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WO2025067360A1 - Antagoniste de dgkzêta et son utilisation en médecine - Google Patents

Antagoniste de dgkzêta et son utilisation en médecine Download PDF

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Publication number
WO2025067360A1
WO2025067360A1 PCT/CN2024/121520 CN2024121520W WO2025067360A1 WO 2025067360 A1 WO2025067360 A1 WO 2025067360A1 CN 2024121520 W CN2024121520 W CN 2024121520W WO 2025067360 A1 WO2025067360 A1 WO 2025067360A1
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Prior art keywords
membered
alkyl
optionally substituted
cycloalkyl
alkylene
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PCT/CN2024/121520
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English (en)
Chinese (zh)
Inventor
张晨
赵明亮
李路
杨定菊
王洪斌
李瑶
严庞科
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Haisco Pharmaceutical Group Co Ltd
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Haisco Pharmaceutical Group Co Ltd
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Publication of WO2025067360A1 publication Critical patent/WO2025067360A1/fr
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a compound described by general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates and preparation methods thereof, as well as use of the compound in preparing drugs for treating diseases related to abnormal DGK ⁇ kinase.
  • DGK is a lipid kinase that downregulates T cell activation by phosphorylating diacylglycerol (DAG) and converting it into phosphatidic acid (PA), thereby acting as a ligand-independent intracellular immune checkpoint.
  • DAG diacylglycerol
  • PA phosphatidic acid
  • DGK ⁇ and DGK ⁇ are two major subtypes in T cells, which regulate the intensity of DAG signals downstream of antigen stimulation to prevent overactivation of T cells. Inhibition of DGK may enhance DAG downstream signals and activate T cells.
  • DGK ⁇ in addition to regulating immune cells, DGK ⁇ also plays a role in cancer, including mediating proliferation, apoptosis, survival, invasion, and tumorigenicity. DGK ⁇ deficiency can lead to a hyper-responsive phenotype in T cells and enhance the activity of T cells against malignant tumors.
  • the development of DGK ⁇ inhibitors has good application prospects for the treatment of tumors. There are currently no reports of DGK ⁇ inhibitors on the market. The development of DGK ⁇ inhibitors is urgently needed and has broad clinical significance.
  • the object of the present invention is to provide a compound having DGK ⁇ kinase inhibitory activity or its stereoisomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as their use in the preparation of drugs for treating diseases related to abnormal DGK ⁇ kinase.
  • the technical problem to be solved by the present invention is to provide a class of small molecule compounds or pharmaceutically acceptable salts thereof for inhibiting DGK ⁇ , thereby regulating T cell immune stimulation, thereby treating cancer, autoimmune diseases and the like.
  • the compound of the invention has good DGK ⁇ kinase inhibitory activity, bioavailability and in vivo safety.
