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WO2018192536A1 - Composé pyrimido-hétérocyclique servant d'inhibiteur de la tyrosine kinase de bruton et ses applications - Google Patents

Composé pyrimido-hétérocyclique servant d'inhibiteur de la tyrosine kinase de bruton et ses applications Download PDF

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Publication number
WO2018192536A1
WO2018192536A1 PCT/CN2018/083599 CN2018083599W WO2018192536A1 WO 2018192536 A1 WO2018192536 A1 WO 2018192536A1 CN 2018083599 W CN2018083599 W CN 2018083599W WO 2018192536 A1 WO2018192536 A1 WO 2018192536A1
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optionally substituted
group
alkyl
phenyl
amino
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Chinese (zh)
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李洪林
丁健
徐玉芳
谢华
赵振江
陈海洋
刁妍妍
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
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East China University of Science and Technology
Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to compounds having Bruton's tyrosine kinase inhibitory activity and uses thereof.
  • Immune cells can usually be divided into two types: T cells and B cells.
  • the main function of B cells is to secrete various antibodies to help the body resist the invasion of various foreign enemies.
  • Bruton tyrosine kinase (Bruton tyrosine kinase) is mainly expressed in B cells and is distributed in the lymphatic system, hematopoiesis and blood system.
  • studies on B cells especially B-cell non-Hodgkin's lymphoma and rheumatoid arthritis, have found that Bruton's tyrosine kinase is often abnormally expressed.
  • Bruton's tyrosine kinase is a key kinase in the B cell antigen receptor (BCR) signaling pathway, which regulates the maturation and differentiation of normal B cells and is also closely related to a variety of B cell lymphoid tissue disorders.
  • BCR B cell antigen receptor
  • Bruton's tyrosine kinase is a member of the Tec family of non-receptor protein tyrosine kinases.
  • the Tec family is the second largest family of human non-receptor kinases, second only to the Src family, and its major members include Bruton's tyrosine kinase, BMX (etk), ITK, TEC, and TXK (RLK).
  • Bruton's tyrosine kinase was identified in 1993 as a defective protein in human X-linked agammaglobulinemia (XLA).
  • This protein is expressed at all stages of development of B cells (except for the final differentiated plasma cells), and Bruton's tyrosine kinase is a gene essential for cell differentiation and proliferation during the transition of pre-B lymphocytes to late B cells. And expressed in B cell lymphoma, acute lymphoblastic leukemia (ALL) and plasmacytoma. In addition, a small amount is expressed in bone marrow cells and erythroid progenitor cells.
  • ALL acute lymphoblastic leukemia
  • plasmacytoma a small amount is expressed in bone marrow cells and erythroid progenitor cells.
  • the Bruton tyrosine kinase structure contains five major domains, namely the PH domain (Pleckstrin homology), the TH domain (Tec homology), the SH3 domain (Src homology 3), and the SH2 domain (Src homology 2). And the SH1 domain (Src homology1).
  • the PH domain contains the transcription factor BAP-135/TFII-I and the binding site of the activity down-regulation factors PIN1, I Bruton's tyrosine kinase, and is also responsible for mediating Bruton's tyrosine kinase and second messenger phospholipids.
  • PIN3 phosphatidylinositol triphosphate
  • the TH domain is adjacent to the PH domain and consists of 80 amino acid residues, including the Bruton tyrosine kinase motif (Zn cofactor binding site), the PKC-beta binding site, and the proline-rich motif. Conservative area.
  • the SH1 domain comprises an activation loop, an ATP binding site, a catalytic converter, and an allosteric inhibitory fragment. Activation (phosphorylation) of Bruton's tyrosine kinase occurs initially in the activation loop of the SH1 domain, and further activation occurs in the SH2 and SH3 domains comprising the major autophosphorylation sites.
  • SH domains also contain the nuclear localization signal (NLS) and nuclear export sequence (NES) required for Bruton's tyrosine kinase for nuclear shuttle.
  • NLS nuclear localization signal
  • NES nuclear export sequence
  • activation of Bruton's tyrosine kinase can trigger a variety of cellular processes such as cell proliferation, survival, differentiation, angiogenesis, cytokine synthesis, and antigen presentation.
  • Bruton's tyrosine kinase activation process is complex, and an important step in this process is the migration of Bruton's tyrosine kinase to the cell membrane.
  • Some receptors on the cell membrane are activated by the stimulation of the corresponding ligand, which activates and phosphorylates the intracellular signal transduction kinase PI3K, which in turn converts the PIP2 on the membrane into the second messenger PIP3. .
  • PIP3 binds to the PH domain of Bruton's tyrosine kinase, Bruton's tyrosine kinase is subsequently recruited to the cell membrane, Tyr-551 residues are phosphorylated by Syk and Lyn kinase, followed by Tyr-223 residues
  • the autophosphorylation reaction and the physiologically active Bruton tyrosine kinase can bind to the adaptor protein BLNK/SLP65 through its SH2 domain, and the resulting complex subsequently activates phospholipase C- ⁇ 2 (PLC- ⁇ 2), which in turn triggers
  • the cascade reaction ultimately leads to continuous intracellular calcium influx and indirectly activates downstream signaling pathways such as the MEK/ERK, p38MAPK, and NK/SAPK pathways.
  • Bruton's tyrosine kinase function-acquired mutations have also been confirmed in colorectal cancer, acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML). Therefore, abnormal activation of Bruton's tyrosine kinase-dependent pathway has been shown to be closely related to the development of various tumors.
  • Bruton's tyrosine kinase small molecule inhibitors have good prospects for the treatment of hematological malignancies and autoimmune disorders.
