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WO2024235203A1 - COMPOSÉ UTILISÉ COMME INHIBITEUR DE DGKζ - Google Patents

COMPOSÉ UTILISÉ COMME INHIBITEUR DE DGKζ Download PDF

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Publication number
WO2024235203A1
WO2024235203A1 PCT/CN2024/092900 CN2024092900W WO2024235203A1 WO 2024235203 A1 WO2024235203 A1 WO 2024235203A1 CN 2024092900 W CN2024092900 W CN 2024092900W WO 2024235203 A1 WO2024235203 A1 WO 2024235203A1
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Prior art keywords
phenyl
membered
alkylene
heteroaryl
independently
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PCT/CN2024/092900
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Chinese (zh)
Inventor
谢雨礼
吴应鸣
吕永聪
刘文中
钱立晖
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Wigen Biomedicine Technology Shanghai Co Ltd
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Wigen Biomedicine Technology Shanghai 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
    • A61K31/41—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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • 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
    • C07D417/10—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 aromatic rings

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and more specifically, relates to a class of compounds having DGK ⁇ protein inhibitory effect, and a preparation method thereof and the use of the compounds in preparing drugs for treating or preventing related diseases mediated by DGK ⁇ .
  • DGK ⁇ , ⁇ , and ⁇ belong to the diacylglycerol kinase (DGK) family.
  • DGK represents a family of enzymes that catalyze the phosphorylation of the membrane ester sn-1,2-diacylglycerol (DAG) to form phosphatidic acid (PA).
  • DAG diacylglycerol
  • PA phosphatidic acid
  • the DGKs family catalyzes the phosphorylation of DAG to PA, thereby regulating DAG-mediated signals.
  • DGK ⁇ and DGK ⁇ are significantly expressed in T cells, and their expression and activity are enhanced upon TCR stimulation, while persistent expression is associated with low responsiveness of tumor-infiltrating T cells.
  • DGK ⁇ -deficient CAR chimeric antigen receptor
  • DGK ⁇ is also associated with natural killer (NK) cells. After stimulation by multiple activating receptors, NK cells from mice lacking DGK ⁇ show increased cytokine production and shedding in an ERK-dependent manner. In addition, they have improved cytotoxic function against tumor cell lines. In addition to immunomodulation, DGK ⁇ also plays other roles in cancer, mediating proliferation, apoptosis, survival, invasion, etc.
  • DGK ⁇ can bind to RasGRP3 and reduce Rap1 activation. Inhibiting the activity of DGK ⁇ can significantly reduce the activation of the Ras signaling pathway. In the phorbol ester-induced tumor model, DGK ⁇ -deficient mice can significantly inhibit tumor formation compared with wild-type mice.
  • DGK ⁇ inhibitors play an important role in malignant solid tumors or blood tumors (such as acute myeloid leukemia, bladder epithelial cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, melanoma, etc.), autoimmune diseases (such as systemic lupus erythematosus, psoriasis, arthritis, etc.) and inflammatory responses.
  • Inhibiting DGK ⁇ activity can reduce the activation of the Ras signaling pathway and inhibit the formation of tumors related to the over-activation of the Ras signaling pathway.
  • the present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • R 3 is -CH 3 or -NH 2 ;
  • Rx is H or F:
  • R 4 is a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group may be independently optionally substituted by 1 of the following groups: phenyl, wherein the phenyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, halogen, -CN, -NO 2 , (C1-C6) alkyl, (C1-C6) haloalkyl, -(C1-C3) alkylene-phenyl, -(C1-C3) alkylene-(5-6-membered) heteroaryl, -(C1-C3) alkylene-(C3-C7) heterocycloalkyl, -(C1-C3) alkylene-(OR 9 ), (C3-C7) cycloalkyl, -OR 9 , -N(R 10 )(R 11 ), -(C1-C3) alkylene-(N(R 10 )(R 11 ), -(C1-
  • R1 is phenyl or (5-6 membered) heteroaryl, wherein the phenyl or (5-6 membered) heteroaryl may each independently be optionally substituted by 1, 2 or 3 of the following groups: -H, halogen, -OH, -CN, -NO2, (C1- C6 ) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C5-C6) cycloalkenyl, (C2-C6) alkynyl, -(C1-C3) alkylene-phenyl, (C1-C6) alkoxy, -(C1-C3) alkyleneoxy-phenyl, (C1-C6) haloalkoxy or -N( R5 )( R6 ), wherein the phenyl in the -(C1-C3) alkylene-phenyl and -(C1-C3) alkyleneoxy-phenyl may each independently be optionally substituted by 1 or
  • R 1 is phenyl or (5-6 membered) heteroaryl, wherein the phenyl or (5-6 membered) heteroaryl may be independently optionally substituted by 1, 2 or 3 of the following groups: (C2-C6) alkenyl, (C5-C6) cycloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkenyl, (C5-C6) halocycloalkenyl or (C2-C6) haloalkynyl;
  • R4 is phenyl or (5-6 membered) heteroaryl, wherein the phenyl or (5-6 membered) heteroaryl may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, halogen, -CN, -NO2, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C5-C6) cycloalkenyl, (C2-C6) alkynyl, (C2-C6) haloalkenyl, (C5-C6) halocycloalkenyl, (C2-C6) haloalkynyl, (4-7 membered) heterocycloalkyl, -O-(C2-C6) alkenyl, -O-(C5-C6) cycloalkenyl, -O-(C5-C6) cycloalkenyl, -O-(C2-C6) alkynyl,
  • R 1 is phenyl or (5-6 membered) heteroaryl, wherein the phenyl or (5-6 membered) heteroaryl can be independently optionally substituted by 1, 2 or 3 of the following groups: -H, halogen, -OH, -CN, -NO 2 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C5-C6) cycloalkenyl, (C2-C6) alkynyl, -(C1-C3) alkylene-phenyl, (C1-C6) alkoxy, -(C1-C3) alkoxy-phenyl, (C1-C6) haloalkoxy or -N(R 5 )(R 6 ), wherein the phenyl in the -(C1-C3) alkylene-phenyl and -(C1-C3) alkyleneoxy-phenyl can be independently optionally substituted by 1 or 2 of the
