Compound as DGKζ inhibitor

Abstract

Disclosed is a compound as a DGKζ inhibitor. Specifically, disclosed are a compound represented by general formula (1) and a preparation method therefor, and a use of the compound of general formula (1) and isomers, crystal forms, pharmaceutically acceptable salt, hydrate, or solvate thereof as a DGKζ inhibitor. The compound and the isomers, crystal forms, pharmaceutically acceptable salt, hydrate, or solvate thereof can be used for preparing a drug for treating or preventing DGKζ protein related diseases.

Description

Compounds that act as DGKζ inhibitors

[0001] This application claims priority to Chinese patent application No. 202410170952.1, filed on February 6, 2024. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and more specifically, relates to a class of compounds having DGKζ protein inhibitory effects, a preparation method thereof, and the use of such compounds in preparing drugs for treating or preventing related diseases mediated by DGKζ. Background Art

[0003] DGKζ is a subtype of 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). Diacylglycerol (DAG) is a second messenger generated by phospholipase Cγ1 upon TCR engagement, triggering a signaling cascade that plays a crucial role in T cell development and function. The DGK family catalyzes the phosphorylation of DAG to PA, thereby regulating DAG-mediated signaling. Among them, DGKζ is prominently expressed in T cells, with its expression and activity enhanced upon TCR stimulation, and its sustained expression is associated with hyporesponsiveness of tumor-infiltrating T cells.

[0004] Studies have shown that the loss of DGKζ in T cells leads to the production of effector cytokines IL-2 and IFNγ, enhancing the killing effect of T cells on tumor cells. In addition, compared with wild-type CAR T cells, adoptively transferred DGKζ-deficient CAR (chimeric antigen receptor)-T cells showed good synergistic effects in treating mouse mesothelioma and glioblastoma xenograft models in combination with DGKα knockout.

[0005] DGKζ is also associated with natural killer (NK) cells. Upon stimulation by multiple activating receptors, NK cells from mice lacking DGKζ exhibit increased cytokine production and shedding in an ERK-dependent manner. Furthermore, they exhibit improved cytotoxicity against tumor cell lines. In addition to immunomodulation, DGKζ plays other roles in cancer, mediating proliferation, apoptosis, survival, and invasion.

[0006] Based on current research results, inhibiting DGKζ activity in T cells and tumor cells can produce a stronger immune response to pathogens and tumors. Due to its important role in immunity, DGKζ inhibitors play a vital role in malignant solid tumors or hematological tumors (such as acute myeloid leukemia, urothelial carcinoma, breast cancer, colon cancer, lung cancer, pancreatic cancer, melanoma, etc.), autoimmune diseases (such as systemic lupus erythematosus, psoriasis, arthritis, etc.), and inflammatory responses. Summary of the Invention

[0007] The present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0008] In the general formula (1):

[0009] R 2 for

[0010] R 3 is -CH3 or -NH2;

[0011] Ring A is phenyl or (5-6 membered) heteroaryl;

[0012] Each R x Each is independently -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-(C2-C6) alkynyl, -O-(C2-C6) haloalkenyl, -O-(C5-C6) halocycloalkenyl, -O-(C2-C6) haloalkynyl, -(C1-C3) alkylene-phenyl, -(C1-C3) alkylene-(5-6 membered) heteroaryl, -(C1-C3) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(OR 9 ), (C3-C7) cycloalkyl, -OR 9 、-N(R 10 )(R 11 )、-(C1-C3)alkylene-(N(R 10 )(R 11 ))、-C(=O)-N(R 12 )(R 13 ), -S(=O) m -R 14 、-C(=O)R 14 、-C(=O)-OR 17 , (5-6 membered) heteroaryl substituted by 1 or 2 halogen or -CH3, or phenyl substituted by 1 or 2 halogen or -CH3, wherein the (4-7 membered) heterocycloalkyl may be optionally substituted by 1 or 2 of the following groups: -H, halogen, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2, or -CF3;

[0013] R 4 For-OR 4a 、-N(R 4b )2, (C1-C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkenyl or (3-9 membered)heterocycloalkyl, wherein R 4a 、R 4b , (C1-C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkenyl or (3-9 membered)heterocycloalkyl substituted by 1 or 2 of the following groups: -OR 4a1 、-N(R 4b1 )2、-C(O)N(R 4c )2、-C(O)OR 4b1 , (C1-C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkenyl or (3-9 membered)heterocycloalkyl, wherein the -OR 4a1 、-N(R 4b1 )2, (C3-C9)cycloalkyl, (C3-C9)cycloalkenyl or (3-9 membered)heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -CN, -NO2, -OR 4a2 、-N(R 4b2 )2、-C(O)N(R 4c )2、-C(O)OR 4b2 , (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C5-C6)cycloalkenyl, (C2-C6)alkynyl, (C3-C9)cycloalkyl, (C6-C10)aryl, (3-9 membered)heteroaryl or (3-9 membered)heterocycloalkyl;

[0014] R 4a 、R 4a1 and R 4a2 are each independently (C1-C6)alkyl or (C1-C6)haloalkyl;

[0015] Each R 4b 、R 4b1 and R 4b2 are each independently H, (C1-C6) alkyl or (C1-C6) haloalkyl, and R on the same nitrogen atom 4b Not at the same time H;

[0016] Each R 4c Each is independently H, (C1-C6)alkyl or (C1-C6)haloalkyl;

[0017] R 1is phenyl or (5-6 membered) heteroaryl, wherein said 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) alkoxy-phenyl, (C1-C6) haloalkoxy or -N(R 5 )(R 6 ), wherein the phenyl group in said -(C1-C3)alkylene-phenyl and -(C1-C3)alkyleneoxy-phenyl may each independently be optionally substituted with 1 or 2 of the following groups: -H, halogen, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3;

[0018] R 5 and R 6 each independently -H, (C1-C4)alkyl, -C(=O)-(C1-C4)alkyl, (C3-C4)cycloalkyl, or -(C1-C3)alkylene-phenyl;

[0019] or R 5 and R 6 Together with the nitrogen atom to which it is attached, a (4-7 membered) heterocycloalkyl group may be formed, wherein the (4-7 membered) heterocycloalkyl group may be independently optionally substituted by 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;

[0020] R 7 is H, -CH3 or -CH2CH3;

[0021] R 8 is -C(=O)NH2 or -S(=O)2NH2;

[0022] 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)-N(R 20 )(R 21 )、-C(=O)-N(R 20 )(R 21 ), phenyl, (5-6 membered) heteroaryl or (5-6 membered) heterocycloalkyl, wherein the phenyl in -(C1-C3)alkylene-phenyl, phenyl, (5-6 membered) heteroaryl, (5-6 membered) heteroaryl and (5-6 membered) heterocycloalkyl in -(C1-C3)alkylene-(5-6 membered) heteroaryl can each independently be optionally substituted with 1 or 2 of the following groups: -H, halogen, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3;

[0023] R 10 and R 11 Each is independently -H, (C1-C4) alkyl, (C1-C4) haloalkyl, hydroxy-substituted (C2-C4) alkyl, -(C2-C3) alkylene-(C1-C3) alkoxy, -(C2-C3) alkylene-(N(R 22 )(R 23 )), -(C1-C6)alkylene-(C3-C7)cycloalkyl, -C(=O)-(C1-C4)alkyl, (C3-C7)cycloalkyl, -C(=O)-(C3-C7)cycloalkyl, -(C1-C3)alkylene-phenyl, -C(=O)-(C1-C3)alkylene-phenyl, -C(=O)-O-(C1-C3)alkylene-phenyl, phenyl or (5-6 membered)heteroaryl, wherein the (C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl and -C (C3-C7)cycloalkyl, -(C1-C3)alkylene-phenyl, -C(=O)-(C1-C3)alkylene-phenyl, -C(=O)-O-(C1-C3)alkylene-phenyl, phenyl or (5-6 membered)heteroaryl in (=O)-(C3-C7)cycloalkyl may each independently be optionally substituted with 1 or 2 of the following groups: -H, -F, -CN, -CH3, -CH2CH3, -CF3, -OCF3, -CH2CF3, -OCH3, -OCH2CH3 or -N(CH3)2;

[0024] or R 10 and R 11 Together with the nitrogen atom to which it is attached, it can form a (4-11 membered) heterocycloalkyl, wherein said (4-11 membered) heterocycloalkyl can 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;

[0025] R 12 and R 13 Each is 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 be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH, -N(CH3)2, (C1-C4)alkyl, (C1-C4)haloalkyl, -C(=O)-(C1-C4)alkyl, (C3-C4)cycloalkyl or (C1-C4)alkoxy;