  • Ibrutinib ibrutinib
  • MCL mantle cell lymphoma
  • CLL mantle cell lymphoma
  • the invention provides the use of a compound of Formula I or a salt thereof for the preparation of a Bruton's tyrosine kinase inhibitor or for the manufacture of a medicament for the treatment or prevention of Bruton's tyrosine kinase mediated disease:
  • R is hydrogen, C 1 -C 3 lower alkyl, C 1 -C 3 lower alkoxy, halogen (eg, F, Cl, Br), amino, substituted amino;
  • X is N or CR 5 R 6 ;
  • Y is C or O
  • B is selected from the group consisting of an optionally substituted (C3-C8)cycloalkyl, (C3-C8)heterocyclyl, (C6-C10)aryl or (C5-C10)arylheterocyclyl;
  • R 1 is selected from the group consisting of: H, an optionally substituted C 1 -C 6 alkyl group, NR 7 R 8 , an optionally substituted C 6 -C 10 aryl group;
  • R 3 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, any A substituted C 1 -C 10 alkoxy group, an optionally substituted aryl group, an optionally substituted benzyl group, an optionally substituted heterocyclic group, an optionally substituted aromatic heterocyclic group, -O-(CH) z -OC 1 -C 3 alkyl; z is an integer from 1 to 3, preferably 1;
  • R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, nitro, amino, halogen, optionally substituted C 1 -C 6 alkoxy, optionally substituted acyloxy, optionally substituted Amido, optionally substituted acyl;
  • n is independently an integer from 0 to 7, preferably from 1 to 7, more preferably from 1 to 3;
  • R 5 and R 6 are each independently H, or C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl);
  • R 7 and R 8 are each independently H or a C 1 -C 6 alkyl group.
  • B is selected from various substituted benzene ring, nitrogen-containing five-membered ring, a nitrogen-containing six-membered ring or a C 3 -C 8 cycloalkyl.
  • B is selected from the group consisting of:
  • R 4 is selected from:
  • the compound is as shown in Formula I-1 below:
  • A is a benzene ring, a five- or six-membered heterocyclic ring, a C 3 -C 8 cycloalkyl group or R';
  • R' When A is R', n is 0, and R' is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 6 -C 10 arylformyl;
  • R 2 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkoxy, hydroxy, optionally substituted acyloxy, amino, optionally substituted acylamino, optionally substituted C 1 -C 6 Alkyl, CN, sulfonate, aminosulfonyl, carbamoyl, carboxy, optionally substituted alkoxycarbonyl, optionally substituted phenyl, optionally substituted N-alkylpiperazinyl, optionally substituted Morpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolyl, optionally substituted pyrrolidinyl, -NR a R b , optionally substituted pyridyl; R a and R b are each independently selected from Alkyl and alkenyl;
  • n is independently an integer from 0 to 7, preferably from 1 to 7, more preferably from 1 to 3;
  • X, Y, B, R 1 , R 3 , R 4 and m are as defined above.
  • the compound is as shown in Formula II-1 below:
  • R 2 , R 3 , R 4 , m and n are as defined above;
  • R 2 , R 4 , R 5 , R 6 , m and n are as defined above;
  • R 1 , R 2 , R 3 , R 4 , m and n are as defined above.
  • R 2 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkoxy, optionally substituted pyrrolidinyl, -NR a R b , carbamoyl, optionally substituted acylamino, -(CH 2 ) o - an optionally substituted N-alkylpiperazinyl group, an optionally substituted morpholino group, an optionally substituted piperidinyl group, o is an integer of 0-2, and R a and R b are each independently selected from C a 1- C 3 alkyl group; wherein R 2 is not at the 2-position of the benzene ring where it is located;
  • R 3 is selected from the group consisting of: hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 8 cycloalkyl;
  • B is selected from a benzene ring or a nitrogen-containing five-membered ring
  • R 4 is selected from the group consisting of: an optionally substituted acylamino group, an optionally substituted acyl group;
  • R 5 and R 6 are independently selected from H, substituted or unsubstituted C 1 -C 6 (preferably C 1 -C 3 )alkyl;
  • B is a benzene ring
  • R 2 is selected from the group consisting of: an optionally substituted C 1 -C 6 alkyl group (preferably a C 1 -C 3 alkyl group), an optionally substituted N-alkyl piperazinyl group, an optionally substituted C 1 -C 6 alkoxy group Base (preferably C 1 -C 3 alkoxy);
  • R 4 is selected from the group consisting of: an optionally substituted acylamino group
  • n are as defined above.
  • the present invention provides a compound selected from the group consisting of a compound or a pharmaceutically acceptable salt thereof for the preparation of a Bruton's tyrosine kinase inhibitor or for the preparation or treatment of a Bruton's tyrosine kinase mediated disease
  • a compound selected from the group consisting of a compound or a pharmaceutically acceptable salt thereof for the preparation of a Bruton's tyrosine kinase inhibitor or for the preparation or treatment of a Bruton's tyrosine kinase mediated disease
  • the Bruton tyrosine kinase mediated disease is cancer or an autoimmune disorder.
  • the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), mantle cell lymphoma (MCL), colorectal cancer; said autoimmune disorders include classes Rheumatoid arthritis, anti-organ transplant rejection, anti-psoriasis, lupus erythematosus.
  • ALL acute lymphoblastic leukemia
  • CML chronic myeloid leukemia
  • MCL mantle cell lymphoma
  • colorectal cancer said autoimmune disorders include classes Rheumatoid arthritis, anti-organ transplant rejection, anti-psoriasis, lupus erythematosus.
  • the present invention provides a method of treating or preventing Bruton's tyrosine kinase-mediated disease comprising administering a compound of the first or second aspect of the invention or a pharmaceutical composition comprising the same The object you need.
