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WO2025082460A1 - Composé inhibiteur de diacylglycérol kinase et son utilisation - Google Patents

Composé inhibiteur de diacylglycérol kinase et son utilisation Download PDF

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Publication number
WO2025082460A1
WO2025082460A1 PCT/CN2024/125638 CN2024125638W WO2025082460A1 WO 2025082460 A1 WO2025082460 A1 WO 2025082460A1 CN 2024125638 W CN2024125638 W CN 2024125638W WO 2025082460 A1 WO2025082460 A1 WO 2025082460A1
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alkyl
compound
optionally substituted
pharmaceutically acceptable
stereoisomer
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English (en)
Chinese (zh)
Inventor
金京海
陈磊
于智勇
祝伟
李正涛
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Shanghai Xianxiang Medical Technology Co Ltd
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Shanghai Xianxiang Medical Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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

  • Patent application No. 202311374250.7 filed with the State Intellectual Property Office on October 20, 2023;
  • Patent application No. 202410296052.1 submitted to the State Intellectual Property Office on March 14, 2024.
  • the present disclosure belongs to the field of medicine, and relates to a diacylglycerol kinase inhibitor compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and use of the diacylglycerol kinase inhibitor in preventing or treating related diseases.
  • T cell receptors are molecules that can recognize and activate T cells. They transmit signals through some small molecules, one of which is called diacylglycerol (DAGs), which can bind to some important proteins to regulate the activity of T cells.
  • DAGs diacylglycerol
  • the present disclosure is committed to developing compounds that can inhibit DGK ⁇ and DGK ⁇ , restore DAGs signal transmission, promote T cell-related signal pathways and enhance T cell activity, for the treatment of cancers associated with immune cell activation or cancers resistant to anti-PD-1 antibody/PD-L1 antibody therapy.
  • the present disclosure relates to a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • X 1 is selected from N and CH;
  • X2 is selected from O, S and NH;
  • R 1 is selected from C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl, wherein the C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl are optionally substituted by R 1a ;
  • R 2 is selected from halogen, C 1 -C 10 alkyl and C 1 -C 10 alkyl-S(O) 2 -, wherein the C 1 -C 10 alkyl and C 1 -C 10 alkyl-S(O) 2 - are optionally substituted with R 2a ;
  • R 1 , X 2 , R 2 and the atoms to which they are connected together form a 5-10 membered heteroaromatic ring, and the 5-10 membered heteroaromatic ring is optionally substituted by R 1a ;
  • R 3 is selected from amino, 4-10 membered heterocycloalkyl and C 1 -C 10 alkoxy, wherein the amino, 4-10 membered heterocycloalkyl and C 1 -C 10 alkoxy are optionally substituted by R 3a ;
  • R 2 , R 3 and the atoms to which they are attached together form a 5-8 membered heterocyclic ring, wherein the 5-8 membered heterocyclic ring is optionally substituted by R 4a ;
  • Ring A is selected from 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted by halogen or C 1 -C 3 alkyl;
  • Ring B is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl, wherein the C 6 -C 10 aryl, 5-10 membered heteroaryl and 4-10 membered heterocyclyl are optionally substituted by R b ;
  • R 1a is independently selected from halogen, hydroxy, amino, cyano, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and 4-10 membered heterocyclyl;
  • R 2a is independently selected from halogen, hydroxy, amino, cyano and C 1 -C 3 alkyl
  • R 3a is independently selected from halogen, hydroxyl, amino, cyano, C 1 -C 6 alkyl, NH(C 1 -C 6 alkyl), C(O)C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 4-10 membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, NH(C 1 -C 6 alkyl), C(O)C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted with R c ;
  • R 4a is independently selected from halogen, hydroxy, amino, cyano and C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally substituted with R d ;
  • R b is independently selected from halogen, oxo, cyano and C 1 -C 3 alkyl
  • R c is independently selected from amino, cyano, NH(C 1 -C 6 alkyl), N(C 1 -C 3 alkyl) 2 , NH(C 3 -C 6 cycloalkyl), 4-7 membered heterocyclyl, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl and -C( ⁇ O)NH 2 , and the amino, NH(C 1 -C 6 alkyl), N(C 1 -C 3 alkyl) 2 , NH(C 3 -C 6 cycloalkyl), 4-7 membered heterocyclyl, C 1 -C 3 alkyl, C 3 -C 6 cycloalkyl and -C( ⁇ O)NH 2 are optionally substituted with R e ;
  • R d is independently selected from NH(C 1 -C 3 alkyl);
  • R e is independently selected from halogen, hydroxy, 4-7 membered heterocyclyl, NH(C 1 -C 3 alkyl), C 1 -C 3 haloalkyl, C 1 -C 8 alkoxy and C 1 -C 3 alkyl.
