WO2024251270A1 - Composé cyclique aromatique contenant de l'azote et son utilisation médicale - Google Patents

Composé cyclique aromatique contenant de l'azote et son utilisation médicale Download PDF

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WO2024251270A1
WO2024251270A1 PCT/CN2024/098202 CN2024098202W WO2024251270A1 WO 2024251270 A1 WO2024251270 A1 WO 2024251270A1 CN 2024098202 W CN2024098202 W CN 2024098202W WO 2024251270 A1 WO2024251270 A1 WO 2024251270A1
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cancer
ring
amino
membered
formula
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Chinese (zh)
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张海生
陈友喜
卓鉥
李林
程辉敏
陈誉
牛春意
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Signet Therapeutics Inc
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Signet Therapeutics Inc
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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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present application relates to a nitrogen-containing aromatic ring compound and its medical use.
  • FAM Focal adhesion kinase
  • PTK2 protein tyrosine kinase 2
  • integrins integrins
  • growth factor receptors growth factor receptors
  • G protein-coupled receptors cytokines
  • FAK can not only participate in signal transduction as a cytoplasmic kinase, but also plays an important role in the cell nucleus. It can promote p53 degradation through ubiquitination, thereby leading to cancer cell growth and proliferation. Tang et al. reported that FAK can also regulate the expression of GATA4 and IL-33, thereby reducing inflammatory responses and immune escape. FAK is widely expressed in the body and plays an important role in cell growth, proliferation, migration, and adhesion. It is involved 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.
  • FAK transmembrane integrin receptors to the extracellular matrix (ECM) recruits FAK to the site where integrins are aggregated.
  • ECM extracellular matrix
  • FAK does not interact directly with integrins, but binds to the cell membrane and other adhesion proteins through its carboxyl-terminal FAT domain.
  • the inactive FAK activates its catalytic activity through autophosphorylation of Y397. After phosphorylation, FAK, as a molecular scaffold, can recruit Src family kinases.
  • 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.
  • Grb2 binds to FAK, it can further recruit SOS to form a complex, thereby further activating the downstream Ras-MAPK signaling pathway.
  • FAK and its signaling pathway-related targets are considered potential targets for the development of anticancer drugs.
  • drugs targeting FAK inhibitors there are currently no drugs targeting FAK inhibitors on the market, 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 regulate the FAK signaling pathway.
  • YAP Yes-associatied protein
  • YAP Yes-associated protein and a transcriptional coactivator of the Hippo pathway. It is located on human chromosome 11q22 and promotes gene expression by enhancing the activity of transcription factors. External signals activate MST1/2, which binds to the regulatory protein SAV1 and then phosphorylates LATS1/2 and MOB, and then directly phosphorylates YAP/TAZ. The phosphorylated YAP/TAZ stagnates in the cytoplasm and inhibits transcription.
  • the core members of this pathway include serine/threonine kinases MST1, MST2, LATS1 and LATS2, scaffold proteins SAV1 (binding to MST1 and MST2), MOB1 (binding to LATS1 and LATS2), transcriptional coactivator YAP, and transcription factor TEAD containing the TEA binding domain.
  • MST1/2 kinase phosphorylates and activates LATS1/2
  • MOB1 binding to LATS1 and LATS2
  • transcriptional coactivator YAP transcription factor TEAD containing the TEA binding domain.
  • MST1/2 kinase phosphorylates and activates LATS1/2
  • the activated LATS1/2 then phosphorylates YAP, and the phosphorylated YAP is inactivated and subsequently exported to the nucleus, while the YAP in the cytoplasm is degraded by the proteasome.
  • Hippo pathway is involved in the progression of various tumors such as lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer, etc.
  • gene mutations in the Hippo pathway rarely occur.
  • the dysregulation of the Hippo pathway in human tumors is not only due to mutations in key proteins of the Hippo pathway itself, but more due to cross-talk between other abnormally expressed proteins or signaling pathways in tumor cells and the Hippo pathway.
  • the role of the Hippo signaling pathway in tumors is closely related to the nuclear translocation of YAP/TAZ. Recently, YAP has been found to be highly expressed in a variety of tumors, which is associated with high pathological grade, advanced TNM stage, lymph node metastasis, etc., and there is a phenomenon of nuclear localization.
  • the present application provides a compound that can be used as a focal adhesion kinase (FAK) inhibitor, as well as a composition containing such a compound and the use of such a compound.
  • FAK focal adhesion kinase
  • the present application provides a compound, which is a compound represented by Formula I or a stereoisomer, tautomer, enantiomer, diastereomer, racemate, geometric isomer, nitrogen oxide, solvate, hydrate, crystal form, ester, isotope-labeled compound, metabolite, pharmaceutically acceptable salt or prodrug of the compound represented by Formula I:
  • X is selected from N or -CH-;
  • Y is selected from -NH-, -CH2- , O, S or a combination thereof;
  • Ring A is selected from a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;
  • Ring B is selected from a 5-15 membered partially unsaturated carbocyclic ring, a 5-15 membered partially unsaturated carboheterocyclic ring, a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;
  • L represents a single bond or a C 1-10 alkylene group
  • ring A and ring B are fused to form a ring
  • ring B and M are fused to form a ring
  • Ring D is selected from a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;
  • R1 is selected from halogen, cyano, nitro, C1-10 alkyl, C1-10 haloalkyl, C1-10 heteroalkyl, C1-10 haloheteroalkyl, C3-15 saturated or partially unsaturated carbocyclyl, C3-15 saturated or partially unsaturated heterocyclyl, 6-15 membered aryl, C7-15 arylalkyl, 5-15 membered heteroaryl or C4-15 heteroarylalkyl;
  • each substituent Ra , Rb , Rc , R1 , R2 , R3 , R4 , R5 and R6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, saturated or partially unsaturated carbocyclyl, saturated or partially unsaturated carbocyclylalkyl, saturated or partially unsaturated heterocyclyl, saturated or partially unsaturated heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • substituents Ra , Rb, Rc , R1 , R2 , R3 , R4 , R5 and R6 are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, alkyl, cycloalkyl, alkoxy, aryl;
  • Ra, Rb , Rc , R1 , R2 , R3 , R4 , R5 and R6 if there are two adjacent substituents, the two adjacent substituents together with the atoms to which they are attached are linked to form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group or a heteroaryl group;
  • n is independently selected from 0, 1, 2, 3 or 4;
  • n is independently selected from 0, 1, 2 or 3;
  • q is independently selected from 0, 1 or 2.
  • Y is selected from -NH-. In some embodiments, Y is selected from -NH-CH 2 -. In some embodiments, Y is selected from -CH 2 -CH 2 -. In some embodiments, Y is selected from O. In some embodiments, Y is selected from S.
  • Ring A is selected from a 6-12 membered aromatic ring (e.g., a 6, 7, 8, 9, 10, 11, or 12 membered aromatic ring) or a 5-12 membered heteroaromatic ring (e.g., a 5, 6, 7, 8, 9, 10, 11, or 12 membered heteroaromatic ring).
  • a 6-12 membered aromatic ring e.g., a 6, 7, 8, 9, 10, 11, or 12 membered aromatic ring
  • a 5-12 membered heteroaromatic ring e.g., a 5, 6, 7, 8, 9, 10, 11, or 12 membered heteroaromatic ring.
  • ring A is selected from a benzene ring, a naphthalene ring, a 5-membered heteroaromatic ring, a 6-membered heteroaromatic ring, a benzene ring and a 5-membered heteroaromatic ring.
  • ring a fused ring formed by a benzene ring and a 6-membered heteroaromatic ring, and a fused ring formed by a 5-membered heteroaromatic ring and a 6-membered heteroaromatic ring.
  • ring A is selected from the group represented by formula A-1 to formula A-7:
  • X1 to X8 are each independently selected from C, N, O, S, -NH- or -CH-,
  • X1 to X8 are each independently selected from C and -CH-.
  • X3 and X4 are both -CH-, X1 and X2 are each independently selected from C, -CH-, N and -NH-, at least one of X5 , X6 , X7 and X8 is selected from N, O, S or -NH-, and three or four adjacent ones of X5 , X6 , X7 and X8 are not N at the same time.
  • X3 and X4 are both -CH-, X1 and X2 are each independently selected from C, -CH-, N and -NH-, and any one of X5 , X6 , X7 and X8 is selected from N, O, S or -NH-.
  • X3 and X4 are both -CH-, X1 and X2 are each independently selected from C, -CH-, N and -NH-, any two of X5 , X6, X7 and X8 are selected from N, O, S or -NH-, and two adjacent ones of X5 , X6 , X7 and X8 are not simultaneously O and not simultaneously S.
  • X3 and X4 are both -CH-, X1 and X2 are each independently selected from C, -CH-, N and -NH-, any three of X5 , X6 , X7 and X8 are selected from N, O, S or -NH-, and three adjacent ones of X5 , X6 , X7 and X8 are not simultaneously N.
  • the substituents Ra in ring A are each independently selected from deuterium, amino, hydroxyl, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1-6 alkoxy, 3-12 -membered saturated or partially unsaturated carbocyclyl, 3-12-membered saturated or partially unsaturated heterocyclyl, 6-15-membered aryl, or 5-15-membered heteroaryl.
  • the substituents Ra in ring A are each independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 alkoxy.
  • Ra is substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, and 6-15-membered aryl.
  • Ra is connected together with the carbon atoms on ring A to form a 3-6-membered ring.
  • Ra and the carbon atoms on ring A are joined together to form a 5-6 membered ring.
  • m is independently selected from 0, 1 or 2.
  • Ring A is selected from the group consisting of:
  • ring A is selected from a benzene ring, a naphthalene ring, a quinoline ring, an isoquinoline ring, a benzopyrrole ring, a benzothiazole ring, and a benzimidazole ring.
  • the substituents Ra in ring A are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl, vinyl, propenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl.
  • the substituents Ra in ring A are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy and propoxy.
  • ring B is selected from a 5-12 membered partially unsaturated carbocyclic ring, a 5-12 membered partially unsaturated carbocyclic ring, a 6-12 membered aromatic ring, or a 5-12 membered heteroaromatic ring. In some embodiments, ring B is selected from a 5-10 membered partially unsaturated carbocyclic ring, a 5-10 membered partially unsaturated carbocyclic ring, a 6-10 membered aromatic ring, or a 5-10 membered heteroaromatic ring.
  • ring B is selected from a 5-6 membered partially unsaturated carbocyclic ring, a 5-6 membered partially unsaturated carbocyclic ring, a benzene ring, or a 5-6 membered heteroaromatic ring.
  • ring B is selected from the group represented by formula B-1 or formula B-2:
  • Y1 to Y6 are each independently selected from C, N, O, S, -NH- or -CH-, "*" indicates the position where ring B is bonded to ring A, Indicates the position where ring B and M are bonded.
