗产物3-(N-甲基甲磺酰胺基)吡嗪-2-羧酸2.5g。MS m/z(ESI):232.0[M+H] +。 The compound N-(3-cyanopyrazin-2-yl)-N-methylmethanesulfonamide (3g, 14.15mmol) was dissolved in EtOH (30ml), then 10% NaOH (60ml) was added, and the reaction solution was 100°C Condensate and reflux the reaction for 16 hours, LCMS monitors that the reaction is complete, spin the reaction solution to dryness, add concentrated hydrochloric acid to adjust the pH to 5, extract with DCM (100ml) 6 times, wash the organic phase with saturated NaCl, dry the organic phase with anhydrous sodium sulfate, and filter The product was concentrated and dried to obtain 2.5 g of the crude product 3-(N-methylmethylsulfonamido)pyrazine-2-carboxylic acid as light yellow oily solid. MS m/z (ESI): 232.0 [M+H] + .
步骤2：合成3-(N-甲基甲磺酰胺基)吡嗪-2-羧酸甲酯Step 2: Synthesis of methyl 3-(N-methylmethylsulfonamido)pyrazine-2-carboxylate
将化合物3-(N-甲基甲磺酰胺基)吡嗪-2-羧酸(1g,4.32mmol)溶于DMF(20ml),再加K 2CO 3(1.19g,8.64mmol),MeI(2.45g,7.28mmol)，反应液25℃反应1h，LCMS监测反应完全后，反应液加20mL水稀释，再用EtOAc(50ml)萃取4次，合并有机相用饱和NaCl洗1次，然后用无水硫酸钠干燥有机相，将干燥产物过滤浓缩后，再通过柱层析(PE：EA＝1:1)纯化浓缩物，得淡黄色油固状产品3-(N-甲基甲磺酰胺基)吡嗪-2-羧酸甲酯500mg。MS m/z(ESI):246.1[M+H] +。 Compound 3-(N-methylmethylsulfonamido)pyrazine-2-carboxylic acid (1 g, 4.32 mmol) was dissolved in DMF (20 ml), and K 2 CO 3 (1.19 g, 8.64 mmol), MeI ( 2.45g, 7.28mmol), the reaction solution was reacted at 25°C for 1h, and after the reaction was complete as monitored by LCMS, the reaction solution was diluted with 20mL of water, extracted 4 times with EtOAc (50ml), the combined organic phase was washed once with saturated NaCl, and then washed with Dry the organic phase with sodium sulfate water, filter and concentrate the dried product, and then purify the concentrate by column chromatography (PE:EA=1:1) to obtain the solid product 3-(N-methylmethylsulfonamide) as light yellow oil ) 500 mg of methyl pyrazine-2-carboxylate. MS m/z (ESI): 246.1 [M+H] + .
步骤3：合成N-(3-(羟甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 3: Synthesis of N-(3-(hydroxymethyl)pyrazin-2-yl)-N-methylmethanesulfonamide
在0℃条件下，将化合物3-(N-甲基甲磺酰胺基)吡嗪-2-羧酸甲酯(1.0g,4.1mmol)溶于THF(20ml)，加入NaBH 4(1.19g,8.64mmol)，将反应液升温至25℃反应1h，LCMS监测反应完全后反应液加甲醇(10ml)稀释，再用EtOAc(10ml)萃取3次，有机相用饱和NaCl洗，然后用无水硫酸钠干燥有机相，将干燥产物过滤浓缩后，再通过柱层析(PE：EA＝4:1)纯化浓缩物，得淡黄色油固状产品N-(3-(羟甲基)吡嗪-2-基)-N-甲基甲磺酰胺270mg。MS m/z(ESI):218.0[M+H] +。 At 0°C, the compound 3-(N-methylmethylsulfonamido)pyrazine-2-carboxylic acid methyl ester (1.0g, 4.1mmol) was dissolved in THF (20ml), and NaBH 4 (1.19g, 8.64mmol), the temperature of the reaction solution was raised to 25°C for 1h. After the reaction was monitored by LCMS, the reaction solution was diluted with methanol (10ml), extracted three times with EtOAc (10ml), the organic phase was washed with saturated NaCl, and then washed with anhydrous sulfuric acid Dry the organic phase with sodium, filter and concentrate the dried product, and then purify the concentrate by column chromatography (PE:EA=4:1) to obtain the solid product N-(3-(hydroxymethyl)pyrazine- 2-yl)-N-methylmethanesulfonamide 270 mg. MS m/z (ESI): 218.0 [M+H] + .
步骤4：合成N-(3-(氯甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 4: Synthesis of N-(3-(chloromethyl)pyrazin-2-yl)-N-methylmethanesulfonamide
在0℃条件下，将化合物N-(3-(羟甲基)吡嗪-2-基)-N-甲基甲磺酰胺(270mg,1.23mmol)溶于DCM(5ml)，缓慢滴加入SOCl 2(0.26ml,3.7mmol)，将反应液升温至25℃反应搅拌过夜，LCMS 监测反应完全后直接旋蒸反应液，加DCM(10ml)稀释，再加入饱和NaHCO 3(10mL)溶液萃取，分离有机相，然后用饱和NaCl(10mL)洗有机相，再用无水硫酸钠干燥有机相，将干燥产物过滤浓缩后，再通过柱层析(PE：EA＝4:1)纯化浓缩物，得淡黄色油固状产品N-(3-(氯甲基)吡嗪-2-基)-N-甲基甲磺酰胺170mg。MS m/z(ESI):236.0[M+H] +。 At 0°C, the compound N-(3-(hydroxymethyl)pyrazin-2-yl)-N-methylmethanesulfonamide (270mg, 1.23mmol) was dissolved in DCM (5ml), and SOCl was slowly added dropwise 2 (0.26ml, 3.7mmol), the temperature of the reaction solution was raised to 25°C and the reaction was stirred overnight. After the completion of the reaction was monitored by LCMS, the reaction solution was directly rotary evaporated, diluted with DCM (10ml), and then saturated NaHCO 3 (10mL) solution was added to extract and separate The organic phase was then washed with saturated NaCl (10 mL), and then dried with anhydrous sodium sulfate. After the dried product was filtered and concentrated, the concentrate was purified by column chromatography (PE:EA=4:1) to obtain 170 mg of N-(3-(chloromethyl)pyrazin-2-yl)-N-methylmethanesulfonamide as solid product in light yellow oil. MS m/z (ESI): 236.0 [M+H] + .
步骤5：合成2-氯-7-(((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶Step 5: Synthesis of 2-chloro-7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine
在冰水浴中，将氢化钠(1.95g，48.8mmol)加入到2-氯-7H-吡咯并[2,3-d]嘧啶(5.0g，32.5mmol)的THF(50mL)溶剂中。在0℃下搅拌30分钟后，向其中加入2-(三甲硅烷基)乙氧甲基氯(6.5g,39.0mmol)。然后将反应装置移至室温下并搅拌2小时，TLC监控发现原料消失后向反应体系中加入冰水(10mL)，分出有机相。水相用乙酸乙酯萃取(50mL)3次。合并后的有机相先用水(50mL)反洗，然后用无水硫酸钠干燥有机相，将干燥物过滤后，真空浓缩干燥，得到2-氯-7-(((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(5.9g)，MS m/z(ESI):284.1[M+H] +。无需纯化，化合物直接用于下一步反应 Sodium hydride (1.95 g, 48.8 mmol) was added to 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.0 g, 32.5 mmol) in THF (50 mL) in an ice-water bath. After stirring at 0° C. for 30 minutes, 2-(trimethylsilyl)ethoxymethyl chloride (6.5 g, 39.0 mmol) was added thereto. Then the reaction device was moved to room temperature and stirred for 2 hours. After TLC monitoring found that the raw material disappeared, ice water (10 mL) was added to the reaction system, and the organic phase was separated. The aqueous phase was extracted 3 times with ethyl acetate (50 mL). The combined organic phases were first backwashed with water (50mL), then dried with anhydrous sodium sulfate, filtered the dry matter, concentrated and dried in vacuo to obtain 2-chloro-7-(((2-(trimethylform Silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5.9g), MS m/z (ESI): 284.1[M+H] + . Without purification, the compound was used directly in the next reaction
步骤6：合成2-氯-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶Step 6: Synthesis of 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-((2-(trimethyl silyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine
向一个250毫升的三口圆底烧瓶中依次加入双(频哪醇合)二硼(3.9g,15.4mmol)、4,4-二叔丁基-2,2-二吡啶(273.8mg，1.02mmol)、1,5-环辛二烯甲氧基铱二聚体(342.6mg，0.51mmol以及正己烷(40mL)。溶解后，在50℃下搅拌10min。接着，向混合液中加入2-氯-7-(((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(2.9g，10.2mmol)的四氢呋喃溶液(12mL)。随后，将反应体系置于90℃下搅拌1小时。LC-MS监控原料消失后，停止加热。待反应液冷却至室温后，向反应体系中加入冰水(100mL)稀释。分离出有机相，水相用乙酸乙酯萃取(60mL)3次。合并后的有机相先用无水硫酸钠干燥，然后减压浓缩，得到的固体残余物用用硅胶柱层析分离纯化(洗脱剂：石油醚/二氯甲烷＝2/1)，得到2-氯-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶1.8g。MS m/z(ESI)：410.2[M+H] +。 In a 250 ml three-neck round bottom flask, add bis(pinacolate) diboron (3.9 g, 15.4 mmol), 4,4-di-tert-butyl-2,2-dipyridine (273.8 mg, 1.02 mmol) successively ), 1,5-cyclooctadienemethoxyiridium dimer (342.6mg, 0.51mmol and n-hexane (40mL). After dissolving, stir at 50°C for 10min. Next, add 2-chloro - 7-(((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2.9 g, 10.2 mmol) in tetrahydrofuran (12 mL). Subsequently, the reaction system was placed at 90° C. and stirred for 1 hour. After the LC-MS monitoring raw material disappeared, the heating was stopped. After the reaction solution was cooled to room temperature, ice water (100 mL) was added to the reaction system for dilution. The organic phase was separated, The aqueous phase was extracted with ethyl acetate (60mL) 3 times. The combined organic phase was first dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and the solid residue obtained was separated and purified by silica gel column chromatography (eluent: petroleum Ether/dichloromethane=2/1) to give 2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7- ((2-(Trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3-d]pyrimidine 1.8 g. MS m/z (ESI): 410.2 [M+H] + .
