WO2023143194A1 - Petite molécule antagoniste du ccr4 et son utilisation - Google Patents

Petite molécule antagoniste du ccr4 et son utilisation Download PDF

Info

Publication number
WO2023143194A1
WO2023143194A1 PCT/CN2023/072403 CN2023072403W WO2023143194A1 WO 2023143194 A1 WO2023143194 A1 WO 2023143194A1 CN 2023072403 W CN2023072403 W CN 2023072403W WO 2023143194 A1 WO2023143194 A1 WO 2023143194A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
room temperature
isomer
formula
Prior art date
Application number
PCT/CN2023/072403
Other languages
English (en)
Chinese (zh)
Inventor
陈鑫德
柳梦林
宋云鹏
郝欣
Original Assignee
瑞石生物医药有限公司
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 瑞石生物医药有限公司 filed Critical 瑞石生物医药有限公司
Publication of WO2023143194A1 publication Critical patent/WO2023143194A1/fr

Links

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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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 medicine, and in particular relates to a CCR4 small molecule antagonist and its application.
  • CCR4 (C-C chemokine receptor type 4) belongs to G protein-coupled receptors and is a member of the chemokine receptor family. It is widely expressed on the surface of immune cells, especially Th2 cells and Treg cells.
  • the main endogenous ligands of CCR4 include CCL22 (also known as macrophage-derived chemokine, MDC) and CCL17 (also known as thymus activation-regulated chemokine, TARC).
  • CCL22 also known as macrophage-derived chemokine, MDC
  • CCL17 also known as thymus activation-regulated chemokine, TARC.
  • the combination of CCR4 and endogenous ligand can activate the coupled G protein, and then a cascade of cell activation effects occurs. Through a series of information transmission, chemotactic target cells migrate to a specific location and exert biological effects.
  • CCR4 is closely related to the occurrence and development of immune-related diseases such as atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus and rheumatoid arthritis.
  • CCR4 plays a regulatory role in the tumor microenvironment, inducing tumor immune escape and promoting tumor cell metastasis. Therefore, CCR4 has become an important drug target for the treatment of immune-related diseases and tumor immunotherapy, and the development of CCR4 small molecule antagonists will provide new options for the treatment of the above diseases.
  • Mogamulizumab a CCR4 monoclonal antibody
  • Mogamulizumab a CCR4 monoclonal antibody
  • WO2018/022992 involves FLX475, which is currently the fastest-growing small-molecule antagonist of CCR4 in clinical practice.
  • RPT193 is another small-molecule antagonist of CCR4 in clinical research.
  • most small-molecule antagonists of CCR4 are in the stage of biological activity testing. It can be seen that the development of small molecule antagonists of CCR4 has a good application prospect.
  • the purpose of the present invention is to provide a new type of CCR4 small molecule antagonist, this type of compound has good activity in inhibiting CCR4, and exhibits excellent effects and functions.
  • the present invention provides a compound of formula (I) or an isotopically labeled compound thereof, or an optical isomer, geometric isomer, tautomer or isomer mixture thereof, or a pharmaceutically acceptable salts, or their prodrugs, or their metabolites,
  • X 1 and X 2 are each independently selected from C or N;
  • X 3 , X 4 and X 5 are each independently selected from CR b or N;
  • Each R 1 is independently selected from H, halogen, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 4 cycloalkyl or cyano;
  • R 2 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 3 -C 4 cycloalkyl;
  • R 3 is selected from H, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 3 -C 4 cycloalkyl;
  • R4 is selected from
  • Y is selected from CH2 or O
  • R a is selected from H, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl or cyano, wherein said C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclic , 5-6 membered heteroaryl or phenyl are each independently optionally selected from one or more groups selected from halogen, hydroxyl, cyano, C 1 -C 3 alkyl or C 1 -C 3 alkoxy replaced by
  • Each R b is independently selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl or cyano, wherein the C 1 -C 3 alk radical, C 1 -C 3 alkoxy or C 3 -C 6 cycloalkyl each independently optionally selected from halogen, hydroxy, amino, cyano, C 1 -C 3 alkyl or C 1 -C 3 One or more groups of alkoxy are substituted;
  • Each R c is independently selected from H, halogen, C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl, wherein each of the C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl is independently optionally substituted by one or more groups selected from halogen, hydroxyl, cyano, C 1 -C 3 alkyl or C 1 -C 3 alkoxy;
  • Each R d is independently selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl or cyano, wherein the C 1 -C 3 alk radical, C 1 -C 3 alkoxy or C 3 -C 6 cycloalkyl each independently optionally selected from halogen, hydroxy, amino, cyano, C 1 -C 3 alkyl or C 1 -C 3 One or more groups of alkoxy are substituted;
  • each Re is independently -LR f ;
  • Each R f is independently selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, 4-7 membered Heterocyclyl, R g C(O)NH-, R g NHC(O)-, R g OC(O)NH-, R g S(O) 2 NH-, R g NHS(O) 2 -, R g g S(O) 2 -, -(CH 2 ) n -hydroxyl, -(CH 2 ) n -amino, -(CH 2 ) n -cyano, -(CH 2 ) n -carboxy or 2-oxa- Spiro[3,3]heptyl, wherein the C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membere
  • Each R g is independently selected from C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl or 3-6 membered heterocyclyl;
  • Each L is independently selected from a chemical bond, a 4-7 membered heterocyclic group, a C 1 -C 3 alkylene group or a C 3 -C 6 cycloalkylene group, wherein the 4-7 membered heterocyclic group, C 1 -C 3 alkylene or C 3 -C 6 cycloalkylene are each independently optionally selected Substituted by one or more groups from halogen, hydroxyl, amino, cyano, C 1 -C 3 alkyl or C 1 -C 3 alkoxy;
  • Z 1 is any integer from 0 to 3;
  • Z 2 is any integer from 0 to 3;
  • Z 3 is any integer from 0 to 4.
  • Z 4 is any integer from 0 to 2;
  • n is independently any integer from 0 to 3.
  • One of X1 and X2 is N, the other is C,
  • At least one of X 3 , X 4 and X 5 is N.
  • the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt , or its prodrug, or its metabolite is a compound of formula (II) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical acceptable salts, or prodrugs thereof, or metabolites thereof,
  • R 1 -R 3 , X 1 -X 5 , Y, R a , R c , R d , R e , Z 1 , Z 2 , Z 3 and Z 4 are as defined in formula (I);
  • R c , R d , Re , Z 2 and Z 3 are as defined in formula (I);
  • R 1 -R 3 , R a , R d , R e , Z 1 and Z 3 are as defined in formula (I).
  • the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt , or its prodrug, or its metabolite is a compound of formula (III) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical acceptable salts, or prodrugs thereof, or metabolites thereof,
  • R 1 -R 3 , R a , R e and Z 1 are as defined in formula (I).
  • the compound of formula (I) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt , or its prodrug, or its metabolite is a compound of formula (IV) or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutical acceptable salts, or prodrugs thereof, or metabolites thereof,
  • R 1 -R 3 , R a , R e and Z 1 are as defined in formula (I).
  • each Re is independently -LR f ;
  • Each R f is independently selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl, C 3 -C 6 cycloalkyl, 4-7 membered hetero Cyclo, R g C(O)NH-, R g NHC(O)-, R g OC(O)NH-, R g S(O) 2 NH-, R g NHS(O) 2 -, R g S(O) 2 -, -(CH 2 ) n -hydroxyl, -(CH 2 ) n -amino, -(CH 2 ) n -cyano, -(CH 2 ) n -carboxy or 2-oxa-spiro [3,3] Heptyl, wherein the C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, 4-7 membered heterocyclyl
  • R g is selected from C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl or 3-4 membered heterocyclic group, preferably selected from methyl, ethyl, cyclopropyl, cyclobutanyl or oxa cyclobutanyl;
  • each n is independently any integer from 0 to 3
  • L is selected from the group consisting of chemical bond, methylene optionally substituted by methyl or ethyl, ethylene, propylene, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, azepine Cyclobutane, pyrrolidinylene or piperidinylene;
  • Each Re is independently selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl,
  • Each R 1 is independently selected from H, halogen, C 1 -C 3 alkylsulfonyl, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl or C 1 -C 3 alkoxy, preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl or methanesulfonyl; and/or
  • R is selected from H or C 1 -C 3 alkyl, preferably from H or methyl;
  • R 3 is selected from H or C 1 -C 3 alkyl, preferably from H or methyl.
