WO2025067360A1 - Dgkzeta antagonist and use thereof in medicine - Google Patents

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

The present invention relates to a compound described by general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates and preparation methods thereof, as well as use of the compound in preparing drugs for treating diseases related to abnormal DGKζ kinase.

Background Art

DGK is a lipid kinase that downregulates T cell activation by phosphorylating diacylglycerol (DAG) and converting it into phosphatidic acid (PA), thereby acting as a ligand-independent intracellular immune checkpoint. DGKα and DGKζ (DGKzeta) are two major subtypes in T cells, which regulate the intensity of DAG signals downstream of antigen stimulation to prevent overactivation of T cells. Inhibition of DGK may enhance DAG downstream signals and activate T cells.

Studies have shown that in addition to regulating immune cells, DGKζ also plays a role in cancer, including mediating proliferation, apoptosis, survival, invasion, and tumorigenicity. DGKζ deficiency can lead to a hyper-responsive phenotype in T cells and enhance the activity of T cells against malignant tumors. The development of DGKζ inhibitors has good application prospects for the treatment of tumors. There are currently no reports of DGKζ inhibitors on the market. The development of DGKζ inhibitors is urgently needed and has broad clinical significance.

Summary of the invention

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, and intermediates and preparation methods thereof, as well as their use in the preparation of drugs for treating diseases related to abnormal DGKζ kinase.

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

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

The present invention provides a compound of general formula (I) or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

In some embodiments, the compound described by general formula (I) is selected from general formula (Ia), (Ib), (Ic),

In some embodiments, R ¹ is selected from C _1-6 alkyl, which is optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ¹ is selected from C _1-4 alkyl, which is optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ¹ is selected from methyl, ethyl, propyl, isopropyl, and the methyl, ethyl, propyl, isopropyl is optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ¹ is selected from CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, -CH ₂ -cyclopropyl;

In some embodiments, R ¹ is selected from CF ₃ , methyl, ethyl;

In some embodiments, R ² is selected from -C(=O)NH ₂ , -S(=O) ₂ NH ₂ , preferably -C(=O)NH ₂ ;

In some embodiments, R ² is selected from -C(=O)NH ₂ ;

In some embodiments, R ³ is selected from R ^3A or R ^3B ;

In some embodiments, R ^3A is selected from non-aromatic C _3-12 carbocyclyl or non-aromatic 4-12 membered heterocyclyl, preferably C _3-7 monocyclic cycloalkyl, C _3-6 monocyclic cycloalkenyl, C _6-12 cycloalkyl, C _{6-12 spirocycloalkyl, C 5-9 bridged} ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered cycloheterocycloalkyl, 6-12 membered cycloheterocycloalkenyl, 6-12 membered spirocycloheterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, said R ^3A is optionally substituted by 1 to 4 R ^3a ;

In some embodiments, R ^3A is selected from The R ^3A is optionally substituted by 1 to 4 R ^3a ;

In some embodiments, R ^3A is selected from The R ^3A is optionally substituted by 1 to 4 R ^3a ;

In some embodiments, R ^3A is selected from The R ^3A is optionally substituted by 1 to 4 R ^3a ;

In some embodiments, R ^3A is selected from

In some embodiments, R ^3B is selected from C _3-12 carbocyclyl or 4-12 membered heterocyclyl, preferably C _6-10 aryl, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, C _3-7 monocyclic carbocycle, C _6-12 cyclic carbocycle, C _6-12 spirocyclic carbocycle, C _5-12 bridged carbocycle, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, and said R ^3B is optionally substituted by 1 to 4 R ^3b ;

In some embodiments, R ^3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C _4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, C _3-7 monocyclic cycloalkyl, C _3-6 monocyclic cycloalkenyl, C _6-12 cycloalkyl, C _6-12 spirocycloalkyl, C _5-9 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered heterocycloalkenyl, 6-12 membered cycloheterocycloalkyl, 6-12 membered cycloheterocycloalkenyl, 6-12 membered spirocycloheterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, said R ^3B is optionally substituted by 1 to 4 R ^3b ;

In some embodiments, R ^3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C _4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, The R ^3B is optionally substituted by 1 to 4 R ^3b ;

In some embodiments, R ^3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, benzothienyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyrazinyl, imidazopyridazinyl, The R ^3B is optionally substituted by 1 to 4 R ^3b ;

In some embodiments, R ^3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, The R ^3B is optionally substituted by 1 to 4 R ^3b ;

In some embodiments, R ^3B is selected from

In some embodiments, R ^3B is selected from

In some embodiments, R ⁴ is selected from H, deuterium, halogen, CN, OH, CN, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -C _0-2 alkylene-C _3-6 cycloalkyl or -OC _3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl is optionally substituted with 1 to 4 R ^k ; in some embodiments, R ⁴ is selected from H, deuterium, halogen, CN, OH, CN, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-2 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 ;

