WO2021233236A1 - Composé hétéroaryle substitué, composition et utilisation associées - Google Patents

Composé hétéroaryle substitué, composition et utilisation associées Download PDF

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WO2021233236A1
WO2021233236A1 PCT/CN2021/094020 CN2021094020W WO2021233236A1 WO 2021233236 A1 WO2021233236 A1 WO 2021233236A1 CN 2021094020 W CN2021094020 W CN 2021094020W WO 2021233236 A1 WO2021233236 A1 WO 2021233236A1
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alkyl
pyrrolo
cycloalkyl
phenyl
pyrimidin
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Chinese (zh)
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习宁
许世民
王婷瑾
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北京范恩柯尔生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
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    • 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
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    • 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • 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
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a new class of substituted heteroaryl compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing the compounds, and the use of the compounds and the pharmaceutical compositions in preparing and treating mammals Use in medicines for proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, cancer, viral infectious diseases or other diseases. More specifically, the compounds of the present invention can regulate the activity of AXL kinase, thereby regulating signal transduction inside and outside the cell.
  • the protein kinase family includes a large class of structurally related enzymes that control various signal transduction processes in cells and catalyze the phosphorylation of target protein substrates.
  • Many diseases are related to abnormal cellular responses triggered by protein kinase-mediated events. These diseases include benign and malignant proliferative diseases, diseases caused by inappropriate activation of the immune system, allograft rejection, graft-versus-host diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological diseases And neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease and hormone-related diseases.
  • the medical field has developed protein kinase inhibitors that are effective in treating the diseases.
  • kinases can be classified into multiple families by phosphorylated substrates (eg, protein-tyrosine, protein-serine/threonine, lipid, etc.). Tyrosine phosphorylation is one of the central events that regulate various biological processes such as cell proliferation, migration, differentiation and survival. Multiple families of receptor and non-receptor tyrosine kinases control the tyrosine groups that catalyze the transfer of phosphoric acid from ATP to specific cellular protein targets.
  • phosphorylated substrates eg, protein-tyrosine, protein-serine/threonine, lipid, etc.
  • Tyrosine phosphorylation is one of the central events that regulate various biological processes such as cell proliferation, migration, differentiation and survival.
  • Multiple families of receptor and non-receptor tyrosine kinases control the tyrosine groups that catalyze the transfer of phosphoric acid from ATP to specific cellular protein targets.
  • kinases in the protein kinase family include, but are not limited to, Aurora, Axl, abl, Akt, bcr-abl, Blk, Brk, Btk, c-Met, c-src, c-fms, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSF1R, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Flt-3, Fak, fes, FGFRl, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, Fyn, AXL, IGF-1R, INS-R, KDR, Lck, Lyn, MEK, Mer, p38, PDGFR, PIK, PKC, PYK2, ros, Tie, Tie-2, TRK, Yes, Tyro3 and Zap70, etc. (Robin
  • Cancer and other hyperproliferative diseases is characterized by uncontrolled cell proliferation. Compared with normal tissues, the activity of many protein kinases in human tumors is increased, and this increased activity may be due to many factors, including increased kinase levels, mutations in the expression of co-activators or inhibitory proteins .
  • AXL is a membrane-bound receptor tyrosine kinase, belonging to the TAM (Tyro3, AXL, Mer) family. It is characterized by their two immunoglobulin-like domains and the double fibronectin repeats in their extracellular domains and the kinase domain with related tyrosines in their cytoplasmic domains. (Linger, R.M.et al., TAM receptor tyrosinekinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Advances in cancer research 2008, 100, 35-83.).
  • TAM receptor tyrosine kinase is involved in cell growth, migration, aggregation and apoptosis in a variety of normal cells.
  • GAS6 growth arrest specific 6
  • protein S protein S
  • the binding of Gas6 to AXL leads to receptor dimerization and AXL autophosphorylation.
  • Stitt, T.N.et al. The anticoagulation factor protein S and its relative, Gas6, are ligands for the Tyro 3/Axl family of receptors. Cell 1995, 80(4), 661-70.).
  • AXL is present in a variety of organs and cells, including epithelial cell lines, mesenchymal and hematopoietic origins, and untransformed cells.
  • AXL kinase is overexpressed or activated in a variety of cancers, including ovarian cancer, melanoma, renal cell carcinoma, uterine leiomyoma, endometrial cancer, thyroid cancer, gastric cancer, breast cancer, NSCLC, CML, AML, colon Cancer, prostate cancer, various lymphomas, and esophageal cancer.
  • Immunotherapy refers to a treatment method that artificially enhances or suppresses the immune function of the body to achieve the purpose of curing diseases. There are many immunotherapy methods, and they are applicable to the treatment of many diseases. Tumor immunotherapy aims to activate the human immune system and kill cancer cells and tumor tissues by relying on autoimmune functions (Myers et al. Molecular Cancer, 2019, 18:94). Unlike previous surgery, chemotherapy, radiotherapy, and targeted therapy, the target of immunotherapy is not tumor cells and tissues, but the body's own immune system.
  • Protein kinase inhibitors have attracted a lot of attention as new immunomodulatory, anti-inflammatory and anti-cancer drugs. Therefore, new or improved agents that inhibit protein kinases such as AXL kinase can be used as immunomodulators, antitumor agents, analgesics, and anti-organ fibrosis drugs for organ transplantation, and new or improved agents for AXL kinase can also be used for prevention and/ Or treat autoimmune diseases (e.g., multiple sclerosis, psoriasis, rheumatoid arthritis, asthma, type I diabetes, inflammatory bowel disease, Crohn’s disease, polycythemia vera, essential thrombocytosis Disease, myelofibrosis, autoimmune thyroid disease, Alzheimer’s disease), diseases involving excessive activation of inflammatory response (e.g., eczema), allergies, chronic obstructive pulmonary disease, bronchitis, fibrosis, cancer (e.g., gastric cancer
  • TAM receptor tyrosine kinases Tyro3, Axl and Mer and their homologous ligand proteins S (Protein S) and Gas6 promote immunity, phagocytosis and clearance of apoptotic cells in the nervous and reproductive systems. They also drive a key negative feedback loop that down-regulates the host's innate immune response mediated by Toll-like receptors (TLR) and type I interferon signaling pathways.
  • TLR Toll-like receptors
  • the TAM receptor-ligand interaction is also related to the promotion of cell entry of enveloped viruses: it has been found that the ectopic introduction of one or more TAM receptors into anti-infective cell lines can enhance filovirus and lentivirus infection.
  • the TAM ligand proteins S and Gas6 both contain a glutamate-rich Gla domain at their amino terminus, which is compatible with those exposed to apoptotic cells and membranes. Phosphatidylserine (PtdSer) on the surface of the virus particle binds.