  • Ra and Rb are each independently (C1-C4)alkyl or (C3-C4)cycloalkyl;
  • R 5 and R 6 together with the N atom to which they are connected may form a (4-7 membered) heterocycloalkyl group, wherein the (4-7 membered) heterocycloalkyl group may be independently Optionally substituted with 1, 2 or 3 of the following groups: -H, halogen, -OH, (C1-C4)alkyl, -C( ⁇ O)-(C1-C4)alkyl, (C3-C4)cycloalkyl or (C1-C4)alkoxy;
  • R 7 is H, -CH 3 or -CH 2 CH 3 ;
  • R 9 is H, (C1-C6) alkyl, (C2-C6) alkenyl, (C5-C6) cycloalkenyl, (C2-C6) alkynyl, (C1-C6) alkyl, -(C1-C3) alkylene-(5-6 membered) heteroaryl, -(C1-C3) alkylene-phenyl, (C1-C6) haloalkyl, hydroxy-substituted (C2-C4) alkyl, -(C2-C3) alkylene-(C1-C3) alkoxy, -(C2-C3) alkylene-OC( ⁇ O)-(C1-C3) alkyl, -C(R 18 )(R 19 )-C( ⁇ O)-OR 17 , -C(R 18 )(R 19 )-C( ⁇ O)-OR 17 , -C(R 18 )(R 19 )-C( ⁇ O)-N(R 20 )(R 21
  • R10 and R11 together with the N atom to which they are attached may form a (4-11 membered) heterocycloalkyl group, wherein the (4-11 membered) heterocycloalkyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, halogen, -CN, -OH, (C1-C4)alkyl, (C1-C4)haloalkyl, -C( ⁇ O)-(C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, -N(R 22 )(R 23 ) or (4-7 membered)heterocycloalkyl;
  • R12 and R13 are each independently -H, (C1-C4) alkyl, (C1-C4) haloalkyl, hydroxy-substituted (C1-C4) alkyl, -(C2-C3) alkylene-(C1-C4) alkoxy, -(C2-C3) alkylene-(C1-C4) haloalkoxy, -(C2-C3) alkylene-phenoxy, (C3-C7) cycloalkyl, (C4-C7) heterocycloalkyl or -(C1-C3) alkylene-phenyl, wherein the phenyl, (C3-C7) cycloalkyl and (C4-C7) heterocycloalkyl in the -(C2-C3) alkylene-phenoxy and -(C1-C3) alkylene-phenyl may each independently be optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH, -N(CH 3
  • R 12 and R 13 together with the N atom to which they are attached may form a (4-7 membered) heterocycloalkyl, wherein the (4-7 membered) heterocycloalkyl may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH, (C1-C4)alkyl, -C( ⁇ O)-(C1-C4)alkyl, (C3-C4)cycloalkyl or (C1-C4)alkoxy;
  • R 14 is (C1-C4) alkyl, (C1-C4) alkoxy or phenyl, wherein the phenyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: Group substitution: -H, -CN, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -N(CH 3 ) 2 or -CF 3 ;
  • R 17 is (C1-C4) alkyl
  • R 18 and R 19 are each independently -H or (C1-C4) alkyl
  • R 20 is H, (C1-C6)alkyl, (C3-C4)alkenyl, (C2-C4)alkynyl or (C1-C3)alkoxy, wherein the (C1-C6)alkyl may be substituted by 1, 2 or 3 of the following groups: -H, halogen, -CN, (C1-C4)alkoxy, -N(R 22 )(R 23 ), (C3-C11)cycloalkyl, (4-11 membered)heterocycloalkyl, phenyl or (5-10 membered)heteroaryl, wherein the phenyl or (5-10 membered)heteroaryl may be substituted by 1, 2 or 3 of the following groups: -H, -F, -CN, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -N(CH 3 ) 2 or -CF 3 ;
  • R 20 is (C3-C11) cycloalkyl, (4-11 membered) heterocycloalkyl, wherein the (C3-C11) cycloalkyl and (4-11 membered) heterocycloalkyl may each independently be optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH, (C1-C4)alkyl, -C( ⁇ O)-(C1-C4)alkyl, (C3-C4)cycloalkyl or (C1-C4)alkoxy;
  • R 20 is phenyl, naphthyl or (5-10 membered)heteroaryl, wherein the phenyl, naphthyl and (5-10 membered)heteroaryl groups are each independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, -N(R 22 )(R 23 ) or -C( ⁇ O)(R 24 )(R 25 );
  • R 21 is H or (C1-C4) alkyl
  • R 20 and R 21 together with the N atom to which they are attached can form a (4-7 membered) heterocycloalkyl group, wherein the (4-7 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2 or 3 of the following groups: -H, halogen, -CN, -OH, (C1-C4)alkyl, (C1-C4)haloalkyl, -(C1-C3)alkylene-phenyl, -C( ⁇ O)-(C1-C4)alkyl, (C3-C4)cycloalkyl, (C1-C4)alkoxy, (C1-C3)haloalkoxy, -N(R 22 )(R 23 ) or -C( ⁇ O)(R 24 )(R 25 );
  • R 24 and R 25 are each independently -H or (C1-C4) alkyl
  • n is an integer of 0, 1 or 2.
  • R 2 is
  • R 4 is phenyl or (5-6 membered) heteroaryl, wherein the phenyl or (5-6 membered) heteroaryl can be independently substituted by 1, 2 or 3 of the following groups: -H, -F, -Cl, -Br, -I, -CN, -NO 2 , (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C5-C6) cycloalkenyl, (C2-C4) alkynyl, (C2-C4) haloalkenyl, (C5-C6) halocycloalkenyl, (C2-C4) haloalkynyl, (4-7 membered) heterocycloalkyl, -O-(C2-C4) alkenyl, -O-(C5-C6) cycloalkenyl, -O-(C2-C4) alkenyl, -O-(C2-C4) alkeny
  • R1 is phenyl or (5-6 membered) heteroaryl, wherein the phenyl or (5-6 membered) heteroaryl can be independently substituted by 1, 2 or 3 of the following groups: -H, -F, -Cl, -Br, -OH, -CN , -NO2, (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C5-C6) cycloalkenyl, (C2-C4) alkynyl, -(C1-C2) alkylene-phenyl, (C1-C4) alkoxy, -(C1-C2) alkyleneoxy-phenyl, (C1-C4) haloalkoxy or -N( R5 )( R6 ), wherein the phenyl in the -(C1-C2) alkylene-phenyl and -(C1-C2) alkyleneoxy-phenyl can be independently substituted
  • R 4 is phenyl or a (5-6-membered) heteroaryl group containing 1, 2 or 3 groups independently selected from N, O or S, wherein the phenyl group and the (5-6-membered) heteroaryl group are each independently optionally substituted by 1, 2 or 3 of the following groups: H, F, Cl, Br, CN, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 ; and
  • R1 is phenyl, wherein the phenyl is independently optionally substituted with 1, 2 or 3 of the following groups: H, F, Cl, Br, CN, -CH3, -CH2CH3 , -OCH3 , -OCH2CH3 .