In some embodiments, R ⁴ is selected from NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _0-2 alkylene-C _3-6 cycloalkyl, wherein the alkyl, alkylene, cycloalkyl is optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ⁴ is selected from NH ₂ , methyl, ethyl, propyl, isopropyl, said methyl, ethyl, propyl, isopropyl being optionally substituted with 1 to 4 R ^k ;

In some embodiments, R ⁴ is selected from NH ₂ , methyl, CF ₃ , CHF ₂ or CH ₂ F;

In some embodiments, R ⁴ is selected from NH ₂ ;

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 ;

In some embodiments, Ring A is selected from Pyridyl, pyrimidinyl, benzopyrrolyl, benzopyrazolyl, thiazolopyrazolyl, pyridopyrazolyl, wherein the ring A is optionally substituted with 1 to 4 ^Ra ;

In some embodiments, Ring A is selected from

In some embodiments, Selected from

In some embodiments, R ⁵ is selected from C _3-12 carbocyclyl or 4-12 membered heterocyclyl, preferably C _3-12 carbocyclyl or 5 to 12 membered heterocyclyl, said R ⁵ is optionally substituted by 1 to 4 R ^5a ;

In some embodiments, R ⁵ is selected from C _3-7 monocyclic carbocycle, C _6-12 cyclic carbocycle, C _6-12 spirocyclic carbocycle, C _5-12 bridged carbocycle, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-10 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, and said R ⁵ is optionally substituted by 1 to 4 R ^5a ;

In some embodiments, R ⁵ is selected from phenyl, 5- to 6-membered heteroaryl, benzoC _4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 8- to 10-membered heterocyclyl, The R ⁵ is optionally substituted by 1 to 4 R ^5a .

In some embodiments, R ⁵ is selected from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, pyrrolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, pyridoimidazolyl, pyridotriazolyl, pyridopyrazolyl, The R ⁵ is optionally substituted by 1 to 4 R ^5a ;

In some embodiments, R ⁵ is selected from phenyl, pyridinyl, pyrimidinyl, thienyl, The R ⁵ is optionally substituted by 1 to 4 R ^5a ;

In some embodiments, R ⁵ is selected from R ^5A ;

In some embodiments, R ^SA is selected from C _3-7 monocyclic cycloalkyl, C _6-10 cycloalkyl, C _6-10 spirocyclic cycloalkyl, C _5-10 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 6-10 membered cycloalkyl, 6-10 membered spirocyclic heterocycloalkyl, 6-10 membered bridged ring heterocycloalkyl, 8 to 10 membered cycloaryl;

In some embodiments, R ^5A is selected from The R ^SA is optionally substituted by 1 to 4 R ^5a ;

In some embodiments, R ^5A is selected from The R ^SA is optionally substituted by 1 to 4 R ^5a ; in some embodiments, R ^a , R ^3a , R ^3b , R ^5a are each independently selected from deuterium, halogen, CN, OH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl or -OC _3-6 cycloalkyl, and the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^k ;

In some embodiments, ^Ra , ^R3a , ^R3b , ^R5a are each independently selected from deuterium, halogen, CN, OH, _NH2 , _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _-C0-2 alkylene- _C3-6 carbocyclyl, _-C0-2 alkylene-4 to 7 membered heterocyclyl, or _-OC3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 ^Rk ;

In some embodiments, ^Ra , ^R3a , ^R3b , and ^R5a are each independently selected from deuterium, F, Cl, Br, I, OH, CN, _NH2 , _NHCH3 , N( _CH3 ) ₂ , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, _-CH2 -cyclopropyl, -CH2-cyclobutyl, _-CH2 -cyclopentyl, _-CH2 -cyclohexyl, _-CH2 -oxetanyl, _-CH2 -oxolanyl, _-CH2 -oxhexyl, _-CH2 -azetidinyl, _-CH2 -pyrrolidinyl, _{-CH2 -} piperidinyl, _-CH2- -piperazinyl, -CH ₂ -morpholinyl, -O-cyclopropyl, wherein the CH ₂ , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 R ^k ;

In some embodiments, R ^3a and R ^3b are each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, and ethyl;

In some embodiments, R ^3a , R ^3b are each independently selected from deuterium, F, Cl, CF ₃ ;

In some embodiments, R ^3b is independently selected from deuterium, F, Cl;

In some embodiments, R ^5a is each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;

In some embodiments, each R ^5a is independently selected from deuterium, F, CHF ₂ , CH ₂ F, CF ₃ , methyl, ethyl, CH ₂ CF ₃ , CH ₂ CHF ₂ , OCF ₃ , OCHF ₂ , methoxy;

In some embodiments, each R ^5a is independently selected from deuterium, F, CF ₃ , methyl, ethyl;