  • ring B is selected from the group represented by formula B-1-1 or formula B-2-1:
  • Y1 to Y5 are each independently selected from C, N, O, S, -NH- or -CH-.
  • At least one of Y 1 to Y 5 is selected from N, O, S and -NH-. In some embodiments, in formula B-1-1 and formula B-2-1, at least two of Y 1 to Y 5 are selected from N and -NH-. In some embodiments, in formula B-1-1 and formula B-2-1, any two or any three of Y 1 to Y 5 are selected from N and -NH-. In some embodiments, in formula B-1-1, Y 1 and Y 4 are selected from -CH-, and Y 2 and Y 3 are selected from N.
  • the substituents R in ring B are each independently selected from deuterium, amino, hydroxyl, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1-6 alkoxy, 3-12 -membered saturated or partially unsaturated carbocyclyl, 3-12-membered saturated or partially unsaturated heterocyclyl, 6-15-membered aryl, or 5-15-membered heteroaryl.
  • the substituents R in ring B are each independently selected from deuterium and C 1-6 alkyl.
  • R is substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, and 6-15-membered aryl.
  • n is independently selected from 0, 1 or 2.
  • Ring B is selected from the group consisting of:
  • Ring B is selected from the group consisting of:
  • the substituents R in ring B are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl, alkenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl; or, the substituents R in ring B are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and pentyl. In some embodiments, the substituents R in ring B are each independently selected from hydrogen and methyl.
  • ring B is fused with ring A to form a 6-15 membered ring, such as a 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 membered ring. In some embodiments, ring B is fused with ring A to form a 6-10 membered ring. In some embodiments, the ring formed by the fusion of ring B and ring A has a structure shown in the following formula AB:
  • the ring formed by the fusion of ring B and ring A is selected from the group consisting of the following structures:
  • the compound represented by Formula I is selected from the structures represented by Formula I-1 to Formula I-6:
  • At least one of Y1 to Y5 is selected from O, S or N. In some embodiments, in Formulas I-1 to I-3, Y2 and Y3 are both N. In some embodiments, in Formulas I-1 to I-3, Y2 and Y1 are both N.
  • the carbocyclic ring in the saturated or partially unsaturated carbocyclic group represented by M is selected from the following structures;
  • each x is independently 0, 1, 2 or 3; each y and z is independently 0, 1, 2 or 3.
  • the carbocyclic ring in the saturated or partially unsaturated carbocyclic group represented by M is selected from the following structures:
  • the heterocyclic ring in the saturated or partially unsaturated heterocyclic group represented by M is selected from the group consisting of the following structures:
  • R4 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or the following groups:
  • M is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, and the following groups:
  • M is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl.
  • the alkyl involved in M is substituted by one or more selected from halogen, hydroxyl, cyano, C 3-8 heterocycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy.
  • ring B and M are fused to form a 6-15 membered ring, such as a 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 membered ring. In some embodiments, ring B and M are fused to form a 6-10 membered ring. In some embodiments, the ring formed by the fusion of ring B and M has the structure shown in the following formula BM-1 and formula BM-2:
  • Y1 to Y3 are each independently selected from C, N, -NH- or -CH-, and Z is selected from -CH2- , -NH-, O, and S.
  • the ring B and M are fused to form a ring selected from the group consisting of the following structures:
  • Y1 and Y2 are each independently selected from C, N, -NH- or -CH-; "*" indicates the position where M and R4 are bonded, Indicates the position where ring B is bonded to ring A.
  • the ring B and M are fused to form a ring selected from the group consisting of the following structures:
  • ring D is selected from a 6-10 membered aromatic ring or a 5-10 membered heteroaromatic ring. In some embodiments, ring D is selected from a 6-10 membered aromatic ring or a 5-10 membered azaaromatic ring. In some embodiments, ring D is selected from a benzene ring or a 6-membered azaaromatic ring.
  • ring D is selected from a benzene ring, an imidazole ring, a pyrazole ring, a triazole ring, a tetrazole ring, an oxazole ring, a thiazole ring, a furan ring, a thiophene ring, a pyrrole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring and the group consisting of the following groups:
  • ring D is selected from a benzene ring, a pyridine ring, a pyrimidine ring, and a pyridazine ring.
  • R c is substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, 6-15 membered aryl.
  • p is independently selected from 0, 1 or 2.
  • the substituents R c in ring D are each independently selected from deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl, alkenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl.
  • R2 is selected from the group consisting of:
  • R 4 and R 5 are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1-6 alkoxy, 3-12-membered saturated or partially unsaturated carbocyclic group, 3-12-membered saturated or partially unsaturated heterocyclic group, 6-15-membered aryl or 5-15-membered heteroaryl.
  • R 4 and R 5 are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, 6-15-membered aryl. In some embodiments, R 4 and R 5 are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 deuterated alkyl and 6-15-membered aryl.
  • R4 and R5 are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, deuterated methyl, deuterated ethyl, deuterated propyl, deuterated isopropyl, deuterated butyl, deuterated tert-butyl, deuterated pentyl, cyclopentyl, pentyl, cyclohexyl, alkenyl, methoxy, ethoxy, propoxy, phenyl and naphthyl.
  • the substituent R 4 in R 2 is connected to a carbon atom or a heteroatom on ring D to form a 5-6 membered ring, for example, R 2 and ring D together are
  • the substituent R 5 in R 2 is connected to a carbon atom or a heteroatom on ring D to form a 5-6 membered ring, for example, R 2 and ring D together are
  • R 4 , R 5 and R c are as defined above.
  • R 1 is selected from halogen, cyano, nitro, C 1-10 alkyl, C 3-10 cycloalkyl and C 1-10 haloalkyl. In some embodiments, R 1 is selected from halogen, cyano and C 1-6 haloalkyl. In some specific embodiments, R 1 is selected from fluorine, chlorine, bromine, iodine, cyano, CF 3 , CHF 2 and CH 2 F. In some specific embodiments, R 1 is selected from fluorine, chlorine, bromine, iodine, cyano and CF 3 .
  • each substituent R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 heteroalkyl, C 1-10 alkoxy, 3-15 membered saturated or partially unsaturated carbocyclyl, C 4-15 saturated or partially unsaturated carbocyclylalkyl, 3-15 membered saturated or partially unsaturated heterocyclyl, C 3-15 saturated or partially unsaturated heterocyclylalkyl, 6-15 membered aryl, C 7-20 arylalkyl, 5-15 membered heteroaryl or C 4-20 heteroarylalkyl; alternatively, the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-10 alkyl, C
  • each substituent R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1-6 alkoxy, 3-12 membered saturated or partially unsaturated carbocyclyl, C 4-12 saturated or partially unsaturated carbocyclylalkyl, 3-12 membered saturated or partially unsaturated heterocyclyl, C 3-12 saturated or partially unsaturated heterocyclylalkyl, 6-12 membered aryl, C 7-15 arylalkyl, 3-12 membered heteroaryl or C 4-15 heteroarylalkyl; alternatively, the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 alkyl, C
  • each substituent R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, propenyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl and naphthyl.
  • the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl and naphthyl. One or more substituted.
  • L represents a single bond or a C 1-6 alkylene group. In some embodiments, in Formula I, L represents a single bond or a C 1-4 alkylene group. In some embodiments, in Formula I, L represents a single bond or a C 1-3 alkylene group. In some embodiments, in Formula I, L represents a single bond. In some embodiments, in Formula I, L represents a methylene group. In some embodiments, in Formula I, L represents an ethylene group. In some embodiments, in Formula I, L represents a propylene group.
  • the compound represented by Formula I has the structure represented by the following Formula I-1-1 to Formula I-1-6:
  • L, M, R1 , R2 , Ra, Rb , Rc , m , n and p are as defined in Formula I, and Y1 to Y4 are as defined in Formula B-1 and Formula B-2.
  • R 1 is fluorine, chlorine, bromine, iodine, trifluoromethyl or cyano.
  • each Ra is independently hydrogen or C1-6 alkoxy.
  • each R b is independently hydrogen or C 1-6 alkyl.
  • Y 2 is selected from -NH-, O or S, and any one or any two of Y 1 , Y 3 and Y 4 are N.
  • any one, any two, or any three of Y1 to Y4 are selected from N and -NH-.
  • the compound of Formula I has the structure shown in the following Formula Ia to Formula Ib:
  • L, M, Ra and R4 are defined as above in this application.
  • the compound of Formula I has a structure shown in any one of the following Formulas I-1-a to I-1-f:
  • Ra is hydrogen, methoxy, ethoxy or propoxy;
  • R4 is selected from C1-4 alkyl, C1-4 alkoxy and C1-4 deuterated alkyl; each M1 is independently selected from hydrogen and C1-6 alkyl, L is a single bond or C1-4 alkylene;
  • Ra is connected to the carbon atom on the benzene ring to form a 5-membered ring. In some embodiments, Ra is connected to the carbon atom on the benzene ring to form a 6-membered ring.
  • R 4 is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methyl, deuterated ethyl, deuterated propyl, or deuterated isopropyl.
  • L is a single bond, methylene, ethylene, or propylene. In some embodiments, L is a single bond. In some embodiments, L is a methylene. In some embodiments, L is ethylene. In some embodiments, L is propylene.
  • each M 1 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl.
  • the alkyl in each M 1 is independently substituted by one or more selected from hydroxyl, 5-6 membered heterocycloalkyl.
  • the compound represented by Formula I is the following compound or its stereoisomers, tautomers, enantiomers, Diastereomers, racemates, geometric isomers, nitrogen oxides, solvates, hydrates, crystal forms, esters, isotopically labeled compounds, metabolites, pharmaceutically acceptable salts or prodrugs:
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound or its stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitrogen oxides, solvates, hydrates, crystal forms, esters, isotope-labeled compounds, metabolites, pharmaceutically acceptable salts or prodrugs, and pharmaceutically acceptable excipients thereof.
  • the present application provides use of the above-mentioned compound or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing or treating FAK-related diseases.
  • the FAK-related disease is selected from cancer, pulmonary hypertension or pathological angiogenesis, and optionally, the cancer includes lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, sheath cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestinal cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis cancer, brain stem glioma, pit
  • the present application provides a compound as described above or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug or the use of the pharmaceutical composition as described above in the preparation of a drug for regulating or treating a disease associated with YAP.
  • the YAP-related disease is selected from cancer; the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral 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 and uterine cancer.
  • the cancer is selected from: gastric cancer, lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer.
  • the cancer is gastric cancer
  • the present application provides a compound as described above or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug or the use of the pharmaceutical composition as described above in the preparation of a drug for regulating or treating diseases related to FAK and YAP.
