Dgkzeta antagonist and use thereof in medicine

Abstract

The present invention relates to a compound as represented by general formula (I) or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof, an intermediate and preparation method therefor, and a use thereof in the preparation of a drug for treating diseases related to DGKζ kinase abnormality.

Description

A DGKzeta antagonist and its application in medicine Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, racemates, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use of the compound in preparing drugs for treating diseases associated with abnormal DGKζ kinase. Background Art

[0002] DGK is a lipid kinase that downregulates T cell activation by phosphorylating diacylglycerol (DAG) and converting it to phosphatidic acid (PA), thereby acting as a ligand-independent intracellular immune checkpoint. DGKα and DGKζ (DGKzeta) are the two major isoforms within T cells, regulating the intensity of DAG signaling downstream of antigen stimulation to prevent T cell overactivation. Inhibiting DGK has the potential to enhance DAG downstream signaling and activate T cells.

[0003] Research has shown that DGKζ plays a role in cancer beyond immune cell regulation, including mediating proliferation, apoptosis, survival, invasion, and tumorigenicity. DGKζ deficiency leads to a hyper-reactive phenotype in T cells and enhances their activity against malignancies. The development of DGKζ inhibitors holds great promise for the treatment of tumors. Currently, there are no reports of marketed DGKζ inhibitors, and the development of DGKζ inhibitors is urgently needed, with broad clinical implications.

[0004] Summary of the Invention

[0005] The object of the present invention is to provide a compound having DGKζ kinase inhibitory activity or its stereoisomers, racemates, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, as well as intermediates and preparation methods, and use thereof in the preparation of drugs for treating diseases related to abnormal DGKζ kinase.

[0006] The technical problem to be solved by the present invention is to provide a class of small molecule compounds or pharmaceutically acceptable salts thereof for inhibiting DGKζ, thereby regulating T cell immune stimulation, and thus treating diseases such as cancer and autoimmune diseases.

[0007] The compound of the present invention has good DGKζ kinase inhibitory activity, bioavailability and in vivo safety.

[0008] The present invention provides a compound of general formula (I) or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0009] In some embodiments, the compound of formula (I) is selected from formula (Ia), (Ib), (Ic),

[0010] In some embodiments, R 1 Selected from C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0011] In some embodiments, R 1 Selected from C 1-4 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0012] In some embodiments, R 1 is selected from methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R k replace;

[0013] In some embodiments, R 1 Selected from CF3, CHF2, CH2F, methyl, ethyl, -CH2-cyclopropyl;

[0014] In some embodiments, R 1 Selected from CF3, methyl, ethyl;

[0015] In some embodiments, R 2 Selected from -C(=O)NH2, -S(=O)2NH2, preferably -C(=O)NH2;

[0016] In some embodiments, R 2 Selected from -C(=O)NH2;

[0017] In some embodiments, R 3 Selected from R 3A or R 3B ;

[0018] In some embodiments, R 3A Selected from non-aromatic C 3-12 Carbocyclic or non-aromatic 4-12 membered heterocyclic group, preferably C 3-7 Monocyclic cycloalkyl, C 3-6 Monocyclic cycloalkenyl, C 6-12 Cycloalkyl, C 6-12 Spirocyclic cycloalkyl, C 5-9 Bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered cyclic heterocycloalkyl, 6-12 membered cyclic heterocycloalkenyl, 6-12 membered spirocyclic heterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, wherein R 3A Optional 1 to 4 R3a replace;

[0019] In some embodiments, R 3A Selected from The R 3A Optional 1 to 4 R 3a replace;

[0020] In some embodiments, R 3A Selected from The R 3A Optional 1 to 4 R 3a replace;

[0021] In some embodiments, R 3A Selected from The R 3A Optional 1 to 4 R 3a replace;

[0022] In some embodiments, R 3A Selected from

[0023] In some embodiments, R 3B Selected from C 3-12 Carbocyclic or 4-12 membered heterocyclic, preferably C 6-10 Aryl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, C 3-7 Monocyclic carbocyclic ring, C 6-12 Ring carbon ring, C 6-12 Spirocarbon ring, C 5-12 Bridged carbon ring, 4-7 membered monocyclic heterocycle, 6-12 membered heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, the R 3B Optional 1 to 4 R 3b replace;

[0024] In some embodiments, R 3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, C 3-7 Monocyclic cycloalkyl, C 3-6 Monocyclic cycloalkenyl, C 6-12 Cycloalkyl, C 6-12 Spirocyclic cycloalkyl, C 5-9Bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered heterocycloalkenyl, 6-12 membered cyclic heterocycloalkyl, 6-12 membered cyclic heterocycloalkenyl, 6-12 membered spirocyclic heterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, wherein R 3B Optional 1 to 4 R 3b replace;

[0025] In some embodiments, R 3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, The R 3B Optional 1 to 4 R 3b replace;

[0026] In some embodiments, R 3B selected from phenyl, naphthyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, benzothienyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyrazinyl, The R 3B Optional 1 to 4 R 3b replace;

[0027] In some embodiments, R 3B Selected from phenyl, naphthyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, The R 3B Optional 1 to 4 R 3b replace;

[0028] In some embodiments, R 3B Selected from

[0029] In some embodiments, R 3B Selected from

[0030] In some embodiments, R 4 Selected from H, deuterium, halogen, CN, OH, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k Substitution; in some embodiments, R 4 Selected from H, deuterium, halogen, CN, OH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0031] In some embodiments, R 4 Selected from NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, the alkyl, alkylene, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0032] In some embodiments, R 4 Selected from NH2, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R k replace;

[0033] In some embodiments, R 4 is selected from NH2, methyl, CF3, CHF2 or CH2F;

[0034] In some embodiments, R 4 Selected from NH2;

[0035] In some embodiments, Ring A is selected from 6-membered heteroaryl, 8- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a replace;

[0036] In some embodiments, Ring A is selected from Pyridyl, pyrimidinyl, benzopyrrolyl, benzopyrazolyl, thiazolopyrazolyl, pyridopyrazolyl, the ring A is optionally substituted by 1 to 4 R a replace;

[0037] In some embodiments, Ring A is selected from

[0038] In some embodiments, Selected from

[0039] In some embodiments, R 5 Selected from C 3-12 Carbocyclic or 4-12 membered heterocyclic, preferably C 3-12 Carbocyclic group or 5 to 12 membered heterocyclic group, said R 5 Optional 1 to 4 R 5a replace;

[0040] In some embodiments, R 5 Selected from C 3-7 Monocyclic carbocyclic ring, C 6-12 Ring carbon ring, C 6-12 Spirocarbon ring, C 5-12 Bridged carbon ring, 4-7 membered monocyclic heterocycle, 6-12 membered heterocycle, 6-10 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, the R 5 Optional 1 to 4 R 5a replace;

[0041] In some embodiments, R 5 Selected from phenyl, 5 to 6 membered heteroaryl, benzo C 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, 8 to 10 membered heterocyclic group, The R 5 Optional 1 to 4 R 5a replace.

