WO2023173480A1 - Inhibiteur sélectif de csf1r et son utilisation - Google Patents

Inhibiteur sélectif de csf1r et son utilisation Download PDF

Info

Publication number
WO2023173480A1
WO2023173480A1 PCT/CN2022/083651 CN2022083651W WO2023173480A1 WO 2023173480 A1 WO2023173480 A1 WO 2023173480A1 CN 2022083651 W CN2022083651 W CN 2022083651W WO 2023173480 A1 WO2023173480 A1 WO 2023173480A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
cancer
pyrrolo
oxy
alkyl
Prior art date
Application number
PCT/CN2022/083651
Other languages
English (en)
Chinese (zh)
Inventor
刘青松
刘静
梁小飞
王纯
王蓓蕾
王傲莉
亓爽
齐紫平
刘青旺
刘娟
操江艳
王文超
王黎
Original Assignee
中国科学院合肥物质科学研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院合肥物质科学研究院 filed Critical 中国科学院合肥物质科学研究院
Publication of WO2023173480A1 publication Critical patent/WO2023173480A1/fr

Links

Images

Classifications

    • 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
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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

Definitions

  • the invention belongs to the field of biomedicine, and specifically relates to a selective CSF1R inhibitor and its application in anti-cancer drugs.
  • Type III receptor tyrosine kinase (RTK type III) family members include colony-stimulating factor 1 (CSF1R), platelet-derived growth factor (PDGFR ⁇ / ⁇ ), KIT, FLT3, etc. Their gene sequences are very similar, and their protein structures include An extracellular region composed of five Ig-like domains, a transmembrane region, a juxtamembrane region, and two intracellular tyrosine kinase regions separated by a kinase insert region (Abu-Duhier FM, et al., Mutational Analysis of class III receptor tyrosine kinases(C-KIT,C-FMS,FLT3) in idiopathic myelofibrosis.
  • KIT protein as a receptor for stem cell factor, participates in the proliferation and differentiation process of hematopoietic stem cells through a series of signaling pathways.
  • FLT3 protein is also known as FMS-like tyrosine kinase 3, which regulates the proliferation and differentiation of hematopoietic cells.
  • CSF1 is a dimeric glycoprotein linked by disulfide bonds. It mainly exists in the bone marrow cavity and is responsible for cellular processes such as the growth, proliferation and differentiation of macrophages.
  • CSF1R as a cell surface receptor for CSF1 and IL34, plays an important role in regulating the survival, proliferation and differentiation of hematopoietic precursors.
  • the signaling axis formed by CSF1 and CSF1R is abnormally expressed in a variety of malignant tumors, such as breast cancer, ovarian cancer, and nasopharyngeal cancer, and is closely related to the occurrence and development of tumors.
  • simultaneous inhibition of FLT3 and KIT will produce myelosuppressive toxicity.
  • One object of the present invention is to provide a class of compounds that can selectively inhibit the activity of CSF1R kinase and related signaling pathways, and therefore can activate autoimmunity by inhibiting the phosphorylation of CSF1R and be used to treat cancer.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof:
  • Ar is selected from aryl and heteroaryl optionally substituted by 1 to 3 independently R 2 groups;
  • R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heterocycloalkyl, hydroxy C1-C6 alkyl, nitrile C1-C6 alkyl, carboxyl C1-C6 alkyl, C3-C6 ring Alkyl C1-C6 alkyl, C1-C6 heterocycloalkyl C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkylamino C1-C6 alkyl, C1-C6 alkyl Amide C1-C6 alkyl, C1-C6 alkyl sulfone, C1-C6 alkanoyl, C1-C6 heterocycloalkylaminoacyl, C1-C6 heterocycloalkyl C1-C6 alkylamine acyl, hydroxyl C1- C6 alkylaminoacyl, C1-C6
  • Each R2 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloC1-C6 alkoxy, and nitrogen protecting group.
  • L is
  • Ar is selected from phenyl, pyridyl, furyl, benzofuryl, thienyl, and pyrrolyl optionally substituted by 1-2 independently R 2 groups; further preferably Ground, each R 2 is independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, haloC1-C3 alkoxy, pivaloyl, tert-butoxycarbonyl, benzyloxy Carbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl and trifluoroacetyl.
  • Ar is selected from phenyl or pyridinyl substituted by 1 R 2 group; more preferably, Ar is selected from phenyl or pyridin-2-yl substituted by R 2 in the para position ; Further preferably, R 2 is selected from C1-C6 haloalkyl, more preferably trifluoromethane.
  • R 1 is selected from C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 heterocycloalkyl, hydroxy C1-C3 alkyl, nitrile C1-C3 alkyl, carboxyl C1- C3 alkyl, C3-C5 cycloalkyl C1-C3 alkyl, C3-C5 heterocycloalkyl C1-C3 alkyl, C1-C3 alkoxy C1-C3 alkyl, C1-C4 alkylamino C1- C3 alkyl, C1-C3 alkylamido, C1-C3 alkyl, C1-C3 alkyl sulfone, C2-C4 alkanoyl, C3-C5 heterocycloalkylaminoacyl, C3-C5 heterocycloalkyl C1-C3 Alkylaminoacyl, hydroxyl C1-C3 alkylaminoacyl
  • the present application also provides a compound comprising formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof, and a pharmaceutically acceptable diluent or carrier, and optionally Pharmaceutical compositions of other active pharmaceutical compounds.
  • the present application also relates to compounds of formula (I) or their pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs for use in the preparation of inhibiting the activity of CSF1R kinase and related signaling pathways, or treating patients with Use in drugs related to cancer or tumors associated with CSF1R kinase activity.
  • the present application also relates to a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof for use in the treatment of tumor microenvironment (TME) Use in drugs for cancers or tumors in which M2 macrophages are the main cells.
  • TAE tumor microenvironment