In some embodiments, each R ^k is independently selected from deuterium, halogen, OH, =O, CN, NH ₂ , COOH, -C(=O)NH ₂ , 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 carbocycle, -NH-3 to 7 membered heterocycle, -C _0-4 alkylene-C _3-6 carbocycle, -C _0-4 alkylene-3 to 7 membered heterocycle, and the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy;

In some embodiments, each R ^k is independently selected from deuterium, halogen, OH, =O, CN, NH ₂ , COOH, -C(=O)NH ₂ , 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 carbocycle, -NH-3 to 7 membered heterocycle, -C _0-2 alkylene-C _3-6 carbocycle, -C _0-2 alkylene-4 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy;

In some embodiments, each R ^k is independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH ₂ , COOH, CONH ₂ , NHCH ₃ , N(CH ₃ ) 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 deuterium, F, Cl, Br, I, =O, CN, OH, NH 2 , C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkyl, C _{1-4 alkyl} , C 1-4 alkyl, C _1-4 alkyl, C substituted by _1-4 alkoxy substituents;

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

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

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

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

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

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

Optionally, provided that: when ring A is selected from ^R5 is selected from one of the following groups optionally substituted by 1 to 4 ^R5a : phenyl, 5 to 6 membered heteroaryl, benzo _C5-6 carbocyclyl, 6 membered heteroaryl and _C5-6 carbocyclyl, 6 membered heteroaryl and 5 to 6 membered oxygen-containing heterocyclyl, benzo 5 to 6 membered oxygen-containing heterocyclyl, when the _C5-6 carbocyclyl or 5 to 6 membered oxygen-containing heterocyclyl is a partially saturated ring, ^R3 is selected from ^R3A .

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,

R ¹ is selected from C _1-6 alkyl, said alkyl being optionally substituted by 1 to 4 R ^k ;

R ² is selected from -C(=O)NH ₂ , -S(=O) ₂ NH ₂ , preferably -C(=O)NH ₂ ;

R ³ is selected from R ^3A or R ^3B ;

R ^3A is selected from non-aromatic C _3-12 carbocyclic group or non-aromatic 4-12 membered heterocyclic group, preferably C _3-7 monocyclic cycloalkyl, C _3-6 monocyclic cycloalkenyl, C _6-12 cycloalkyl, C _6-12 spirocycloalkyl, C _5-9 bridged ring cycloalkyl, _4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered cycloheterocycloalkyl, 6-12 membered cycloheterocycloalkenyl, 6-12 membered spirocycloheterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, wherein the R ^SA is optionally substituted by 1 to 4 R ^3a ;

R ^3B is selected from C _3-12 carbocyclyl or 4-12 membered heterocyclyl, preferably C _6-10 aryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, C _3-7 monocyclic carbocycle, C _6-12 cyclic carbocycle, C _6-12 spirocyclic carbocycle, C _5-12 bridged carbocycle, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, said R ^3B is optionally substituted by 1 to 4 R ^3b ;

R ⁴ is selected from H, deuterium, halogen, CN, OH, CN, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -C _0-2 alkylene-C _3-6 cycloalkyl or -OC _3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy and cycloalkyl are optionally substituted by 1 to 4 R ^k ;

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

R ⁵ is selected from C _3-12 carbocyclyl or 4-12 membered heterocyclyl, preferably C _3-12 carbocyclyl or 5 to 12 membered heterocyclyl, wherein said R ⁵ is optionally substituted by 1 to 4 R ^5a ;

R ^a , R ^3a , R ^3b , R ^5a are each independently selected from deuterium, halogen, CN, OH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl or -OC _3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R ^k ;

R ^k is each independently selected from deuterium, halogen, OH, ＝O, CN, NH ₂ , COOH, -C(＝O)NH ₂ , 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 carbocycle _, -NH-3 to 7 membered heterocycle, -C _0-4 alkylene-C _3-6 carbocycle, -C _0-4 alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, ＝O, CN, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy;

Provided that: when ring A is selected from ^R5 is selected from one of the following groups optionally substituted by 1 to 4 ^R5a : phenyl, 5 to 6 membered heteroaryl, benzo _C5-6 carbocyclyl, 6 membered heteroaryl and _C5-6 carbocyclyl, 6 membered heteroaryl and 5 to 6 membered oxygen-containing heterocyclyl, benzo 5 to 6 membered oxygen-containing heterocyclyl, when the _C5-6 carbocyclyl or 5 to 6 membered oxygen-containing heterocyclyl is a partially saturated ring, ^R3 is selected from ^R3A .