  • Phosphatidylserine (PtdSer) on the surface of the virus particle binds.
  • the enveloped virus contains a high level of PtdSer on its surface and binds to the TAM ligand protein S and Gas6 through the PtdSer-Gla domain interaction.
  • the function of TAM receptor-ligand interaction is considered to be limited to promoting the binding of the virus to the target cell, thereby promoting virus infection.
  • Membrane-bound TAM ligands are significantly more effective than free ligands in activating TAM receptor signal transduction, indicating that TAM ligands change the ligand's influence on TAM signal transduction through the PtdSer binding of its gla domain.
  • AXL kinase inhibitors can block the interaction between AXL ligand and phosphatidylserine (PtdSer) in the membrane. Therefore, new reagents or improved reagents that inhibit protein kinases such as AXL kinase can be used as drugs for the treatment and/or prevention of viral infectious diseases, such as anti-Zika virus (iScience, 2019, 13,339-350), coronavirus, new coronavirus ( Such as covid-19, etc.) and hepatitis B virus (HBV) (Journal of Hepatology 2015 vol.63 j670-678).
  • viral infectious diseases such as anti-Zika virus (iScience, 2019, 13,339-350), coronavirus, new coronavirus ( Such as covid-19, etc.) and hepatitis B virus (HBV) (Journal of Hepatology 2015 vol.63 j670-678).
  • the present invention provides a class of compounds that inhibit, modulate and/or modulate the activity of AXL kinase for the treatment and/or prevention of proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, pain, fibrosis, Transplant rejection, or viral infectious disease or its complications.
  • the compound of the present invention has better pharmacological activity.
  • the compound of the present invention shows excellent inhibitory activity and kinase selectivity for the target kinase.
  • the compound of the present invention also has excellent membrane permeability and exhibits excellent pharmacokinetic properties in animals. Therefore, the compound of the present invention has very good development prospects.
  • the articles “a”, “an” and “said” used in the present invention are intended to include “at least one” or “one or more”. Therefore, these articles used in the present invention refer to articles of one or more than one (ie, at least one) object.
  • a component refers to one or more components, that is, there may be more than one component considered to be adopted or used in the embodiment of the described embodiment.
  • Stereoisomers refer to compounds that have the same chemical structure but differ in the arrangement of the atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis/trans) isomers, atropisomers, etc. .
  • tautomer or "tautomeric form” refers to structural isomers with different energies that can be converted into each other through a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be reached.
  • proton tautomers also called prototropic tautomers
  • keto-enol tautomerism include interconversion through the recombination of some bond-forming electrons.
  • keto-enol tautomerism are the tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-ketone tautomerism.
  • a specific example of phenol-ketone tautomerism is the interconversion of pyridine-4-ol and pyridine-4(1H)-one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the compounds of the general formula of the present invention, or special examples, subclasses, and the present invention includes A class of compounds.
  • C 1 -C 6 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may optionally Ground is substituted with one or more substituents described in this invention.
  • alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in another embodiment, the alkyl group contains 1 -4 carbon atoms; in yet another embodiment, the alkyl group contains 1-3 carbon atoms.
  • the alkyl group may be optionally substituted with one or more substituents described in the present invention.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl -2-butyl (-C(CH 3 ) 2
  • alkenyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one site of unsaturation, that is, a carbon-carbon sp 2 double bond, which includes “cis” and ""Reverse” positioning, or “E” and “Z” positioning.
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • the alkenyl group may be optionally substituted with one or more substituents described in this invention.
  • alkynyl means a linear or branched monovalent hydrocarbon group containing 2-12 carbon atoms, in which there is at least one unsaturation site, that is, a carbon-carbon sp triple bond.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • Examples of alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), etc. .
  • the alkynyl group may be optionally substituted with one or more substituents described in this invention.
  • alkoxy means that the alkyl group is connected to the rest of the molecule through an oxygen atom, where the alkyl group has the definition as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described in this invention.
  • haloalkyl or “haloalkoxy” means that an alkyl or alkoxy group is substituted by one or more halogen atoms. Examples of this include, but are not limited to, trifluoromethyl (-CF 3 ), Trifluoromethoxy (-OCF 3 ), difluoroethyl (-CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F), trifluoroethyl (-CH 2 CF 3 , -CF 2 CH 2 F, -CFHCHF 2 ) and so on.
  • -CF 3 trifluoromethyl
  • -OCF 3 Trifluoromethoxy
  • difluoroethyl -CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F
  • trifluoroethyl -CH 2 CF 3 , -CF 2 CH 2 F, -CFHCHF 2
  • hydroxyalkyl or "hydroxy-substituted alkyl” and “hydroxyalkoxy” or “hydroxy-substituted alkoxy” respectively denote an alkyl or alkoxy group, as the case may be, with one or more A hydroxyl group is substituted, where "hydroxyalkyl” and “hydroxyalkyl” can be used interchangeably.
  • Examples of this include, but are not limited to, hydroxymethyl (-CH 2 OH), 2-hydroxyethyl ( -CH 2 CH 2 OH), 1-hydroxyethyl (-CH(OH)CH 3 ), 2-hydroxyprop-2-yl (-COH(CH 3 ) 2 ), 2-hydroxy-2-methylpropane Group (-CH 2 COH(CH 3 ) 2 ), 3-hydroxypropyl (-CH 2 CH 2 CH 2 OH), 2-hydroxypropyl (-CH 2 CH(OH)CH 3 ), 2-hydroxy- 2Methylpropyl (-CH 2 CH(OH)(CH 3 )CH 3 ), hydroxymethoxy (-OCH 2 OH), etc.
  • cyano substituted alkyl or "cyanoalkyl” includes C 1-10 straight or branched chain alkyl groups substituted with one or more cyano groups.
  • the cyanoalkyl group is a C 1-6 "lower cyanoalkyl group” substituted with one or more cyano groups.
  • the cyanoalkyl group is substituted by one or more cyano groups.
  • C 1-4 "lower cyanoalkyl" substituted by one or more cyano groups such examples include, but are not limited to, CNCH 2 -, CNCH 2 CH 2 -, CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 -etc.
  • cycloalkyl refers to a monovalent or multivalent saturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms.
  • Bicyclic cycloalkyls include spirobicycloalkyls, fused bicycloalkyls, and bridged bicycloalkyls.
  • the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-10 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms.
  • the cycloalkyl group contains 3-7 carbon atoms; in other embodiments, the cycloalkyl group contains 3-6 carbon atoms; still in some embodiments, the cycloalkyl group is C 7 -C 12 cycloalkyl, which includes C 7 -C 12 monocycloalkyl, C 7 -C 12 bicycloalkyl (such as C 7 -C 12 spiro bicycloalkyl, C 7 -C 12 fused bicycloalkyl and C 7 -C 12 bridged bicycloalkyl) or C 7 -C 12 tricycloalkyl.