  • the cancer or tumor is selected from the group consisting of ovarian cancer, cervical cancer, pancreatic cancer, prostate cancer, bladder cancer, lung cancer, thyroid cancer, breast cancer, pancreatic cancer, kidney cancer, gastric cancer, liver cancer, cervical cancer, endometrial cancer, Colorectal cancer, nasopharyngeal cancer, esophageal cancer, cholangiocarcinoma, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, small cell lung cancer, colon cancer, solid tumors, brain tumors, lymphoma, glioma, One or more of glioblastoma, melanoma, mesothelioma, glioblastoma, osteosarcoma, gastrointestinal stromal tumor, multiple myeloma, biliary carcinosarcoma, and leukemia.
  • the lymphoma includes non-Hodgkin lymphoma, B-cell or T-cell lymphoma; the leukemia includes chronic mye
  • the present invention also relates to a method for inhibiting the activity of CSF1R kinase and related signaling pathways, or treating cancer or tumors dominated by M2 macrophages in the tumor microenvironment, which is characterized by comprising administering a therapeutically effective amount of formula (I) to the patient.
  • a method for inhibiting the activity of CSF1R kinase and related signaling pathways, or treating cancer or tumors dominated by M2 macrophages in the tumor microenvironment which is characterized by comprising administering a therapeutically effective amount of formula (I) to the patient.
  • Figure 1 shows the promoting effect of compound 54, BLZ945, and PLC3397 on the transformation of macrophages from M2 to M1 type.
  • Figure 2 shows the effects of compound 54 and PLX3397 on the body weight of mice after administration in the M-NFS-60 cell tumor transplantation mouse model.
  • Figure 3 shows the effect of compound 54 and PLX3397 on tumor volume after administration in M-NFS-60 cell tumor transplantation mouse model.
  • Figure 4 shows the effect of compound 54 and PLX3397 on tumor weight after administration in M-NFS-60 cell tumor transplantation mouse model.
  • Figure 5 shows the effects of compound 54 and PLX3397 on mouse body weight after administration in MC38 cell tumor transplantation mouse model.
  • Figure 6 shows the effect of compound 54 and PLX3397 on tumor volume after administration in MC38 cell tumor transplantation mouse model.
  • Figure 7 shows the effect of compound 54 and PLX3397 on tumor weight after administration in MC38 cell tumor transplantation mouse model.
  • the present invention adopts conventional methods such as mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology within the technical scope of the art.
  • mass spectrometry NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology
  • specific definitions are provided, the nomenclature and laboratory procedures and techniques chemically relevant to the analytical chemistry, synthetic organic chemistry, and medical and medicinal chemistry described herein are known to those skilled in the art.
  • the foregoing techniques and steps may be carried out by conventional methods that are well known in the art and described in various general and more specific documents, which are cited and discussed in this specification.
  • alkyl refers to an aliphatic hydrocarbon group, which may be branched or straight chain. Depending on the structure, an alkyl group can be a monovalent group or a bivalent group (i.e., an alkylene group). In the present invention, the alkyl group is preferably an alkyl group having 1 to 8 carbon atoms, more preferably a “lower alkyl group” having 1 to 6 carbon atoms, and even more preferably an alkyl group having 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • alkyl includes all possible configurations and conformations of the alkyl group.
  • the "propyl” mentioned herein includes n-propyl and isopropyl
  • the "butyl” includes n-butyl. base, isobutyl and tert-butyl
  • "pentyl” includes n-pentyl, isopentyl, neopentyl, tert-pentyl, and pentyl-3-yl, etc.
  • alkoxy refers to -O-alkyl, where alkyl is as defined herein. Typical alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, etc.
  • cycloalkyl refers to a monocyclic or polycyclic group containing only carbon and hydrogen. Cycloalkyl groups include groups having 3 to 12 ring atoms. Depending on the structure, a cycloalkyl group can be a monovalent group or a bivalent group (eg, cycloalkylene). In the present invention, the cycloalkyl group is preferably a cycloalkyl group having 3 to 8 carbon atoms, and more preferably a “lower cycloalkyl group” having 3 to 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and adamantane base.
  • aryl refers to a planar ring having a delocalized pi electron system and containing 4n+2 pi electrons, where n is an integer.
  • Aryl rings may be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted.
  • aryl includes carbocyclic aryl (eg, phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaryl”) groups (eg, pyridine).
  • the term includes monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) groups.
  • aryl means an aryl ring in which each ring-constituting atom is a carbon atom.
  • Aryl rings can be composed of five, six, seven, eight, nine, or more than nine atoms.
  • Aryl groups may be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthrenyl, anthracenyl, fluorenyl, and indenyl.
  • an aryl group can be a monovalent group or a bivalent group (i.e., arylene group).
  • aryloxy refers to -O-aryl, where aryl is as defined herein.
  • heteroaryl refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the N-containing “heteroaryl” part refers to an aromatic group in which at least one skeleton atom in the ring is a nitrogen atom.
  • a heteroaryl group can be a monovalent group or a bivalent group (i.e., a heteroarylene group).
  • heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazole base, isothiazolyl, pyrrolyl, quinolyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, isoindole Indolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl , naphthyridinyl and furopyr