  • the present invention provides a compound of general formula (I) or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  • the compound described by general formula (I) is selected from general formula (Ia), (Ib), (Ic),
  • R 1 is selected from C 1-6 alkyl, which is optionally substituted with 1 to 4 R k ;
  • R 1 is selected from C 1-4 alkyl, which is optionally substituted with 1 to 4 R k ;
  • R 1 is selected from methyl, ethyl, propyl, isopropyl, and the methyl, ethyl, propyl, isopropyl is optionally substituted with 1 to 4 R k ;
  • R 1 is selected from CF 3 , CHF 2 , CH 2 F, methyl, ethyl, -CH 2 -cyclopropyl;
  • R 1 is selected from CF 3 , methyl, ethyl
  • R 3 is selected from R 3A or R 3B ;
  • R 3A is selected from non-aromatic C 3-12 carbocyclyl or non-aromatic 4-12 membered heterocyclyl, preferably C 3-7 monocyclic cycloalkyl, C 3-6 monocyclic cycloalkenyl, C 6-12 cycloalkyl, C 6-12 spirocycloalkyl, C 5-9 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered cycloheterocycloalkyl, 6-12 membered cycloheterocycloalkenyl, 6-12 membered spirocycloheterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, said R 3A is optionally substituted by 1 to 4 R 3a ;
  • R 3A is selected from The R 3A is optionally substituted by 1 to 4 R 3a ;
  • R 3A is selected from The R 3A is optionally substituted by 1 to 4 R 3a ;
  • R 3A is selected from The R 3A is optionally substituted by 1 to 4 R 3a ;
  • R 3A is selected from
  • R 3B is selected from C 3-12 carbocyclyl or 4-12 membered heterocyclyl, preferably C 6-10 aryl, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, C 3-7 monocyclic carbocycle, C 6-12 cyclic carbocycle, C 6-12 spirocyclic carbocycle, C 5-12 bridged carbocycle, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, and said R 3B is optionally substituted by 1 to 4 R 3b ;
  • R 3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, C 3-7 monocyclic cycloalkyl, C 3-6 monocyclic cycloalkenyl, C 6-12 cycloalkyl, C 6-12 spirocycloalkyl, C 5-9 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered heterocycloalkenyl, 6-12 membered cycloheterocycloalkyl, 6-12 membered cycloheterocycloalkenyl, 6-12 membered spirocycloheterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, said R 3B is optionally substituted by 1 to 4 R 3b ;
  • R 3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, The R 3B is optionally substituted by 1 to 4 R 3b ;
  • R 3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, benzothienyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyrazinyl
  • R 3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,
  • the R 3B is optionally substituted by 1 to 4 R 3b ;
  • R 3B is selected from
  • R 3B is selected from
  • R 4 is selected from H, deuterium, halogen, CN, OH, CN, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -C 0-2 alkylene-C 3-6 cycloalkyl or -OC 3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted with 1 to 4 R k ; in some embodiments, R 4 is selected from H, deuterium, halogen, CN, OH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -C 0-2 al
  • R 4 is selected from NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, wherein the alkyl, alkylene, cycloalkyl is optionally substituted with 1 to 4 R k ;
  • R 4 is selected from NH 2 , methyl, ethyl, propyl, isopropyl, said methyl, ethyl, propyl, isopropyl being optionally substituted with 1 to 4 R k ;
  • R 4 is selected from NH 2 , methyl, CF 3 , CHF 2 or CH 2 F;
  • R 4 is selected from NH 2 ;
  • Ring A is selected from 6-membered heteroaryl, 8- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a ;
  • Ring A is selected from Pyridyl, pyrimidinyl, benzopyrrolyl, benzopyrazolyl, thiazolopyrazolyl, pyridopyrazolyl, wherein the ring A is optionally substituted with 1 to 4 Ra ;
  • Ring A is selected from
  • R 5 is selected from C 3-12 carbocyclyl or 4-12 membered heterocyclyl, preferably C 3-12 carbocyclyl or 5 to 12 membered heterocyclyl, said R 5 is optionally substituted by 1 to 4 R 5a ;
  • R 5 is selected from C 3-7 monocyclic carbocycle, C 6-12 cyclic carbocycle, C 6-12 spirocyclic carbocycle, C 5-12 bridged carbocycle, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-10 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, and said R 5 is optionally substituted by 1 to 4 R 5a ;
  • R 5 is selected from phenyl, 5- to 6-membered heteroaryl, benzoC 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 8- to 10-membered heterocyclyl, The R 5 is optionally substituted by 1 to 4 R 5a .
