WO2022253081A1 - Dérivé d'oxyde de phosphine, son procédé de préparation et son application - Google Patents

Dérivé d'oxyde de phosphine, son procédé de préparation et son application Download PDF

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WO2022253081A1
WO2022253081A1 PCT/CN2022/095064 CN2022095064W WO2022253081A1 WO 2022253081 A1 WO2022253081 A1 WO 2022253081A1 CN 2022095064 W CN2022095064 W CN 2022095064W WO 2022253081 A1 WO2022253081 A1 WO 2022253081A1
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amino
phenyl
pyrimidin
cancer
trifluoromethyl
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PCT/CN2022/095064
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Chinese (zh)
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张海生
代长贵
程辉敏
牛春意
陈誉
方磊
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希格生科（深圳）有限公司
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Priority to CN202280039481.XA priority Critical patent/CN117412981A/zh
Publication of WO2022253081A1 publication Critical patent/WO2022253081A1/fr

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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus

Definitions

  • the invention belongs to the field of medicine, and relates to a phosphine oxide derivative, a preparation method and application thereof.
  • 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 is considered as a potential target for anticancer drug development.
  • 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 necessary to develop new FAK inhibitors.
  • the object of the present invention is to provide a compound that can be used as a focal adhesion kinase (FAK) inhibitor, its preparation method, a medicament or a composition containing this compound, and use this compound to treat diseases caused by excessive or abnormal cell proliferation, such as cancer Methods.
  • FAK focal adhesion kinase
  • the compound provided by the invention has good clinical application prospect.
  • the compound of the invention not only has a good inhibitory effect on FAK, but also has better pharmacokinetic, drug efficacy and toxicological properties.
  • A is selected from: 5-6 membered heteroaryl or phenyl
  • X is selected from: CH or N;
  • R 1 and R 2 are each independently selected from the following groups of substituted or unsubstituted groups: hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 3-6 membered heterocyclic group; Or R 1 and R 2 together form a 3-6 membered heterocyclic group with the P atom they are connected to;
  • R 3 is independently selected from: halogen, C1-C6 alkyl, C3-C6 cycloalkyl, CF 3 , CHF 2 , CH 2 F, CN, NO 2 , CONR a R b ; wherein, R a and R b are each Independently selected from: H, C1-C6 alkyl, C3-C6 cycloalkyl;
  • R 4 is independently selected from: H, OH, halogen, CF 3 , CHF 2 , CH 2 F, CN, NO 2 , NR 11 R 12 , 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 aromatic Base, 5-10 membered heteroaryl can be substituted by 1-3 R 13 ;
  • R 5 is selected from: OR 10 , CH 2 R 19 , H, OH, halogen, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , -CN, -NO 2 , -S(O) m R 11 , 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 group, C6-C10 aryl group, 5-10 membered heteroaryl group can
  • R 6 and R 7 form a 5-7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl with the atoms connected to them; wherein, the cycloalkyl, heterocyclyl, aryl, and heteroaryl Can be replaced by 1-3 R 13 ;
  • R 8 , R 9 and the atoms connected to them form 5-7 membered cycloalkyl, heterocyclyl, aryl, heteroaryl; wherein, the cycloalkyl, heterocyclyl, aryl, heteroaryl Can be replaced by 1-3 R 13 ;
  • R 5 and R 7 or R 9 form a 5-7 membered cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group with the atom connected to it; wherein, the cycloalkyl group, heterocyclyl group, aryl group, Heteroaryl can be substituted by 1-3 R 13 ;
  • R 10 , R 11 and R 12 are independently selected from: H, OH, halogen, CF 3 , CHF 2 , CH 2 F, CN, NO 2 , CH 2 CF 3 , NR 14 R 15 , S(O) m R 14.