  • heteroalkyl as used herein means an alkyl group as defined herein in which one or more of the backbone chain atoms are heteroatoms, such as oxygen, nitrogen, sulfur, silicon, phosphorus, or combinations thereof.
  • the heteroatom(s) may be located anywhere within the heteroalkyl group or at the position where the heteroalkyl group is attached to the rest of the molecule.
  • heterocycloalkyl or “heterocyclyl” as used herein refers to a non-aromatic ring in which one or more of the ring-constituting atoms is a heteroatom selected from the group consisting of nitrogen, oxygen and sulfur.
  • Heterocycloalkyl rings can be composed of three, four, five, six, seven, eight, nine or more than nine atoms. Heterocycloalkyl rings may be optionally substituted.
  • heterocycloalkyl groups include, but are not limited to, lactams, lactones, cyclic imines, cyclic thioimines, cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4- Oxathiane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, apeloline Bituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, Te
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • haloalkyl examples include alkyl, alkoxy or heteroalkyl structures in which at least one hydrogen is replaced by a halogen atom. In certain embodiments, if two or more hydrogen atoms are replaced by halogen atoms, the halogen atoms may be the same as or different from each other.
  • amino refers to the -NH group .
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • ester group refers to a chemical moiety having the formula -COOR, wherein R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (attached through a ring carbon) and heterocyclyl (attached through a ring carbon).
  • amide or “amido” refers to -NR-CO-R', where R and R' are each independently hydrogen or alkyl.
  • aminoacyl or “aminoacyl” refers to the -CO- NH2 group.
  • alkylaminoacyl or “alkylaminoacyl” refers to the group -CO-NH-R, where R is alkyl as defined herein.
  • optional means that one or more of the events described below may or may not occur, and includes both events that occur and events that do not occur.
  • optionally substituted or “substituted” means that the mentioned group may be substituted by one or more additional groups each and independently selected from alkyl, cycloalkyl , aryl, heteroaryl, heterocyclyl, hydroxyl, alkoxy, cyano, halogen, amide, nitro, haloalkyl, amino, methanesulfonyl, alkylcarbonyl, alkoxycarbonyl, heteroaryl Alkyl, heterocycloalkylalkyl, aminoacyl, amino protecting group, etc.
  • the amino protecting group is preferably selected from pivaloyl, tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenemethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl, trifluoroacetyl, and the like.
  • tyrosine protein kinase used in this article is a type of kinase that catalyzes the transfer of ⁇ -phosphate from ATP to protein tyrosine residues. It can catalyze the transfer of tyrosine residues in a variety of substrate proteins. Phosphorylation plays an important role in cell growth, proliferation, and differentiation.
  • the term “inhibition,” “inhibition,” or “inhibitor” of a kinase means that the phosphotransferase activity is inhibited.
  • a “metabolite” of a compound disclosed herein is a derivative of the compound that is formed when the compound is metabolized.
  • active metabolite refers to a biologically active derivative of a compound that is formed when the compound is metabolized.
  • metabolism refers to the sum of the processes by which a specific substance is changed by an organism (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes, such as oxidation reactions). Therefore, enzymes can produce specific structural changes into compounds.
  • cytochrome P450 catalyzes various oxidation and reduction reactions
  • diphosphate glucuryltransferase catalyzes the conversion of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups.
  • Metabolites of the compounds disclosed herein can be identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound. Both methods are known in the art.
  • the metabolites of the compounds are formed by oxidation processes and correspond to the corresponding hydroxyl-containing compounds.
  • the compound is metabolized to a pharmaceutically active metabolite.
  • the term "modulate" means interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.
  • IC50 refers to the amount, concentration or dose of a particular test compound that achieves 50% inhibition of the maximal effect in an assay measuring such effect.
  • EC50 refers to the dose, concentration, or amount of a test compound that causes a maximum expression of 50% of the specific response induced, stimulated, or potentiated by a particular test compound in a dose-dependent response.
  • the GI50 used herein refers to the drug concentration required to inhibit the growth of 50% of cells, that is, the drug concentration at which the growth of 50% of cells (such as cancer cells) is inhibited or controlled.
  • Novel kinase inhibitor of the present invention Novel kinase inhibitor of the present invention
  • the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof:
  • Ar is selected from aryl and heteroaryl optionally substituted by 1 to 3 independently R 2 groups;
  • R 1 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heterocycloalkyl, hydroxy C1-C6 alkyl, nitrile C1-C6 alkyl, carboxyl C1-C6 alkyl, C3-C6 ring Alkyl C1-C6 alkyl, C1-C6 heterocycloalkyl C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkylamino C1-C6 alkyl, C1-C6 alkyl Amide C1-C6 alkyl, C1-C6 alkyl sulfone, C1-C6 alkanoyl, C1-C6 heterocycloalkylaminoacyl, C1-C6 heterocycloalkyl C1-C6 alkylamine acyl, hydroxyl C1- C6 alkylaminoacyl, C1-C6
  • Each R2 is independently selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, haloC1-C6 alkoxy, and nitrogen protecting group.
  • L is