  • R 5 is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, pyrrolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyridoimidazolyl, pyridotriazolyl, pyridopyrazolyl, The R 5 is optionally substituted by 1 to 4 R 5a ;
  • R 5 is selected from phenyl, pyridinyl, pyrimidinyl, thienyl, The R 5 is optionally substituted by 1 to 4 R 5a ;
  • R 5 is selected from R 5A ;
  • R SA is selected from C 3-7 monocyclic cycloalkyl, C 6-10 cycloalkyl, C 6-10 spirocyclic cycloalkyl, C 5-10 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 6-10 membered cycloalkyl, 6-10 membered spirocyclic heterocycloalkyl, 6-10 membered bridged ring heterocycloalkyl, 8 to 10 membered cycloaryl;
  • R 5A is selected from The R SA is optionally substituted by 1 to 4 R 5a ;
  • R 5A is selected from The R SA is optionally substituted by 1 to 4 R 5a ; in some embodiments, R a , R 3a , R 3b , R 5a are each independently selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-4 to 10 membered heterocyclyl or -OC 3-6 cycloalkyl, and the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R k ;
  • Ra , R3a , R3b , R5a are each independently selected from deuterium, halogen, CN, OH, NH2 , NHC1-4 alkyl, N( C1-4 alkyl) 2 , C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, -C0-2 alkylene- C3-6 carbocyclyl, -C0-2 alkylene-4 to 7 membered heterocyclyl, or -OC3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 Rk ;
  • Ra , R3a , R3b , and R5a are each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2 , NHCH3 , N( CH3 ) 2 , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2 -cyclopropyl, -CH2-cyclobutyl, -CH2 -cyclopentyl, -CH2 -cyclohexyl, -CH2 -oxetanyl, -CH2
  • R 3a and R 3b are each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, and ethyl;
  • R 3a , R 3b are each independently selected from deuterium, F, Cl, CF 3 ;
  • R 3b is independently selected from deuterium, F, Cl;
  • R 5a is each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;
  • each R 5a is independently selected from deuterium, F, CHF 2 , CH 2 F, CF 3 , methyl, ethyl, CH 2 CF 3 , CH 2 CHF 2 , OCF 3 , OCHF 2 , methoxy;
  • each R 5a is independently selected from deuterium, F, CF 3 , methyl, ethyl;
  • s1, s3, s5, s8 are each independently selected from 0, 1 or 2;
  • s2 and s4 are each independently selected from 0 or 1;
  • s6 is selected from 0, 1, 2 or 3;
  • s7 is selected from 1, 2 or 3;
  • s1 and s8 on the same ring are not 2 at the same time;
  • R5 when ring A is selected from R5 is selected from one of the following groups optionally substituted by 1 to 4 R5a : phenyl, 5 to 6 membered heteroaryl, benzo C5-6 carbocyclyl, 6 membered heteroaryl and C5-6 carbocyclyl, 6 membered heteroaryl and 5 to 6 membered oxygen-containing heterocyclyl, benzo 5 to 6 membered oxygen-containing heterocyclyl, when the C5-6 carbocyclyl or 5 to 6 membered oxygen-containing heterocyclyl is a partially saturated ring, R3 is selected from R3A .