  • R 13 is independently selected from: H, OH, halogen, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , -CN, -NO 2 , OR 14 , C(O)R 14 , OC(O)R 14 , OC(O)R 14 , -OC(O)OR 14 , -C(O)NR 14 R 15 , -NR 14 C(O)NR 15 R 16 , -NR 14 R 15 , -NR 14 C( O)R 15 , -NR 14 S(O) m R 15 , -S(O) m R 14 , -S(O) m NR 14 , 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
  • R 14 , R 15 , R 16 , R 17 and R 18 are each independently selected from: H, 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 groups selected from the following group: OH, halogen, CN, NO 2 , NH 2 , CHF 2 , CH 2 CF 3
  • R 19 is a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group may be substituted by a group selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl Base, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclyl, C3-C12 cycloalkenyl, C6-C10 aryl, 5-10 membered heteroaryl;
  • n is independently selected from 0, 1, 2, 3 or 4;
  • n is independently selected from 0, 1 or 2;
  • R 5 is independently OR 10 , CH 2 R 19 or -S(O) m R 11 ;
  • R 6 and R 7 form 5-7 membered cycloalkyl, heterocyclyl, aryl, and heteroaryl with the atoms connected to them; wherein, the cycloalkyl, heterocyclyl , aryl, heteroaryl can be substituted by 1-3 R 13 .
  • R 5 is independently OR 10 , CH 2 R 19 or -S(O) m R 11 ;
  • R 6 and R 7 form 5-7 membered cycloalkyl, heterocyclyl, aryl, and heteroaryl with the atoms connected to them; wherein, the cycloalkyl, heterocyclyl , aryl, heteroaryl can be substituted by 1-3 R 13 ,
  • R 10 , R 19 , R 11 , R 13 and m are as defined above.
  • R 5 is independently OR 10 ; wherein, the definition of R 10 is as above.
  • R 5 is independently selected from: H, OH, halogen, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , -CN, -NO 2 , -S(O) m R 11 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered hetero Cyclic group, C3-C12 cycloalkenyl group, C6-C10 aryl group, 5-10 membered heteroaryl group; wherein, the C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2- C6 alkynyl, C3-C12 cycloalkyl, 3-12 membered heterocyclic group, C3-C12 cycloalkenyl, C6-
  • X1 is N.
  • the 5-7 membered cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are selected from: 5-6 membered heterocyclic group or 5-6 membered heteroaryl group; preferably For pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxadiazolyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, thiazolyl, isothiazolyl, pyrazolyl, oxazole base, isoxazolyl, thiadiazolyl,
  • the heterocyclic group includes heterocycloalkyl or heterocycloalkenyl.
  • the compound has the structure shown in the following formula (I-1):
  • X 1 , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and n are as defined above.
  • the compound has the structure shown in the following formula (II-1):
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined above.
  • R 10 is selected from: H, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, 3-12 member 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 R 13 ; wherein , R 13 is as defined above.
  • R 10 is selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; wherein, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic group, phenyl or 5-
  • the 6-membered heteroaryl group can be substituted by 1-3 R 13 ; wherein, R 13 is as defined above.
  • R 6 , R 7 , R 8 and R 9 are each independently selected from: H, halogen, CF 3 , -CHF 2 , CH 2 F, CN, NO 2 , NR 11 R 12 , C1 -C6 alkyl, C1-C6 alkoxy; or the atoms connected to R 6 and R 7 form a 5-6 membered heterocyclic group or 5-6 membered heteroaryl; or R 8 , R 9 connected to them Atoms form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; wherein, the heterocyclic group and heteroaryl group can be substituted by 1-3 R 13 ;
  • R 11 , R 12 and R 13 are as defined above.
  • R 5 and R 6 or R 9 form a 5-6 membered heterocyclic group or a 5-6 membered heteroaryl group; wherein, the heterocyclic group and heteroaryl group can be 1-3 R 13 substitutions, R 13 as defined above.
  • the compound has the structure shown in the following formulas (I-2)-(I-7):
  • R 20 is selected from: H, OH, halogen, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkyl, C1-C6 alkoxy;
  • p 0, 1 or 2;
  • A, X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 and n are as defined above.
  • A is selected from: pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxadiazolyl, furyl, pyrrolyl, thienyl, Thiazolyl, isothiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl.
  • R 1 and R 2 can form a 4-6 membered heterocyclic group with the atoms they are connected to.
  • the heterocyclic group includes but not limited to the following groups:
  • * indicates the linking site.
  • R 3 is selected from: halogen, CF 3 , CHF 2 , CH 2 F, CN, C1-C6 alkyl.