  • X 1 is CH.
  • X2 is O or S.
  • X2 is O.
  • X2 is S.
  • R 1 is selected from C 1 -C 6 alkyl and C 6 -C 10 aryl, and the C 1 -C 6 alkyl and C 6 -C 10 aryl are optionally substituted with R 1a .
  • R 1 is selected from C 1 -C 4 alkyl and phenyl, and the C 1 -C 4 alkyl and phenyl ring are optionally substituted with R 1a .
  • R 1a is independently selected from halogen, C 3 -C 6 cycloalkyl, and 4-10 membered heterocyclyl.
  • R 1a is independently selected from fluoro, cyclopropyl, cyclobutyl and
  • R 1 is selected from isopropyl, cyclopropylmethyl, cyclobutylmethyl,
  • R 2 is selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkyl-S(O) 2 —, said C 1 -C 6 alkyl and C 1 -C 6 alkyl-S(O) 2 — being optionally substituted with R 2a .
  • R 2 is selected from halogen, C 1 -C 3 alkyl, and C 1 -C 3 alkyl-S(O) 2 —, said C 1 -C 3 alkyl and C 1 -C 3 alkyl-S(O) 2 — being optionally substituted with R 2a .
  • R 2 is selected from chloro, methyl, CH 3 —S(O) 2 —, said methyl being optionally substituted with R 2a .
  • R 2 is selected from methyl optionally substituted with R 2a .
  • R 2a is independently selected from halogen.
  • R 2a is fluoro
  • R 2 is selected from chloro, methyl, trifluoromethyl, and CH 3 —S(O) 2 —.
  • R 2 is trifluoromethyl.
  • R 1 , X 2 , R 2 and the atoms to which they are attached together form a 5-8 membered heteroaryl ring, which is optionally substituted with R 1a .
  • R 1 , X 2 , R 2 and the atoms to which they are attached together form a pyrazole ring, which is optionally substituted with R 1a .
  • R 1 , X 2 , R 2 and the atoms to which they are attached together form Wherein a bond represents the bond shared with the connected ring.
  • R 3 is selected from amino, 4-10 membered heterocycloalkyl and C 1 -C 6 alkoxy, wherein the amino, 4-10 membered heterocycloalkyl and C 1 -C 6 alkoxy are optionally substituted with R 3a .
  • R 3 is selected from amino, 5-10 membered heterocycloalkyl and C 1 -C 3 alkoxy, wherein the amino, 5-10 membered heterocycloalkyl and C 1 -C 3 alkoxy are optionally substituted with R 3a .
  • R3 is selected from amino, piperidinyl, ethyloxy, piperazinyl, The amino, piperidinyl, ethyloxy, piperazinyl, Optionally substituted with R 3a .
  • R3 is selected from amino, piperidinyl, ethyloxy, The amino, piperidinyl, ethyloxy, Optionally substituted with R 3a .
  • R 3a is independently selected from cyano, C 1 -C 6 alkyl, NH(C 1 -C 6 alkyl), C(O)C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 4-10 membered heterocycloalkyl, and the C 1 -C 6 alkyl, NH(C 1 -C 6 alkyl), C(O)C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted with R c .
  • R 3a is independently selected from cyano, C 1 -C 6 alkyl, NH(C 1 -C 6 alkyl), C(O)C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 4-10 membered heterocycloalkyl, and the C 1 -C 6 alkyl, C(O)C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl and 4-10 membered heterocycloalkyl are optionally substituted with R c .