  • R 1 is selected from C 1-6 alkyl, said alkyl being optionally substituted by 1 to 4 R k ;
  • R 3 is selected from R 3A or R 3B ;
  • R 3A is selected from non-aromatic C 3-12 carbocyclic group or non-aromatic 4-12 membered heterocyclic group, preferably C 3-7 monocyclic cycloalkyl, C 3-6 monocyclic cycloalkenyl, C 6-12 cycloalkyl, C 6-12 spirocycloalkyl, C 5-9 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered cycloheterocycloalkyl, 6-12 membered cycloheterocycloalkenyl, 6-12 membered spirocycloheterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, wherein the R SA is optionally substituted by 1 to 4 R 3a ;
  • R 3B is selected from C 3-12 carbocyclyl or 4-12 membered heterocyclyl, preferably C 6-10 aryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, C 3-7 monocyclic carbocycle, C 6-12 cyclic carbocycle, C 6-12 spirocyclic carbocycle, C 5-12 bridged carbocycle, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, said R 3B is optionally substituted by 1 to 4 R 3b ;
  • R 4 is selected from H, deuterium, halogen, CN, OH, CN, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -C 0-2 alkylene-C 3-6 cycloalkyl or -OC 3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy and cycloalkyl are optionally substituted by 1 to 4 R k ;
  • Ring A is selected from 6-membered heteroaryl, 8- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a ;
  • R 5 is selected from C 3-12 carbocyclyl or 4-12 membered heterocyclyl, preferably C 3-12 carbocyclyl or 5 to 12 membered heterocyclyl, wherein said R 5 is optionally substituted by 1 to 4 R 5a ;
  • R a , R 3a , R 3b , R 5a are each independently selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -C 0-4 alkylene-C 3-10 carbocyclyl, -C 0-4 alkylene-4 to 10 membered heterocyclyl or -OC 3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R5 when ring A is selected from R5 is selected from one of the following groups optionally substituted by 1 to 4 R5a : phenyl, 5 to 6 membered heteroaryl, benzo C5-6 carbocyclyl, 6 membered heteroaryl and C5-6 carbocyclyl, 6 membered heteroaryl and 5 to 6 membered oxygen-containing heterocyclyl, benzo 5 to 6 membered oxygen-containing heterocyclyl, when the C5-6 carbocyclyl or 5 to 6 membered oxygen-containing heterocyclyl is a partially saturated ring, R3 is selected from R3A .
  • R 5 is selected from C 3-7 monocyclic carbocycle, C 6-12 cyclic carbocycle, C 6-12 spirocyclic carbocycle, C 5-12 bridged carbocycle, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, and said R 5 is optionally substituted by 1 to 4 R 5a ;
  • R 3B is selected from phenyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, benzo C 4-6 carbocyclyl, benzo 4-6 membered heterocyclyl, C 3-7 monocyclic cycloalkyl, C 3-6 monocyclic cycloalkenyl, C 6-12 cycloalkyl, C 6-12 spirocycloalkyl, C 5-9 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered heterocycloalkenyl, 6-12 membered cycloheterocycloalkyl, 6-12 membered cycloheterocycloalkenyl, 6-12 membered spirocycloheterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, said R 3B is optionally substituted by 1 to 4 R 3b ;
  • R 1 is selected from C 1-4 alkyl, said alkyl being optionally substituted by 1 to 4 R k ;
  • R 4 is selected from H, deuterium, halogen, CN, OH, CN, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -C 0-2 alkylene-C 3-6 cycloalkyl or -OC 3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy and cycloalkyl are optionally substituted by 1 to 4 R k ;
  • R a , R 3a , R 3b , R 5a are each independently selected from deuterium, halogen, CN, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -C 0-2 alkylene-C 3-6 carbocyclyl, -C 0-2 alkylene-4 to 7 membered heterocyclyl or -OC 3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R k ;
  • R 3A is selected from The R 3A is optionally substituted by 1 to 4 R 3a ;
  • R 3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, The R 3B is optionally substituted by 1 to 4 R 3b ;
  • s1, s3, s5, s8 are each independently selected from 0, 1 or 2;
  • s2 and s4 are each independently selected from 0 or 1;
  • s6 is selected from 0, 1, 2 or 3;
  • s7 is selected from 1, 2 or 3;
  • Ring A is selected from Pyridyl, pyrimidinyl, benzopyrrolyl, benzopyrazolyl, thiazolopyrazolyl, pyridopyrazolyl, wherein the ring A is optionally substituted with 1 to 4 Ra ;
  • R 4 is selected from NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, wherein the alkyl, alkylene and cycloalkyl are optionally substituted by 1 to 4 R k ;
  • R 5 is selected from phenyl, 5- to 6-membered heteroaryl, benzoC 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 8- to 10-membered heterocyclyl, The R 5 is optionally substituted by 1 to 4 R 5a ;
  • R 1 is selected from methyl, ethyl, propyl, isopropyl, and the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R k ;
  • R 4 is selected from NH 2 , methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted with 1 to 4 R k ;
  • R 3A is selected from The R 3A is optionally substituted by 1 to 4 R 3a ;
  • R3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, benzothienyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazin
  • R is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, pyrrolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, pyridoimidazolyl, pyridotriazolyl, pyridopyrazolyl,
  • the R 5 is optionally substituted by 1 to 4 R 5a ;
  • Ra , R3a , R3b , and R5a are each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2 , NHCH3 , N( CH3 ) 2 , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2 -cyclopropyl, -CH2-cyclobutyl, -CH2 -cyclopentyl, -CH2 -cyclohexyl, -CH2 -oxetanyl, -CH2 -ox
  • the compound of general formula (I) is selected from general formula (Ia), (Ib), (Ic),
  • R 1 is selected from CF 3 , CHF 2 , CH 2 F, methyl, ethyl, -CH 2 -cyclopropyl;
  • R 4 is selected from NH 2 , methyl, CF 3 , CHF 2 or CH 2 F;
  • R 5 is selected from phenyl, pyridyl, pyrimidinyl, thienyl, The R 5 is optionally substituted by 1 to 4 R 5a ;
  • R SA is selected from The R 5A is optionally substituted by 1 to 4 R 5a ;
  • R 5a is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;
  • R 3A is selected from The R 3A is optionally substituted by 1 to 4 R 3a ;
  • R3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,
  • the R 3B is optionally substituted by 1 to 4 R 3b ;
  • R 3a and R 3b are each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, and ethyl;
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is selected from the general formula (Ia), (Ib), (Ic),
  • R 3A is selected from
  • R 3B is selected from
  • the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound described in the general formula (I) is selected from the general formula (Ic),
  • R 1 is selected from CF 3 , methyl, ethyl
  • R 3B is selected from
  • R 4 is selected from NH 2 ;
  • R 5A is selected from The R 5A is optionally substituted by 1 to 4 R 5a ;
  • R 3b are each independently selected from deuterium, F, and Cl;
  • R 5a is independently selected from deuterium, F, CF 3 , methyl, and ethyl.
  • the present invention relates to the following compound or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table A below:
  • the present invention relates to a pharmaceutical composition, comprising the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition contains 1-1500 mg of the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal.
  • the present invention relates to a pharmaceutical composition, comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.
  • the present invention relates to use of the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in preparing a drug for treating diseases related to abnormal DGK ⁇ kinase, preferably in preparing a drug for cancer or autoimmune disease.
  • the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation strength").
  • an "effective amount” or “therapeutically effective amount” described in this application refers to the administration of a sufficient amount of the compound disclosed in this application, which will alleviate one or more symptoms of the disease or condition being treated (e.g., DGK ⁇ kinase abnormality-related diseases such as cancer, autoimmune diseases) to some extent.
  • the result is a reduction and/or alleviation of the signs, symptoms or causes of the disease, or any other desired changes in the biological system.
  • an "effective amount” for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 1 00-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg , 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 1 50-500mg, 200-500mg, 250-500
  • the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 1 25 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease associated with abnormal DGK ⁇ kinase (such as cancer, autoimmune disease).
  • a method for treating a disease in a mammal comprising administering a drug compound of the present invention or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1000 mg/day
  • the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day / day, 25-400 mg/day, 50-400 mg/day, 100-400 mg/day, 200-400 mg/day, in some embodiments, daily doses include but are not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.
  • the present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in the preparation of drugs for treating diseases related to abnormal DGK ⁇ kinase.
  • the present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease related to abnormal DGK ⁇ kinase.
  • the disease is selected from cancer and autoimmune disease, preferably solid tumor.
  • the amount of the compound according to the invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is in each case calculated as the free base.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include pro
  • CN refers to cyano
  • Halogen refers to F, Cl, Br or I.
  • Halogen substituted refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I.
  • Halogen substituted is abbreviated as "halo”.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.
  • Alkylene refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including (CH 2 ) v -(v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc.