  • R 4 is H, C1-C6 alkoxy, 3-6 membered cycloalkyl, 5-6 membered heteroaryl, 5-6 membered heterocyclic group, NR 11 R 12 , wherein, The 3-6-membered cycloalkyl group, 5-6-membered heteroaryl group, and 5-6-membered heterocyclic group may be substituted by C1-C6 alkyl groups; the definitions of R 11 and R 12 are as above.
  • R 4 is selected from: H or
  • R 4 is H, OH, halogen, CF 3 , CHF 2 , CH 2 F, CN or NO 2 .
  • A, X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 20 and n are in the embodiment The groups corresponding to each specific compound.
  • the compound is selected from:
  • 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 conformers, geometric isomers, nitrogen oxides, metabolites or pharmaceutically acceptable salts, hydrates, isotopes or prodrugs thereof; and pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition further comprises one or more selected from the following group: PD-1 inhibitors, PD-L1 inhibitors, ALK inhibitors, PI3K inhibitors, BTK inhibitors, EGFR Inhibitors, VEGFR inhibitors, HDAC inhibitors, CDK inhibitors, MEK inhibitors, Akt inhibitors, mTOR inhibitors, SHP2 inhibitors, or combinations thereof.
  • the third aspect of the present invention provides a use of the compound as described in the first aspect or the pharmaceutical composition as described in the second aspect in the preparation of a medicament for treating diseases related to FAK.
  • the FAK-related diseases include various cancers, pulmonary hypertension, and pathological angiogenesis.
  • the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer, adrenal gland cancer, bladder cancer, esophagus cancer, head or neck cancer, liver cancer, parathyroid cancer, Cancer of the penis, small intestine, thyroid, urethra, cervix, endometrium, fallopian tube, renal pelvis, vagina, vulva, chronic or acute leukemia, colon, melanoma, hematological malignancies, hormonal Oddkin'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, etc.
  • the cancer is gastric cancer.
  • the cancer is diffuse gastric cancer.
  • A, X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and n are as defined above.
  • the method also includes the steps of:
  • A, X 1 , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 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 a pharmaceutically effective amount thereof to a subject identified or diagnosed as having FAK-related diseases An acceptable salt or solvate, or the pharmaceutical composition as described in the second aspect.
  • 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 to the subject a compound as described in the first aspect Or the steps of the pharmaceutical composition as described in the second aspect.
  • the cells are mammalian cells.
  • the subject is a mammal, preferably a human.
  • Figure 1 shows the relationship between tumor volume and time in a mouse tumor model.
  • the present inventors unexpectedly discovered a class of compounds with better FAK kinase inhibitory activity.
  • 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. Preference is given to C1-C3 alkoxy.
  • heteroalkyl refers to a group in which the carbon atoms in the alkyl group are replaced by 1, 2, 3 heteroatoms selected from N, O, S, Si or P, and wherein the nitrogen and sulfur atoms are optionally Oxidized
  • C1-C6 heteroalkyl in the present invention refers to containing 1-6 (ie 1, 2, 3, 4, 5 or 6) carbon atoms, and 1, 2, 3 selected from N, O , S or P heteroatom groups, representative examples include (but not limited to): CH 3 OCH 2 -, CH 3 SCH 2 -, CH 3 CH 2 OCH 2 -, etc.
  • 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.
  • Representative 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.
  • heterocycles include, but are not limited to: azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidine base, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepine Gene group, 4-piperidinonyl, 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, heterocyclic or aromatic rings 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.
  • the terms "compound of the present invention” or “active ingredient of the present invention” are used interchangeably to refer to the compound of formula I and 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, X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and n are as defined above.
  • A is phenyl, and R 5 is independently OR 10 ; wherein, R 10 is as defined above.
  • the compound has a structure shown in the following formula (I-1):
  • X 1 , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 and n are as defined above.
  • the compound has a structure shown in the following formula (II-1):
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined above.
  • the compound has the structures shown in the following formulas (I-2)-(I-7):
  • R 20 is selected from: H, OH, halogen, CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 , -CN, -NO 2 , C1-C6 alkyl, C1-C6 alkoxy;
  • p 0, 1 or 2;
  • A, X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 and n are as defined above.
  • 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 , Hypamine (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 definitions of the compounds of the present invention include both cis (Z) and trans (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 present 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 pharmaceutical composition of the present invention is used for preventing and/or treating the following diseases: cancer, pulmonary hypertension, pathological angiogenesis and the like.
