WO2019242689A1 - Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, procédé de préparation correspondant et utilisation associée - Google Patents

Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, procédé de préparation correspondant et utilisation associée Download PDF

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WO2019242689A1
WO2019242689A1 PCT/CN2019/092089 CN2019092089W WO2019242689A1 WO 2019242689 A1 WO2019242689 A1 WO 2019242689A1 CN 2019092089 W CN2019092089 W CN 2019092089W WO 2019242689 A1 WO2019242689 A1 WO 2019242689A1
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substituted
alkyl
amino
methyl
cyano
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PCT/CN2019/092089
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Chinese (zh)
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张强
于善楠
孙月明
刘彦生
李兴福
郑南桥
杨磊夫
胡晨明
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北京赛特明强医药科技有限公司
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Priority to CN201980038142.8A priority Critical patent/CN112313207B/zh
Publication of WO2019242689A1 publication Critical patent/WO2019242689A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a cyano-substituted pyridine and a cyano-substituted pyrimidine compound, a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, and a preparation method and application thereof.
  • FGFR activation mutation or expansion in cells can lead to excessive activation of the FGF-FGFR signaling pathway, allowing cells to obtain oncogenic properties such as excessive proliferation, escape from apoptosis, and easy migration, so FGFRs can be used as targets for direct or indirect tumor treatment.
  • FGFR is mainly divided into 4 subtypes, namely FGFR1, FGFR2, FGFR3 and FGFR4. Each subtype has the general structural characteristics of receptor tyrosine kinases: extracellular domains that bind to ligands, transmembrane domains, and intracellular domains that are phosphorylated by receptors.
  • FGFR When the ligand specifically binds to the receptor, it induces FGFR autophosphorylation and then dimerizes, causing its domain to change from an inactive state to an active state. Activated FGFR is in close proximity to intracellular kinases and phosphorylates each other, thereby activating a series of downstream related signaling pathways, and ultimately stimulating cell proliferation, differentiation, and inhibiting apoptosis. Because FGFR plays an important role in the development of tumors, targeted therapy for FGFR has become a hot area of clinical research.
  • Existing drugs that target FGFR can be divided into two categories according to their source: the first is a small chemical inhibitor, which can competitively or noncompetitively bind to the FGFR intracellular kinase domain and inhibit FGFR itself Ability to phosphorylate, dimerize, and catalyze phosphorylation of downstream proteins, thereby inhibiting the FGFR signaling pathway.
  • the second type is a biological monoclonal antibody or a polypeptide inhibitor, which can bind to the extracellular region of FGFR, prevent the binding of FGF and FGFR, thereby inhibiting FGFR activation and blocking the transduction of FGFR signals (Seiji Mori, Yoshikazu Takada, Med .Sci. 2013, 1, 20-36).
  • Small molecule tyrosine kinase inhibitors block cell proliferation signals by blocking the activity of intracellular kinase binding to ATP. Because the structures of the FGFR1, FGFR2, and FGFR3 kinase domains are similar, the inhibitors developed for these three kinases are not much different at this stage. However, there are some differences between the FGFR4 kinase domain and the FGFR1-3 kinase domain, so many can effectively inhibit FGFR1 -3 inhibitors do not work well on FGFR4.
  • FGFR inhibitors can be divided into: 1) ATP competitive reversible inhibitors, 2) covalently bound irreversible inhibitors, 3) ATP non-competitive inhibitors (Wu Daichao et al., Cancer Research 2017, 44 (1): 61-65).
  • AZD-4547 is a small molecule selective ATP competitive reversible inhibitor that linearly interacts with FGFR. From the protein-ligand complex co-crystal structure of FGFR1 / AZD-4547, it can be seen that the 3-aminopyrazole parent ring of AZD-4547 has 3 hydrogen bonds with Ala564 and Glu562 in the hinge region. The methoxyphenyl side chain extends into the hydrophobic pocket inward of the hinge region, and the para-chiral piperazine-substituted benzoyl group undergoes a hydrophilic or hydrophobic interaction with the near-solvent terminal domain extending outside the hinge region.
  • JNJ-42756493 interacts with FGFR in a small T-type selective ATP competitive reversible inhibitor.
  • the N-position of quinoxaline parent ring of Ala564 forms a hydrogen bond
  • the 3,5-dimethoxyphenyl side chain occupies the hydrophobic pocket inward of the hinge region, while the isopropylamine side chain and the pocket downward in the hinge region have a hydrophilic or hydrophobic effect.
  • NH also has a hydrogen bond with Asp641.
  • FGFR1, 2 and 3 are tyrosine residues. Based on this small structural difference, a PDG inhibitor PD173074, which has nanomolar inhibitory activity, was found. Based on this, 2-aminoquinazoline derivatives that specifically inhibit FGFR4 were found. When the amino ⁇ When a substituent of acrylamide was introduced at the position, the compound BLU-9931 was obtained. It was found that the acrylamide can produce irreversible covalent binding with Cys552 of FGFR4. Its IC 50 for FGFR4 inhibitory activity is 3nmol / L, and its selectivity is higher than that of FGFR1.
  • BLU-554 was found to be a selective FGFR4 covalent irreversible inhibitor. In September 2015, it was approved by the FDA for clinical trials for treating hepatocellular carcinoma. TAS-120 and PRN-1371 are also FGFR covalent inhibitors, and their enzyme inhibitory activity on each subtype of FGFR can reach nanomolar level.
  • ARQ-087 is a non-ATP-competitive inhibitor. Its selectivity to FGFR1, 2 and 3 is more than eight times greater than that of FGFR4.
  • FGFR small molecule inhibitors can be divided into pan-FGFR and FGFR4-specific small molecule inhibitors. Due to the similar structure of the FGFR1, FGFR2, and FGFR3 kinase domains, the inhibitors developed for these three kinases at the current stage have similar effects. FGFR4 has been reported to play an important role especially in liver cancer (PLoS One, 2012, Volume 7, 36713). There are some differences between FGFR4 kinase domain and FGFR1-3 kinase domain, so many inhibitors that can effectively inhibit FGFR1-3 have a poor effect on FGFR4.
  • H3 Biomedicine has patented WO20152015938938A120150423Pyrimidines and FGFR4inhibitors and their preparation and WO2015057963A120150423N-Aryl-heteroarylamines FGFR4-specific inhibitors were disclosed, of which H3B-6527 has entered the FDA's Phase I clinical stage and obtained orphan drug qualification. Its structure is as follows:
  • H3B6527 has strong antitumor activity on FGF19 gene-amplified cells, and has no bile acid-related adverse reactions in animal models of mice and monkeys.
  • single administration of H3B-6527 only controls the growth of cancer cells and cannot clear cancer cells (Cancer Res; 77 (24) December 15, 2017).
  • the resistance of H3B-6527 to V550L or V550 mutations at key sites reduces or invalidates the efficacy. How to break through the restriction of these mutations leading to drug resistance will become the focus of the next phase of FGFR4 inhibitor research.
  • Inhibitors targeting the FGFR4 target have many advantages, especially their excellent selectivity and resistance to mutation. There are few drugs currently on the market. Therefore, it is found that such small molecule inhibitors targeting FGFR4 will have better therapeutic effects and application prospects. The development of a new, highly selective and potent inhibitor of FGFR4 has become an urgent problem in the clinic.