  • the cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic.
  • Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,
  • the heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • alkenyl refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms.
  • alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2 ...
  • alkenyl group can be monovalent, divalent, trivalent or tetravalent.
  • Alkynyl refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, 2 to 4 carbon atoms in the backbone, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system.
  • the carbocyclyl group can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl- 3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se.
  • the C, N, S or Se selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states.
  • the heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring.
  • the heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring.
  • Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxane, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl,
  • Spiro or “spirocyclic group” refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom).
  • "Spirocycle” or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10.
  • Non-limiting examples include: "Bicyclic" or "bicyclic group” can be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” wherein the ring system consists of only carbon atoms.
  • Carbocyclic refers to a “cyclic” ring system consisting of only carbon atoms.
  • Carbobridged ring refers to a “bridged ring” wherein the ring system consists of only carbon atoms.
  • Heteromonocycle refers to a monocyclic ring system of "heterocyclyl” or “heterocycle”,
  • Heterocyclic ring refers to a "cyclo" containing a heteroatom.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms.
  • the aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl” or “aromatic ring” can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
  • heteroaryl examples include but are not limited to pyridyl, furanyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, and the like.
  • the heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include
  • the heteroaryl groups appearing in this article have the same definition as this definition.
  • the heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.
  • X-Y membered rings (X, Y are integers, and 3 ⁇ X ⁇ Y, X ⁇ Y ⁇ 20 are selected from any integer between 4 and 20) include X, X+1, X+2, X+3, X+4...Y membered rings.
  • Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings.
  • 4--7 membered heteromonocyclic rings refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings
  • 5--10 membered heterocyclic rings refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings
  • Cxy carbocycle (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, cyclic carbocycle or bridged carbocycle) includes Cx , Cx +1, Cx +2 , Cx +3 , Cx +4 ... Cy -membered ring (x is an integer, and 3 ⁇ x ⁇ y, y is selected from any integer between 4 and 20), for example.
  • C3-6 cycloalkyl refers to C3 , C4 , C5 or C6 cycloalkyl;
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence.
  • any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes
  • connection directions include connection from left to right and from right to left in reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.
  • alkyl optionally substituted with F means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
  • Stepoisomers refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imide-alcohol isomerism.
  • IC50 is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.
  • DMA N,N-dimethylacetamide
  • DMF N,N-dimethylformamide
  • DCM dichloromethane
  • X is selected from a leaving group, preferably halogen, OMs, OTs or Otf;
  • the compound of general formula (A-3) and the compound of general formula (A-4) are reacted with an alkaline reagent (such as TEA, DIEA, K2CO3) through a nucleophilic substitution reaction to obtain a compound of general formula A.
  • an alkaline reagent such as TEA, DIEA, K2CO3
  • Dissolve 1b (0.50 g, 3.10 mmol) in acetic acid (5 mL), add pyridinium tribromide (0.99 g, 3.10 mmol) and 33% hydrogen bromide acetic acid solution (2.20 g, 8.97 mmol), and react at room temperature for 1 h.
  • Dissolve 4a 200 mg, 1.45 mmol and 1,1-thiocarbonyl DI-2(1H)-pyridine (337 mg, 1.45 mmol) in dichloromethane (10 mL), add N,N-diisopropylethylamine (190 mg, 1.45 mmol), and react at room temperature for 16 hours. Concentrate under reduced pressure to obtain a crude product. Dissolve the crude product in acetonitrile (10 mL), add cyanamide (73 mg, 1.74 mmol) and 1,8-diazobispiro[5.4.0]undec-7-ene (221 mg, 1.45 mmol), and react at room temperature for 1 hour.
  • Compound 5 was prepared using 5a as the starting material by referring to the synthesis method of Example 4.
  • Preparation method The crude product was dissolved in N, N-dimethylformamide and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% trifluoroacetic acid).