  • Ar is selected from phenyl, pyridyl, furyl, benzofuryl, thienyl, and pyrrolyl optionally substituted by 1-2 independently R 2 groups; further preferably Ground, each R 2 is independently selected from halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, haloC1-C3 alkoxy, pivaloyl, tert-butoxycarbonyl, benzyloxy Carbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyloxycarbonyl and trifluoroacetyl.
  • Ar is selected from phenyl or pyridinyl substituted by 1 R 2 group; more preferably, Ar is selected from phenyl or pyridin-2-yl substituted by R 2 in the para position ; Further preferably, R 2 is selected from C1-C6 haloalkyl, more preferably trifluoromethane.
  • R 1 is selected from C1-C3 alkyl, C1-C3 haloalkyl, C3-C5 heterocycloalkyl, hydroxy C1-C3 alkyl, nitrile C1-C3 alkyl, carboxyl C1- C3 alkyl, C3-C5 cycloalkyl C1-C3 alkyl, C3-C5 heterocycloalkyl C1-C3 alkyl, C1-C3 alkoxy C1-C3 alkyl, C1-C4 alkylamino C1- C3 alkyl, C1-C3 alkylamido, C1-C3 alkyl, C1-C3 alkyl sulfone, C2-C4 alkanoyl, C3-C5 heterocycloalkylaminoacyl, C3-C5 heterocycloalkyl C1-C3 Alkylaminoacyl, hydroxyl C1-C3 alkylaminoacyl
  • the present invention relates to a compound of Table 1 below, or a pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug thereof.
  • a compound described herein is administered to an organism in need thereof and is metabolized in the body to produce metabolites that are then used to produce the desired effect, including the desired therapeutic effect.
  • compositions described herein can be prepared and/or used as pharmaceutically acceptable salts.
  • Types of pharmaceutically acceptable salts include, but are not limited to: (1) Acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, metaphosphoric acid, etc.; or formed by reaction with organic acids such as acetic acid, propionic acid, caproic acid, cyclopentane propionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, lemon Acid, succinic acid, maleic acid, tartaric acid, fumaric acid, trifluoroacetic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methane sulfonic acid, ethane sulfonate Acid, 1,2-ethanedisulfonic acid, 2-hydroxy
  • the corresponding counterions of pharmaceutically acceptable salts can be analyzed and identified using a variety of methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectrometry, mass spectrometry, or any thereof. combination.
  • the salt is recovered using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, solvent evaporation, or in the case of aqueous solutions, lyophilization.
  • Screening and characterization of pharmaceutically acceptable salts, polymorphs and/or solvates can be accomplished using a variety of techniques including, but not limited to, thermal analysis, X-ray diffraction, spectroscopy, microscopic methods, elemental analysis.
  • Various spectroscopic techniques used include, but are not limited to, Raman, FTIR, UVIS, and NMR (liquid and solid states).
  • Various microscopy techniques include, but are not limited to, IR microscopy and Raman microscopy.
  • the compound of formula (I) of the present invention can convert macrophages in the TME from the M2 type that promotes tumor growth to the M1 type, thereby Change the TME to achieve the purpose of treating cancer.
  • the compound of formula (I) of the present invention or its pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug can inhibit the activity of CSF1R kinase and related signaling pathways, thereby achieving the purpose of treating cancer.
  • the compound of formula (I) of the present application or its pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug is used in the preparation of inhibiting the activity of CSF1R kinase and related signaling pathways, or treating the activity of CSF1R kinase.
  • the compound of formula (I) of the present invention or its pharmaceutically acceptable salt, solvate, ester, acid, metabolite or prodrug can be used to treat cancers or tumors dominated by M2 macrophages in the tumor microenvironment. Tumor.
  • the cancer or tumor is selected from the group consisting of ovarian cancer, cervical cancer, pancreatic cancer, prostate cancer, bladder cancer, lung cancer, thyroid cancer, breast cancer, pancreatic cancer, kidney cancer, gastric cancer, liver cancer, cervical cancer, endometrial cancer, Colorectal cancer, nasopharyngeal cancer, esophageal cancer, cholangiocarcinoma, bone metastatic cancer, papillary thyroid cancer, non-small cell lung cancer, small cell lung cancer, colon cancer, solid tumors, brain tumors, lymphoma, glioma, One or more of glioblastoma, melanoma, mesothelioma, glioblastoma, osteosarcoma, gastrointestinal stromal tumor, multiple myeloma, biliary carcinosarcoma, and leukemia.
  • the lymphoma includes non-Hodgkin lymphoma, B-cell or T-cell lymphoma; the leukemia includes chronic mye
  • a medicament comprising a compound of the present invention may be administered to a patient by at least one of injection, oral administration, inhalation, rectal and transdermal administration.
  • the amount of a given drug will depend on factors such as the specific dosage regimen, the type and severity of the disease or condition, and the uniqueness of the subject or host in need of treatment (e.g., body weight). ), however, the dosage to be administered may be routinely determined by methods known in the art, depending upon the particular surrounding circumstances, including, for example, the particular drug being employed, the route of administration, the condition being treated, and the subject or host being treated.
  • the dosage administered will typically be in the range of 0.02-5000 mg/day, for example about 1-1500 mg/day.
  • the required dose may conveniently be presented as one dose, or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, for example two, three, four or more divided doses per day.
  • the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • the reactions can be used sequentially to provide the compounds described herein; or they can be used to synthesize fragments that are added subsequently by methods described herein and/or methods known in the art.