  • the cycloalkyl group may be independently unsubstituted or substituted with one or more substituents described in the present invention.
  • the term "monocyclic cycloalkyl” or “monocyclic alkyl” refers to a cycloalkyl of a monocyclic system, wherein the cycloalkyl has the definition as described above, and the monocyclic cycloalkyl group may independently Unsubstituted or substituted by one or more substituents described in the present invention.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclo Pentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl , Cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.
  • cycloalkylalkyl includes cycloalkyl substituted alkyl groups.
  • a cycloalkylalkyl group refers to a "lower cycloalkylalkyl” group, that is, a cycloalkyl group is attached to a C1-6 alkyl group.
  • the cycloalkylalkyl group refers to a "phenylalkylene" containing a C 1-3 alkyl group.
  • cyclopropylmethyl cyclobutylmethyl
  • cyclopentylmethyl cyclohexylmethyl
  • cyclopentylethyl cyclohexylethyl
  • the cycloalkyl group on the cycloalkylalkyl group may be further substituted with one or more substituents described in the present invention.
  • heterocyclic group and “heterocyclic ring” are used interchangeably herein, and both refer to a monovalent or multivalent, saturated or partially unsaturated, non-aromatic monocyclic ring containing 3-12 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 4-12 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 5-12 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 5-8 ring atoms.
  • the heterocyclyl or heterocyclic ring contains 5-7 ring atoms.
  • the nitrogen atom of the ring can be optionally oxidized to an N-oxygen compound.
  • the heterocyclic group includes a saturated heterocyclic group (heterocycloalkyl) and a partially unsaturated heterocyclic group.
  • the heterocyclic group has one or more points of attachment to the rest of the molecule.
  • heterocyclic groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, pyrazoline, pyrazole Alkyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxanyl, dithiocyclopentyl, tetrahydropyranyl , Dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithia Alkyl, Thioxanyl, Homopiperazinyl, Homopiperidinyl, Oxepanyl,
  • 1,4-thiazepine Base 1,2-thiazepine Group
  • indolinyl 1,2,3,4-tetrahydroisoquinolinyl, 1,3-benzodioxanyl, 2-oxa-5-azabicyclo[2.2.1]heptan- 5-yl, 2-azaspiro[4.4]nonyl, 1,6-dioxaspiro[4.4]nonyl, 2-azaspiro[4.5]decyl, 8-azaspiro[4.5 ]Decyl, 7-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 2-azaspiro[5.5]undecyl, octahydro-1H-isoindyl Dolyl, octahydrocyclopenta[c]pyrrolyl, indolinyl, 1,2,3,4-tetrahydroisoquinolinyl, hexahydrofuro[3,2-b]
  • Examples in which the sulfur atom in the heterocyclic group is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl.
  • the heterocyclic group may be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclic group is a heterocyclic group composed of 4-7 atoms, which refers to a monovalent or multivalent, saturated or partially unsaturated non-aromatic monocyclic ring containing 4-7 ring atoms Or a bicyclic ring, where at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • the sulfur atom of the ring can optionally be oxidized to S-oxide.
  • the nitrogen atom of the ring can optionally be oxidized to an N-oxygen compound.
  • the heterocyclic group consisting of 4-7 atoms has one or more connection points to connect to the rest of the molecule.
  • examples of monocyclic heterocyclic groups composed of 4-7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietane, pyrrolidinyl, pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, tetrahydropyranyl, dihydropyranyl, 2H -Pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazinyl, 1,2-
  • heterocyclylalkyl includes heterocyclyl-substituted alkyl groups, wherein both heterocyclyl and alkyl have the meanings described in the present invention. Examples of this include, but are not limited to, tetrahydrofurylmethyl, pyrrole- 2-ylmethyl, morpholin-4-ylethyl, piperazin-4-ylethyl, piperidin-4-ylethyl, etc.
  • aryl means a monocyclic, bicyclic and tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic Family, where each ring system contains a ring composed of 3-7 atoms, and has one or more points of attachment to the rest of the molecule.
  • aryl can be used interchangeably with the term “aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, and anthracenyl. The aryl group may be independently optionally substituted with one or more substituents described in the present invention.
  • arylalkyl or “aralkyl” includes aryl substituted alkyl groups.
  • an arylalkyl group refers to a "lower arylalkyl” group, that is, the aryl group is attached to a C1-6 alkyl group.
  • the arylalkyl group refers to a "phenylalkylene” containing a C 1-3 alkyl group. Specific examples thereof include, but are not limited to, benzyl, diphenylmethyl, phenethyl and the like.
  • the aryl group on the arylalkyl group may be further substituted with one or more substituents described in the present invention.
  • heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, in which at least one ring is aromatic, and At least one aromatic ring contains one or more heteroatoms, and each ring system contains a ring composed of 5-7 atoms, and there are one or more connection points connected to the rest of the molecule.
  • heteroaryl can be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic compound”.
  • the heteroaryl group is a heteroaryl group consisting of 5-12 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In another embodiment, the heteroaryl group is a heteroaryl group consisting of 5-10 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N. In another embodiment, the heteroaryl group is a heteroaryl group consisting of 5-6 atoms including 1, 2, 3, or 4 heteroatoms independently selected from O, S, and N.
  • the heteroaryl group is optionally substituted with one or more substituents described in the present invention.
  • heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-thi
  • heteroarylalkyl means that an alkyl group is substituted by one or more heteroaryl groups, wherein both the heteroaryl group and the alkyl group have the meanings described in the present invention.
  • heteroarylalkyl include, but not Limited to pyridine-2-methyl, imidazole-2-methyl, furan-2-ethyl, indole-3-methyl, etc.
  • halogen refers to F, Cl, Br or I.
  • the "pharmaceutically acceptable salt” used in the present invention refers to the organic and inorganic salts of the compound of the present invention.
  • Pharmaceutically acceptable salts are well-known in the field, as described in the literature: SMBerge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66:1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups include hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or through other methods described in books and literature such as ion exchange These salts.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate Salt, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, caproate, hydroiodide, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3 -Phenylpropylprop
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also intends to contemplate any quaternary ammonium salts formed by compounds containing N groups. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 Sulfonates and aromatic sulfonates.
  • solvate of the present invention refers to an association formed by one or more solvent molecules and the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to the association formed by the solvent molecule being water.
  • the present invention discloses a class of novel compounds, which can be used as inhibitors of protein kinase activity, especially AXL kinase activity.