  • the compound of general formula I can be used in combination with other drugs known to treat or improve similar conditions.
  • the administration method and dose of the original drug can be kept unchanged, and the compound of formula I can be taken simultaneously or subsequently.
  • the pharmaceutical composition containing one or several known drugs and the compound of formula I can be preferably used.
  • Drug combinations also include administration of a compound of formula I and one or more other known drugs for overlapping periods of time.
  • the dosage of the compound of formula I or known drugs may be lower than that of their single administration.
  • Drugs or active ingredients that can be combined with the compound described in general formula I include but are not limited to: PD-1 inhibitors, PD-L1 inhibitors, ALK inhibitors, PI3K inhibitors, BTK inhibitors, EGFR inhibitors , a VEGFR inhibitor, an HDAC inhibitor, a CDK inhibitor, a MEK inhibitor, an Akt inhibitor, an mTOR inhibitor, a SHP2 inhibitor, or a combination thereof.
  • 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 pharmacologically 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 enough 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
  • 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 general formula I of the present invention or its crystal form, pharmaceutically acceptable salt, hydrate or solvate substances 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
  • A, X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and n are as defined above.
  • the compound of the present invention has excellent inhibitory ability to FAK kinase
  • 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 2 Synthesis of (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide
  • Step 3 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid
  • Step 4 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(((1 -Methylpiperidin-4-yl)methyl)benzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxybenzene formic acid
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxy- N-(((1-methylpiperidin-4-yl)methyl)benzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzene Formamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethyl Oxybenzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylbenzoic acid
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy- 3-(Methyl)benzamide
  • Step 1 4-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy base) benzoic acid
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy- 3-(Trifluoromethoxy)benzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(isopropoxy base) benzoic acid
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy- 3-(isopropoxy)benzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(ethoxy )benzoic acid
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy- 3-(Ethoxy)benzamide
  • Step 4 Synthesis of (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-5-morpholinephenyl)dimethylphosphine oxide
  • Step 5 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-morpholinephenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3 -Methoxybenzoic acid
  • Step 4 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-morpholinephenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N ,3-Dimethoxybenzamide
  • Step 1 Synthesis of 1'-(3-iodo-4-nitrophenyl)-1,4'-dipiperidine
  • Step 4 Synthesis of (5-([1,4'-dipiperidin]-1'-yl)-2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzene base) dimethyl phosphine oxide
  • Step 5 Synthesis of 4-((4-((4-([1,4'-bipyridyl]-1'-yl)-2-(dimethylphosphoryl)phenyl)amino)-5-(tri Fluoromethyl)pyrimidin-2-yl)amino)-3-methoxybenzoic acid
  • Step 4 Synthesis of 4-((4-((4-([1,4'-bipyridyl]-1'-yl)-2-(dimethylphosphoryl)phenyl)amino)-5-(tri Fluoromethyl)pyrimidin-2-yl)amino)-N,3-dimethoxybenzamide
  • Step 4 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxy- N-(methylsulfonyl)benzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxybenzene Formamide
  • Step 1 Synthesis of N-(benzyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) benzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-hydroxybenzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxy Ethoxy)benzamide
  • Step 3 Synthesis of benzyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate
  • Step 4 Synthesis of (R)-(2-amino-5-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)dimethylphosphine oxide
  • Step 5 Synthesis of (R)-4-((4-((4-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-(dimethylphosphoryl)phenyl)amino)- Benzyl 5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate
  • Step 6 Synthesis of (R)-4-((4-((4-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-(dimethylphosphoryl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid
  • Step 7 Synthesis of (R)-4-((4-((4-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-(dimethylphosphoryl)phenyl)amino)- 5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide
  • Step 3 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl ) Aminobenzylbenzyl ester
  • Step 4 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )amino)benzoic acid
  • Step 5 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )amino)-N-methoxybenzamide
  • Step 2 (2-amino-5-(4,4,5,5-tetramethyl-1,3-dioxo-2-borolan-2-yl)phenyl)dimethylphosphine oxide