  • R 4 is:
  • R1 is phenyl or (5-6 membered) heteroaryl, wherein the phenyl or (5-6 membered) heteroaryl can be independently substituted by 1, 2 or 3 of the following groups: -H, -F, -Cl, -Br, -OH, -CN , -NO2, (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C5-C6) cycloalkenyl, (C2-C4) alkynyl, -(C1-C2) alkylene-phenyl, (C1-C4) alkoxy, -(C1-C2) alkyleneoxy-phenyl, (C1-C4) haloalkoxy or -N( R5 )( R6 ), wherein the phenyl in the -(C1-C2) alkylene-phenyl and -(C1-C2) alkyleneoxy-phenyl can be independently substituted
  • R1 is phenyl, wherein the phenyl is independently optionally substituted with 1, 2 or 3 of the following groups: H, F, Cl, Br, CN, -CH3, -CH2CH3 , -OCH3 , -OCH2CH3 .
  • R4 is phenyl, pyridyl or oxadiazolyl, wherein the phenyl, pyridyl or oxadiazolyl are each independently optionally substituted by 1, 2 or 3 of the following groups:
  • R1 is phenyl, wherein said phenyl is independently optionally substituted with 1, 2 or 3 of the following groups: H, F and Cl.
  • R 4 is:
  • R 4 is:
  • R 4 is phenyl or (5-6 membered) heteroaryl, wherein the phenyl or (5-6 membered) heteroaryl can be independently substituted by 1, 2 or 3 of the following groups: -H, -F, -Cl, -Br, -I, -CN, -NO 2 , (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C5-C6) cycloalkenyl, (C2-C4) alkynyl, (C2-C4) haloalkenyl, (C5-C6) halocycloalkenyl, (C2-C4) haloalkynyl, -O-(C2-C4) alkenyl, -O-(C5-C6) cycloalkenyl, -O-(C2-C4) alkynyl, -O-(C2-C4) alkenyl, -O-(C5-C6)
  • R1 is phenyl or (5-6 membered) heteroaryl, wherein the phenyl or (5-6 membered) heteroaryl may each independently be optionally substituted by 1, 2 or 3 of the following groups: (C2-C4) alkenyl, (C5-C6) cycloalkenyl, (C2-C4) alkynyl, (C2-C4) haloalkenyl, (C5-C6) halocycloalkenyl or (C2-C4) haloalkynyl.
  • R 4 is a phenyl group, wherein the phenyl group is independently optionally substituted by 1, 2 or 3 of the following groups: H, F, Cl, Br, CN, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 ; and
  • R 1 is phenyl, wherein the phenyl group is independently optionally substituted by 1, 2 or 3 of the following groups: (C2-C3)alkenyl, (C2-C3)alkynyl, (C2-C3)haloalkenyl, (C5-C6)cycloalkenyl, (C5-C6)halocycloalkenyl.
  • R 4 is a phenyl group, wherein the phenyl group is independently optionally substituted by 1, 2 or 3 of the following groups: H, F and Cl; and
  • R 1 is phenyl, wherein the phenyl group is independently optionally substituted by 1, 2 or 3 of the following groups:
  • R 4 is:
  • R 4 is a 6-membered heteroaryl group, wherein the 6-membered heteroaryl group can be independently substituted by one of the following groups: phenyl, wherein the phenyl group can be independently substituted by one, two or three of the following groups: -H, -F, -Cl, -Br, -CN, -NO 2 , (C1-C4) alkyl, (C1-C4) haloalkyl, -(C1-C2) alkylene-phenyl, -(C1-C2) alkylene-(5-6-membered) heteroaryl, -(C1-C2) alkylene-(C3-C7) heterocycloalkyl, -(C1-C2) alkylene-(OR 9 ), (C3-C7) cycloalkyl, -OR 9 , -N(R 10 )(R 11 ), -(C1-
  • R 1 is phenyl or (5-6 membered) heteroaryl, wherein the phenyl or (5-6 membered) heteroaryl may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -F, -Cl, -Br, -OH, -CN, -NO 2 , (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C5- -C6)cycloalkenyl, (C2-C4)alkynyl, -(C1-C2)alkylene-phenyl, (C1-C4)alkoxy, -(C1-C2)alkyleneoxy-phenyl, (C1-C4)haloalkoxy or -N( R5 )( R6 ), wherein the phenyl group in said -(C1-C2)alkylene-phenyl and -(C1-C2)alkyleneoxy-phenyl may
  • R1 is phenyl, wherein the phenyl is independently optionally substituted with 1, 2 or 3 of the following groups: H, F, Cl, Br, CN, -CH3, -CH2CH3 , -OCH3 , -OCH2CH3 .
  • R1 is phenyl, wherein said phenyl is independently optionally substituted with 1, 2 or 3 of the following groups: H, F and Cl.
  • R 4 is:
  • R 4 is
  • Ra and Rb are each independently -CH3 or -CH2CH3 .
  • R 9 is H, -CHF 2 , -CF 3 , -CH 2 CF 3 ,
  • R 12 and R 13 are each independently -H, (C1-C3) alkyl, (C1-C3) haloalkyl, hydroxy-substituted (C1-C3) alkyl, -(C2-C3) alkylene-(C1-C3) alkoxy, -(C2-C3) alkylene-(C1-C3) haloalkoxy, -(C2-C3) alkylene-phenoxy, (C3-C7) cycloalkyl, (C4-C7) heterocycloalkyl or -(C1-C2) alkylene-phenyl, wherein the phenyl, (C3-C7) cycloalkyl and (C4-C7) heterocycloalkyl in the -(C2-C3) alkylene-phenoxy and -(C1-C2) alkylene-phenyl can be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN,
  • R 12 and R 13 are each independently -H, -CH 3 , -CH 2 CH 3 ,
  • R 14 is (C1-C2) alkyl, (C1-C2) alkoxy or phenyl, wherein the phenyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -OCF 3 , -N(CH 3 ) 2 or -CF 3 .
  • R 14 is -CH 3 , -CH 2 CH 3 , -OCH 3 or -OCH 2 CH 3 .
  • R 17 is -CH 3 or -CH 2 CH 3 .
  • R 18 and R 19 are each independently -H, -CH 3 or -CH 2 CH 3 .