  • Each R a is independently selected from H, halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, C 3 -C 4 cycloalkyl or cyano, wherein The C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 3 -C 4 cycloalkyl are each independently optionally replaced by halogen, hydroxyl, cyano, C 1 -C 3 alkyl or C 1 - C3alkoxy substitution, R is preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl, difluoromethyl, trifluoromethyl, trifluoroethyl, Methoxy, ethoxy, hydroxymethyl, 1,1-dimethylhydroxymethyl, cyano, or methoxymethylene; and/or
  • Each R b is independently selected from H, halogen, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl or cyano, wherein the C 1 -C 3 alkyl or C 3 -C 4 cycloalkyl Each is independently optionally substituted by halogen, hydroxyl, amino, cyano or C 1 -C 3 alkyl, R b is preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, isopropyl, cyclopropyl group, difluoromethyl, trifluoromethyl, trifluoroethyl or cyano; and/or
  • Each R c is independently selected from H, halogen or C 1 -C 3 alkyl, preferably selected from H, fluorine, chlorine, methyl or ethyl; and/or
  • Each R d is independently selected from H, halogen, C 1 -C 3 alkyl or cyano, preferably selected from H, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl or cyano .
  • Z 1 is 2; and/or
  • Z2 is 0 or 1;
  • Z3 is 0 or 1;
  • Z 4 is 1; and/or
  • n is independently 0 or 1.
  • the "compound of formula (I), (II), (III), (IV)” or “compound of the present invention” described hereinafter may also cover formula (I), (II), (III), (IV) Any isotope-labeled compound of the compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its prodrug, or its Metabolites.
  • optical isomer means that when a compound has one or more chiral centers, each chiral center can have an R configuration or an S configuration, and the various isomers thus constituted are optical isomers. Construct. Optical isomers include all diastereoisomers, enantiomers, mesoforms, racemates or mixtures thereof. For example, optical isomers can be separated by chiral chromatographic columns or by chiral synthesis.
  • Geometric isomer means that when a double bond exists in the compound, the compound may exist as a cis-isomer, a trans-isomer, an E-isomer and a Z-isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers, or mixtures thereof.
  • tautomer refers to isomers that result from the rapid movement of an atom in a molecule between two positions. Those skilled in the art can understand that tautomers can transform into each other, and may reach an equilibrium state and coexist in a certain state.
  • references herein to "compounds of formula (I)" or “compounds of the present invention” also encompass isotopically labeled compounds in which any atom in the compound is replaced by its isotopic atom.
  • the present invention includes all pharmaceutically acceptable isotope-labeled compounds of compounds of formula (I) in which one or more atoms are replaced by atoms having the same atomic number but a different atomic mass or mass number as atoms normally found in nature. replace.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H(D) and 3 H(T), isotopes of carbon, such as 11 C, 13 C and 14 C, isotopes of chlorine, such as 36 Cl, isotopes of fluorine such as 18 F, isotopes of iodine such as 123 I and 125 I, isotopes of nitrogen such as 13 N and 15 N, isotopes of oxygen such as 15 O, 17 O and 18 O, and of sulfur Isotopes such as35S .
  • isotopes of hydrogen such as 2 H(D) and 3 H(T)
  • isotopes of carbon such as 11 C, 13 C and 14 C
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13
  • Isotope-labeled compounds of formula (I), (II), (III), (IV) can generally be prepared by conventional techniques known to those skilled in the art or by using a suitable isotope-labeled reagent instead of a previously used non-labeled reagent The preparation was carried out as described in the Examples and Preparations appended hereto.
  • Formula (I), (II), (III), (IV) compound can exist in the form of pharmaceutically acceptable salt, for example, the acid addition of formula (I), (II), (III), (IV) compound Salt formation and/or base addition salts.
  • pharmaceutically acceptable salt includes acid addition salts or base addition salts that may occur in compounds of formula (I), (II), (III), (IV).
  • the pharmaceutically acceptable salts of the compound of formula (I), (II), (III), (IV) include its acid plus Salt and base addition salt.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate , camphorsulfonate, citrate, cyclamate, ethanedisulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, six Fluorophosphate, 2-(4-Hydroxybenzyl)benzoate, Hydrochloride/Chloride, Hydrobromide/Bromide, Hydroiodide/Iodide, 2-Isethionate, Lactate , malate, maleate, malonate, methanesulfonate, methylsulfate,
  • Suitable base addition salts are formed from bases which form non-toxic salts. Examples include, but are not limited to: aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts. Half-salts of acids and bases, such as the hemisulfate and hemicalcium salts, may also be formed.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties, Selection and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds described herein are known to those skilled in the art.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • compounds of formula (I), (II), (III), (IV) are included within the scope of the present invention whether they exist in solvated or unsolvated form.
  • Certain compounds of the present invention may exist in different crystalline or amorphous forms, and no matter in which form they exist, the compounds of formula (I), (II), (III) and (IV) are included within the scope of the present invention.
  • pharmaceutically acceptable means that the corresponding compound, carrier or molecule is suitable for administration to a human.
  • the term refers to the use in mammals, preferably humans, certified by any national regulatory agency such as CFDA (China), EMEA (Europe), FDA (USA), etc.
  • Prodrug refers to a derivative that is converted into the compound of the present invention by reacting with enzymes, gastric acid, etc. under physiological conditions in vivo, for example, by oxidation, reduction, hydrolysis, etc. catalyzed by enzymes.
  • Metal refers to all molecules derived from any compound of the invention in a cell or organism, preferably a human.
  • hydroxyl refers to -OH; the term “amino” refers to -NH2 ; the term “nitro” refers to -NO2 ; and the term “cyano” refers to -CN; the term “carboxy” refers to -COOH.
  • substituted means that one or more (preferably 1 to 5, more preferably 1 to 3, even more effectively 1 or 2) hydrogen atoms in a group are independently replaced by the corresponding number of substituents are substituted.
  • the term “optional” or “optionally” means that the event it describes can or cannot occur.
  • a group “optionally substituted” means that the group can be unsubstituted or substituted.
  • alkyl refers to saturated aliphatic hydrocarbons, including straight and branched chains.
  • an alkyl group has 1-8, or 1-6, or 1-3 carbon atoms.
  • C 1-8 alkyl refers to a straight-chain or branched chain radical having 1-8 carbon atoms
  • C 1-6 alkyl refers to a straight-chain or branched chain having 1-6 carbon atoms.
  • a branched chain radical the term “C 1-3 alkyl” refers to a straight chain or branched chain radical having 1 to 3 carbon atoms.
  • C 1-8 alkyl includes within its definition the terms “C 1-6 alkyl", “C 1 -C 3 alkyl” and "C 1 -C 4 alkyl”.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, iso Pentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3- Dimethylbutyl, hexyl, etc.
  • Alkyl groups may optionally be substituted with one or more (eg, 1 to 5, preferably 1 to 3, even more effectively 1 or 2) suitable substituents.
  • haloalkyl refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom) .
  • C 1- C 6 haloalkyl refers to a C 1- C 6 alkyl group (up to perhaloalkyl, i.e., each hydrogen atom of the alkyl group has one or more halogen substituents replaced by halogen atoms).
  • C 1- C 4 haloalkyl refers to a C 1- C 4 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., each hydrogen of the alkyl group atoms are all replaced by halogen atoms);
  • C 1- C 3 haloalkyl refers to a C 1- C 3 alkyl group (up to perhaloalkyl, i.e., alkyl each hydrogen atom of the group is replaced by a halogen atom);
  • C 1- C 2 haloalkyl refers to a C 1- C 2 alkyl group having one or more halogen substituents (i.e., methyl or ethyl) (up to perhaloalkyl, ie, each hydrogen atom of the alkyl group is replaced by a halogen atom).
  • C haloalkyl refers to a methyl group having 1, 2 or 3 halo substituents .
  • haloalkyl groups include: CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl , and the like.
  • alkylene refers to a divalent alkyl group, wherein alkyl is as defined above.
  • the alkylene group is preferably an alkylene group having 1-6 carbon atoms (i.e. C 1- C 6 alkylene group), more preferably an alkylene group having 1-3 carbon atoms (i.e. C 1- C 3 alkylene group alkyl).
  • alkylene groups include, but are not limited to -CH2- , -CH( CH3 ) -, -C( CH3 ) 2- , -CH2CH2- , -CH( CH2CH3 )-, -CH 2 CH(CH 3 )-, -CH 2 C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, etc.