  • Compounds that are protein kinase inhibitors can be used to treat and/or prevent diseases, disorders, or conditions associated with inappropriate protein kinase activity, particularly inappropriate AXL kinase activity.
  • the compound of the present invention has better pharmacological activity.
  • the compound of the present invention shows excellent inhibitory activity and kinase selectivity for the target kinase.
  • the compound of the present invention also has excellent membrane permeability and exhibits excellent pharmacokinetic properties in animals. Therefore, the compound of the present invention has very good development prospects.
  • the compounds disclosed in the present invention can show strong inhibitory activity against one or more protein kinases.
  • the present invention relates to a compound having a structure represented by formula (I):
  • U 1 and U 2 are each independently N or -C(R a )-;
  • R 1 and R 2 are each independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 hydroxyalkyl, C 2-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl , C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-6 alkyl, C 1 -6 haloalkyl, C 2-6 hydroxyalkyl, C 2-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl, C 1-6 alkane C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12
  • R 4 is C 2-6 hydroxyalkyl, C 4-10 cycloalkyl, C 4-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, or C 2-7 heterocyclyl C 1-6 alkyl; wherein each of the C 2-6 hydroxyalkyl, C 4-10 cycloalkyl, C 4-10 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl and C 2 -7 heterocyclyl C 1-6 alkyl is independently optionally substituted with 0, 1, 2, 3 or 4 R 11a ;
  • R a , R 3 , R 5 , R 6 , R 7 and R 8 is independently H, D, F, Cl, Br, -OH, -CN, -NO 2 , -NR c R d , C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-8 ring Alkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 Aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each -NR c R d , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl,
  • R 2 and R 3 together with the carbon atom and nitrogen atom to which they are connected, optionally form a heterocyclic ring consisting of 4-12 atoms, wherein the heterocyclic ring consisting of 4-12 atoms optionally includes 1, 2 Or 3 N, O, and/or S atoms and optionally substituted with 0, 1, 2, 3, 4 or 5 R 13 ;
  • n 0, 1, or 2.
  • R 2 is H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, or C 1-4 cyanoalkyl; wherein each C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl and C 1-4 cyanoalkyl are independently optionally 0, 1, 2, 3 or 4 R 11 substitutions;
  • R 3 is H, D, F, Cl, Br, -OH, -CN, -NO 2 , -NH 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, or C 1-4 cyanoalkyl; wherein each of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl And C 1-4 cyanoalkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 12 ;
  • R 2 and R 3 together with the carbon atom and nitrogen atom to which they are connected, optionally form a heterocyclic ring consisting of 4-7 atoms, wherein the heterocyclic ring consisting of 4-7 atoms optionally contains 1, 2 Or 3 N, O, and/or S atoms and optionally substituted with 0, 1, 2, 3, 4, or 5 R 13 .
  • R 2 and R 3 are each independently H, D, methyl, ethyl, or propyl, or R 2 and R 3 together with the carbon atom and nitrogen atom to which they are attached are optionally
  • a heterocyclic ring consisting of 5-7 atoms is formed, wherein the heterocyclic ring consisting of 4-7 atoms optionally contains 1, 2 or 3 N, O, and/or S atoms and is optionally substituted by 0, 1 , 2, 3, 4, or 5 R 13 substitutions.
  • the compound of the present invention has a structure represented by formula (II):
  • Each t1 and t2 are independently 0, 1, 2, or 3;
  • n 0, 1, 2, 4, or 5.
  • each t1 and t2 are independently 0, 1, 2, or 3; and m is 0, 1, 2, or 4, respectively.
  • R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, or C 1-9 heteroaryl; wherein each of C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 amino Alkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl and C 1-9 heteroaryl are independently optionally substituted with 0, 1, 2, 3 or 4 R 11 .
  • R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or 5-atom heteroaryl; wherein each C 1-4 alkyl, C 1-4 haloalkane Group, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidine
  • the group and the 5-atom heteroaryl group are independently optionally substituted with 0, 1, 2, 3, or 4 R 11 .
  • R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrazolyl or triazolyl; wherein each C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 hydroxyalkyl, C 2-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-8 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, Pyrazolyl and triazolyl are independently optionally substituted with 0, 1, 2, 3, or 4 R 11 .
  • U 1 and U 2 are each independently N or -C(R a )-;
  • Each R a and R 8 are each independently H, D, F, Cl, Br, -OH, -CN, -NO 2, -NH 2, or C 1-4 alkyl; wherein each of said C 1-4 Alkyl groups are independently optionally substituted with 0, 1, 2, 3 or 4 R 12 ; and
  • n 0, 1, or 2.
  • R 4 is C 2-4 hydroxyalkyl, C 4-6 cycloalkyl, C 4-6 cycloalkyl, C 1-4 alkyl, C 3-6 heterocyclyl, or C 3-6 heterocyclyl C 1-4 alkyl; wherein each C 2-4 hydroxyalkyl, C 4-6 cycloalkyl, C 4-6 cycloalkyl C 1-4 alkyl, C 3- 6 heterocyclyl and C 3-6 heterocyclyl C 1-4 alkyl are independently optionally substituted with 0, 1, 2, 3, or 4 R 11a .
  • R 4 is Wherein R 4 is optionally substituted with 0, 1, 2, 3 or 4 R 11a .
  • R 5 is H, D, -NR c R d , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, Or C 1-4 cyanoalkyl.
  • R 6 and R 7 are each independently H, D, F, Cl, Br, -OH, -NR c R d , -CN, -NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, or C 1-4 cyanoalkyl.
  • the compound of the present invention is a compound having one of the following structures:
  • the compounds disclosed in the present invention may contain asymmetric or chiral centers, and therefore may exist in different stereoisomer forms.
  • the present invention aims to make all stereoisomers forms of compounds represented by formula (I) or (II), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or Conformation) isomers, and their mixtures, such as racemic mixtures, form part of the present invention.
  • stereochemistry of any specific chiral atom when the stereochemistry of any specific chiral atom is not specified, all stereoisomers of the structure are considered in the present invention and are included in the present invention as the compound disclosed in the present invention .
  • stereochemistry is indicated by a solid wedge or dashed line representing a specific configuration, then the stereoisomer of the structure is clear and defined.
  • the compound represented by formula (I) or (II) may exist in the form of a salt.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal to be treated with it.
  • the salt is not necessarily a pharmaceutically acceptable salt, and can be used to prepare and/or purify the compound of formula (I) or (II) and/or to isolate the compound of formula (I) Or an intermediate of the enantiomer of the compound shown in (II).
  • the present invention relates to intermediates for the preparation of compounds represented by formula (I) and (II).
  • the present invention relates to methods for the preparation, separation and purification of compounds represented by formula (I) and (II).