[0026] or R 12 and R 13 Together with the nitrogen atom to which it is attached, a (4-7 membered) heterocycloalkyl group may be formed, wherein the (4-7 membered) heterocycloalkyl group 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;

[0027] R 14 is (C1-C4)alkyl, (C1-C4)alkoxy or phenyl, wherein the phenyl group may be independently optionally substituted with 1, 2 or 3 of the following groups: -H, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3;

[0028] R 17 is (C1-C4)alkyl;

[0029] R 18 and R 19 Each is independently -H or (C1-C4)alkyl;

[0030] R 20is 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, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3;

[0031] or R 20 is (C3-C11)cycloalkyl, (4-11 membered)heterocycloalkyl, wherein said (C3-C11)cycloalkyl and (4-11 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;

[0032] or 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, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, -N(R 22 )(R 23 ) or -C(=O)(R 24 )(R 25 );

[0033] R 21 is H or (C1-C4) alkyl;

[0034] or R 20 and R 21 Together with the nitrogen atom to which it is attached, it can form a (4-7 membered) heterocycloalkyl, wherein said (4-7 membered) heterocycloalkyl 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)(R24 )(R 25 );

[0035] R 22 and R 23 Each is independently -H, (C1-C2)alkyl or -C(=O)-(C1-C2)alkyl;

[0036] R 24 and R 25 are each independently -H or (C1-C4)alkyl; and

[0037] m is an integer of 0, 1 or 2, and n is an integer of 0, 1, 2, 3 or 4.

[0038] In another preferred embodiment, wherein in the general formula (1), R 2 for

[0039] In another preferred embodiment, in the general formula (1), ring A is a phenyl group or a (5-6 membered) heteroaryl group containing 1, 2 or 3 independently selected from N, O or S.

[0040] In another preferred embodiment, wherein in the general formula (1), ring A is:

[0041] In another preferred embodiment, wherein in the general formula (1), each R x Each is independently -H, -F, -Cl, -Br, -I, -CN, -NO2, (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)alkynyl, -O-(C2-C4)haloalkenyl, -O-(C5-C6)halocycloalkenyl, -O-(C2-C4)haloalkynyl, -(C1-C2)alkylene-phenyl, -(C1-C2)alkylene-(5-6 membered)heteroaryl, -(C1-C2)alkylene-(C3-C7)cycloalkyl, -(C1-C4)alkylene-(OR 9 )、(C3-C7)cycloalkyl, -OR 9 、-N(R 10 )(R 11 )、-(C1-C3)alkylene-N(R 10 )(R 11 )、-C(=O)-N(R 12 )(R13 ),-SR 14 、-S(=O)-R 14 、-S(=O)2-R 14 、-C(=O)R 14 、-C(=O)-OR 17 , (5-6 membered) heteroaryl substituted by 1 or 2 -F, -Cl, -Br or -CH3, or phenyl substituted by 1 or 2 -F, -Cl, -Br or -CH3, wherein the (4-7 membered) heterocycloalkyl may be optionally substituted by 1 or 2 of the following groups: -H, halogen, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3.

[0042] In another preferred embodiment, wherein in the general formula (1), R 4 For-OR 4a 、-N(R 4b )2, (C1-C3) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkenyl or (3-6 membered) heterocycloalkyl, wherein the -OR 4a 、-N(R 4b )2, (C1-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or (3-6 membered)heterocycloalkyl substituted by 1 or 2 of the following groups: -OR 4a1 、-N(R 4b1 )2、-C(O)N(R 4c )2、-C(O)OR 4b1 , (C1-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or (3-6 membered)heterocycloalkyl, wherein the -OR 4a1 、-N(R 4b1 )2, (C1-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or (3-6 membered)heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -CN, -NO2, -OR 4a2 、-N(R 4b2 )2、-C(O)N(R 4c )2、-C(O)OR 4b2 , (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C5-C6)cycloalkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, phenyl, (3-6 membered)heteroaryl or (3-6 membered)heterocycloalkyl.

[0043] In another preferred embodiment, wherein in the general formula (1), R 4a 、R 4a1and R 4a2 Each is independently (C1-C3)alkyl or (C1-C3)haloalkyl.

[0044] In another preferred embodiment, wherein in the general formula (1), each R 4b 、R 4b1 and R 4b2 are each independently H, (C1-C3) alkyl or (C1-C3) haloalkyl, and R on the same nitrogen atom 4b Not H at the same time.

[0045] In another preferred embodiment, wherein in the general formula (1), each R 4c Each is independently H, (C1-C3)alkyl or (C1-C3)haloalkyl.

[0046] In another preferred embodiment, wherein in the general formula (1), R 4 for:

[0047] In another preferred embodiment, wherein in the general formula (1), R 1 is phenyl or (5-6 membered) heteroaryl, wherein said phenyl or (5-6 membered) heteroaryl may each independently be optionally 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(R 5 )(R 6 ), wherein the phenyl group in the -(C1-C2)alkylene-phenyl group and the -(C1-C2)alkyleneoxy-phenyl group may each independently be optionally substituted by 1 or 2 of the following groups: -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3.

[0048] In another preferred embodiment, wherein in the general formula (1), R 1 is phenyl, wherein the phenyl group may be independently optionally substituted with 1, 2 or 3 of the following groups: -H, -F, -Cl, -Br, -OH, -CN, -NO2, (C1-C2)alkyl, (C1-C2)haloalkyl, (C1-C2)alkoxy.

[0049] In another preferred embodiment, wherein in the general formula (1), R 1 for:

[0050] In another preferred embodiment, wherein in the general formula (1), R 5 and R 6 each independently -H, (C1-C3)alkyl, -C(=O)-(C1-C3)alkyl, (C3-C4)cycloalkyl, or -(C1-C2)alkylene-phenyl;

[0051] or R 5 and R 6 Together with the nitrogen atom to which it is attached, a (4-6 membered) heterocycloalkyl group may be formed, wherein the (4-6 membered) heterocycloalkyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -F, -OH, -CH3, -CH2CH3, -C(=O)-CH3, -OCH3 or -OCH2CH3.

[0052] In another preferred embodiment, wherein in the general formula (1), R 5 and R 6 Each is independently -H, -CH3, -CH2CH3, -C(=O)-CH3,

[0053] In another preferred embodiment, wherein in the general formula (1), R 9 is H, (C1-C4) alkyl, (C2-C4) alkenyl, (C5-C6) cycloalkenyl, (C2-C4) alkynyl, (C1-C4) alkyl, -(C1-C2) alkylene-(5-6 membered) heteroaryl, -(C1-C2) alkylene-phenyl, (C1-C4) haloalkyl, hydroxy-substituted (C2-C3) alkyl, -(C2-C3) alkylene-(C1-C2) alkoxy, -(C2-C3) alkylene-OC(=O)-(C1-C2) alkyl, -C(R 18 )(R 19 )-C(=O)-OR 17 、-C(R 18 )(R 19 )-C(=O)-N(R 20 )(R 21 )、-C(=O)-N(R 20 )(R 21), phenyl, (5-6 membered) heteroaryl or (5-6 membered) heterocycloalkyl, wherein the phenyl in -(C1-C2)alkylene-phenyl, phenyl, (5-6 membered) heteroaryl, (5-6 membered) heteroaryl and (5-6 membered) heterocycloalkyl can each independently be optionally substituted by 1 or 2 of the following groups: -H, -F, -Cl, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3.

[0054] In another preferred embodiment, wherein in the general formula (1), R 9 For H, -CHF2, -CF3, -CH2CF3,

[0055] In another preferred embodiment, wherein in the general formula (1), R 10 and R 11 Each is independently -H, (C1-C2) alkyl, (C1-C2) haloalkyl, hydroxy-substituted (C2-C3) alkyl, -(C2-C3) alkylene-(C1-C2) alkoxy, -(C2-C3) alkylene-N(R 22 )(R 23 ), -(C1-C2)alkylene-(C3-C7)cycloalkyl, -C(=O)-(C1-C2)alkyl, (C3-C7)cycloalkyl, -C(=O)-(C3-C7)cycloalkyl, -(C1-C2)alkylene-phenyl, -C(=O)-(C1-C2)alkylene-phenyl, -C(=O)-O-(C1-C2)alkylene-phenyl, phenyl or (5-6 membered)heteroaryl, wherein the (C3-C7)cycloalkyl, -(C1-C6)alkyl-(C3-C7)cycloalkyl and -C(=O)-(C3-C7)cycloalkyl The (C3-C7)cycloalkyl group in -(C1-C2)alkylene-phenyl and -C(=O)-(C1-C2)alkylene-phenyl and the phenyl, phenyl or (5-6 membered)heteroaryl group in -C(=O)-O-(C1-C2)alkylene-phenyl may each independently be optionally substituted with 1 or 2 of the following groups: -H, -F, -CN, -CH3, -CH2CH3, -CF3, -OCF3, -CH2CF3, -OCH3, -OCH2CH3 or -N(CH3);

[0056] or R 10 and R 11Together with the nitrogen atom to which it is attached, a (4-7 membered) heterocycloalkyl group may be formed, wherein the (4-7 membered) heterocycloalkyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -F, -Cl, -CN, -OH, -CH3, -CH2CH3, -CF3, CH3-C(=O)-, -OCH3, -OCH2CH3, -NH2, -N(CH3)2 or (4-7 membered)heterocycloalkyl.