[0042] In some embodiments, R 5Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, pyrrolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyridoimidazolyl, pyridotriazolyl, pyridopyrazolyl, The R 5 Optional 1 to 4 R 5a replace;

[0043] In some embodiments, R 5 Selected from phenyl, pyridyl, pyrimidinyl, thienyl, The R 5 Optional 1 to 4 R 5a replace;

[0044] In some embodiments, R 5 Selected from R 5A ;

[0045] In some embodiments, R SA Selected from C 3-7 Monocyclic cycloalkyl, C 6-10 Cycloalkyl, C 6-10 Spirocyclic cycloalkyl, C 5-10 Bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 6-10 membered cyclic heterocycloalkyl, 6-10 membered spirocyclic heterocycloalkyl, 6-10 membered bridged ring heterocycloalkyl, 8 to 10 membered cyclic heteroaryl;

[0046] In some embodiments, R 5A Selected from The R SA Optional 1 to 4 R 5a replace;

[0047] In some embodiments, R 5A Selected from The R SA Optional 1 to 4 R 5a Substitution; in some embodiments, R a 、R 3a 、R 3b 、R 5a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0048] In some embodiments, R a 、R 3a 、R 3b 、R 5a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-4 to 7 membered heterocyclic group or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0049] In some embodiments, R a 、R 3a 、R 3b 、R 5aEach independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -C H2-oxolanyl, -CH2-oxahexanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-cyclopropyl, the CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally replaced by 1 to 4 R k replace;

[0050] In some embodiments, R 3a 、R 3b Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;

[0051] In some embodiments, R 3a 、R 3b Each independently selected from deuterium, F, Cl, CF3;

[0052] In some embodiments, R 3b Each independently selected from deuterium, F, and Cl;

[0053] In some embodiments, R 5a Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;

[0054] In some embodiments, R 5aEach independently selected from deuterium, F, CHF2, CH2F, CF3, methyl, ethyl, CH2CF3, CH2CHF2, OCF3, OCHF2, methoxy;

[0055] In some embodiments, R 5a Each independently selected from deuterium, F, CF3, methyl, ethyl;

[0056] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC1-6 alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0057] In some embodiments, R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocycle, -O-4 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbocyclic ring, -C 0-2 Alkylene-4 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0058] In some embodiments, R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 moieties selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0059] In some embodiments, s1, s3, s5, and s8 are each independently selected from 0, 1, or 2;

[0060] In some embodiments, s2 and s4 are each independently selected from 0 or 1;

[0061] In some embodiments, s6 is selected from 0, 1, 2, or 3;

[0062] In some embodiments, s7 is selected from 1, 2, or 3;

[0063] In some embodiments, is selected from a single bond or a double bond;

[0064] Optionally, s1 and s8 on the same ring are not 2 at the same time;

[0065] Optionally, provided that: when ring A is selected from And R 5 Selected from 1 to 4 R 5a Substituted one of the following groups: phenyl, 5- to 6-membered heteroaryl, benzo C 5-6 Carbocyclic group, 6-membered heteroaryl and C 5-6 Carbocyclic group, 6-membered heteroaryl and 5 to 6-membered oxygen-containing heterocyclic group, benzo 5 to 6-membered oxygen-containing heterocyclic group, the C 5-6 When the carbocyclic group or the 5- to 6-membered oxygen-containing heterocyclic group is a partially saturated ring, R 3 Selected from R 3A .

[0066] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0067] R 1 Selected from C 1-6 Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0068] R 2 Selected from -C(=O)NH2, -S(=O)2NH2, preferably -C(=O)NH2;

[0069] R 3 Selected from R 3A or R 3B ;

[0070] R 3A Selected from non-aromatic C 3-12 Carbocyclic or non-aromatic 4-12 membered heterocyclic group, preferably C 3-7 Monocyclic cycloalkyl, C 3-6 Monocyclic cycloalkenyl, C 6- 12 Cycloalkyl, C 6-12 Spirocyclic cycloalkyl, C 5-9 Bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered cyclic heterocycloalkyl, 6-12 membered cyclic heterocycloalkenyl, 6-12 membered spirocyclic heterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, wherein R SA Optional 1 to 4 R 3a replace;

[0071] R 3B Selected from C 3-12 Carbocyclic or 4-12 membered heterocyclic, preferably C 6-10 Aryl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, C 3-7 Monocyclic carbocyclic ring, C 6-12 Ring carbon ring, C 6-12 Spirocarbon ring, C 5-12 Bridged carbon ring, 4-7 membered monocyclic heterocycle, 6-12 membered heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, the R 3B Optional 1 to 4 R 3b replace;

[0072] R 4 Selected from H, deuterium, halogen, CN, OH, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0073] Ring A is selected from 6-membered heteroaryl, 8- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a replace;

[0074] R 5 Selected from C 3-12 Carbocyclic or 4-12 membered heterocyclic, preferably C 3-12 Carbocyclic group or 5 to 12 membered heterocyclic group, said R 5 Optional 1 to 4 R 5a replace;

[0075] R a 、R 3a 、R 3b 、R 5a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0076] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocycle, -O-3 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbocyclic ring, -C 0-4Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0077] Provided that: when ring A is selected from And R 5 Selected from 1 to 4 R 5a Substituted one of the following groups: phenyl, 5- to 6-membered heteroaryl, benzo C 5-6 Carbocyclic group, 6-membered heteroaryl and C 5-6 Carbocyclic group, 6-membered heteroaryl and 5 to 6-membered oxygen-containing heterocyclic group, benzo 5 to 6-membered oxygen-containing heterocyclic group, the C 5-6 When the carbocyclic group or the 5- to 6-membered oxygen-containing heterocyclic group is a partially saturated ring, R 3 Selected from R 3A .