  • the present invention provides a pharmaceutical composition comprising the compound of the present invention.
  • the pharmaceutical composition of the present invention further includes pharmaceutically acceptable excipients, diluents or carriers, or a combination thereof.
  • the pharmaceutical composition may be in liquid, solid, semi-solid, gel or spray form.
  • the pharmaceutical composition of the present invention further comprises an additional therapeutic agent.
  • the present invention relates to a use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for the prevention and/or treatment of diseases and/or disorders mediated by AXL protein kinase .
  • the disease and/or condition is selected from proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, or viral infectious diseases.
  • the disease and/or disorder is selected from treatment and/or prevention of AXL kinase, mediated diseases involving signaling pathways.
  • diseases and/or disorders include proliferative diseases, autoimmune diseases, allergic diseases, inflammatory diseases, transplant rejection, and their complications.
  • the compounds of the present invention can be used to treat and/or prevent the following diseases and/or disorders, including, but not limited to, cancer (including solid tumors and blood cancers), polycythemia vera, essential thrombocythemia, and myelofibrosis , Myelogenous leukemia, acute lymphocytic leukemia, chronic myeloid leukemia (CML), chronic obstructive pulmonary disease (COPD), asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes, respiratory allergic diseases, sinusitis, eczema, measles, food allergy, insect venom allergy, inflammatory bowel disease, Crohn's disease, rheumatoid arthritis, juvenile joints Inflammation, psoriatic arthritis, organ transplant rejection, tissue transplant rejection
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound disclosed in the present invention, or the compound listed in the examples, or its stereoisomers, tautomers, nitrogen oxides, solvates, metabolites or pharmaceutically Acceptable salts; and pharmaceutically acceptable excipients, diluents, carriers, vehicles, or combinations thereof.
  • the amount of the compound in the pharmaceutical composition disclosed in the present invention refers to the amount that can effectively detect the inhibition of protein kinase in biological samples or patients.
  • certain compounds of the present invention may exist in free form for treatment, or, if appropriate, may exist in the form of their pharmaceutically acceptable derivatives.
  • Some non-limiting embodiments of pharmaceutically acceptable derivatives include pharmaceutically acceptable salts, esters, and salts of these esters, or can directly or indirectly provide the compound of the present invention or its compounds when administered to a patient in need. Any additional adducts or derivatives of metabolites or residues.
  • the pharmaceutical composition provided by the present invention can be formulated with other active ingredients that do not impair the expected therapeutic effect, or with substances that supplement the expected effect.
  • the present invention provides the use of the compounds and pharmaceutical compositions disclosed in the present invention to treat, prevent, or ameliorate diseases or conditions that are mediated or otherwise affected by one or more protein kinases, such as AXL kinase, or are affected by AXL kinase.
  • the present invention provides a class of compounds disclosed in the present invention or pharmaceutical compositions containing the compounds disclosed in the present invention for the treatment, prevention or amelioration of inappropriate AXL kinase behavior mediated or otherwise affected Or one or more symptoms of a disease or disorder that is mediated or otherwise affected by inappropriate AXL kinase behavior.
  • Inappropriate AXL kinase behavior refers to AXL kinase behavior that deviates from normal AXL kinase behavior in a specific patient. Inappropriate AXL kinase behavior can take the form of, for example, an abnormal increase in activity, or a deviation in the time point and control of AXL kinase behavior. This inappropriate kinase behavior stems from, for example, inappropriate or uncontrolled behavior caused by overexpression or mutation of protein kinase. Therefore, the present invention provides methods for treating these diseases and conditions.
  • myeloproliferative diseases such as polycythemia vera (PCV), idiopathic thrombocythemia, idiopathic myelofibrosis (IMF); leukemia,
  • myeloid leukemia includes chronic myeloid leukemia (CML), imatinib-resistant CML forms, acute myeloid leukemia (AML) and subtypes of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative diseases, such as Acute lymphocytic leukemia (ALL) and myeloma
  • cancers include head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer, urothelial cancer, liver cancer, stomach cancer and kidney cancer Etc.
  • inflammatory diseases or disorders related to immune dysfunction, immune deficiency, immune regulation, autoimmune diseases, tissue transplant rejection include inflammatory diseases or disorders related to immune dysfunction, immune deficiency, immune regulation,
  • the present invention provides a class of compounds disclosed in the present invention or pharmaceutical compositions containing the compounds disclosed in the present invention, which are used to prevent and/or treat proliferative diseases, autoimmune diseases, and allergic diseases in mammals (including humans). Disease, inflammatory disease, or transplant rejection.
  • the present invention provides a method of treating a mammal suffering from or at risk of suffering from the disease disclosed in the present invention, the method comprising administering an amount effective to treat the disorder or an amount effective to prevent the disorder in one or more of the present disclosures
  • the pharmaceutical composition or compound is administered to a mammal suffering from or at risk of suffering from the disease disclosed in the present invention, the method comprising administering an amount effective to treat the disorder or an amount effective to prevent the disorder in one or more of the present disclosures.
  • the proliferative disease is selected from cancers such as colon cancer, malignant glioma, endometrial cancer, liver cancer, lung cancer, melanoma, kidney cancer, thyroid cancer, lymphoma, lymphoproliferative disorder, small cell Lung cancer, squamous cell lung cancer, glioma, breast cancer, prostate cancer, ovarian cancer, cervical cancer, etc.; hematological malignancies, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myelodysplastic disease ( MPD), chronic myelogenous leukemia (CML), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin's lymphoma (NHL), B-cell lymphoma; Polycythemia vera, essential thrombocythemia, myelofibrosis, multiple myeloma, etc.
  • cancers such as colon cancer
  • the present invention provides a method for treating and/or preventing a mammal susceptible to or suffering from an autoimmune disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the present invention Pharmaceutical composition or compound.
  • the autoimmune disease is selected from COPD, asthma, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren's syndrome, psoriasis, type I diabetes and inflammatory bowel disease.
  • the present invention provides a method of treating and/or preventing mammals susceptible to or suffering from allergic diseases, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the present invention Pharmaceutical composition or compound.
  • the allergic disease is selected from respiratory allergic diseases, sinusitis, eczema and measles, food allergy and insect venom allergy.
  • the allergic disease is selected from respiratory allergic diseases, sinusitis, eczema and measles, food allergy and insect venom allergy.
  • the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from an inflammatory disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the disclosed Pharmaceutical composition or compound.
  • the present invention provides a method of treating and/or preventing a mammal susceptible to or suffering from a viral infectious disease, the method comprising administering an effective therapeutic amount or an effective preventive amount of one or more of the present disclosures
  • the pharmaceutical composition or compound is administered to a mammal susceptible to or suffering from a viral infectious disease.