  • R 20 is H, (C1-C3) alkyl, (C3-C4) alkenyl, (C2-C4) alkynyl or (C1- C3 )alkoxy, wherein the (C1-C3)alkyl group may be substituted by 1, 2 or 3 of the following groups: -H, -F, -Cl, -CN, -OCH3 , -OCH2CH3 , -NH2 , -N( CH3 ) 2 , (C3-C7)cycloalkyl, (4-7 membered)heterocycloalkyl, phenyl or (5-10 membered)heteroaryl, wherein the phenyl or (5-10 membered)heteroaryl group may be substituted by 1, 2 or 3 of the following groups: -H, -F, -CN, -CH3 , -CH2CH3 , -OCH3 , -OCH2CH3
  • R 20 is phenyl, naphthyl or (5-10 membered)heteroaryl, wherein the phenyl, naphthyl and (5-10 membered)heteroaryl may each independently be optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -CF 3 , -N(CH 3 ) 2 or -C( ⁇ O)(CH 3 ) 2 .
  • R 21 is H, -CH 3 or -CH 2 CH 3 ;
  • the (4-7 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2 or 3 of the following groups: -H, halogen, -CN, -OH, -CH 3 , -CH 2 CH 3 , -CF 3 , -(C1-
  • R 24 and R 25 are each independently -H, -CH 3 or -CH 2 CH 3 .
  • the compound of formula (1) has one of the following structures:
  • the compound of formula (1) has one of the following structures:
  • the compound of formula (1) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and a compound of the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.
  • Another object of the present invention is to provide the use of the compound represented by the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above pharmaceutical compositions for preparing drugs for treating, regulating or preventing diseases related to DGK ⁇ protein.
  • the disease is preferably cancer, and the cancer is blood cancer and solid tumor.
  • Another object of the present invention is to provide a method for treating, regulating or preventing diseases related to DGK ⁇ protein, comprising administering to a subject a therapeutically effective amount of a compound represented by the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical compositions.
  • the compounds of formula (1) described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein.
  • the solvents, temperatures and other reaction conditions mentioned herein can be varied.
  • the starting materials used for the synthesis of the compounds can be synthesized or obtained from commercial sources.
  • the compounds described herein and other related compounds with different substituents can be synthesized using known techniques and raw materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4th Ed., Vols.
  • the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, the amount of compounds used, reaction temperature, reaction time, etc., are not limited to the following explanation.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily performed by a person skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared using the following general reaction schemes 1-4:
  • Embodiments of the compound of formula (1) can be prepared according to general reaction scheme 1, wherein R 1 , R 4 , R 7 and R x are as defined above, N represents nitrogen, O represents oxygen, S represents sulfur, Cl represents chlorine, and Br represents bromine.
  • R 1 , R 4 , R 7 and R x are as defined above, N represents nitrogen, O represents oxygen, S represents sulfur, Cl represents chlorine, and Br represents bromine.
  • compound 1-1 undergoes substitution reaction with NH 2 CN to generate compound 1-2
  • compound 1-2 and compound 1-3 undergo condensation reaction to generate compound 1-4
  • compound 1-4 reacts with (Boc) 2 O to generate compound 1-5
  • compound 1-5 and compound 1-6 undergo substitution reaction to generate target compound 1-7.
  • compound 1-7 is subjected to chiral resolution to obtain optical isomers 1-7-A and 1-7-B.
  • Embodiments of compounds of formula (1) can be prepared according to general reaction scheme 2, wherein R 1 , R 7 and R x are as defined above, ring A is a substituted benzene ring or a substituted heteroaryl ring, ring B is a substituted cycloalkenyl ring or a substituted heterocycloalkenyl ring, ring C is a substituted cycloalkyl ring or a substituted heterocycloalkyl ring, N represents nitrogen, O represents oxygen, S represents sulfur, Cl represents chlorine, Br represents bromine, and X represents Br, Cl or I.
  • compound 2-1 undergoes substitution reaction with NH 2 CN to generate compound 2-2
  • compound 2-2 and compound 2-3 undergo condensation reaction to generate compound 2-4
  • compound 2-4 reacts with (Boc) 2 O to generate compound 2-5
  • compound 2-5 and compound 2-6 undergo coupling reaction to generate compound 2-7
  • compound 2-7 and compound 2-8 undergo substitution reaction to generate target compound 2-9
  • compound 2-9 undergoes hydrogenation reaction to generate compound 2-10
  • compound 2-10 is subjected to chiral separation to obtain optical isomers 2-10-A and 2-10-B.
  • the embodiments of the compound of formula (1) can be prepared according to general reaction scheme 3, wherein R 1 , R 7 and R x are as defined above, ring A is a substituted benzene ring or a substituted heteroaryl, ring D is a substituted benzene ring or a substituted heteroaryl, N represents nitrogen, O represents oxygen, S represents sulfur, Cl represents chlorine, Br represents bromine, and X represents Br, Cl or I.
  • compound 3-1 and NH 2 CN undergo substitution reaction to generate compound 3-2
  • compound 3-2 and compound 3-3 undergo condensation reaction to generate compound 3-4
  • compound 3-4 reacts with (Boc) 2 O to generate compound 3-5
  • compound 3-5 and compound 3-6 undergo coupling reaction to generate compound 3-7
  • compound 3-7 and compound 3-8 undergo substitution reaction to generate target compound 3-9
  • compound 3-9 is subjected to chiral resolution to obtain optical isomers 3-9-A and 3-9-B.
  • the embodiments of the compound of formula (1) can be prepared according to the general reaction scheme 4, wherein R 1 , R 7 and R x are as defined above, ring A is a substituted benzene ring or a substituted heteroaryl, R 0 is a substituted alkyl, a substituted alkenyl, a substituted alkynyl, a substituted cycloalkyl, a substituted cycloalkenyl, a substituted cycloalkynyl, a substituted haloalkyl, a substituted haloalkenyl or a substituted haloalkynyl, N represents nitrogen, O represents oxygen, S represents sulfur, Cl represents chlorine, Br represents bromine, and X represents Br, Cl or I.
  • compound 4-1 undergoes substitution reaction with NH 2 CN to generate compound 4-2, compound 4-2 and compound 4-3 undergo condensation reaction to generate compound 4-4, compound 4-4 reacts with (Boc) 2 O to generate compound 4-5, compound 4-5 and compound 4-6 undergo coupling reaction to generate compound 4-7, compound 4-7 and compound 4-8 undergo substitution reaction to generate target compound 4-9, and in some cases, compound 4-9 is subjected to chiral resolution to obtain optical isomers 4-9-A and 4-9-B.