步骤7：合成2-氯-6-(三氟甲基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶Step 7: Synthesis of 2-chloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidine
向一个250mL三口圆底烧瓶中，依次加入2-噻吩甲酸铜(186.9g，0.98mmol)、1,10-菲啰啉(353.2mg，1.96mmol)、一水合氢氧化锂(820.7mg,19.6mmol)、1-(三氟甲基)-1,2-苯碘酰-3-(1)-酮(4.0g，9.8mmol)和2-氯-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶(3.9g，11.74mmol)。随后，将反应装置抽真空置换氮气，反复三次。然后，加入二氯甲烷(120mL)。混合物搅拌溶解后，将反应混合物在45℃下搅拌10小时。待反应液冷却至室温，减压浓缩，得固体残余物，然后用硅胶柱层析分离纯化(洗脱剂:石油醚/乙酸乙酯＝1/1)。收集产物，减压浓缩，得到2-氯-6-(三氟甲基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶802mg。MS m/z(ESI):352.0[M+H] +。 In a 250mL three-neck round bottom flask, add copper 2-thiophenecarboxylate (186.9g, 0.98mmol), 1,10-phenanthroline (353.2mg, 1.96mmol), lithium hydroxide monohydrate (820.7mg, 19.6mmol ), 1-(trifluoromethyl)-1,2-phenyliodide-3-(1)-one (4.0g, 9.8mmol) and 2-chloro-6-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3- d] Pyrimidine (3.9 g, 11.74 mmol). Subsequently, the reaction device was evacuated to replace nitrogen, and this was repeated three times. Then, dichloromethane (120 mL) was added. After the mixture was stirred to dissolve, the reaction mixture was stirred at 45°C for 10 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain a solid residue, which was then separated and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1). The product was collected and concentrated under reduced pressure to give 2-chloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2, 3-d] pyrimidine 802mg. MS m/z (ESI): 352.0 [M+H] + .
步骤8：合成2-氯-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶Step 8: Synthesis of 2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine
将化合物2-氯-6-(三氟甲基)-7-((2-(三甲基甲硅烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶(0.82g，2.03mmol)溶于二氯甲烷(20mL)溶液中，加入三氟乙酸(20mL)。在60℃下，搅拌2小时。随后，将反应液减压浓缩。向得到的棕色残留物中加入甲醇(40mL)、水(20mL)以及碳酸钾(1.38g，10.00mmol)。搅拌溶解后，在60℃下搅拌2小时。待反应液冷却至室温，减压浓缩，除去反应液中的甲醇。所得的液体用乙酸乙酯萃取(20mL)3次，合并有机相。有机相先用饱和盐水(20mL)反洗3次，然后用无水硫酸钠干燥有机相，最后真空浓缩干燥产物，得到呈白色固体的2-氯-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶0.68g，无需纯化，化合物直接用于下一步反应。MS m/z(ESI)：222.0[M+H] +。 The compound 2-chloro-6-(trifluoromethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine ( 0.82g, 2.03mmol) was dissolved in dichloromethane (20mL) solution, and trifluoroacetic acid (20mL) was added. At 60°C, stir for 2 hours. Subsequently, the reaction solution was concentrated under reduced pressure. To the resulting brown residue were added methanol (40 mL), water (20 mL) and potassium carbonate (1.38 g, 10.00 mmol). After stirring and dissolving, it stirred at 60 degreeC for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to remove methanol in the reaction solution. The resulting liquid was extracted 3 times with ethyl acetate (20 mL), and the organic phases were combined. The organic phase was first backwashed 3 times with saturated brine (20 mL), then dried with anhydrous sodium sulfate, and finally the product was concentrated in vacuo to obtain 2-chloro-6-(trifluoromethyl)-7H- Pyrrolo[2,3-d]pyrimidine 0.68g, without purification, the compound was directly used in the next reaction. MS m/z (ESI): 222.0 [M+H] + .
步骤9：合成N-(3-((2-氯-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺Step 9: Synthesis of N-(3-((2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl )-N-Methylmethanesulfonamide
在45℃下，将化合物2-氯-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶(120mg，0.54mmol)和N-(3-(氯甲基)吡嗪-2-基)-N-甲基甲磺酰胺(153.0mg,0.65mmol)溶于ACN(20mL)的溶液中，加入K 2CO 3(149.0mg，1.08mmol)。然后将混合物在90℃下搅拌8小时。LCMS显示反应完成后将反应混合物用水(10mL)淬灭，用DCM(10mL)缓慢萃取2次。合并的有机相用盐水(20mL)洗涤，再用无水Na 2SO 4干燥有机相。将干燥产物过滤并浓缩，将浓缩物通过FCC(石油醚/乙酸乙酯＝3/1)纯化，得到N-(3-((2- 氯-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺100mg，MS m/z(ESI)：421.0[M+H] +。 At 45°C, the compound 2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (120mg, 0.54mmol) and N-(3-(chloromethyl)pyrimidine Azin-2-yl)-N-methylmethanesulfonamide (153.0 mg, 0.65 mmol) was dissolved in a solution of ACN (20 mL), and K 2 CO 3 (149.0 mg, 1.08 mmol) was added. The mixture was then stirred at 90°C for 8 hours. After LCMS showed the reaction was complete, the reaction mixture was quenched with water (10 mL), extracted slowly with DCM (10 mL) twice. The combined organic phases were washed with brine (20 mL), and the organic phase was dried over anhydrous Na2SO4 . The dry product was filtered and concentrated, and the concentrate was purified by FCC (petroleum ether/ethyl acetate=3/1) to give N-(3-((2-chloro-6-(trifluoromethyl)-7H-pyrrole And[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N-methylmethanesulfonamide 100 mg, MS m/z (ESI): 421.0 [M+H] + .