  • n-membered cycloalkyl refers to an all-carbocyclic ring system having n carbon atoms.
  • C 3 -C 6 cycloalkyl refers to a fully carbocyclic ring system having 3-6 carbon atoms
  • C 3 -C 4 cycloalkyl refers to a fully carbocyclic ring system having 3-4 carbon atoms .
  • Examples of C 3 -C 6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl.
  • cycloalkyl groups may be optionally substituted with one or more suitable substituents.
  • cycloalkylene refers to a divalent cycloalkyl group, wherein cycloalkyl is as defined above.
  • n-membered heterocyclyl refers to a heterocycloalkyl group having m ring-forming carbon atoms and (nm) ring-forming heteroatoms selected from O, S, S(O) 2 and N.
  • 4-7 membered heterocyclic groups include, but are not limited to, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, Piperidine, morpholine, piperazine, oxepane, thiepane, azepane, 1,1-dioxothietane.
  • heterocyclyl may be optionally substituted with one or more suitable substituents.
  • heterocyclylene refers to a divalent heterocyclyl group, wherein heterocyclyl is as defined above.
  • n-membered heteroaryl refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (n-m) heteroatoms forming an aromatic ring selected from O, S and N.
  • 5-6 membered heteroaryl groups include, but are not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, pyridine.
  • heteroaryl groups may be optionally substituted with one or more suitable substituents.
  • the number ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms represent enumeration of all integers within the range one by one, and the range is only used as a simplified representation.
  • “1-4 substituents” means 1, 2, 3 or 4 substituents
  • "3-8 ring atoms” means 3, 4, 5, 6, 7 or 8 ring atoms . Therefore, the number ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms also cover any sub-range thereof, and each sub-range is also deemed to be disclosed herein.
  • the compounds of the present invention can be prepared in a variety of ways known to those skilled in the art of organic synthesis. Those skilled in the art can refer to the synthetic routes of the specific compounds in the specific examples of the present invention, and make appropriate adjustments to the reaction raw materials and reaction conditions to obtain the synthetic methods of other compounds.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), (II), (III), (IV) or its isotope-labeled compound, or its optical isomers, geometric isomers isomer, tautomer or isomer mixture, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers can be organic or inorganic inert carrier materials, for example, suitable carriers include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, Mannitol, cellulose, cellulose derivatives, sodium saccharin, glucose, sucrose, magnesium carbonate, saline, glycerin, ethanol, etc.
  • the pharmaceutical composition may also contain other pharmaceutical additives, such as flavoring agents, preservatives, stabilizers, emulsifiers, buffers, diluents, binders, wetting agents, disintegrants, lubricants, glidants and the like.
  • the dosage form of the pharmaceutical composition of the present invention may be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true solutions and colloid solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including aqueous injections, powder injections and infusion solutions), eye drops Agents, nasal drops, lotions and liniments, etc.
  • solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pills, suppositories, films, patches, aerosols, sprays, etc.
  • semi-solid dosage forms can be ointments, Gels, pastes, etc.
  • the pharmaceutical composition of the present invention can be made into common preparations, sustained
  • the dosage form of the pharmaceutical composition is selected from tablet, granule, powder, syrup, inhalation and injection.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one inert excipient (or carrier) (for example, sodium citrate or dicalcium phosphate), which may also include: (a) fillers or mixing agents (for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid); (b) binders (e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic); (c) Moisturizers (eg, glycerol); (d) disintegrants (eg, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain synthetic silicates, sodium carbonate); (e) solutions Blocking agents (e.g., paraffin); (f) absorption enhancers (e.g., quaternary ammonium compounds); (g) we
  • Formulations suitable for parenteral administration may include aqueous and nonaqueous isotonic sterile solutions suitable for injection, as well as aqueous and nonaqueous sterile suspensions.
  • the parenteral formulations provided herein are optionally contained in unit-dose or multi-dose sealed containers, such as ampoules, and can be stored in freeze-dried (lyophilized) containers that require only the addition of a sterile liquid carrier (such as water for injection) immediately before use. ) conditions.
  • Suitable diluents for reconstitution of the pharmaceutical composition include bacteriostatic water for injection, 5% dextrose in water, phosphate buffered saline, Ringer's solution, saline, sterile water, Deionized water and combinations thereof.
  • Sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Inhalants may contain excipients such as lactose, or aqueous solutions containing, for example, polyethylene oxide-9-lauryl ether, glycocholate and deoxycholate, or oily solutions as nasal drops or spray , or in gel form.
  • the content of the compound of the present invention in its pharmaceutical composition can be adjusted according to actual needs (such as dosage form, administration method, administration object, etc.), such as 0.1-95% by weight, such as 1-95% by weight, 5-90% by weight , 10-80% by weight, etc.
  • 0.01-10 g (eg, 0.05 g, 0.1 g, 0.5 g, 1 g or 5 g, etc.) of the compound of the present invention may be included in the pharmaceutical composition of the present invention.
  • the present invention relates to compounds of formula (I), (II), (III), (IV) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomers thereof Use of a mixture of conformers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof in the preparation of a medicament for treating or preventing a disease or condition mediated by CCR4 as a CCR4 antagonist.
  • Compounds of formula (I), (II), (III), (IV) or their isotope-labeled compounds, or their optical isomers, geometric isomers, Tautomers or mixtures of isomers, or pharmaceutically acceptable salts thereof, or prodrugs thereof, or metabolites thereof may be used to treat or prevent diseases mediated by CCR4 in a subject in need thereof or illness.
  • subject refers to any human or non-human organism that could potentially benefit from treatment with a compound of formula (I), (II), (III), (IV).
  • exemplary subjects include humans or mammals of any age.
  • the subject is a human.
  • treatment includes treating a disease or condition in a mammal, especially a human and includes: (a) inhibiting an infection, disease or condition, i.e. arresting or delaying the development of an infection, disease or condition; (b) alleviating an infection, disease or condition; A disease or condition, ie causing regression of the disease or condition, and/or (c) cure of the infection, disease or condition.
  • prevention includes prophylactic therapy in mammals, especially humans, aimed at reducing the likelihood of an infection, disease or condition occurring. Patients may be selected for prophylactic therapy based on an increased risk of infection or having a disease or condition compared to the general population as a factor. "Preventing” can include treating a subject who has not yet exhibited an infection or clinical condition, and preventing a second occurrence of the same or similar infection or clinical condition.
  • the compounds of the present invention can inhibit CCR4-mediated cell migration. Therefore, the compounds of the present invention can be used in the prevention or treatment of diseases or conditions mediated by CCR4.
  • the disease or condition mediated by CCR4 may be selected from one or more of atopic dermatitis, asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus and rheumatoid arthritis.
  • atopic dermatitis asthma, allergic rhinitis, atopic dermatitis, systemic lupus erythematosus and rheumatoid arthritis.
  • Various immune-related diseases may be cancer.
  • the cancer is preferably selected from cholangiocarcinoma, liver cancer, breast cancer, prostate cancer, lung cancer, nasopharyngeal cancer, thyroid cancer, gastric cancer, ovarian cancer, colorectal cancer, endometrial cancer, urothelial cell carcinoma, testicular cancer, Cervical cancer, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, esophageal cancer, head and neck cancer, kidney cancer, pancreatic cancer, bone cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelial tumor, glia tumors, ependymomas, neuroblastomas, ganglioneuromas, medulloblastomas, pineal cell tumors, meningiomas, neurofibromas, schwannomas, and Wilms tumors.