[0057] In another preferred embodiment, wherein in the general formula (1), R 10 and R 11 Each is independently -H, -CH3, -CH2CH3, -C(=O)-CH3,

[0058] In another preferred embodiment, wherein in the general formula (1), R 12 and R 13 Each is independently -H, (C1-C3) alkyl, (C1-C3) haloalkyl, hydroxy-substituted (C1-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 may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH, -N(CH3)2, -CH3, -CH2CH3, -CF3, -C(=O)-CH3, -OCH3 or -OCH2CH3;

[0059] or R 12 and R 13 Together with the nitrogen atom to which it is attached, a (4-7 membered) heterocycloalkyl group may be formed, wherein the (4-7 membered) heterocycloalkyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH, -CH3, -CH2CH3, CH3-C(=O)-, -OCH3 or -OCH2CH3.

[0060] In another preferred embodiment, wherein in the general formula (1), R 12 and R 13 are independently -H, -CH3, -CH2CH3,

[0061] In another preferred embodiment, wherein in the general formula (1), 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, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3.

[0062] In another preferred embodiment, wherein in the general formula (1), R 14 is -CH3, -CH2CH3, -OCH3 or -OCH2CH3.

[0063] In another preferred embodiment, wherein in the general formula (1), R 17 It is -CH3 or -CH2CH3.

[0064] In another preferred embodiment, wherein in the general formula (1), R 18 and R 19 Each is independently -H, -CH3 or -CH2CH3.

[0065] In another preferred embodiment, wherein in the general formula (1), R 20 is H, (C1-C3)alkyl, (C3-C4)alkenyl, (C2-C4)alkynyl or (C1-C3)alkoxy, wherein the (C1-C3)alkyl 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 may be substituted by 1, 2 or 3 of the following groups: -H, -F, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3;

[0066] or R 20 is (C3-C7) cycloalkyl, (4-7 membered) heterocycloalkyl, wherein the (C3-C7) cycloalkyl and (4-7 membered) heterocycloalkyl may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH, -CH3, -CH2CH3, CH3-C(=O)-, -OCH3 or -OCH2CH3;

[0067] or R 20is 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, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CF3, -N(CH3)2 or -C(=O)(CH3)2.

[0068] In another preferred embodiment, wherein in the general formula (1), R 21 is H, -CH3 or -CH2CH3;

[0069] or R 20 and R 21 Together with the nitrogen atom to which it is attached, a (4-7 membered) heterocycloalkyl group may be formed, wherein the (4-7 membered) heterocycloalkyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, halogen, -CN, -OH, -CH3, -CH2CH3, -CF3, -(C1-C2)alkylene-phenyl, -C(=O)-CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -C(=O)(CH3)2.

[0070] In another preferred embodiment, wherein in the general formula (1), R 22 and R 23 Each is independently -H, -CH3, -CH2CH3 or -C(=O)-CH3.

[0071] In another preferred embodiment, wherein in the general formula (1), R 24 and R 25 Each is independently -H, -CH3 or -CH2CH3.

[0072] In another specific embodiment of the present invention, the compound of formula (1) has one of the structures shown in Table 1 of the specification.

[0073] Another object of the present invention is to provide 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.

[0074] Another object of the present invention is to provide the use of the compound represented by general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition thereof, for preparing a drug for treating, regulating or preventing a disease associated with the DGKζ protein. The disease is preferably cancer, and the cancer is a blood cancer or a solid tumor.

[0075] Another object of the present invention is to provide a method for treating, regulating or preventing diseases related to DGKζ protein, comprising administering to a subject a therapeutically effective amount of a compound represented by general formula (1) of the present invention, or its isomers, crystalline forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition.

[0076] By synthesizing and carefully studying a variety of new compounds with DGKζ inhibitory effects, the inventors found that among the compounds of formula (1), the compounds unexpectedly have strong DGKζ inhibitory activity.

[0077] It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0078] Synthesis of compounds

[0079] The preparation methods of the compounds of the present invention are described in detail below, but these specific methods do not constitute any limitation to the present invention.

[0080] The compounds described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures, and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of the compounds can be synthesized or obtained from commercial sources such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.) or Sigma Chemical Co. (St. Louis, Mo.). The compounds described herein and other related compounds having various substituents can be synthesized using known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulae provided herein.

[0081] In one aspect, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of the compounds used, reaction temperatures, reaction times, etc., are not limited to the following explanations. 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 combinations can be easily performed by those skilled in the art. In one aspect, the present invention also provides a method for preparing the compounds, wherein the compounds of formula (1) can be prepared using the following general reaction scheme 1:

[0082] General reaction scheme 1

[0083] An embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein R 1 、R 4 、R 7 、R x and n are as defined above, N represents nitrogen, O represents oxygen, S represents sulfur, Cl represents chlorine, and Br represents bromine. As shown in General Reaction Scheme 1, compound 1-1 undergoes a substitution reaction with NH2CN to produce compound 1-3, compound 1-3 and compound 1-4 undergo a condensation reaction to produce compound 1-4, compound 1-4 reacts with (Boc)2O to produce compound 1-5, and compound 1-6 undergoes a substitution reaction to produce target compound 1-7. In some cases, compound 1-7 can be subjected to chiral resolution to yield optical isomers 1-7-A and 1-7-B.

[0084] Further forms of compounds

[0085] "Pharmaceutically acceptable" as used herein refers to a substance, 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 substance that does not cause undesirable biological effects or interact in a deleterious manner with any of its components when administered to a subject.

[0086] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of the formula with an acid or base, wherein the acid or base includes, but is not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1. st Acids and Bases in Ed., (Wiley, 2002).

[0087] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystallized 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, using organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, 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 forms are considered to be equivalent to the unsolvated forms.

[0088] In other embodiments, the compound of formula (1) is prepared in different forms, including but not limited to, amorphous, crushed and nano-particle forms. In addition, the compound of formula (1) includes crystalline forms and can also be polymorphic. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs generally 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 solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.

[0089] In another aspect, compounds of formula (1) may have chiral centers and / or axial chirality and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially purified compounds are included within the scope of the present invention. The present invention is intended to include all such isomeric forms of these compounds.

[0090] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), oxygen-18 ( 18 O), iodine-125 ( 125 I) and C-14( 14 C). For example, deuterated compounds can 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. Compared with non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0091] Unless otherwise specified, any reference to an atom in the compounds of the present invention refers to its stable atomic isotope. Unless otherwise specified, when a position in a molecular structure is designated as "H" or "hydrogen," such position should be understood to have the natural abundance of the hydrogen isotope. Similarly, when a position is designated as "D" or "deuterium," such position should be understood to have a deuterium isotope abundance at least 3000 times its natural abundance (the natural abundance of the deuterium isotope is 0.015%).

[0092] More preferably, 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).

[0093] the term

[0094] Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and the appended claims, unless otherwise clearly indicated in the text, the singular form "a" includes the plural meaning. Unless otherwise specified, the substituents in this application (such as alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc.) are all optionally substituted, that is, they can be substituted substituents or unsubstituted substituents. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology and pharmacology are used. In this application, unless otherwise specified, the use of "or" or "and" means "and / or".

[0095] Unless otherwise specified, "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, and tert-butyl. More preferred are lower alkyl groups containing 1 to 3 carbon atoms, such as methyl, ethyl, propyl, and 2-propyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr,i Bu, n Bu or t Bu.

[0096] Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

[0097] Unless otherwise specified, "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. Preferred are lower alkenyl groups containing 1 to 4 carbon atoms, such as ethenyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl. More preferred are lower alkenyl groups containing 1 to 2 carbon atoms.

[0098] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl group as defined above.

[0099] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight-chain and branched groups having 1 to 14 carbon atoms. Preferred are lower alkynyl groups having 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl. More preferred are lower alkynyl groups having 1 to 2 carbon atoms.

[0100] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl group as defined above.