步骤10：合成N-甲基-4-((7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯甲酰胺Step 10: Synthesis of N-methyl-4-((7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-6-(trifluoromethyl)- 7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)benzamide
在氮气保护下，向N-(3-((2-氯-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(130mg，0.31mmol)和4-氨基苯甲酰胺(69.5mg，0.46mmol)的1，4-二氧六环(15mL)溶液中分别加入Pd 2(dba) 3(27.5mg，0.03mmol)，BINAP(37.3mg，0.06mmol)和tBuONa(59.6mg，0.62mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，并用乙酸乙酯(30mL)萃取2次。合并的有机相用饱和食盐水(20mL)洗涤，再用无水Na 2SO 4干燥有机相，然后对干燥产物抽滤并浓缩得到化合物粗品。粗品通过快速柱层析(石油醚/乙酸乙酯＝0/1)纯化，得到N-甲基-4-((7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)苯甲酰胺54mg。 1HNMR(400MHz,DMSO-d 6)δ10.02(s,1H),8.98(s,1H),8.58(d,J＝2.4Hz,1H),8.48(d,J＝2.4Hz,1H),8.22(q,J＝4.3Hz,1H),7.73(d,J＝8.9Hz,2H),7.68(d,J＝8.9Hz,2H),7.24(s,1H),5.83(s,2H),3.32(s,3H),3.22(s,3H),2.75(d,J＝4.5Hz,3H).MS m/z(ESI)：535.1[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 Pd 2 ( dba) 3 (27.5 mg, 0.03 mmol), BINAP (37.3 mg, 0.06 mmol) and tBuONa (59.6 mg, 0.62 mmol). Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous Na 2 SO 4 , and then the dried product was filtered with suction and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to give N-methyl-4-((7-((3-(N-methylmethylsulfonamido)pyrazine- 2-yl)methyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)benzamide 54 mg. 1 HNMR (400MHz, DMSO-d 6 )δ10.02(s, 1H), 8.98(s, 1H), 8.58(d, J=2.4Hz, 1H), 8.48(d, J=2.4Hz, 1H), 8.22(q, J=4.3Hz, 1H), 7.73(d, J=8.9Hz, 2H), 7.68(d, J=8.9Hz, 2H), 7.24(s, 1H), 5.83(s, 2H), 3.32 (s, 3H), 3.22 (s, 3H), 2.75 (d, J = 4.5 Hz, 3H). MS m/z (ESI): 535.1 [M+H] + .
实施例28Example 28
N-甲基-7-((7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酰胺的制备N-methyl-7-((7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-6-(trifluoromethyl)-7H-pyrrolo Preparation of [2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxamide
Figure PCTCN2022117868-appb-000049
Figure PCTCN2022117868-appb-000049
在氮气保护下，向N-(3-((2-氯-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(100mg，0.24mmol)和7-氨基-N-甲基-2,3-二氢苯并呋喃-4羧酰胺(69.1mg，0.36mmol)的1，4-二氧六环(10mL)溶液中分别加入Pd 2(dba) 3(21.9mg，0.024mmol)、BINAP(29.8mg，0.048mmol)和tBuONa(46.1mg，0.48mmol)。然后，在氮气保护下，将反应液在120℃环境中搅拌12h。LCMS显示反应结束后将反应混合物倒入水(20mL)中，再用乙酸乙酯(10mL)萃取2次。合并的有机相用饱和食盐水(20mL)洗涤，然后用无水Na 2SO 4干燥有机相，再对干燥产物抽滤并浓缩，得到化合物粗品。粗品通过快速柱层析纯化(石油醚/乙酸乙酯＝0/1)，得到N-甲基-7-((7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-6-(三氟甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2,3-二氢苯并呋喃-4-羧酰胺46mg。 1HNMR(400MHz,DMSO-d 6)δ8.90(s,1H),8.57(d,J＝2.4Hz,1H),8.49(d,J＝2.4Hz,1H),8.45(s,1H),8.11(q,J＝4.3Hz,1H),7.64(d,J＝8.4Hz,1H),7.21(s,1H),7.06(d,J＝8.4Hz,1H),5.74(s,2H),4.50(t,J＝8.8Hz,2H),3.41(t,J＝8.8Hz,2H),3.25(s,3H),3.19(s,3H),2.74(d,J＝4.5Hz,3H)。MS m/z(ESI)：577.2[M+H] +。 Under nitrogen protection, N-(3-((2-chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazine-2 -yl)-N-methylmethanesulfonamide (100mg, 0.24mmol) and 7-amino-N-methyl-2,3-dihydrobenzofuran-4carboxamide (69.1mg, 0.36mmol) of 1, Pd 2 (dba) 3 (21.9 mg, 0.024 mmol), BINAP (29.8 mg, 0.048 mmol) and tBuONa (46.1 mg, 0.48 mmol) were added to 4-dioxane (10 mL) solution, respectively. Then, under the protection of nitrogen, the reaction solution was stirred at 120° C. for 12 h. After LCMS showed that the reaction was complete, the reaction mixture was poured into water (20 mL), and extracted twice with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (20 mL), then dried over anhydrous Na 2 SO 4 , and the dried product was suction filtered and concentrated to obtain a crude compound. The crude product was purified by flash column chromatography (petroleum ether/ethyl acetate=0/1) to give N-methyl-7-((7-((3-(N-methylmethylsulfonamido)pyrazine- 2-yl)methyl)-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxy Amide 46mg. 1 HNMR (400MHz,DMSO-d 6 )δ8.90(s,1H),8.57(d,J=2.4Hz,1H),8.49(d,J=2.4Hz,1H),8.45(s,1H), 8.11(q, J=4.3Hz, 1H), 7.64(d, J=8.4Hz, 1H), 7.21(s, 1H), 7.06(d, J=8.4Hz, 1H), 5.74(s, 2H), 4.50 (t, J = 8.8Hz, 2H), 3.41 (t, J = 8.8Hz, 2H), 3.25 (s, 3H), 3.19 (s, 3H), 2.74 (d, J = 4.5Hz, 3H). MS m/z (ESI): 577.2 [M+H] + .
实施例29Example 29
4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟-N-异丁氧基-5-甲氧基苯甲酰胺的制备4-((6-(Difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3- d] Preparation of pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide
Figure PCTCN2022117868-appb-000050
Figure PCTCN2022117868-appb-000050
步骤1：合成4-氨基-2-氟-5-甲氧基苯甲酸甲酯Step 1: Synthesis of methyl 4-amino-2-fluoro-5-methoxybenzoate
将4-氨基-2-氟-5-甲氧基苯甲酸(500mg,2.70mmol)，溶于THF(4mL)和甲醇(1mL)中，冰浴下，逐滴加入2M(2-重氮乙基)三甲基硅烷(2mL,4.05mmol)，室温反应3h，监测反应完全后加醋酸淬灭反应，浓缩反应液，柱层析得到4-氨基-2-氟-5-甲氧基苯甲酸甲酯506mg，MS m/z(ESI):200.0[M+H] +。 Dissolve 4-amino-2-fluoro-5-methoxybenzoic acid (500mg, 2.70mmol) in THF (4mL) and methanol (1mL), add 2M (2-diazoethyl Base) trimethylsilane (2mL, 4.05mmol), react at room temperature for 3h, monitor the completion of the reaction, add acetic acid to quench the reaction, concentrate the reaction solution, and obtain 4-amino-2-fluoro-5-methoxybenzoic acid by column chromatography Methyl ester 506 mg, MS m/z (ESI): 200.0 [M+H] + .
步骤2：合成甲基4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟-5-甲氧基苯甲酸酯Step 2: Synthesis of methyl 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrole [2,3-d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoate
将N-(3-((2-氯-6-(二氟甲基)-7H-吡咯并[2,3-d]嘧啶-7-基)甲基)吡嗪-2-基)-N-甲基甲磺酰胺(180mg,0.45mmol)、4-氨基-2-氟-5-甲氧基苯甲酸甲酯(106mg,0.54mmol)、BINAP(56mg,0.09mmol)、Pd 2(dba) 3(41mg,0.04mmol)和叔丁醇钠(86mg,0.90mmol)溶于二氧六环(18mL)中，氮气保护，100℃反应4.5h，监测反应完全后将反应混合物倒入水(30mL)中，再用乙酸乙酯(15mL)萃取2次。合并有机相，然后用饱和食盐水(30mL)洗涤，再用无水Na 2SO 4干燥有机相，对干燥产物抽滤并浓缩，柱层析纯化浓缩物，得到甲基4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟-5-甲氧基苯甲酸酯160mg，MS m/z(ESI):566.2[M+H] +。 N-(3-((2-chloro-6-(difluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)pyrazin-2-yl)-N -Methylmethanesulfonamide (180mg, 0.45mmol), methyl 4-amino-2-fluoro-5-methoxybenzoate (106mg, 0.54mmol), BINAP (56mg, 0.09mmol), Pd 2 (dba) 3 (41mg, 0.04mmol) and sodium tert-butoxide (86mg, 0.90mmol) were dissolved in dioxane (18mL), under nitrogen protection, reacted at 100°C for 4.5h, and poured the reaction mixture into water (30mL ), and extracted twice with ethyl acetate (15 mL). The organic phases were combined, then washed with saturated brine (30 mL), and then dried with anhydrous Na 2 SO 4 , the dried product was suction filtered and concentrated, and the concentrate was purified by column chromatography to obtain methyl 4-((6- (Difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine-2- (yl)amino)-2-fluoro-5-methoxybenzoate 160 mg, MS m/z (ESI): 566.2 [M+H] + .