  • the present invention provides a method of treating or preventing a disease or condition mediated by CCR4, the method comprising administering to a subject in need a therapeutically effective amount of formula (I), (II), (III), (IV) compound or its isotope-labeled compound, or its optical isomer, geometric isomer, tautomer or isomer mixture, or its pharmaceutically acceptable salt, or its precursor drugs, or their metabolites.
  • the present invention relates to compounds of formula (I), (II), (III), (IV) or isotopically labeled compounds thereof, or optical isomers, geometric isomers, tautomers or isomers thereof A mixture of conformers, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, or a metabolite thereof, wherein it is used for preventing or treating a disease or condition mediated by CCR4.
  • the compounds of the present invention can be administered orally, parenterally, intravenously, intramuscularly, subcutaneously, nasally, buccally, ocularly, via the lungs, via the respiratory tract, vaginally, rectally, intraperitoneally, intralesionally, Administer around the lesion and other routes.
  • a “therapeutically effective amount” refers to an amount of a compound of the present invention effective to treat or prevent a disease or condition mediated by CCR4 when administered alone or in combination.
  • the daily dose of the compound of the invention may specifically be 0.001-150 mg/kg body weight (eg 0.1 mg/kg body weight, 1 mg/kg body weight, 10 mg/kg body weight or 100 mg/kg body weight etc.).
  • the specific administration frequency can be determined by those skilled in the art, for example, once a day, once a day, once a day, once a day, once a day, once a day, once a day, once a day, twice a day, 1 day 3 times etc.
  • Figure 1 shows the inhibitory effect of test compounds on FITC-induced ear swelling in an animal model.
  • Figure 2 shows the effect of test compounds on body weight in FITC-induced animal models.
  • Figure 3 shows the inhibitory effect of test compounds on OXA-induced ear swelling in animal models.
  • the compounds of formula (I) of the present invention can be synthesized by various methods familiar to those skilled in the art of organic synthesis. Some exemplary synthetic methods of compounds of formula (I) are given in the following specific examples, and these methods are well known in the field of synthetic chemistry. Consequently, with reference to the exemplary schemes in this patent, those skilled in the art can easily design the synthetic routes of other compounds of formula (I) by appropriately adjusting the reactants, reaction conditions and protecting groups.
  • compound B-1 (25.00g, 158.95mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (25.00g, 88.31mmol) were dissolved in isopropanol (400mL), and added Nickel iodide (2.76g, 8.83mmol), (1R,2R)-2-aminocyclohexanol hydrochloride (1.34g, 8.83mmol) and sodium bis(trimethylsilyl)amide (176.60mL, 176.61mmol , 1mol/L tetrahydrofuran solution), the reaction mixture was stirred at 80°C for 18 hours under nitrogen protection.
  • compound B-2 26.00g, 96.75mmol
  • (S)-4-isopropyloxazolidin-2-one 24.99g, 193.50mmol
  • anhydrous toluene 400mL
  • tris(dibenzylideneacetone)dipalladium 4.43g, 4.84mmol
  • 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl 2.31g, 4.84mmol
  • cesium carbonate 31.52 g, 96.75mmol
  • reaction mixture was cooled to room temperature, filtered, the filter cake was washed with methyl tert-butyl ether (500 mL), the organic phase was washed with saturated brine (500 mL ⁇ 4), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue
  • compound B-3 (10.00g, 27.67mmol) was dissolved in anhydrous acetic acid (200mL), under the protection of nitrogen, slowly added platinum dioxide (1.00g, 4.40mmol), hydrogen replacement, the reaction mixture in hydrogen (15Psi ) atmosphere at room temperature for 15 hours.
  • the reaction solution was filtered, the filter cake was washed with methanol (100 mL), and the filtrate was concentrated under reduced pressure.
  • the crude product was dissolved in dichloromethane (50 mL), and 1 mol/L aqueous sodium hydroxide solution (80 mL) was added to adjust the pH to 13.
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude intermediate B.
  • the crude intermediate B was dissolved in methyl tert-butyl ether (1000 mL), and S-mandelic acid (13.61 g, 89.45 mmol) was added in portions under reflux, and the reaction mixture was stirred at room temperature for 16 hours.
  • a large amount of white solid precipitated, filtered, and the filter cake was washed with methyl tert-butyl ether (400 mL), and dissolved in dichloromethane (500 mL) and 1 mol/L sodium hydroxide aqueous solution (800 mL).
  • the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product.
  • the crude product was dissolved in methyl tert-butyl ether (500 mL), and S-mandelic acid (8.23 g, 54.09 mmol) was added in portions under reflux, and the reaction mixture was reacted at room temperature for 16 hours.
  • intermediate B (10.00g, 36.13mmol) and 2-iodoethanol (12.43g, 72.25mmol) were dissolved in acetonitrile (100mL), potassium carbonate (14.98g, 108.38mmol) was slowly added, and the reaction solution was stirred at 80°C 16 hours. After the reaction solution was cooled to room temperature, dichloromethane (200 mL) was added to dilute, filtered, and the filtrate was concentrated under reduced pressure.
  • intermediate B (3.00g, 12.48mmol), compound D-2 (1.76g, 13.73mmol) and sodium triacetoxyborohydride (3.95g, 18.72mmol) were dissolved in 1,2-dichloroethyl Acetic acid (0.70 mL, 12.48 mmol) was slowly added dropwise to the reaction solution at -5°C, and stirred at 20°C for 15 hours after the addition was complete.
  • compound D-3 (2.60g, 7.38mmol) was dissolved in a mixed solvent of dichloromethane (30mL) and methanol (3mL), and trimethylsilyldiazomethane (14.70mL , 29.51 mmol), followed by stirring at 20°C for 2 hours. After completion of the reaction, acetic acid was slowly added dropwise to the reaction solution until the color of the reaction solution changed from yellow to colorless and no longer bubbled, diluted with water (30mL), extracted with dichloromethane (30mL), saturated aqueous sodium chloride ( 25 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound D-4.
  • compound D-4 (1.75g, 4.78mmol) was dissolved in 1,4-dioxane (30mL), and 4mol/L dioxane hydrochloride solution (6.00mL, 24.00mmol) was slowly added to react The solution was stirred at 20°C for 15 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate D. The crude product was directly used in the next reaction without further purification.
  • Example 5 4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(3-((R)-1-(2-hydroxyethyl)piper Pyridin-3-yl)azetidin-1-yl)pyrazol[1,5-a][1,3,5]triazine-7-carbonitrile (5)
  • reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: water (10mM ammonium bicarbonate ), acetonitrile; gradient ratio: acetonitrile phase (0-8min, 52-82%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 5.
  • MS-ESI m/z 515.2 [M+H] + .
  • Example 7 2-((R)-3-(1-(8-chloro-4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)pyrazol[1 ,5-a][1,3,5]triazin-2-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (7)
  • compound 7-2 (170mg, 0.39mmol), intermediate C (131mg, 0.59mmol), N,N-diisopropylethylamine (203mg, 1.57mmol) were dissolved in acetonitrile (6mL) and dimethyl sulfoxide (2 mL), and the reaction solution was stirred at 30°C for 16 hours.
  • reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge C18 150*25mm*5 ⁇ m; mobile phase: water (10mM ammonium bicarbonate), acetonitrile ; Gradient ratio: acetonitrile phase (0-10min, 50-80%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 7.
  • MS-ESI m/z 524.0 [M+H] + .
  • Example 8 4-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(3-((R)-1-(2-hydroxyethyl)piper Pyridin-3-yl)azetidin-1-yl)pyrazol[1,5-a][1,3,5]triazine-8-carbonitrile (8)
  • compound 8-1 (300 mg, 0.62 mmol) was added to 1-methyl-2-pyrrolidone (2 mL), followed by cuprous cyanide (277 mg, 3.09 mmol), replaced by nitrogen, and reacted at 140°C for 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water (30 mL) for dilution, extracted with ethyl acetate (20 mL ⁇ 2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution was poured into water (30 mL) for dilution, washed with ethyl acetate (20 mL ⁇ 2), the organic phase was discarded, the aqueous phase was concentrated under reduced pressure, and the resulting residue was subjected to preparative high performance liquid chromatography (formic acid/acetonitrile/water system, Chromatographic column: Waters Xbridge C18 150*25mm*5 ⁇ m; mobile phase: water (0.0225% formic acid), acetonitrile; gradient ratio: acetonitrile phase (0-10min, 37-67%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 9.
  • MS-ESI m/z 557.2 [M+H] + .
  • compound 10-8 (330mg, 0.29mmol, 53% purity) and lithium hydroxide monohydrate (36mg, 0.87mmol) were dissolved in tetrahydrofuran (3mL) and water (3mL), and the reaction mixture was stirred at room temperature for 3 hours .