[0078] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0079] R 5 Selected from C 3-7 Monocyclic carbocyclic ring, C 6-12 Ring carbon ring, C 6-12 Spirocarbon ring, C 5-12 Bridged carbon ring, 4-7 membered monocyclic heterocycle, 6-12 membered heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, the R 5 Optional 1 to 4 R 5a replace;

[0080] R 3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, C 3-7 Monocyclic cycloalkyl, C 3-6 Monocyclic cycloalkenyl, C 6-12 Cycloalkyl, C 6-12 Spirocyclic cycloalkyl, C 5-9 Bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered heterocycloalkenyl, 6-12 membered cyclic heterocycloalkyl, 6-12 membered cyclic heterocycloalkenyl, 6-12 membered spirocyclic heterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, wherein R 3B Optional 1 to 4 R 3b replace;

[0081] R 1 Selected from C 1-4Alkyl, said alkyl being optionally substituted by 1 to 4 R k replace;

[0082] R 4 Selected from H, deuterium, halogen, CN, OH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0083] R a 、R 3a 、R 3b 、R 5a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-4 to 7 membered heterocyclic group or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0084] R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1- 4 alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocycle, -O-4 to 7 membered heterocycle, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7 membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbocyclic ring, -C 0-2Alkylene-4 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0085] The definitions of the remaining substituents are consistent with those described in Scheme 1 of the present invention.

[0086] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0087] R 3A Selected from The R 3A Optional 1 to 4 R 3a replace;

[0088] R 3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, The R 3B Optional 1 to 4 R 3b replace;

[0089] s1, s3, s5, and s8 are each independently selected from 0, 1, or 2;

[0090] s2 and s4 are each independently selected from 0 or 1;

[0091] s6 is selected from 0, 1, 2 or 3;

[0092] s7 is selected from 1, 2 or 3;

[0093] s1 and s8 on the same ring are not 2 at the same time;

[0094] is selected from a single bond or a double bond;

[0095] Ring A is selected from Pyridyl, pyrimidinyl, benzopyrrolyl, benzopyrazolyl, thiazolopyrazolyl, pyridopyrazolyl, the ring A is optionally substituted by 1 to 4 R a replace;

[0096] R 4 Selected from NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, the alkyl, alkylene, cycloalkyl is optionally substituted by 1 to 4 R k replace;

[0097] R 5 Selected from phenyl, 5 to 6 membered heteroaryl, benzo C 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, 8 to 10 membered heterocyclic group, The R 5 Optional 1 to 4 R 5a replace;

[0098] The definitions of the remaining substituents are consistent with those described in Schemes 1 and 2 of the present invention.

[0099] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0100] R 1 is selected from methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R k replace;

[0101] R 2 Selected from -C(=O)NH2;

[0102] R 4 Selected from NH2, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R k replace;

[0103] R 3A Selected from The R 3A Optional 1 to 4 R 3a replace;

[0104] R 3Bselected from phenyl, naphthyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, benzothienyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyrazinyl, The R 3B Optional 1 to 4 R 3b replace;

[0105] R 5 Selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, pyrrolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, pyridoimidazolyl, pyridotriazolyl, pyridopyrazolyl, The R 5 Optional 1 to 4 R 5a replace;

[0106] R a 、R 3a 、R 3b 、R 5aEach independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -C H2-oxolanyl, -CH2-oxahexanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-cyclopropyl, the CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxetanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally replaced by 1 to 4 R k replace;

[0107] R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 moieties selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0108] The definitions of the remaining substituents are consistent with those described in Schemes 1, 2, and 3 of the present invention.

[0109] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0110] The compound of general formula (I) is selected from general formula (Ia), (Ib), (Ic),

[0111] R 1 Selected from CF3, CHF2, CH2F, methyl, ethyl, -CH2-cyclopropyl;

[0112] R 4 is selected from NH2, methyl, CF3, CHF2 or CH2F;

[0113] Selected from

[0114] R 5 Selected from phenyl, pyridyl, pyrimidinyl, thienyl, The R 5 Optional 1 to 4 R 5a replace;

[0115] R SA Selected from The R 5A Optional 1 to 4 R 5a replace;

[0116] R 5a Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;

[0117] R 3A Selected from The R 3A Optional 1 to 4 R 3a replace;

[0118] R 3B Selected from phenyl, naphthyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, The R 3B Optional 1 to 4 R 3b replace;

[0119] R 3a 、R 3bEach independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;

[0120] The definitions of the remaining substituents are consistent with those described in Scheme 1 of the present invention.

[0121] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound of general formula (I) is selected from general formula (Ia), (Ib), (Ic),

[0122] R 3A Selected from

[0123] R 3B Selected from

[0124] The definitions of the remaining substituents are consistent with those described in Schemes 1 and 5 of the present invention.

[0125] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound of general formula (I) is selected from general formula (Ic),

[0126] R 1 Selected from CF3, methyl, ethyl;

[0127] R 3B Selected from

[0128] R 4 Selected from NH2;

[0129] R 5A Selected from The R 5A Optional 1 to 4 R 5a replace;

[0130] R 3b Each independently selected from deuterium, F, and Cl;

[0131] R 5aEach is independently selected from deuterium, F, CF3, methyl, and ethyl.

[0132] The present invention relates to the following compound or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table A below:

[0133] Table A

[0134] The present invention relates to a pharmaceutical composition comprising the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1-1500 mg of the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal.

[0135] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0136] The present invention relates to use of the compound of the present invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a medicament for treating diseases associated with abnormal DGKζ kinase, preferably in the preparation of medicaments for cancer and autoimmune diseases.

[0137] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation strength").

[0138] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., a disease associated with abnormal DGKζ kinases such as cancer, autoimmune diseases). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 1 00-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg , 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 1 50-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 2 00-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-3 00mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-3 00mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

[0139] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 1 25 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0140] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg. The disease is preferably a disease associated with abnormal DGKζ kinase (e.g., cancer, autoimmune disease).

[0141] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1000 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day.

[0142] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0143] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in the preparation of a drug for treating diseases related to abnormal DGKζ kinase.

[0144] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the above-mentioned pharmaceutical composition in the preparation of a medicament for treating a disease associated with abnormal DGKζ kinase. Preferably, the disease is selected from cancer and autoimmune disease, preferably solid tumor.

[0145] The amount of the compound of the invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is in each case calculated as the free base.

[0146] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0147] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0148] "CN" refers to cyano.

[0149] "Halogen" refers to F, Cl, Br or I.

[0150] "Halogen-substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halo".

[0151] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0152] "Alkylene" refers to substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon groups, including (CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0153] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0154] " Heterocycloalkyl " refers to a saturated cyclic hydrocarbon radical containing heteroatoms that is substituted or unsubstituted, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocycle, a ring, a bridged ring and a spirocycle. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0155] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0156] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentyn Alkynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, and the like; an alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0157] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0158] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0159] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary ring, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally monocyclic, bridged, fused or spirocyclic. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxane, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0160] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 atoms selected from N, O or S (=O) n (n is 0, 1 or 2). "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0161] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0162] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five atoms selected from heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0163] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0164] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0165] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" in which the ring system consists of only carbon atoms.