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,

R ⁵ is selected from C _3-7 monocyclic carbocycle, C _6-12 cyclic carbocycle, C _6-12 spirocyclic carbocycle, C _5-12 bridged carbocycle, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, and said R ⁵ is optionally substituted by 1 to 4 R ^5a ;

R ^3B is selected from phenyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, benzo C _4-6 carbocyclyl, benzo 4-6 membered heterocyclyl, C _3-7 monocyclic cycloalkyl, C _3-6 monocyclic cycloalkenyl, C _6-12 cycloalkyl, C _6-12 spirocycloalkyl, C _5-9 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered heterocycloalkenyl, 6-12 membered cycloheterocycloalkyl, 6-12 membered cycloheterocycloalkenyl, 6-12 membered spirocycloheterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, said R ^3B is optionally substituted by 1 to 4 R ^3b ;

R ¹ is selected from C _1-4 alkyl, said alkyl being optionally substituted by 1 to 4 R ^k ;

R ⁴ is selected from H, deuterium, halogen, CN, OH, CN, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-2 alkylene-C _3-6 cycloalkyl or -OC _3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy and cycloalkyl are optionally substituted by 1 to 4 R ^k ;

R ^a , R ^3a , R ^3b , R ^5a are each independently selected from deuterium, halogen, CN, OH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-2 alkylene-C _3-6 carbocyclyl, -C _0-2 alkylene-4 to 7 membered heterocyclyl or -OC _3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R ^k ;

R ^k is each independently selected from deuterium, halogen, OH, =O, CN, NH ₂ , COOH, -C(=O)NH ₂ , 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 carbocycle, -NH-3 to 7 membered heterocycle, -C _0-2 alkylene-C _3-6 carbocycle, -C _0-2 alkylene-4 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy;

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

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,

R ^3A is selected from The R ^3A is optionally substituted by 1 to 4 R ^3a ;

R ^3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C _4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, The R ^3B is optionally substituted by 1 to 4 R ^3b ;

s1, s3, s5, s8 are each independently selected from 0, 1 or 2;

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

s6 is selected from 0, 1, 2 or 3;

s7 is selected from 1, 2 or 3;

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, wherein the ring A is optionally substituted with 1 to 4 ^Ra ;

R ⁴ is selected from NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _0-2 alkylene-C _3-6 cycloalkyl, wherein the alkyl, alkylene and cycloalkyl are optionally substituted by 1 to 4 R ^k ;

R ⁵ is selected from phenyl, 5- to 6-membered heteroaryl, benzoC _4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 8- to 10-membered heterocyclyl, The R ⁵ is optionally substituted by 1 to 4 R ^5a ;

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

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,

R ¹ is selected from methyl, ethyl, propyl, isopropyl, and the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R ^k ;

R ² is selected from -C(=O)NH ₂ ;

R ⁴ is selected from NH ₂ , methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted with 1 to 4 R ^k ;

R ^3A is selected from The R ^3A is optionally substituted by 1 to 4 R ^3a ;

^R3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, benzothienyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyrazinyl, imidazopyridazinyl, The R ^3B is optionally substituted by 1 to 4 R ^3b ;

R is selected from ^{the group} consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, pyrrolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl, pyridoimidazolyl, pyridotriazolyl, pyridopyrazolyl, The R ⁵ is optionally substituted by 1 to 4 R ^5a ;

^Ra , ^R3a , ^R3b , and ^R5a are each independently selected from deuterium, F, Cl, Br, I, OH, CN, _NH2 , _NHCH3 , N( _CH3 ) ₂ , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, _-CH2 -cyclopropyl, _{-CH2-cyclobutyl, -CH2} -cyclopentyl, _-CH2 -cyclohexyl, _-CH2 -oxetanyl, _-CH2 -oxolanyl, _-CH2 -oxhexyl, _-CH2 -azetidinyl, _-CH2 -pyrrolidinyl, _{-CH2 -} piperidinyl, _-CH2- -piperazinyl, -CH ₂ -morpholinyl, -O-cyclopropyl, wherein the CH ₂ , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 R ^k ;

R ^k is each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH ₂ , COOH, CONH ₂ , NHCH ₃ , N(CH ₃ ) 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 deuterium, F, Cl, Br, I, =O, CN, OH, NH ₂ , C _1-4 alkyl ... substituted by _1-4 alkoxy substituents;

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

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,

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

R ¹ is selected from CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, -CH ₂ -cyclopropyl;

R ⁴ is selected from NH ₂ , methyl, CF ₃ , CHF ₂ or CH ₂ F;

Selected from

R ⁵ is selected from phenyl, pyridyl, pyrimidinyl, thienyl, The R ⁵ is optionally substituted by 1 to 4 R ^5a ;

R ^SA is selected from The R ^5A is optionally substituted by 1 to 4 R ^5a ;

R ^5a is independently selected from deuterium, F, Cl, Br, I, OH, CN, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl;

R ^3A is selected from The R ^3A is optionally substituted by 1 to 4 R ^3a ;

^R3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, The R ^3B is optionally substituted by 1 to 4 R ^3b ;

R ^3a and R ^3b are each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, and ethyl;

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

As a sixth 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, the compound described in the general formula (I) is selected from the general formula (Ia), (Ib), (Ic),

R ^3A is selected from

R ^3B is selected from

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

As a seventh 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, the compound described in the general formula (I) is selected from the general formula (Ic),

R ¹ is selected from CF ₃ , methyl, ethyl;

R ^3B is selected from

R ⁴ is selected from NH ₂ ;

R ^5A is selected from The R ^5A is optionally substituted by 1 to 4 R ^5a ;

R ^3b are each independently selected from deuterium, F, and Cl;

R ^5a is independently selected from deuterium, F, CF ₃ , methyl, and ethyl.