步骤3：合成4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟-5-甲氧基苯甲酸Step 3: Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid
将甲基4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟-5-甲氧基苯甲酸酯(160mg,0.28mmol)溶于THF(5mL)和水(5mL)中，加入NaOH(34mg,0.85mmol)，室温反应过夜，监测反应完全后浓缩反应液，再加入2M盐酸溶液调节pH至弱酸性，浓缩反应液，再通过柱层析得到4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟-5-甲氧基苯甲酸80mg。MS m/z(ESI):552.1[M+H] +。 Methyl 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2 ,3-d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoate (160 mg, 0.28 mmol) was dissolved in THF (5 mL) and water (5 mL), NaOH (34 mg , 0.85mmol), react overnight at room temperature, concentrate the reaction solution after monitoring the reaction is complete, then add 2M hydrochloric acid solution to adjust the pH to weak acidity, concentrate the reaction solution, and then obtain 4-((6-(difluoromethyl) -7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-2 - Fluoro-5-methoxybenzoic acid 80 mg. MS m/z (ESI): 552.1 [M+H] + .
步骤4：合成4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟-N-异丁氧基-5-甲氧基苯甲酰胺Step 4: Synthesis of 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide
将4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟-5-甲氧基苯甲酸(80mg,0.15mmol)、HATU(67mg,0.17mmol)和O-异丁氧基胺盐酸盐(37mg,0.29mmol)溶于DMF(3mL)中，加入DIPEA(0.1mL,0.58mmol)，室温反应12h，监测反应完全后将反应混合物倒入水(30mL)中，再用乙酸乙酯(15mL)萃取2次。合并有机相，然后用饱和食盐水(30mL)洗涤，然后用无水Na 2SO 4干燥有机相，再对干燥产物抽滤并浓缩，对浓缩物柱层析得到4-((6-(二氟甲基)-7-((3-(N-甲基甲基磺酰胺基)吡嗪-2-基)甲基)-7H-吡咯并[2,3-d]嘧啶-2-基)氨基)-2-氟-N-异丁氧基-5-甲氧基苯甲酰胺63mg。 1H NMR(400MHz,DMSO)δ11.22(s,1H),8.94(s,1H),8.53(d,J＝2.3Hz,1H),8.45(d,J＝2.4Hz,1H),8.26–8.15(m,2H),7.20(s,1H),7.15(d,J＝6.2Hz,1H),6.98(s,1H),5.82(s,2H),3.88(s,3H),3.64(d,J＝6.6Hz,2H),3.28(s,3H),3.18(s,3H),1.90(m,1H),0.92(d,J＝6.6Hz,6H).MS m/z(ESI):623.2[M+H] +。 4-((6-(difluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3 -d]pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid (80mg, 0.15mmol), HATU (67mg, 0.17mmol) and O-isobutoxyamine hydrochloride (37mg , 0.29mmol) was dissolved in DMF (3mL), DIPEA (0.1mL, 0.58mmol) was added, and reacted at room temperature for 12h. After monitoring the completion of the reaction, the reaction mixture was poured into water (30mL), and then extracted with ethyl acetate (15mL) 2 times. The organic phases were combined, washed with saturated brine (30 mL), then dried with anhydrous Na 2 SO 4 , then the dried product was filtered and concentrated, and the concentrate was chromatographed to obtain 4-((6-(di Fluoromethyl)-7-((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl) Amino)-2-fluoro-N-isobutoxy-5-methoxybenzamide 63 mg. 1 H NMR (400MHz, DMSO) δ11.22(s,1H),8.94(s,1H),8.53(d,J=2.3Hz,1H),8.45(d,J=2.4Hz,1H),8.26– 8.15(m,2H),7.20(s,1H),7.15(d,J=6.2Hz,1H),6.98(s,1H),5.82(s,2H),3.88(s,3H),3.64(d ,J=6.6Hz,2H),3.28(s,3H),3.18(s,3H),1.90(m,1H),0.92(d,J=6.6Hz,6H).MS m/z(ESI): 623.2[M+H] + .
化合物生物学评价Compound Biological Evaluation
试验例1：本发明化合物体外酶学抑制活性Test Example 1: In vitro enzyme inhibitory activity of the compound of the present invention
1.试剂、消耗品、仪器1. Reagents, consumables, instruments
Figure PCTCN2022117868-appb-000051
Figure PCTCN2022117868-appb-000051
2.实验步骤2. Experimental steps
1)加50μL化合物到384孔稀释板。1) Add 50 μL of compound to a 384-well dilution plate.
2)用DMSO将每列的化合物以1：3连续稀释，每次稀释10个点加上只含有DMSO的对照。2) The compounds in each column were serially diluted 1:3 with DMSO, 10 points for each dilution plus a control containing only DMSO.
3)使用Echo将每行中的稀释的化合物溶液转移0.1μL至384测定板中，每列包含2个重复。3) Transfer 0.1 μL of the diluted compound solution in each row to a 384 assay plate using Echo, each column containing 2 replicates.
4)将5μL 2X酶溶液添加至测定板，以1000rpm离心1分钟。在25℃孵育15分钟。4) Add 5 μL of 2X enzyme solution to the assay plate and centrifuge at 1000 rpm for 1 minute. Incubate for 15 minutes at 25°C.
5)将5μL 2X底物溶液加入384孔测定板。5) Add 5 μL of 2X substrate solution to a 384-well assay plate.
6)25℃孵育60分钟。6) Incubate at 25°C for 60 minutes.
7)将5μL Sa-XL665溶液和5μL TK抗体-Eu3 +添加至测定板。1000rpm离心1分钟。 7) Add 5 μL of Sa-XL665 solution and 5 μL of TK antibody-Eu3 + to the assay plate. Centrifuge at 1000 rpm for 1 minute.
8)25℃孵育60分钟。8) Incubate at 25°C for 60 minutes.
9)在Envision 2104读板器上读取荧光信号。9) Read the fluorescent signal on the Envision 2104 plate reader.
3.数据分析3. Data analysis
1)对于每个筛选板，计算DMSO和100nM Defactinib(作为对照)的平均数据和标准偏差(SD)1) For each screening plate, calculate the mean data and standard deviation (SD) of DMSO and 100nM Defactinib (as a control)
2)化合物的抑制百分率(％inh)＝100*(最大值-样品值)/(最大值-最小值)2) Inhibition percentage of compound (%inh)=100*(maximum value-sample value)/(maximum value-minimum value)
3)采用XLfit 5.3.1的非线性回归方程计算IC50,公式如下：3) Calculate IC50 using the nonlinear regression equation of XLfit 5.3.1, the formula is as follows:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X:Log(化合物浓度)X: Log (compound concentration)
Y:抑制率(％inh)Y: Inhibition rate (%inh)
Top and Bottom:和Y的单位一致Top and Bottom: Consistent with the unit of Y
logIC50:和X的单位一致logIC50: same unit as X
HillSlope:坡度系数或坡度HillSlope: slope coefficient or slope
4.实验结果4. Experimental results
具体化合物的FAK激酶活性IC50活性数据见表1。See Table 1 for the FAK kinase activity IC50 activity data of specific compounds.
表1Table 1
Figure PCTCN2022117868-appb-000052
Figure PCTCN2022117868-appb-000052
Figure PCTCN2022117868-appb-000053
Figure PCTCN2022117868-appb-000053
Figure PCTCN2022117868-appb-000054
Figure PCTCN2022117868-appb-000054
Figure PCTCN2022117868-appb-000055
Figure PCTCN2022117868-appb-000055
Figure PCTCN2022117868-appb-000056
Figure PCTCN2022117868-appb-000056
上述结果表明本发明的化合物对FAK具有较好的抑制作用，其IC 50均在0.001μM和10μM之间，即具有较好的体外FAK酶学抑制活性。 The above results show that the compound of the present invention has a good inhibitory effect on FAK, and its IC 50 is between 0.001 μM and 10 μM, that is, it has good in vitro FAK enzyme inhibitory activity.