  • the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof:
  • X, Y, B, R 1 , R 3 , R 4 and m are as defined above;
  • R is hydrogen, C 1 -C 3 lower alkyl, C 1 -C 3 lower alkoxy, halogen (eg, F, Cl, Br), amino or NR c R d , and R c , R d are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or (C 6 -C 10 ) arylcarbonyl;
  • R 3 is selected from the group consisting of hydrogen, (C 3 -C 6 )cycloalkyl, (C 1 -C 8 )heterocyclyl, (C 1 -C 8 )alkoxy, -O-(CH) n - OC 1 -C 3 alkyl, benzyl, (C 6 -C 10 )aryl or (C 5 -C 10 )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, (C 3 -C 6 )cycloalkane , (C 6 -C 10 ) aryloxy, (C 5 -C 10 )heterocyclyl, -O-(CH) z -OC 1 -C 3 alkyl, C 3 -
  • R 4 is selected from the group consisting of:
  • R is hydrogen, C 1 -C 3 lower alkyl, C 1 -C 3 lower alkoxy, halogen (eg, F, Cl, Br), amino;
  • R 3 is selected from the group consisting of hydrogen, (C 3 -C 6 )cycloalkyl, (C 1 -C 8 )heterocyclyl, (C 1 -C 8 )alkoxy, -O-(CH) n - OC 1 -C 3 alkyl, benzyl, (C 6 -C 10 )aryl or (C 5 -C 10 )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, (C 3 -C 6 )cycloalkane , (C 6 -C 10 ) aryloxy, (C 5 -C 10 )heterocyclyl, -O-(CH) z -OC 1 -C 3 alkyl, C 3 -
  • R is hydrogen, C 1 -C 3 lower alkyl, C 1 -C 3 lower alkoxy, halogen (eg, F, Cl, Br), amino;
  • R 4 is selected from the group consisting of:
  • R 3 is selected from the group consisting of hydrogen, (C 3 -C 6 )cycloalkyl, (C 1 -C 8 )heterocyclyl, (C 1 -C 8 )alkoxy, -O-(CH) n - OC 1 -C 3 alkyl, benzyl, (C 6 -C 10 )aryl or (C 5 -C 10 )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, (C 3 -C 6 )cycloalkane , (C 6 -C 10 ) aryloxy, (C 5 -C 10 )heterocyclyl, -O-(CH) z -OC 1 -C 3 alkyl, C 3 -
  • R 4 is selected from the group consisting of:
  • the compound is as shown in Formula I-1 below:
  • A is R', n is 0, and R' is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or (C 6 -C 10 ) arylcarbonyl;
  • X, Y, B, R 1 , R 3 , R 4 and m are as defined above.
  • R ' is C 1 -C 6 alkyl (preferably C 1 -C 3 alkyl), C 1 -C 6 haloalkyl (preferably C 1 -C 3 haloalkyl).
  • R 3 is selected from the group consisting of
  • R 3 is:
  • the present inventors synthesized a series of candidate compounds having Bruton's tyrosine kinase inhibitory activity. Through the structural optimization design of the obtained candidate compounds, a number of novel pyrimidopyrimidine heterocyclic compounds with potential Bruton's tyrosine kinase inhibitory activity were discovered. The obtained compound was evaluated for molecular level activity, and the IC 50 value of the Bruton tyrosine kinase inhibitory activity of the plurality of compounds reached the nM level.
  • alkyl refers to a saturated branched or straight-chain alkyl group having a carbon chain length of from 1 to 10 carbon atoms, and preferred alkyl groups include 2-8, 1-6, 1-4, 3-8 alkyl groups of 1-3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, heptyl, and the like.
  • the alkyl group may be substituted by one or more substituents, for example by halogen or haloalkyl.
  • the alkyl group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.
  • the alkyl groups described herein may also be substituted with an aryl group to form, for example, a benzyl group.
  • cycloalkyl refers to a substituted or unsubstituted saturated cyclic alkyl group having a carbon chain length of from 3 to 10, preferably from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • alkoxy refers to an oxy group substituted with an alkyl group.
  • the preferred alkoxy group is an alkoxy group having 1 to 6 carbon atoms, more preferably an alkoxy group having 1 to 4 carbon atoms, and more preferably an alkoxy group having 1 to 3 carbon atoms.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, and the like.
  • the alkoxy group may be substituted by one or more substituents, for example by halogen or haloalkyl.
  • the alkoxy group may be an alkyl group substituted with 1 to 4 fluorine atoms, or the alkyl group may be an alkyl group substituted with a fluoroalkyl group.
  • alkenyl generally denotes a monovalent hydrocarbon radical having at least one double bond, usually containing from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms, and may be straight or branched.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • alkynyl generally denotes a monovalent hydrocarbon radical having at least one triple bond, usually containing from 2 to 8 carbon atoms, preferably from 2 to 6 carbon atoms, more usually from 2 to 4 carbon atoms, and may be straight-chain Or branching.
  • alkenyl groups include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, hexynyl and the like.
  • halogen means fluoro, chloro, bromo or iodo.
  • aryl refers to a monocyclic, bicyclic or tricyclic aromatic group containing from 6 to 14 carbon atoms, including phenyl, naphthyl, phenanthryl, anthryl, fluorenyl, fluorenyl, tetrahydronaphthalene. Base, indanyl group, and the like.
  • the aryl group may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C1-4 aldehyde group, C1-6 alkyl group, cyano group, Nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1-4 alkoxy, ethoxy A formyl group, a N(CH3) group, a C1-4 acyl group or the like, a heterocyclic group or a heteroaryl group.