[0166] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

[0167] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0168] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0169] "Heterobridged ring", "heterobridged cyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0170] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0171] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1 or 2). The number of ring atoms in the heteroaromatic ring is, but not limited to, 5 to 15, 5 to 10 or 5 to 6. The ring atoms C, N, and S are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0172] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c Rb and Rc are independently selected from the group consisting of H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, Rb and Rc can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0173] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0174] A ring of X - Y members (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, and X and Y are any integers selected from 4 to 20) includes rings of X, X + 1, X + 2, X + 3, X + 4.... Y members. The ring includes heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, hetero - fused rings, heterospiro rings or heterobridged rings. For example, "4 - 7 - membered heteromonocyclic ring" means a 4 - membered, 5 - membered, 6 - membered or 7 - membered heteromonocyclic ring, and "5 - 10 - membered hetero - fused ring" means a 5 - membered, 6 - membered, 7 - membered, 8 - membered, 9 - membered or 10 - membered hetero - fused ring.

[0175] C x-y A carbocyclic ring (including aryl groups, cycloalkyl groups, monocyclic carbocyclic rings, spirocarbocyclic rings, fused carbocyclic rings or bridged carbocyclic rings) includes C x 、C x+1、 C x+2 、C x+3 、C x+4 ....C y A ring of x members (where x is an integer, and 3 ≤ x < y, and y is any integer selected from 4 to 20), for example. Such as C 3-6 "Cycloalkyl group" means a C3, C4, C5 or C6 cycloalkyl group;

[0176] When a certain group has one or more connectable sites, any one or more of these sites of the group can be connected to other groups by chemical bonds. When the connection mode of the chemical bond is non - specific and there are hydrogen atoms at the connectable sites, then when connecting the chemical bond, the number of H atoms at this site will correspondingly decrease according to the number of connected chemical bonds to form a group with the corresponding valence. For example indicates that any connectable site on this piperidyl group can be connected to other groups by 1 chemical bond, including at least these 4 connection modes, even if a H atom is drawn on - N - also includes For example indicates that the R group on this piperidyl group can be located on C or on N, including at least

[0177] When the listed connecting groups do not specify their connection directions, their connection directions include connecting in the directions of the reading orders from left to right and from right to left. For example, for A - L - B, when L is selected from - M - W -, it includes A - M - W - B and A - W - M - B.

[0178] "Optionally" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the occasions where the event or circumstance occurs or does not occur. For example: "An alkyl group optionally substituted by F" means that the alkyl group can but does not have to be substituted by F, and the description includes the situation where the alkyl group is substituted by F and the situation where the alkyl group is not substituted by F.

[0179] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0180] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0181] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0182] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0183] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0184] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0185] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0186] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0187] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imide-alcohol isomers.

[0188] “IC 50"It is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0189] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0190] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0191] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0192] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0193] Thin layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0194] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0195] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0196] Reagent and Solvent Abbreviations:

[0197] DMA: N,N-dimethylacetamide; DMF: N,N-dimethylformamide; DCM: dichloromethane;

[0198] Synthesis scheme:

[0199] X is selected from a leaving group, preferably halogen, OMs, OTs or Otf;

[0200] The definitions of the remaining groups are consistent with those of the aforementioned compound of formula (I);

[0201] The compound of general formula (A-1) and the compound of general formula (A-2) undergo a ring-closure reaction to obtain the compound of general formula (A-3);

[0202] The compound of general formula (A-3) and the compound of general formula (A-4) react with an alkaline reagent (such as TEA, DIEA, K2CO3) through a nucleophilic substitution reaction to obtain a compound of general formula A.

[0203] Example 1: Preparation of Compound 1

[0204] Step 1: Preparation of 1b

[0205] 1a (5.00 g, 25.25 mmol), bistriphenylphosphine palladium dichloride (1.78 g, 2.54 mmol), and tributyl(1-ethoxyethylene)tin (1.19 g, 3.30 mmol) were added to dry 1,4-dioxane (50 mL) and reacted at 100°C under a nitrogen atmosphere for 16 h. The mixture was cooled to 50°C, and aqueous hydrochloric acid (21 mL, 1N) was added and stirred for 1 h. The mixture was cooled to room temperature, and saturated aqueous potassium fluoride (60 mL) was added and stirred for 30 min. The mixture was filtered, and water (50 mL) was added to the filtrate, which was then extracted with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate (v:v) = 40:60) to afford 1b (2.40 g, 59% yield).

[0206] LCMS m / z=162.1[M+H] +

[0207] Step 2: Preparation of 1c

[0208] Dissolve 1b (0.50 g, 3.10 mmol) in acetic acid (5 mL), add pyridinium tribromide (0.99 g, 3.10 mmol) and 33% hydrogen bromide in acetic acid (2.20 g, 8.97 mmol), and react at room temperature for 1 h. Add water (20 mL) and extract with ethyl acetate (20 mL x 3). The organic phases are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to afford 1c (0.70 g, 94% yield).

[0209] LCMS m / z=240.2[M+1] +

[0210] Step 3: Preparation of 1d

[0211] 4-Fluorophenyl isothiocyanate (450 mg, 2.94 mmol) was dissolved in acetonitrile (5 mL), and cyanamide (150 mg, 3.57 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (450 mg, 2.96 mmol) were added. The mixture was allowed to react at room temperature for 1 h. 1c (700 mg, 2.92 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (220 mg, 1.45 mmol) were then added. The reaction was continued at room temperature for 16 h. Water (20 mL) was added and stirred for 30 min. A solid precipitated, which was filtered, washed with water, and concentrated under reduced pressure to afford 1d (400 mg, 39% yield).

[0212] LCMS m / z=355.0[M+H] +

[0213] Step 4: Preparation of compound 1

[0214] 1d (100 mg, 0.28 mmol) was dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (390 mg, 2.82 mmol) and 2-bromopropionamide (210 mg, 1.38 mmol) were added. The mixture was reacted at 90°C for 2 h. The mixture was filtered, and the filtrate was purified by Pre-HPLC (apparatus and preparative column: SHIMADZU LC-20AP preparative liquid phase, Phenomenex C18, 5 μm, inner diameter x length = 19 mm x 150 mm). Preparation method: The filtrate was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare the sample solution. The mobile phase system was acetonitrile / water (containing 0.05% ammonium acetate). Gradient elution method: Acetonitrile was gradiently eluted from 32% to 62% (elution time 15 min). After lyophilization, compound 1 (20 mg, 17% yield) was obtained.