  • R 3a is independently selected from cyano, C 1 -C 3 alkyl, NH(C 1 -C 3 alkyl), C(O)C 1 -C 3 alkyl and C 3 -C 6 cycloalkyl, and the C 1 -C 3 alkyl, NH(C 1 -C 3 alkyl), C(O)C 1 -C 3 alkyl and C 3 -C 6 cycloalkyl are optionally substituted with R c .
  • R 3a is independently selected from cyano, methyl, ethyl, cyclopropyl, -NHCH 3 , -C(O)CH 2 CH 3 , -C(O)CH 3 , and -CH 2 CH 2 CH 3 , wherein the methyl, ethyl, cyclopropyl, -NHCH 3 , -C(O)CH 2 CH 3 , -C(O)CH 3 , and -CH 2 CH 2 CH 3 are optionally substituted with R c .
  • R e is independently selected from NH(C 1 -C 3 alkyl) and C 1 -C 3 alkyl.
  • R e is independently selected from halogen, 4-7 membered heterocyclyl, C 1 -C 8 alkoxy, NH(C 1 -C 3 alkyl), and C 1 -C 3 alkyl.
  • Re is independently selected from fluoro, methoxy, oxetanyl, -NHCH3 , and methyl.
  • Re is independently selected from -NHCH3 and methyl.
  • Re is methyl
  • R3 is selected from
  • R3 is selected from
  • R3 is selected from
  • R 2 and R 3 together with the atoms to which they are attached form a 6-membered heterocyclic ring, which is optionally substituted with R 4a .
  • R 2 and R 3 and the atoms to which they are attached together form a 6-membered nitrogen heterocyclic ring, which is optionally substituted with R 4a .
  • R 4a is independently selected from halogen and C 1 -C 3 alkyl, said C 1 -C 3 alkyl being optionally substituted with R d .
  • R 4a is independently selected from fluoro and ethyl, said ethyl being optionally substituted with R d .
  • R d is -NHCH 3 .
  • R2 and R3 together with the atoms to which they are attached form Wherein a bond represents the bond shared with the connected ring.
  • Ring A is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted with halogen or C 1 -C 3 alkyl.
  • Ring A is selected from thiazolyl, pyrazinyl, oxazolyl, pyrazolyl and
  • Ring A is selected from Wherein, * indicates connection with ring B.
  • Ring B is selected from C 6 -C 10 aryl, 6-10 membered heteroaryl and 4-10 membered heterocyclyl, wherein the C 6 -C 10 aryl, 6-10 membered heteroaryl and 4-10 membered heteroaryl are optionally substituted with R b .
  • Ring B is selected from phenyl, pyridinyl, pyridazinyl, The phenyl, pyridyl, pyridazinyl, Optionally substituted with R b .
  • R b is independently selected from fluoro, oxo, methyl, and cyano.
  • Ring B is selected from phenyl
  • the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt:
  • the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (III) or its stereoisomer Construct or a pharmaceutically acceptable salt thereof:
  • the compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compound of formula (IV) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X2 , R1 , R2 , R3 , Ring A and Ring B are as defined above, and R1 is not cycloalkyl, heterocyclyl, aryl or heteroaryl; or X2 , R1 , R2 , R3 and Ring B are as defined above, Ring A is pyrazolyl or pyrazinyl, and R3 is not heterocycloalkyl.
  • the compound of formula (I) of the present disclosure or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or its stereoisomer or its pharmaceutically acceptable salt,
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for treating a disease mediated by DGK in an individual (e.g., a mammal), comprising administering a therapeutically effective amount of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to an individual (e.g., a mammal, preferably a human) in need of such treatment.
  • the present disclosure provides use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating a DGK-mediated disease.
  • the present disclosure provides use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating a DGK-mediated disease.
  • the present disclosure provides a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a DGK-mediated disease.
  • the DGK-mediated disease is a tumor.
  • the compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures.
  • asymmetric carbon atoms asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and their mixtures involved in all substituents are also included within the definition of the compounds of the present invention.