  • substituents selected from the group consisting of halogen, C1-4 aldehyde group, C1-6 alkyl group, cyano group, Nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1-4 alkoxy
  • heterocyclyl includes, but is not limited to, a 5- or 6-membered heterocyclic group containing from 1 to 3 heteroatoms selected from O, S or N, including but not limited to furyl, thienyl, pyrrolyl, Pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, pyranyl, pyridyl, pyrimidinyl, pyrazinyl, piperidinyl, morpholinyl and the like.
  • aromatic heterocyclic means having from 5 to 14 ring atoms and having 6, 10 or 14 electrons are shared on the ring system. Further, the ring atom contained is a carbon atom and optionally 1-3 hetero atoms from oxygen, nitrogen, and sulfur.
  • Useful aromatic heterocyclic groups include piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, including but not limited to 2-pyridyl, 3-pyridyl and 4-pyridyl, pyrazinyl, pyrimidinyl and the like.
  • the aromatic heterocyclic group may be optionally substituted with from 1 to 5 (for example, 1, 2, 3, 4 or 5) substituents selected from the group consisting of halogen, C1-4 aldehyde group, C1-6 straight chain or branch Alkenyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1- 4 alkoxy, ethoxycarbonyl, N(CH3) and C1-4 acyl.
  • substituents selected from the group consisting of halogen, C1-4 aldehyde group, C1-6 straight chain or branch Alkenyl, cyano, nitro, amino, hydroxy, hydroxymethyl, halogen substituted alkyl (eg trifluoromethyl), halogen substituted alkoxy (eg trifluoromethoxy), carboxyl, C1- 4 alkoxy, ethoxycarbonyl, N(CH
  • acyloxy refers to a group of the formula "-OC(O)-R", wherein R may be selected from alkyl, alkenyl (eg, C1-6 or C1-3 alkenyl) And alkynyl groups. The R can be optionally substituted.
  • “amido” refers to a group of the formula "-R'-NH-C(O)-R" wherein R' may be selected from hydrogen or alkyl and R may be selected from alkyl, alkenyl. (e.g., C1-6, or C1-3 alkenyl), alkynyl, NR c R d is substituted alkyl, NR c R d is substituted alkenyl and NR c R d group substituted alkynyl, halogen a substituted alkyl group, an alkenyl group substituted by a cyano group, wherein R c and R d may be selected from an alkyl group and an alkenyl group.
  • R' may be selected from hydrogen or alkyl and R may be selected from alkyl, alkenyl. (e.g., C1-6, or C1-3 alkenyl), alkynyl, NR c R d is substituted alkyl, NR c R d is substituted al
  • acyl refers to an atomic group remaining after removal of one or more hydroxyl groups by an organic or inorganic oxyacid, the general formula of which is represented by RC(O)-, wherein R may be selected from alkyl or alkenyl groups (eg, , C1-6, or C1-3 alkenyl), alkynyl, NR c R d is substituted alkyl, NR c R d is substituted alkenyl and NR c R d group substituted alkynyl, substituted by halogen An alkyl group, an alkenyl group substituted by a cyano group, wherein R c and R d may be selected from the group consisting of an alkyl group and an alkenyl group.
  • R may be selected from alkyl or alkenyl groups (eg, , C1-6, or C1-3 alkenyl), alkynyl, NR c R d is substituted alkyl, NR c R d is substituted
  • arylcarbonyl refers to an aryl group, such as a (C6-C10) aryl group, formed with a formyl group, and attached to the host structure of the compound via a formyl group.
  • substituent to which it is modified may be optionally substituted with from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from halogen: C1 a 4-aldehyde group, a C1-6 straight or branched alkyl group, a cyano group, a nitro group, an amino group, a hydroxyl group, a hydroxymethyl group, a halogen-substituted alkyl group (for example, a trifluoromethyl group), a halogen-substituted alkoxy group ( For example, trifluoromethoxy), carboxyl, C1-4 alkoxy, ethoxycarbonyl, N(CH3), and C1-4 acyl.
  • substituents selected from 1 to 5 (eg, 1, 2, 3, 4 or 5) substituents selected from halogen: C1 a 4-aldehyde group, a C1-6 straight or branched alkyl group, a cyano group, a nitro group, an amino group, a
  • the present invention provides the use of a compound of the formula I below or a salt thereof for the preparation of a Bruton's tyrosine kinase inhibitor or for the preparation of a medicament for the treatment or prevention of a Bruton's tyrosine kinase mediated disease :
  • R is hydrogen, C 1 -C 3 lower alkyl, C 1 -C 3 lower alkoxy, halogen (eg, F, Cl, Br), amino, substituted amino;
  • X is N or CR 5 R 6 ;
  • Y is C or O
  • B is selected from the group consisting of: an optionally substituted (C3-C8) cycloalkyl, (C3-C8) heterocyclyl, (C6-C10) aryl or (C5-C10) aromatic heterocyclic group;
  • R 1 is selected from :H, optionally substituted C 1 -C 6 alkyl, NR 7 R 8 , optionally substituted C 6 -C 10 aryl;
  • R 3 is selected from: hydrogen, optionally substituted C 1 -C 10 alkyl , C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 1 -C 10 alkoxy, optionally substituted aryl , optionally substituted benzyl, optionally substituted heterocyclic, optionally substituted aromatic heterocyclic, -O-(CH) z -OC 1 -C 3 alkyl; z is an integer from 1 to 3, preferably 1
  • B is selected from various substituted benzene ring, nitrogen-containing five-membered ring, a nitrogen-containing six-membered ring or a C 3 -C 8 cycloalkyl.