  • reaction solution was cooled to room temperature, poured into water (10 mL) for dilution, and washed with dichloromethane (20 mL ⁇ 2).
  • the organic phase was discarded, and the aqueous phase was subjected to preparative high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatographic column: Phenomenex C18 75*30mm*3 ⁇ m; mobile phase: water (10mM formic acid), acetonitrile; gradient ratio: acetonitrile phase ( 0-7min, 8-38%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 11.
  • MS-ESI m/z 557.2 [M+H] + .
  • compound 12-3 (2.63g, crude product) and N,N-diisopropylethylamine (2.90mL, 17.57mmol) were dissolved in a mixed solvent of methanol (20mL) and ethanol (20mL), and then separated Hydroxylamine hydrochloride (814mg, 11.71mmol) was added in batches, and the reaction solution was reacted at 45°C for 2 hours.
  • MS-ESI m/z 357.0 [M+H] + .
  • compound 15-1 (5.00g, 59.47mmol) was dissolved in N,N-dimethylformamide (50mL), and ethoxycarbonyl isothiocyanate (7.80g, 59.47mmol) was slowly added dropwise, The reaction solution was reacted at 25° C. for 15 hours. After the reaction was completed, the reaction solution was poured into water (500 mL), filtered, the filter cake was washed with water (100 mL), and dried in vacuo to obtain compound 15-2.
  • reaction solution was cooled to room temperature, filtered, and the filter cake was dissolved by adding water (10mL), and the pH was adjusted to 6-7 with 1mol/L hydrochloric acid aqueous solution, and the mixture was passed through a reverse-phase column (acetonitrile/water system, chromatographic column: C18spherical20 -35 ⁇ m 40g, mobile phase: water, acetonitrile; gradient ratio: acetonitrile phase (0-8min, 0-5%); flow rate: 35mL/min; column temperature: room temperature) separation to obtain compound 15-3.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 11.53 (brs, 1H), 7.92 (s, 1H).
  • reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was separated by preparative thin-layer chromatography on silica gel (pure methanol), and then separated by preparative high-performance liquid chromatography (formic acid/acetonitrile/water system, chromatographic column: Unisil 3-100C18Ultra 150* 50mm*3 ⁇ m; mobile phase: water (0.5% formic acid), acetonitrile; gradient ratio: acetonitrile phase (0-7min, 10-40%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 15.
  • MS-ESI m/z 491.2 [M+H] + .
  • Example 17 2-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(trifluoromethyl)- [1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)azetidin-3-yl)piperidin-1-yl)ethane -1-ol(17)
  • Example 20 was prepared referring to the synthesis method of Example 19. MS-ESI: m/z 504.2 [M+H] + .
  • 1 H NMR 400MHz, CD 3 OD
  • Example 22 2-(R)-3-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(methoxymethyl) -[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (22)
  • reaction solution was poured into water (30 mL), extracted with dichloromethane (20 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to preparative high performance liquid chromatography ( Acetonitrile/ammonium bicarbonate system, chromatographic column: ACSWH-GX-A Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: water (0.1% ammonium bicarbonate), acetonitrile; gradient ratio: acetonitrile phase (0-9min,60- 90%); flow rate: 25mL/min; column temperature: room temperature) to obtain compound 25.
  • preparative high performance liquid chromatography Acetonitrile/ammonium bicarbonate system, chromatographic column: ACSWH-GX-A Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: water (0.1% ammonium bicarbonate), acetonitrile; gradient ratio: acetonit
  • compound 25-2 (100mg, 0.22mmol) was dissolved in acetonitrile (6mL), then 3-iodopropanol (83mg, 0.44mmol) and potassium carbonate (92mg, 0.67mmol) were added, and the reaction mixture was heated at 80°C Stir for 3 hours.
  • reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge C18 150*25mm*5 ⁇ m; mobile phase: water (10mM ammonium bicarbonate), acetonitrile ; Gradient ratio: acetonitrile phase (0-10min, 35-65%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 26.
  • MS-ESI m/z 504.3 [M+H] + .
  • Example 28 N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-2-(2-(methylsulfonyl)ethyl) Piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (28)
  • reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to preparative high performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge C18 150*25mm*5 ⁇ m; mobile phase: water (10mM ammonium bicarbonate), acetonitrile; Gradient ratio: acetonitrile phase (0-10min, 46-76%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 29.
  • MS-ESI m/z 542.3[M+H] + .
  • Example 31 and Example 32 (1R,4r)-4-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl) Amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclohexyl alkan-1-ol and (1S,4s)-4-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2 ,4] Triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclohexane-1-alcohol (31 and 32)
  • compound 31-2 (1.00g, 4.65mmol, 80% purity) was dissolved in tetrahydrofuran (15mL), then 1mol/L dilute hydrochloric acid (8.00mL, 8.00mmol) was added, and the reaction solution was stirred at 25°C for 16 hours .
  • Example 33 (1S,3s)-3-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[ 1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1- Base (33) and Example 34: (1R,3r)-3-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl )amino)-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methyl ring Butan-1-ol(34)
  • compound 25-2 200 mg, 0.44 mmol was dissolved in methanol (6 mL), followed by addition of compound 33-1 (147 mg, 0.88 mmol, 60% purity), sodium cyanoborohydride (83 mg, 1.32 mmol) and acetic acid (79mg, 1.32mmol), the reaction mixture was stirred at 25°C for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 33-2.
  • Compound 33-2 (200mg, 90% purity) was subjected to normal phase liquid chromatography (column: DAICEL CHIRALPAK IC (250mm*50mm*10 ⁇ m); mobile phase: hexane, ethanol (0.1% ammonia water); gradient ratio: ethanol Phase 70%; flow rate: 100mL/min; column temperature: room temperature) separation, and then separated by preparative thin-layer chromatography (pure methanol) to obtain compound 33 and compound 34.
  • Compound 33 MS-ESI: m/z 530.2 [M+H] + .
  • Example 35 and Example 36 N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-1-((1s,3S)-3 -Methoxycyclobutyl)piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine and N - ((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-2-((1r,3R)-3-methoxycyclobutyl)piperidine -3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (35 and 36)
  • Compound 35-1 (70mg, 0.13mmol) was resolved by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250mm*30mm*10 ⁇ m); mobile phase: supercritical carbon dioxide, ethanol (0.1% ammonia monohydrate); gradient Ratio: methanol phase 25%; flow rate: 55mL/min; column temperature: room temperature), compound 35 and compound 36 were obtained. (Compound 35 was the first eluting peak, compound 36 was the second eluting peak). Compound 35: MS-ESI: m/z 530.2 [M+H] + .
  • Example 37 and Example 38 N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-1-((1s,3S)-3 -(methylsulfonyl)cyclobutyl)piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidine-7- Amine and N-((R)-1-(2,4-dichlorophenyl)ethyl)-5-(3-(R)-1-((1r,3R)-3-(methylsulfonyl )cyclobutyl)piperidin-3-yl)azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine (37 and 38)
  • compound 37-1 (5.00 g, 28.37 mmol) was dissolved in methanol (20 mL), sodium borohydride (1.14 g, 30.14 mmol) was added in three batches, and the reaction mixture was stirred at 0°C for 1 hour. After the reaction was completed, it was quenched by adding water (20 mL), and concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), washed with water (30 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 37-2.
  • compound 37-2 (4.50g, 25.25mmol), methanesulfonic anhydride (6.60g, 37.87mmol) and triethylamine (10.50mL, 75.75mmol) were dissolved in dichloromethane (50mL), and the reaction The mixture was stirred at room temperature for 4 hours. After the reaction was completed, it was diluted with dichloromethane (100 mL), and washed with water (50 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 37-3.
  • compound 37-4 (1.00g, 4.80mmol) was dissolved in dichloromethane (10mL), then m-chloroperoxybenzoic acid (2.44g, 12.00mmol, 85% purity) was added, and the reaction mixture was stirred at room temperature for 2 Hour.
  • Compound 37-8 was separated by supercritical fluid chromatography (column: DAICEL CHIRALPAK AS (250mm ⁇ 30mm*10 ⁇ m); mobile phase: supercritical carbon dioxide, ethanol (0.1% ammonia monohydrate); gradient ratio: ethanol phase 40 %; flow rate: 70mL/min; column temperature: room temperature), compound 37 and compound 38 were obtained. (Compound 37 was the first eluting peak, compound 38 was the second eluting peak). Compound 37: MS-ESI: m/z 578.4 [M+H] + .