  • the viral infectious disease is selected from influenza, coronavirus infection, new coronavirus infection, dengue virus infection, Zika virus infection, Ebola virus infection, respiratory syncytial virus infection, or HBV.
  • the present invention provides a class of compounds disclosed in the present invention for use as a medicament, especially as a medicament for the treatment and/or prevention of the diseases and/or disorders described in the present invention.
  • the present invention also provides the use of the compounds disclosed in the present invention to prepare drugs for the treatment and/or prevention of the diseases and/or disorders described in the present invention.
  • the compounds of the present invention can be administered as a single active agent, or can be administered in combination with other therapeutic agents, including other compounds that have the same or similar therapeutic activity and are determined to be safe and effective for such combined administration.
  • the present invention provides a method for treating, preventing or ameliorating a disease or condition, which comprises administering a safe and effective amount of a combination drug comprising a compound disclosed in the present invention and one or more therapeutically active agents.
  • the combination drug contains one or two other therapeutic agents.
  • therapeutic agents include, but are not limited to: anti-cancer agents, including chemotherapeutic agents and anti-proliferative agents; anti-inflammatory agents; and immunomodulators or immunosuppressive agents.
  • the present invention provides a product comprising the compound of the present invention and at least one other therapeutic agent, which can be prepared as a combination for simultaneous, separate or sequential administration during treatment.
  • the treatment is for the treatment of diseases or symptoms mediated by the activity of one or more protein kinases, such as AXL kinase, or NTRK kinase.
  • the products provided by the joint preparation include a composition containing the compound disclosed in the present invention and other therapeutic agents in the same pharmaceutical composition, or the compound disclosed in the present invention and other therapeutic agents in different forms, for example, a kit.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound disclosed in the present invention and another one or more therapeutic agents.
  • the pharmaceutical composition may include pharmaceutically acceptable excipients as described above.
  • the present invention provides a kit containing two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains the compound disclosed in the present invention.
  • the kit includes means for separately holding the composition, such as a container, a separate bottle, or a separate foil box.
  • a container such as a container, a separate bottle, or a separate foil box.
  • An example of such a kit is a blister pack, which is commonly used for packaging tablets, capsules and the like.
  • the compounds disclosed in the present invention can be administered as a single active ingredient or as, for example, adjuvants, co-administered with other therapeutic agents.
  • the other therapeutic agents include chemotherapeutic agents and/or anti-proliferative agents.
  • chemotherapeutics include, but are not limited to, other therapies that can be used in combination with the compounds of the present invention or anticancer drugs, surgery, and radiotherapy (a few examples are gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton Therapies, brachytherapy and systemic radioisotope therapy), endocrine therapy, taxanes (taxol, docetaxel, etc.), platinum derivatives (cisplatin, carboplatin) ), biological response modifiers (interferon, interleukin), tumor necrosis factor (TNF, TRAIL receptor target), hyperthermia and cryotherapy, agents to reduce any adverse reactions (such as antiemetics), and other drugs Approved chemotherapy drugs, including but not limited to alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide)
  • Anti-angiogenic agents (avastin, etc.). Monoclonal antibodies (belimumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, panitumumab) Monoclonal antibody (ranibizumab), rituximab (rituximab), tositumomab (tositumomab), trastuzumab (trastuzumab)).
  • kinase inhibitors imatinib, sunitinib, sorafenib, erlotinib, gefitinib, dasatinib
  • nilotinib lapatinib
  • crizotinib ruxolitinib
  • vemurafenib vandetanib
  • par Zopanib pazopanib, etc.
  • Drugs inhibit or activate cancer pathways such as mTOR, HIF (hypoxia inducible factor) pathway and others.
  • the compound disclosed in the present invention can also be combined with other treatment processes to improve curative effect. For example, administering hormone therapy or special radiation therapy.
  • the compounds disclosed in the present invention are especially useful as radiosensitizers, especially for the treatment of tumors that are less sensitive to radiotherapy.
  • “Combination” means a fixed combination in a single dosage unit form or a kit of parts for combined administration, wherein the compound disclosed in the present invention and the combination partner can be administered independently at the same time or can be administered separately within a certain time interval , Especially for joint partners to show cooperation, such as synergy.
  • the terms "co-administration” or “co-administration” and the like are intended to encompass the administration of a selected joint partner to a single individual (for example, a patient) in need thereof, and are intended to include substances in which the substance does not have to pass through the same route of administration or Simultaneous administration of the treatment plan.
  • the treatment methods disclosed in the present invention include administering a safe and effective amount of the compound of the present invention or a pharmaceutical composition containing the compound of the present invention to a patient in need.
  • the various embodiments disclosed in the present invention include methods for treating the diseases or disorders described in the present invention by administering to a patient in need a safe and effective amount of the compound disclosed in the present invention or a pharmaceutical composition containing the compound disclosed in the present invention.
  • the compound disclosed in the present invention or a pharmaceutical composition containing the compound disclosed in the present invention may be administered at one time, or according to the dosage regimen, administered several times at different time intervals within a specified time period. For example, it may be administered once, twice, three or four times a day. In one embodiment, it is administered once a day. In yet another embodiment, the administration is twice a day. It can be administered until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely.
  • the appropriate dosage regimen of the compound disclosed in the present invention or a pharmaceutical composition containing the compound disclosed in the present invention depends on the pharmacokinetic properties of the compound, such as dilution, distribution, and half-life, which can be determined by a skilled person.
  • the appropriate dosage regimen of the compound disclosed in the present invention or the pharmaceutical composition containing the compound disclosed in the present invention depends on the disease being treated, the severity of the disease being treated, the age of the patient being treated, and The physical condition, medical history of the patient being treated, the nature of simultaneous therapy, the desired therapeutic effect, and other factors that are within the scope of the technician’s knowledge and experience.
  • an appropriate dosing regimen may be required to be adjusted.
  • the compounds disclosed in the present invention can be administered simultaneously with one or more other therapeutic agents, or before or after them.
  • the compound of the present invention and other therapeutic agents can be administered separately through the same or different administration routes, or they can be administered in the same pharmaceutical composition.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless otherwise specified, wherein the definition of the substituents is as shown in formula (I) or (II).
  • the following reaction schemes and examples are used to further illustrate the content of the present invention.
  • Anhydrous THF, dioxane, DCM, toluene and DMF were all purchased from commercial suppliers, such as Energy Chemical Company and Aldrich Chemical Company.
  • EtOAc, PE, CH 3 CN, NMP and DMSO were all treated with anhydrous Na 2 SO 4 before use.
  • reaction flask is plugged with a suitable rubber stopper, and the substrate is injected through a syringe.