  • the cancer is selected from one or more of skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral 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 lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, and uterine cancer.
  • the cancer in the YAP-related disease is selected from one or more of lung cancer, colon cancer, ovarian cancer, prostate cancer, liver cancer, and gastric cancer.
  • the FAK-related disease is selected from cancer, pulmonary hypertension, and pathological angiogenesis.
  • the present application provides a method for preventing or treating a YAP-related disease, comprising administering a compound as described above or its enantiomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or a pharmaceutically acceptable salt, hydrate, isotope or prodrug thereof, or a pharmaceutical composition as described above.
  • the YAP-associated disease comprises a combination of one or more of skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral 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 lymphoma, lung cancer, lymphocytic lymphoma, central nervous system tumors (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, prostate cancer, soft tissue sarcoma, gastric cancer, and uterine cancer.
  • the present application provides a method for preventing or treating a FAK-related disease, comprising administering the above-mentioned compound or its enantiomer. isomer, diastereomer, racemate, tautomer, stereoisomer, geometric isomer, nitrogen oxide, metabolite or pharmaceutically acceptable salt, hydrate, isotope or prodrug thereof or pharmaceutical composition as described above.
  • the FAK-related disease is selected from cancer, pulmonary hypertension, or pathological angiogenesis.
  • the cancer comprises lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, sheath cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, cancer of the endocrine system, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis cancer, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers.
  • CNS
  • the cancer is gastric cancer. In some embodiments, the cancer is diffuse gastric cancer.
  • the cell is a mammalian cell. In some embodiments, the subject is a mammal, preferably a human.
  • the compounds provided in the embodiments of the present application have good inhibitory effects on FAK and YAP, and have good therapeutic effects and good clinical application prospects on cancer, pulmonary hypertension, and pathological angiogenesis.
  • FIG3 shows the inhibitory effects of Compound 13, Compound 15 and Compound 16 prepared in the examples of the present application on FAK in the diffuse gastric cancer (DGC) mouse organoid MDO-MCR model.
  • DGC diffuse gastric cancer
  • Figure 5 shows the inhibitory effects of Compound 26, Compound 27, Compound 28, Compound 29, Compound 30 and Compound 14 prepared in the examples of the present application on FAK and YAP in the diffuse gastric cancer (DGC) mouse organoid MDO-MCR model.
  • DGC diffuse gastric cancer
  • FIG6 shows the inhibitory effects of Compound 01 and Compound 02 prepared in the examples of the present application on FAK in the human diffuse gastric cancer cell line SNU668 model.
  • FIG. 7 shows the inhibitory effects of Compound 03 and Compound 04 prepared in the Examples of the present application on FAK in the human diffuse gastric cancer cell line SNU668 model.
  • FIG8 shows the inhibitory effects of Compound 26, Compound 27, Compound 28, Compound 29 and Compound 30 prepared in the Examples of the present application on FAK and YAP in the human diffuse gastric cancer tumor cell line SNU668 model.
  • Figure 9 shows the inhibitory effects of Compound 31, Compound 32, Compound 33, Compound 34, Compound 35, Compound 36 and Compound 37 prepared in the Examples of the present application on FAK and YAP in the human diffuse gastric cancer tumor cell line SNU668 model.
  • subject refers to an animal. Typically, the animal is a mammal. A subject, for example, also refers to a primate. In some embodiments, the subject is a primate. In other embodiments, the subject is a human.
  • patient refers to humans (including adults and children) or other animals. In some embodiments, “patient” refers to humans.
  • stereoisomer refers to compounds having the same chemical structure but with different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans isomers), atropisomers, and the like. Unless otherwise indicated, all stereoisomers or mixtures of stereoisomers of the structural formula described in this application are within the scope of this application.
  • enantiomer refers to stereoisomers that are real objects and mirror images of each other and are not superimposable.
  • diastereomer refers to stereoisomers that have two or more chiral centers and are not mirror images of each other.
  • racemic modification refers to a form of optical movement of molecules, including racemates and mesomers.
  • a raceme is an equimolar mixture of an optically active chiral molecule and its enantiomer, which is composed of equal amounts of molecules with opposite optical rotation directions and equal optical rotation abilities. The optical activities cancel each other out due to the interaction between these molecules, so it is optically inactive and is usually labeled with D, L.
  • a mesomer is a molecule with two or more asymmetric centers but other symmetry factors, such as the existence of a symmetry plane, which makes the entire molecule optically inactive and has no enantiomers. It is usually represented by meso or i.
  • geometric isomers used in this application includes: cis-trans isomers, isomeric polymers and syndiotactic polymers, rotational isomers caused by steric hindrance, etc.
  • tautomer or “tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions that occur via reorganization of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • Another example of tautomerism is phenol-keto tautomerism.
  • a specific example of phenol-keto tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present application are within the scope of the present application.
  • nitrogen oxide refers to when the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides.
  • Special examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocyclic rings.
  • the corresponding amines can be treated with oxidants such as hydrogen peroxide or peracids (such as peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • oxidants such as hydrogen peroxide or peracids (such as peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th edition, Jerry March, pages).
  • N-oxides can be prepared by the method of L. W. Deady (Syn. Comm. 1977, 7, 509-514), in which, for example, the amine compound is reacted with meta-chloro
  • solvate used in this application refers to an association formed by one or more solvent molecules and the compound of the present application.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid and aminoethanol.
  • hydrate refers to an association formed by water as a solvent molecule.
  • metabolite refers to a product obtained by metabolism of a specific compound or its salt in vivo.
  • a metabolite of a compound can be identified by techniques known in the art, and its activity can be characterized by experimental methods as described in the present application.
  • Such a product can be obtained by administering a compound through oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc.
  • the present application includes metabolites of a compound, including metabolites produced by contacting a compound of the present application with a mammal for a period of time.
  • esters includes compounds or fragments containing carbon atoms or heteroatoms bonded to an oxygen atom bonded to the carbon on the carbonyl group.
  • ester includes alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, etc.
  • pharmaceutically acceptable refers to compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for contact with patient tissues without excessive toxicity, irritation, allergic response or other problems and complications commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • prodrug used in this application refers to organic salts and inorganic salts of the compounds of this application.
  • prodrug used in this application represents a compound that is converted into a compound shown in formula I, Ia, Ib, I-1 to I-6, I-1-1 to I-1-6, I-1-a to I-1-f in vivo. Such conversion is affected by the hydrolysis of the prodrug in the blood or the conversion of the prodrug to the parent structure by enzymes in the blood or tissues.
  • the prodrug compounds of this application can be esters.
  • esters that can be used as prodrugs include phenyl esters, aliphatic (C 1-24 ) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
  • a compound in this application contains a hydroxyl group, that is, it can be acylated to obtain a compound in the form of a prodrug.
  • Other prodrug forms include phosphate esters, such as these phosphate ester compounds obtained by phosphorylation of the hydroxyl group on the parent.
  • any disease or condition refers to improving a disease or condition (i.e., slowing down or preventing or alleviating the development of a disease or at least one clinical symptom thereof) in some embodiments.
  • “treating” refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • “treating” refers to regulating a disease or condition physically (e.g., stabilizing perceptible symptoms) or physiologically (e.g., stabilizing physical parameters) or both.
  • “treating” refers to preventing or delaying the onset, occurrence, or deterioration of a disease or condition.
  • C mn refers to any group having m to n carbon atoms
  • C m refers to any group having m carbon atoms.
  • C 1-20 alkyl refers to an alkyl group containing 1 to 20 carbon atoms
  • C 1-8 alkoxy refers to an alkoxy group containing 1 to 8 carbon atoms
  • C 2-6 alkenyl refers to an alkenyl group containing 2 to 6 carbon atoms
  • C 6 haloalkyl refers to a haloalkyl group containing 6 carbon atoms.
  • C mn and C m -C n can be used interchangeably, both of which refer to a group having m to n carbon atoms, for example, “C 1-6 " and “C 1 -C 6 " both refer to the group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • m-n membered used alone as a prefix refers to a ring having m to n ring atoms, such as "3-6 membered saturated or partially unsaturated carbocyclic group” means that the carbocyclic group has 3 to 6 ring atoms, "3-6 membered saturated or partially unsaturated heterocyclic group” means that the heterocyclic group has 3 to 6 ring atoms; "6-10 membered aryl” means that the aryl group has 6 to 10 ring atoms; “5-10 membered heteroaryl” means that the heteroaryl group has 5 to 10 ring atoms.
  • substituted or “substituted” as used herein means that one or more hydrogen atoms in a given structure are replaced by a specific substituent.
  • substituents selected from a specific group, the substituent can be replaced identically or differently at each position.
  • C 1-6 alkyl specifically refers to the independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • linking substituents are described.
  • the Markush variables listed for that group should be understood as linking groups.
  • the Markush group definition for that variable lists “alkyl” or “aryl”, it should be understood that the "alkyl” or “aryl” represents an alkylene group or an arylene group, respectively, that is connected.
  • heteroalkyl refers to a group in which the carbon atoms in the alkyl group are substituted by 1, 2 or 3 heteroatoms selected from N, O, S, Si or P, and wherein the nitrogen and sulfur atoms are optionally oxidized.
  • C1 - C6 heteroalkyl refers to a group containing 1-6 (i.e., 1, 2, 3, 4, 5 or 6) carbon atoms, and 1 , 2 or 3 heteroatoms selected from N, O, S or P. Representative examples include (but are not limited to): CH3OCH2-, CH3SCH2- , CH3CH2OCH2- , etc.
  • haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, monochloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl, 1-chloroethyl, 1,2-dichloroethyl, 1,1-dichloroethyl, 2,2-dichloroethyl, 1,1-dibromoethyl, and the like.
  • alkenyl refers to a straight or branched hydrocarbon group containing one or more double bonds and having a specified number of carbon atoms.
  • C2-6 alkenyl refers to a group containing 2 to 6 carbon atoms.
  • Alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, etc.
  • alkynyl refers to a straight or branched hydrocarbon group containing one or more triple bonds and having a specified number of carbon atoms.
  • C2-6 alkynyl refers to a hydrocarbon group containing 2 to 6 carbon atoms.
  • Alkynyl includes, but is not limited to, ethynyl, propynyl, butynyl, etc.
  • cycloalkyl refers to a saturated monocyclic (e.g., C 3-6 ), bicyclic (e.g., C 5-12 fused bicyclic, C 5-12 membered spiro bicyclic) or polycyclic cyclic alkyl, "C 3-6 cycloalkyl” means that the cycloalkyl contains 3 to 6 carbon atoms, "C 3-12 cycloalkyl” means that the cycloalkyl contains 3 to 12 carbon atoms.
  • Representative cycloalkyl groups of the present application include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, etc.