[0215] LCMS m / z=426.2[M+1] +

[0216] 1 H NMR (400MHz, DMSO-d6) δ8.95 (dd, 1H), 8.55 (s, 1H), 8.52-7.98 (m, 2H), 7.88-7.82 (m, 1H), 7.70- 7.61(m, 2H), 7.57(s, 1H), 7.36-7.28(m, 2H), 7.27-7.21(m, 2H), 5.18-4.97(m, 1H), 1.17(d, 3H).

[0217] Example 2: Preparation of Compound 2

[0218] Compound 2 was obtained using 2a as the starting material by referring to the synthetic method of compound 1.

[0219] LCMS m / z=426.2[M+1] +

[0220] 1 H NMR (400MHz, DMSO-d6) δ9.03 (s, 1H), 8.55 (s, 1H), 8.45-8.01 (m, 2H), 7.88-7.82 (m, 1H), 7.78-7.72 (m, 1H), 7.69-7.61(m, 2H), 7.60-7.53(m, 1H), 7.38-7.29(m, 1H), 7.28-7.21(m, 1H), 5.18-4.97(m, 1H), 1.17(d, 3H).

[0221] Example 3: Preparation of Compound 3

[0222] Compound 3 was obtained using 3a as the starting material by referring to the synthetic method of compound 1.

[0223] LCMS m / z=426.1[M+1] +

[0224] Example 4: Synthesis of Compound 4

[0225] Step 1: Preparation of 4b

[0226] Dissolve 4a (200 mg, 1.45 mmol) and 1,1-thiocarbonyl DI-2(1H)-pyridine (337 mg, 1.45 mmol) in dichloromethane (10 mL). Add N,N-diisopropylethylamine (190 mg, 1.45 mmol) and react at room temperature for 16 hours. Concentrate under reduced pressure to obtain a crude product. Dissolve the crude product in acetonitrile (10 mL). Add cyanamide (73 mg, 1.74 mmol) and 1,8-diazobisspiro[5.4.0]undec-7-ene (221 mg, 1.45 mmol) and react at room temperature for 1 hour. Add 2-bromo-4′-methoxyacetophenone (399 mg, 1.74 mmol) and 1,8-diazobisspiro[5.4.0]undec-7-ene (110 mg, 10.72 mmol) and react at room temperature for 16 hours. The residue was concentrated under reduced pressure and purified by column chromatography (petroleum ether:tetrahydrofuran (v:v) = 50:50) to give 4b (260 mg, yield: 54%).

[0227] LCMS m / z=334.1[M+1] +

[0228] Step 2: Synthesis of compound 4

[0229] 4b (50 mg, 0.15 mmol), 2-iodopropionamide (60 mg, 0.30 mmol), and potassium phosphate (160 mg, 0.75 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted at 50°C for 8 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by Pre-HPLC to obtain compound 4.

[0230] LCMS m / z=405.2[M+1] +

[0231] 1 H NMR (400MHz, DMSO-d6) δ8.31-7.71(m, 2H), 7.70-7.55(m, 2H), 7.36(s, 1H), 7.20(s, 1H) ), 7.05-6.93(m, 2H), 4.78-4.63(m, 1H), 3.82(s, 3H), 2.70-2.55(m, 6H), 1.42(d, 3H).

[0232] Example 5: Synthesis of Compound 5

[0233] Compound 5 was prepared using 5a as the starting material by referring to the synthesis method of Example 4.

[0234] LCMS m / z=447.3[M+1] +

[0235] Example 6: Preparation of Compound 6-A and Compound 6-B

[0236] Using 6a as the substrate, the crude product of compound 6 was obtained according to the synthetic method of Example 1. The crude product was then purified by Pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative liquid phase, preparative column model: Phenomenex C18, 5 μm, inner diameter * length = 19 mm * 150 mm). Preparation method: The crude product was dissolved in N,N-dimethylformamide and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.05% trifluoroacetic acid). Gradient elution method: Acetonitrile was gradiently eluted from 32% to 62% (elution time: 15 min). After lyophilization, the trifluoroacetic acid salt of compound 6 was obtained.

[0237] LCMS m / z=439.3[M+1] +

[0238] Compound 6 was purified by SFC on Chiral OD column (instrument and preparative column: Waters 150 Prep-SFC, preparative column model: Chiral OD column. Preparation method: Compound 6 was dissolved in acetonitrile and ethanol and filtered through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2; B for 0.1% NH3·H2O in ethanol. Gradient elution method: 50% mobile phase B isocratic elution (flow rate: 100mL / min; elution time 3min), and after lyophilization, compounds 6-A and 6-B were obtained. Analytical method (instrument and preparative column: SHIMADZU LC-30AD sf, analytical column model: Chiral OD column, mobile phase system: A for CO2; B for 0.05% DEA in Ethanol, gradient elution method: 5-40% mobile phase B; column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 2.080 min for compound 6-A, retention time T = 5.698 min for compound 6-B (compounds 6-A and 6-B, one of which is compound 6-1, the other is compound 6-2).

[0239] Compound 6-A

[0240] LCMS m / z=439.0[M+1] +

[0241] 1 H NMR (400MHz, DMSO-d6) δ8.46-7.94(m, 3H), 7.91(s, 1H), 7.67-7.60(m, 3H), 7.59-7.52(m , 2H), 7.35-7.27(m, 2H), 7.24-7.19(m, 1H), 5.14-4.97(m, 1H), 4.02(s, 3H), 1.16(d, 3H).

[0242] Compound 6-B

[0243] LCMS m / z=439.0[M+1] +

[0244] 1H NMR (400MHz, DMSO-d6) δ8.46-7.94(m, 3H), 7.91(s, 1H), 7.67-7.60(m, 3H), 7.59-7.52(m , 2H), 7.35-7.27(m, 2H), 7.24-7.19(m, 1H), 5.14-4.97(m, 1H), 4.02(s, 3H), 1.16(d, 3H).

[0245] Example 7: Preparation of Compound 7-A and Compound 7-B

[0246] The trifluoroacetate salt of compound 7 was prepared using 7a as the starting material according to the synthesis method of Example 6.