  • the compound represented by formula (I) provided by the present invention is a pharmaceutically acceptable salt, isomer, hydrate, solvate, or prodrug thereof, which can be used to treat or prevent diseases caused by tyrosine kinase FGFR4. Including certain variants of the tyrosine kinase FGFR4 receptor.
  • X is N or CH
  • Y is N or C-M, where M is -H, -F, -Cl, methyl, methoxy;
  • Z is N or C-R
  • R is -H, -F, -Cl, hydroxyl, amino, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, mono- or di-C 1 -C 3 Alkyl substituted amino, substituted or unsubstituted 4-6 membered heterocyclyl, or the following groups:
  • n 2 or 3
  • R a is amino, C 1 -C 3 alkoxy, mono- or bis C 1 -C 3 alkyl substituted amine
  • R b is -H, C 1 -C 3 alkyl
  • the substituted or unsubstituted 4-6 membered heterocyclic group described in R contains 1-2 heteroatoms selected from N, O or S.
  • the substituted 4-6 membered heterocyclic group is independently Or different substituents selected from the group consisting of hydroxy, amino, cyano, formyl, acetyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, mono- or di-C 1 -C 3 Alkylamino
  • R 1 is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR 3 ,
  • L is L 1 or L 2 .
  • L 1 is: n1 is an integer from 0 to 4,
  • n2 is an integer from 0-3, n3 is an integer from 0-2,
  • R 4 is -H or C 1 -C 3 alkyl
  • the 4- to 6-membered heterocyclic group in R 1 contains 1-2 heteroatoms selected from N, O or S, and the substituted 4-to-6-membered heterocyclic group is independently selected from 1-2 selected from hydroxyl, halogen , C 1 -C 3 alkyl, C 1 -C 3 alkoxy,
  • R 3 is -H, C 1 -C 8 alkyl, halo C 2 -C 4 alkyl, hydroxy substituted C 2 -C 4 alkyl, cyano substituted C 2 -C 4 alkyl, carboxy substituted C 1 -C 3 alkyl, C 1 -C 3 alkoxy substituted C 2 -C 4 alkyl, bridged ring structure, substituted or unsubstituted fused ring structure, substituted or unsubstituted C 3 -C 8 ring Alkyl, substituted or unsubstituted 4-6 membered heterocyclyl, substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted aryl,
  • the bridge ring structure in R 3 is a bridge ring structure of C 5 -C 11 ,
  • the substituted or unsubstituted fused ring structure described in R 3 is selected from the group consisting of an aromatic ring and a 5-6 membered heteroaryl group, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaryl ring group, and an aromatic ring and a 5-6 membered ring.
  • the substituent of the ring structure is selected from the group consisting of halogen, hydroxy, cyano, carbamoyl, C 1 -C 3 methoxy, C 1 -C 6 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkyl substituted C 1 -C 3 alkyl, hydroxy substituted C 2 -C 4 alkyl, C 1 -C 3 methoxy substituted C 2 -C 4 alkyl, cyano substituted C 1 -C 3 alkyl, carbamoyl substituted C 1 -C 3 alkyl,
  • the substituted C 3 -C 8 cycloalkyl described in R 3 is independently substituted by 1-2 identical or different substituents, the substituents being selected from halogen, hydroxyl, cyano, C 1 -C 3 alkoxy , C 1 -C 3 alkyl,
  • the 4- to 6-membered heteroaryl and 5- to 6-membered heteroaryl in R 3 contain 1-2 heteroatoms selected from N, O or S,
  • the substituted 4-6 membered heterocyclic group described in R 3 is independently substituted by 1-2 identical or different substituents, and the substituents are selected from halogen, hydroxyl, cyano, and C 1 -C 3 alkoxy , C 1 -C 3 alkyl, formyl, acetyl, carbamoyl, methylaminoformyl, dimethylaminoformyl,
  • the substituted aryl and 5- to 6-membered heteroaryl described in R 3 are independently substituted by 1-4 identical or different substituents, and the substituents are selected from halogen, hydroxyl, amino, cyano, carboxyl, and fluorine Methoxy, difluoromethoxy, trifluoromethoxy, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 alkynyl , C 2 -C 3 alkenyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono- or bis C 1 -C 3 alkylamino, C 3 -C 4 cycloalkyloxy, C 3 -C 4 cycloalkyl substituted C 1 -C 3 alkyl, cyano substituted C 1 -C 3 alkyl, carbamoyl substituted C 1 -C 3 alkyl, or the following groups
  • q is an integer of 2-3
  • R s is -H, C 1 -C 3 alkyl
  • R p is -H, C 1 -C 3 alkyl
  • R ′ and R ′′ are each independently -H, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl,
  • R 5 is -H, halogen, hydroxy, cyano, amino, carboxyl, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 3 alkoxy, mono- or di-C 1 -C 3 alkyl substituted amine groups;
  • R 2 is -L 3 -R 6 or -L 4 -R 7 ,
  • p1 is an integer of 0-4, p2 is an integer of 2-4, p3 is an integer of 0-1,
  • R p is -H or C 1 -C 3 alkyl
  • R 6 is -H, halogen, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono- or di-C 1 -C 3 alkylamino, substituted or unsubstituted 4-6 membered heterocyclic ring base,
  • the 4- to 6-membered heterocyclic group described in R 6 contains 1-2 heteroatoms selected from N, O or S, and the substituted 4-6-membered heterocyclic group is independently substituted with 1-2 identical or different substituents, respectively.
  • the substituent of the 4- to 6-membered heterocyclic group is selected from the group consisting of hydroxy, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, formyl, acetyl, propionyl, Isopropyl, hydroxy-substituted C 1 -C 3 alkyl, carboxy-substituted C 1 -C 3 alkyl, or -NR 8 R 9 ,
  • R 8 and R 9 are each independently -H, C 1 -C 6 alkyl, C 3 -C 4 cycloalkyl, hydroxyl substituted C 2 -C 3 alkyl, cyano substituted C 1 -C 2 alkyl Group, C 1 -C 3 alkoxy-substituted C 2 -C 3 alkyl group, or R 8 , R 9 and the nitrogen atom to which it is attached form a substituted or unsubstituted 4-6 membered heterocyclic group,
  • the 4- to 6-membered heterocyclic group described in R 8 and R 9 contains 1-2 heteroatoms selected from N, O or S, and the substituent of the substituted 4- to 6-membered heterocyclic group is selected from -H, hydroxyl, Cyano, amino, formyl, acetyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, mono- or bis C 1 -C 3 alkylamino, hydroxy-substituted C 2 -C 3 alkyl ,
  • R 7 is -H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-6 membered heterocyclic group,
  • the 4- to 6-membered heterocyclic group in R 7 contains 1-2 heteroatoms selected from N, O or S, and the 4- to 6-membered heterocyclic group is unsubstituted or independently 1-2 Substituted by hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, formyl, acetyl, propionyl, isopropyl.