试验例2：化合物体外弥漫性胃癌(DGC)类器官模型中的药效学评价Test Example 2: Pharmacodynamic evaluation of compounds in diffuse gastric cancer (DGC) organoid model in vitro
实验步骤：在评估之前，类器官在6孔板(每孔7Matrigel等分试样)中扩增2-3天。传代后，将1000个细胞以5μL Matrigel等分试样接种到含有100μL 50％L-WRN培养基的96孔板的每个孔中。在类器官培养24小时后，加入化合物。用DMSO将化合物溶解，配置成终浓度为10μM储液，后用DMSO将储液稀释至使用浓度的1000倍，再加入培养基将其稀释至使用浓度，将稀释液加到培养孔板中，化合物加入一次后，后面不再更换培养基，也不再重新加入化合物。后将类器官培养指定的天数，随后用以下三种方式评价化合物的效果，这三种方式均以DMSO作为阴性对照，地法替尼(Defactinib)或IN10018为阳性对照。Experimental procedure: Organoids were expanded in 6-well plates (7 Matrigel aliquots per well) for 2-3 days prior to evaluation. After passaging, 1000 cells were seeded in 5 μL Matrigel aliquots into each well of a 96-well plate containing 100 μL 50% L-WRN medium. After 24 hours of organoid culture, compounds were added. Dissolve the compound in DMSO, prepare the stock solution with a final concentration of 10 μM, and then dilute the stock solution to 1000 times the used concentration with DMSO, then add the medium to dilute it to the used concentration, and add the diluted solution to the culture well plate, After the compound was added once, the medium was not replaced and the compound was not re-added thereafter. Afterwards, the organoids were cultured for a specified number of days, and then the effects of the compounds were evaluated in the following three ways, all of which used DMSO as a negative control, and Defactinib or IN10018 as a positive control.
1.通过显微镜观察细胞形态，正常细胞与弥漫性胃癌类器官模型在细胞形态上存在区别，如图1所示，正常的类器官形态呈球形真空状，弥漫性胃癌的类器官呈实心的葡萄状不规则形状，因此观察药物对细胞形态的影响也成为评价药物效果的重要表征之一；实验结果显示，本发明的化合物能够在体外DGC类器官模型中恢复细胞形态，如图1-5所示(本发明部分化合物结果未示出)，本发明化合物4、6、8、9在2.5μM的浓度下处理DGC类器官模型均可以恢复细胞形态，化合物8、9的效果明显优于Defactinib，同时，也很明显的观察到相比Defactinib更优的细胞增殖抑制效果。1. Observing the cell morphology through a microscope, there are differences in cell morphology between normal cells and diffuse gastric cancer organoid models. As shown in Figure 1, normal organoids are spherical and vacuum-shaped, while diffuse gastric cancer organoids are solid grapes Therefore, observing the influence of drugs on cell morphology has also become one of the important characterizations for evaluating drug effects; the experimental results show that the compounds of the present invention can restore cell morphology in the DGC organoid model in vitro, as shown in Figures 1-5 (the results of some compounds of the present invention are not shown), compounds 4, 6, 8, and 9 of the present invention can restore cell morphology when treated with DGC organoid models at a concentration of 2.5 μM, and the effects of compounds 8 and 9 are significantly better than Defactinib. At the same time, it is also clearly observed that it has a better inhibitory effect on cell proliferation than Defactinib.
2.使用来自CellTiter-Glo(Promega G7570)的试剂和方案进行细胞活力评估。将50μL CellTiter-Glo试剂和50μL培养基混合后加入每个孔中，并在室温下轻轻摇动板30分钟，使基质胶溶解，在Tecan读板器上读取板。2. Cell viability assessment was performed using reagents and protocols from CellTiter-Glo (Promega G7570). Mix 50 μL of CellTiter-Glo Reagent and 50 μL of culture medium into each well, shake the plate gently for 30 minutes at room temperature to dissolve the Matrigel, and read the plate on a Tecan plate reader.
实验结果表明本发明化合物均可以抑制人弥漫性类器官细胞模型的细胞生长。如图6所示，在2.5μM时，化合物9相对于Defactinib可以更显著抑制细胞增殖。The experimental results show that all the compounds of the present invention can inhibit the cell growth of human diffuse organoid cell model. As shown in Figure 6, at 2.5 μM, Compound 9 can inhibit cell proliferation more significantly than Defactinib.
3.通过上述方法进行细胞培养以及给药培养48小时后，对细胞进行裂解，提取蛋白质，利用Western Blot技术进行蛋白检测，凝胶成像后进行蛋白条带的灰度值分析，考察化合物在DGC类器官模型当中对磷酸化的FAK(P-FAK(Y397))以及活化的YAP的影响。(详细方法参见Haisheng Zhang,Cancer Discovery,2020)。结果如图7-8所示。3. After 48 hours of cell culture and drug administration by the above method, the cells were lysed, the protein was extracted, and the protein was detected by Western Blot technology. Effects on phosphorylated FAK (P-FAK(Y397)) and activated YAP in organoid models. (For detailed methods, see Haisheng Zhang, Cancer Discovery, 2020). The result is shown in Figure 7-8.
实验结果表明，本发明化合物在DGC类器官模型中，可以抑制FAK的磷酸化(抑制FAK激酶活性，减少磷酸化的FAK)，同时减少活化的YAP，且呈现剂量依赖型。而Defactinib却不能抑制YAP活性。Experimental results show that the compound of the present invention can inhibit the phosphorylation of FAK (inhibit FAK kinase activity, reduce phosphorylated FAK) and reduce activated YAP in a dose-dependent manner in the DGC organoid model. However, Defactinib could not inhibit the activity of YAP.
试验例3：化合物体外在人弥漫性胃癌肿瘤细胞系SNU668模型中的药效学评价Test Example 3: Pharmacodynamic evaluation of the compound in vitro in the human diffuse gastric cancer tumor cell line SNU668 model
1.细胞铺板1. Cell Plating
a.SNU-668细胞(供应商：KCLB；货号：00668)长到70％-80％，吸除培养基上清，用PBS润洗一次吸除；a. SNU-668 cells (supplier: KCLB; article number: 00668) grow to 70%-80%, remove the medium supernatant, rinse with PBS once and remove;
b.10cm皿中加入1ml 0.25％胰酶，左右上下摇晃均匀，放入培养箱中消化2-3min；b. Add 1ml of 0.25% trypsin to a 10cm dish, shake it up and down evenly, put it in an incubator for 2-3 minutes to digest;
c.拿出培养皿，加入2-3ml完全培养基终止消化，移至15ml离心管中，放入离心机中1000rpm离心5min；c. Take out the petri dish, add 2-3ml of complete medium to stop digestion, transfer to a 15ml centrifuge tube, and centrifuge at 1000rpm for 5min in a centrifuge;
d.吸除上清，加入1ml完全培养基重悬，计数；d. Aspirate the supernatant, add 1ml of complete medium to resuspend, and count;
e.拿出12孔板，每孔铺150000个细胞和900μL培养基，放入细胞培养箱中过夜培养。e. Take out the 12-well plate, spread 150,000 cells and 900 μL medium in each well, and put it into the cell culture incubator for overnight culture.
2.细胞给药2. Cell Delivery
a.提前拿出小分子药物母液Defactinib、IN10018、化合物24、化合物25、化合物26、化合物27、化合物28、DMSO溶化，并吹打数次混合均匀；a. Take out the small molecule drug mother solution Defactinib, IN10018, compound 24, compound 25, compound 26, compound 27, compound 28, DMSO to dissolve in advance, and mix well by pipetting several times;
b.每个小分子每孔的给药浓度为1μM或2.5μM，先用1mM或2.5mM的stock，用培养基分别将每种小分子稀释成10μM或25μM；b. The administration concentration of each small molecule in each well is 1 μM or 2.5 μM, first use 1 mM or 2.5 mM stock, and use medium to dilute each small molecule to 10 μM or 25 μM respectively;
c.拿出种好细胞的培养板，标记好每孔的编号，分别将对应的小分子及浓度，用200μL移液枪吸100μL轻轻的一滴一滴地绕着圈加入孔中；c. Take out the culture plate in which the cells have been seeded, mark the number of each well, and use a 200 μL pipette to suck up 100 μL of the corresponding small molecules and concentrations, and gently add them to the wells in circles drop by drop;
d.所有的孔都加完后，稍微晃两下，使药物扩散均匀，记录好时间，放回细胞培养箱中。d. After adding all the wells, shake it a little to make the drug diffuse evenly, record the time, and put it back into the cell culture incubator.
3.提取蛋白3. Protein extraction
a.给药24h或48h后，弃培养基，用PBS清洗，弃去PBS；a. After 24h or 48h of administration, discard the medium, wash with PBS, and discard the PBS;
b.在孔板中加入用含磷酸酶抑制剂和PMSF的RIPA裂解液裂解细胞，12000rpm离心5min，取上清，测定蛋白浓度并调整蛋白浓度，加入4×loading buffer，煮蛋白。b. Add RIPA lysate containing phosphatase inhibitors and PMSF to the well plate to lyse the cells, centrifuge at 12000rpm for 5min, take the supernatant, measure the protein concentration and adjust the protein concentration, add 4×loading buffer, and cook the protein.