[0101] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), preferably containing 3 to 14 ring carbon atoms (C 3-14 In some embodiments, the cycloalkyl group has 3-10 ring carbon atoms (C 3-10 In some embodiments, a cycloalkyl group has 3-8 ring carbon atoms (C 3-8 In some embodiments, the cycloalkyl group has 3-7 ring carbon atoms (C 3-7 In some embodiments, the cycloalkyl group has 3-6 ring carbon atoms (C 3-6 In some embodiments, the cycloalkyl group has 4-6 ring carbon atoms (C 4-6 In some embodiments, the cycloalkyl group has 5-6 ring carbon atoms (C 5-6 In some embodiments, a cycloalkyl group has 5-10 ring carbon atoms (C 5-10Cycloalkyl). If the carbocyclic ring contains at least one double bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl group," or if the carbocyclic ring contains at least one triple bond, 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. In some embodiments, 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 optionally be 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). In some embodiments, 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 groups can be fused with aryl groups and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl groups and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.

[0102] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

[0103] Unless otherwise specified, "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. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially those 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.

[0104] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group. Aryl is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

[0105] Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.

[0106] Unless otherwise specified, "arylene" refers to a divalent aromatic radical as defined above. Examples of arylene groups include, but are not limited to, 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, naphthylene, and phenanthrenylene.

[0107] Unless otherwise specified, "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms, the heteroatoms being independently selected from O, N or S, preferably 1, 2, 3 or 4 heteroatoms, 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. The heteroaryl group is monocyclic or polycyclic. The monocyclic 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. Examples of 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-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,

[0108] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0109] Unless otherwise specified, "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, more preferably a saturated or partially unsaturated ring containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen. In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 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). In some embodiments, 5-6 membered heterocycloalkyl contains 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 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. In some embodiments, 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 groups contain 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 10-13 membered heterocycloalkyl groups contain 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 10-13 membered heterocycloalkyl groups contain 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. If the heterocycloalkyl group contains at least one double bond, the partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl group," or if the heterocycloalkyl group contains at least one triple bond, the partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkynyl group." Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, heterocycloalkyl groups are monocyclic groups 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 or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl group may be connected via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds.In some embodiments, heterocycloalkyl contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties (also referred to as partially unsaturated heterocycles) with one or more aromatic rings fused to the heterocycloalkyl ring (i.e., sharing a key therewith), such as benzo derivatives of piperidine, morpholine, azacycloheptane or tetrahydrothienyl, and pyrido derivatives of piperidine, morpholine, azacycloheptane or tetrahydrothienyl. Heterocycloalkyl containing fused aromatic rings can be connected via any ring-forming atoms, including ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups 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, tropanediyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazole , 4-nitro-2-nitro-1-pyridine, 4 ...1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine,

[0110] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

[0111] Unless otherwise specified, "oxo" refers to =0; for example, a carbonyl group substituted with an oxo group is a "carbonyl group." "; the group formed by sulfur being replaced by an oxo group is called "sulfinyl" ", the group formed by sulfur being substituted by two oxo groups is called "sulfonyl" ”.

[0112] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group indicates 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.

[0113] Unless otherwise specified, the term "substituted" refers to a substituent group other than one or more hydrogen atoms on a specified atom or group that is substituted by one or more hydrogen atoms, without exceeding the normal valence of the specified atom. For example, one or more hydrogen atoms of an alkyl, alkylene, alkenyl, alkynyl, hydroxyl or amido group can be substituted by one or more substituent groups. Wherein the substituent group includes but is not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or its combination. The definition of "substituted" does not include similar indefinite structures obtained by defining a substituent group having a further substituent attached to infinity (for example, a substituted aryl group itself substituted by a substituted aryl group with a substituted alkyl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, a substituted aryl group is continuously substituted by two other substituted aryls to an aryl group substituted by ((substituted aryl) substituted aryl). Similarly, the above definition does not include substitution patterns that are not allowed (for example, a methyl group substituted by 5 fluorines or a heteroaryl group with two adjacent oxygen ring atoms). This substitution pattern that is not allowed is well known to those skilled in the art. Whenever used to modify a chemical group, "substituted" can describe other chemical groups defined herein. For example, the term "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.

[0114] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0115] Unless otherwise specified, "acyl" refers to -C(=O)-R, where R is selected from optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocycloalkyl.

[0116] Unless otherwise specified, it will be understood that the word "comprise", or variations such as "comprises" or "comprising", imply the inclusion of a stated element or integer, or group of elements or integers, but not the exclusion of any other element or integer, or group of elements or integers.

[0117] The substituent "-O-CH2-O-" refers to the substituent in which two oxygen atoms are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, for example:

[0118] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0119] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0120] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thiopyranyl are six-membered rings, while cyclopentyl, pyrrolyl, furanyl, and thiophenyl are five-membered rings.

[0121] The term "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.

[0122] The term "isomer" means any tautomer, stereoisomer, atropisomer, isotopomer, enantiomer or diastereomer of any compound of the present invention. The compounds of the present invention may have one or more chiral centers or double bonds and therefore exist in stereoisomeric form, for example, as double bond isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). Therefore, the compounds of the present 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. 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 as 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, reagents and catalysts by well-known asymmetric synthetic methods.

[0123] The term "isotopomers" refers to different molecules whose structures differ only in one isotope but are otherwise identical.

[0124] The term "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 other parts of the molecule and the substituents at either end of the single bond are asymmetric, i.e., atropisomers do not require a stereocenter. When the barrier to rotation about the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation of the individual isomers is permitted (LaPlante et al., J. Med. Chem. 2011, 54, 20, 7005), preferably by chiral resolution.

[0125] Unless otherwise specified, when a group has one or more linkable sites, any one or more sites of the group can be linked to other groups through chemical bonds. When the linking mode of the chemical bond is non-positional and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example, "pyridyl" means "Oxazolyl" means

[0126] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0127] Unless otherwise stated, Indicates a single bond or a double bond.

[0128] Specific pharmaceutical and medical terms

[0129] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0130] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0131] "Active ingredient" refers to the compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of 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 centers that may exist depend 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.

[0132] The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0133] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0134] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0135] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0136] Therapeutic uses

[0137] The compounds of formula (1) or pharmaceutical compositions of the present invention are generally useful for inhibiting DGKζ protein, and thus can be used to treat one or more conditions associated with DGKζ protein activity. Therefore, in certain embodiments, the present invention provides a method for treating a condition mediated by DGKζ protein, comprising administering to a patient in need thereof a compound of formula (1) or a pharmaceutically acceptable composition thereof.

[0138] In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of formula (1). In some embodiments, 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). Preferably, the cancer is head and neck cancer, kidney cancer, ovarian cancer, intestinal cancer, urothelial carcinoma, melanoma, liver cancer, gastric cancer, lung cancer, bladder cancer, and cancer metastasis thereof.

[0139] Route of administration

[0140] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0141] "Pharmaceutically acceptable excipients or carriers" refer 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. Some examples of 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 ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0142] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0143] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, 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 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 example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0144] Solid dosage forms such as tablets, dragees, 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 opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0145] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, 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, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0146] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0147] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0148] Compositions for parenteral injection may comprise 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.

[0149] Dosage forms for topical administration of the compounds of this 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.

[0150] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compounds of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, all of which are within the skill of a skilled physician.

[0151] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features. DETAILED DESCRIPTION

[0152] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0153] In all embodiments, 1 H-NMR was recorded on a Vian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were by volume.

[0154] The present invention uses the following abbreviations: (Boc)2O represents di-tert-butyl dicarbonate; CDCl3 represents deuterated chloroform; Cs2CO3 represents cesium carbonate; EtOAc represents ethyl acetate; Hexane represents n-hexane; HPLC represents high performance liquid chromatography; MeCN represents acetonitrile; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; Dioxane represents 1,4-dioxane; DME represents ethylene glycol dimethyl ether; DMF represents N,N-dimethylformamide; DMAP represents 4-(dimethylamino)pyridine; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; hr represents hour; IPA represents isopropyl alcohol; =Biotage Isolera Prime rapid preparative liquid chromatograph; min = minute; K2CO3 = potassium carbonate; KOAc = potassium acetate; KOH = potassium hydroxide; K3PO4 = potassium phosphate; LiBH4 = lithium borohydride; min = minute; MeOH = methanol; MeONa = sodium methoxide; MS = mass spectrometry; NaBH(OAc)3 = sodium triacetoxyborohydride; NaH = sodium hydrogen; NMR = nuclear magnetic resonance; NIS = iodosuccinimide; Pd / C = palladium on carbon; Pd(PPh3)4 = tetraphenylethylene Phosphine palladium; Pd(OAc)2 represents palladium acetate; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride; PE represents petroleum ether; PPh3 represents triphenylphosphine; TEA represents triethylamine; TFA represents trifluoroacetic acid; TsOH represents p-toluenesulfonic acid; XantPhos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; TfOH represents trifluoromethanesulfonic acid; TLC represents thin layer chromatography; XPhos represents 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0155] Example 1 Synthesis of Compounds 1 and 2

[0156] Step 1: Synthesis of compound int_1-2:

[0157] Int_1-1 (15.3 g, 0.1 mol), THF (200 mL), and cyanamide (4.2 g, 0.1 mol) were added to a 500 mL single-necked flask. NaOEt (6.8 g, 0.1 mol) was added portionwise to the mixture under argon. The mixture was stirred at room temperature under argon for 1-2 hours. After completion of the reaction, monitored by LC-MS, the resulting solution was used directly in the next step.