  • Z is N or C-R
  • R is -H, F, Cl, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, Propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, substituted or unsubstituted 4-6 Heterocyclic group, or the following group:
  • n 2 or 3
  • R a is -H, methoxy, ethoxy, propoxy, isopropoxy, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino,
  • R b is -H, methyl, ethyl
  • the substituted or unsubstituted 4-6 membered heterocyclic group described in R is selected from the following groups:
  • R 10 is selected from -H, methyl, ethyl, propyl, isopropyl,
  • R 11 and R 12 are each independently selected from -H, -F, hydroxyl, cyano, methyl, and ethyl.
  • R 1 is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR 3 , wherein L is L 1 or L 2 ,
  • L 1 is:
  • n1 is an integer from 0 to 3;
  • n2 is an integer from 0-2, n3 is an integer from 0-1,
  • R 4 is -H or methyl
  • the substituted or unsubstituted 4-6 membered heterocyclic group in R 1 is selected from the following groups:
  • R 13 and R 14 are each independently selected from -H, -F, hydroxyl, cyano, methyl, ethyl, and methoxy;
  • R 3 is -H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, hydroxyethyl, hydroxypropyl , Cyanoethyl, cyanopropyl, carboxyethyl, carboxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, Isopropoxypropyl, fluoroethyl, difluoroethyl, trifluoroethyl, 2-hydroxypropyl, 2-methoxypropyl, or the following groups:
  • R 15 is selected from -H, methyl, ethyl, propyl, isopropyl,
  • R 16 , R 17 , R 18 , and R 19 are each independently selected from -H, -F, -Cl, -Br, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, and tert-butyl.
  • q is an integer of 2-3
  • R s is -H, methyl, ethyl
  • R p is -H, methyl, ethyl
  • R ′ and R ′′ are independently -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,
  • R 5 is -H, -F, hydroxyl, cyano, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamine Group, ethylamino group, dimethylamino group;
  • R 20 is -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl, Carbamoylethyl, carbamoylpropyl,
  • R 21 and R 22 are each independently -H, -F, hydroxyl, cyano, methyl, ethyl, methoxy, or ethoxy.
  • R 2 is -L 3 -R 6 or -L 4 -R 7 ,
  • p1 is an integer of 0-3, and p2 is an integer of 2-3;
  • p3 is an integer of 0-1
  • R p is -H, methyl, ethyl
  • R 6 is -H, F, -Cl, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, butyl, hexyl, iso Propyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, isopropyl Oxy, methylthio, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethyl Amine, substituted or unsubstituted 4-6 membered heterocyclyl,
  • the substituted or unsubstituted 4-6 membered heterocyclic group described in R 6 is selected from the following groups:
  • R 23 is -H, -F, methyl, ethyl,
  • R 24 is -H, -F, hydroxyl, hydroxymethyl, cyano, methyl, ethyl, methoxy, or -NR 26 R 27 ,
  • R 26 and R 27 are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, and methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, or the nitrogen atom to which R 26 or R 27 is attached
  • the substituted or unsubstituted 4-6 membered heterocyclic group is selected from the following groups:
  • R 28 is -H, methyl, ethyl, formyl, acetyl,
  • R 29 is -H, methyl, ethyl
  • R 30 is -H, hydroxyl, amino, methylamino, dimethylamino, hydroxymethyl, cyano, methyl, ethyl, methoxy,
  • R 25 is -H, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propanoyl, isopropyl, carboxymethyl, carboxyethyl, hydroxyethyl, hydroxypropyl,
  • R s1 and R s2 are independently H and methyl
  • R 7 is -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted 4-6 Membered heterocyclic group, the substituted or unsubstituted 4-6 membered heterocyclic group is selected from the following groups:
  • R 1 is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR 3 , wherein L is L 1 or L 2 ,
  • L 1 is: n1 is an integer from 0-2;
  • n2 is an integer from 0-2, n3 is an integer from 0-1,
  • R 4 is -H or methyl
  • R 1 is -L 1 -R 3 or -L 2 -R 3 , wherein -L 1 -R 3 is preferably from the following groups:
  • R 20 is -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl, Carbamoylethyl, carbamoylpropyl.
  • R 1 is -H, a substituted or unsubstituted 4-6 membered heterocyclic group, or -LR 3 , wherein L is L 1 or L 2 ,
  • L 1 is: n1 is an integer from 0-2;
  • n2 is an integer from 0-2, n3 is an integer from 0-1,
  • R 4 is -H or methyl
  • R 1 is -L 1 -R 3 or -L 2 -R 3 ,
  • R 3 is selected from: -H, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl , Hexyl, hydroxyethyl, cyanoethyl, methoxyethyl, fluoroethyl, difluoroethyl, trifluoroethyl, 2-hydroxypropyl, 2-methoxypropyl, or the following groups :
  • R 15 is selected from -H, methyl, ethyl,
  • R 16 , R 17 , R 18 , and R 19 are each independently selected from -H, -F, -Cl, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, tert-butyl, and methyl.
  • q is an integer of 2-3
  • R s is H, methyl, ethyl
  • R p is -H, methyl, ethyl
  • R ′ and R ′′ are each independently -H, methyl, ethyl, propyl, isopropyl, cyclopropyl,
  • R 5 is -H, -F, hydroxyl, cyano, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylamine Group, ethylamino group, dimethylamino group,
  • R 20 is -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, hydroxy Ethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl, Carbamoylethyl, carbamoylpropyl,
  • R 21 and R 22 are each independently -H, -F, hydroxyl, methyl, ethyl, or methoxy.
  • a compound represented by formula (I) an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt thereof, and a prodrug thereof,
  • X is N or CH
  • Y is N or C-M, where M is -H, -F, -Cl, methyl or methoxy;
  • Z is N or C-R
  • R is -H, -F, -Cl, hydroxyl, amino, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, mono- or di-C 1 -C 3 Alkyl substituted amino, substituted or unsubstituted 4-6 membered heterocyclyl, or the following groups:
  • n 2 or 3
  • R a is amino, C 1 -C 3 alkoxy, mono- or bis C 1 -C 3 alkyl substituted amine
  • R b is -H, or C 1 -C 3 alkyl
  • the substituted or unsubstituted 4-6 membered heterocyclic group described in R contains 1-2 heteroatoms selected from N, O or S.
  • the substituted 4-6 membered heterocyclic group is independently Or different substituents selected from the group consisting of halogen, hydroxy, amino, cyano, formyl, acetyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, mono or bis C 1- C 3 alkylamino;
  • R 1 is -LR 3 ,
  • L is L 1 or L 2 .
  • L 1 is: n1 is an integer from 0 to 4,
  • L 2 is selected from:
  • n2 is an integer from 0 to 3
  • n3 is an integer from 0 to 2
  • R 4 is -H or C 1 -C 3 alkyl
  • R 3 is selected from a substituted or unsubstituted fused ring structure, a substituted or unsubstituted 5-6 membered heteroaryl group, a substituted or unsubstituted aryl group,
  • the substituted or unsubstituted fused ring structure described in R 3 is selected from the group consisting of an aromatic ring and a 5-6 membered heteroaromatic ring, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaromatic ring, and an aromatic ring and a 5-6 membered carbon.