[0247] LCMS m / z=439.1[M+1] +

[0248] Compound 7 was purified by SFC on Chiral OD column (instrument and preparative column: Waters 150 Prep-SFC, preparative column model: Chiral OD column. Preparation method: Compound 7 was dissolved in acetonitrile and ethanol and filtered through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2; B for 0.1% NH3·H2O in ethanol. Gradient elution method: 50% mobile phase B isocratic elution (flow rate: 100mL / min; elution time 3min), and after lyophilization, compounds 7-A and 7-B were obtained. Analytical method (instrument and preparative column: SHIMADZU LC-30AD sf, analytical column model: Chiral OD column, mobile phase system: A for CO2; B for 0.05% DEA in Ethanol, gradient elution method: 5-40% mobile phase B; column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 2.177 min for compound 7-A, retention time T = 5.505 min for compound 7-B (compounds 7-A and 7-B, one of which is compound 7-1, the other is compound 7-2).

[0249] Compound 7-A

[0250] LCMS m / z=439.1[M+1] +

[0251] 1H NMR (400MHz, DMSO-d6) δ8.41 (s, 1H), 8.34-7.75 (m, 3H), 7.68-7.60 (m, 2H), 7.59-7.50 (m, 2H), 7.4 2-7.35(m, 1H), 7.34-7.26(m, 2H), 7.25-7.17(m, 1H), 5.16-4.97(m, 1H), 4.14(s, 3H), 1.16(d, 3H).

[0252] Compound 7-B

[0253] LCMS m / z=439.0[M+1] +

[0254] 1 H NMR (400MHz, DMSO-d6) δ8.41 (s, 1H), 8.34-7.75 (m, 3H), 7.68-7.60 (m, 2H), 7.59-7.50 (m, 2H), 7.4 2-7.35(m, 1H), 7.34-7.26(m, 2H), 7.25-7.17(m, 1H), 5.16-4.97(m, 1H), 4.14(s, 3H), 1.16(d, 3H).

[0255] Example 8: Preparation of Compound 8-A and Compound 8-B

[0256] The trifluoroacetate salt of compound 8 was prepared using 8a as the starting material according to the synthesis method of Example 6.

[0257] LCMS m / z=443.0[M+H] + .

[0258] Compound 8 was purified by SFC on an IK column (instrument and preparative column: Waters 150 Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 8 was dissolved in acetonitrile and dichloromethane and filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in isopropanol and acetonitrile). Gradient elution method: 50% mobile phase B isocratic elution (flow rate: 100 mL / min; elution time: 4 min)), and lyophilized to obtain compounds 8-A and 8-B.

[0259] Analytical method (instrument and preparative column: SHIMADZULC-30AD sf, analytical column model: Chiral IK column, mobile phase system: A for CO2; B for 0.05% DEA in isopropanol and acetonitrile, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 1.080 min for compound 8-A. Retention time T = 1.389 min for compound 8-B (compounds 8-A and 8-B, one of which is compound 8-1 and the other is compound 8-2).

[0260] Compound 8-A:

[0261] LCMS m / z=442.9[M+H] + .

[0262] 1 H NMR (400MHz, DMSO-d6) δ8.56-7.92 (m, 4H), 7.84-7.76 (m, 1H), 7.69-7.60 (m, 2H), 7.5 9-7.51(m, 1H), 7.36-7.27(m, 2H), 7.26-7.19(m, 1H), 5.16-4.97(m, 1H), 1.17(d, 3H).

[0263] Compound 8-B:

[0264] LCMS m / z=443.0[M+H] + .

[0265] 1 H NMR (400MHz, DMSO-d6) δ8.56-7.92 (m, 4H), 7.84-7.76 (m, 1H), 7.69-7.60 (m, 2H), 7.5 9-7.51(m, 1H), 7.36-7.27(m, 2H), 7.26-7.19(m, 1H), 5.16-4.97(m, 1H), 1.17(d, 3H).

[0266] Example 9: Preparation of Compound 9-A and Compound 9-B

[0267] Compound 9 was prepared using 9a as the starting material according to the synthesis method of Example 1.

[0268] LCMS m / z=427.0[M+H] + .

[0269] Compound 9 was purified by SFC on an IK column (instrument and preparative column: Waters 150 Prep-SFC, preparative column model: Chiral IK column. Preparation method: Compound 9 was dissolved in acetonitrile and dichloromethane and filtered through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO2 and B for 0.1% NH3·H2O in isopropanol). Gradient elution method: 40% mobile phase B isocratic elution (flow rate: 120mL / min; elution time: 4min)) and lyophilized to obtain compounds 9-A and 9-B.

[0270] Analytical method (instrument and preparative column: SHIMADZULC-30AD sf, analytical column model: Chiral IK column, mobile phase system: A for CO2; B for 0.05% DEA in isopropanol, column temperature: 35°C, flow rate: 3.0 mL / min. Retention time T = 2.337 min for compound 9-A, retention time T = 2.679 min for compound 9-B (compounds 9-A and 9-B, one of which is compound 9-1 and the other is compound 9-2).

[0271] Compound 9-A:

[0272] LCMS m / z=427.0[M+H] + .

[0273] 1 H NMR (400MHz, DMSO-d6) δ 8.67-7.91 (m, 4H), 7.72-7.46 (m, 4H), 7.41-7.15 (m, 3H), 5.16-4.97 (m, 1H), 1.17 (d, 3H).

[0274] Compound 9-B:

[0275] LCMS m / z=427.0[M+H] + .

[0276] 1 H NMR (400MHz, DMSO-d6) δ 8.67-7.91 (m, 4H), 7.72-7.46 (m, 4H), 7.41-7.15 (m, 3H), 5.16-4.97 (m, 1H), 1.17 (d, 3H).

[0277] Biological test cases

[0278] 1. Determination of DGKζ Inhibitory Activity

[0279] Compounds were serially diluted three-fold using DMSO in a 384 PP Plate. Using an Echo (655, LABCYTE), 0.1 μL of compound was transferred to a 384-well microplate (Optiplate 384) to ensure a final DMSO concentration of 1% (in duplicate). 5 μL of 2X DGKζ (D30-10G, Signalchem) solution was added to each well of the 384-well microplate and centrifuged at 1000 rpm for 1 minute. Wells containing 1% DMSO and enzyme served as high controls, while wells containing 1% DMSO and buffer served as low controls. The mixture was incubated at 25°C for 10 minutes. 5 μL of 2X ATP and DAG solution (S359043, Aladdin) was added to each well and centrifuged at 1000 rpm for 1 minute. The mixture was incubated at 25°C for 60 minutes. 5 μL of ADP-Glo ​​Reagent (V9102, Promega) was added to each well and centrifuged at 1000 rpm for 1 minute. Incubate at 25°C for 40 minutes. Add 10 μL ADP-Glo ​​Detection to each well and centrifuge at 1000 rpm for 1 minute. Incubate at 25°C for 40 minutes. Read the RLU (Relative Luminescence Unit) signal on a BMG (PHERAstar FSX) microplate reader (final working concentration of reagents: 0.2 nM DGKZ, 20 μM ATP, 50 μM DAG). The percentage of inhibition of the compound-treated wells was standardized between the High Control and the Low Control (% inhibition = (AVE High Control-RLU compound reading) / (AVE High Control-AVE Low Control) * 100). The four-parameter IC was then fitted by XLfit 5.5.0 50 Curve and analysis, IC 50 It is the concentration of compound corresponding to 50% inhibition rate.