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

Table A

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 contains 1-1500 mg of the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal.

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

The present invention relates to use of the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in preparing a drug for treating diseases related to abnormal DGKζ kinase, preferably in preparing a drug for cancer or autoimmune disease.

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 "preparation strength").

The "effective amount" or "therapeutically effective amount" described in this application refers to the administration of a sufficient amount of the compound disclosed in this application, which will alleviate one or more symptoms of the disease or condition being treated (e.g., DGKζ kinase abnormality-related diseases such as cancer, autoimmune diseases) to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms. 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.

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.

A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease associated with abnormal DGKζ kinase (such as cancer, autoimmune disease).

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

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

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

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

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

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

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes include ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"CN" refers to cyano.

"Halogen" refers to F, Cl, Br or I.

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

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

"Alkylene" refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including (CH ₂ ) _v -(v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, and the like.

"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc. The cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.

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

"Alkenyl" refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. 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-1-butenyl, 2-methyl-2 ... -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.

"Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, 2 to 4 carbon atoms in the backbone, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-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-pentynyl 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; the alkynyl group may be monovalent, divalent, trivalent or tetravalent.

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

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

"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxane, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, 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]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spiro" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic 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 may optionally contain 0 to 5 heteroatoms selected from N, O or S(=O) _n (n is 0, 1 or 2). "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

"Cyclic" or "Cyclic radical" 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 cyclic system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from 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, 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

"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 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 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 Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

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

"Carbocyclic", "cyclic carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "cyclic" ring system consisting of only carbon atoms.

"Carbobridged ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.

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

"Heterocyclic ring", "heterocyclic group", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

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

"Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing a heteroatom.

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

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

"Substituted" or "substituted" means substituted 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, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring group, spirocyclyl, cyclocyclyl, 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 ) _mS (=O) _nR ^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 , wherein R ^b and R ^c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl Alternatively, Rb and Rc may form a five- or six-membered cycloalkyl or heterocyclic group, and ^Ra and ^Rd are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spirocyclic group or cyclized group.

"1 to X substituents selected from..." means substituted by 1, 2, 3, .... X substituents selected from...", X is selected from any integer between 1 and 10. For example, "1 to 4 R ^k substituted" means substituted by 1, 2, 3 or 4 R ^k . For example, "1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from...". For example, "the 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.

X-Y membered rings (X, Y are integers, and 3≤X＜Y, X＜Y≤20 are selected from any integer between 4 and 20) include X, X+1, X+2, X+3, X+4...Y membered rings. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings. For example, "4-7 membered heteromonocyclic rings" refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings, and "5-10 membered heterocyclic rings" refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings.

_Cxy carbocycle (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, cyclic carbocycle or bridged carbocycle) includes _Cx , Cx _+1, Cx ₊₂ , Cx ₊₃ , Cx ₊₄ ... _Cy -membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. For example, " _C3-6 cycloalkyl" refers to _C3 , _C4 , _C5 or _C6 cycloalkyl;

When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence. For example It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

When the listed connecting groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.

"Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

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

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

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

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

"Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

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

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

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

" _IC50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.

DETAILED DESCRIPTION

The following embodiments 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.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard;

For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

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

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

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

Reagent and Solvent Abbreviations:

DMA: N,N-dimethylacetamide; DMF: N,N-dimethylformamide; DCM: dichloromethane;

Synthesis scheme:

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

The remaining groups are defined in accordance with the above general formula compound (I);

The compound of general formula (A-1) and the compound of general formula (A-2) are reacted by ring-closing reaction to obtain the compound of general formula (A-3);

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

Example 1: Preparation of Compound 1

Step 1: Preparation of 1b

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 for 16 h under nitrogen atmosphere. Cool to 50 ° C, add aqueous hydrochloric acid solution (21 mL, 1N), and stir for 1 h. Cool to room temperature, add saturated aqueous potassium fluoride solution (60 mL), and stir for 30 min. Filter, add water (50 mL) to the filtrate, and extract with ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate (v: v) = 40: 60) to obtain 1b (2.40 g, yield 59%).