  • the 5-6 membered heteroaryl group in R 3 contains 1-2 heteroatoms selected from N, O or S,
  • the substituted aryl and 5- to 6-membered heteroaryl described in R 3 are independently substituted with 1-4 identical or different substituents, which are selected from halogen, hydroxyl, amino, cyano, carboxyl, Fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 alkyne Alkyl, C 2 -C 3 alkenyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono- or bis C 1 -C 3 alkylamino, C 3 -C 4 cycloalkyloxy , C 3 -C 4 cycloalkyl substituted C 1 -C 3 alkyl, cyano substituted C 1 -C 3 alkyl, carbamoyl substituted C 1 -C 3 alkyl, hydroxy substituted C 1- C 3
  • q is an integer of 2-3
  • R s is selected from -H, C 1 -C 3 alkyl
  • R p is selected from -H, C 1 -C 3 alkyl
  • R ′ and R ′′ are each independently -H, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl,
  • R 5 is selected from -H, halogen, hydroxy, cyano, amino, carboxyl, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 1 -C 3 alkoxy, mono- or di-C 1- C 3 alkyl substituted amine groups;
  • R 2 is -L 3 -R 6 ,
  • R p is -H or C 1 -C 3 alkyl
  • R 6 is selected from -H, halogen, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl , C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, mono- or di-C 1 -C 3 alkylamino, substituted or unsubstituted 4-6 membered hetero Ring base,
  • the 4- to 6-membered heterocyclic group described in R 6 contains 1-2 heteroatoms selected from N, O or S.
  • the substituted 4- to 6-membered heterocyclic group is substituted with 1-2 same or different substituents.
  • the substituent of the 4- to 6-membered heterocyclic group is selected from the group consisting of hydroxyl, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, formyl, acetyl, propionyl, iso Propionyl, hydroxy-substituted C 1 -C 3 alkyl, carboxy-substituted C 1 -C 3 alkyl, or -NR 8 R 9 ,
  • R 8 and R 9 are each independently selected from -H, C 1 -C 6 alkyl, C 3 -C 4 cycloalkyl, hydroxy substituted C 2 -C 3 alkyl, cyano substituted C 1 -C 2 Alkyl, C 1 -C 3 alkoxy-substituted C 2 -C 3 alkyl, or R 8 , R 9 and the nitrogen atom to which they are attached form a substituted or unsubstituted 4-6 membered heterocyclic group,
  • the 4- to 6-membered heterocyclic group described in R 8 and R 9 contains 1-2 heteroatoms selected from N, O or S, and the substituent of the substituted 4- to 6-membered heterocyclic group is selected from -H, hydroxyl, Cyano, amino, formyl, acetyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, mono- or bis C 1 -C 3 alkylamino, hydroxy-substituted C 2 -C 3 alkyl .
  • Z is C-R
  • R is selected from -H, F, Cl, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy , Propoxy, isopropoxy, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, substituted or unsubstituted 4- 6-membered heterocyclic group, or the following group:
  • n 2 or 3
  • R a is -H, methoxy, ethoxy, propoxy, isopropoxy, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, Or N-methyl-N-ethylamino,
  • R b is -H, methyl, or ethyl
  • the substituted or unsubstituted 4-6 membered heterocyclic group described in R is selected from the following groups:
  • R 10 is selected from -H, methyl, ethyl, propyl, isopropyl,
  • R 11 and R 12 are each independently selected from -H, -F, hydroxyl, cyano, methyl, and ethyl.
  • R 1 is -LR 3 , wherein L is L 1 or L 2 ,
  • L 1 is: n1 is an integer from 0 to 3;
  • L 2 is selected from:
  • n2 is an integer of 0-2, n3 is an integer of 0-1, R 4 is -H or methyl;
  • R 3 is selected from the following groups:
  • R 16 , R 17 , R 18 , and R 19 are each independently selected from -H, -F, -Cl, -Br, hydroxyl, carboxyl, cyano, methyl, ethyl, propyl, isopropyl, Tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclobutyloxy, methylthio, ethylthio, propylthio, isopropylthio, Fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, cyclopropylmethyl , Cyclobutylmethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethy
  • q is an integer of 2-3
  • R s is selected from -H, methyl, ethyl
  • R p is selected from -H, methyl, ethyl
  • R ′ and R ′′ are each independently selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl,
  • R 5 is selected from -H, -F, hydroxyl, cyano, carboxyl, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methyl Amine, ethylamino, dimethylamine;
  • R 20 is selected from -H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, Hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, cyanomethyl, cyanoethyl, cyanopropyl, carbamoylmethyl , Carbamoylethyl, carbamoylpropyl, CH 3 OCOCH 2 CH 2- , CH 3 CH 2 OCOCH 2 CH 2- .
  • R 2 is -L 3 -R 6
  • L 3 is selected from:
  • p1 is an integer from 0-3, and p2 is an integer from 0-3;
  • R p is selected from -H, methyl, ethyl
  • R 6 is selected from -H, F, -Cl, hydroxyl, amino, cyano, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methyl, ethyl, propyl, butyl, hexyl, Isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, iso Propoxy, methylthio, ethylthio, propylthio, isopropylthio, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, N-methyl-N-ethyl Amino, substituted or unsubstituted 4-6 membered heterocyclyl,
  • the substituted or unsubstituted 4-6 membered heterocyclic group described in R 6 is selected from the following groups:
  • R 23 is -H, -F, methyl, ethyl,
  • R 24 is -H, -F, hydroxyl, hydroxymethyl, cyano, methyl, ethyl, methoxy, or -NR 26 R 27 ,
  • R 26 and R 27 are each independently -H, methyl, ethyl, propyl, isopropyl, hydroxyethyl, hydroxypropyl, cyanomethyl, cyanoethyl, methoxyethyl, and methyl Oxypropyl, ethoxyethyl, ethoxypropyl, isopropoxyethyl, isopropoxypropyl, cyclopropyl, cyclobutyl, or the nitrogen atom to which R 26 or R 27 is attached
  • the substituted or unsubstituted 4-6 membered heterocyclic group is selected from the following groups:
  • R 28 is selected from -H, methyl, ethyl, formyl, acetyl,
  • R 29 is selected from -H, methyl, ethyl,
  • R 30 is selected from -H, hydroxyl, amino, methylamino, dimethylamino, hydroxymethyl, cyano, methyl, ethyl, methoxy,
  • R 25 is selected from -H, methyl, ethyl, propyl, isopropyl, formyl, acetyl, propanoyl, isopropyl, carboxymethyl, carboxyethyl, hydroxyethyl, hydroxypropyl,
  • R s1 and R s2 are each independently selected from H and methyl.
  • substituted as referred to herein includes complex substituents (for example, phenyl, aryl, heteroalkyl, heteroaryl), more suitably 1 to 5 substituents, more preferably 1 to 3
  • substituents for example, phenyl, aryl, heteroalkyl, heteroaryl
  • 1 to 5 substituents more preferably 1 to 3
  • alkyl groups include saturated straight-chain and branched hydrocarbon groups.
  • C 1 -C 8 represents an alkyl group having 1 to 8 carbon atoms.
  • C 1 -C 3 represents an alkyl group.
  • Carbon atoms having 1-3 carbon atoms, for example, C 1 -C 6 alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- Butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
  • Alkoxy is an alkyl ether composed of the linear, branched chains previously described.
  • alkenyl and alkynyl include straight-chain, branched-chain alkenyl or alkynyl.
  • Cycloalkyl refers to a cyclic group formed by carbon atoms, for example, C 3 -C 7 represents a carbon atom having 3 to 7 carbon atoms in an alkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Cycloheptyl, and similarly, also include cyclic alkenyl.