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )amino)benzyl benzoate
  • Step 3 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )amino)benzoic acid
  • Step 4 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(pyridin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl )amino)-N-methoxybenzamide
  • Step 3 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoro Benzyl methyl)pyrimidin-2-yl)aminobenzoate
  • Step 4 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoro Methyl)pyrimidin-2-yl)aminobenzoic acid
  • Step 5 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoro Methyl)pyrimidin-2-yl)amino)-N-methoxybenzamide
  • Step 1 Synthesis of (2-amino-5-(2-(methylamino)pyrimidin-4-yl)phenyl)dimethylphosphine oxide
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(2-(methylamino)pyrimidin-4-yl)phenyl)amino)-5-(trifluoroform Base) pyrimidin-2-yl) amino) benzyl benzoate
  • Step 3 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(2-(methylamino)pyrimidin-4-yl)phenyl)amino)-5-(trifluoroform Base) pyrimidin-2-yl) amino) benzoic acid
  • Step 4 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(2-(methylamino)pyrimidin-4-yl)phenyl)amino)-5-(trifluoroform Base) pyrimidin-2-yl) amino) -N-methoxybenzamide
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoro Benzyl methyl)pyrimidin-2-yl)aminobenzoate
  • Step 3 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoro Methyl)pyrimidin-2-yl)aminobenzoic acid
  • Step 4 Synthesis of 4-((4-((2-(dimethylphosphoryl)-4-fluorophenyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino) -N-Methoxybenzamide
  • Step 5 Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methyl-2 ,3-Dihydrobenzofuran-4-carboxamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy -3-Methoxybenzamide
  • Step 1 Synthesis of N-(benzyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino )-3-methoxybenzamide
  • Step 1 Synthesis of N-(propoxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) benzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isopropoxy benzamide
  • Step 1 Synthesis of N-(cyclopropylmethoxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-2- base) amino) benzamide
  • Step 1 4-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-5-methanol Oxybenzoic acid
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N- Isobutoxy-5-methoxybenzamide
  • Step 2 Synthesis of benzyl 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoate
  • Step 3 Synthesis of 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid
  • Step 4 Synthesis of 4-((4-(2-(dimethylphosphoryl)phenoxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylbenzoic acid
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy -2-Methylbenzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorobenzoic acid
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N- Isobutoxybenzamide
  • Step 2 Synthesis of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid
  • Step 3 Synthesis of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide
  • Step 2 Synthesis of (E)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N, 3-Dimethoxybenzoyl chloride
  • Step 1 Synthesis of methyl 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)aminomethylnicotinate
  • Step 2 Synthesis of 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)nicotinic acid
  • Step 3 Synthesis of 6-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy Nicotinamide
  • 5-aminopicolinic acid 200mg, 1.45mmol
  • O-isobutoxyamine hydrochloride 546.4mg, 4.4mmol
  • 2-(7-azobenzotriazole)-N,N,N ', N'-Tetramethylurea hexafluorophosphate 1.1g, 2.9mmol
  • 4-dimethylaminopyridine 18.3mg, 0.15mmol
  • N,N-diisopropylethylamine 1.5mL, 8.7 mmol
  • Step 2 Synthesis of 5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy picolinamide
  • 2,4-Dichloropyrimidine-5-trifluoromethyl (0.71g, 3.55mmol) was dissolved in EtOH (20mL), and dimethyl (2-aminophenyl)phosphonate (0.7g, 3.2mmol) was added , NaHCO 3 (542.7mg, 6.5mmol) was added slowly under ice-bath conditions, heated to 50°C and reacted for 1h, monitoring the completion of the reaction.
  • Step 3 Synthesis of 4-((4-((2-(dimethoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid
  • Step 4 2-((2-(((4-(methoxycarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyldimethylphosphine Ester
  • Step 1 (2-((2-(((4-(isobutoxycarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyldimethyl Phosphonate
  • Step 1 4-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro-N,5 -Dimethoxybenzamide
  • Step 1 4-((4-((2-(Dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxy-2 -Fluoro-5-methoxybenzamide
  • Step 1 Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydro Benzofuran-4-carboxylic acid
  • Step 2 Synthesis of 7-(((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethoxy -2,3-Dihydrobenzofuran-4-carboxamide
  • Step 1 Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy -2,3-Dihydrobenzofuran-4-carboxamide
  • allylmagnesium bromide tetrahydrofuran solution (1M, 65.1mL) was added dropwise to dimethyl phosphate (3.0g, 21.7mmol) in Et 2 O solution (5mL), slowly warmed to room temperature, and the reaction 1 hour. Then an aqueous solution (1.1 mL) of K 2 CO 3 (4.3 g, 54.8 mmol) was added into the reaction system at 0° C. and stirred for 10 minutes. The reaction was filtered, washed with ethanol, and the filtrate was concentrated.