[0158] ESI-MS m / z:196[M+H] + .

[0159] Step 2: Synthesis of compound int_1-4:

[0160] To the reaction mixture from step 1, int_1-3 (28.7 g, 0.1 mol) was added. The mixture was stirred at room temperature under argon for 20 hours. LC-MS analysis indicated that the reaction was nearly complete. The mixture was then concentrated under reduced pressure to obtain the crude product. This crude product was purified by column chromatography to afford a solid product (27.5 g, 68.5% yield).

[0161] ESI-MS m / z:402[M+H] + .

[0162] Step 3: Synthesis of compound int_1-5:

[0163] Int_1-4 (5 g, 12.45 mmol), DIPEA (4 g, 31.13 mmol), and DMAP (304 mg, 2.49 mmol) were dissolved in DCM (50 mL). BoccO (2.71 g, 12.45 mmol) was added at room temperature under argon. The mixture was stirred at room temperature for 72 hours. After completion of the reaction, as monitored by LC-MS, water (100 mL) was added, stirred, and the layers separated. The organic phase was washed with saturated sodium chloride solution and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain a solid product (5.5 g, yield: 88.7%).

[0164] ESI-MS m / z:502[M+H] + .

[0165] Step 4: Synthesis of compound int_1-6:

[0166] Int_1-5 (100 mg, 0.2 mmol), KCO (69 mg, 0.5 mmol), NaI (30 mg, 0.2 mmol), and 2-chloropropionamide (21 mg, 0.2 mmol) were dissolved in DMF (3 mL). The mixture was heated to 120°C under argon for 1 hour. LC-MS analysis revealed the presence of product. The mixture was then purified by column chromatography to afford a solid product (78 mg, 82.9% yield).

[0167] ESI-MS m / z:473[M+H] + .

[0168] Step 5: Synthesis of Compound 1 and Compound 2

[0169] Inte_1-6 (78 mg, 0.165 mmol) was subjected to SFC chiral separation to obtain compound 1 (23 mg, yield: 29.4%) and compound 2 (30 mg, yield: 38.4%).

[0170] Compound 1: MS (ESI): 473 [M+H] + .

[0171] Compound 2: MS (ESI): 473 [M+H] + .

[0172] Using the above synthesis method and different raw materials, the target compounds in Table 1 can be obtained.

[0173] Table 1

[0174] The NMR data of some compounds in this patent are listed in Table 2 below:

[0175] Table 2

[0176] Biological Example 1 DGKζ kinase inhibitory activity assay

[0177] We used ADP-Glo ​​in the presence or absence of compounds TM Kinase Assay (Progema) was used to detect the inhibitory effect of the test compounds on human recombinant DGKζ.

[0178] To a 384-well plate, add 3 μL of DGKζ enzyme (90 ng / mL) dissolved in assay buffer (40 mM Tris-HCl, 7.5%, 10 mM MgCl2; 0.1 mg / ml BSA; 50 μM DTT). Add 3 μL of the test compound diluted in assay buffer to the target final concentration. After incubation at room temperature for 15 minutes, add 3 μL of substrate (150 μM 1-oleoyl-2-acetyl-sn-glycerol, 480 μM phosphatidylserine, 150 μM UltraPure-ATP) dissolved in lipid dilution buffer (40 mM Tris-HCl, 7.5%, 10 mM MgCl2; 0.1 mg / ml BSA; 50 μM DTT). Incubate at room temperature for 30 minutes. Then, add 3 μL of ADP-Glo ​​reagent and incubate at room temperature for 40 minutes to terminate the enzyme reaction. Then, 6 μL of kinase detection reagent was added and the cells were allowed to stand at room temperature for 30 minutes. Luminescence was measured using ARVOX3. The signal value in solvent treatment was set to 0% inhibition, and the signal value in the absence of DGKζ enzyme was set to 100% inhibition. The IC was calculated using Sigmoid-Emax model nonlinear regression analysis. 50 The results are shown in Table 3 below.

[0179] Table 3. Inhibitory activity of the compounds of the present invention on DGKζ kinase (IC 50 ,nM)

[0180] +++ indicates IC 50 Less than or equal to 200nM

[0181] ++ indicates IC 50 200nM to 500nM

[0182] + indicates IC 50 Greater than 500nM

[0183] Biological Example 2 The compounds of the present invention induce IL-2 secretion in Jurkat-ADCC cells in vitro

[0184] 1. The experimental cells are shown in Table A:

[0185] Table A Experimental Materials

[0186] 2. Experimental instruments, reagents and consumables are shown in Table B, Table C and Table D:

[0187] Table B Experimental Instruments

[0188] Table C Experimental Reagents

[0189] Table D Experimental Consumables

[0190] 3. Experimental steps:

[0191] Day 1: Jurkat ADCC cells were seeded in 96-well plates at 1×10 5 cells / well, duplicate plates.

[0192] Day 2: For single-drug use, the Cbl-b inhibitor was diluted 5-fold at the highest concentration of 500nM and added to the cell plate in a volume of 15μL; for combined use, the compound in this patent was diluted 5-fold at the highest concentration of 500nM and added to the cell plate in a volume of 15μL, and the Cbl-b inhibitor was added to the cell plate at a constant concentration of 30nM in a volume of 15μL. Centrifuge at 1000rmp for 10 seconds at room temperature, then place the cells in a 37℃ incubator and culture them for 2 hours. Add 3.7μL of Immunoculture TM Human CD3 / CD28 T cell Activator was added, and the cells were centrifuged at 1000 rpm for 10 seconds at room temperature. Finally, the cells were cultured in a 37°C incubator.

[0193] Day 5: Remove the cell culture plate from 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 remove 60 μL 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.

[0194] 4.HTRF detection:

[0195] a) Dilute Diluent*#5 in HUMAN IL2 KITS 5-fold with distilled water. (Operate on ice)

[0196] b) Take 15 μL of the IL2 standard solution and add it to 30 μL of diluent. Mix gently. This will generate Standard 7 (8000 pg / mL). Using Standard 7, dilute Standard 6, Standard 5, Standard 4, Standard 3, Standard 2, and Standard 1 according to the table. Use this serial dilution to create a standard curve. (Work on ice)

[0197] c) Dispense 16 μL of each IL2 standard (Standard 0-Standard 7) into each standard well, and dispense 16 μL of each cell supernatant obtained in step 3 into the remaining sample wells.

[0198] d) Dispense 4 μL of pre-mixed IL2 antibody into all wells (mix the IL2 Eu Cryptate antibody and IL2-d2 antibody in the HUMAN IL2 KITS at a 1:1 ratio, then add equal volumes of Detection Buffer*#3 and water in the HUMAN IL2 KITS). (Operate on ice)

[0199] e) Seal the plate and incubate at room temperature. The signal remains stable for 24 hours.

[0200] f) Remove the plate sealer and place it in a compatible LANCE was read on a machine (PerkinElmer EnVision).

[0201] Table 4: The IL-2 secretion induction activity of the compounds of the present invention (EC 50 , nM)

[0202] ND means not detected

[0203] The RC1 structure is:

[0204] It can be seen from the data in the above table that the IL-2 secretion inducing activity of the compound of the present invention is much stronger than that of the control compound RC1.

[0205] Biological Example 3 In vitro test of the killing activity of the compounds of the present invention on NK cells against tumor cells OVCAR3

[0206] Approximately 8,000 OVCAR3 cells / well and approximately 80,000 NK92MI cells / well were seeded into 96-well black clear cell culture plates, with 90 μL per well. The cells were incubated overnight at 37°C for 24 hours. The test compound was diluted to a 10-fold final concentration and 10 μL was added to the cell culture plate. The cells were incubated at 37°C for 48 hours. The OVCAR3 cell culture medium was discarded, and the OVCAR3 cells were stained with 1 μM calcein AM for 50 minutes. The cells were washed once with PBS, and 100 μL of culture medium was added. The NK92MI cells were mixed and then gently added to the OVCAR3 cells. After approximately 4 hours of co-incubation, the DMSO control group and the high-concentration drug group were photographed using PICO to observe the cytotoxicity of the NK92MI cells against the OVCAR3 cells. Co-incubation was terminated when a significant difference in cytotoxicity between the two groups was observed. The culture medium was discarded, and the cells were rinsed once with 100 μL of PBS. Add 100 μL of 4% PFA to each well and fix the cells at room temperature for 20 minutes. Rinse once with PBS and detect the fluorescence signal of the sample through the FITC channel of the microplate reader. Compare with the DMSO group and calculate the inhibition rate and IC 50 .