  • “Pharmaceutically acceptable” as used herein refers to a material, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a material that, when administered to a subject, does not cause undesirable biological effects or interact in a deleterious manner with any of its constituent components.
  • a pharmaceutically acceptable salt refers to a form of a compound that does not cause significant irritation to the administered organism and does not eliminate the biological activity and properties of the compound.
  • a pharmaceutically acceptable salt is obtained by reacting a compound of the general formula with an acid or base, wherein the acid or base includes, but is not limited to, acids and bases found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1st Ed., (Wiley, 2002).
  • references to pharmaceutically acceptable salts include solvent-added forms or crystal forms, particularly solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvents used include, but are not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated form is considered to be equivalent to the unsolvated form.
  • the compound of formula (1) is prepared in different forms, including but not limited to amorphous, crushed and nano-particle forms.
  • the compound of formula (1) includes crystalline forms and can also be used as polymorphs. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvents, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • the compounds of formula (1) may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, Single enantiomers, diastereomeric compounds and single diastereomeric forms, and cis-trans isomers occur.
  • Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures and pure or partially purified compounds are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more atoms constituting the compound.
  • compounds may be labeled with radioactive isotopes, such as tritium ( 3H ), iodine-125 ( 125I ) and C-14 ( 14C ).
  • radioactive isotopes such as tritium ( 3H ), iodine-125 ( 125I ) and C-14 ( 14C ).
  • deuterated compounds may be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs Compared with undeuterated drugs, deuterated drugs generally have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the half-life of drugs in vivo. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • any atom of the compounds of the present invention refers to the isotope of the atom in its stable state.
  • the site when a site on the molecular structure is selected as "H” or “hydrogen”, the site should be understood to have the natural abundance of hydrogen isotopes.
  • the site when a site is selected as "D” or “deuterium”, the site should be understood to have a deuterium isotope abundance of at least 3000 times its natural abundance (the natural abundance of deuterium isotopes is 0.015%).
  • the deuterium atom abundance at each deuterated site of the deuterated compound of the present invention is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, it is at least 4500 times (67.5% deuterium atom enrichment). More preferably, it is at least 5000 times (75% deuterium atom enrichment). More preferably, it is at least 6000 times (90% deuterium atom enrichment). More preferably, it is at least 6333 times (95% deuterium atom enrichment). More preferably, it is at least 6466.7 times (97% deuterium atom enrichment). More preferably, it is at least 6600 times (99% deuterium atom enrichment). More preferably, it is at least 6633.3 times (99.5% deuterium atom enrichment).
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. Preferred are lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. More preferred are lower alkyl groups containing 1-3 carbon atoms, such as methyl, ethyl, propyl, 2-propyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted by one or more halogens.
  • Preferred alkyl groups are selected from CH 3 , CH 3 CH 2 , CF 3 , CHF 2 , CF 3 CH 2 , CF 3 (CH 3 )CH, i Pr, n Pr, i Bu, n Bu or t Bu.
  • alkylene refers to a divalent alkyl group as defined above.
  • alkylene groups include, but are not limited to, methylene and ethylene.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups of 1 to 14 carbon atoms.
  • the lower alkenyl group contains 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl. More preferably, the lower alkenyl group contains 1 to 2 carbon atoms.
  • alkenylene refers to a divalent alkenyl group as defined above.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chains of 1 to 14 carbon atoms.
  • a chain group Preferably, it is a lower alkynyl group having 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl. More preferably, it is a lower alkynyl group having 1 to 2 carbon atoms.
  • alkynylene refers to a divalent alkynyl group as defined above.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), preferably a non-aromatic hydrocarbon ring system containing 3-14 ring carbon atoms (C 3-14 cycloalkyl).
  • the cycloalkyl has 3-10 ring carbon atoms (C 3-10 cycloalkyl).
  • the cycloalkyl has 3-8 ring carbon atoms (C 3-8 cycloalkyl).
  • the cycloalkyl has 3-7 ring carbon atoms (C 3-7 cycloalkyl).
  • the cycloalkyl has 3-6 ring carbon atoms (C 3-6 cycloalkyl). In some embodiments, the cycloalkyl has 4-6 ring carbon atoms (C 4-6 cycloalkyl). In some embodiments, the cycloalkyl has 5-6 ring carbon atoms (C 5-6 cycloalkyl). In some embodiments, the cycloalkyl has 5-10 ring carbon atoms (C 5-10 cycloalkyl).
  • Cycloalkyl If the carbocyclic ring contains at least one double bond, then the partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl group", or if the carbocyclic ring contains at least one triple bond, then the partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl group”. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic.
  • the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is tricyclic. The ring-forming carbon atoms of the cycloalkyl group may be optionally oxidized to form an oxo or thio group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl groups).
  • the cycloalkyl group may be fused with an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, the cycloalkyl group may be fused with an aryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, cycloalkyl can be fused with aryl and heterocycloalkyl. In some embodiments, cycloalkyl can be fused with aryl and cycloalkyl.
  • cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinenyl, norcarbyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, etc.
  • cycloalkylene refers to a divalent cycloalkyl group as defined above.
  • alkoxy refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy groups, especially alkoxy groups substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH3 , OCF3 , CHF2O , CF3CH2O , i- PrO , n- PrO, i- BuO, n- BuO or t- BuO.
  • aryl refers to a hydrocarbon aromatic group, which is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups.
  • aryl include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.
  • aryloxy refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom.
  • aryloxy include, but are not limited to, phenoxy and naphthoxy.
  • arylene refers to a divalent aromatic radical as defined above.
  • arylene radicals include, but are not limited to, 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, naphthylene, and phenanthrenylene.
  • heteroaryl refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms, the heteroatoms being independently selected from O, N or S, the number of heteroatoms being preferably 1, 2, 3 or 4, preferably a 5-14-membered aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, more preferably a 5-9-membered aromatic group containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen, more preferably a 5-6-membered aromatic group containing 1-3 heteroatoms selected from oxygen, sulfur or nitrogen.
  • Heteroaryl is monocyclic or polycyclic.
  • Monocyclic heteroaryl is preferably The heteroaryl group is preferably a 5-6 membered aromatic group containing 1-3 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6 membered aromatic group containing 1-2 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6 membered aromatic group containing 1 heteroatom selected from oxygen, nitrogen or sulfur. In some embodiments, the monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrol
  • heteroarylene refers to a divalent heteroaryl group as defined above.