  • provided herein are methods of making the tyrosine kinase inhibitor compounds described herein and methods of using them.
  • the compounds described herein can be synthesized using the following synthetic scheme. Compounds can be synthesized using methods similar to those described below, using appropriate alternative starting materials.
  • reaction product can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and other methods. These products can be characterized using conventional methods, including physical constants and spectral data.
  • the organic phase was washed with 30 mL of water, 30 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow product (4-((7-methyl-7H-pyrrolo[2,3-D]pyrimidin-4-yl)oxy) )phenyl) tert-butyl carbamate.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 1, N-(4-((7-methyl-7H-pyrrolo[2,3-D]pyrimidine-4 -(yl)oxy)phenyl)-2-(3-(trifluoromethoxy)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 3,2-(4-(difluoromethoxy)phenyl)-N-(4-((7-methyl) yl-7H-pyrrolo[2,3-D]pyrimidin-4-yl)oxy)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain yellow solid compound 4, N-(4-((7-methyl-7H-pyrrolo[2,3-D]pyrimidine-4 -yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain yellow solid compound 5, N-(4-((7-methyl-7H-pyrrolo[2,3-D]pyrimidine-4 -(yl)oxy)phenyl)-2-(4-(trifluoromethoxy)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 7, N-(4-((7-methyl-7H-pyrrolo[2,3-D]pyrimidine-4 -yl)oxy)phenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)acetamide.
  • the organic phase was washed with 20 mL of water and 20 mL of saturated NaCl respectively, and then dried over anhydrous Na2SO4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow product (4-((7H-pyrrolo[2,3-D]pyrimidin-4-yl)oxy)phenyl)amino Tert-butyl formate.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 9, N-(4-((7-(methylsulfonyl)-7H-pyrrolo[2,3-D ]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 10, N-(4-((7-acetyl-7H-pyrrolo[2,3-D]pyrimidine-4 -yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 11, N-(4-((7-isopropyl-7H-pyrrolo[2,3-D]pyrimidine- 4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 12, N-(4-((7-(2,2,2-trifluoroethyl)-7H-pyrrolo) [2,3-D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 13, N-(4-((7-(2,2-difluoroethyl)-7H-pyrrolo[2 ,3-D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain yellow solid compound 15, N-(4-((7-ethyl-7H-pyrrolo[2,3-D]pyrimidine-4 -yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 16, N-(4-((7-propionyl-7H-pyrrolo[2,3-D]pyrimidine-4 -yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 17, N-(4-((7-isobutyryl-7H-pyrrolo[2,3-D]pyrimidine- 4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 18, N-(4-((7-butyryl-7H-pyrrolo[2,3-D]pyrimidine-4 -yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 19, N-(4-((7-(2-(diethylamino)ethyl)-7H-pyrrolo[ 2,3-D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 20, N-(4-((7-(2-fluoroethyl)-7H-pyrrolo[2,3- D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 21, N-(4-((7-(cyclopentylmethyl)-7H-pyrrolo[2,3- D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 22, N-(4-((7-(2-ethoxyethyl)-7H-pyrrolo[2, 3-D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain yellow solid compound 23, N-(4-((7-((3-methyloxetan-3-yl)methyl) yl)-7H-pyrrolo[2,3-D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 24, N-(4-((7-(2-(dimethylamino)ethyl)-7H-pyrrolo[ 2,3-D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 25, N-(4-((7-(cyanomethyl)-7H-pyrrolo[2,3-D] Pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 27, N-(4-((7-(2-hydroxyethyl)-7H-pyrrolo[2,3- D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain N-(4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)- 2-(4-(trifluoromethoxy)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain yellow solid compound 28, N-(4-((7-acetyl-7H-pyrrolo[2,3-D]pyrimidine-4 -(yl)oxy)phenyl)-2-(4-(trifluoromethoxy)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain yellow solid compound 29, N-(4-((7-(oxetan-3-yl)-7H-pyrrolo[ 2,3-D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 30, N-(4-((7-(3-hydroxypropyl)-7H-pyrrolo[2,3- D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 31, (4-(4-(2-(4-(trifluoromethyl)phenyl)acetamido)phenoxy) yl)-7H-pyrrolo[2,3-D]pyrimidin-7-yl)acetic acid.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 32, phenyl 4-(4-(2-(4-(trifluoromethyl)phenyl)acetamido)benzene.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 33, N-methyl-4-(4-(2-(4-(trifluoromethyl)phenyl)acetyl). Amino)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 34, N-ethyl-4-(4-(2-(4-(trifluoromethyl)phenyl)acetyl). Amino)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 36, N-(4-((7-isopropyl-7H-pyrrolo[2,3-D]pyrimidine- 4-yl)oxy)phenyl)-2-(4-(trifluoromethoxy)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain yellow solid compound 37, N-(4-((7-(piperidin-4-ylmethyl)-7H-pyrrolo[2 ,3-D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 41, N-(4-((7-methyl-7H-pyrrole[2,3-D]pyrimidine-4- (yl)oxy)phenyl)-2-(pyridin-3-yl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 44, 2-(benzofuran-2-yl)-N-(4-((7-methyl-7H- Pyrro[2,3-D]pyrimidin-4-yl)oxy)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain yellow solid compound 49, N-propyl-4-(4-(2-(4-(trifluoromethyl)phenyl)acetyl). Amino)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 50, N-butyl-4-(4-(2-(4-(trifluoromethyl)phenyl)acetyl). Amino)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 51, N-cyclopropyl-4-(4-(2-(4-(trifluoromethyl)phenyl)) Acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 52, N-cyclobutyl-4-(4-(2-(4-(trifluoromethyl)phenyl)) Acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 55, N-(4-((7-methyl-7H-pyrrole[2,3-D]pyrimidine-4- (yl)oxy)phenyl)-3-(6-(trifluoromethyl)pyridin-3-yl)propionamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain yellow solid compound 56, N-(4-((7-methyl-7H-pyrrolo[2,3-D]pyrimidine-4 -(yl)oxy)phenyl)-2-(5-(trifluoromethyl)pyridin-2-yl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain yellow solid compound 59, N-cyclohexyl-4-(4-(2-(4-(trifluoromethyl)phenyl)acetyl). Amino)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 60, N-isobutyl-4-(4-(2-(4-(trifluoromethyl)phenyl)) Acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 62, N-(oxetan-3-yl)-4-(4-(2-(4-(tri Fluoromethyl)phenyl)acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 63, N-((tetrahydro-2H-pyran-4-yl)methyl)-4-(4-( 2-(4-(Trifluoromethyl)phenyl)acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 64, N-(4-((7-(pyridin-3-yl)-7H-pyrrolo[2,3- D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain yellow solid compound 65, N-(4-((7-(o-tolyl)-7H-pyrrolo[2,3-D] Pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 66, N-(4-((7-(pyridin-2-yl)-7H-pyrrolo[2,3- D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 67, N-(4-((7-(thiophen-2-yl)-7H-pyrrolo[2,3- D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 68, N-(4-((7-(2-fluorophenyl)-7H-pyrrolo[2,3- D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 69, N-(morpholin-4-yl)-4-(4-(2-(4-(trifluoromethyl) (yl)phenyl)acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 70, N-(4-methylpiperazin-1-yl)-4-(4-(2-(4- (Trifluoromethyl)phenyl)acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain the yellow product N-(1-methylpiperidin-4-yl)-4-(4-(2-(4-(trifluoro) Methyl)phenyl)acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 72, N-(2-(morpholin-4-yl)ethyl)-4-(4-(2-( 4-(Trifluoromethyl)phenyl)acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 73, N-(3-(4-methylpiperazin-1-yl)propyl)-4-(4- (2-(4-(Trifluoromethyl)phenyl)acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 74, N-(2-hydroxyethyl)-4-(4-(2-(4-(trifluoromethyl) )phenyl)acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 75, N-(3-hydroxypropyl)-4-(4-(2-(4-(trifluoromethyl) )phenyl)acetamido)phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carboxamide.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound, 4-(4-(2-(4-(trifluoromethyl)phenyl)acetamido)phenoxy) -7H-pyrrolo[2,3-D]pyrimidine-7-carboxylic acid methyl ester.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product.
  • the crude product was subjected to silica gel column chromatography to obtain a yellow solid compound 77, N-(4-((7-(pyridin-4-yl)-7H-pyrrolo[2,3- D]pyrimidin-4-yl)oxy)phenyl)-2-(4-(trifluoromethyl)phenyl)acetamide.
  • Example 78 4-((7-methyl-7H-pyrrolo[2,3-D]pyrimidin-4-yl)oxy)-N-((6-(trifluoromethyl)pyridine-3- methyl)aniline
  • the organic phase was washed with 30 mL of water, 30 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow product (4-((7-methyl-7H-pyrrolo[2,3-D]pyrimidin-4-yl)oxy) )benzyl)tert-butylcarbamate.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow solid compound 82, 4-(4-(4-(2-(4-(trifluoromethyl)phenyl)acetamido)) Phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carbonyl)piperidine-1-carboxylic acid tert-butyl ester.
  • the mixed solution was extracted three times with 20 mL of ethyl acetate, and the organic phases were combined.
  • the organic phase was washed with 20 mL of water, 20 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain yellow solid compound 83, 3-(4-(4-(2-(4-(trifluoromethyl)phenyl)acetamide)) Phenoxy)-7H-pyrrolo[2,3-D]pyrimidine-7-carbonyl)piperidine-1-carboxylic acid tert-butyl ester.
  • the organic phase was washed with 30 mL of water, 30 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain phenyl (4-((7H-pyrrolo[2,3-D]pyrimidin-4-yl)oxy)phenyl)amino formate.
  • the organic phase was washed with 30 mL of water, 30 mL of saturated NaCl, and then dried over anhydrous Na 2 SO 4 .
  • the organic phase was distilled under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography to obtain a yellow product (4-((7-methyl-7H-pyrrolo[2,3-D]pyrimidin-4-yl)oxy) ) phenyl) phenyl carbamate.
  • Example 84 Effect on cancer cell proliferation
  • TEL-CSF1R-BaF3 (cell line stably expressing CSF1R kinase), TEL-cKIT-BaF3 (cell line stably expressing cKIT kinase), and TEL-FLT3-BaF3 (cell line stably expressing FLT3 kinase) are as follows : PCR amplified the human CSF1R, cKIT, and FLT3 kinase region sequences respectively, and inserted them into the MSCV-Puro vector (Clontech) with an N-terminal TEL fragment. They were stably transferred into mouse BaF3 cells (purchased from the United States) through a retroviral method. ATCC), and removed the IL-3 growth factor, and finally obtained a cell line that relied on CSF1R, cKIT, and FLT3 kinase transfer proteins.
  • the compounds of the present invention have a strong inhibitory effect on the proliferation of mouse myeloblast cell line M-NSF-60 mediated by TEL-CSF1R-BaF3 expressing CSF1R kinase and M-CSF, which shows that This series of compounds has a strong inhibitory effect on the CSF1R target and can be used to treat related diseases caused by the activation of signaling pathways mediated by CSF1R kinase.
  • the compound of the present invention can selectively inhibit the proliferation of TEL-CSF1R-BaF3 cells expressing CSF1R kinase.
  • CSF1R kinase is a key protein that controls macrophage polarization in the tumor microenvironment
  • inhibiting the activity of CSF1R kinase can reduce the transformation of macrophages into M2 macrophages that promote cancer development and increase M1 macrophages that inhibit cancer development. Transformation of macrophages.
  • interleukin 10 If the secretion concentration of interleukin 10 increases, it means that RAW264.7 cells have been induced into M2 macrophages. After the cells were successfully induced, the randomly selected compound 54 of the present invention, control compounds BLZ945 and PLX3397 (purchased from MedChem Express, China) were added with gradient dilutions and treated for 72 hours, and then the cells and supernatant were collected for qPCR and ELISA experiments respectively.