  • Gradient elution method Acetonitrile was gradient eluted from 32% to 62% (elution time 15min), and the trifluoroacetate of compound 6 was obtained after freeze-drying.
  • Compound 6 was purified by SFC on Chiral OD column (instrument and preparation column: Waters 150 Prep-SFC, preparation column model: Chiral OD column.
  • Preparation method Compound 6 was dissolved in acetonitrile and ethanol, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in ethanol.
  • Gradient elution method 50% mobile phase B isocratic elution (flow rate: 100mL/min; elution time 3min), and compound 6-A and compound 6-B were obtained after freeze-drying.
  • the trifluoroacetate salt of compound 7 was prepared using 7a as the starting material by referring to the synthesis method of Example 6.
  • Compound 7 was purified by SFC on Chiral OD column (instrument and preparation column: Waters 150 Prep-SFC, preparation column model: Chiral OD column.
  • Preparation method Compound 7 was dissolved in acetonitrile and ethanol, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system A for CO 2 ; B for 0.1% NH 3 ⁇ H 2 O in ethanol.
  • Gradient elution method 50% mobile phase B isocratic elution (flow rate: 100mL/min; elution time 3min), and compound 7-A and compound 7-B were obtained after freeze-drying.
  • the trifluoroacetate salt of compound 8 was obtained using 8a as the starting material by referring to the synthesis method of Example 6.
  • Compound 8 was purified by SFC on IK column (Instrument and preparation column: Waters 150 Prep-SFC, preparation column model: Chiral IK column.
  • Preparation method Compound 8 was dissolved in acetonitrile and dichloromethane, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system A for CO 2 and B for 0.1% NH 3 ⁇ H 2 O in isopropanol and acetonitrile).
  • Gradient elution method 50% mobile phase B isogradient elution (flow rate: 100 mL/min; elution time 4 min)), and compound 8-A and compound 8-B were obtained after lyophilization.
  • Compound 9 was purified by SFC on IK column (Instrument and preparation column: Waters 150 Prep-SFC, preparation column model: Chiral IK column.
  • Preparation method Compound 9 was dissolved in acetonitrile and dichloromethane, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase System A for CO 2 and B for 0.1% NH 3 ⁇ H 2 O in isopropanol).
  • Gradient elution method 40% mobile phase B isogradient elution (flow rate: 120 mL/min; elution time 4 min)), and after freeze-drying, compound 9-A and compound 9-B were obtained.
  • RLU Relative Luminescence Unit
  • the compounds of the present invention such as the example compounds, have DGK ⁇ inhibitory activity, and specifically compounds 6, 8, 6-B, 8-B, and 9-B have good DGK ⁇ inhibitory activity.
  • mice/compound Male Balb/c mice, about 22-25 g, 6-8 weeks old, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, Balb/c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 5% DMSO + 95% (20% SBE- ⁇ -CD)
  • the compounds of the present invention such as the example compounds, specifically compounds 9-B and 6-B, have higher exposure, lower clearance and good bioavailability in mice, and are significantly superior to the control compound BAY-2965501.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 5% DMSO + 95% (20% SBE- ⁇ -CD)
  • the purpose of this study was to evaluate the effects of the test substances on the activities of four isoenzymes (CYP1A2, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system.
  • Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH).
  • the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC50 values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype.
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • the compounds of the present invention have poor inhibitory activity against CYP enzymes. Specifically, the IC50 values of compound 6-B and compound 9-B against CYP1A2, CYP2C19, CYP2D6 and CYP3A4 are all greater than 20 ⁇ M.
  • Cell line Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
  • CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature.
  • the glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller.
  • the tip resistance after perfusion of the electrode liquid was about 2-5M ⁇ .
  • the glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier.
  • the clamping voltage and data recording were controlled and recorded by pClamp 10 software through a computer, with a sampling frequency of 10kHz and a filter frequency of 2kHz.