4.WB检测4. WB detection
进行SDS-PAGE电泳：80v,30mm,120v,60min；转膜：80v,60min；封闭：5％脱脂牛奶1h，一抗(non-p-YAP(1：1500，Abcam)，p-FAK Y397(1:1000，CST)，actin(1：10000，CST)：用5％BSA·TBST配制，4℃过夜孵育；二抗(Goat-anti-mouse-IgG和Goat-anti-rabbit-IgG，1:3000，Proteintech)：用5％脱脂牛奶配制，室温孵育1-2h。SDS-PAGE electrophoresis: 80v, 30mm, 120v, 60min; transfer membrane: 80v, 60min; blocking: 5% skimmed milk for 1h, primary antibody (non-p-YAP (1:1500, Abcam), p-FAK Y397( 1:1000, CST), actin (1:10000, CST): prepared with 5% BSA·TBST, incubated overnight at 4°C; secondary antibodies (Goat-anti-mouse-IgG and Goat-anti-rabbit-IgG, 1: 3000, Proteintech): prepared with 5% skimmed milk, incubated at room temperature for 1-2h.
结果如图9-10所示，结果显示本发明化合物在人弥漫性胃癌肿瘤细胞系SNU668模型中，可以抑制FAK的磷酸化(抑制FAK激酶活性，减少磷酸化的FAK)，同时减少活化的YAP。而Defactinib和IN10018却没有抑制YAP活性的效果。The results are shown in Figures 9-10. The results show that the compound of the present invention can inhibit the phosphorylation of FAK (inhibit FAK kinase activity and reduce phosphorylated FAK) in the human diffuse gastric cancer tumor cell line SNU668 model, while reducing the activated YAP . However, Defactinib and IN10018 did not inhibit the activity of YAP.
按前述SNU668的培养和给药方法，在96孔细胞板，铺1000细胞/孔。第二天加入0.5uM和2.5μM的Defactinib和化合物9，加药后的第2、4和6天，使用来自CellTiter-Glo(Promega G7570)的试剂和方案进行细胞活力评估。将50μL CellTiter-Glo试剂和50μL培养基混合后加入每个孔中，并在室温下轻轻摇动板30分钟，在Tecan读板器上读取板。According to the aforementioned culture and administration method of SNU668, 1000 cells/well were plated in a 96-well cell plate. 0.5uM and 2.5uM Defactinib and Compound 9 were added the next day, and cell viability was assessed using reagents and protocols from CellTiter-Glo (Promega G7570) on days 2, 4 and 6 after dosing. Mix 50 μL of CellTiter-Glo Reagent and 50 μL of medium into each well, shake the plate gently for 30 minutes at room temperature, and read the plate on a Tecan plate reader.
实验结果表明本发明化合物9可以抑制人弥漫性胃癌肿瘤细胞系模型的细胞生长。如图11示，在0.5μM和2.5μM时，化合物9相对于Defactinib可以更显著抑制细胞增殖。The experimental results show that the compound 9 of the present invention can inhibit the cell growth of the human diffuse gastric cancer tumor cell line model. As shown in Figure 11, at 0.5 μM and 2.5 μM, Compound 9 can inhibit cell proliferation more significantly than Defactinib.
因此，本发明化合物可以通过抑制FAK激酶活性和/或减少活化的YAP，以达到治疗疾病(尤其是癌症)的目的。Therefore, the compound of the present invention can achieve the purpose of treating diseases (especially cancer) by inhibiting FAK kinase activity and/or reducing activated YAP.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (13)

  1. 一种式I化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，A compound of formula I, or its enantiomer, diastereoisomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or its pharmaceutical acceptable salts, hydrates, solvates, isotopes or prodrugs of
    Figure PCTCN2022117868-appb-100001
    Figure PCTCN2022117868-appb-100001
    其中，in,
    A环独立地选自：C3-C20杂芳基和C6-C20芳基，例如5-6元杂芳基和苯基；Ring A is independently selected from: C3-C20 heteroaryl and C6-C20 aryl, such as 5-6 membered heteroaryl and phenyl;
    B环独立地选自：C3-C20杂芳基和C6-C20芳基，例如5-6元杂芳基和苯基；优选地，B环为六元芳基或杂芳基；Ring B is independently selected from: C3-C20 heteroaryl and C6-C20 aryl, such as 5-6 membered heteroaryl and phenyl; preferably, B ring is a six-membered aryl or heteroaryl;
    L独立地选自：键或CH 2，优选地，L为CH 2； L is independently selected from: a bond or CH 2 , preferably, L is CH 2 ;
    X独立地选自CH或N，优选地，X为N；X is independently selected from CH or N, preferably, X is N;
    R 1独立地选自：卤素、-C(＝O)N(CH 3) 2、-C(＝O)NHCH 3、-C(＝O)NH 2、-CH(＝O)、-COOH、CN、C1-C6烷基、-CF 3、-CHF 2、-CH 2F、-CO 2CH 3； R 1 is independently selected from the group consisting of halogen, -C(=O)N(CH 3 ) 2 , -C(=O)NHCH 3 , -C(=O)NH 2 , -CH(=O), -COOH, CN, C1-C6 alkyl, -CF 3 , -CHF 2 , -CH 2 F, -CO 2 CH 3 ;
    R 2独立地选自：-N(R 5)S(O) mR 6、-P(＝O)R' 5R' 6、-S(O) mNR 5R 6、-C(＝O)NR 5R 6、-NR 5C(＝O)R 6、-C(＝O)R 5、-C(＝O)OR 5、-OC(＝O)R 5、-S(O) mR 5； R 2 is independently selected from: -N(R 5 )S(O) m R 6 , -P(=O)R' 5 R' 6 , -S(O) m NR 5 R 6 , -C(=O )NR 5 R 6 , -NR 5 C(=O)R 6 , -C(=O)R 5 , -C(=O)OR 5 , -OC(=O)R 5 , -S(O) m R 5 ;
    R 3各自独立地选自：-H、-OH、卤素、-CF 3、-CHF 2、-CH 2F、-CN、-NO 2、-NR 5R 6、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述的C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基可以被1-3个R 9取代； Each R 3 is independently selected from: -H, -OH, halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -NO 2 , -NR 5 R 6 , C1-C6 alkyl, C1- C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heterocyclic Aryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3- C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 R9 ;
    R 4各自独立地选自：-H、-OR 5、卤素、-CF 3、-CHF 2、-CH 2F、-CN、-NO 2、-NR 5R 6、-C(＝O)NR 5R 6、-C(＝O)NR 5OR 6、-C(R 5)＝NR 6、-NR 5C(＝O)R 6、-C(＝O)R 5、-C(＝O)C(＝O)R 5、-C(＝O)OR 5、-OC(＝O)R 5、-OC(＝O)OR 5、-P(＝O)R' 5R' 6、-S(＝O)(＝NR 5)R 6、-S(O) mR 5、-NR 5S(O) mR 6、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基可以被1-3个R 9取代； Each R 4 is independently selected from: -H, -OR 5 , halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -NO 2 , -NR 5 R 6 , -C(=O)NR 5 R 6 , -C(=O)NR 5 OR 6 , -C(R 5 )=NR 6 , -NR 5 C(=O)R 6 , -C(=O)R 5 , -C(=O )C(=O)R 5 , -C(=O)OR 5 , -OC(=O)R 5 , -OC(=O)OR 5 , -P(=O)R' 5 R' 6 , - S(=O)(=NR 5 )R 6 , -S(O) m R 5 , -NR 5 S(O) m R 6 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkene Base, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1- C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl , 5-10 membered heteroaryl can be substituted by 1-3 R9 ;
    或者任意相邻的两个R 4和与它们连接的原子共同形成的C5-C7环烷基、5-7元杂环基、苯基、5-6元杂芳基；其中，所述C5-C7环烷基、5-7元杂环基、苯基、5-6元杂芳基可以被1-3个R 9取代； Or any adjacent two R 4 and the C5-C7 cycloalkyl, 5-7 membered heterocyclic group, phenyl, 5-6 membered heteroaryl that are jointly formed with their connected atoms; Wherein, the C5- C7 cycloalkyl, 5-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl can be substituted by 1-3 R9 ;
    R 5、R 6、R' 5和R' 6各自独立地选自：H、-OH、卤素、-CF 3、-CHF 2、-CH 2F、-CN、-NO 2、-CH 2CF 3、-NR 7R 8、-S(O) mR 7、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；或者在NR 7R 8中，R 7和R 8与其连接的N原子共同形成3-10元杂环基(包括桥环以及螺环)；其中，所述C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基可以被1-3个R 9取代； R 5 , R 6 , R' 5 and R' 6 are each independently selected from: H, -OH, halogen, -CF 3 , -CHF 2 , -CH 2 F, -CN, -NO 2 , -CH 2 CF 3. -NR 7 R 8 , -S(O) m R 7 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3 -12-membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group; or in NR 7 R 8 , R 7 and R 8 together form a 3- 10-membered heterocyclic group (including bridged ring and spiro ring); wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group can be substituted by 1-3 R9 ;