  • Step 3 Synthesis of benzyl (2-(diallylphosphoryl)phenyl]carbamate
  • Step 4 Synthesis of benzyl (2-(1-oxygen-2,5-dihydrophosphin-1-yl)phenyl]carbamate
  • Step 7 Synthesis of 4-((5-chloro-4-((2-(1-phosphinyl-1-yl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-iso Butoxy-5-methoxybenzamide
  • Step 1 Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-ethyl-2 ,3-Dihydrobenzofuran-4-carboxamide
  • Step 4 Synthesis of ethyl 7-aminobenzofuran-4-carboxylate
  • Step 6 Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzofuran-4-carboxy acid
  • Step 7 Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzene Furan-4-carboxamide
  • Step 1 Synthesis of methyl 2-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-5-carboxylate
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(methoxycarbonyl)pyrimidin-2-yl)amino)benzoic acid
  • Methyl 2-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidine-5-carboxylate (300mg, 0.88mmol) and p-aminobenzoic acid (146mg, 1.06mmol) were dissolved in Add 4N hydrochloric acid in 1,4-dioxane (0.22 mL) to isopropanol (10 mL), react at 70° C. for 6 h, and monitor the completion of the reaction.
  • Step 3 Synthesis of methyl 4-((2-(dimethylphosphoryl)phenyl)amino)-2-((4-(methoxycarbamoyl)phenyl)amino)pyrimidine-5-carboxylate
  • Step 4 Synthesis of 4-((2-(dimethylphosphoryl)phenyl)amino)-2-((4-(methoxycarbamoyl)phenyl)amino)pyrimidine-5-carboxylic acid
  • Step 5 Synthesis of 4-((2-(dimethylphosphoryl)phenyl)amino)-2-((4-(methoxycarbamoyl)phenyl)amino)-N-methylpyrimidine-5 -carboxamide
  • Step 2 Synthesis of 4-((5-chloro-4-((2-(dimethylphosphono)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid
  • Step 3 Synthesis of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidineamino-2-yl)amino)-N-isobutoxybenzamide
  • Step 2 Synthesis of 4-((5-bromo-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)benzoic acid
  • Step 3 Synthesis of 4-((5-bromo-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide
  • Step 2 Synthesis of 4-(((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyridylamino-2-yl)amino)benzoic acid
  • Step 3 Synthesis of 4-((4-((2-(2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyridylamino-2-yl)amino)-N-methoxybenzene Formamide
  • Step 2 Synthesis of 7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidinedimethyl-2-yl)amino)-2,3-dihydrobenzo Furan-4-carboxylic acid
  • Step 3 Synthesis of 7-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyridylamino-2-yl)amino)-N-methoxy-2,3- Dihydrobenzofuran-4-carboxamide
  • Step 2 Synthesis of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidineamino-2-yl)amino)-2-fluoro-5-methoxybenzene formic acid
  • Step 3 Synthesis of 4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy- 5-methoxybenzamide
  • Step 2 Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-5-methoxybenzoic acid
  • Step 3 Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-2-fluoro-N-isobutoxy-5-methoxybenzene Formamide
  • Step 4 Synthesis of (2-((5-chloro-2-((5-fluoro-4-(isobutoxycarbamoyl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino ) phenyl dimethyl phosphonate
  • Step 1 Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)benzoic acid
  • Step 2 Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-methoxybenzamide
  • Step 3 Synthesis of dimethyl (2-((5-chloro-2-((4-(methoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate
  • Step 1 Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)benzoic acid
  • Step 2 Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-isobutoxybenzamide
  • Step 3 Synthesis of dimethyl (2-((5-chloro-2-((4-(isobutoxycarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyldiphosphonate
  • Step 1 Synthesis of 4-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-methylbenzamide
  • Step 2 Synthesis of dimethyl (2-((5-chloro-2-((4-(methylcarbamoyl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphonate
  • Step 3 Synthesis of 7-((4-((2-(2-(dimethoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2, 3-Dihydrobenzofuran-4-carboxylic acid