  • B can be selected from:
  • R 4 is selected from:
  • A is a benzene ring, a five- or six-membered heterocyclic ring, a C 3 -C 8 cycloalkyl group or R';
  • R' When A is R', n is 0, and R' is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 6 -C 10 arylformyl;
  • R 2 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkoxy, hydroxy, optionally substituted acyloxy, amino, optionally substituted acylamino, optionally substituted C 1 -C 6 Alkyl, CN, sulfonate, aminosulfonyl, carbamoyl, carboxy, optionally substituted alkoxycarbonyl, optionally substituted phenyl, optionally substituted N-alkylpiperazinyl, optionally substituted Morpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolyl, optionally substituted pyrrolidinyl, -NR a R b , optionally substituted pyridyl; R a and R b are each independently selected from Alkyl and alkenyl;
  • n is independently an integer from 0 to 7, preferably from 1 to 7, more preferably from 1 to 3;
  • X, Y, B, R 1 , R 3 , R 4 and m are as defined above.
  • R 2 , R 3 , R 4 , m and n are as defined above;
  • R 2 , R 4 , R 5 , R 6 , m and n are as defined above;
  • R 1 , R 2 , R 3 , R 4 , m and n are as defined above.
  • R 2 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 alkoxy, optionally substituted pyrrolidinyl, -NR a R b , carbamoyl, optionally substituted acylamino, -(CH 2 ) o - an optionally substituted N-alkylpiperazinyl group, an optionally substituted morpholino group, an optionally substituted piperidinyl group, o is an integer of 0-2, and R a and R b are each independently selected from C a 1- C 3 alkyl group; wherein R 2 is not at the 2-position of the benzene ring where it is located;
  • R 3 is selected from the group consisting of: hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 8 cycloalkyl;
  • B is selected from a benzene ring or a nitrogen-containing five-membered ring
  • R 4 is selected from the group consisting of: an optionally substituted acylamino group, an optionally substituted acyl group;
  • R 5 and R 6 are independently selected from H, substituted or unsubstituted C 1 -C 6 (preferably C 1 -C 3 )alkyl;
  • B is a benzene ring
  • R 2 is selected from the group consisting of: an optionally substituted C 1 -C 6 alkyl group (preferably a C 1 -C 3 alkyl group), an optionally substituted N-alkyl piperazinyl group, an optionally substituted C 1 -C 6 alkoxy group Base (preferably C 1 -C 3 alkoxy);
  • R 4 is selected from the group consisting of: an optionally substituted acylamino group
  • n are as defined above.
  • the invention provides a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof for the preparation of a Bruton's tyrosine kinase inhibitor or for the preparation or treatment of Bruton's tyrosine kinase-mediated Use of drugs for disease:
  • the compound having the activity designated "A” has an IC 50 ⁇ 10 nM;
  • the compound having the activity designated "B” has an IC 50 of 10 ⁇ IC 50 ⁇ 100 nM;
  • the compound having the activity designated as "C” has an IC 50 of 100 ⁇ IC 50 ⁇ 1000 nM;
  • the compound having the activity designated "D” has an IC 50 of 1000 nM ⁇ IC 50 .
  • the present invention provides a pharmaceutical composition for inhibiting Bruton's tyrosine kinase comprising a therapeutically effective amount of the present invention, based on the ability of the compound of the present invention to have Bruton's tyrosine kinase inhibitory activity.
  • Examples of pharmaceutically acceptable salts of the compounds of the invention include, but are not limited to, inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate; and inorganic and formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine Organic base salt.
  • inorganic and organic acid salts such as the hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate salts. , fumarate, mandelate and oxalate
  • bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine) and N-methyl glucosamine Organic base salt.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof is orally administered to a mammal per day in an amount of from about 0.0025 to 50 mg/kg body weight. Preferably, however, it is about 0.01 to 10 mg per kilogram of oral administration.
  • a unit oral dose can include from about 0.01 to 50 mg, preferably from about 0.1 to 10 mg, of a compound of the invention.
  • the unit dose may be administered one or more times per day in one or more tablets, each tablet containing from about 0.1 to 50 mg, conveniently from about 0.25 to 10 mg of the compound of the invention or a solvate thereof.
  • the pharmaceutical composition of the present invention can be formulated into a form suitable for various administration routes, including but not limited to being formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, intrathecal, intracranial A form of administration, intranasal or topical, for the treatment of tumors and other diseases.
  • the amount administered is an amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is an amount sufficient to ameliorate or in some way alleviate the symptoms associated with the disease.
  • Such doses can be administered as a single dose or can be administered according to an effective therapeutic regimen.
  • the amount administered may cure the disease, but administration is usually to improve the symptoms of the disease. Repeated administration is generally required to achieve the desired improvement in symptoms.
  • the dosage of the drug will be determined by the age of the patient, the health and weight, the type of concurrent treatment, the frequency of treatment, and the desired therapeutic benefit.
  • the pharmaceutical preparation of the present invention can be administered to any mammal as long as they can obtain the therapeutic effect of the compound of the present invention.
  • the most important of these mammals is humans.
  • the compounds of the invention or pharmaceutical compositions thereof are useful in the treatment of a variety of diseases mediated by Bruton's tyrosine kinase.
  • the Bruton's tyrosine kinase-mediated disease is a cancer or an autoimmune disease; wherein the cancer includes a hematological malignancy or a solid tumor, such as acute lymphoblastic leukemia (ALL), chronic granulocytes Leukemia (CML), mantle cell lymphoma (MCL), colorectal cancer; the autoimmune diseases include rheumatoid arthritis, anti-organ transplant rejection, anti-psoriasis or lupus erythematosus.