[0207] Biological Example 4 In vivo pharmacokinetic study of the compounds of the present invention

[0208] Female CD-1 mice aged 7 to 10 weeks were enrolled and administered intravenously and orally at doses of 1 mg / kg and 10 mg / kg, respectively. Mice were fasted for at least 12 hours prior to administration and resumed feeding 4 hours after administration. Water was freely available throughout the experiment. On the day of the experiment, animals in the intravenous group received a single injection of the corresponding compound via the tail vein at a volume of 10 mL / kg. Animals in the oral group received a single injection of the corresponding compound via gavage at a volume of 10 mL / kg. Animals were weighed before administration, and the administration volume was calculated based on body weight. Samples were collected at 0.083 (injection group), 0.167, 0.5, 1, 2, 4, 8, and 24 hours. Approximately 200 μL of whole blood was collected from the submandibular venous plexus at each time point for plasma preparation for concentration determination by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). All animals were euthanized by CO2 anesthesia after the collection of the PK sample at the last time point. Phoenix WinNonlin was used. TM Plasma concentrations were treated using a non-compartmental model using the Certara pharmacokinetic software version 8.3, and pharmacokinetic parameters were calculated using the linear-log trapezoidal method.

[0209] Biological Example 5 In vivo efficacy study - mouse MC38 subcutaneous transplant tumor model

[0210] Each C57BL / 6 mouse was subcutaneously inoculated with 1×10 6 MC38 cells, wait until the tumor grows to 100-200 mm3 Tumor volumes were measured twice weekly and at the endpoint of dosing for the following treatments: vehicle, compound alone (oral administration, once daily), anti-PD-1 antibody alone (intravenous injection, once weekly), anti-VEGF antibody alone (intraperitoneal injection, once weekly), combination of anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), compound (oral administration, once daily) in combination with anti-PD-1 antibody (intravenous injection, once weekly), compound (oral administration, once daily) in combination with anti-VEGF antibody (intraperitoneal injection, once weekly), or compound (oral administration, once daily) in combination with anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly). Tumor growth inhibition rate (TGI) of the compound was calculated as 1-(tumor volume of the dosing group on day 20 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the dosing group on day 1).

[0211] Biological Example 6 In Vivo Efficacy Study - Mouse MC38 Subcutaneous Transplant Tumor Model

[0212] Each C57BL / 6 mouse was subcutaneously inoculated with 1×10 6 MC38 cells, wait until the tumor grows to 50-80 mm 3Tumor volumes were measured twice weekly and at the endpoint of dosing for the following treatments: vehicle, compound alone (oral administration, once daily), anti-PD-1 antibody alone (intravenous injection, once weekly), anti-VEGF antibody alone (intraperitoneal injection, once weekly), combination of anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), compound (oral administration, once daily) in combination with anti-PD-1 antibody (intravenous injection, once weekly), compound (oral administration, once daily) in combination with anti-VEGF antibody (intraperitoneal injection, once weekly), or compound (oral administration, once daily) in combination with anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly). Tumor growth inhibition rate (TGI) of the compound was calculated as 1-(tumor volume of the dosing group on day 20 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the dosing group on day 1).

[0213] Biological Example 7 In vivo efficacy study - mouse MC38 subcutaneous transplant tumor model

[0214] Each C57BL / 6 mouse was subcutaneously inoculated with 1×10 6 MC38 cells were inoculated and immediately dosed with the following: vehicle, compound alone (oral, once daily), anti-PD-1 antibody alone (intravenous, once weekly), anti-VEGF antibody alone (intraperitoneal, once weekly), anti-PD-1 antibody (intravenous, once weekly) in combination with anti-VEGF antibody (intraperitoneal, once weekly), compound (oral, once daily) in combination with anti-PD-1 antibody (intravenous, once weekly), compound (oral, once daily) in combination with anti-VEGF antibody (intraperitoneal, once weekly), or compound (oral, once daily) in combination with anti-PD-1 antibody (intravenous, once weekly) and anti-VEGF antibody (intraperitoneal, once weekly). Tumor volume was measured twice weekly at the endpoint. Tumor growth inhibition (TGI) was calculated as 1 - (tumor volume of the treatment group on day 20 - tumor volume of the treatment group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the treatment group on day 1).

[0215] Biological Example 8 In Vivo Efficacy Study - Mouse CT26 Subcutaneous Transplant Tumor Model

[0216] Each BALB / c mouse was subcutaneously inoculated with 2×10 5 CT26 cells, wait until the tumor grows to 100-200 mm 3 Tumor volumes were measured twice weekly and at the endpoint of dosing for the following treatments: vehicle, compound alone (oral administration, once daily), anti-PD-1 antibody alone (intravenous injection, once weekly), anti-VEGF antibody alone (intraperitoneal injection, once weekly), combination of anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), compound (oral administration, once daily) in combination with anti-PD-1 antibody (intravenous injection, once weekly), compound (oral administration, once daily) in combination with anti-VEGF antibody (intraperitoneal injection, once weekly), or compound (oral administration, once daily) in combination with anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly). Tumor growth inhibition rate (TGI) of the compound was calculated as 1-(tumor volume of the dosing group on day 20 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the dosing group on day 1).

[0217] Biological Example 9 In Vivo Efficacy Study - Mouse CT26 Subcutaneous Transplant Tumor Model

[0218] Each BALB / c mouse was subcutaneously inoculated with 2×10 5 CT26 cells, wait until the tumor grows to 50-80 mm 3Tumor volumes were measured twice weekly and at the endpoint of dosing for the following treatments: vehicle, compound alone (oral administration, once daily), anti-PD-1 antibody alone (intravenous injection, once weekly), anti-VEGF antibody alone (intraperitoneal injection, once weekly), combination of anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly), compound (oral administration, once daily) in combination with anti-PD-1 antibody (intravenous injection, once weekly), compound (oral administration, once daily) in combination with anti-VEGF antibody (intraperitoneal injection, once weekly), or compound (oral administration, once daily) in combination with anti-PD-1 antibody (intravenous injection, once weekly) and anti-VEGF antibody (intraperitoneal injection, once weekly). Tumor growth inhibition rate (TGI) of the compound was calculated as 1-(tumor volume of the dosing group on day 20 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the dosing group on day 1).

[0219] Biological Example 10 In vivo efficacy study - mouse CT26 subcutaneous transplant tumor model

[0220] Each BALB / c mouse was subcutaneously inoculated with 2×10 5 CT26 cells were inoculated and immediately dosed with the following: vehicle, compound alone (oral, once daily), anti-PD-1 antibody alone (intravenous, once weekly), anti-VEGF antibody alone (intraperitoneal, once weekly), anti-PD-1 antibody (intravenous, once weekly) in combination with anti-VEGF antibody (intraperitoneal, once weekly), compound (oral, once daily) in combination with anti-PD-1 antibody (intravenous, once weekly), compound (oral, once daily) in combination with anti-VEGF antibody (intraperitoneal, once weekly), or compound (oral, once daily) in combination with anti-PD-1 antibody (intravenous, once weekly) and anti-VEGF antibody (intraperitoneal, once weekly). Tumor volume was measured twice weekly at the endpoint. Tumor growth inhibition (TGI) was calculated as 1 - (tumor volume of the treatment group on day 20 - tumor volume of the treatment group on day 1) / (tumor volume of the vehicle control group on day 20 - tumor volume of the treatment group on day 1).