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and selenium, preferably a saturated or partially unsaturated ring containing 1-4 heteroatoms selected from oxygen, sulfur or nitrogen, and more preferably a saturated or partially unsaturated ring containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen.
  • heterocycloalkyl is a 5-14-membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-14-membered heterocycloalkyl).
  • heterocycloalkyl is a 3-9-membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (3-9-membered heterocycloalkyl).
  • heterocycloalkyl is a 5-8 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-8 membered heterocycloalkyl).
  • heterocycloalkyl is a 5-6 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-6 membered heterocycloalkyl).
  • 5-6 membered heterocycloalkyl contains 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • 5-6 membered heterocycloalkyl contains 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocycloalkyl contains 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur.
  • heterocycloalkyl is a 10-13 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (10-13 membered heterocycloalkyl). In some embodiments, 10-13 membered heterocycloalkyl contains 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • 10-13 membered heterocycloalkyl contains 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 10-13 membered heterocycloalkyl contains 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. If the heterocycloalkyl contains at least one double bond, the partially unsaturated heterocycloalkyl may be referred to as "heterocycloalkenyl", or if the heterocycloalkyl contains at least one triple bond, the partially unsaturated heterocycloalkyl may be referred to as "heterocycloalkynyl".
  • Heterocycloalkyl may include monocyclic, bicyclic, spirocyclic or polycyclic (e.g., having two fused or bridged rings) ring systems.
  • heterocycloalkyl is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen.
  • the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group may be optionally oxidized to form oxo or thio groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) 2 , N-oxides, etc.), or the nitrogen atom may be quaternized.
  • the heterocycloalkyl group may be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group may be substituted with a quaternary ammonium atom. Cycloalkyl contains 0 to 3 double bonds. In certain embodiments, heterocycloalkyl contains 0 to 2 double bonds.
  • heterocycloalkyl also includes a portion (also referred to as partially unsaturated heterocycle) of an aromatic ring with one or more fused to a heterocycloalkyl ring (i.e., sharing a key with it), such as the benzo derivatives of piperidine, morpholine, azacycloheptatriene or tetrahydrothienyl, and the pyrido derivatives of piperidine, morpholine, azacycloheptatriene or tetrahydrothienyl, etc.
  • the heterocycloalkyl containing a fused aromatic ring can be connected via any ring-forming atoms, including the ring-forming atoms of a fused aromatic ring.
  • heterocycloalkyl examples include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazole, oxazolo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydr
  • heterocycloalkylene refers to a divalent heterocycloalkyl group as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substituted
  • appearing before the name of a group means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.
  • substituted means that one or more hydrogen atoms on a specified atom or group are replaced by one or more substituents other than hydrogen, without exceeding the normal valence of the specified atom.
  • substituents for example, one or more hydrogens of an alkyl, alkylene, alkenyl, alkynyl, hydroxyl or amine group may be replaced by one or more substituents.
  • substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxyl, hydrazine, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione or a combination thereof.
  • substituted does not include similar indefinite structures obtained by defining substituents with further substituents attached to infinity (e.g., a substituted aryl with a substituted alkyl group is itself substituted by a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.).
  • the maximum number of consecutive substitutions in the compounds described herein is 1. The maximum number is three.
  • the substituted aryl is continuously substituted by two other substituted aryls and is limited to the aryl substituted by ((substituted aryl) substituted aryl).
  • substituted can describe other chemical groups defined herein.
  • substituted aryl includes but is not limited to "alkyl aryl”. Unless otherwise specified, if a group is described as optionally substituted, any substituent of the group itself is unsubstituted.
  • the substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, for example:
  • linking group When the number of a linking group is 0, such as -(CH2) 0- , it means that the linking group is a single bond.
  • membered ring includes any cyclic structure.
  • membered means the number of backbone atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, thiopyranyl are six-membered rings
  • cyclopentyl, pyrrolyl, furanyl, and thienyl are five-membered rings.
  • fragment refers to a specific part or functional group of a molecule.
  • a chemical fragment is generally considered to be a chemical entity contained in or attached to a molecule.
  • isomer means any tautomer, stereoisomer, atropisomer, isotope, enantiomer or diastereomer of any compound of the invention.
  • the compounds of the invention may have one or more chiral centers or double bonds and therefore exist in stereoisomeric form, for example, in double bond isomers (i.e., E/Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis/trans isomers).
  • the compounds of the invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) forms as well as enantiomers and stereoisomer mixtures, such as racemates.
  • stereoisomerically pure e.g., geometrically pure, enantiomerically pure or diastereomerically pure
  • enantiomers and stereoisomer mixtures such as racemates.
  • Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can be separated into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, and crystallization of the compounds in the form of chiral salt complexes or crystallization of the compounds in chiral solvents.
  • Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates,
  • isotope isomers refers to different molecules whose structures differ only in their isotopes but are otherwise identical.
  • atropisomer refers to a conformational stereoisomer produced when rotation about a single bond within a molecule is prevented or greatly slowed due to steric interactions with the rest of the molecule and the substituents at either end of the single bond are asymmetric, i.e., atropisomers do not require a stereogenic center.
  • atropisomers do not require a stereogenic center.
  • single isomers may be allowed to Separation (LaPlante et al., J. Med. Chem. 2011, 54, 20, 7005), preferably separation by chiral resolution.
  • the key is a solid wedge. and dotted wedge key
  • a straight solid bond To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key
  • a wavy line Denotes a solid wedge bond or dotted wedge key
  • use a wavy line Represents a straight solid bond or straight dashed key
  • acceptable means that a formulation component or active ingredient has no undue deleterious effect on health and well-being for the general purpose of treatment.
  • treat include alleviating, inhibiting or improving symptoms or conditions of a disease; inhibiting the occurrence of complications; improving or preventing potential metabolic syndrome; inhibiting the occurrence of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom.
  • a compound or pharmaceutical composition after administration, can improve a disease, symptom or condition, especially improve its severity, delay the onset, slow the progression of the disease, or reduce the duration of the disease. Whether fixed or temporary administration, continuous administration or intermittent administration, can be attributed to or related to the administration.
  • Active ingredient refers to the compound shown in the general formula (1), and the pharmaceutically acceptable inorganic or organic salt of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers.
  • the asymmetric center that may exist depends on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition refers to a compound or composition that, when administered to a subject (human or animal), is capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administered refers to directly administering the compound or composition, or administering a prodrug, derivative, or analog of the active compound.