  • the compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • an ethyl group is "optionally" substituted with one or more halogens, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2, etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or cannot be synthesized will be introduced.
  • any variable eg, Ra , Rb
  • its definition is independent at each occurrence. For example, if a group is substituted with 2 Rb , each Rb has an independent option.
  • L 1 When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary.
  • L 1 When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary.
  • L 1 When L 1 is selected from “C 1 -C 3 alkylene-O", L 1 can connect ring Q and R 1 from left to right to form “ring QC 1 -C 3 alkylene-OR 1 ", or connect ring Q and R 1 from right to left to form “ring QOC 1 -C 3 alkylene-R 1 ".
  • Cm - Cn refers to an integer number of carbon atoms in the range of mn.
  • C1 - C10 means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 , which may be linear or branched.
  • C1 - C10 alkyl is understood to mean a linear or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 -C 1 -C 1 -C 1 -C 1 -C 1
  • C 1 -C 3 alkyl may be understood to mean a straight chain or branched saturated alkyl group having 1 to 3 carbon atoms.
  • the "C 1 -C 10 alkyl” may include “C 1 -C 6 alkyl", “C 1 -C 4 alkyl” or “C 1 -C 3 alkyl” and the like, and the “C 1 -C 6 alkyl” may further include “ C 1 -C 4 alkyl " or "C 1 -C 3 alkyl” and the like .
  • alkoxy refers to a group resulting from the loss of a hydrogen atom from a hydroxyl group of a straight or branched alcohol, and may be understood as an “alkyloxy” or “alkyl-O-".
  • C 1 -C 10 alkoxy may be understood as a “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-”;
  • C 1 -C 6 alkoxy may be understood as a "C 1 -C 6 alkyloxy” or "C 1 -C 6 alkyl-O-".
  • the "C 1 -C 10 alkoxy” may include a “C 1 -C 6 alkoxy” and a “C 1 -C 3 alkoxy", and the "C 1 -C 6 alkoxy” may further include a "C 1 -C 3 alkoxy”.
  • cycloalkyl refers to a fully saturated carbocyclic group that exists in the form of a monocyclic ring, a fused ring, a bridged ring, or a spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3-20 membered ring.
  • C 3 -C 10 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms.
  • C 3 -C 6 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, or 6 ring carbon atoms.
  • N nitrogen atom
  • O oxygen atom
  • S sulfur atom
  • P phosphorus
  • 4-10 membered heterocyclyl refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1-5 heteroatoms or heteroatomic groups independently selected from the above-mentioned in the ring atoms.
  • “4-10 membered heterocyclyl” may include “4-7 membered heterocyclyl”.
  • the term “4-7 membered heterocyclyl” refers to a heterocyclyl having 4, 5, 6 or 7 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above.
  • 4-membered heterocyclyl include, but are not limited to, azetidinyl or oxetanyl
  • 5-membered heterocyclyl include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl
  • specific examples of 6-membered heterocyclyl include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl
  • specific examples of 7-membered heterocyclyl include, but are not limited to, diazepanyl.
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrole-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic group, specific examples of which include, but are not limited to, dihydroisoquinolinyl and the like.
  • “4-10 membered heterocyclyl” may include “5-10 membered heterocyclyl”, “4-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, etc., and “4-7 membered heterocyclyl” may further include “4-6 membered heterocyclyl", “5-6 membered heterocyclyl”, “4-7 membered heterocycloalkyl”, “4-6 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, etc. Although some bicyclic heterocyclyls in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl as a whole is still non-aromatic.
  • the term "4-10 membered heterocycloalkyl” refers to a heterocycloalkyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, wherein the ring atoms of the heterocycloalkyl group contain 1 to 5 heteroatoms or heteroatomic groups independently selected from the above.
  • the term "5-10 membered heterocycloalkyl” refers to a heterocycloalkyl group having 5, 6, 7, 8, 9 or 10 heterocycloalkyl groups, and the ring atoms contain 1-5 heteroatoms or heteroatom groups independently selected from the above.