  • heterocycloalkyl and “saturated heterocyclic group” can be used interchangeably, and refers to a group formed by replacing at least one carbon atom of a cycloalkyl ring with a heteroatom, and the heteroatom can be oxygen, nitrogen, sulfur, phosphorus, silicon, etc.
  • heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, thiazolidinyl, oxazolidinyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, glycidyl, azepanyl, oxetanyl, thiepanyl, glycidyl, azepanyl, oxetanyl, thiepanyl, 4-methoxy-piperidin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, and dioxanyl.
  • heterocyclic groups also include 1,
  • alkoxy means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein.
  • the alkoxy group may optionally be substituted with one or more substituents described herein.
  • alkoxy group is a linking group, and "alkoxy” is listed for the Markush group definition, then “alkoxy” means the attached alkyleneoxy group.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n-propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n-butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butoxy (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, —OCH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • hydroxyl refers to "-OH”.
  • amino refers to "-NH 2 ".
  • cyano refers to "-CN” or "-C ⁇ N”.
  • hydrogen refers to H, including 1 H, 2 H, 3 H.
  • heteroatom refers to N, O, S, P, Si and the like.
  • saturated or partially unsaturated carbocyclyl and “saturated or partially unsaturated carbocycle” can be used interchangeably to refer to a non-aromatic saturated or partially unsaturated monocyclic or polycyclic system consisting of carbon atoms as ring atoms.
  • the polycyclic system is a bicyclic or tricyclic ring.
  • Saturated or partially unsaturated carbocyclyl includes saturated or partially unsaturated monocyclic carbocyclyl, saturated or partially unsaturated spirocarbocyclyl, saturated or partially unsaturated fused carbocyclyl, and saturated or partially unsaturated bridged carbocyclyl.
  • saturated or partially unsaturated carbocyclyl represents a 3-15-membered saturated or partially unsaturated carbocyclyl; in some embodiments, saturated or partially unsaturated carbocyclyl represents a 3-12-membered saturated or partially unsaturated carbocyclyl; in other embodiments, saturated or partially unsaturated carbocyclyl represents a 3-10-membered saturated or partially unsaturated carbocyclyl; in other embodiments, saturated or partially unsaturated carbocyclyl represents a 3-7-membered saturated or partially unsaturated carbocyclyl.
  • the saturated or partially unsaturated carbocyclic group may be independently and optionally substituted by one or more substituents described herein.
  • saturated or partially unsaturated carbocyclic group is a linking group
  • saturated or partially unsaturated carbocyclic group is represented by "saturated or partially unsaturated carbocyclylene".
  • saturated or partially unsaturated heterocyclic group is used interchangeably with “saturated or partially unsaturated heterocyclic ring", “saturated or partially unsaturated carboheterocyclic ring”, and “saturated or partially unsaturated carboheterocyclic group” to refer to a non-aromatic saturated or partially unsaturated monocyclic or polycyclic ring system in which the ring atoms contain at least one carbon atom and one or more heteroatoms.
  • the heteroatoms have the meanings as described in the present application. Unless otherwise specified, a saturated or partially unsaturated heterocyclic group may be connected to the rest of the molecule through its carbon atoms or through heteroatoms.
  • the polycyclic system is bicyclic or tricyclic.
  • Saturated or partially unsaturated heterocyclic groups include saturated or partially unsaturated monoheterocyclic groups, saturated or partially unsaturated spiroheterocyclic groups, saturated or partially unsaturated fused heterocyclic groups, and saturated or partially unsaturated bridged heterocyclic groups.
  • the saturated or partially unsaturated heterocyclic group represents a 3-15-membered saturated or partially unsaturated heterocyclic group; in some embodiments, the saturated or partially unsaturated heterocyclic group represents a 3-12-membered saturated or partially unsaturated heterocyclic group; in other embodiments, the saturated or partially unsaturated heterocyclic group represents a 3-10-membered saturated or partially unsaturated heterocyclic group; in other embodiments, the saturated or partially unsaturated heterocyclic group represents a 3-7-membered saturated or partially unsaturated heterocyclic group; in other embodiments, the saturated or partially unsaturated heterocyclic group represents a 3-6-membered saturated or partially unsaturated heterocyclic group.
  • the saturated or partially unsaturated heterocyclic group may be independently Optionally substituted with one or more substituents described herein.
  • a saturated or partially unsaturated heterocyclic group is a linking group
  • the term "saturated or partially unsaturated heterocyclic group" is represented as “saturated or partially unsaturated heterocyclic group”.
  • aryl and aromatic ring are used interchangeably to refer to aromatic monocyclic and polycyclic ring systems composed of carbon atoms as ring atoms.
  • the polycyclic ring system is a bicyclic or tricyclic ring.
  • the aryl group is a 6-15 membered aryl group; in some embodiments, the aryl group is a 6-12 membered aryl group; in other embodiments, the aryl group is a 6-10 membered aryl group; in other embodiments, the aryl group is a phenyl or naphthyl group.
  • the aryl group represents a linked arylene group.
  • the aryl group may be independently and optionally substituted with one or more substituents described herein.
  • heteroaryl is used interchangeably with “heteroaromatic ring” and refers to an aromatic monocyclic or polycyclic ring system consisting of at least one carbon atom and one or more heteroatoms as ring atoms.
  • the heteroatoms have the meanings as described herein.
  • heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, pyrazinyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidin ...
  • pyrimidinyl 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), pur
  • the combined groups used in the present application such as hydroxyalkyl, aminoalkyl, hydroxyalkoxy, aminoalkoxy, alkylamino, saturated or partially unsaturated carbocyclylalkyl, saturated or partially unsaturated heterocyclylalkyl, arylalkyl, heteroarylalkyl, and the groups involved, such as amino, hydroxy, alkyl, alkoxy, saturated or partially unsaturated carbocyclyl, saturated or partially unsaturated heterocyclyl, aryl, and heteroaryl, have the definitions described in the present application.
  • ring substituents such as saturated or partially unsaturated carbocyclic groups, saturated or partially unsaturated heterocyclic groups, aryls, heteroaryls, can be connected to the rest of the molecule through any connectable position on the ring.
  • piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl.
  • a ring system formed by a substituent R connected to a central ring by a bond represents that the substituent R can be substituted at any substitutable or any reasonable position on the ring to which it is connected.
  • a ring system formed by a bond connected to the center of the ring represents that the connecting bond can be connected to the rest of the molecule at any connectable position on the ring system.
  • the two attachment points can be connected to the rest of the molecule at any connectable position on the ring, and the two ends of the connection can be interchanged.
  • pharmaceutically acceptable excipient means a pharmaceutically acceptable material, mixture or solvent associated with the consistency of the dosage form or pharmaceutical composition.
  • Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that greatly reduce the efficacy of the compounds disclosed in the present application when administered to the patient and interactions that will result in a pharmaceutical composition that is not pharmaceutically acceptable.
  • each excipient must be pharmaceutically acceptable, for example, having a sufficiently high purity. Suitable pharmaceutically acceptable excipients will vary depending on the specific dosage form selected.
  • pharmaceutically acceptable excipients can be selected based on their specific functions in the composition. For example, certain pharmaceutically acceptable excipients that can help produce uniform dosage forms can be selected.
  • Certain pharmaceutically acceptable excipients that can help produce stable dosage forms can be selected. Certain pharmaceutically acceptable excipients that can help carry or transport the compounds of the present application from one organ or part of the body to another organ or part of the body when administered to the patient can be selected. Certain pharmaceutically acceptable excipients that enhance patient compliance can be selected.
  • excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, cellulose, water, syrup and methylcellulose.
  • Suitable pharmaceutically acceptable excipients also include the following types of excipients: solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adherents, antioxidants, chelating agents, penetration enhancers, pH adjusters, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents and filter aids.
  • excipients may serve more than one function, and may provide alternative functions, depending on the formulation. How much of the excipient is present in the formulation and what other excipients are present in the formulation.
  • the compounds of the present invention can be formulated using methods known in the art so as to release the active ingredient quickly, continuously or delayed after administration to the patient.
  • pharmaceutically acceptable carrier includes any and all solvents and solvent mixtures, coatings, complexing agents, solid carriers, dispersion media, surface active excipients, antibacterial and antifungal agents, isotonic and absorption delaying agents for pharmaceutically active substances, and mixtures thereof, which are also known in the art.
  • Suitable pharmaceutically acceptable carriers depend on the form of the drug and are known to those skilled in the art.
  • Non-limiting examples for pharmaceutically acceptable carriers include those having components selected from the group consisting of lactose, gelatin, sugar alcohols (e.g., starch, mannitol, corn starch, etc.), vegetable oils, talc, magnesium stearate, colloidal silicon dioxide, carboxymethyl cellulose, microcrystalline cellulose, sodium lauryl sulfate, Tween buffered aqueous solution, copolyvidone, polysorbate, ethanol, propylene glycol, polyglycol (preferably polyethylene glycol, e.g., PEG400), 80 (i.e., PEG (20), sorbitol monooleate), DMSO, A mixture of water and a cosolvent, for example, an aqueous solution comprising an alcohol such as ethanol and/or a polyglycol such as polyethylene glycol, an ester of a polyol such as glycerol
  • any structural formula given in the present application is also intended to represent the isotopically unenriched forms and isotopically enriched forms of these compounds.
  • Isotopically enriched compounds have the structure described by the general formula given in the present application, except that one or more atoms are replaced by atoms with selected atomic weights or mass numbers.
  • Exemplary isotopes that can be introduced into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • Radioactive isotopes are present therein , such as those compounds of 3 H, 14 C and 18 F, or non-radioactive isotopes are present therein, such as 2 H and 13 C.
  • Such isotopically enriched compounds can be used in metabolic studies (using 14 C), reaction kinetic studies (using, for example, 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determinations, or can be used in radiotherapy of patients.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • 18 F-enriched compounds are particularly ideal for PET or SPECT studies.
  • Isotopically enriched compounds of Formula I, Ia, Ib, I-1 to I-6, I-1-1 to I-1-6, I-1-a to I-1-f can be prepared by conventional techniques familiar to those skilled in the art or as described in the examples and preparations herein using an appropriate isotopically labeled reagent in place of the unlabeled reagent originally used.
  • isotopic enrichment factor used in the present application refers to the ratio between the isotopic abundance and the natural abundance of the specified isotope.
  • a substituent of a compound of the present application is designated as deuterium
  • the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • Pharmaceutically acceptable solvates herein include those wherein the solvent of crystallization may be isotopically substituted, eg D2O , acetone-d6, DMSO-d6.