  • the cell was clamped at -80mV, and the step voltage to induce the hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, then repolarized to -50mV, and returned to -80mV after 1s.
  • This voltage stimulation was given every 10s, and the drug administration process was started after the hERG potassium current was determined to be stable (at least 1 minute).
  • Compounds were administered for at least 1 min at each tested concentration, and at least 2 cells (n ⁇ 2) were tested at each concentration.
  • Inhibition% represents the inhibition percentage of the compound on hERG potassium current
  • I and Io represent the amplitude of hERG potassium current after and before drug addition, respectively.
  • X is the Log value of the test sample detection concentration
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages, respectively.
  • the compounds of the present invention such as the compounds in the examples, have poor hERG inhibitory activity.
  • test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain reaction time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS method. T 1/2 was calculated by the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CL int(Liver) was further calculated.
  • the compounds of the present invention such as the compounds in the examples, specifically compound 6-B and compound 9-B, have good metabolic stability in human liver microsomes.
  • Test purpose To administer the test substance to beagle dogs by single-dose intravenous and oral gavage, determine the concentration of the test substance in beagle dog plasma, and evaluate the pharmacokinetic characteristics of the test substance in beagle dogs.
  • mice Male beagle dogs, about 8-11 kg, 6 per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • test method On the day of the test, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and were fed 4 hours after administration.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 5% DMSO + 95% (20% SBE- ⁇ -CD)
  • the compounds of the present invention such as the compounds in the examples, have higher exposure and good pharmacokinetic properties in beagle dogs.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline; intragastric administration solvent: 5% DMSO + 95% (20% SBE- ⁇ -CD)
  • 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube.
  • the blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.
  • the blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h.
  • all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

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Abstract

La présente invention concerne un composé représenté par la formule générale (I) ou un stéréoisomère, un racémate, une substance deutérée, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un cristal eutectique de celui-ci, un procédé intermédiaire et de préparation associé, et une utilisation de celui-ci dans la préparation d'un médicament pour le traitement de maladies associées à une anomalie de kinase DGKζ.
PCT/CN2024/121520 2023-09-27 2024-09-26 Antagoniste de dgkzêta et son utilisation en médecine Pending WO2025067360A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113365994A (zh) * 2019-12-25 2021-09-07 安斯泰来制药株式会社 哒嗪基噻唑甲酰胺类化合物
WO2021214019A1 (fr) * 2020-04-24 2021-10-28 Bayer Aktiengesellschaft Aminothiazoles substitués utilisés comme inhibiteurs de la dgk zêta pour l'activation immunitaire
CN115515685A (zh) * 2020-03-03 2022-12-23 皮克医疗公司 Eif4e抑制剂及其用途
WO2023028238A1 (fr) * 2021-08-25 2023-03-02 PIC Therapeutics, Inc. Inhibiteurs d'eif4e et leurs utilisations
CN116528864A (zh) * 2020-11-30 2023-08-01 安斯泰来制药株式会社 杂芳基甲酰胺化合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113365994A (zh) * 2019-12-25 2021-09-07 安斯泰来制药株式会社 哒嗪基噻唑甲酰胺类化合物
CN115515685A (zh) * 2020-03-03 2022-12-23 皮克医疗公司 Eif4e抑制剂及其用途
WO2021214019A1 (fr) * 2020-04-24 2021-10-28 Bayer Aktiengesellschaft Aminothiazoles substitués utilisés comme inhibiteurs de la dgk zêta pour l'activation immunitaire
CN115697979A (zh) * 2020-04-24 2023-02-03 拜耳公司 作为用于免疫激活的dgkzeta抑制剂的取代的氨基噻唑类
CN116528864A (zh) * 2020-11-30 2023-08-01 安斯泰来制药株式会社 杂芳基甲酰胺化合物
WO2023028238A1 (fr) * 2021-08-25 2023-03-02 PIC Therapeutics, Inc. Inhibiteurs d'eif4e et leurs utilisations

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