  • 4-10 membered heterocycloalkyl and “5-10 membered heterocycloalkyl” include “4-7 membered heterocycloalkyl", wherein specific examples of 4 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl or thietanyl; specific examples of 5 membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6 membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ electron system.
  • the aryl group may have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
  • C 6 -C 10 aryl is understood to mean an aryl group having 6 to 10 carbon atoms.
  • C 6 aryl a ring having 6 carbon atoms
  • C 9 aryl a ring having 9 carbon atoms
  • C 10 aryl a ring having 10 carbon atoms
  • heteroaryl refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system with aromaticity, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C.
  • 5-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9 or 10 ring atoms, such as 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, such as 1-3 heteroatoms independently selected from N, O and S.
  • the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, in
  • 6-10 membered heteroaryl is understood to include monocyclic or bicyclic aromatic ring systems having 6, 7, 8, 9 or 10 ring atoms, such as 6 or 9 or 10 ring atoms, and containing 1-5, such as 1-3, heteroatoms independently selected from N, O and S.
  • the term “5-6 membered heteroaryl” refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1-3, such as 1-2, heteroatoms independently selected from N, O and S.
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to an -OH group.
  • cyano refers to a -CN group.
  • amino refers to a -NH2 group.
  • treatment means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder.
  • the amount of a compound of the present disclosure that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and the present disclosure.
  • prevention means administering the compounds or formulations described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing a disease or disease state from occurring in an individual (e.g., a mammal), particularly when such individual (e.g., a mammal) is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • subject includes mammals and non-mammals.
  • mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.
  • non-human mammals include, but are not limited to, birds and fish, etc.
  • the mammal is a human.
  • patient and “subject” are used interchangeably.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or an organic acid, and a salt formed between a compound and an inorganic base or an organic base.
  • pharmaceutical composition refers to a pharmaceutical composition comprising one or more compounds of the present disclosure or their stereoisomers or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from that normally found in nature.
  • isotopes that may be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, etc., respectively.
  • Certain isotopically labeled compounds of the present disclosure can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability.
  • Positron emitting isotopes, such as 15 O, 13 N, 11 C, and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
  • the daily dosage in the case of oral administration, is 0.001 mg/kg to 100 mg/kg body weight, preferably 0.1 mg/kg to 50 mg/kg body weight, more preferably 0.1 mg/kg to 30 mg/kg body weight, in the form of a single or divided dose.
  • the daily dosage is about 0.0001 to 10 mg/kg per unit body weight, which is administered once a day or divided into multiple doses.
  • a transmucosal agent about 0.001 to 100 mg/kg per unit body weight is administered once a day or divided into multiple doses. The dosage is appropriately determined according to each case in consideration of symptoms, age, sex, etc.
  • the compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the embodiments with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples disclosed herein.
  • i-PrOH represents isopropanol; THF represents tetrahydrofuran; DMF represents N,N-dimethylformamide; DCM represents dichloromethane; TFA represents trifluoroacetic acid; PE represents petroleum ether; EA represents ethyl acetate; LC-MS represents liquid chromatography-mass spectrometry; MS represents mass spectrometry; 1 H NMR represents hydrogen nuclear magnetic resonance; 19 F NMR represents fluorine nuclear magnetic resonance; ESI represents electrospray ionization; NMP represents N-methyl-2-pyrrolidone; DIPEA represents N,N-diisopropylethylamine; EtOH represents ethanol; MeOH represents methanol; HATU represents 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DCE represents 1,2-dichloroethane; MeCN represents acetonitrile; Bu 3 Sn
  • the ratios expressed for mixed solvents are volume mixing ratios.
  • % refers to weight %.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvent for NMR determination is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS);
  • the eluent or mobile phase may be a mixed eluent or mobile phase consisting of two or more solvents, the ratio of which is the volume ratio of each solvent.