  • aryl refers to an unsubstituted or substituted aromatic group, such as phenyl, naphthyl, anthracenyl.
  • aroyl refers to -C (O) -aryl.
  • Oxidized by one or two oxygen atoms means that a sulfur atom is oxidized by one oxygen atom to form a double bond between sulfur and oxygen, or is oxidized by two oxygen atoms to form a double bond between sulfur and two oxygen.
  • heterocyclyl represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system, which is selected from carbon atoms and selected from N, O, and S It consists of 1 to 3 heteroatoms, of which N, S heteroatoms can be oxidized at will, and N heteroatoms can also be quaternized at will. Heterocyclic rings can be combined with any heteroatom or carbon atom to form a stable structure.
  • heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidine Pyridyl, piperazinyl, piperazinyl oxide, piperidinyl oxide, dioxocyclopentyl, dioxocyclohexane tetrahydroimidazolyl, tetrahydrooxazolyl, thiomorpholine sulfoxide, thio Morpholine sulfone and oxadiazolyl.
  • heteroaryl represents an unsubstituted or substituted stable 5- or 6-membered monocyclic aromatic ring system, and may also represent an unsubstituted or substituted 9 or A 10-ring benzene fused heteroaromatic ring system or a bicyclic heteroaromatic ring system, which consists of carbon atoms and 1 to 3 heteroatoms selected from N, O, and S, among which the N and S heteroatoms can be Oxidation, N heteroatoms can also be quaternized. Heteroaryl groups can be linked to any heteroatom or carbon atom to form a stable structure.
  • Heteroaryl includes but is not limited to thienyl, furyl, imidazolyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, pyranyl, pyridyl, piperazinyl, pyrimidinyl, pyrazine, Pyridazinyl, pyrazolyl, thiadiazolyl, triazolyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, benzofuranyl, benzothiophene Benzoxazolyl, benzoxazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, or isoquinoline base.
  • carbonyl refers to a C (O) group.
  • alkyl or “aryl” or any of their prefixes appears in the name of a substituent (eg, aralkyl, dialkylamine), it will be considered to include the above “alkane And "aryl”.
  • the specified number of carbon atoms e.g., C 1 -C 6
  • C 1 -C 6 will independently represent the number of carbon atoms in an alkyl moiety or an alkyl moiety in a larger substituent (where alkyl is used as its prefix stem) Quantity.
  • the present invention also provides a method for preparing the corresponding compound.
  • a variety of synthetic methods can be used to prepare the compounds described herein, including the following methods.
  • the compound of the present invention or a pharmaceutically acceptable salt, isomer or hydrate thereof may be The following methods are used to synthesize synthetic methods known in the field of organic chemical synthesis, or by those skilled in the art to understand variations of these methods. Preferred methods include, but are not limited to, the following methods.
  • the final product of the present invention can be prepared by the following scheme, wherein R1, R2, X, Y, Z are as defined above,
  • M in the intermediate A1 is nitro or BocNH-
  • Q in the intermediate B1 is chlorine or methylsulfone (sulfoxide).
  • the reaction can be carried out by heating under acid catalysis, neutral conditions or basic conditions.
  • the substitution reaction synthesizes compound (C1).
  • Q in the intermediate B1 is chlorine
  • the compound (C1) can also be synthesized through a Buchwald coupling reaction;
  • Second step If M is BocNH- in intermediate C1, the tert-butyloxycarbonyl protecting group can be removed under acidic conditions to obtain intermediate D1. If M is nitro in intermediate C1, compounds can be generated by reducing nitro D1.
  • Step 3 Synthesis of the final product (I) from intermediate D1 and acryloyl chloride.
  • the method for preparing the compound of the present invention includes the preparation of each of the above intermediates,
  • the intermediate (A1) is prepared as follows,
  • Step 1 Compound (A2) is reacted with (Boc) 2 O to obtain compound (A3).
  • X may be Cl, F, Br or I;
  • Step 2 Compound (A3) is reacted with R 2 -H (amine or alcohol) under basic or neutral conditions to obtain compound (A4).
  • R 2 -H amine or alcohol
  • the compound (A4) can also be obtained by Buchwald coupling reaction;
  • Step 3 The compound (A4) is reacted with a reducing agent to form an intermediate (A1), where M is BocNH-.
  • the base described in step 2 is selected from one or a combination of two or more inorganic bases such as cesium carbonate, triethylamine, sodium hydride, sodium bis (trimethylsilyl) amino, or organic bases. Puch 2 is preferred for Buchwald conditions.
  • (dba) 3 a combination of XantPhos and cesium carbonate;
  • the reducing agent in step 3 is selected from the group of reducing agents such as stannous chloride, hydrogen and palladium-carbon, hydrogen and Raney nickel, zinc powder and acid, iron powder and acid.
  • the intermediate (B1) is prepared as follows.
  • Step 1 Compound (B2) is subjected to substitution reaction with R 1 -H (amine or alcohol) in the presence of a base to obtain (B3);
  • Step 2 Compound (B3) is dehydrated to compound (B1) under the condition of a dehydrating agent.
  • (B1) can be prepared by (B4) performing a substitution reaction with R 1 -H (amine or alcohol) in the presence of a base.
  • Q in B1 is chlorine.
  • the present invention provides a preferred embodiment of the above reaction, preferably,
  • the base is selected from organic or inorganic bases, such as triethylamine, N'N-diisopropylethylamine, sodium hydride, sodium bis (trimethylsilyl) amino, n-butyllithium One or a combination of two or more of them;
  • organic or inorganic bases such as triethylamine, N'N-diisopropylethylamine, sodium hydride, sodium bis (trimethylsilyl) amino, n-butyllithium One or a combination of two or more of them;
  • the dehydrating agent is selected from the group consisting of phosphorus oxychloride, aluminum trichloride, phosphorus pentoxide, phosphorus chloride (phosphorus pentachloride or phosphorus trichloride), and the like;
  • Step 1 Compound (B5) reacts with 1- (4-methoxyphenyl) ethyl-1-amine to form compound (B6) under the action of a base;
  • Step 2 Compound (B6) is heated to react to form compound (B7) under acidic conditions;
  • Step 3 Compound (B7) reacts with acid chloride under the action of base to form compound (B1).
  • Q is chlorine.
  • the first step base is selected from DIEA, triethylamine, or a combination of two or more;
  • the second step acid is selected from one or a combination of two or more of trifluoroacetic acid, phosphorus oxychloride, hydrochloric acid, and acetic acid;
  • the base described in step 3 is selected from one or two of triethylamine, N'N-diisopropylethylamine, sodium hydride, sodium bis (trimethylsilyl) amino, and n-butyllithium. A combination of the above;
  • Step 1 Compound (B8) undergoes substitution reaction with R1-H (amine or alcohol) under the action of acid or base, or reacts with R1 substituted boric acid or boric acid ester through Suzuki coupling reaction, or with indole heterocyclic ring Synthesis of intermediates (B9) containing different R1 substituents under Lewis acid conditions;
  • Step 2 Compound (B9) is reacted with an oxidant to form compound (B1).
  • Q is methylsulfoxide.