[0221] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: In the general formula (1): R 2 for R 3 is -CH3 or -NH2; Ring A is phenyl or (5-6 membered) heteroaryl; Each R x Each is independently -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-(C2-C6) alkynyl, -O-(C2-C6) haloalkenyl, -O-(C5-C6) halocycloalkenyl, -O-(C2-C6) haloalkynyl, -(C1-C3) alkylene-phenyl, -(C1-C3) alkylene-(5-6 membered) heteroaryl, -(C1-C3) alkylene-(C3-C7) cycloalkyl, -(C1-C6) alkylene-(OR 9 ), (C3-C7) cycloalkyl, -OR 9 、-N(R 10 )(R 11 )、-(C1-C3)alkylene-(N(R 10 )(R 11 ))、-C(=O)-N(R 12 )(R 13 ), -S(=O) m -R 14 、-C(=O)R 14 、-C(=O)-OR 17 , (5-6 membered) heteroaryl substituted by 1 or 2 halogen or -CH3, or phenyl substituted by 1 or 2 halogen or -CH3, wherein the (4-7 membered) heterocycloalkyl may be optionally substituted by 1 or 2 of the following groups: -H, halogen, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2, or -CF3; R 4 For-OR 4a 、-N(R 4b )2, (C1-C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkenyl or (3-9 membered)heterocycloalkyl, wherein the -OR 4a 、-N(R 4b )2, (C1-C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkenyl or (3-9 membered)heterocycloalkyl substituted by 1 or 2 of the following groups: -OR 4a1 、-N(R 4b1 )2、-C(O)N(R 4c )2、-C(O)OR 4b1 , (C1-C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkenyl or (3-9 membered)heterocycloalkyl, wherein the -OR 4a1 、-N(R 4b1 )2, (C3-C9)cycloalkyl, (C3-C9)cycloalkenyl or (3-9 membered)heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -CN, -NO2, -OR 4a2 、-N(R 4b2 )2、-C(O)N(R 4c )2、-C(O)OR 4b2 , (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C5-C6)cycloalkenyl, (C2-C6)alkynyl, (C3-C9)cycloalkyl, (C6-C10)aryl, (3-9 membered)heteroaryl or (3-9 membered)heterocycloalkyl; R 4a 、R 4a1 and R 4a2 are each independently (C1-C6)alkyl or (C1-C6)haloalkyl; Each R 4b 、R 4b1 and R 4b2 are independently H, (C1-C6) alkyl or (C1-C6) haloalkyl, and R on the same nitrogen atom 4b Not at the same time H; Each R 4c Each is independently H, (C1-C6)alkyl or (C1-C6)haloalkyl; R 1 is phenyl or (5-6 membered) heteroaryl, wherein said 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) alkoxy-phenyl, (C1-C6) haloalkoxy or -N(R 5 )(R 6 ), wherein the phenyl group in said -(C1-C3)alkylene-phenyl and -(C1-C3)alkyleneoxy-phenyl may each independently be optionally substituted with 1 or 2 of the following groups: -H, halogen, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3; R 5 and R 6 each independently -H, (C1-C4)alkyl, -C(=O)-(C1-C4)alkyl, (C3-C4)cycloalkyl, or -(C1-C3)alkylene-phenyl; or R 5 and R 6 Together with the nitrogen atom to which it is attached, a (4-7 membered) heterocycloalkyl group may be formed, wherein said (4-7 membered) heterocycloalkyl group may be independently optionally substituted by 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, -CH3 or -CH2CH3; R 8 is -C(=O)NH2 or -S(=O)2NH2; 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)-N(R 20 )(R 21 )、-C(=O)-N(R 20 )(R 21 ), phenyl, (5-6 membered) heteroaryl or (5-6 membered) heterocycloalkyl, wherein the phenyl in -(C1-C3)alkylene-phenyl, phenyl, (5-6 membered) heteroaryl, (5-6 membered) heteroaryl and (5-6 membered) heterocycloalkyl in -(C1-C3)alkylene-(5-6 membered) heteroaryl can each independently be optionally substituted with 1 or 2 of the following groups: -H, halogen, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3; R 10 and R 11 Each is independently -H, (C1-C4) alkyl, (C1-C4) haloalkyl, hydroxy-substituted (C2-C4) alkyl, -(C2-C3) alkylene-(C1-C3) alkoxy, -(C2-C3) alkylene-(N(R 22 )(R 23 )), -(C1-C6)alkylene-(C3-C7)cycloalkyl, -C(=O)-(C1-C4)alkyl, (C3-C7)cycloalkyl, -C(=O)-(C3-C7)cycloalkyl, -(C1-C3)alkylene-phenyl, -C(=O)-(C1-C3)alkylene-phenyl, -C(=O)-O-(C1-C3)alkylene-phenyl, phenyl or (5-6 membered)heteroaryl, wherein the (C3-C7)cycloalkyl, -(C1-C6)alkylene-(C3-C7)cycloalkyl and -C (C3-C7)cycloalkyl, -(C1-C3)alkylene-phenyl, -C(=O)-(C1-C3)alkylene-phenyl, -C(=O)-O-(C1-C3)alkylene-phenyl, phenyl or (5-6 membered)heteroaryl in (=O)-(C3-C7)cycloalkyl may each independently be optionally substituted with 1 or 2 of the following groups: -H, -F, -CN, -CH3, -CH2CH3, -CF3, -OCF3, -CH2CF3, -OCH3, -OCH2CH3 or -N(CH3)2; or R 10 and R 11 Together with the nitrogen atom to which it is attached, it can form a (4-11 membered) heterocycloalkyl, wherein the (4-11 membered) heterocycloalkyl can 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; R 12 and R 13 Each is 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 be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH, -N(CH3)2, (C1-C4)alkyl, (C1-C4)haloalkyl, -C(=O)-(C1-C4)alkyl, (C3-C4)cycloalkyl or (C1-C4)alkoxy; or R 12 and R 13 Together with the nitrogen atom to which it is attached, a (4-7 membered) heterocycloalkyl group may be formed, wherein the (4-7 membered) heterocycloalkyl group 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 with 1, 2 or 3 of the following groups: -H, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3; R 17 is (C1-C4)alkyl; R 18 and R 19 Each is 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, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3; or R 20 is (C3-C11)cycloalkyl, (4-11 membered)heterocycloalkyl, wherein said (C3-C11)cycloalkyl and (4-11 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; or 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, (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; or R 20 and R 21 Together with the nitrogen atom to which it is attached, it can form a (4-7 membered) heterocycloalkyl, wherein said (4-7 membered) heterocycloalkyl 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 22 and R 23 Each is independently -H, (C1-C2)alkyl or -C(=O)-(C1-C2)alkyl; R 24 and R 25 are each independently -H or (C1-C4)alkyl; and m is an integer of 0, 1 or 2, and n is an integer of 0, 1, 2, 3 or 4.

2. The compound according to claim 1 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 2 for 3. The compound according to claim 1 or 2, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring A is a phenyl group or a (5-6 membered) heteroaryl group containing 1, 2 or 3 independently selected from N, O or S.

4. The compound according to claim 3 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Ring A is:

5. The compound according to any one of claims 1 to 4 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R x Each is independently -H, -F, -Cl, -Br, -I, -CN, -NO2, (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)alkynyl, -O-(C2-C4)haloalkenyl, -O-(C5-C6)halocycloalkenyl, -O-(C2-C4)haloalkynyl, -(C1-C2)alkylene-phenyl, -(C1-C2)alkylene-(5-6 membered)heteroaryl, -(C1-C2)alkylene-(C3-C7)cycloalkyl, -(C1-C4)alkylene-(OR 9 )、(C3-C7)cycloalkyl, -OR 9 、-N(R 10 )(R 11 )、-(C1-C3)alkylene-N(R 10 )(R 11 )、-C(=O)-N(R 12 )(R 13 ),-SR 14 、-S(=O)-R 14 、-S(=O)2-R 14 、-C(=O)R 14 、-C(=O)-OR 17 , (5-6 membered) heteroaryl substituted by 1 or 2 -F, -Cl, -Br or -CH3, or phenyl substituted by 1 or 2 -F, -Cl, -Br or -CH3, wherein the (4-7 membered) heterocycloalkyl may be optionally substituted by 1 or 2 of the following groups: -H, halogen, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3.

6. The compound according to any one of claims 1 to 5, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 4 For-OR 4a 、-N(R 4b )2, (C1-C3) alkyl, (C3-C6) cycloalkyl, (C3-C6) cycloalkenyl or (3-6 membered) heterocycloalkyl, wherein the -OR 4a 、-N(R 4b )2, (C1-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or (3-6 membered)heterocycloalkyl substituted by 1 or 2 of the following groups: -OR 4a1 、-N(R 4b1 )2、-C(O)N(R 4c )2、-C(O)OR 4b1 , (C1-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or (3-6 membered)heterocycloalkyl, wherein the -OR 4a1 、-N(R 4b1 )2, (C1-C3)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkenyl or (3-6 membered)heterocycloalkyl may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -CN, -NO2, -OR 4a2 、-N(R 4b2 )2、-C(O)N(R 4c )2、-C(O)OR 4b2 , (C1-C3)alkyl, (C1-C3)alkoxy, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C5-C6)cycloalkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, phenyl, (3-6 membered)heteroaryl or (3-6 membered)heterocycloalkyl.

7. The compound according to any one of claims 1 to 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 4a 、R 4a1 and R 4a2 Each is independently (C1-C3)alkyl or (C1-C3)haloalkyl.