  • Step 2 (S)-tert-butyl ((1-(3-isopropoxy-6-nitro-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)carbamate (Compound 1-4)
  • Step 3 (R)-tert-butyl ((1-(3-isopropoxy-6-nitro-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 1-5)
  • Step 4 (R)-tert-butyl ((1-(6-amino-3-isopropoxy-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 1-6)
  • Step 5 (R)-tert-butyl ((1-(3-isopropoxy-6-(2-(pyridazin-4-yl)thiazole-4-carboxamido)-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 1-8)
  • Step 6 (S)-N-(4-isopropoxy-2-(3-((methylamino)methyl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-2-(pyridazin-4-yl)thiazole-4-carboxamide (Compound 1)
  • Step 2 (S)-tert-butyl ((1-(3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)carbamate (Compound 2-2)
  • Step 3 (R)-tert-butyl ((1-(3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 2-3)
  • Step 4 (R)-tert-butyl ((1-(6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 2-4)
  • Step 5 (R)-tert-butyl ((1-(3-(2-fluorophenoxy)-6-(2-phenylthiazole-4-carboxamido)-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 2-6)
  • Step 6 (S)-N-(4-(2-fluorophenoxy)-2-(3-((methylamino)methyl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-2-phenylthiazole-4-carboxamide (Compound 2)
  • Step 4 (R)-tert-butyl((1-(3-(2-fluorophenoxy)-6-(6-(pyridazin-4-yl)pyrazine-2-carboxamido)-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 3-5)
  • Step 5 (S)-N-(4-(2-fluorophenoxy)-2-(3-(((methylamino)methyl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-6-(pyridazin-4-yl)pyrazine-2-carboxamide (Compound 3)
  • Step 2 (S)-tert-butyl ((1-(1-cyclopropyl-5-nitro-1H-indazol-4-yl)piperidin-3-yl)methyl)carbamate (Compound 4-3)
  • Step 3 (R)-tert-butyl ((1-(1-cyclopropyl-5-nitro-1H-indazol-4-yl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 4-4)
  • Step 4 (R)-tert-butyl ((1-(5-amino-1-cyclopropyl-1H-indazol-4-yl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 4-5)
  • Step 5 (R)-tert-butyl ((1-(1-cyclopropyl-5-(2-(pyridazin-4-yl)thiazole-4-carboxamido)-1H-indazol-4-yl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 4-6)
  • Step 6 (S)-N-(1-cyclopropyl-4-(3-((methylamino)methyl)piperidin-1-yl)-1H-indazol-5-yl)-2-(pyridazin-4-yl)thiazole-4-carboxamide (Compound 4)
  • Step 1 tert-Butyl 2-(((3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl)amino)methyl)pyrrolidine-1-carboxylate (Compound 5-1)
  • Step 2 tert-Butyl 2-(((3-(2-fluorophenoxy)-6-nitro-2-(trifluoromethyl)phenyl)(methyl)amino)methyl)pyrrolidine-1-carboxylate (Compound 5-2)
  • Step 3 tert-Butyl 2-(((6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl)(methyl)amino)methyl)pyrrolidine-1-carboxylate (Compound 5-3)
  • Step 4 tert-Butyl 2-(((3-(2-fluorophenoxy)-6-(2-(pyridazin-4-yl)thiazole-4-carboxamido)-2-(trifluoromethyl)phenyl)(methyl)amino)methyl)pyrrolidine-1-carboxylate (Compound 5-5)
  • Step 5 N-(4-(2-fluorophenoxy)-2-(methyl(pyrrolidin-2-ylmethyl)amino)-3-(trifluoromethyl)phenyl)-2-(pyridazin-4-yl)thiazole-4-carboxamide (Compound 5)
  • Step 1 (R)-tert-butyl ((1-(6-(4-bromothiazole-2-carboxamido-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 8-1)
  • Step 2 (R)-tert-butyl((1-(3-(2-fluorophenoxy)-6-(4-(pyridazin-4-yl)thiazole-2-carboxamido)-2-(trifluoromethyl)phenyl)piperidin-3-yl)methyl)(methyl)carbamate (Compound 8-2)
  • Step 3 (S)-N-(4-(2-fluorophenoxy)-2-(3-((methylamino)methyl)piperidin-1-yl)-3-(trifluoromethyl)phenyl)-2-phenylthiazole-4-carboxamide (Compound 8)
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with 2-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with compound 3-3 to obtain the title compound 10 (8 mg, yield 78%).