  • the acid described in step 1 is selected from trifluoroacetic acid, hydrochloric acid, p-toluenesulfonic acid, etc.
  • the coupling condition catalyst is selected from Pd (PPh 3 ) 4 , Pd (dppf) Cl 2 , Pd (PPh 3 ) 2 Cl 2 Etc.
  • the base is selected from potassium acetate, potassium carbonate, cesium carbonate, potassium phosphate, etc.
  • the Lewis acid is selected from aluminum trichloride, titanium tetrachloride, tin tetrachloride, etc .;
  • the oxidant described in step 2 is selected from one or a combination of two or more of m-chloroperoxybenzoic acid and potassium persulfate complex salt.
  • intermediates containing specific functional groups in R2 or Z can be further derivatized to obtain different intermediate C1 compounds.
  • Such compounds can also be passed through the aforementioned methods through intermediates A1 and B1.
  • the reaction is obtained.
  • the derivatization method is as follows.
  • the base mentioned in the first reaction is selected from cesium carbonate, potassium carbonate, triethylamine, sodium hydride, etc .;
  • the base in the second type of reaction is selected from one or a combination of two or more of cesium carbonate, potassium carbonate, triethylamine, and sodium hydride.
  • solvated form may be a water-soluble form.
  • the invention includes all of these solvated and unsolvated forms.
  • the compounds of the present invention may have asymmetric carbon atoms. Based on their physical and chemical differences, such diastereomeric mixtures can be separated by known methods, such as chromatography or fractional crystallization. Into a single diastereomer. Enantiomers can be separated by first reacting with an appropriate optically active compound to convert the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and then converting the single diastereomer Enantiomers are converted (hydrolyzed) to the corresponding pure enantiomers. All such isomers, including diastereomeric mixtures and pure enantiomers, are considered to be part of the invention.
  • the compound of the present invention as an active ingredient, and a method for preparing the same are the contents of the present invention.
  • the crystalline forms of some compounds can exist as polycrystals, and this form can also be included in the current invention.
  • some compounds can form solvates with water (ie, hydrates) or common organic solvents, and such solvates are also included in the scope of this invention.
  • the compounds of the present invention can be used for treatment in free form or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative.
  • pharmaceutically acceptable salt refers to the organic and inorganic salts of the compounds of the present invention. This salt is suitable for humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and is reasonable. Benefit / risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art.
  • the salt can be formed by reacting a compound of the present invention with a suitable free base or acid.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, Alternatively, these salts can be obtained by using methods well known in the art, such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphor sulfonate, citrate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glyceryl phosphate, gluconic acid Salt, hemisulfate, hexanoate, hydroiodate, 2-hydroxyethanesulfonate, lactate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, per-3-phenylpropionate, Phosphate, picrate, propionate
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include appropriate non-toxic ammonium, quaternary ammonium, and use such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate Ammonium cations formed by acid salts.
  • prodrug as used herein means that a compound can be converted into a compound represented by formula (I) of the present invention in vivo. This conversion is affected by the hydrolysis of the prodrug in the blood or the enzymatic conversion into the parent compound in the blood or tissue.
  • the pharmaceutical composition of the present invention comprises a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressive agent, an anticancer drug, an antiviral agent, an Inflammatory agents, antifungal agents, antibiotics or additional active agents of anti-hyperplasia compounds; and any pharmaceutically acceptable carrier, adjuvant or excipient.
  • a kinase inhibitor small molecule, polypeptide, antibody, etc.
  • an immunosuppressive agent an anticancer drug
  • an antiviral agent an antiviral agent
  • Inflammatory agents antifungal agents
  • antibiotics or additional active agents of anti-hyperplasia compounds antibiotics or additional active agents of anti-hyperplasia compounds
  • the compounds of the invention can be used alone or in combination with one or more other compounds of the invention or with one or more other agents.
  • the therapeutic agents can be formulated to be administered simultaneously or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • the so-called "combination therapy" refers to the use of the compound of the present invention together with another agent.
  • the mode of administration is simultaneous administration of each agent or sequential administration of each agent. To achieve the best results of the drug.
  • Co-administration includes simultaneous delivery of the dosage forms, as well as separate dosage forms for each compound.
  • the administration of the compound of the present invention can be used concurrently with other known therapies in the art, for example, the use of radiation therapy or additional therapies such as cytostatic agents, cytotoxic agents, other anticancer agents in cancer treatment to improve Symptoms of cancer.
  • additional therapies such as cytostatic agents, cytotoxic agents, other anticancer agents in cancer treatment to improve Symptoms of cancer.
  • the invention is not limited to the order of administration; the compounds of the invention may be administered previously, concomitantly, or after other anticancer or cytotoxic agents.
  • one or more compounds or salts of formula (I) as its active ingredient can be intimately mixed with the pharmaceutical carrier, which is performed according to the traditional pharmaceutical ingredient technology,
  • the carrier can adopt various forms according to the preparation form designed according to different administration modes (for example, oral or parenteral administration).
  • Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, a book jointly published by the American Pharmaceutical Association and the British Pharmaceutical Society.
  • the pharmaceutical composition of the present invention may have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear liquids, suspensions, Emulsions; or for topical application such as creams, creams; or as suppositories for rectal administration.
  • Pharmaceutical ingredients may also be suitable for precise single-dose administration in unit dosage form.
  • the pharmaceutical ingredient will include a traditional pharmaceutical carrier or excipient and a compound made as an active ingredient according to the current invention, and may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.
  • Therapeutic compounds can also be administered to mammals rather than humans.
  • the dosage of a drug administered to a mammal will depend on the species of the animal and its disease status or its disorder.
  • the therapeutic compound can be administered to animals in the form of capsules, boluses, or tablet potions.
  • Therapeutic compounds can also be introduced into animals by injection or infusion. We prepare these medicinal forms in a traditional way that meets the standards of veterinary practice.
  • pharmaceutical synthetic drugs can be mixed with animal feed and fed to animals. Therefore, concentrated feed additives or premixes can be prepared to mix ordinary animal feed.
  • Yet another object of the present invention is to provide a method for treating cancer in a subject in need, comprising administering to the subject a method of treating a therapeutically effective amount of a composition containing a compound of the present invention.
  • the compounds of the present invention have selectivity over FGFR4 over other receptors, especially over other FGF receptors, such as FGFR1, FGFR2, and FGFR3. Accordingly, the present invention relates to compounds that are selective FGFR4 inhibitors.
  • compounds of formula (I) in the form of free or pharmaceutically acceptable salts are suitable for treating conditions (such as cancer) mediated by the activity of the FGFR4 protein and / or being reactive to the inhibition of FGFR4 (In particular, refers to a condition in a therapeutically beneficial manner), most particularly a disease or condition as mentioned herein below.
  • the compounds of the invention are useful in the treatment of cancer.
  • the compound of the present invention is useful for treating an indication selected from the group consisting of liver cancer, breast cancer, glioblastoma, prostate cancer, rhabdomyosarcoma, gastric cancer, ovarian cancer, lung cancer, and colon cancer.
  • the compounds of the invention can also be used to treat solid malignancies characterized by positive FGFR4 expression.
  • the compounds of the invention can also be used to treat solid malignancies characterized by positive KLB ( ⁇ -klotho) expression.