  • the compound of formula (1) or pharmaceutical composition of the present invention can generally be used to inhibit DGK ⁇ protein, and thus can be used to treat one or more diseases associated with the activity of DGK ⁇ protein. Therefore, in certain embodiments, the present invention provides a method for treating a disease mediated by DGK ⁇ protein, the method comprising the step of administering the compound of formula (1) of the present invention, or a pharmaceutically acceptable composition thereof, to a patient in need thereof.
  • a method for treating cancer comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of general formula (1).
  • the cancer includes, but is not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myeloproliferative syndrome) and solid tumors (cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, as well as stromal tumors), etc.
  • hematological malignancies leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myeloproliferative syndrome
  • solid tumors cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, as well as stromal tumors
  • head and neck cancer kidney cancer,
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts within the safe and effective amount range and pharmacologically acceptable excipients or carriers.
  • the "safe and effective amount” means that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective amount of the compound is determined according to the specific circumstances such as the age, condition, and course of treatment of the subject.
  • “Pharmaceutically acceptable excipients or carriers” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose
  • the compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compounds of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health status, which are all within the skill range of skilled physicians.
  • int_16-4 (33 g, crude product, 0.1 mol), DCM (400 mL), DIPEA (32.3 g, 0.25 mol) and DMAP (2.44 g, 0.02 mol) were added, and Boc 2 O (21.6 g, 0.1 mol) was added at room temperature under argon protection.
  • the mixture was stirred at room temperature for 72 h.
  • water 200 mL was added to the mixture, stirred, and separated.
  • the organic phase was washed with saturated sodium chloride solution and concentrated. The residue was purified by column chromatography to obtain a light brown solid product (25 g, yield: 57%).
  • Int_16-2 (3 g, 15.36 mmol), int_48-1 (4.69 g, 16.89 mmol) and sodium ethoxide (3.1 g, 46.08 mmol) were dissolved in tetrahydrofuran (150 mL), and the mixture was stirred at room temperature for 20 hours under argon protection. The reaction was completed by LC-MS monitoring, and the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid product (5.5 g, yield: 91.6%).
  • Int_48-3 500 mg, 1.07 mmol
  • K 3 PO 4 (687 mg, 3.23 mmol)
  • Pd(dppf)Cl 2 73 mg, 0.1 mmol
  • int_48-4 337 mg, 1.6 mmol
  • the reaction was completed by LC-MS monitoring, and the reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid product (377 mg, yield: 75.5%).
  • int_60-1 (10 g, 64.93 mmol) was dissolved in tetrahydrofuran (200 mL), the mixed solution was cooled to -78 ° C, LDA (2M, 32.46 mL, 64.93 mmol) was slowly added dropwise to the reaction solution, stirred at -78 ° C for 0.5 hours, and then int_60-2 (14.23 g, 97.39 mmol) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at -78 ° C for 2 hours and slowly warmed to room temperature.
  • LDA 32.46 mL, 64.93 mmol
  • Int_60-5 (6 g, 18.25 mmol) and lithium hydroxide monohydrate (1.53 g, 36.50 mmol) were dissolved in a mixed solvent of THF (100 mL) and water (50 mL), and the reaction solution was reacted at room temperature for 12 hours. The reaction was completed by LC-MS monitoring, and the pH value of the reaction solution was adjusted to 2-3 with dilute hydrochloric acid. The reaction solution was filtered and the filter cake was collected. The filter cake was dried to obtain a solid product (5 g, yield: 91.2%).
  • Int_60-7 (5 g, 15.66 mmol), int_60-8 (2.71 g, 18.80 mmol) and triethylamine (4.75 g, 46.98 mmol) were dissolved in DCM (150 mL), and the reaction solution was heated to 50°C for 12 hours. The reaction was completed after LC-MS monitoring, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid product (5.1 g, yield: 79.6%).
  • Int_60-10 (650 mg, 1.35 mmol) was dissolved in methanol (5 mL), and ammonia methanol solution (7N, 20 mL) was added, and the mixture was reacted at room temperature for 16 hours. The reaction was completed by LC-MS monitoring, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid product (450 mg, yield: 72.2%).
  • Int_16-2 (3 g, 15.36 mmol), int_72-1 (6.6 g, 30.72 mmol) and sodium ethoxide (3.1 g, 46.08 mmol) were dissolved in tetrahydrofuran (200 mL), and the mixture was stirred at room temperature for 20 hours under argon protection. The reaction was completed by LC-MS monitoring, and the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid product (4.3 g, yield: 86%).
  • Int_16-2 (3 g, 15.36 mmol), int_82-1 (4.7 g, 16.89 mmol) and sodium ethoxide (3.1 g, 46.08 mmol) were dissolved in tetrahydrofuran (150 mL), and the mixture was stirred at room temperature for 20 hours under argon protection. The reaction was completed by LC-MS monitoring, and the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 5.1 g of a solid product, with a yield of 85%).
  • Int_82-3 500 mg, 1.07 mmol
  • K 3 PO 4 (687 mg, 3.23 mmol)
  • Pd(dppf)Cl 2 73 mg, 0.1 mmol
  • int_82-4 545 mg, 2.67 mmol
  • the reaction was completed by LC-MS monitoring, and the reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid product (410 mg, yield: 83.1%).
  • the target compounds 1-15, 19-45, 47, 49-59, 63-71, 75-81, 83-101, 104-348 and 351-365 in Table 1 can be obtained.
  • 3uL of DGK ⁇ enzyme (90ng/mL) dissolved in Assay buffer (40mM Tris-HCl, 10mM MgCl 2 , 0.1mg/mL BSA, 50 ⁇ M DTT) was added to a 384-well plate, and 3uL of the test compound diluted in Assay buffer was added to reach the target final concentration.
  • Assay buffer 40mM Tris-HCl, 10mM MgCl 2 , 0.1mg/mL BSA, 50 ⁇ M DTT
  • +++ indicates IC50 less than or equal to 200nM
  • the Cbl-b inhibitor (compound 21 in PCT/CN2024/087003, with the structural formula ) was diluted 5 times at the highest concentration of 500nM and added to the cell plate in a volume of 15 ⁇ L; for combined use, the compound in this patent was diluted 5 times at the highest concentration of 500nM and added to the cell plate in a volume of 15 ⁇ L, and the Cbl-b inhibitor was added to the cell plate at a constant concentration of 30nM and a volume of 15 ⁇ L. Centrifuge at 1000rmp for 10 seconds at room temperature, and then place the cells in a 37°C incubator for culture. After 2 hours, 3.7 ⁇ L of Immunocult TM Human CD3/CD28 T cell Activator was added, centrifuged at 1000rmp for 10 seconds at room temperature, and finally the cells were placed in a 37°C incubator for culture.