  • ALL acute lymphoblastic leukemia
  • CML chronic granulocytes Leukemia
  • MCL mantle cell lymphoma
  • colorectal cancer the autoimmune diseases include rheumatoid arthritis, anti-organ transplant rejection, anti-psoriasis or l
  • the pharmaceutical preparations of the invention can be made in a known manner. For example, it is manufactured by a conventional mixing, granulating, tableting, dissolving, or freeze drying process. In the manufacture of oral formulations, the mixture can be selectively milled by combining the solid adjuvant with the active compound. If necessary or necessary, after adding an appropriate amount of auxiliary agent, the mixture of particles is processed to obtain a tablet or tablet core.
  • Suitable excipients are, in particular, fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or calcium hydrogen phosphate; and binders, such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, or polyvinylpyrrolidone.
  • fillers such as sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulose preparations or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate
  • binders such as starch pastes, including corn starch. , wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl
  • a disintegrating agent such as the above-mentioned starch, and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added.
  • Adjuvants are especially flow regulators and lubricants, for example, silica, talc, stearates such as calcium magnesium stearate, stearic acid or polyethylene glycol.
  • the tablet core can be provided with a suitable coating that is resistant to gastric juice. For this purpose, a concentrated sugar solution can be applied.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • a suitable cellulose solution such as cellulose acetate phthalic acid or hydroxypropyl methylcellulose phthalic acid can be used.
  • a dye or pigment can be added to the coating of the tablet or tablet core. For example, a combination for identifying or for characterizing the dosage of an active ingredient.
  • the invention further provides a method of treating or preventing Bruton's tyrosine kinase mediated diseases, comprising administering to a subject in need thereof a compound or pharmaceutical composition of the invention.
  • Methods of administration include, but are not limited to, various methods of administration well known in the art, which can be determined based on the actual circumstances of the patient. These methods include, but are not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, nasal or topical routes of administration.
  • the invention provides a novel structure of a compound of formula I or a salt thereof:
  • X, Y, B, R 1 , R 3 , R 4 and m are as defined above;
  • R is hydrogen, C 1 -C 3 lower alkyl, C 1 -C 3 lower alkoxy, halogen (eg, F, Cl, Br), amino or NR c R d , and R c , R d are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or (C 6 -C 10 ) arylcarbonyl;
  • R 3 is selected from the group consisting of hydrogen, (C 3 -C 6 )cycloalkyl, (C 1 -C 8 )heterocyclyl, (C 1 -C 8 )alkoxy, -O-(CH) n - OC 1 -C 3 alkyl, benzyl, (C 6 -C 10 )aryl or (C 5 -C 10 )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, (C 3 -C 6 )cycloalkane , (C 6 -C 10 ) aryloxy, (C 5 -C 10 )heterocyclyl, -O-(CH) z -OC 1 -C 3 alkyl, C 3 -
  • R 4 is selected from the group consisting of:
  • R, R 3 and R 4 may be arbitrarily combined.
  • R, R 3 and R 4 may be arbitrarily combined.
  • it can be the following combination:
  • R is hydrogen, C 1 -C 3 lower alkyl, C 1 -C 3 lower alkoxy, halogen (eg, F, Cl, Br), amino;
  • R 3 is selected from the group consisting of hydrogen, (C 3 -C 6 )cycloalkyl, (C 1 -C 8 )heterocyclyl, (C 1 -C 8 )alkoxy, -O-(CH) n - OC 1 -C 3 alkyl, benzyl, (C 6 -C 10 )aryl or (C 5 -C 10 )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, (C 3 -C 6 )cycloalkane , (C 6 -C 10 ) aryloxy, (C 5 -C 10 )heterocyclyl, -O-(CH) z -OC 1 -C 3 alkyl, C 3 -
  • R is hydrogen, C 1 -C 3 lower alkyl, C 1 -C 3 lower alkoxy, halogen (eg, F, Cl, Br), amino;
  • R 4 is selected from the group consisting of:
  • R 3 is selected from the group consisting of hydrogen, (C 3 -C 6 )cycloalkyl, (C 1 -C 8 )heterocyclyl, (C 1 -C 8 )alkoxy, -O-(CH) n - OC 1 -C 3 alkyl, benzyl, (C 6 -C 10 )aryl or (C 5 -C 10 )arylheterocyclyl, wherein the aryl and aromatic heterocyclic groups may optionally be one Substituted to five or less groups: halogen, nitro, cyano, hydroxy, amino, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy, (C 3 -C 6 )cycloalkane , (C 6 -C 10 ) aryloxy, (C 5 -C 10 )heterocyclyl, -O-(CH) z -OC 1 -C 3 alkyl, C 3 -
  • R 4 is selected from the group consisting of:
  • novel compounds of the invention are represented by the following formula I-1:
  • A is R', n is 0, and R' is selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or (C 6 -C 10 ) arylcarbonyl;
  • X, Y, B, R 1 , R 3 , R 4 and m are as defined above.
  • R' may be a C 1 -C 6 alkyl group (preferably a C 1 -C 3 alkyl group), a C 1 -C 6 haloalkyl group (preferably a C 1 -C 3 haloalkyl group).
  • R 3 may be selected from the group consisting of:
  • the substituents in the formula of the present invention are each a corresponding group in any of the specific compounds disclosed herein.
  • the compound of the present invention has excellent inhibitory activity against Bruton's tyrosine kinase
  • the compounds of the invention are highly selective for Bruton's tyrosine kinase
  • the compound of the present invention lays a foundation for the development of a drug capable of inhibiting Bruton's tyrosine kinase with high activity and high selectivity, and has great industrialization and commercialization prospects as well as market value, and has significant economic benefits.
  • the Bruton tyrosine kinase target fragment (M1-S695) was amplified by PCR, and the PCR product and the vector PfastBac 1 were digested with BamHI and XhoI, and the digested products were ligated and transformed into DH5 ⁇ competent cells. Cloning and sequencing confirmed that the correct recombinant plasmid pFastBac1-brutton tyrosine kinase was finally obtained.