  • compound of the present application or “active ingredient of the present application” is used interchangeably to refer to a compound of formula I or Stereoisomers, tautomers, enantiomers, diastereomers, racemates, geometric isomers, nitrogen oxides, solvates, hydrates, crystalline forms, esters, isotopically labeled compounds, metabolites, pharmaceutically acceptable salts or prodrugs:
  • X is selected from N or -CH-;
  • Y is selected from -NH-, -CH2- , O, S or a combination thereof;
  • Ring A is selected from a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;
  • Ring B is selected from a 5-15 membered partially unsaturated carbocyclic ring, a 5-15 membered partially unsaturated carboheterocyclic ring, a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;
  • L represents a single bond or a C 1-10 alkylene group
  • M is selected from hydrogen, C 1-10 alkyl, 3-15 membered saturated or partially unsaturated carbocyclic group, 3-15 membered saturated or partially unsaturated heterocyclic group, optionally, the alkyl, saturated or partially unsaturated carbocyclic group, saturated or partially unsaturated heterocyclic group involved in M is substituted by one or more R 3 ,
  • ring A and ring B are fused to form a ring
  • ring B and M are fused to form a ring
  • Ring D is selected from a 6-15 membered aromatic ring or a 5-15 membered heteroaromatic ring;
  • R1 is selected from halogen, cyano, nitro, C1-10 alkyl, C1-10 haloalkyl, C1-10 heteroalkyl, C1-10 haloheteroalkyl, C3-15 saturated or partially unsaturated carbocyclyl, C3-15 saturated or partially unsaturated heterocyclyl, 6-15 membered aryl, C7-15 arylalkyl, 5-15 membered heteroaryl or C6-15 heteroarylalkyl;
  • each substituent Ra , Rb , Rc , R1 , R2 , R3 , R4 , R5 and R6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, saturated or partially unsaturated carbocyclyl, saturated or partially unsaturated carbocyclylalkyl, saturated or partially unsaturated heterocyclyl, saturated or partially unsaturated heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
  • substituents Ra , Rb, Rc , R1 , R2 , R3 , R4 , R5 and R6 are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, alkyl, cycloalkyl, alkoxy, aryl;
  • Ra, Rb , Rc , R1 , R2 , R3 , R4 , R5 and R6 if there are two adjacent substituents, the two adjacent substituents together with the atoms to which they are attached are linked to form a saturated or partially unsaturated carbocyclic group, a saturated or partially unsaturated heterocyclic group, an aryl group or a heteroaryl group;
  • n is independently selected from 0, 1, 2, 3 or 4;
  • n is independently selected from 0, 1, 2 or 3;
  • p is independently selected from 0, 1, 2, 3 or 4;
  • q is independently selected from 0, 1 or 2.
  • the compound represented by Formula I is selected from the structures represented by Formula I-1 to Formula I-6:
  • X, Y, R 1 , R 2 , Ra, R b , R c , L , M, ring D, m, n, p, and Y 1 to Y 5 are as defined above in the present application.
  • the compound represented by Formula I has the structure represented by the following Formula I-1-1 to Formula I-1-6:
  • L, M, R 1 , R 2 , Ra, R b , R c , m, n, p, and Y 1 to Y 4 are the same as those described above in the present application.
  • R 1 is selected from halogen, cyano, nitro, C 1-10 alkyl, C 3-10 cycloalkyl and C 1-10 haloalkyl. In some embodiments, R 1 is selected from halogen, cyano and C 1-6 haloalkyl. In some embodiments, R 1 is selected from fluorine, chlorine, bromine, iodine, cyano, CF 3 , CHF 2 and CH 2 F. In some embodiments, R 1 is selected from fluorine, chlorine, bromine, iodine, cyano and CF 3 .
  • each substituent R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 heteroalkyl , C 1-10 alkoxy, 3-15 membered saturated or partially unsaturated carbocyclyl, C 4-15 saturated or partially unsaturated carbocyclylalkyl, 3-15 membered saturated or partially unsaturated heterocyclyl, C 3-15 saturated or partially unsaturated heterocyclylalkyl, 6-15 membered aryl, C 7-20 arylalkyl, 5-15 membered heteroaryl or C 4-20 heteroarylalkyl.
  • substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, 6-15 membered aryl.
  • each substituent R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 heteroalkyl, C 1-6 alkoxy, 3-10 membered saturated or partially unsaturated carbocyclyl, C 4-12 saturated or partially unsaturated carbocyclylalkyl, 3-10 membered saturated or partially unsaturated heterocyclyl, C 3-12 saturated or partially unsaturated heterocyclylalkyl, 6-10 membered aryl, C 7-15 arylalkyl, 5-10 membered heteroaryl or C 4-15 heteroarylalkyl.
  • substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently substituted by one or more selected from deuterium, hydroxyl, amino, cyano, fluorine, chlorine, bromine, iodine, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, and 6-12 membered aryl.
  • each substituent R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is independently selected from hydrogen, deuterium, amino, hydroxyl, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, propenyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl and naphthyl.
  • the substituents R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from one or more of deuterium, hydroxyl, amino, cyano, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, phenyl and naphthyl.
  • the compound of Formula I has the structure shown in the following Formula Ia to Formula Ib:
  • L, M, Ra and R4 are as defined above.
  • the compound represented by Formula I has the structure represented by the following Formula I-1-a to Formula I-1-f:
  • R a is hydrogen, methoxy, ethoxy or propoxy
  • R4 is selected from C1-4 alkyl, C1-4 alkoxy and C1-4 deuterated alkyl; or, R4 is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, deuterated methyl, deuterated ethyl, deuterated propyl or deuterated isopropyl;
  • Each M 1 is independently selected from hydrogen and C 1-6 alkyl, or each M 1 is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl; optionally, the alkyl in each M 1 is independently substituted by one or more selected from hydroxyl, 5-6 membered heterocycloalkyl;
  • L is a single bond or a C 1-4 alkylene group
  • the carbon atoms on the benzene ring to which Ra is connected are connected to form a 5-membered ring. In some embodiments, in the above formulas I-1-a to I-1-f, the carbon atoms on the benzene ring to which Ra is connected are connected to form a 6-membered ring.
  • the pharmaceutical composition of the present application comprises the compound described in the present application and a pharmaceutically acceptable excipient thereof.
  • the amount of the compound in the composition of the present application can effectively treat or alleviate the FAK and/or YAP-related diseases of the patient.
  • the present application provides a pharmaceutical composition, which further comprises an additional therapeutic agent, wherein the additional therapeutic agent includes other anticancer agents, other drugs for treating pulmonary arterial hypertension, or a combination thereof.
  • the pharmaceutical composition of the present application further comprises a pharmaceutically acceptable excipient, which, as used in the present application, includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc., suitable for a specific target dosage form.
  • a pharmaceutically acceptable excipient includes any solvent, diluent, or other liquid excipient, dispersant or suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, etc.
  • the pharmaceutical composition of the present application further comprises i) one or more other FAK inhibitors and/or ii) one or more other types of protein kinase inhibitors and/or one or more other types of therapeutic agents.
  • the one or more other types of protein kinase inhibitors include, for example, PYK2 or src inhibitors, and other types of therapeutic agents include other anticancer agents, other drugs for treating pulmonary hypertension, and the like.
  • terapéuticaally effective amount refers to the total amount of each active component sufficient to show a significant patient benefit (e.g., viral load reduction).
  • a therapeutically effective amount of the present application's compound especially Formula I, Formula I-1 to I-6, Formula I-1-1 to I-1-6, Formula I-1-a to I-1-f compounds and pharmaceutically acceptable salts thereof can be given as unprocessed chemicals, and can also be provided as an active ingredient of a pharmaceutical composition.
  • the present application also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the present application's compound, especially Formula I, Formula I-1 to I-6, Formula I-1-1 to I-1-6, Formula I-1-a to I-1-f compounds or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the term refers only to the ingredient.
  • the term refers to the combined amount of active ingredients that cause a therapeutic effect regardless of the combination, when administered sequentially or simultaneously.
  • the compounds of the present application especially compounds of formula I, formula I-1 to I-6, formula I-1-1 to I-1-6, formula I-1-a to I-1-f and pharmaceutically acceptable salts thereof are as described above.
  • the carrier, diluent or excipient must be acceptable.
  • a method for preparing a pharmaceutical preparation comprising mixing the compounds of the present application, especially compounds of formula I, formula I-1 to I-6, formula I-1-1 to I-1-6, formula I-1-a to I-1-f or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the amount of active ingredient combined with one or more excipients to prepare a single dosage form will necessarily vary depending on the host being treated and the specific route of administration.
  • a formulation intended for oral administration to a human will typically contain, for example, 0.5 mg-2 g of active ingredient (suitably 0.5 mg-1 g of active ingredient, such as 0.5 mg-0.5 g of active agent, more suitably 0.5-100 mg, such as 1-30 mg) compounded with a suitable and convenient amount of excipient, which may be about 5% to about 98% by weight of the total composition.
  • the amount of active ingredient that the compound of Formula I, Formula I-1 to I-6, Formula I-1-1 to I-1-6, Formula I-1-a to I-1-f is mixed with a carrier material to prepare a single dosage form will vary depending on the disease to be treated, the severity of the disease, the time of administration, the route of administration, the excretion rate of the compound used, the duration of treatment, and the age, sex, weight and condition of the patient.
  • a preferred unit dosage form is a unit dosage form containing a daily dose or divided dose of the active ingredient described herein above, or a suitable fraction thereof. Treatment may be initiated with a small dose significantly below the optimal dose of the compound. Thereafter, the dose is increased in small increments until the optimum effect is achieved under the circumstances.
  • the concentration level at which the compound is most desirably administered is that which generally provides effective results in terms of anti-tumor effects without causing any harmful or toxic side effects.
  • the daily dose obtained is, for example, 0.1 mg/kg-75 mg/kg body weight.
  • a lower dose will be given when a parenteral route is adopted.
  • a dose of, for example, 0.1 mg/kg-30 mg/kg body weight is usually used.
  • a dose of, for example, 0.05 mg/kg–25 mg/kg body weight is used.
  • Oral administration is also suitable, particularly in tablet form.
  • a unit dosage form will contain about 0.5 mg-0.5 g of the compounds of the present application and the unit dosage form can be administered once, twice, three times or four times a day or, if necessary, with a higher frequency of administration.
  • the pharmaceutical dosage forms of the compounds and compositions of the present application can be provided in the form of quick release, controlled release, sustained release or targeted drug release systems.
  • conventional dosage forms include solutions and suspensions, (micro) emulsions, ointments, gels and patches, liposomes, tablets, sugar-coated pills, soft or hard shell capsules, suppositories, ovules, implants, amorphous or crystalline powders, aerosols and lyophilized preparations.
  • special devices may be required to apply or administer the drug, such as syringes and needles, inhalers, pumps, injection pens, applicators or special flasks.
  • compositions are often composed of drugs, excipients and containers/sealing systems.