  • the compounds of the invention can also be used to treat solid malignancies characterized by positive FGF19 expression.
  • the compounds of the invention can also be used to treat solid malignancies characterized by positive FGFR4 and positive KLB expression.
  • the compounds of the invention can also be used to treat solid malignancies characterized by positive FGFR4 and positive FGF19 expression.
  • the compounds of the invention can also be used to treat solid malignancies characterized by positive FGFR4, positive KLB and positive FGF19 expression.
  • Any positive expression in FGFR4, KLB and / or FGF19 as described above can be evaluated by methods known to the skilled person, such as RT-qPCR, Western blotting, ELISA, immunohistochemistry.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy.
  • the treatment is selected from a disease that can be treated by inhibiting FGFR4.
  • the disease is selected from the list mentioned above, suitably liver cancer.
  • the invention provides a method of treating a disease treated by inhibiting FGFR4, comprising administering a therapeutically acceptable amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the disease is selected from the list mentioned above, suitably liver cancer.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.
  • the medicament is used to treat a disease that can be treated by inhibiting FGFR4.
  • the disease is selected from the list mentioned above, suitably liver cancer.
  • the reaction solvent was provided by Sinopharm Reagent
  • Thin layer chromatography silica gel plate (thickness 0.5mm, 1mm, 200X200mm) provided by Yantai Xinnuo Chemical Co., Ltd.
  • reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and evaporated to dry out column chromatography to obtain 850 mg of a yellow oil, MS: 487 [M + H] + ;
  • step 1 4-chloro-5-fluoro-2-nitroaniline is used, and N-ethyl-N-methylpiperidine is used.
  • step 2 ethylpiperazine to give a light purple solid product, MS: 383 [M + H] + ;
  • Steps 2) to 4) The experimental operation is the same as that of steps 2) to 4) in Example 1, and 2-chloro-4-((2-chlorophenyl) amino) pyrimidine-5-carboxamide is used instead of step 2) in Example 1. Of 2-chloro-4- (isopropylamino) pyrimidine-5-carboxamide to give the product as a white solid.
  • 1-Acetyl-4-aminopiperidine was slowly added dropwise to a tetrahydrofuran solution (5 mL) of 2,4-dichloro-5-cyanopyrimidine (180 mg, 1 mmol) containing DIEA (0.5 mL) under ice salt bath conditions.
  • a solution of pyridine (150 mg, 1 mmol) in tetrahydrofuran (1 mL) was stirred at room temperature overnight, quenched with water, filtered, and dried to obtain a white solid, which was purified from a preparation plate (0.5 mm, silica gel) to obtain 120 mg of the target product.
  • Step 2 (2-((4-((1-acetylpiperidin-4-yl) amino) -5-cyanopyrimidin-2-yl) amino) -5- (4-ethylpiperazine -1-yl) phenyl) amino tert-butyl carbamate
  • Example 1 The same operation as in step 4) of Example 1 was performed to obtain a white solid product.
  • step 4 of Example 1 The operation is the same as that in step 4 of Example 1, using (2-((5-cyano-4-((2- (dimethylphosphoryl) phenyl) amino) pyrimidin-2-yl) amino) -5 -(4-ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester instead of (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amino ) Tert-Butyl-5- (4-ethylpiperazin-1-yl) phenyl) carbamate.
  • step 1) of Example 1 The operation is the same as step 1) of Example 1, and ethanolamine is used instead of isopropylamine.
  • Step 6 N- (2-((5-cyano-4-((2-hydroxyethyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1- Of phenyl) phenyl) acrylamide
  • Step 4) (2-((4-((4-aminoformylphenyl) amino) -5-cyanopyrimidin-2-yl) amino) -5- (4-ethylpiperazine-1 -Yl) phenyl) amino t-butyl carbamate
  • step 1) of Example 1 The operation is the same as step 1) of Example 1, and 4-methoxyaniline is used instead of isopropylamine.
  • Step 4) (2-((5-cyano-4-((4-hydroxyphenyl) amino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazin-1-yl ) Phenyl) t-butylaminocarbamate
  • Example 4 step 4 The operation is the same as that in Example 4 step 4), using (2-((5-cyano-4-((4-hydroxyphenyl) amino) pyrimidin-2-yl) amino) -5- (4-ethyl Piperazin-1-yl) phenyl) carbamic acid tert-butyl ester instead of (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amino) -5- (4 -Ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester.
  • Step 1) to Step 4) are the same as Step 1) to Step 4) of Example 136.
  • Step 5 3- (4-((2-((2-((tert-butoxycarbonyl) amino-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyano Of Pyrimidin-4-yl) amino) phenoxy) propionic acid
  • Step 6) 3- (4-((2-((2-Allylacylamino-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyrimidine- Preparation of 4-yl) amino) phenoxy) propionic acid
  • step 4) of Example 1 using 3- (4-((2-((2-((tert-butoxycarbonyl) amino-4- (4-ethylpiperazin-1-yl) phenyl)) Amine) -5-cyanopyrimidin-4-yl) amino) phenoxy) propionic acid instead of (2-((5-cyano-4- (isopropylamino) pyrimidin-2-yl) amine ) -5- (4-ethylpiperazin-1-yl) phenyl) carbamic acid tert-butyl ester.
  • Step 1) and step 2) were performed in the same manner as in step 1) and step 2) of Example 1, and cyclobutylamine was used instead of isopropylamine.
  • Step 3 2- (4- (3-((tert-butoxycarbonyl) amino) -4-((5-cyano-4- (cyclobutylamino) pyrimidin-2-yl) amino) benzene Of phenyl) piperazin-1-yl) t-butyl acetate
  • Example 1 The same operation as in step 1) of Example 1 was performed from N- (2-((5-cyano-4- (phenylamino) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine- 1-yl) -3-methylphenyl) acrylamide reacts to give a white solid product.
  • step 1) isopropylamine.
  • (2-amino-4-chloro-5- (4-ethylpiperazin-1-yl) described in intermediate 17 Phenyl) tert-butylaminoformate was used in place of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) tert-butylaminoformate in step 3) to obtain a white solid product.
  • Example 180 N- (4-Chloro-2-((5-cyano-4-((2-fluoro-6-methoxybenzyl) amino) pyrimidin-2-yl) amino) -5 -(4-ethylpiperazin-1-yl) phenyl) acrylamide
  • Example 2 The same operation as in Example 1 was carried out, in which cyclobutylamine was used instead of step 1) isopropylamine, and (2-amino-4-chloro-5- (4-ethylpiperazin-1-yl) phenyl) described in intermediate 17 Tert-butyl aminoformate was used in place of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminocarbamic acid tert-butyl ester of step 3), and a white solid product was obtained.
  • step 1) isopropylamine was replaced by aniline, and (2-amino-4-chloro-5- (4-ethylpiperazin-1-yl) phenyl) amino group described in intermediate 17 Tert-butyl formate was used instead of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) amino formate in step 3) and the same reaction was performed to obtain a white solid product;
  • step 1) isopropylamine was replaced by 3-methoxyaniline, and (2-amino-4-chloro-5- (4- (dimethylamino) piperidine) described in Intermediate 11- 1-yl) phenyl) t-butylaminoformate was used in place of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminotformate in step 3) to obtain the same reaction.