  • Step 4 Synthesis of (2-((2-((4-(methoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidine -4-yl)amino)phenyl diphosphonic acid dimethyl ester
  • Step 1 Synthesis of 7-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-carboxylic acid
  • Step 2 Synthesis of 7-((5-chloro-4-((2-iodophenyl)amino)pyrimidin-2-yl)amino)-N-methoxy-2,3-dihydrobenzofuran-4 -carboxamide
  • Step 3 Synthesis of (2-((5-chloro-2-((4-(methoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)pyrimidin-4-yl) Amino)phenyl dimethyl diphosphonate
  • Step 3 Synthesis of 7-((4-((2-(2-(dimethoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2, 3-Dihydrobenzofuran-4-carboxylic acid
  • Step 4 Synthesis of (2-((2-(((4-(isobutoxycarbamoyl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl )pyrimidin-4-yl)amino)phenyl diphosphonic acid dimethyl ester
  • Step 2 Synthesis of 4-((4-((2-(di(methoxyphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluoro- 5-methoxybenzoic acid
  • Step 3 Synthesis of (2-((2-((5-fluoro-4-(isobutoxycarbamoyl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidine- 4-yl)amino)phenyl dimethylphosphonate
  • Step 2 Synthesis of (2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)diethylphosphine oxide
  • Step 3 Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzoic acid
  • Step 4 Synthesis of 4-((4-((2-(diethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxybenzene Formamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-chlorobenzoic acid
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy -2-Chlorobenzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methoxybenzene formic acid
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy -2-Methoxybenzamide
  • Step 1 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanobenzoic acid methyl ester
  • Step 2 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-cyanobenzoic acid
  • Step 3 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-isobutoxy -2-Cyanobenzamide
  • Step 3 Synthesis of N-(cyclopentyloxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl) Amino) benzamide
  • Step 3 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-((tetrahydro -2H-pyran-4-yl)methoxy)benzamide
  • Step 3 Synthesis of 4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-((tetrahydro -2H-pyran-4-yl)oxy)benzamide
  • Step 3 Synthesis of N-(cyclopentylmethoxy)-4-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-2- base) amino) benzamide
  • Step 1 Synthesis of 7-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methoxy- 2,3-Dihydrobenzofuran-4-carboxamide

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Abstract

L'invention concerne un dérivé d'oxyde de phosphine, son procédé de préparation et son application. Spécifiquement, le dérivé d'oxyde de phosphine a une structure représentée par la formule I, a un bon effet inhibiteur sur la kinase d'adhérence focale (FAK), et peut être utilisée pour traiter des maladies provoquées par une prolifération cellulaire excessive ou anormale, telle que le cancer.
PCT/CN2022/095064 2021-06-03 2022-05-25 Dérivé d'oxyde de phosphine, son procédé de préparation et son application WO2022253081A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102105150A (zh) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 用作激酶抑制剂的磷衍生物
CN102448955A (zh) * 2009-06-01 2012-05-09 Osi药物有限责任公司 氨基嘧啶抗癌化合物
WO2013169401A1 (fr) * 2012-05-05 2013-11-14 Ariad Pharmaceuticals, Inc. Composés pour inhiber la prolifération cellulaire dans les cancers induits par l'egfr
CN106699810A (zh) * 2015-11-17 2017-05-24 清华大学 一种含氮杂环化合物及其制备方法与在抑制激酶活性中的应用
CN112538072A (zh) * 2019-09-21 2021-03-23 齐鲁制药有限公司 新型氨基嘧啶类egfr抑制剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102105150A (zh) * 2008-05-21 2011-06-22 阿里亚德医药股份有限公司 用作激酶抑制剂的磷衍生物
CN102448955A (zh) * 2009-06-01 2012-05-09 Osi药物有限责任公司 氨基嘧啶抗癌化合物
WO2013169401A1 (fr) * 2012-05-05 2013-11-14 Ariad Pharmaceuticals, Inc. Composés pour inhiber la prolifération cellulaire dans les cancers induits par l'egfr
CN106699810A (zh) * 2015-11-17 2017-05-24 清华大学 一种含氮杂环化合物及其制备方法与在抑制激酶活性中的应用
CN112538072A (zh) * 2019-09-21 2021-03-23 齐鲁制药有限公司 新型氨基嘧啶类egfr抑制剂

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