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with (2-aminoethyl)(methyl)carbamic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with 1-(pyridazine-4-yl)-1H-pyrazole-3-carboxylic acid to obtain the title compound 11 (6 mg, yield 59%).
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with (3-aminopropyl)(methyl)carbamic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with 1-(pyridazine-4-yl)-1H-pyrazole-3-carboxylic acid to obtain the title compound 12 (9 mg, yield 71%).
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with 2-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with 1-(pyridazine-4-yl)-1H-pyrazole-3-carboxylic acid to obtain the title compound 14 (7 mg, yield 63%).
  • Step 1 4-(pyridazin-4-yl)thiazole-2-carboxylic acid methyl ester (Compound 15-2)
  • Step 3 tert-Butyl (2-((6-amino-3-(2-fluorophenoxy)-2-(trifluoromethyl)phenyl)(methyl)amino)ethyl)(methyl)carbamate (Compound 15-4)
  • Step 4 tert-Butyl (2-((3-(2-fluorophenoxy)-6-(4-(pyridazin-4-yl)thiazole-2-carboxamido)-2-(trifluoromethyl)phenyl)methyl)amino)ethyl(methyl)carbamate (Compound 15-5)
  • Step 5 N-(4-(2-fluorophenoxy)-2-(methyl(2-(methylamino)ethyl)amino)-3-(trifluoromethyl)phenyl)-4-(pyridazin-4-yl)thiazole-2-carboxamide (Compound 15)
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with 3-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with compound 3-3 to obtain the title compound 16 (42.0 mg, yield 82%).
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with (3-aminopropyl)(methyl)carbamic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with compound 3-3 to obtain the title compound 17 (50.0 mg, yield 98%).
  • Step 1 (R)-tert-butyl ((4-(3-(2-fluorophenoxy)-6-(4-(pyridazin-4-yl)thiazole-2-carboxamido)-2-(trifluoromethyl)phenyl)-1-methylpiperazin-2-yl)methyl)(methyl)carbamate (Compound 18-2)
  • Step 2 (S)-N-(4-(2-fluorophenoxy)-2-(4-methyl-3-((methylamino)methyl)piperazin-1-yl)-3-(trifluoromethyl)phenyl)-4-(pyridazin-4-yl)thiazole-2-carboxamide (Compound 18)
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with (2-aminoethyl)(methyl)carbamic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with compound 3-3 to obtain the title compound 19 (39.0 mg, yield 77%).
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with (3-aminopropyl)(methyl)carbamic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with compound 15-3 to obtain the title compound 20 (30.0 mg, yield 88%).
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with (2-aminoethyl)(cyclopropyl)carbamic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with compound 3-3 to obtain the title compound 21 (16.0 mg, yield 99%).
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with (2-aminoethyl)(cyclopropyl)carbamic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with 1-(pyridazine-4-yl)-1H-pyrazole-3-carboxylic acid to obtain the title compound 22 (13.0 mg, yield 95%).
  • the 2-(aminomethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in the first step was replaced with 2-(aminomethyl)morpholine-4-carboxylic acid tert-butyl ester, and the compound 1-7 in the fourth step was replaced with compound 15-3 to obtain the title compound 23 (8 mg, 78%).
  • the Echo650 sonic pipetting system uses the Echo650 sonic pipetting system to dilute the compound and pipette it into the corresponding position in a 384-well plate (the compound stock solution is diluted in a gradient manner through the dose-response program of the compound dilution and pipetting instrument, the starting concentration of the test compound is 10 ⁇ M, 3-fold dilution, 10 concentration points, and the diluent is 1640 medium containing 10% (w/w) fetal bovine serum).
  • the Echo650 sonic pipetting system uses the Echo650 sonic pipetting system to dilute the compound and pipette it into the corresponding position in a 384-well plate (the compound stock solution is diluted in a gradient manner through the dose-response program of the compound dilution and pipetting instrument, the starting concentration of the test compound is 10 ⁇ M, 3-fold dilution, 10 concentration points, and the diluent is 1640 medium containing 10% (w/w) fetal bovine serum).