  • RNA extraction kit purchased from China Tiangen Biochemical, Cat. No.: DP451. Perform RNA extraction according to the instructions. Use the NanoDrop nucleic acid concentration meter to detect the concentration of RNA in the sample, and dilute the RNA solution to the same concentration.
  • This experiment used TaKaRa’s One Step TB PrimeScript TM PLUS RT-PCR Kit (purchased from Bao Bioengineering Co., Ltd., product number: RR096A), this kit contains the following ingredients:
  • the first step is reverse transcription reaction: 42°C for 5 minutes, 95°C for 10 seconds, 1Cycle;
  • the second step is PCR amplification: 95°C for 5 seconds, 60°C for 20 seconds, 40Cycles.
  • M0 represents the amount of IL-10 secreted by RAW264.7 cells without any treatment
  • M2 represents the polarization of RAW264.7 cells into M2 macrophages after treatment with interleukin 4 factor as described in this example.
  • the amount of IL-10 secreted other columns indicate the amount of IL-10 secreted after M2 macrophages are polarized into M2 macrophages and then treated with Compound 54 of the present invention or control compounds BLZ945 and PLC3397.
  • the secretion level of IL-10 in M2 macrophages showed a dose-dependent decrease as the drug concentration increased, indicating that M2 cells in macrophages were gradually decreasing and gradually transforming into M1 cells.
  • This example proves that the compounds involved in the present invention can reduce the transformation of macrophages into the M2 type and promote the transformation of macrophages into the M1 type, thereby inhibiting tumor growth and enhancing the efficacy of cancer immunity.
  • This example uses male SD rats, 180-220 g (purchased from the Experimental Animal Center of Anhui Medical University, China). The animals were kept in independent air-supply cages, with 6 animals per cage. The feeding conditions are as follows: temperature is 20-26°C, humidity is 35-75%, light is 12 hours, darkness is 12 hours, corncob bedding is changed once a week, food and water are freely available, and tail numbers are marked. During the experiment, the raising and use of animals strictly followed the regulations of the International Laboratory Animal Assessment and Certification Management Committee.
  • the compounds are formulated as follows. Precisely weigh 10 mg of the compound to be tested and place it in a sterile vial, then dissolve it with a small amount of DMSO, and then add 5% glucose solution to adjust the volume to 5 ml to obtain a test solution for intragastric administration with a concentration of 2 mg/mL; measure accurately Take 0.5 ml of the above test solution for intragastric administration of 2 mg/mL, and add 4.5 ml of 5% glucose solution to adjust the volume to 5 ml to obtain an intravenous test solution with a concentration of 0.2 mg/mL. It is ready for use during the experiment.
  • rat plasma Take 100 ⁇ L of rat plasma to be tested stored at –80°C, add 20 ⁇ L of internal standard caffeine solution (200ng/mL), vortex for 10 s, then add 400 ⁇ L of methanol, vortex for 10 min, centrifuge at 16000 rpm for 5 min, and take the supernatant. 70 ⁇ L was put into the inner tube of the injection bottle, and 5 ⁇ L was injected for LC-MS/MS analysis.
  • the LC-MS/MS measurement method is as follows.
  • Experimental instrument API 4000 triple quadrupole detector (AB SCIEX, USA), operating software Analyst 1.5.1 (Applied Biosystems, USA); Shimadzu LC-30AD liquid phase pump, Shimadzu DGU-20A decontamination Gas unit, Shimadzu CTO-30A column oven, SIL-30AC automatic sampler (Shimadzu Corporation, Japan).
  • Chromatographic conditions The chromatographic column is Hanbang Hedera ODS-2 (Jiangsu Hanbang Technology Co., Ltd., China), Dim.
  • Mass spectrometry conditions ion source is Turbo Spray source, CAD is 10; curtain gas (CUR) is 25; heating temperature is 500°C; ion source gas GS1 is 45; ion source gas GS2 is 45; spray voltage 5500V; source temperature is 500°C °C.
  • Example 87 In vivo drug efficacy detection
  • mice purchased 6-week-old Balb/c nu male mice used in the M-NFS-60 cell transplanted tumor model and C57BL/6J male mice used in the MC38 cell transplanted tumor model from Jiangsu Jicui Yaokang Biotechnology Co., Ltd. Rats, the above mice are all raised in SPF-level laboratories, drinking water and bedding are sterilized by high-pressure sterilization, and all operations related to mice are performed under sterile conditions.
  • M-NFS-60 cells purchased from ATCC
  • MC38 cells purchased from ATCC
  • mice were orally administered methylcellulose (HKI) (purchased from Sinopharm, China) vehicle once a day (5 mice) ; Compound 54 at doses of 25, 50, and 100 mg/kg mouse weight once a day (5 mice); PLX-3397 at a dose of 50 mg/kg mouse weight once a day (5 mice).
  • MHI methylcellulose
  • mice were orally administered with 10% HS-15 (purchased from BASF, Germany) vehicle (5 mice) every day; the dose of compound 54 was 25 mg/kg mouse weight.
  • HS-15 purchasedd from BASF, Germany
  • mice were euthanized, and the tumor tissue of the mice was peeled off with tissue tweezers and placed on an analytical balance to weigh the tumor mass. The results are shown in Figures 4 and 7.
  • Inhibiting CSF1R kinase can transform M1 macrophages that are beneficial to tumor proliferation into tumor-killing M2 macrophages. This example also proves that inhibiting CSF1R can inhibit MC38 immunity. Proliferation of tumors in the model.
  • the present invention provides a type of selective CSF1R inhibitor, which can selectively inhibit the activity of CSF1R kinase and related signaling pathways, and therefore can activate autoimmunity by inhibiting the phosphorylation of CSF1R and be used to treat cancer. Therefore, the present invention is suitable for industrial applications.