  • Example 39 and Example 40 (R)-1-((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino) -[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)propan-2-ol and (S)- 1-((R)-3- (1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4]triazolo[1,5-a]pyrimidine-5 -yl)azetidin-3-yl)piperidin-1-yl)propan-2-ol (39 and 40)
  • Compound 39-1 (140mg, 0.28mmol) was resolved by supercritical fluid chromatography (column: DAICEL CHIRALCEL OJ (250mm*30mm*10 ⁇ m); mobile phase: supercritical carbon dioxide, ethanol (0.1% ammonia monohydrate); gradient Ratio: ethanol phase 25%; flow rate: 60mL/min; column temperature: room temperature), compound 39 and compound 40 were obtained. (Compound 39 was the first eluting peak, compound 40 was the second eluting peak). Compound 39: MS-ESI: m/z 504.4 [M+H] + .
  • Example 41 1-(((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4 ]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)methyl)cyclopropan-1-ol (41)
  • compound 41-1 (1.80g, 13.83mmol) was dissolved in N,N-dimethylformamide (30mL), the temperature was lowered to 0°C, and sodium hydrogen (830mg, 20.75mmol, 60% purity ), the reaction solution was stirred at 0°C for 20 minutes, p-methoxybenzyl chloride (2.38 g, 15.21 mmol) was added, and stirred at room temperature for 3 hours. After the reaction was completed, saturated ammonium chloride aqueous solution (50 mL) was added to the reaction liquid to quench, and ethyl acetate (50 mL ⁇ 2) was extracted.
  • Example 43 3-(((R)-3-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2,4 ]triazol[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)methyl)thietane-1,1-dioxide ( 43)
  • Example 45 (1R,3r)-3-(4-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2, 4] Triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-ol (45) and
  • Example 46 (1S,3s)-3-(4-(1-(7-(((R)-1-(2,4-dichlorophenyl)ethyl)amino)-[1,2 ,4] Triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-alcohol (46 )
  • compound 45-5 150 mg, 0.34 mmol
  • compound 33-1 48 mg, 0.34 mmol, 70% purity
  • acetic acid 2 mg, 0.03 mmol
  • methanol 3 mL
  • Sodium cyanoborohydride 63 mg, 1.01 mmol
  • the reaction solution was concentrated under reduced pressure, and the residue was separated by silica gel preparative thin-layer chromatography (pure methanol) to obtain compound 45-6.
  • Compound 45-6 was resolved by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250mm*30mm*10 ⁇ m); mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient ratio: methanol phase 40 %; flow rate: 70mL/min; column temperature: room temperature), compound 45 and compound 46 were obtained.
  • compound 52-3 (180mg, 0.34mmol, 93% purity) was dissolved in acetonitrile (8mL), then 2-iodoethanol (116mg, 0.67mmol) and potassium carbonate (140mg, 1.01mmol) were added, and the reaction mixture Stir at 80°C for 16 hours.
  • reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to preparative high-performance liquid chromatography (ammonium bicarbonate/acetonitrile/water system, chromatographic column: Waters Xbridge C18 150*25mm*5 ⁇ m; mobile phase: water (10mM ammonium bicarbonate), acetonitrile ; Gradient ratio: acetonitrile phase (0-10min, 36-66%); flow rate: 25mL/min; column temperature: room temperature) separation to obtain compound 52.
  • MS-ESI m/z 504.3 [M+H] + .
  • Example 53 and Example 54 2-((R)-3-(1-(7-(((R)-1-(2-chloro-4-methylphenyl)ethyl)amino)-[ 1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol and 2-(R) -3-(1-(7-((R)-1-(4-chloro-2-methylphenyl)ethyl)amino)-[1,2,4]triazolo[1,5-a ]pyrimidin-5-yl)azetidin-3-yl)piperidin-1-yl)ethan-1-ol (53 and 54)
  • compound 53-1 500mg, 3.30mmol was dissolved in toluene (6mL), replaced with nitrogen, and a solution of methylmagnesium bromide in tetrahydrofuran (3.30mL, 9.90mmol, 3mol/L) was added, and the reaction mixture was heated at 110 °C and stirred for 18 hours. After the reaction solution was cooled to 0°C, dilute hydrochloric acid was slowly added dropwise to pH ⁇ 2, the temperature was raised to reflux and stirred for 1 hour, and then cooled to room temperature.
  • compound 53-3 (450 mg, 1.52 mmol, 62% purity) was dissolved in tetrahydrofuran (10 mL), slowly added dropwise into borane dimethyl sulfide solution (0.50 mL, 5.00 mmol, 10 mol/L), and the reaction mixture Stir at 60°C for 16 hours. The reaction solution was cooled to 0°C, and methanol (10 mL) was slowly added dropwise until no obvious bubbles were generated. Stirring was continued at room temperature for 1 hour, and concentrated under reduced pressure to obtain compound 53-4. MS-ESI: m/z 153.0 [M-NH 3 +H] + .
  • Example 58 2-(R)-2-(1-(7-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-2-(trifluoromethyl)- [1,2,4]triazolo[1,5-a]pyrimidin-5-yl)azetidin-3-yl)morpholinyl)ethan-1-ol (58)
  • compound 58-1 (3.00g, 16.20mmol) was dissolved in anhydrous methanol (30mL), under ice cooling, nitromethane (2.97g, 48.59mmol) and triethylamine (3.28g, 32.39mmol) were added ), and the reaction mixture was stirred at room temperature for 16 hours.
  • compound 58-2 (3.60 g, 14.62 mmol) and platinum dioxide (664 mg, 2.92 mmol) were added into methanol (50 mL), and reacted at room temperature for 16 hours under hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 58-3.
  • compound 58-3 (3.10g, 14.33mmol) and triethylamine (3.99mL, 28.67mmol) were dissolved in dichloromethane (50mL), and chloroacetyl chloride (1.78g, 15.77mmol) was slowly added dropwise, at room temperature React for 16 hours.
  • the reaction solution was diluted with water (50 mL), extracted with dichloromethane (50 mL ⁇ 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 58-4.
  • compound 58-6 (2.60g, 6.66mmol) was dissolved in anhydrous tetrahydrofuran (50mL), and borane dimethyl sulfide (3.30mL, 33.29mmol, 10mol/L) was added dropwise under ice cooling, and the reaction mixture was Stir at 50°C for 16 hours.
  • Compound 58-7 (1.67g) was resolved by supercritical fluid chromatography (chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10 ⁇ m); mobile phase: supercritical carbon dioxide, methanol (0.1% ammonia monohydrate); gradient formulation Ratio: methanol phase 30%; flow rate: 60mL/min; column temperature: room temperature), to obtain compound 58-8 and compound 58-9.
  • Compound 58-8 was the first eluting peak
  • compound 58-9 was the second eluting peak
  • the in vitro CCR4 receptor cell functional assay was used to detect the activity of the compound to be tested by using a cell line stably expressing CCR4 and FLIPR assay.
  • the initial concentration of the test compound was 10 ⁇ M, diluted 3 times, and a total of 10 concentrations were tested in duplicate wells.
  • a cell line stably expressing CCR4 (CCR4-HEK293) was cultured in DMEM medium supplemented with fetal bovine serum, G418 and penicillin-streptomycin. Configure 250mM FLIPR experimental buffer, 2 ⁇ Fluo-4Direct TM loading buffer. Collect and resuspend CCR4-HEK293 cells to 1x10 6 /mL, and add 20 ⁇ L of cell suspension to each reaction well of a 384-well cell culture microplate. Cells were cultured overnight. The next day, discard the supernatant from the cell reaction plate, and add 20 ⁇ L of assay buffer and 20 ⁇ L of Fluo-4Direct TM loading buffer.
  • Compound plate pre-gradiently diluted in 384-well PP microplate
  • 10 ⁇ L of the dilution of the compound to be tested was added to the cell reaction plate with 10 ⁇ L of the dilution of the compound to be tested, incubated at 37°C in a 5% carbon dioxide environment for 50 minutes, and then incubated at room temperature for 10 minutes.
  • the reaction plate was transferred to a FLIPR Tetra System (Molecular Devices).
  • the inhibitory activity of the disclosed compounds on CCR4 receptor cell calcium flow was determined by the above tests, and the measured IC 50 values are shown in Table 1.
  • the experimental results show that the test compound of the present invention has significant inhibitory activity on the calcium flow of CCR4 receptor cells.
  • Comparative Example 1 was prepared according to WO2018/02299; Comparative Example 2 was prepared according to Example 38 of WO2019/147862
  • Centrifuge the CCRF-CEM cells remove the supernatant, resuspend in FBS, adjust the cell density to 2 ⁇ 10 6 /mL, and divide the cells into 96-well cell plates, 99 ⁇ L per well.
  • hCCL22 solution with a concentration of 2.5 nM
  • hCCL22 Using DPBS as a solvent, prepare a hCCL22 solution with a concentration of 2.5 nM, take out the lower cell plate of ChemoTX, and dispense hCCL22 into the cell plate, 30 ⁇ L per well. Cover the lower plate with a ChemoTX microporous membrane, remove the cells from the incubator, transfer 50 ⁇ L of cells to the microporous membrane per well, cover the lid, and incubate for another 1.5 hours at 37°C in a 5% carbon dioxide incubator .
  • the inhibitory activity of the compounds of the present invention on CCR4-mediated chemotaxis of CCRF-CEM cells was determined by the above tests, and the measured IC 50 values are shown in Table 2.
  • the experimental results show that the test compounds of the present invention have significant inhibitory activity on CCRF-CEM cell chemotaxis, and the inhibitory activity of most compounds is obviously stronger than that of Comparative Example 1 and Comparative Example 2.