  • 96-well cell plates (Corning) were coated with 2 ⁇ g/mL Anti-Human CD3 Clone OKT3 (BD) at 37°C for 4 hours.
  • Compounds were diluted three-fold (final concentration was 10 ⁇ M-4.6nM, starting concentration was 10 ⁇ M, three-fold dilution was performed, 8 points, the 8th point was 4.6nM, and the diluent was 10% (w/w) fetal bovine serum in 1640 medium) and incubated with 220 ⁇ L 1.11 6 /mL Jurkat T cells (ATCC) for 1 hour, 5 ⁇ L 45 ⁇ g/mL Anti-Human CD28 Clone CD28.2 (BD) was added, mixed evenly, and 100 ⁇ L was transferred to CD3-coated cell plates, cultured in a cell culture incubator at 37°C for 48 hours, and the supernatant was collected and the IL-2 release was detected using the BD IL-2 ELISA kit (BD). EC 50 was analyzed using Prism.
  • Test Example 3 Determination of metabolic stability of the disclosed compounds in liver microsomes
  • the positive compound verapamil and the test compound were prepared into 10 mM DMSO stock solutions, respectively, and diluted to 100 ⁇ M with acetonitrile.
  • the incubation system was prepared as shown in the table below and preheated in a 37°C incubator for 10 minutes before use.
  • the entire incubation process was carried out in a 96-well plate. First, 178 ⁇ L of the incubation system was added to the 96-well plate, followed by the addition of 2 ⁇ L of 100 ⁇ M stock solution of the disclosed compound or the positive control compound verapamil. Before initiating the reaction with 20 ⁇ L of 10 mM NADPH solution or PBS solution, the incubation system was preheated at 37°C for 10 minutes.
  • the pNL3.2[NlucP/IL-2/Hygro] vector (containing the IL2 promoter, which drives the transcription of the luciferase reporter gene NanoLuc in response to TCR activation.
  • Cell plate coating Use Anti-Human CD3Clone OKT3 (BD) at a concentration of 1 ⁇ g/mL to coat 96-well cell plates (Corning) at 4°C for 16 hours.
  • BD Anti-Human CD3Clone OKT3
  • Emax fold refers to the maximum activation fold of IL2 compared to the baseline value.
  • mice were used as test animals, and the drug concentration in plasma at different times after injection or oral administration of the test compound was determined by LC-MS/MS. The pharmacokinetic behavior of the compound in mice was studied and the pharmacokinetic characteristics were evaluated.
  • mice Three healthy Balbc female mice were selected and orally administered with a dose of 5 mg/kg. The mice were free to eat and drink water throughout the experiment. A complete solvent 5% NMP + 20% PEG400 + 75% (10% VETPGS) (reagent purchased from Sigma) was used as the solvent. On the day of the experiment, the corresponding compound (0.5 mg/mL) was prepared and the corresponding dose of the compound was given by single intragastric injection. The administration volume was 10 mL/kg. The animal was weighed before administration, and the administration volume was calculated based on the animal's weight. The collection time was: 0 (before administration), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. Approximately 100 microliters of whole blood was collected through the jugular vein at each sampling time point for the preparation of plasma, and the plasma samples were stored in a refrigerator at 80°C.
  • the drug concentration in plasma samples was determined by LC-MS/MS method, and the minimum detection limit of this method was 1 ng/mL. All animals were euthanized by CO2 anesthesia after the plasma sample at the last time point was collected.
  • the non-compartmental model of Phoenix WinNonlin (version 8.3.4) pharmacokinetic software was used to calculate the plasma concentration and the corresponding pharmacokinetic parameters.

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Abstract

La présente divulgation concerne un composé inhibiteur de DGK représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, une composition pharmaceutique le contenant, et son utilisation dans la préparation d'un médicament pour la prévention ou le traitement de maladies médiées par DGK.
PCT/CN2024/125638 2023-10-20 2024-10-18 Composé inhibiteur de diacylglycérol kinase et son utilisation Pending WO2025082460A1 (fr)

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