  • the glassware is all dried.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • LC/MS was performed on Agilent 1260 (binary pump/DAD detector) coupled with Agilent 6120/6125 mass spectrometer.
  • MeCN aqueous solution (0.1% HCOOH), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10 ⁇ m; wavelength: 210-400nm.
  • the sample was injected into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, and eluted for 10 minutes.
  • MeCN aqueous solution (0.1% trifluoroacetic acid), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10 ⁇ m; wavelength: 210-400nm.
  • the sample was injected into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, and eluted for 10 minutes.
  • MeCN aqueous solution (0.1% NH 3 -H 2 O/10mM NH 4 AC), flow rate: 20ml/min, 50ml/min, column 30x250mm, 10 ⁇ m; wavelength: 210-400nm.
  • the sample was injected into DMSO (+ optional formic acid and water), with a linear gradient from 10% to 95% MeCN, and eluted for 10 minutes.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , U 1 , U 2 and n has the definition as described in the present invention;
  • PG 1 and PG 2 is a protecting group.
  • the compound of the present invention having the structure represented by formula (6) can be prepared by the general synthesis method described in Synthetic Scheme 1, and the specific steps can be referred to the examples.
  • the boron ester derivative (1) in a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, etc.
  • a suitable Pd catalyst such as Pd(OAc) 2 , Pd( Under the action of dppf) 2 Cl 2 or Pd 2 (dba) 3, etc.
  • the compound (3) can be obtained by coupling reaction with the substituted heteroaryl compound (2 ).
  • an aromatic amine derivative (4) is obtained .
  • the carboxylic acid derivative (5) is condensed with the compound (4) in the presence of a condensing agent (such as EDCI or HATU) to obtain the target kinase inhibitor (6) .
  • a condensing agent such as EDCI or HATU
  • Carboxylic acid derivatives (5) can be found in the literature (see, for example, "Practical synthesis of bicyclic pyrazol-5-one derivatives.” Xuejin Feng, Michael A. Xi, Yanjun Wu, Xiaogang Wang, Ning Xi Tetrahedron Lett. 2017, 58, 46-49; Facile synthesis of bicyclic1-arylpyrazol-5-ones.”Wu,Y.;Wang,K.;Li,Z.;Bai,X.; Xi,N.Tetrahedron Lett.2014,55,142-147) The synthesis method described is obtained.
  • the compound of the present invention having the structure represented by formula (6) can also be prepared by the general synthesis method described in Synthesis Scheme 2, and the specific steps can be referred to the examples.
  • the aryl or heteroaryl compound (7) is condensed with the compound (5) in the presence of a condensing agent (such as EDCI or HATU) to obtain the compound (8) .
  • a condensing agent such as EDCI or HATU
  • the boronic ester derivative (10) can be used in a suitable base (such as cesium carbonate, potassium carbonate, sodium carbonate, etc.), and a suitable Pd catalyst (such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2) Or under the action of Pd 2 (dba) 3, etc.), the compound (9) can be obtained by coupling reaction with the substituted heteroaryl compound (8 ).
  • the boronic ester derivative (9) can be used in a suitable base (such as cesium carbonate, potassium carbonate, sodium carbonate, etc.), and a suitable Pd catalyst (such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2) Or under the action of Pd 2 (dba) 3, etc.), a coupling reaction occurs with the substituted heteroaryl derivative (2) to obtain the target kinase inhibitor (6) .
  • a suitable base such as cesium carbonate, potassium carbonate, sodium carbonate, etc.
  • a suitable Pd catalyst such as Pd(OAc) 2 , Pd(dppf) 2 Cl 2
  • Step 2 tert-Butyl 2-(2-(2-hydroxyethoxy)acetyl)-1-phenylhydrazino-1-carboxylate
  • Step 2) (4-(4-chloro-7-(2-oxopropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate
  • Step 2) 1-(4-Amino-5-(4-amino-2-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)propan-2-one
  • Step 2) (R)-N-(4-(4-amino-7-(2-hydroxypropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluorophenyl )-2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrrolo[5,1-c][1,4]oxazine-3-carboxamide
  • Step 2) 4-(4-Chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
  • Step 2) 4-(4-Chloro-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoroaniline
  • Step 2) 4-(4-Chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)aniline
  • Step 2) 4-(4-Chloro-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-3-fluoroaniline
  • the resulting mixture was stirred at 40°C for 3 h, and after cooling to room temperature, the reaction was quenched with water (100 mL). The resulting mixture was extracted with ethyl acetate (3 ⁇ 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Example 21 was isolated by the method described in Example 20 as a white solid (106.0 mg, 10.5% yield). LCMS (ES, m/z) 510.2 [M+H] + .
  • Step 2) (4-(4-Chloro-7-(2-hydroxy-2-methylpropyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)tert-butyl carbamate ester
  • Step 2) (4-(4-chloro-7-(2-hydroxyethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl) tert-butyl carbamate
  • Step 4) 4-(4-Amino-5-(4-(2-oxo-1-phenyl-2,4,6,7-tetrahydro-1H-pyrazolo[5,1-c][1 ,4]oxazine-3-carboxamido)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)piperidine-1-carboxylic acid tert-butyl ester
  • the LC/MS/MS system used for analysis includes Agilent 1200 series vacuum degassing furnace, binary syringe pump, orifice automatic sampler, column thermostat, Agilent G6430 three-stage quadrupole mass spectrometer with electrospray ionization (ESI) source . Quantitative analysis is carried out in MRM mode, and the parameters of MRM conversion are shown in Table A:
  • the Agilent XDB-C18, 2.1 ⁇ 30mm, 3.5 ⁇ M column was used for analysis, and 5 ⁇ L of sample was injected. Analysis conditions: the mobile phase is 0.1% formic acid aqueous solution (A) and 0.1% formic acid methanol solution (B). The flow rate is 0.4 mL/min.
  • the mobile phase gradient is shown in Table B:
  • Agilent 6330 series LC/MS/MS spectrometer is used for analysis, equipped with G1312A binary syringe pump, G1367A automatic sampler and G1314C UV detector; LC/MS/MS spectrometer uses ESI radiation source.
  • the Capcell MP-C18 column was used, the specification was: 100 ⁇ 4.6mm I.D., 5 ⁇ M (Phenomenex, Torrance, California, USA).
  • the mobile phase is 5mM ammonium acetate, 0.1% methanol aqueous solution (A): 5mM ammonium acetate, 0.1% methanol acetonitrile solution (B) (70:30, v/v); the flow rate is 0.6mL/min; the column temperature is kept at room temperature; Inject 20 ⁇ L of sample.
  • the kinase test is done by detecting myelin base protein (MBP) incorporated into ⁇ -33 P-ATP.