  • Test Example 3 CCR4-mediated Th2 and Treg cell chemotaxis inhibitory activity test
  • the hTh2 (or hTreg) cells were centrifuged to remove the culture medium, resuspended in 100% fetal bovine serum, adjusted the cell density to 2 ⁇ 10 6 /mL, and split the cells into 96-well cell plates, 99 ⁇ L per well.
  • DPBS DPBS
  • a recombinant human CCL22 solution with a concentration of 2.5 nM take out the lower cell plate of ChemoTX, and dispense recombinant human CCL22 into the cell plate, 30 ⁇ L per well.
  • Cover the lower plate with a ChemoTX microporous membrane take out the cells from the incubator, transfer 50 ⁇ L of cells per well to the microporous membrane, cover the lid, and store at 37°C in a fine atmosphere of 5% carbon dioxide. Incubate for another 1.5 hours in the incubator.
  • the inhibitory activity of the compounds of the present invention on CCR4-mediated chemotaxis of Th2 and Treg cells was determined by the above tests, and the measured IC 50 values are shown in Table 3. Experimental results show that the test compound of the present invention has significant inhibitory activity on both Th2 cell chemotaxis and Treg cell chemotaxis.
  • Test Example 4 Evaluation of the occupancy rate of the compound on the cell surface CCR4 receptor
  • the CCRF-CEM cells were centrifuged at 300 rcf to remove the medium, resuspended in 100% fetal calf serum, adjusted the cell density to 2 ⁇ 10 6 /mL, and split the cells into 96-well cell plates, 99 ⁇ L per well.
  • Two wells were set for each concentration of the compound, 1 ⁇ L of the compound to be tested was transferred to each well of the 96-well plate, and placed in a cell culture incubator with 5% carbon dioxide at 37° C. for 0.5 hours.
  • DPBS DPBS
  • hCCL22 solution with a concentration of 20 ⁇ M was prepared, and the 96-well plate was taken out of the cell culture incubator, and 1 ⁇ L of hCCL22 solution was added to one well of each concentration of the compound, and 1 ⁇ L of DPBS solution was added to the other well, and placed at 37 °C again. , and incubate for 0.5 hr in a 5% carbon dioxide incubator. Take out the cell plate, add 1 ⁇ L of PE-conjugated anti-human CD194 (CCR4) antibody to each cell well, and incubate in a refrigerator at 4°C in the dark for 0.5 hours.
  • CCR4 PE-conjugated anti-human CD194
  • the occupancy rate of the compound of the present invention on the CCR4 receptor on the cell surface was determined by the above method, and the experimental results are shown in Table 4.
  • the experimental results show that the test compound of the present invention can show a higher occupancy rate of CCR4 at a lower concentration, and under the premise of producing the same CCR4 occupancy rate, the required concentration of the test compound of the present invention is significantly lower than that of Comparative Example 1 and Comparative example 2.
  • test compound was dissolved in 5% DMSO + 5% Solutol + 90% saline, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use.
  • Balb/c male mice were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg.
  • the test compound was dissolved in 4% DMSO+96% (0.5% HPMC+0.1% TW-80) or 5% DMSO+40% PEG400+10% Solutol+45% water, vortexed and sonicated to prepare the corresponding concentration of clear
  • the solution was filtered through a microporous membrane for later use.
  • Balb/c male mice were selected, and the candidate compound solution was orally administered at a dose of 10 mg/kg or 50 mg/kg.
  • Whole blood was collected at a certain time point, and plasma was prepared, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated.
  • the experimental results are shown in Table 5.
  • the experimental results show that the test compound of the present invention has better pharmacokinetic properties in mice.
  • test compound was dissolved in 5% DMSO + 5% Solutol + 90% saline, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use.
  • Male SD rats were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg.
  • the test compound was dissolved in 5% DMSO + 40% PEG400 + 10% Solutol + 45% water, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use.
  • Male SD rats were selected, and the candidate compound solution was orally administered at a dose of 50 mg/kg.
  • Whole blood was collected at a certain time point, and plasma was prepared, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated.
  • the experimental results are shown in Table 6.
  • the experimental results show that the test compound of the present invention has better pharmacokinetic properties in rats.
  • test compound was dissolved in 5% DMSO + 5% Solutol + 90% saline, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use.
  • Male Beagle dogs were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg.
  • the test compound was dissolved in 5% DMSO + 40% PEG400 + 10% Solutol + 45% water, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use.
  • Male Beagle dogs were selected, and the candidate compound solution was orally administered at a dose of 5 mg/kg. Collect whole blood at a certain time point, prepare plasma, analyze drug concentration by LC-MS/MS method, and calculate pharmacokinetics mechanical parameters.
  • the experimental results are shown in Table 7.
  • the experimental results show that the test compound of the present invention has better in vivo pharmacokinetic properties in Beagle dogs.
  • Test Example 8 Evaluation of the Inhibitory Activity of Compounds on the hERG Potassium Ion Channel
  • CHO cells stably expressing hERG were cultured in a cell culture dish with a diameter of 35 mm, placed in an incubator at 37°C and 5% CO 2 , and subcultured at a ratio of 1:5 every 48 hours.
  • the medium formula: 90% Ham's F12 culture Base, 10% fetal bovine serum, 100g/mL geneticin and 100g/mL hygromycin. Aspirate the cell culture medium, rinse with extracellular fluid once, add 0.25% trypsin-EDTA solution, and digest at room temperature for 3-5 minutes. Aspirate the digestion solution, resuspend the cells with extracellular solution, and transfer the cells to a laboratory dish for electrophysiological recording.
  • hERG potassium channel currents were recorded by whole-cell voltage-clamp technique at room temperature.
  • the resistance of the tip after perfusion with the inner solution of the electrode is about 2-5M ⁇ , and the glass microelectrode is inserted into the amplifier probe to connect to the patch clamp amplifier.
  • the clamping voltage and data recording are controlled and recorded by the pClamp software through the computer, the sampling frequency is 10kHz, and the filtering frequency is 2kHz.
  • the cell was clamped at -100mV, and the step voltage of the evoked hERG potassium current was given a 2s depolarization voltage from -100mV to +20mV, then repolarized to -50mV, and returned to - for 1s. 100mV. Give this voltage stimulation every 5s, and start the administration process after confirming that the hERG potassium current is stable (at least 1 minute), and give each test concentration of the compound at least 1 minute until the steady state of action.
  • Data analysis and processing used pClamp 10, GraphPad and Excel software.
  • the experimental results are shown in Table 8.
  • the experimental results showed that the test compounds had weak inhibitory activity on the hERG potassium ion channel, and the IC 50 values of most test compounds were greater than 10 ⁇ M, showing a low risk of hERG potassium ion channel inhibition.
  • the compound of Comparative Example 1 has strong inhibitory activity on the hERG potassium ion channel, with an IC 50 value of 0.15 ⁇ M.
  • Test Example 9 Pharmacodynamic experiment of FITC-induced delayed-type hypersensitivity in mice in vivo
  • mice 7-week-old BALB/c mice (Victoria Lihua) acclimatized for 1 week after arriving at the animal room. According to body weight, they were divided into model control group, positive control dexamethasone group and test compound group. On days 0 and 1, BALB/c mice were anesthetized with isoflurane, and their abdomens were shaved with 400 ⁇ L of 0.5% FITC (dissolved in 50% acetone + 50% dibutyl phthalate). sensitization. On days 6, 7, 8, and 9, 20 ⁇ L of 0.5% FITC was applied to the inner and outer sides of the left ear of the mice for modeling stimulation.
  • 0.5% FITC dissolved in 50% acetone + 50% dibutyl phthalate
  • Test Example 10 Pharmacodynamic experiment of OXA-induced mouse atopic dermatitis in vivo
  • mice 7-week-old BALB/c mice (Shanghai Jihui) acclimatized for 1 week after arriving in the animal room. According to body weight, they were divided into model control group, positive control dexamethasone group and test compound group. On day 0, BALB/c mice were anesthetized with isoflurane, shaved their abdomen, and sensitized with 100 ⁇ L of 1.5% OXA (dissolved in 80% acetone + 20% olive oil). On day 7, 20 ⁇ L of 1.5% OXA was applied to the inner and outer sides of the left ear of the mice for modeling stimulation.
  • OXA dissolved in 80% acetone + 20% olive oil