  • Example 2 The same operation as in Example 1 was carried out, in which cyclobutylamine was used instead of step 1) isopropylamine, and (2-amino-4-chloro-5- (4- (dimethylamino) piperidin-1-yl) described in intermediate 11 ) Phenyl) tert-butylaminoformate was used instead of tert-butyl (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminoformate in step 3) to give a white solid product. ;
  • step 1) isopropylamine was replaced by aniline, and (2-amino-4-chloro-5- (4- (dimethylamino) piperidin-1-yl) benzene described in intermediate 11 Tert-butylaminocarbamate instead of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminocarbamate in step 3) and the same reaction was performed to obtain a white solid product;
  • Step 3 (2-((5-cyano-4- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino) -5- (4-ethylpiperazine- Preparation of 1-yl) phenyl) amino carboxylic acid tert-butyl ester:
  • step 3 The operation is the same as step 3) in Example 1, and 2-chloro-4- (1H-indol-3-yl) pyrimidine-5-carbonitrile is used instead of 2-chloro-4- (isopropylamino) pyrimidine-5- Nitrile to give a brown solid, MS: 539 [M + H] + .
  • Step 3 (2-((5-cyano-4- (1- (2-hydroxyethyl) -1H-indol-3-yl) pyrimidin-2-yl) amino) -5- (4- Preparation of tert-butyl ethylpiperazin-1-yl) phenyl) carbamate
  • Step 3 (2-((4- (1- (3-amino-3-oxopropyl) -1H-indol-3-yl) -5-cyanopyrimidin-2-yl) amino)- Preparation of 5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester
  • Step 4) (2-((4- (1- (3-amino-3-oxopropyl) -1H-pyrazol-4-yl) -5-cyanopyrimidin-2-yl) amino)- Preparation of 5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester
  • Step 5 N- (2-((4-((1- (3-amino-3-oxopropyl) -1H-pyrazol-4-yl) -5-cyanopyrimidin-2-yl) amine Of phenyl) -5- (4-ethylpiperazin-1-yl) phenyl) acrylamide
  • Example 3 The operation was the same as in Example 3, and 1- (3-aminoazetidin-1-yl) ethyl-1-one was used in place of step 1) 1-acetyl-4-aminopiperidine in Example 3, and the same reaction was performed.
  • Example 2 The same operation as in Example 1 was carried out, in which cyclobutylamine was used instead of step 1) isopropylamine, and (2-amino-4-chloro-5- (4-((3-methoxypropyl)) ( Methyl) amino) piperidine-1-yl) phenyl) carbamic acid tert-butyl ester instead of (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) amine of step 3) Tert-butyl carbamate was subjected to the same reaction to obtain a white solid product;
  • Trifluoroacetic acid (1 mL) was added to a dichloride solution (3 mL) of butyl ester (100 mg, 0.2 mmol), and the reaction was stirred at room temperature for 1 hour. The resulting yellow oil was dissolved in anhydrous tetrahydrofuran (2 mL) under ice-water bath conditions.
  • 6-Chloro-4- (cyclohexylamino) nicotinonitrile 100 mg, 0.4 mmol
  • (2-amino-5- (4-ethylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester 120mg, 0.4mmol
  • Pd 2 (dba) 3 10mg
  • Xantphos 10mg
  • sodium carbonate 110mg, 1mmol
  • Example 1 The same operation as in step 5) of Example 1 was carried out to obtain a white solid product.
  • Step 5 The product acetic acid 1-((2-((2-acrylamido-4- (4-ethylpiperazin-1-yl) phenyl) amino) -5-cyanopyridine-4-yl ) Amino) propyl-2-yl ester was dissolved in a mixed solution of THF (3 mL), methanol (3 mL), water (0.5 mL), and then lithium hydroxide (50 mg) was added, and the mixture was stirred at room temperature for 2 hours.
  • Step 4) (2-((5-cyano-4-((2-hydroxybenzyl) amino) pyridin-2-yl) amino) -5- (4-ethylpiperazin-1-yl) Tert-butyl phenyl) carbamate
  • 6-chloro-4- (cyclohexylamino) nicotinonitrile 100 mg, 0.4 mmol
  • (2-amino-5- (4-methylpiperazin-1-yl) phenyl) aminocarboxylic acid tert-butyl ester 120mg, 0.4mmol
  • Pd 2 (dba) 3 10mg
  • Xantphos 10mg
  • sodium carbonate 110mg, 1mmol

Abstract

L'invention concerne un composé tel que représenté par la formule (I), un isomère, un hydrate, un solvate, un sel pharmaceutiquement acceptable et un promédicament de celui-ci, l'invention concerne également un procédé de préparation et d'utilisation dudit composé dans la préparation d'un médicament en tant qu'inhibiteur de kinase. Le composé présente une bonne activité inhibitrice contre FGFR4, FGFR4 V550L mutant et d'autres kinases.
PCT/CN2019/092089 2018-06-22 2019-06-20 Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, procédé de préparation correspondant et utilisation associée WO2019242689A1 (fr)

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WO2021129561A1 (fr) * 2019-12-23 2021-07-01 北京赛特明强医药科技有限公司 Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, et leur procédé de préparation et leur utilisation
CN113754591A (zh) * 2020-06-05 2021-12-07 山东大学 一种hdac、jak和bet三靶点抑制剂及其制备方法和应用
CN114560815A (zh) * 2022-03-04 2022-05-31 北京工业大学 (2-((5-氯-取代苯基氨基嘧啶-2-基)氨基)苯基)氨基甲酸叔丁酯类衍生物

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WO2015057963A1 (fr) * 2013-10-18 2015-04-23 Eisai R&D Management Co., Ltd. Inhibiteurs de fgfr4
WO2016164703A1 (fr) * 2015-04-09 2016-10-13 Eisai R & D Management Co., Ltd. Inhibiteurs du récepteur fgfr4
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CN104540809A (zh) * 2012-07-11 2015-04-22 蓝印药品公司 成纤维细胞生长因子受体的抑制剂
WO2015057963A1 (fr) * 2013-10-18 2015-04-23 Eisai R&D Management Co., Ltd. Inhibiteurs de fgfr4
WO2016164703A1 (fr) * 2015-04-09 2016-10-13 Eisai R & D Management Co., Ltd. Inhibiteurs du récepteur fgfr4
WO2018072707A1 (fr) * 2016-10-18 2018-04-26 保诺科技（北京）有限公司 Dérivé d'éther aromatique, son procédé de préparation, et ses applications médicales

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WO2021129561A1 (fr) * 2019-12-23 2021-07-01 北京赛特明强医药科技有限公司 Composé de pyridine à substitution cyano et composé de pyrimidine à substitution cyano, et leur procédé de préparation et leur utilisation
CN113754591A (zh) * 2020-06-05 2021-12-07 山东大学 一种hdac、jak和bet三靶点抑制剂及其制备方法和应用
CN113754591B (zh) * 2020-06-05 2024-01-05 山东大学 一种hdac、jak和bet三靶点抑制剂及其制备方法和应用
CN114560815A (zh) * 2022-03-04 2022-05-31 北京工业大学 (2-((5-氯-取代苯基氨基嘧啶-2-基)氨基)苯基)氨基甲酸叔丁酯类衍生物

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