LCMS m/z＝162.1[M+H] ⁺

Step 2: Preparation of 1c

Dissolve 1b (0.50 g, 3.10 mmol) in acetic acid (5 mL), add pyridinium tribromide (0.99 g, 3.10 mmol) and 33% hydrogen bromide acetic acid solution (2.20 g, 8.97 mmol), and react at room temperature for 1 h. Add water (20 mL) and extract with ethyl acetate (20 mL x 3). Combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 1c (0.70 g, yield 94%).

LCMS m/z＝240.2[M+1] ⁺

Step 3: Preparation of 1d

4-Fluorophenyl isothiocyanate (450 mg, 2.94 mmol) was dissolved in acetonitrile (5 mL) solution, cyanamide (150 mg, 3.57 mmol) and 1,8-diazacyclo[5,4,0]undecene-7 (450 mg, 2.96 mmol) were added, and the mixture was reacted 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 added, and the mixture was reacted at room temperature for 16 h. Water (20 mL) was added and stirred for 30 min. Solids were precipitated, filtered, washed with water, and concentrated under reduced pressure to obtain 1d (400 mg, yield 39%).

LCMS m/z＝355.0[M+H] ⁺

Step 4: Preparation of compound 1

1d (100 mg, 0.28 mmol) was dissolved in N, N-dimethylformamide (5 mL), potassium carbonate (390 mg, 2.82 mmol) and 2-bromopropionamide (210 mg, 1.38 mmol) were added, and the mixture was reacted at 90 °C for 2 h. Filtered, the filtrate was purified by Pre-HPLC (instrument and preparation column: SHIMADZU LC-20AP was used for preparation of liquid phase, the preparation column model was Phenomenex C18, 5 μm, inner diameter * length = 19 mm * 150 mm). Preparation method: The filtrate was dissolved in N, N-dimethylformamide, filtered with a 0.45 μm filter membrane, and prepared into a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonium acetate). Gradient elution method: Acetonitrile was gradient eluted from 32% to 62% (elution time 15 min). After freeze-drying, compound 1 (20 mg, yield 17%) was obtained.

LCMS m/z＝426.2[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )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).

Example 2: Preparation of Compound 2

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

LCMS m/z＝426.2[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )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).

Example 3: Preparation of Compound 3

Compound 3 was prepared using 3a as the starting material by referring to the synthesis method of compound 1.

LCMS m/z＝426.1[M+1] ⁺

Example 4: Synthesis of Compound 4

Step 1: Preparation of 4b

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

LCMS m/z＝334.1[M+1] ⁺

Step 2: Synthesis of compound 4

4b (50 mg, 0.15 mmol), 2-iodopropionamide (60 mg, 0.30 mmol), 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 purified by Pre-HPLC to obtain compound 4.

LCMS m/z＝405.2[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )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).

Example 5: Synthesis of Compound 5

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

LCMS m/z＝447.3[M+1] ⁺

Example 6: Preparation of Compound 6-A and Compound 6-B

Using 6a as substrate, the crude product of compound 6 was obtained by referring to the synthesis method of Example 1, and the crude product was purified by Pre-HPLC (instrument and preparation column: SHIMADZU LC-20AP was used to prepare the liquid phase, and the preparation column model was Phenomenex C18, 5μm, inner diameter * length = 19mm * 150mm). Preparation method: The crude product was dissolved in N, N-dimethylformamide and filtered with a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% trifluoroacetic acid). Gradient elution method: Acetonitrile was gradient eluted from 32% to 62% (elution time 15min), and the trifluoroacetate of compound 6 was obtained after freeze-drying.

LCMS m/z＝439.3[M+1] ⁺

Compound 6 was purified by SFC on Chiral OD column (instrument and preparation column: Waters 150 Prep-SFC, preparation column model: Chiral OD column. Preparation method: Compound 6 was dissolved in acetonitrile and ethanol, and filtered with a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO ₂ ; B for 0.1% NH ₃ ·H ₂ O in ethanol. Gradient elution method: 50% mobile phase B isocratic elution (flow rate: 100mL/min; elution time 3min), and compound 6-A and compound 6-B were obtained after freeze-drying. Analytical method (instrument and preparation column: SHIMADZU LC-30AD sf, analytical column model: Chiral OD column, mobile phase system: A for CO ₂ ; 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 (compound 6-A and compound 6-B, one of which is compound 6-1, the other is compound 6-2).

Compound 6-A

LCMS m/z＝439.0[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )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).

Compound 6-B

LCMS m/z＝439.0[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )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).

Example 7: Preparation of Compound 7-A and Compound 7-B

The trifluoroacetate salt of compound 7 was prepared using 7a as the starting material by referring to the synthesis method of Example 6.