  • excipients also known as inactive ingredients
  • the method of line. Therefore, the type of excipient added to the drug can depend on various factors, such as the physical and chemical properties of the drug, the route of administration and the preparation steps.
  • pharmaceutical excipients in this field include those listed in various pharmacopoeias.
  • the pharmaceutical composition is suitable for administration by any suitable route, for example, by oral (including oral or sublingual), rectal, nasal, topical (including oral, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion) route.
  • oral including oral or sublingual
  • rectal nasal
  • topical including oral, sublingual or transdermal
  • vaginal or parenteral including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion
  • vaginal or parenteral including subcutaneous, intradermal, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous or subdermal injection or infusion
  • Such preparations can be prepared by any known method in the field of pharmacy, for
  • compositions suitable for oral administration are provided as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water emulsions or water-in-oil emulsions.
  • the active drug component can be mixed with a pharmaceutically acceptable oral non-toxic inert carrier (e.g., ethanol, glycerol, water, etc.).
  • a pharmaceutically acceptable oral non-toxic inert carrier e.g., ethanol, glycerol, water, etc.
  • Powders are prepared by pulverizing the compound into a suitable fine size and mixing it with a pharmaceutical carrier (e.g., edible sugars such as starch or mannitol) that is also pulverized.
  • a pharmaceutical carrier e.g., edible sugars such as starch or mannitol
  • Flavoring agents, preservatives, dispersants, and coloring agents may also be present.
  • Capsules are prepared by preparing a powder mixture as described above and filling it into a formed gelatin shell. Before the filling operation, glidants and lubricants (e.g., colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol) may be added to the powder mixture. Disintegrants or solubilizers (e.g., agar, calcium carbonate or sodium carbonate) may also be added to improve the availability of the drug when the capsule is taken.
  • glidants and lubricants e.g., colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol
  • Disintegrants or solubilizers e.g., agar, calcium carbonate or sodium carbonate
  • Suitable binders include starch, gelatin, natural sugars (e.g., glucose or ⁇ -lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth or sodium alginate), carboxymethyl cellulose, polyethylene glycol, etc.
  • Lubricants used in these dosage forms include sodium oleate, sodium chloride, etc.
  • Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, etc.
  • tablets are prepared.
  • the appropriately crushed compound is mixed with a diluent or base as described above, optionally with a binder (e.g., carboxymethyl cellulose, alginate, gelatin or polyvinyl pyrrolidone), a dissolution inhibitor (e.g., paraffin), an absorption accelerator (quaternary salt) and/or an absorbent (e.g., bentonite, kaolin or dicalcium phosphate) to prepare a powdered mixture.
  • a binder e.g., carboxymethyl cellulose, alginate, gelatin or polyvinyl pyrrolidone
  • a dissolution inhibitor e.g., paraffin
  • an absorption accelerator quaternary salt
  • an absorbent e.g., bentonite, kaolin or dicalcium phosphate
  • the powder mixture can be granulated by wetting with a binder (e.g., syrup, starch paste, acadia mucilage, or a solution of a cellulosic or polymeric material) and then forcing it through a screen.
  • a binder e.g., syrup, starch paste, acadia mucilage, or a solution of a cellulosic or polymeric material
  • An alternative to granulation is to run the powder mixture through a tabletting machine, resulting in poorly formed lumps being broken up to form granules.
  • the granules can be lubricated by adding stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the die of the tabletting machine. The lubricated mixture is then compressed into tablets.
  • the compounds of the present application can also be mixed with a free-flowing inert carrier and compressed into tablets without going through the granulation or pre-compression steps.
  • Protective coatings consisting of a shellac seal coat, a sugar coat or a polymeric material coat and a polish coating of wax can be provided, which may be transparent or opaque. Dyestuffs can be added to these coatings to distinguish different unit doses.
  • Oral liquid preparations such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given amount contains a predetermined amount of compound.
  • Syrups can be prepared by dissolving the compound in an aqueous solution of appropriate flavoring, while elixirs can be prepared by using a non-toxic solvent.
  • Solubilizers and emulsifiers e.g., ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether
  • preservatives e.g., peppermint oil or natural sweeteners or saccharin or other artificial sweeteners
  • flavor additives e.g., peppermint oil or natural sweeteners or saccharin or other artificial sweeteners
  • dosage unit preparations for oral administration can be microencapsulated.
  • the preparations can also be formulated to delay or sustain release, for example, by coating or embedding in particulate materials such as polymers, wax, etc.
  • the compounds of the present application can also be administered in a liposome delivery system, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be composed of a variety of phospholipids (e.g., cholesterol, octadecylamine or phosphatidylcholine).
  • the compounds of the present application can also be delivered by using monoclonal antibodies as separate carriers (to which the compound molecules are coupled).
  • the compounds can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers may include polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide phenol, polyhydroxyethyl asparagine phenol or polyethylene oxide polylysine substituted with palmitoyl residues.
  • the compounds can be coupled with a class of biodegradable polymers for achieving controlled release of the drug, such polymers as cross-linked copolymers or amphiphilic block copolymers of polylactic acid, poly- ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.
  • a class of biodegradable polymers for achieving controlled release of the drug, such polymers as cross-linked copolymers or amphiphilic block copolymers of polylactic acid, poly- ⁇ -caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.
  • compositions suitable for transdermal administration may be presented as discrete patches to maintain close contact with the recipient's epidermis for a prolonged period of time.
  • the active ingredient may be delivered by iontophoresis patches, generally see Pharmaceutical Research 1986, 3(6), 318.
  • Pharmaceutical formulations suitable for topical administration may be prepared as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, oils or transdermal patches.
  • Pharmaceutical formulations suitable for rectal administration may be presented as suppositories or as enemas.
  • Pharmaceutical formulations suitable for vaginal administration may be presented as vaginal suppositories, vaginal tampons, creams, gels, pastes, foams or sprays.
  • compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions and aqueous and non-aqueous sterile suspensions
  • aqueous and non-aqueous sterile injection solutions may contain antioxidants, buffers, antibacterial agents and solutes that make the preparation isotonic with the blood of the recipient
  • aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents.
  • the preparations can be provided in unit dose or multi-dose containers, such as sealed Ankai and vials, and can be stored under freeze drying (lyophilization) conditions, and only sterile liquid carriers, such as water for injection, need to be added before use.
  • the injection solutions and suspensions prepared at the time of use can be prepared by sterile powder injections, granules and tablets.
  • Pharmaceutical preparations suitable for nasal administration include coarse powders with a particle size of, for example, 20-500 microns, which are administered by nasal inhalation, i.e., rapid inhalation from a coarse powder container close to the nose through the nasal passage.
  • Suitable formulations in which the carrier is a liquid and suitable for administration as a nasal spray or nasal drops include aqueous or oily solutions of the active ingredient.
  • Pharmaceutical formulations suitable for administration by inhalation include dry powders, aerosols, suspensions or solution compositions.
  • Dry powder compositions delivered to the lungs by inhalation typically include a compound of formula (I) of the present application or a pharmaceutically acceptable salt as a finely pulverized powder together with one or more pharmaceutically acceptable excipients as a finely pulverized powder.
  • Pharmaceutically acceptable excipients particularly suitable for dry powders are known to those skilled in the art and include lactose, starch, mannitol and mono-, di- and polysaccharides.
  • Finely pulverized powders can be prepared, for example, by micronization and milling.
  • a size-reduced (e.g., micronized) compound can be defined by a D50 value of about 1 to about 10 microns (e.g., as detected by laser diffraction).
  • the dry powder can be administered to a patient via a reservoir dry powder inhaler (RDPI), which has a reservoir suitable for storing multiple doses (unmetered doses) of the drug in the form of dry powder.
  • the RDPI typically includes a device for metering each dose of the drug from the reservoir to the delivery position.
  • the metering device may include a metering cup, which can be moved from a first position to a second position, where the cup can be loaded with the drug from the reservoir, and where a metered dose of the drug that can be used for inhalation by the patient is prepared in the second position.
  • the dry powder can be presented as a capsule (such as gelatin or plastic), cartridge or blister package for a multi-dose dry powder inhaler (MDPI).
  • MDPI multi-dose dry powder inhaler
  • An MDPI is an inhaler in which the drug is contained in a multi-dose package, containing (or otherwise carrying) multiple defined doses (or portions thereof) of the drug.
  • the dry powder When the dry powder is presented as a blister package, it includes a plurality of blisters for containing the drug in the form of dry powder.
  • the blisters are typically arranged in a regular manner to facilitate the release of the drug therefrom.
  • the blisters may be arranged in a generally circular manner on a disc-type blister pack, or may be elongated, for example, to comprise a strip or ribbon.
  • Aerosol can be formed by suspending or dissolving the compound of formula I of the application or a pharmaceutically acceptable salt in a liquefied propellant.
  • Suitable propellants include halogenated hydrocarbons, hydrocarbons and other liquefied gases.
  • Representational propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane.
  • formulations may include other ingredients conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the compounds of the present application or compositions containing the compounds of the present application are suitable for the prevention and treatment of FAK-related diseases, wherein FAK-related diseases include cancer, pulmonary hypertension, immune diseases, arthritis, inflammatory bowel disease, pathological angiogenesis, etc.
  • FAK-related diseases include cancer, pulmonary hypertension, immune diseases, arthritis, inflammatory bowel disease, pathological angiogenesis, etc.
  • the compounds of the present application and their pharmaceutical compositions are particularly used to prepare drugs for the treatment of cancer, pulmonary hypertension, and pathological angiogenesis.
  • the compounds of the present application or their pharmaceutical compositions can be used therapeutically in combination with: i) one or more other FAK inhibitors and/or, ii) one or more other types of protein kinase inhibitors and/or one or more other types of therapeutic agents, which can be orally administered in the same dosage form, orally administered in separate oral dosage forms (e.g., sequentially or non-sequentially), or injected together or separately (e.g., sequentially or non-sequentially).
  • other types of therapeutic agents include other anticancer agents and other drugs for the treatment of pulmonary hypertension.
  • the compounds of the present application or their pharmaceutical compositions can be used to treat diseases or medical conditions mediated solely or in part by FAK, i.e.
  • the compounds can be used to produce FAK inhibitory effects in warm-blooded animals that need such treatment. Therefore, the compounds of the present application provide a method for treating malignant cells, characterized by inhibiting FAK.
  • the compounds of the present application or their pharmaceutical compositions can be used to produce anti-proliferation and/or pro-apoptosis and/or anti-invasion and/or anti-cell movement and/or anti-angiogenesis activity effects mediated alone or in part by inhibiting FAK function.