8. The compound according to any one of claims 1 to 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 4b 、R 4b1 and R 4b2 are each independently H, (C1-C3) alkyl or (C1-C3) haloalkyl, and R on the same nitrogen atom 4b Not H at the same time.

9. The compound according to any one of claims 1 to 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 4c Each is independently H, (C1-C3)alkyl or (C1-C3)haloalkyl.

10. The compound according to any one of claims 1 to 9 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 4 for:

11. The compound according to any one of claims 1 to 10, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 1 is phenyl or (5-6 membered) heteroaryl, wherein said phenyl or (5-6 membered) heteroaryl may each independently be optionally 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(R 5 )(R 6 ), wherein the phenyl group in the -(C1-C2)alkylene-phenyl group and the -(C1-C2)alkyleneoxy-phenyl group may each independently be optionally substituted by 1 or 2 of the following groups: -H, -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3.

12. The compound according to claim 11 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 1 is phenyl, wherein the phenyl group may be independently optionally substituted with 1, 2 or 3 of the following groups: -H, -F, -Cl, -Br, -OH, -CN, -NO2, (C1-C2)alkyl, (C1-C2)haloalkyl, (C1-C2)alkoxy.

13. The compound according to claim 11 or 12, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 1 for:

14. The compound according to any one of claims 1 to 13 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 5 and R 6 each independently -H, (C1-C3)alkyl, -C(=O)-(C1-C3)alkyl, (C3-C4)cycloalkyl, or -(C1-C2)alkylene-phenyl; or R 5 and R 6 Together with the nitrogen atom to which it is attached, a (4-6 membered) heterocycloalkyl group may be formed, wherein the (4-6 membered) heterocycloalkyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -F, -OH、-CH3、-CH2CH3、-C(=O)-CH3、 -OCH3 or -OCH2CH3.

15. The compound according to claim 14 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 5 and R 6 Each is independently -H, -CH3, -CH2CH3, -C(=O)-CH3, 16. The compound according to any one of claims 1 to 15 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 9 is H, (C1-C4) alkyl, (C2-C4) alkenyl, (C5-C6) cycloalkenyl, (C2-C4) alkynyl, (C1-C4) alkyl, -(C1-C2) alkylene-(5-6 membered) heteroaryl, -(C1-C2) alkylene-phenyl, (C1-C4) haloalkyl, hydroxy-substituted (C2-C3) alkyl, -(C2-C3) alkylene-(C1-C2) alkoxy, -(C2-C3) alkylene-OC(=O)-(C1-C2) alkyl, -C(R 18 )(R 19 )-C(=O)-OR 17 、-C(R 18 )(R 19 )-C(=O)-N(R 20 )(R 21 )、-C(=O)-N(R 20 )(R 21 ), phenyl, (5-6 membered) heteroaryl or (5-6 membered) heterocycloalkyl, wherein the phenyl in -(C1-C2)alkylene-phenyl, phenyl, (5-6 membered) heteroaryl, (5-6 membered) heteroaryl and (5-6 membered) heterocycloalkyl can each independently be optionally substituted by 1 or 2 of the following groups: -H, -F, -Cl, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3.

17. The compound according to claim 16 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 9 For H, -CHF2, -CF3, -CH2CF3, 18. The compound according to any one of claims 1 to 17 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 10 and R 11 Each is independently -H, (C1-C2) alkyl, (C1-C2) haloalkyl, hydroxy-substituted (C2-C3) alkyl, -(C2-C3) alkylene-(C1-C2) alkoxy, -(C2-C3) alkylene-N(R 22 )(R 23 ), -(C1-C2)alkylene-(C3-C7)cycloalkyl, -C(=O)-(C1-C2)alkyl, (C3-C7)cycloalkyl, -C(=O)-(C3-C7)cycloalkyl, -(C1-C2)alkylene-phenyl, -C(=O)-(C1-C2)alkylene-phenyl, -C(=O)-O-(C1-C2)alkylene-phenyl, phenyl or (5-6 membered)heteroaryl, wherein the (C3-C7)cycloalkyl, -(C1-C6)alkyl-(C3-C7)cycloalkyl and -C(=O)-(C3-C7)cycloalkyl The (C3-C7)cycloalkyl group in -(C1-C2)alkylene-phenyl and -C(=O)-(C1-C2)alkylene-phenyl and the phenyl, phenyl or (5-6 membered)heteroaryl group in -C(=O)-O-(C1-C2)alkylene-phenyl may each independently be optionally substituted with 1 or 2 of the following groups: -H, -F, -CN, -CH3, -CH2CH3, -CF3, -OCF3, -CH2CF3, -OCH3, -OCH2CH3 or -N(CH3); or R 10 and R 11 Together with the nitrogen atom to which it is attached, a (4-7 membered) heterocycloalkyl group may be formed, wherein the (4-7 membered) heterocycloalkyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -F, -Cl, -CN, -OH、-CH3、-CH2CH3、-CF3、CH3-C(=O)-、 -OCH3, -OCH2CH3, -NH2, -N(CH3)2 or (4-7 membered)heterocycloalkyl.

19. The compound according to claim 18 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 10 and R 11 Each is independently -H, -CH3, -CH2CH3, -C(=O)-CH3, 20. The compound according to any one of claims 1 to 19 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 12 and R 13 Each is independently -H, (C1-C3) alkyl, (C1-C3) haloalkyl, hydroxy-substituted (C1-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 may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH, -N(CH3)2, -CH3, -CH2CH3, -CF3, -C(=O)-CH3, -OCH3 or -OCH2CH3; or R 12 and R 13 Together with the nitrogen atom to which it is attached, a (4-7 membered) heterocycloalkyl group may be formed, wherein the (4-7 membered) heterocycloalkyl group may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH、-CH3、-CH2CH3、CH3-C(=O)-、 -OCH3 or -OCH2CH3.

21. The compound according to claim 20 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 12 and R 13 are independently -H, -CH3, -CH2CH3, 22. The compound according to any one of claims 1 to 21 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), 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, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3.

23. The compound according to claim 22 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 14 is -CH3, -CH2CH3, -OCH3 or -OCH2CH3.

24. The compound according to any one of claims 1 to 23 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 17 It is -CH3 or -CH2CH3.

25. The compound according to any one of claims 1 to 24, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 18 and R 19 Each is independently -H, -CH3 or -CH2CH3.

26. The compound according to any one of claims 1 to 25, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 20 is H, (C1-C3)alkyl, (C3-C4)alkenyl, (C2-C4)alkynyl or (C1-C3)alkoxy, wherein the (C1-C3)alkyl 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 may be substituted by 1, 2 or 3 of the following groups: -H, -F, -CN, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -CF3; or R 20 is (C3-C7) cycloalkyl, (4-7 membered) heterocycloalkyl, wherein the (C3-C7) cycloalkyl and (4-7 membered) heterocycloalkyl may be independently optionally substituted by 1, 2 or 3 of the following groups: -H, -CN, -OH、-CH3、-CH2CH3、CH3-C(=O)-、 -OCH3 or -OCH2CH3; or 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, -CH3, -CH2CH3, -OCH3, -OCH2CH3, -CF3, -N(CH3)2 or -C(=O)(CH3)2.

27. The compound according to any one of claims 1 to 26, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), R 21 is H, -CH3 or -CH2CH3; or R 20 and R 21 Together with the nitrogen atom to which it is attached, it can form a (4-7 membered) heterocycloalkyl, wherein said (4-7 membered) heterocycloalkyl can be independently optionally substituted by 1, 2 or 3 of the following groups: -H, halogen, -CN, -OH, -CH3, -CH2CH3, -CF3, -(C1-C2)alkylene-phenyl, -C(=O)-CH3, -OCH3, -OCH2CH3, -OCF3, -N(CH3)2 or -C(=O)(CH3)2.

28. The compound according to any one of claims 1 to 27 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 22 and R 23 Each is independently -H, -CH3, -CH2CH3 or -C(=O)-CH3.

29. The compound according to any one of claims 1 to 28, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 24 and R 25 Each is independently -H, -CH3 or -CH2CH3.

30. The compound according to any one of claims 1 to 29, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), the compound has one of the following structures:

31. A pharmaceutical composition, characterized in that It contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1 to 30, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.

32. Use of a compound according to any one of claims 1 to 30, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to claim 31 in the preparation of a medicament for treating or preventing diseases mediated by DGKζ.

33. The method of claim 32, wherein the disease is cancer, wherein the cancer is a blood cancer and a solid tumor, preferably head and neck cancer, kidney cancer, ovarian cancer, intestinal cancer, urothelial cancer, melanoma, liver cancer, gastric cancer, lung cancer, bladder cancer and cancer metastases thereof.

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