  • Day 5 Take the cell culture plate out of the incubator and observe the cell status under a microscope. If the cells are in good condition, centrifuge at 1000 rpm for 3 minutes. Gently take out 60 ⁇ L of supernatant from the cell plate, transfer it to a 96-well flat-bottom plate, seal it with sealing film, and freeze it in a -80°C refrigerator.
  • CD-1 female mice aged 7 to 10 weeks were selected, and the intravenous and oral doses were 1 mg/kg and 10 mg/kg, respectively.
  • the mice were fasted for at least 12 hours before administration, and food was resumed 4 hours after administration. Water was freely available during the entire experiment.
  • the animals in the intravenous group were given a single injection of the corresponding compound through the tail vein, and the administration volume was 10 mL/kg.
  • the animals in the oral group were given a single injection of the corresponding compound by gavage, and the administration volume was 10 mL/kg.
  • the animals were weighed before administration, and the administration volume was calculated based on the body weight.
  • the sample collection time was: 0.083 (injection group), 0.167, 0.5, 1, 2, 4, 8, 24h.
  • the reference compound BAY2965501 is compound 62.2 in WO2021214019A1.
  • OVCAR3 cells and about 80000/well of NK92MI cells were seeded into 96-well black transparent cell culture plates, 90 ⁇ L per well. Incubate overnight at 37°C for 24 hours. Dilute the test compound to 10 times the final concentration and add 10 ⁇ L to the cell culture plate. Incubate the cells at 37°C for 48 hours. Discard the OVCAR3 cell culture medium and stain the OVCAR3 cells with 1 ⁇ M Calcein AM. After 50 minutes, wash once with PBS, add 100 ⁇ L culture medium, mix the NK92MI cells, and gently add them to the OVCAR3 cells.
  • mice were subcutaneously inoculated with 1X10 6 MC38 cells.
  • the mice were treated with vehicle, compound alone (oral administration, once a day), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (oral administration, once a day) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination.
  • TGI tumor growth inhibition rate
  • mice were subcutaneously inoculated with 1X10 6 MC38 cells.
  • the mice were treated with vehicle, compound alone (oral administration, once a day), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (oral administration, once a day) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination.
  • TGI tumor growth inhibition rate
  • Each C57BL/6 mouse was subcutaneously inoculated with 1X106 MC38 cells.
  • the drugs were administered, vehicle, compound alone (oral administration, once a day), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (oral administration, once a day) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, once a week.
  • Tumor volume was measured twice and at the end of administration.
  • mice were subcutaneously inoculated with 2X10 5 CT26 cells.
  • the mice were treated with vehicle, compound alone (oral administration, once a day), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (oral administration, once a day) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination.
  • TGI tumor growth inhibition rate
  • Each BALB/c mouse was subcutaneously inoculated with 2X10 5 CT26 cells.
  • the mouse was treated with vehicle, compound alone (oral administration, once a day), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (oral administration, once a day) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination.
  • TGI tumor growth inhibition rate
  • Each BALB/c mouse was subcutaneously inoculated with 2X105 CT26 cells.
  • the drugs were administered, vehicle, compound alone (oral administration, once a day), anti-PD-1 antibody alone (intravenous injection, once a week), anti-VEGF antibody alone (intraperitoneal injection, once a week), anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) in combination, compound (oral administration, once a day) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination, or compound (oral administration, once a day) and anti-PD-1 antibody (intravenous injection, once a week) and anti-VEGF antibody (intraperitoneal injection, once a week) in combination.
  • Tumor volume was measured twice a week and at the endpoint of administration.

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Abstract

L'invention concerne une classe de composés utilisés comme inhibiteurs de DGKζ. Plus précisément, la présente invention concerne un composé tel que représenté par la formule générale (1) et son procédé de préparation, ainsi que l'utilisation du composé tel que représenté par la formule générale (1) et des isomères, des formes cristallines, des sels pharmaceutiquement acceptables, des hydrates ou des solvates de celui-ci en tant qu'inhibiteurs de DGKζ. Le composé et les isomères, formes cristallines, sels pharmaceutiquement acceptables, hydrates ou solvates de celui-ci peuvent être utilisés pour préparer des médicaments pour le traitement ou la prévention de maladies associées à la protéine DGKζ.
PCT/CN2024/092900 2023-05-15 2024-05-13 COMPOSÉ UTILISÉ COMME INHIBITEUR DE DGKζ Pending WO2024235203A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025167814A1 (fr) * 2024-02-06 2025-08-14 微境生物医药科技(上海)有限公司 COMPOSÉ UTILISÉ EN TANT QU'INHIBITEUR DE DGKζ

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1942464A (zh) * 2004-04-20 2007-04-04 霍夫曼-拉罗奇有限公司 新型哌啶取代的二氨基噻唑类化合物
WO2018089902A1 (fr) * 2016-11-13 2018-05-17 Apogee Biotechnology Corporation Composés de diaminothiazole, compositions et procédés d'utilisation associés
WO2019133445A1 (fr) * 2017-12-28 2019-07-04 Inception Ibd, Inc. Aminothiazoles utilisés en tant qu'inhibiteurs de vanin-1
WO2020102804A2 (fr) * 2018-11-16 2020-05-22 Arqule, Inc. Combinaison pharmaceutique pour le traitement du cancer
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

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1942464A (zh) * 2004-04-20 2007-04-04 霍夫曼-拉罗奇有限公司 新型哌啶取代的二氨基噻唑类化合物
WO2018089902A1 (fr) * 2016-11-13 2018-05-17 Apogee Biotechnology Corporation Composés de diaminothiazole, compositions et procédés d'utilisation associés
WO2019133445A1 (fr) * 2017-12-28 2019-07-04 Inception Ibd, Inc. Aminothiazoles utilisés en tant qu'inhibiteurs de vanin-1
WO2020102804A2 (fr) * 2018-11-16 2020-05-22 Arqule, Inc. Combinaison pharmaceutique pour le traitement du cancer
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
CN115697980A (zh) * 2020-04-24 2023-02-03 拜耳公司 作为dgkzeta抑制剂用于免疫活化的取代的氨基噻唑

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025167814A1 (fr) * 2024-02-06 2025-08-14 微境生物医药科技(上海)有限公司 COMPOSÉ UTILISÉ EN TANT QU'INHIBITEUR DE DGKζ

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