LCMS m/z＝439.1[M+1] ⁺

Compound 7 was purified by SFC on Chiral OD column (instrument and preparation column: Waters 150 Prep-SFC, preparation column model: Chiral OD column. Preparation method: Compound 7 was dissolved in acetonitrile and ethanol, and filtered with a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO ₂ ; B for 0.1% NH ₃ ·H ₂ O in ethanol. Gradient elution method: 50% mobile phase B isocratic elution (flow rate: 100mL/min; elution time 3min), and compound 7-A and compound 7-B were obtained after freeze-drying. Analytical method (instrument and preparation column: SHIMADZU LC-30AD sf, analytical column model: Chiral OD column, mobile phase system: A for CO ₂ ; 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 and the other is compound 7-2).

Compound 7-A

LCMS m/z＝439.1[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ8.41(s, 1H), 8.34-7.75(m, 3H), 7.68-7.60(m, 2H), 7.59-7.50(m, 2H), 7.42-7.35(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).

Compound 7-B

LCMS m/z＝439.0[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ8.41(s, 1H), 8.34-7.75(m, 3H), 7.68-7.60(m, 2H), 7.59-7.50(m, 2H), 7.42-7.35(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).

Example 8: Preparation of Compound 8-A and Compound 8-B

The trifluoroacetate salt of compound 8 was obtained using 8a as the starting material by referring to the synthesis method of Example 6.

LCMS m/z = 443.0 [M+H] ⁺ .

Compound 8 was purified by SFC on IK column (Instrument and preparation column: Waters 150 Prep-SFC, preparation column model: Chiral IK column. Preparation method: Compound 8 was dissolved in acetonitrile and dichloromethane, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A for CO ₂ and B for 0.1% NH ₃ ·H ₂ O in isopropanol and acetonitrile). Gradient elution method: 50% mobile phase B isogradient elution (flow rate: 100 mL/min; elution time 4 min)), and compound 8-A and compound 8-B were obtained after lyophilization.

Analytical method (instrument and preparation column: SHIMADZULC-30AD sf, analytical column model: Chiral IK column, mobile phase system: A for CO ₂ ; 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 is compound 8-A. Retention time T=1.389 min is compound 8-B (compounds 8-A and 8-B, one of which is compound 8-1 and the other is compound 8-2).

Compound 8-A:

LCMS m/z = 442.9 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.56-7.92(m, 4H), 7.84-7.76(m, 1H), 7.69-7.60(m, 2H), 7.59-7.51(m, 1H), 7.36-7.27(m, 2H), 7.26-7.19(m, 1H), 5.16-4.97(m, 1H), 1.17(d, 3H).

Compound 8-B:

LCMS m/z = 443.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ8.56-7.92(m, 4H), 7.84-7.76(m, 1H), 7.69-7.60(m, 2H), 7.59-7.51(m, 1H), 7.36-7.27(m, 2H), 7.26-7.19(m, 1H), 5.16-4.97(m, 1H), 1.17(d, 3H).

Example 9: Preparation of Compound 9-A and Compound 9-B

Compound 9 was prepared using 9a as the starting material by referring to the synthesis method of Example 1.

LCMS m/z = 427.0 [M+H] ⁺ .

Compound 9 was purified by SFC on IK column (Instrument and preparation column: Waters 150 Prep-SFC, preparation column model: Chiral IK column. Preparation method: Compound 9 was dissolved in acetonitrile and dichloromethane, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase System: A for CO ₂ and B for 0.1% NH ₃ ·H ₂ O in isopropanol). Gradient elution method: 40% mobile phase B isogradient elution (flow rate: 120 mL/min; elution time 4 min)), and after freeze-drying, compound 9-A and compound 9-B were obtained.

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

Compound 9-A:

LCMS m/z = 427.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) 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).

Compound 9-B:

LCMS m/z = 427.0 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) 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).

Biological test cases

1. Determination of DGKζ Inhibitory Activity

Compounds were diluted 3-fold in a 384 PP Plate using DMSO. 0.1 μL of compound was transferred to a 384 reaction microplate (Optiplate 384) using an Echo (655, LABCYTE) to ensure that the final DMSO concentration was 1% (duplicate). 5 μL of 2X DGKζ (D30-10G, Signalchem) solution was added to each well of the 384 reaction microplate and centrifuged at 1000 rpm for 1 minute. Wells containing 1% DMSO and enzyme were used as High Controls, and wells containing 1% DMSO and buffer were used as Low Controls. Incubate 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. Incubate 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: 0.2nM DGKZ, 20μM ATP, 50μM DAG). The inhibition percentage of the compound-treated wells was standardized between High Control and Low Control (%inhibition＝(AVE High Control-RLU compound reading)/(AVE High Control-AVE Low Control)*100). Then fit the four-parameter IC ₅₀ curve and analyze it by XLfit 5.5.0. IC ₅₀ is the compound concentration corresponding to 50% inhibition.