    R 9各自独立地选自：H、-OH、氧代基(＝O)、卤素、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CN、-NO 2、-OR 10、-C(＝O)R 10、-OC(＝O)R 10、-OC(＝O)R 10、-OC(＝O)OR 10、-C(＝O)NR 10R 11、-NR 10C(＝O)NR 11R 12、-NR 10R 11、-NR 10C(＝O)R 11、-NR 10S(O) mR 11、-S(O) mR 10、-S(O) mNR 10、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述的C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基可以被1-3个选自下组的基团取代：C1-C6烷基、卤素、-OH、-CN、-NO 2、-CHF 2、-CH 2CF 3、-CF 3、-C(O)R 13、-C(O)NR 13R 14、-S(O) mR 13、-S(O) mNR 13R 14取代； Each R 9 is independently selected from: H, -OH, oxo (=O), halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , - OR 10 , -C(=O)R 10 , -OC(=O)R 10 , -OC(=O)R 10 , -OC(=O)OR 10 , -C(=O)NR 10 R 11 , -NR 10 C(=O)NR 11 R 12 , -NR 10 R 11 , -NR 10 C(=O)R 11 , -NR 10 S(O) m R 11 , -S(O) m R 10 , -S(O) m NR 10 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3 -C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl can be substituted by 1-3 groups selected from the group below: C1-C6 alkyl, halogen, -OH, -CN, -NO 2 , -CHF 2 , -CH 2 CF 3 , -CF 3 , -C(O)R 13 , -C(O)NR 13 R 14 , -S(O) m R 13 , -S(O) m NR 13 R 14 are substituted;
    R 7、R 8、R 10、R 11、R 12、R 13和R 14各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中， 所述的C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基可以被1-3个选自下组的基团取代：-OH、卤素、-CN、-NO 2、-NH 2、-CHF 2、-CH 2CF 3、-CF 3、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、-C(O)-(C1-C6烷氧基)、C3-C12环烷基、3-12元杂环烷基、C1-C6烷基胺； R 7 , R 8 , R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 Alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 The heteroaryl group may be substituted by 1-3 groups selected from the group consisting of -OH, halogen, -CN, -NO 2 , -NH 2 , -CHF 2 , -CH 2 CF 3 , -CF 3 , C1 -C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -C(O)-(C1-C6 alkoxy), C3-C12 cycloalkyl, 3-12 members Heterocycloalkyl, C1-C6 alkylamine;
    n和n'各自独立地选自0、1、2、3或4；n and n' are each independently selected from 0, 1, 2, 3 or 4;
    m独立地选自0、1或2。m is independently selected from 0, 1 or 2.
  2. 如权利要求1所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，其特征在于，
    Figure PCTCN2022117868-appb-100002
    选自：
    Figure PCTCN2022117868-appb-100003
    Figure PCTCN2022117868-appb-100004
    The compound as claimed in claim 1, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or a pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof, characterized in that,
    Figure PCTCN2022117868-appb-100002
    selected from:
    Figure PCTCN2022117868-appb-100003
    Figure PCTCN2022117868-appb-100004
    其中，p为0、1或2；Wherein, p is 0, 1 or 2;
    R 4的定义如权利要求1所述。 The definition of R 4 is as described in claim 1.
  3. 如权利要求1所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，其特征在于，所述化合物具有式II、式III、式IV或式V所示的结构The compound as claimed in claim 1, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites Or its pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug, it is characterized in that, described compound has the structure shown in formula II, formula III, formula IV or formula V
    Figure PCTCN2022117868-appb-100005
    Figure PCTCN2022117868-appb-100005
    其中，in,
    p为0、1或2；p is 0, 1 or 2;
    R 1、R 2、R 3、R 4、R 5、R 6、B和n'的定义如权利要求1所述。 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , B and n' are as defined in claim 1.
  4. 如权利要求1所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，其特征在于，R 1独立地选自：F、Cl、-C(＝O)NH 2、-CH(＝O)、-COOH、-CN、C1-C6烷基、-CF 3、-CHF 2、-CH 2F。 The compound as claimed in claim 1, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or a pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof, characterized in that R 1 is independently selected from: F, Cl, -C(=O)NH 2 , -CH(=O) , -COOH, -CN, C1-C6 alkyl, -CF 3 , -CHF 2 , -CH 2 F.
  5. 如权利要求1-4任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，其特征在于，B环选自：苯基、吡啶基或吡嗪基。The compound as claimed in any one of claims 1-4, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen Oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, characterized in that ring B is selected from: phenyl, pyridyl or pyrazinyl.
  6. 如权利要求1-5中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，其特征在于，R 4独立地选自：H、卤素、C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基、-C(O)NR 5R 6；其中，R 5和R 6各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，所述的C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基可以被选自下组的1-3个取代基取代：卤素、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CN、-NO 2、C1-C6烷基、C1-C6烷氧基。 The compound according to any one of claims 1-5, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, Nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, characterized in that R4 is independently selected from: H, halogen, C1-C6 alkyl, C1-C6 Alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered heteroaryl, -C(O)NR 5 R 6 ; Among them, R 5 and R 6 Each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5 -10 membered heteroaryl; wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C6-C10 aryl, 5-10 membered Heteroaryl may be substituted by 1-3 substituents selected from the group consisting of halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkane Group, C1-C6 alkoxy group.
  7. 如权利要求1-6中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，其特征在于，R 1独立地选自：F、Cl、-C(＝O)NH 2、-CH(＝O)、-COOH、-CN、甲基、-CF 3、-CHF 2、-CH 2F；和/或 The compound according to any one of claims 1-6, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, Nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, characterized in that R 1 is independently selected from: F, Cl, -C(=O)NH 2 , -CH(=O), -COOH, -CN, methyl, -CF3 , -CHF2 , -CH2F ; and/or
    R 4各自独立地选自：F、Cl、C1-C6烷氧基、C3-C6环烷基、3-6元杂环基、-C(＝O)NH(C1-C6烷基)、-C(＝O)NH(C3-C6环烷基)、-C(＝O)NH(3-6元杂环基)；其中，所述C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、3-6元杂环基可以被选自下组的1-3个取代基取代：卤素、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CN、-NO 2、C1-C6烷基、C1-C6烷氧基；和/或 R 4 are each independently selected from: F, Cl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, -C (=O) NH (C1-C6 alkyl), - C(=O)NH(C3-C6 cycloalkyl), -C(=O)NH(3-6 membered heterocyclyl); wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3 -C6 cycloalkyl, 3-6 membered heterocyclic group can be substituted by 1-3 substituents selected from the group: halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , - CN, -NO 2 , C1-C6 alkyl, C1-C6 alkoxy; and/or
    R 2独立地选自：-N(R 5)S(O) mR 6、-P(＝O)R' 5R' 6、-S(O) mR 5；其中，R 5、R 6、R' 5和R' 6各自独立地选自：H、-OH、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基；其中，m为1或2；和/或 R 2 is independently selected from: -N(R 5 )S(O) m R 6 , -P(=O)R' 5 R' 6 , -S(O) m R 5 ; wherein, R 5 , R 6 , R'5 and R'6 are each independently selected from: H, -OH, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl , 3-12 membered heterocyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group; wherein, m is 1 or 2; and/or
    R 3各自独立地选自：-S(O) 2CH 3、-NCH 3S(O) 2CH 3、-NHS(O) 2CH 3、-P(＝O)(CH 3) 2、-P(＝O)(OH) 2；和/或 Each R 3 is independently selected from: -S(O) 2 CH 3 , -NCH 3 S(O) 2 CH 3 , -NHS(O) 2 CH 3 , -P(=O)(CH 3 ) 2 , - P(=O)(OH) 2 ; and/or
    Figure PCTCN2022117868-appb-100006
    选自：
    Figure PCTCN2022117868-appb-100007
    Figure PCTCN2022117868-appb-100006
    selected from:
    Figure PCTCN2022117868-appb-100007