  • the constructed plasmid was transposed to DH10Bac competent cells for blue and white spot screening, and the transposon was successfully picked.
  • the rods were extracted after shaking, and the rods were identified by bacterial PCR.
  • the correct bacmids were transfected into Sf9 cells to obtain P1 virus strains of P1, P2 and higher titers, respectively.
  • Sf9 cells were cultured to the log phase (about 2 ⁇ 10 6 cells/mL), and the P3 virus strain with high titer was added to the Sf9 cell culture medium containing the log phase growth, and cultured at 27 ° C for 3 days, 500 ⁇ g Centrifuge for 5 min, discard the supernatant, collect the bacteria, and store at -80 °C. Protein expression was then detected by Western Blot.
  • the cell pellet expressed by the P3 virus strain was collected by centrifugation at 1790 rpm at room temperature.
  • the lysate used for lysing the cells was 250 mM NaCl, 0.25% NP-40, 50 mM CHES (pH 9.0).
  • the cells were disrupted by a high-pressure cell disrupter, and then centrifuged at 12000 rpm for 45 min at 4 ° C, and the supernatant was collected.
  • the supernatant was added to a Ni-NTA column, and the protein of interest was eluted using an imidazole concentration gradient method, and the eluted protein solution was collected. Concentrate the eluate containing the protein of interest and switch to the lowest concentration of imidazole.
  • the TEV enzyme was added for dialysis and digestion for 16 h, and the Ni-NTA column was again passed, and the His-Tag-free flow-through solution was collected.
  • the buffer used for the digestion was 200 mM NaCl, 20 mM CHES (pH 9.0). 1 mM TCEP.
  • the purified protein was separated by HiTrap Superdex 75 molecular sieve, and the equilibrium buffer used for the molecular sieve was 100 mM NaCl, 10 mM Tris-HCl pH 8.5, 1 mM TCEP.
  • the experimental method is: the concentration of the compound to be tested is diluted by concentration, and 2.5 ⁇ L of Test Compounds is added to the 384-well plate, three parallel controls of each group, plus 5 ⁇ L of Bruton tyrosine kinase Kinase/Peptide Substrate Mixture, 2.5 ⁇ L ATP.
  • Reagents and conditions (a) amine, DIPEA, 1,4-dioxane, rt; (b) ArNH2, DIPEA, 1,4-dioxane, rt; (c) Pd/C, H2, EtOH (d) R2COCOOEt, HOAc, EtOH, reflux.
  • R 1 , R 2 , R 3 , R 4 and R 5 refer to the definition of the corresponding group above.
  • One skilled in the art can prepare the compounds of the present invention by using various starting compounds conventionally obtained in the art as starting materials according to actual preparation needs.
  • Reagents and conditions (a) tert-butyl (3-aminophenyl)carbamate, DIPEA, CH 3 CN, reflux, 6 h; (b) LiAlH 4 , THF, 0 ° C, 4 h; (c) MnO 2 , CH 2 Cl 2 , room temperature, overnight; (d) Grignard reagent, THF, 0 ° C, 5 h; (e) CDI, K 2 CO 3 , THF, reflux, overnight; (f) arylamine, trifluoroacetic acid, fluoro ethanol, reflux, 24h; (g) trifluoroacetic acid, CH 2 Cl 2, rt, 5h; (h) acryloyl chloride, Et 3 N, CH 2 Cl 2, 0 °C to room temperature overnight.
  • Ethyl 2,4-dichloro-5-pyrimidinecarboxylate (22.100 g, 100 mmol)
  • DIPEA (12.900 g, 100 mmol)
  • tert-butyl (3-aminophenyl)carbamate (20.800 g, 100 mmol) was dissolved in 100 mL of acetonitrile, and the mixture was added dropwise to the mixture.
  • Boc removal product (0.187 g, 0.39 mmol) was dissolved in dichloromethane (5 mL) and triethylamine (0.060 g, 0.6 mmol) Further, acryloyl chloride (42 ⁇ L, 0.51 mmol) was dissolved in 1 mL of dichloromethane, and the mixture was stirred and stirred at room temperature overnight.
  • the TLC tracks the conversion of the starting material and is neutralized to a basic state by adding a saturated aqueous solution of NaHCO 3 .
  • Reagents and conditions (a) Grignard reagent, THF, 0 ° C, 6 h; (b) CDI, K 2 CO 3 , THF, reflux, overnight; (c) arylamine, trifluoroacetic acid, trifluoroethanol, reflux , 24h; (d) trifluoroacetic acid, CH 2 Cl 2 , rt, 5h; (e) acryloyl chloride, Et 3 N, CH 2 Cl 2 , 0 ° C to room temperature overnight.
  • Boc product 0.335 g, 0.68 mmol was dissolved in dichloromethane (5 mL) and triethylamine (0.102 g, 1.02 mmol). Further, acryloyl chloride (72 ⁇ L, 0.88 mmol) was dissolved in 1 mL of dichloromethane, and the mixture was stirred and stirred at room temperature overnight.
  • the TLC tracks the conversion of the starting material and is neutralized to a basic state by adding a saturated aqueous solution of NaHCO 3 .
  • Reagents and conditions (a) R 1 NH 2 , DIPEA, 1,4-dioxane, rt; (b) R 2 H 2 , DIPEA, 1,4-dioxane, rt; (c) Pd /C, H2, EtOH; (d) YCOCOOEt, HOAc, EtOH, reflux.
  • R, R1, R2, Y refer to the definition of the corresponding group above.
  • One skilled in the art can prepare the compounds of the present invention by using various starting compounds conventionally obtained in the art as starting materials according to actual preparation needs.