  • MBP myelin base protein
  • TBS Tris Buffered Salt Solution
  • Greiner high binding white 384-well plate
  • kinase reaction in a total volume of 34 ⁇ L kinase buffer (prepared as needed, for example, 5mM Hepes pH 7.6, 15mM NaCl, 0.01% bovine serum albumin (Sigma#I-5506), 10mM MgCl 2 , 1mM DTT, 0.02% TritonX -100).
  • the compound was dissolved in DMSO and added to each well.
  • the final concentration of the compound in the DMSO solution was 1%. At least two tests are carried out for the determination of each compound. For example, the final concentration of the enzyme is 10 nM or 20 nM.
  • the reaction started after the MgATP mixture was added. After incubating for 40 minutes at room temperature, a phosphoric acid solution was added to it to a concentration of 0.5% to terminate the reaction. Distribute 10 ⁇ L of the reaction solution on the P30 filter in the form of spots, wash 4 times with 0.425% phosphoric acid solution in 4 minutes, and wash once with methanol. After drying, use a scintillation counter to measure.
  • the reagents used in the experiment are AXL (Carna Bioscience, Cat No.: 08-107) and FLPeptide 30 (PerkinElmer, Cat No.: 760430).
  • the instruments involved are incubator (Thermo Scientific), oscillator (QILINBEIER), EZ Reader (PerkinElmer, Cat No.: 122919), non-contact level pipetting system (Labcyte Inc., Cat No.: Echo 550), And non-contact nano-upgraded pipetting system (TECAN, Cat No.: EVO200).
  • Compound dilution 1) Dissolve the compound in DMSO to an appropriate concentration; 2) Use TECAN EVO200 to 3-fold 10 concentrations in a 384 microwell plate, the highest concentration is 1mM; use Echo550 to transfer 20nL solution from the dilution plate to the experiment In the board.
  • Reagent name Solution 1 MgCl 2 10mM Brij-35 0.050% DTT 2mM BSA 0.05% EGTA 1mM HEPE(pH7.5) 50mM AXL 1.333nM
  • Reagent name Solution 2 MgCl 2 10mM Brij-35 0.050% DTT 2mM BSA 0.05% EGTA 1mM HEPE(pH7.5) 50mM FLPeptide 6 ⁇ M ATP 400 ⁇ M
  • Test method described above can be obtained IC 50 and / or suppression of the inhibitory constant K i.
  • the IC 50 is defined as the concentration of the compound that inhibits 50% of the enzyme activity under the test conditions.
  • Use the 1/2log dilution factor to make a curve containing 10 concentration points, and estimate the IC 50 value (for example, make a typical curve with the following compound concentrations: 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M , 0.003 ⁇ M, 0.001 ⁇ M, 0.0003 ⁇ M, 0 ⁇ M), or 10 ⁇ M, 3 ⁇ M, 1 ⁇ M, 0.3 ⁇ M, 0.1 ⁇ M, 0.03 ⁇ M, 0.01 ⁇ M, 0.003 ⁇ M, 0.001 ⁇ M, 0 ⁇ M).
  • This test is done by testing the compound's inhibitory effect on the growth of the Ba/F3 AXL cell line and the Ba/F3 parent cell line.
  • cell survival rate (%) (Lum test drug-Lum culture medium control )/(Lum cell control-Lum culture medium control) ⁇ 100%.
  • Table 1 below provides the AXL(h) kinase test results of the compounds of the present invention, indicating that the compounds of the present invention have a very good inhibitory effect on AXL kinase.

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Abstract

La présente invention se rapporte au domaine des produits pharmaceutiques, et concerne en particulier un composé hétéroaryle substitué tel que représenté par la formule (I) ou un stéréoisomère, un tautomère, un oxyde d'azote, un solvate, un métabolite ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique contenant le composé, et l'utilisation du composé et de la composition pharmaceutique associée dans la préparation de médicaments pour le traitement et/ou la prévention de maladies prolifératives, de maladies auto-immunes, de maladies allergiques, de maladies inflammatoires, du rejet de greffe, du cancer, de maladies infectieuses virales ou d'autres maladies chez des mammifères. Le composé selon la présente invention a une excellente activité inhibitrice et une excellente sélectivité vis-à-vis d'une kinase cible.
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WO2023051464A1 (fr) * 2021-09-29 2023-04-06 Shanghai Antengene Corporation Limited Composés de pyrazolopyridine comme inhibiteurs de tam

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104974162A (zh) * 2014-04-09 2015-10-14 广东东阳光药业有限公司 双环吡唑酮化合物及其使用方法和用途
WO2018121228A1 (fr) * 2016-12-28 2018-07-05 中国科学院上海药物研究所 Composé ayant une activité inhibitrice d'axl, sa méthode de préparation et son utilisation
CN109348715A (zh) * 2016-03-28 2019-02-15 因赛特公司 作为tam抑制剂的吡咯并三嗪化合物
CN110511218A (zh) * 2018-05-21 2019-11-29 中国科学院上海药物研究所 一类并环吡唑啉酮甲酰胺类化合物及其制备方法、药物组合物和用途
CN110627796A (zh) * 2018-06-21 2019-12-31 北京越之康泰生物医药科技有限公司 含氮杂环类衍生物及其在医药上的应用
WO2020182188A1 (fr) * 2019-03-13 2020-09-17 习峰 Composé hétéroaryle substitué, composition correspondante et utilisations associées

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111689991B (zh) * 2019-03-13 2023-06-09 习峰 取代的杂芳基化合物及其组合物和用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104974162A (zh) * 2014-04-09 2015-10-14 广东东阳光药业有限公司 双环吡唑酮化合物及其使用方法和用途
CN109348715A (zh) * 2016-03-28 2019-02-15 因赛特公司 作为tam抑制剂的吡咯并三嗪化合物
WO2018121228A1 (fr) * 2016-12-28 2018-07-05 中国科学院上海药物研究所 Composé ayant une activité inhibitrice d'axl, sa méthode de préparation et son utilisation
CN110511218A (zh) * 2018-05-21 2019-11-29 中国科学院上海药物研究所 一类并环吡唑啉酮甲酰胺类化合物及其制备方法、药物组合物和用途
CN110627796A (zh) * 2018-06-21 2019-12-31 北京越之康泰生物医药科技有限公司 含氮杂环类衍生物及其在医药上的应用
WO2020182188A1 (fr) * 2019-03-13 2020-09-17 习峰 Composé hétéroaryle substitué, composition correspondante et utilisations associées

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023051464A1 (fr) * 2021-09-29 2023-04-06 Shanghai Antengene Corporation Limited Composés de pyrazolopyridine comme inhibiteurs de tam

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