  8. 如权利要求1-7任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，其特征在于，所述化合物具有下组其中之一的结构：The compound as claimed in any one of claims 1-7, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen Oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof, characterized in that the compound has a structure of one of the following groups:
    Figure PCTCN2022117868-appb-100008
    Figure PCTCN2022117868-appb-100008
    Figure PCTCN2022117868-appb-100009
    Figure PCTCN2022117868-appb-100009
    其中，in,
    R 1、R 2、R 3、R 4的定义同所述式I、式II、式III、式IV或式V，R 5和R 6各自独立地选自：H、C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C3-C12环烯基、C6-C10芳基、5-10元杂芳基，R’选自C1-C6烷基；其中，所述的C1-C6烷基、C1-C6烷氧基、C3-C12环烷基、3-12元杂环基、C6-C10芳基、5-10元杂芳基可以被选自下组的1-3个取代基取代：卤素、-CF 3、-CHF 2、-CH 2F、-CH 2CF 3、-CN、-NO 2、C1-C6烷基、C1-C6烷氧基； The definitions of R 1 , R 2 , R 3 , and R 4 are the same as those of formula I, formula II, formula III, formula IV or formula V, and R 5 and R 6 are each independently selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl, R' is selected from C1-C6 Alkyl group; wherein, the C1-C6 alkyl group, C1-C6 alkoxy group, C3-C12 cycloalkyl group, 3-12 membered heterocyclic group, C6-C10 aryl group, and 5-10 membered heteroaryl group can be Substituted by 1-3 substituents selected from the group consisting of halogen, -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkyl, C1- C6 alkoxy;
    优选地，所述化合物具有如下结构之一：Preferably, the compound has one of the following structures:
    Figure PCTCN2022117868-appb-100010
    Figure PCTCN2022117868-appb-100010
  9. 一种药物组合物，其包含如权利要求1-8中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药；和药学上可接受的载体、稀释剂或赋形剂；优选地，所述药物组合物还包含选自下组的一种或多种：化疗药物、PD-1抑制剂、PD-1抗体、PD-L1抑制剂、PD-L1抗体、ALK抑制剂、PI3K抑制剂、BTK抑制剂、EGFR抑制剂、EGFR抗体、VEGFR抑制剂、VEGFR抗体、HDAC抑制剂、CDK抑制剂、MEK抑制剂、Akt抑制剂、mTOR抑制剂、SHP2抑制剂、KRAS G12C抑制剂、KRAS G12D抑制剂、KRAS G12V抑制剂、c-MET抑制剂、Her2抑制剂、Her2抗体、Claudin18.2抗体。A pharmaceutical composition comprising the compound according to any one of claims 1-8, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers Conformers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, solvates, isotopes or prodrugs thereof; and pharmaceutically acceptable carriers, diluents or excipients; preferably Preferably, the pharmaceutical composition further comprises one or more selected from the group consisting of chemotherapy drugs, PD-1 inhibitors, PD-1 antibodies, PD-L1 inhibitors, PD-L1 antibodies, ALK inhibitors, PI3K Inhibitors, BTK inhibitors, EGFR inhibitors, EGFR antibodies, VEGFR inhibitors, VEGFR antibodies, HDAC inhibitors, CDK inhibitors, MEK inhibitors, Akt inhibitors, mTOR inhibitors, SHP2 inhibitors, KRAS G12C inhibitors, KRAS G12D inhibitor, KRAS G12V inhibitor, c-MET inhibitor, Her2 inhibitor, Her2 antibody, Claudin18.2 antibody.
  10. 一种如权利要求1-8中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如权利要求9所述的药物组合物在制备用于预防或治疗与FAK相关疾病的药物中的用途；优选地，所述的FAK相关疾病为癌症、肺动脉高压、或病理性血管生成；更优选地，所述癌症选自：皮肤癌、骨癌、神经胶质瘤、乳腺癌、肾上腺癌、膀胱癌、食道癌、头部或颈部癌症、肝癌、甲状旁腺癌、***癌、小肠癌、甲状腺癌、尿道癌、子***、子宫内膜癌、输卵管癌、肾盂癌、***癌、外阴癌、慢性或急性白血病、结肠癌、黑色素瘤、血液***恶性肿瘤、霍奇金淋巴瘤、肺癌、淋巴细胞性淋巴瘤、中枢神经***肿瘤(CNS)、卵巢癌、胰腺癌、垂体腺瘤、***癌、软组织肉瘤、胃癌、子宫癌。A compound as described in any one of claims 1-8, or its enantiomers, diastereomers, racemates, tautomers, stereoisomers, geometric isomers Body, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, solvate, isotope or prodrug thereof, or the pharmaceutical composition as claimed in claim 9 is used for preventing or treating diseases related to FAK The purposes in the medicine; Preferably, described FAK related disease is cancer, pulmonary arterial hypertension, or pathological angiogenesis; More preferably, described cancer is selected from: skin cancer, bone cancer, glioma, breast cancer , adrenal gland, bladder, esophagus, head or neck, liver, parathyroid, penis, small intestine, thyroid, urethra, cervix, endometrium, fallopian tube, renal pelvis , vaginal cancer, vulvar cancer, chronic or acute leukemia, colon cancer, melanoma, hematological malignancies, Hodgkin's lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer , Pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, uterine cancer.
  11. 一种制备如权利要求1所述的化合物的方法，其特征在于，包括步骤A method for preparing a compound as claimed in claim 1, characterized in that it comprises the steps
    Figure PCTCN2022117868-appb-100011
    Figure PCTCN2022117868-appb-100011
    s4)在惰性溶剂中，催化剂存在下，化合物I-1与I-2发生反应，得到式I化合物；s4) In an inert solvent, in the presence of a catalyst, compound I-1 reacts with I-2 to obtain a compound of formula I;
    式中，X'为卤素；In the formula, X' is halogen;
    优选地，所述方法还包括步骤：Preferably, the method also includes the steps of:
    Figure PCTCN2022117868-appb-100012
    Figure PCTCN2022117868-appb-100012
    s1)在惰性溶剂(如i-PrOH)中，碱(如DIPEA)存在下，化合物I-3与I-4发生反应，得到式I-5化合物；s1) In an inert solvent (such as i-PrOH), in the presence of a base (such as DIPEA), react compound I-3 with I-4 to obtain a compound of formula I-5;
    s2)在惰性溶剂(如DMF)中，催化剂(如Pd(PPh 3) 2Cl 2和CuI)存在下和碱性(如DIPEA)条件下，化合物I-5与I-6发生反应，得到式I-7化合物； s2) In an inert solvent (such as DMF), in the presence of a catalyst (such as Pd(PPh 3 ) 2 Cl 2 and CuI) and under basic (such as DIPEA) conditions, compound I-5 reacts with I-6 to obtain the formula I-7 compound;
    s3)在惰性溶剂(如NMP)中，碱性(如tBuOK)存在下，化合物I-7发生反应，得到式I-1化合物；s3) In an inert solvent (such as NMP), in the presence of a base (such as tBuOK), compound I-7 is reacted to obtain a compound of formula I-1;
    式中，In the formula,
    X'、X”和X”'各自独立地为卤素(如Cl、Br、I)；X', X" and X"' are each independently halogen (such as Cl, Br, I);
    A环、B环、X、L、R 1、R 2、R 3、R 4、n和n'的定义如权利要求1所述。 The definitions of ring A, ring B, X, L, R 1 , R 2 , R 3 , R 4 , n and n' are as described in claim 1.
  12. 一种治疗FAK相关疾病的方法，其特征在于，所述方法包括给予被鉴定或诊断为具有FAK 相关疾病的受试者治疗有效量的如权利要求1-8中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如权利要求9所述的药物组合物。A method for treating FAK-related diseases, characterized in that the method comprises administering a therapeutically effective amount of the compound according to any one of claims 1-8 to a subject identified or diagnosed as having a FAK-related disease, or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts thereof, Hydrate, solvate, isotope or prodrug, or pharmaceutical composition as claimed in claim 9.
  13. 一种用于抑制细胞或受试者中的FAK激酶活性的方法，其特征在于，所述方法包括使所述细胞接触或向所述受试者施用权利要求1-8中任一项所述的化合物、或其对映异构体、非对映异构体、消旋体、互变异构体、立体异构体、几何异构体、氮氧化物、代谢产物或其药学上可接受的盐、水合物、溶剂化物、同位素或前药，或如权利要求9所述的药物组合物的步骤；优选地，所述细胞为哺乳动物细胞；优选地，所述受试者为哺乳动物；更优选为人。A method for inhibiting FAK kinase activity in a cell or a subject, wherein the method comprises contacting the cell or administering any one of claims 1-8 to the subject. or its enantiomers, diastereoisomers, racemates, tautomers, stereoisomers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable Salt, hydrate, solvate, isotope or prodrug of the salt, hydrate, solvate, isotope or prodrug, or the step of the pharmaceutical composition as claimed in claim 9; Preferably, the cell is a mammalian cell; Preferably, the subject is a mammal ; more preferably a human.
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