[0280] Table 1. Inhibitory activity of compounds against DGKζ enzyme

[0281] Conclusion: The compounds of the present invention, such as the example compounds, have DGKζ inhibitory activity, and specifically compounds 6, 8, 6-B, 8-B, and 9-B have good DGKζ inhibitory activity.

[0282] 2. Pharmacokinetic Testing in Mice

[0283] 2.1 Experimental Animals: Male Balb / c mice, 22-25 g, 6-8 weeks old, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0284] 2.2 Experimental Design: On the day of the experiment, Balb / c mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0285] Table 2. Dosing Information

[0286] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 95% (20% SBE-β-CD)

[0287] (DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; SBE-β-CD: sulfobutyl-β-cyclodextrin)

[0288] Before and after administration, 0.03 ml of blood was collected from the eye sockets and placed in EDTA-K2 centrifuge tubes. The tubes were centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, 1, 2, 4, 7, and 24 hours. All samples were stored at -80°C prior to analysis.

[0289] Table 3. Pharmacokinetic parameters of test compounds in mouse plasma

[0290] -:not applicable.

[0291] Conclusion: The compounds of the present invention, such as the example compounds, specifically compounds 9-B and 6-B, have higher exposure, lower clearance and good bioavailability in mice, and are significantly superior to the control compound BAY-2965501.

[0292] 3. Pharmacokinetic Test in Rat

[0293] 3.1 Experimental Animals: Male SD rats, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0294] 3.2 Experimental Design: On the day of the experiment, SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0295] Table 4. Dosing Information

[0296] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 95% (20% SBE-β-CD)

[0297] (DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; SBE-β-CD: sulfobutyl-β-cyclodextrin)

[0298] Before and after dosing, 0.10 ml of blood was collected from the eye sockets and placed in EDTA-K2 centrifuge tubes. The blood was centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected at the following time points for both the intravenous and oral administration groups: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0299] Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic properties in rats.

[0300] 4.CYP450 enzyme inhibition test

[0301] The purpose of this study was to evaluate the effects of test substances on the activities of four cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C19, CYP2D6, and CYP3A4) in human liver microsomes using an in vitro assay system. Specific probe substrates for each CYP450 isoform were incubated with human liver microsomes and varying concentrations of the test substances. The reaction was initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the samples were processed and metabolites generated from the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and IC50 values ​​were calculated to evaluate the inhibitory potential of the test substances against each CYP enzyme isoform.

[0302] Conclusion: The compounds of the present invention, such as the example compounds, have poor inhibitory activity against CYP enzymes. Specifically, the IC50 values ​​of compound 6-B and compound 9-B against CYP1A2, CYP2C19, CYP2D6 and CYP3A4 are all greater than 20 μM.

[0303] 5. hERG potassium channel effect test

[0304] Experimental platform: electrophysiology manual patch clamp system

[0305] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0306] Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusing the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (for at least 1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0307] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%

[0308] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0309] Compound IC 50 Calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC50-X)*HillSlope))

[0310] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0311] Conclusion: The compounds of the present invention, such as the compounds in the examples, have poor hERG inhibitory activity.

[0312] 6. Liver Microsome Stability Test

[0313] In this study, human liver microsomes were used as an in vitro model to evaluate the metabolic stability of the test substances.

[0314] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, and 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(Liver) .

[0315] Table 5. Human liver microsome stability results

[0316] Conclusion: The compounds of the present invention, such as the compounds in the examples, specifically compound 6-B and compound 9-B, have good metabolic stability in human liver microsomes.

[0317] 7. Beagle Dog Pharmacokinetic Test

[0318] Experimental purpose: To administer the test substance to beagle dogs by single-dose intravenous and oral gavage, determine the concentration of the test substance in beagle dog plasma, and evaluate the pharmacokinetic characteristics of the test substance in beagle dogs.

[0319] Experimental animals: Male beagle dogs, weighing about 8-11 kg, 6 per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0320] Experimental method: On the day of the experiment, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0321] Table 6. Dosing Information

[0322] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 95% (20% SBE-β-CD)

[0323] (DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; SBE-β-CD: sulfobutyl-β-cyclodextrin)

[0324] Sampling: Before and after administration, 1 ml of blood was collected from the limb vein and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm, 4°C for 10 min to collect plasma.

[0325] Blood was collected at 0, 5, 15, 30 min, and 1, 2, 4, 6, 8, 10, 12, and 24 h. All samples were stored at -80°C prior to analysis. Quantitative analysis was performed using LC-MS / MS.

[0326] Conclusion: The compounds of the present invention, such as the compounds in the examples, have higher exposure and good pharmacokinetic properties in beagle dogs.

[0327] 8. Monkey Pharmacokinetic Test

[0328] 8.1 Experimental Animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0329] 8.2 Experimental Methods: On the day of the experiment, cynomolgus monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before dosing and fed 4 hours after dosing.

[0330] Table 7. Dosing Information

[0331] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 95% (20% SBE-β-CD)

[0332] (DMA: N,N-dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; SBE-β-CD: sulfobutyl-β-cyclodextrin)

[0333] *Dosage is based on the free base.

[0334] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0335] Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic properties in monkeys.