  • the compounds of the present application can be used to prevent or treat those tumors that are sensitive to inhibition of FAK, which are related to, for example, angiogenesis, proliferation and signal transduction steps, which cause proliferation, invasion, migration and particularly angiogenesis of these tumor cells. Therefore, the compounds of the present application can be used to treat hyperproliferative diseases, including cancer.
  • the compounds of the present application can be used to treat pathogenic angiogenesis (pathological angiogenesis), for example, for the treatment of the cancers mentioned above and other diseases that produce inappropriate or pathogenic angiogenesis, such as age-related macular degeneration (AMD) and cancers associated with solid tumors.
  • pathogenic angiogenesis pathological angiogenesis
  • AMD age-related macular degeneration
  • the compounds of the present application or compositions containing the compounds of the present application are suitable for regulating or treating diseases associated with FAK and YAP.
  • the diseases associated with FAK and YAP are selected from cancer; the cancer is selected from: skin cancer, bone cancer, glioma, breast cancer, adrenal cancer, bladder cancer, esophageal cancer, head or neck cancer, liver cancer, parathyroid cancer, penile cancer, small intestine cancer, thyroid cancer, urethral 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 and uterine cancer
  • the cancer is selected from: skin cancer
  • the compounds of the present application or their pharmaceutical compositions can be used alone or, if necessary, in combination with other active compounds.
  • the compounds of Formula I, Formula I-1 to I-6, Formula I-1-1 to I-1-6, Formula I-1-a to I-1-f are considered to be effective when used with the following: alkylating agents, angiogenesis inhibitors, antibodies, metabolic antagonists, antimitotic agents, antiproliferative agents, antiviral agents, Aurora kinase inhibitors, other cell apoptosis promoters (e.g., Bcl-xL, Bcl-w and Bfl-1) inhibitors, activators of death receptor pathways, Bcr-Abl kinase inhibitors, BiTE (Bi-specific T cell engager (Engager)) antibodies, antibody drug conjugates, biological response modifiers, cell cycle protein-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs, leukemia virus oncogene homolog (ErbB2) receptor
  • the compound or pharmaceutical composition described in the present application and other active drugs that can be used in combination are made into separate preparations, and the two dosage forms can be the same or different, and can be used sequentially or simultaneously; when used sequentially, the first drug has not lost its effective effect in the body when the second drug is administered; 2) the compound or pharmaceutical composition of the present application and other active drugs that can be used in combination are made into a single preparation and administered simultaneously.
  • the compounds of Formula I, Formula I-1 to I-6, Formula I-1-1 to I-1-6, Formula I-1-a to I-1-f of the present application or their pharmaceutically acceptable salts can be administered in combination with other therapeutic agents, including other therapeutic agents that can be used to treat pulmonary hypertension (PHA).
  • therapeutic agents include vasodilators, such as epoprostenol (Flolan TM), tadalafil (AdcircaTM) or ambrisentan (VolibrisTM), etc.
  • the “effective amount” or “effective dose” of the compound or pharmaceutically acceptable composition of the present application refers to an amount that treats or alleviates one or more of the present application. Please refer to the effective amount of the severity of the mentioned disease.
  • the compound and composition can be any dosage and any administration route to effectively treat or alleviate the severity of the disease. The exact amount required will vary according to the patient's condition, which depends on race, age, the patient's general condition, the severity of the infection, special factors, mode of administration, etc.
  • the compound or composition can be co-administered with one or more other therapeutic agents, as discussed in the present application.
  • the structure of the compound of the present application is determined by nuclear magnetic resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
  • NMR nuclear magnetic resonance
  • LC-MS liquid chromatography-mass spectrometry
  • DMSO-d6 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 spectrometry
  • HPLC is determined using an Agilent 1100 high pressure chromatograph (Microsorb 5 micron C18 5 100x3.0mm chromatographic column).
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, TLC uses 0.15-0.20 mm, and preparative thin layer chromatography uses 0.4 mm-0.5 mm.
  • Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as a carrier.
  • Step 1 2-( ⁇ 2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methylbenzamide
  • Step 2 2-methylpropan-2-yl 4-[4-(3-methoxy-4- ⁇ [4-( ⁇ 2-[(methylamino)carbonyl]phenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ phenyl)pyrazol-1-yl]piperidin-1-carboxylate
  • Step 3 2- ⁇ [2-( ⁇ 4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-methylbenzamide
  • Step 4 2-( ⁇ 2-[(4- ⁇ 1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-4-yl ⁇ -2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methylbenzamide
  • Step 1 2-( ⁇ 2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methylbenzamide
  • Step 2 2- ⁇ [2-( ⁇ 2-methoxy-4-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]phenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-methylbenzamide
  • reaction mixture was stirred at 100 ° C for 18 hours. After LCMS showed that the reaction was complete.
  • the reaction solution was poured into 5 mL of water and extracted with EtOAc (5 mL). The combined organic phase was washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by reverse preparative chromatography to obtain compound 02 (10.86 mg, 0.02 mmol, yield: 9.28%).
  • Step 1 2-( ⁇ 2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methylbenzamide
  • Step 2 2- ⁇ [2-( ⁇ 4-[1-(1,1-dioxo-1 ⁇ 6-thiazin-4-yl)pyrazol-4-yl]-2-methoxyphenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-methylbenzamide
  • Step 1 2-( ⁇ 2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methylbenzamide
  • Step 2 2-methylpropan-2-yl 4-[4-(3-methoxy-4- ⁇ [4-( ⁇ 2-[(methylamino)carbonyl]phenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ phenyl)pyrazol-1-yl]piperidin-1-carboxylate
  • Step 3 2- ⁇ [2-( ⁇ 4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-methylbenzamide
  • Step 4 2- ⁇ [2-( ⁇ 2-methoxy-4-[1-(1-propionylpiperidin-4-yl)pyrazol-4-yl]phenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-methylbenzamide
  • Step 1 2-( ⁇ 2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methylbenzamide
  • Step 2 2-methylpropan-2-yl 4-[4-(3-methoxy-4- ⁇ [4-( ⁇ 2-[(methylamino)carbonyl]phenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ phenyl)pyrazol-1-yl]piperidin-1-carboxylate
  • Step 3 2- ⁇ [2-( ⁇ 4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-methylbenzamide
  • Step 1 2-( ⁇ 2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methylbenzamide
  • Step 2 2-methylpropan-2-yl 4-[4-(3-methoxy-4- ⁇ [4-( ⁇ 2-[(methylamino)carbonyl]phenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino ⁇ phenyl)pyrazol-1-yl]piperidin-1-carboxylate
  • Step 3 2- ⁇ [2-( ⁇ 4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]-2-methoxyphenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-methylbenzamide
  • Step 4 2-( ⁇ 2-[(4- ⁇ 1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-4-yl ⁇ -2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methylbenzamide
  • reaction solution was poured into 1 mL of water and extracted with EtOAc (5 mL), and the combined organic phases were washed with saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product.
  • the crude product was purified by reverse preparative chromatography to give compound 06 (19.97 mg, 0.032 mmol, yield: 36.33%).
  • Step 1 2-((2-((4-bromophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide
  • Step 2 tert-Butyl 4-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
  • the mixture was evacuated with nitrogen three times and heated to 90 °C under nitrogen protection and stirred overnight. After the reaction was completed by TLC monitoring, the mixture was filtered, concentrated under reduced pressure to remove most of the solvent, 20 mL of water was added, extracted with ethyl acetate (20 mL ⁇ 3), the organic phases were combined, washed twice with 10% sodium chloride solution (30 mL) and then washed once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide
  • Step 4 2-(4-(4-(4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)piperidin-1-yl)acetic acid
  • reaction mixture was poured into 40 mL water for quenching, extracted with ethyl acetate (20 mL ⁇ 3), and the organic phases were combined and then 10% The mixture was washed twice with sodium chloride solution (30 mL) and once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by reverse preparative chromatography to give compound 09 (18 mg, 0.03 mmol, yield: 17.24%).
  • Step 1 2-(2-(4-bromo-5-fluoro-2-methoxyphenyl)amino)-5-trifluoromethylpyrimidin-4-amino)-N-methylbenzamide
  • Step 2 tert-Butyl 4-(4-(2-fluoro-5-methoxy-4-(4-(2-methylcarbamoyl)phenyl)amino-5-trifluoromethylpyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
  • the mixture was cooled to room temperature and 20 mL of water was added.
  • the mixture was extracted with dichloromethane (15 mL ⁇ 3).
  • the organic phases were combined, washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 2-(2-(5-fluoro-2-methoxy-4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide
  • Step 4 2-(2-(5-fluoro-4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2-methoxyphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-amino)-N-methylbenzamide
  • Step 1 Synthesis of 2-((2-((4-bromo-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide
  • Step 2 Synthesis of N-methyl-2-((2-((4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino
  • Step 1 Synthesis of 2-((2-((4-bromo-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide
  • Step 2 Synthesis of tert-butyl 4-(4-(7-(4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate
  • Step 3 Synthesis of N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino
  • Step 4 Synthesis of 2-((2-((4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino
  • N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino 130 mg, 0.22 mmol
  • 2-hydroxyacetic acid 20 mg, 0.27 mmol
  • EDCI 86 mg, 0.44 mmol
  • HOBt 61 mg, 0.44 mmol
  • DIEA (0.11 mL, 0.66 mmol
  • N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydrobenzofuran-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino 50 mg, 0.09 mmol
  • acetic acid 20 mg, 0.1 mmol
  • EDCI 33 mg, 0.17 mmol
  • HOBt 23 mg, 0.17 mmol
  • DIEA 33 mg, 0.26 mmol
  • Step 1 2-methylpropan-2-yl 4-[3-(4-aminophenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-carboxylate
  • Step 2 2- ⁇ [2-( ⁇ 4-[5-(hexahydropyridin-4-yl)-1,2,4-oxadiazol-3-yl]phenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-methylbenzamide
  • Step 3 2-( ⁇ 2-[(4- ⁇ 5-[1-(2-hydroxyacetyl)piperidin-4-yl]-1,2,4-oxadiazol-3-yl ⁇ phenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methylbenzamide
  • Step 1 tert-Butyl 4-(4-(4-aminophenyl)-1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate
  • Step 2 N-methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide
  • Step 3 2-((2-((4-(1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylbenzamide
  • N-Methyl-2-((2-((4-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzamide 100 mg, 0.19 mmol
  • 2-hydroxyacetic acid (17.0 mg, 0.22 mmol)
  • 1-hydroxybenzotriazole 50.3 mg, 0.37 mmol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (71.3 mg, 0.37 mmol) were dissolved in 5 mL of N,N-dimethylformamide, N,N-diisopropylethylamine (162 ⁇ L, 0.93 mmol) was added and stirred at room temperature for 18 h.