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

La présente invention concerne une petite molécule antagoniste du CCR4 et son utilisation. Spécifiquement, la présente invention concerne un composé de formule (I) ou des composés marqués par un isotope de celui-ci, ou des isomères optiques, des isomères géométriques, des tautomères ou des mélanges d'isomères associés, ou des sels pharmaceutiquement acceptables de celui-ci, ou des promédicaments associés, ou des métabolites associés, et leur utilisation dans la préparation d'un médicament pour le traitement ou la prévention de maladies ou de troubles médiés par CCR4.
PCT/CN2023/072403 2022-01-25 2023-01-16 Petite molécule antagoniste du ccr4 et son utilisation WO2023143194A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202210087598.7 2022-01-25
CN202210087598 2022-01-25
CN202210928357 2022-08-03
CN202210928357.0 2022-08-03

Publications (1)

Publication Number Publication Date
WO2023143194A1 true WO2023143194A1 (fr) 2023-08-03

Family

ID=87470522

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/072403 WO2023143194A1 (fr) 2022-01-25 2023-01-16 Petite molécule antagoniste du ccr4 et son utilisation

Country Status (2)

Country Link
TW (1) TW202340197A (fr)
WO (1) WO2023143194A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1592624A (zh) * 2000-06-30 2005-03-09 惠氏公司 被取代的三唑并嘧啶类化合物作为抗癌药
CN101268038A (zh) * 2005-09-22 2008-09-17 塞诺菲-安万特股份有限公司 作为ccr3受体液体的氨基-烷基-酰胺衍生物
WO2008146914A1 (fr) * 2007-06-01 2008-12-04 Mitsubishi Tanabe Pharma Corporation Composition hétérocyclique
US20090131666A1 (en) * 2006-03-24 2009-05-21 Astellas Pharma Inc. Acylaminopiperidine compound
CN103974950A (zh) * 2011-12-01 2014-08-06 凯莫森特里克斯股份有限公司 作为ccr(4)拮抗剂的取代的苯并咪唑类和苯并吡唑类
CN111971279A (zh) * 2018-01-26 2020-11-20 拉普特医疗公司 趋化因子受体调节剂及其用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1592624A (zh) * 2000-06-30 2005-03-09 惠氏公司 被取代的三唑并嘧啶类化合物作为抗癌药
CN101268038A (zh) * 2005-09-22 2008-09-17 塞诺菲-安万特股份有限公司 作为ccr3受体液体的氨基-烷基-酰胺衍生物
US20090131666A1 (en) * 2006-03-24 2009-05-21 Astellas Pharma Inc. Acylaminopiperidine compound
WO2008146914A1 (fr) * 2007-06-01 2008-12-04 Mitsubishi Tanabe Pharma Corporation Composition hétérocyclique
CN103974950A (zh) * 2011-12-01 2014-08-06 凯莫森特里克斯股份有限公司 作为ccr(4)拮抗剂的取代的苯并咪唑类和苯并吡唑类
CN111971279A (zh) * 2018-01-26 2020-11-20 拉普特医疗公司 趋化因子受体调节剂及其用途

Also Published As

Publication number Publication date
TW202340197A (zh) 2023-10-16

Similar Documents

Publication Publication Date Title
EP3932919B1 (fr) Composé inhibiteur de jak et son utilisation
JP6494624B2 (ja) カゼインキナーゼ１ｄ／ｅ阻害剤としての置換された４，５，６，７−テトラヒドロピラゾロ［１，５−ａ］ピラジン誘導体
EP3674307B1 (fr) Macrocycle contenant de l'aminopyrazole et de la pyrimidine, composition pharmaceutique et utilisation de celui-ci
CN114349750A (zh) Kras突变蛋白抑制剂
EP2315521B1 (fr) Modulateurs de diamino-pyridine, pyrimidine et pyridazine du récepteur de l'histamine h 4
CN112552295A (zh) Kras突变蛋白抑制剂
EP4083038A1 (fr) Composé pyridazinyl thiazolecarboxamide
EP3766882A1 (fr) Dérivés alcoxy de phtalazine isoxazole, procédé de préparation associé, composition pharmaceutique et utilisation correspondantes
WO2023041055A1 (fr) Inhibiteur de kif18a
CN113121509A (zh) Jak抑制剂化合物及其用途
EP3971176A1 (fr) Composé chimère de dégradation de protéine ciblant une amine aromatique ar et bet et son utilisation
JP2023536891A (ja) 重症肺炎を治療するためのｊａｋ阻害剤化合物
CN112654605B (zh) 桥杂环基取代的嘧啶类化合物及其制备方法和医药用途
WO2016091207A1 (fr) Composé nitromidazole, procédé de préparation de ce composé et utilisation de ce composé dans la fabrication de médicaments
WO2023143194A1 (fr) Petite molécule antagoniste du ccr4 et son utilisation
CN111315750B (zh) 作为mTORC1/2双激酶抑制剂的吡啶并嘧啶类化合物
WO2024094190A1 (fr) Agent de dégradation d'irak 4 et son utilisation
WO2024120424A1 (fr) Composé ciblant un agent de dégradation de la protéine pan-kras et son utilisation
WO2022135390A1 (fr) Inhibiteur de cétohexokinase et son utilisation
RU2779497C2 (ru) Макроцикл, содержащий аминопиразол и пиримидин, и его фармацевтическая композиция и применение
EP4159738A1 (fr) Inhibiteur de jak macrocyclique et ses utilisations
WO2023143384A1 (fr) Composé pour inhiber ou dégrader la kinase hpk1 et son utilisation médicale
WO2024125532A1 (fr) Nouveau composé hétérocyclique agissant en tant qu'inhibiteur des cdk, et utilisation associée
WO2023151635A1 (fr) Composé à base de squelette de glutarimide à substitution quinazoline et son utilisation
TW202311260A (zh) 含有亞磺醯亞胺基的atr抑制劑化合物

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: 23746076

Country of ref document: EP

Kind code of ref document: A1