Claims

1. A compound or a stereoisomer, racemate, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds described in general formula (I), R 1 Selected from C 1-6 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R 2 Selected from -C(=O)NH2, -S(=O)2NH2, preferably -C(=O)NH2; R 3 Selected from R 3A or R 3B ; R 3A Selected from non-aromatic C 3-12 A carbocyclic group or a non-aromatic 4-12 membered heterocyclic group, preferably C 3-7 Monocyclic cycloalkyl, C 3-6 Monocyclic cycloalkenyl, C 6- 12 Cycloalkyl, C 6-12 Spirocyclic cycloalkyl, C 5-9 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered cyclic heterocycloalkyl, 6-12 membered cyclic heterocycloalkenyl, 6-12 membered spirocyclic heterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, wherein R 3A Optional 1 to 4 R 3a replace; R 3B Selected from C 3-12 Carbocyclic or 4-12 membered heterocyclic, preferably C 6-10 aryl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, C 3-7 Monocyclic carbocyclic ring, C 6-12 Ring carbon ring, C 6-12 Spirocarbon ring, C 5-12 bridged carbon ring, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, wherein R 3B Optional 1 to 4 R 3b replace; R 4 Selected from H, deuterium, halogen, CN, OH, CN, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace; Ring A is selected from 6-membered heteroaryl, 8- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a replace; R 5 Selected from C 3-12 Carbocyclic or 4-12 membered heterocyclic, preferably C 3-12 A carbocyclic group or a 5- to 12-membered heterocyclic group, wherein R 5 Optional 1 to 4 R 5a replace; R a , R 3a , R 3b , R 5a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, C 1-6 Alkyl, OC 1-6 Alkyl, SC 1- 6 alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 0-4 Alkylene-C 3-6 Carbon ring, -C 0-4 Alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent; Provided that: when ring A is selected from And R 5 Selected from 1 to 4 R 5a Substituted with one of the following groups: phenyl, 5- to 6-membered heteroaryl, benzo C 5-6 Carbocyclic group, 6-membered heteroaryl and C 5-6 carbocyclic group, 6-membered heteroaryl and 5- to 6-membered oxygen-containing heterocyclic group, benzo 5- to 6-membered oxygen-containing heterocyclic group, wherein the C 5-6 When the carbocyclic group or the 5- to 6-membered oxygen-containing heterocyclic group is a partially saturated ring, R 3 Selected from R 3A .

2. The compound according to claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 5 Selected from C 3-7 Monocyclic carbocyclic ring, C 6-12 Ring carbon ring, C 6-12 Spirocarbon ring, C 5-12 bridged carbocyclic ring, 4-7 membered monocyclic heterocyclic ring, 6-12 membered cyclic heterocyclic ring, 6-12 membered spirocyclic heterocyclic ring, 6-12 membered bridged heterocyclic ring, 8-10 membered cyclic heteroaryl, wherein R 5 Optional 1 to 4 R 5a replace; R 3B is selected from phenyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, benzo 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, C 3-7 Monocyclic cycloalkyl, C 3-6 Monocyclic cycloalkenyl, C 6-12 Cycloalkyl, C 6-12 Spirocyclic cycloalkyl, C 5-9 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered heterocycloalkenyl, 6-12 membered cyclic heterocycloalkyl, 6-12 membered cyclic heterocycloalkenyl, 6-12 membered spirocyclic heterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, wherein R 3B Optional 1 to 4 R 3b replace; R 1 Selected from C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R k replace; R 4 Selected from H, deuterium, halogen, CN, OH, CN, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Cycloalkyl or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted by 1 to 4 R k replace; R a , R 3a , R 3b , R 5a Each independently selected from deuterium, halogen, CN, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-2 Alkylene-C 3-6 Carbocyclic group, -C 0-2 Alkylene-4 to 7 membered heterocyclic group or -OC 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, OH, =O, CN, NH2, COOH, -C(=O)NH2, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1- 4 alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-4 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 0-2 Alkylene-C 3-6 Carbon ring, -C 0-2 Alkylene-4 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; The remaining groups are defined in accordance with those described in claim 1.

3. The compound according to claim 2 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 3A Selected from The R 3A Optional 1 to 4 R 3a replace; R 3B is selected from phenyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, benzo 4-6 Carbocyclic group, benzo 4 to 6 membered heterocyclic group, The R 3B Optional 1 to 4 R 3b replace; s1, s3, s5, s8 are each independently selected from 0, 1 or 2; s2 and s4 are each independently selected from 0 or 1; s6 is selected from 0, 1, 2 or 3; s7 is selected from 1, 2 or 3; s1 and s8 on the same ring are not 2 at the same time; is selected from a single bond or a double bond; Ring A is selected from pyridyl, pyrimidinyl, benzopyrrolyl, benzopyrazolyl, thiazolopyrazolyl, pyridopyrazolyl, the ring A is optionally substituted by 1 to 4 R a replace; R 4 Selected from NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, the alkyl, alkylene, cycloalkyl is optionally substituted by 1 to 4 R k replace; R 5 is selected from phenyl, 5- to 6-membered heteroaryl, benzo 4-6 Carbocyclic group, benzo 4- to 6-membered heterocyclic group, 8- to 10-membered heterocyclic group, The R 5 Optional 1 to 4 R 5a replace.

4. The compound according to claim 3 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, R 1 is selected from methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R k replace; R 2 Selected from -C(=O)NH2; R 4 is selected from NH2, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R k replace; R 3A Selected from The R 3A Optional 1 to 4 R 3a replace; R 3B is selected from the group consisting of phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, benzothienyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyrazinyl, The R 3B Optional 1 to 4 R 3b replace; R 5 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, pyrrolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyridoimidazolyl, pyridotriazolyl, pyridopyrazolyl, The R 5 Optional 1 to 4 R 5a replace; R a , R 3a , R 3b , R 5a Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-oxetanyl, -CH2-oxolanyl, -CH2-oxetanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-cyclopropyl, the CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, -CH2-azetidinyl, -CH2-pyrrolidinyl, -CH2-piperidinyl, -CH2-piperazinyl, -CH2-morpholinyl, -O-cyclopropyl, the CH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl butyl, oxolanyl, oxacyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, optionally substituted with 1 to 4 R k replace; R k each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH2, COOH, CONH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, =O, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

5. The compound according to claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound of general formula (I) is selected from general formula (Ia), (Ib), (Ic), R 1 Selected from CF3, CHF2, CH2F, methyl, ethyl, -CH2-cyclopropyl; R 4 is selected from NH2, methyl, CF3, CHF2 or CH2F; Selected from R 5 is selected from phenyl, pyridyl, pyrimidinyl, thienyl, The R 5 Optional 1 to 4 R 5a replace; R 5A Selected from The R 5A Optional 1 to 4 R 5a replace; R 5a Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl; R 3A Selected from The R 3A Optional 1 to 4 R 3a replace; R 3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, The R 3B Optional 1 to 4 R 3b replace; R 3a , R 3b Each is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, NHCH3, N(CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, and ethyl.

6. The compound according to claim 5 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, R 3A Selected from R 3B Selected from 7. The compound according to claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table A.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of the compound according to any one of claims 1 to 7 or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. Use of the compound according to any one of claims 1 to 8 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for preparing a medicament for treating a disease associated with abnormal DGKζ kinase.

10. The use according to claim 9, characterized in that: The disease is selected from cancer, autoimmune disease, and preferably solid tumor.

11. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease associated with abnormal DGKζ kinase.

Images