  • reaction solution was poured into 40 mL of water for quenching and ethyl acetate (20 The organic phases were combined, washed twice with 10% sodium chloride solution (30 mL) and once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the compound 27 (26 mg, 0.04 mmol, yield: 27.10%) was obtained by purification by reverse preparative chromatography.
  • reaction solution was poured into 40 mL of water for quenching, extracted with ethyl acetate (20 mL ⁇ 3), and the organic phases were combined and washed twice with 10% sodium chloride solution (30 mL) and once with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the compound 28 (25.2 mg, 0.04 mmol, yield: 21.36%) was obtained by purification by reverse preparative chromatography.
  • Step 2 2-Methylpropan-2-yl 4- ⁇ 4-[4-( ⁇ 4-[(2- ⁇ [(trideuteriomethyl)amino]carbonyl ⁇ phenyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl ⁇ amino)phenyl]pyrazol-1-yl ⁇ piperidin-1-carboxylate
  • Step 3 2- ⁇ [2-( ⁇ 4-[1-(hexahydropyridin-4-yl)pyrazol-4-yl]phenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-(trideuteriomethyl)benzamide
  • Step 4 2-( ⁇ 2-[(4- ⁇ 1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-4-yl ⁇ phenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-(trideuteriomethyl)benzamide
  • Step 1 2-( ⁇ 2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methoxybenzamide
  • Step 2 2-methylpropan-2-yl-4-(4- ⁇ 3-methoxy-4-[(4- ⁇ [2-(4-oxo-3-aza-2-oxabutan-4-yl)phenyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-2-yl)amino]phenyl ⁇ pyrazol-1-yl)piperidin-1-carboxylate
  • reaction solution was poured into 20 mL of water and extracted with EtOAc (5 mL). The combined organic phase was washed with a saturated sodium chloride solution (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product.
  • Step 3 2- ⁇ [2-( ⁇ 4-[1-(hexahydropyridin-4-yl)pyrazol-3-yl]-2-methoxyphenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-methoxybenzamide
  • Step 4 2-( ⁇ 2-[(4- ⁇ 1-[1-(2-hydroxyacetyl)piperidin-4-yl]pyrazol-3-yl ⁇ -2-methoxyphenyl)amino]-5-(trimethoxyphenyl)- (fluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methoxybenzamide
  • Step 1 2-( ⁇ 2-[(4-bromo-2-methoxyphenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methoxybenzamide
  • Step 2 N-methoxy-2- ⁇ [2-( ⁇ 2-methoxy-4-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]phenyl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ benzamide
  • N,N-diisopropylethylamine (0.798mL, 4.569mmol) was added to a solution of 2-amino-N-(trideuteriomethyl)benzamide (700mg, 4.57mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (991.38mg, 4.569mmol) in n-butanol (20mL). The mixture was stirred at 25°C for 2 hours. The product was detected. The mixture was diluted with water (100mL) and extracted with ethyl acetate (100mL*2).
  • Step 1 4-(4-bromo-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid methyl ester
  • Step 2 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]cyclohexane-1-carboxylic acid methyl ester
  • Step 3 4-(4-((4-(2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3-dihydrobenzofuran-4-yl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid methyl ester (36)
  • Step 4 4-(4-(4-((2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-amino)-2,3-dihydrobenzofuran-4-yl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid (37)
  • Step 1 4-(4-(4-((2-methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid methyl ester
  • Step 2 4-(4-(4-(2-methylcarbamoyl)phenylamino)-5-trifluoromethylpyrimidin-2-ylamino)phenyl)-1H-pyrazol-1-yl)cyclohexane-1-carboxylic acid
  • Step 2 N-methyl-2-[(2- ⁇ [4-(1-methylpyrazol-4-yl)phenyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-amino]benzamide
  • Step 1 2-( ⁇ 2-[(4-bromo-2,3-dihydro-1-benzofuran-7-yl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-(trideuteriomethyl)benzamide
  • Step 2 2- ⁇ [2-( ⁇ 4-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]-2,3-dihydro-1-benzofuran-7-yl ⁇ amino)-5-(trifluoromethyl)pyrimidin-4-yl]amino ⁇ -N-(trideuteriomethyl)benzamide
  • Step 2 N-methyl-2-[(2- ⁇ [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl)amino]benzamide
  • potassium acetate 210.48 mg, 0.858 mmol was added to a solution of 2-( ⁇ 2-[(4-bromophenyl)amino]-5-(trifluoromethyl)pyrimidin-4-yl ⁇ amino)-N-methylbenzamide (400 mg, 0.858 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (326.78 mg, 1.287 mmol) in dioxane (5 mL).
  • the mixture was stirred at 100° C. for 2 hours under nitrogen protection.
  • LCMS detected the formation of the product.
  • the mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL*2).
  • the organic phases were combined and washed once with a saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the combined organic layer was dried and concentrated to obtain a residue.
  • Test Example 1 In vitro enzyme inhibition activity of the compounds of the present application
  • the FAK kinase activity IC50 activity data of specific compounds are shown in Table 2.
  • MDO-MCR grows to 70%-80%, remove the culture medium supernatant, rinse twice with PBS and remove the supernatant; add 1mL Tryple to each well, shake evenly from left to right and up and down, and place in the incubator for digestion for 5 minutes; blow the cells into single cells or two or three cell clusters, add PBS containing 2% FBS to stop digestion, transfer to a 15mL centrifuge tube, add cold PBS to 10mL, and place in a centrifuge at 1000rpm for 5 minutes. Remove the supernatant, add 1mL PBS to resuspend, and count;
  • b Resuspend the cells in matrix gel to a suspension of 1.6 ⁇ 10 6 cells per ml. Add 6 drops to each well of a 6-well plate, and add 25 ⁇ L of cells to each drop. Place the 6-well plate upside down in the incubator for 30 minutes to allow the matrix gel to solidify. Add 2 mL of culture medium to each well and culture in a cell incubator overnight.
  • a Take out the small molecule drug mother solution in advance to thaw, and vortex to mix evenly; b. Take out the culture plate with cells, aspirate 2 ⁇ L of 1mM mother solution (diluted 1000 times) and gently add it along the wall of the well, and shake it gently to mix it immediately after adding; the dosage concentration of each small molecule in each well is 1 ⁇ M; c. After all the wells are added, shake it gently to mix, record the time, put it back into the cell culture incubator, and collect the samples after 48 hours.
  • SDS-PAGE electrophoresis 80v, 30min, 120v, 60min; transfer: 80v, 60min; blocking: 5% skim milk for 1H
  • primary antibody P-FAKY397 (1:1000, CST), non-p-YAP (1:2000, Abcam), p-YAP (1:1000, CST), actin (1:10000, CST), incubated with 5% BSA ⁇ TBST, incubated at 4°C overnight
  • secondary antibody Goat-anti-mouse-IgG and Goat-anti-rabbit-IgG, 1:3000, Proteintech
  • Thermo developer was used.
  • the compounds of the present application can achieve the purpose of treating diseases (especially cancer) by inhibiting FAK kinase and/or inhibiting activated YAP.
  • SNU-668 cells Add 1 mL of 0.25% trypsin to a 10 cm dish, shake it evenly, and place it in an incubator for digestion for 2-3 minutes; take out the dish, add 2-3 mL of complete culture medium to terminate digestion, transfer to a 15 mL centrifuge tube, and centrifuge it at 1000 rpm for 5 minutes; remove the supernatant, add 1 mL of complete culture medium to resuspend, and count; take out a 96-well plate, plate 1000 cells per well, and place it in a cell culture incubator for overnight culture;
  • MDO-MCR Add 1 mL of typle to each well of a 6-well plate, shake evenly from side to side and up and down, and place in an incubator for digestion for 5 minutes; observe under a microscope, blow off into single or two or three cell clusters, add PBS containing 2% FBS to stop digestion, transfer to a 15 mL centrifuge tube, add cold PBS to 10 mL, place in a centrifuge and centrifuge at 1000 rpm for 5 minutes; remove the supernatant, add 1 mL of PBS to resuspend, and count; resuspend the cells with matrix gel to a concentration of 2 ⁇ 10 5 cells per milliliter, and place 5 ⁇ L of cell suspension in the center of each well of a 96-well plate, place in a cell culture incubator upside down for 15 minutes to allow the matrix gel to solidify, add 100 ⁇ L of culture medium, and culture in an incubator overnight.
  • Each small molecule was diluted 1:3 into 9 concentration gradients using culture medium based on the 10 mM stock solution;
  • Three male SD rats were intragastrically administered with 5 mg/kg or 10 mg/kg of the compound once, and blood was collected before administration and at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration.
  • Preparation of 5mg/kg dosing solution accurately weigh 5.5mg of compound (according to purity), add 0.55mL DMSO, stir and sonicate to obtain a clear solution. Take 0.5mL of the above solution, add 1mL Solutol, stir for 1min; add 8.5mL of physiological saline, stir for 1min, and obtain a clear solution with a solution concentration of 0.5mg/mL.
  • Preparation of 10mg/kg dosing solution accurately weigh 12mg of compound (according to purity), add 0.6mL DMSO, stir and ultrasonicate to obtain a clear solution. Take 0.5mL of the above solution, add 1mL Solutol, stir for 1min; add 8.5mL of physiological saline, stir for 1min, and obtain a clear solution with a solution concentration of 1.0mg/mL.
  • the preparation prepared in step 2 was administered to rats by gavage at a dose of 10 mL/kg.
  • the rats were fasted overnight before administration and resumed feeding 4 hours after administration; the animals had normal drinking water during the entire experimental period.
  • Plasma concentrations were determined using LC-MS/MS methods.
  • Test Example 5 Pharmacodynamic evaluation of the present compound in vitro in the human diffuse gastric cancer cell line SNU-668 model (western blot detection of FAK and YAP activity)
  • SDS-PAGE electrophoresis 80v, 30min, 120v, 60min; transfer: 80v, 60min; blocking: 5% skim milk for 1H
  • primary antibody P-FAKY397 (1:1000, CST), non-p-YAP (1:2000, Abcam), p-YAP (1:1000, CST), actin (1:10000, CST), incubated with 5% BSA ⁇ TBST, incubated at 4°C overnight
  • secondary antibody Goat-anti-mouse-IgG and Goat-anti-rabbit-IgG, 1:3000, Proteintech
  • Thermo developer was used.

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Abstract

La présente invention concerne un composé tel que représenté dans la formule I, une composition comprenant le composé et une utilisation médicale du composé. Le composé de la présente invention a un effet thérapeutique relativement bon sur le cancer, l'hypertension pulmonaire et l'angiogenèse pathologique.
PCT/CN2024/098202 2023-06-08 2024-06-07 Composé cyclique aromatique contenant de l'azote et son utilisation médicale Ceased WO2024251270A1 (fr)

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