Abstract

L'invention concerne un composé représenté par la formule (I) ou un sel, solvate, ester, acide, métabolite ou promédicament pharmaceutiquement acceptable de celui-ci, et son utilisation dans l'inhibition de l'activité de la kinase CSF1R et de voies de signalisation associées, ou dans le traitement d'un cancer ou d'une tumeur avec un micro-environnement tumoral dominé par des macrophages de type M2 ; L, Ar et R1 étant tels que définis dans la description.
PCT/CN2022/083651 2022-03-17 2022-03-29 Inhibiteur sélectif de csf1r et son utilisation WO2023173480A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210262929.6A CN116789670A (zh) 2022-03-17 2022-03-17 一种选择性csf1r抑制剂及其用途
CN202210262929.6 2022-03-17

Publications (1)

Publication Number Publication Date
WO2023173480A1 true WO2023173480A1 (fr) 2023-09-21

Family

ID=88022047

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/083651 WO2023173480A1 (fr) 2022-03-17 2022-03-29 Inhibiteur sélectif de csf1r et son utilisation

Country Status (2)

Country Link
CN (1) CN116789670A (fr)
WO (1) WO2023173480A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101296928A (zh) * 2005-10-28 2008-10-29 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
US20090137580A1 (en) * 2005-07-05 2009-05-28 Takeda Pharmaceutical Company Limited Fused Heterocyclic Derivatives and Use Thereof
CN102827186A (zh) * 2011-06-16 2012-12-19 中国科学院上海药物研究所 一类吡啶并五元杂环衍生物及其制备方法和用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090137580A1 (en) * 2005-07-05 2009-05-28 Takeda Pharmaceutical Company Limited Fused Heterocyclic Derivatives and Use Thereof
CN101296928A (zh) * 2005-10-28 2008-10-29 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
CN102827186A (zh) * 2011-06-16 2012-12-19 中国科学院上海药物研究所 一类吡啶并五元杂环衍生物及其制备方法和用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
OGURO, Y. ; MIYAMOTO, N. ; OKADA, K. ; TAKAGI, T. ; IWATA, H. ; AWAZU, Y. ; MIKI, H. ; HORI, A. ; KAMIYAMA, K. ; IMAMURA, S.: "Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine derivatives: Novel VEGFR2 kinase inhibitors binding to inactive kinase conformation", BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 18, no. 20, 15 October 2010 (2010-10-15), AMSTERDAM, NL, pages 7260 - 7273, XP027357149, ISSN: 0968-0896 *

Also Published As

Publication number Publication date
CN116789670A (zh) 2023-09-22

Similar Documents

Publication Publication Date Title
US10968221B2 (en) Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
EP3207035B1 (fr) Composés et compositions destinés à moduler les activités kinase de l'egfr mutant
RU2633694C2 (ru) Дейтерированный фениламинопиримидин и фармацевтическая композиция, содержащая такое соединение
WO2015022926A1 (fr) Nouveau composé pyrimidine fusionnée ou son sel
JP2021050231A (ja) 結晶性ｆｇｆｒ４阻害剤化合物およびその使用
WO2014135028A1 (fr) Composé de pyridopyrimidine ou de pyrimidopyrimidine, procédé de préparation, composition pharmaceutique et utilisation de celui-ci
US11267815B2 (en) Class of amino-substituted nitrogen-containing fused ring compounds, preparation method therefor, and use thereof
CN109721600B (zh) 一类含氮稠环化合物及其制备方法和用途
CN110546145B (zh) 一种氮杂芳基衍生物、其制备方法和在药学上的应用
US20220017520A1 (en) Macrocyclic compound as cdk inhibitor, preparation method therefor, and use thereof in medicine
US20220289719A1 (en) Heterocyclic compounds as mnk inhibitors
US11572359B2 (en) PARP/PI3K double-target inhibit containing pyridopyrimidine structure
CN111825719A (zh) 一种含有芳胺基取代的吡咯并嘧啶类化合物、制备方法及其应用
WO2023173480A1 (fr) Inhibiteur sélectif de csf1r et son utilisation
WO2019223777A1 (fr) Composé pyrrolopyrimidine contenant une substitution arylamine, son procédé de préparation et son application
WO2022068860A1 (fr) Forme cristalline d'un dérivé pyrrolo-hétérocyclique et son procédé de préparation
WO2021249319A1 (fr) Composé tricyclique, composition pharmaceutique et utilisation de celui-ci
WO2021239727A1 (fr) Dérivés de 4-(7h-pyrrolo[2,3-d]pyrimidin-4-yl)-3,6-dihydropyridine-1-(2h)-carboxamide servant d'inhibiteurs de kinases limk et/ou rock destinés à être utilisés dans le traitement du cancer
US11021479B2 (en) Pyridoquinazoline derivatives useful as protein kinase inhibitors
WO2020118753A1 (fr) Inhibiteur de kinase pan-kit ayant une structure quinoléine et son utilisation
WO2023168740A1 (fr) Nouvelle utilisation d'un composé de quinoléine
WO2023206655A1 (fr) INHIBITEUR DE PI3Kδ ET SON UTILISATION
TWI820414B (zh) 喹唑啉類化合物、製備方法及其應用
CN112794855A (zh) N-芳基嘧啶-4-胺类衍生物及其应用
CN116655638A (zh) 氘代prmt5抑制剂

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22931509

Country of ref document: EP

Kind code of ref document: A1