  • 2,4-Dichloro-6-methyl-5-nitropyrimidine 2.07 g (10 mmol) and potassium carbonate 2.07 g (15 mmol) were weighed into a 250 mL round bottom flask, and 100 mL of dichloromethane was added thereto, and mechanical stirring was carried out at room temperature.
  • reaction solution was rotary evaporated to remove the solvent, and then added dropwise to aqueous sodium hydrogencarbonate, and a red solid was precipitated, filtered, filtered, washed with deionized water, dried and purified by dichloromethane/methanol to afford N-(3-( 2-((2-Methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-4-methyl-7-oxo-6-phenyl-8(7H)- Pteridine)phenyl)acrylamide orange red solid 1.0 g, yield 67%.
  • Reagents and conditions (a) R 1 NH 2 , DIPEA, acetonitrile, reflux, 6h.; (b) lithium aluminum hydride, THF, 0 ° C, 4h.; (c) manganese dioxide, dichloromethane, 6h; d) Grignard reagent, THF, 0 ° C, 4 h; (e) manganese dioxide manganese dioxide, dichloromethane, 6 h; (f) YCH 2 COOEt, K 2 CO 3 , DMF, 8 h; (g) m- CPBA, dichloromethane, 12 h; (h) R 2 NH 2 , TFA, 2-Butanol, 110 °C.
  • R 1 , R 2 , R 5 and Y refer to the definition of the corresponding group above.
  • One skilled in the art can prepare the compounds of the present invention by using various starting compounds conventionally obtained in the art as starting materials according to actual preparation needs.

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Abstract

La présente invention concerne un composé hétérocyclique servant d'inhibiteur de la tyrosine kinase de Bruton et ses applications. Spécifiquement, la présente invention concerne un composé qui est représenté par la formule I et qui a une activité d'inhibition de la tyrosine kinase de Bruton, une composition pharmaceutique contenant le composé représenté par la formule I, et les applications du composé dans la préparation de médicaments pour le traitement ou la prévention de maladies liées à la tyrosine kinase de Bruton ou pour inhiber la tyrosine kinase de Bruton.
PCT/CN2018/083599 2017-04-19 2018-04-18 Composé pyrimido-hétérocyclique servant d'inhibiteur de la tyrosine kinase de bruton et ses applications Ceased WO2018192536A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022042755A1 (fr) 2020-08-28 2022-03-03 华东理工大学 Composé destiné à inhiber un mutant d'egfr et son utilisation

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113801139A (zh) * 2020-06-12 2021-12-17 华东理工大学 作为rsk抑制剂的嘧啶并恶嗪衍生物及其应用
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CN115607551A (zh) * 2021-07-14 2023-01-17 上海汇伦医药股份有限公司 Egfr抑制剂的新用途
WO2023046114A1 (fr) * 2021-09-24 2023-03-30 华东理工大学 Dérivé de ptéridinone et son utilisation
CN115974878A (zh) * 2021-10-15 2023-04-18 上海汇伦医药股份有限公司 抗肿瘤药物的盐及其晶型
WO2024056091A1 (fr) * 2022-09-16 2024-03-21 华东师范大学 Dérivé de pyridonopyrimidine en tant qu'inhibiteur de rsk et son utilisation

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1373763A (zh) * 1999-09-15 2002-10-09 沃尼尔·朗伯公司 作为激酶抑制剂的蝶啶酮
WO2006021547A1 (fr) * 2004-08-26 2006-03-02 Boehringer Ingelheim International Gmbh Pteridinones utilisees en tant qu'inhibiteurs des plk (polo-like-kinases)
CN103421010A (zh) * 2012-05-14 2013-12-04 华东理工大学 作为egfr抑制剂的蝶啶酮衍生物及其应用
CN106279173A (zh) * 2015-05-29 2017-01-04 华东理工大学 蝶啶酮衍生物作为egfr抑制剂的应用
CN106467540A (zh) * 2015-08-21 2017-03-01 华东理工大学 蝶啶酮衍生物作为flt3抑制剂的应用
CN107129506A (zh) * 2016-02-26 2017-09-05 华东理工大学 作为EGFR抑制剂的嘧啶并[4,5-d][1,3]噁嗪-2-酮衍生物及其应用
CN107151249A (zh) * 2016-03-04 2017-09-12 华东理工大学 作为flt3抑制剂的蝶啶酮衍生物及应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1373763A (zh) * 1999-09-15 2002-10-09 沃尼尔·朗伯公司 作为激酶抑制剂的蝶啶酮
WO2006021547A1 (fr) * 2004-08-26 2006-03-02 Boehringer Ingelheim International Gmbh Pteridinones utilisees en tant qu'inhibiteurs des plk (polo-like-kinases)
CN103421010A (zh) * 2012-05-14 2013-12-04 华东理工大学 作为egfr抑制剂的蝶啶酮衍生物及其应用
CN106279173A (zh) * 2015-05-29 2017-01-04 华东理工大学 蝶啶酮衍生物作为egfr抑制剂的应用
CN106467540A (zh) * 2015-08-21 2017-03-01 华东理工大学 蝶啶酮衍生物作为flt3抑制剂的应用
CN107129506A (zh) * 2016-02-26 2017-09-05 华东理工大学 作为EGFR抑制剂的嘧啶并[4,5-d][1,3]噁嗪-2-酮衍生物及其应用
CN107151249A (zh) * 2016-03-04 2017-09-12 华东理工大学 作为flt3抑制剂的蝶啶酮衍生物及应用

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
WO2022042755A1 (fr) 2020-08-28 2022-03-03 华东理工大学 Composé destiné à inhiber un mutant d'egfr et son utilisation

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