Table 1. Inhibitory activity of compounds against DGKζ enzyme

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.

2. Pharmacokinetics test in mice

2.1 Experimental animals: Male Balb/c mice, about 22-25 g, 6-8 weeks old, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

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 one day before administration and fed 4 hours after administration.

Table 2. Dosing Information

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

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

Before and after administration, 0.03 ml of blood was collected from the eye sockets, placed in EDTA-K ₂ centrifuge tubes, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 7 h, and 24 h; all samples were stored at -80°C before analysis and testing.

Table 3. Pharmacokinetic parameters of test compounds in mouse plasma

-:not applicable.

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.

3. Pharmacokinetic Test in Rats

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

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 one day before administration and fed 4 hours after administration.

Table 4. Dosing Information

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

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

Before and after administration, 0.10 ml of blood was collected from the eye sockets, placed in EDTA-K ₂ centrifuge tubes, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Conclusion: Compounds of the present invention, such as the Example compounds, have good pharmacokinetic properties in rats.

4.CYP450 enzyme inhibition test

The purpose of this study was to evaluate the effects of the test substances on the activities of four isoenzymes (CYP1A2, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC50 values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype.

Conclusion: The compounds of the present invention, such as the compounds in the examples, 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.

5. hERG potassium channel effect test

Experimental platform: electrophysiological manual patch clamp system

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

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. The glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller. The tip resistance after perfusion of the electrode liquid was about 2-5MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by pClamp 10 software through a computer, with a sampling frequency of 10kHz and a filter frequency of 2kHz. After obtaining the whole-cell recording, the cell was clamped at -80mV, and the step voltage to induce the hERG potassium current (I _hERG ) was given a 2s depolarization voltage from -80mV to +20mV, then repolarized to -50mV, and returned to -80mV after 1s. This voltage stimulation was given every 10s, and the drug administration process was started after the hERG potassium current was determined to be stable (at least 1 minute). Compounds were administered for at least 1 min at each tested concentration, and at least 2 cells (n≥2) were tested at each concentration.

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

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

The _IC50 of the compounds was calculated using GraphPad Prism 5 software by fitting the following equation:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))

Among them, X is the Log value of the test sample detection concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

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

6. Liver microsome stability test

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

At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain reaction time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS method. T _1/2 was calculated by the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CL _int(Liver) was further calculated.

Table 5. Human liver microsome stability results

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.

7. Beagle dog pharmacokinetic test

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.

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

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

Table 6. Dosing Information

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

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

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

Blood sampling time points: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. All samples were stored at -80 °C before analysis. Samples were quantitatively analyzed by LC-MS/MS.

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

8. Monkey Pharmacokinetic Test

8.1 Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

8.2 Experimental Method: 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 one day before administration and fed 4 hours after administration.

Table 7. Dosing Information

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

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

*Dosage is based on free base.

Before and after administration, 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Conclusion: Compounds of the present invention, such as the Example compounds, have good pharmacokinetic properties in monkeys.

Claims (11)

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 is selected from C _1-6 alkyl, said alkyl being optionally substituted by 1 to 4 R ^k ; R ² is selected from -C(=O)NH ₂ , -S(=O) ₂ NH ₂ , preferably -C(=O)NH ₂ ; R ³ is selected from R ^3A or R ^3B ; R ^3A is selected from non-aromatic C _3-12 carbocyclic group or non-aromatic 4-12 membered heterocyclic group, preferably C _3-7 monocyclic cycloalkyl, C _3-6 monocyclic cycloalkenyl, C _6-12 cycloalkyl, C _6-12 spirocycloalkyl, C _5-9 bridged ring cycloalkyl, _4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered cycloheterocycloalkyl, 6-12 membered cycloheterocycloalkenyl, 6-12 membered spirocycloheterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, said R ^3A is optionally substituted by 1 to 4 R ^3a ; R ^3B is selected from C _3-12 carbocyclyl or 4-12 membered heterocyclyl, preferably C _6-10 aryl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, C _3-7 monocyclic carbocycle, C _6-12 cyclic carbocycle, C _6-12 spirocyclic carbocycle, C _5-12 bridged carbocycle, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, said R ^3B is optionally substituted by 1 to 4 R ^3b ; R ⁴ is selected from H, deuterium, halogen, CN, OH, CN, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -C _0-2 alkylene-C _3-6 cycloalkyl or -OC _3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy and cycloalkyl are optionally substituted by 1 to 4 R ^k ; Ring A is selected from 6-membered heteroaryl, 8- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R ^a ; R ⁵ is selected from C _3-12 carbocyclyl or 4-12 membered heterocyclyl, preferably C _3-12 carbocyclyl or 5 to 12 membered heterocyclyl, wherein said R ⁵ is optionally substituted by 1 to 4 R ^5a ; R ^a , R ^3a , R ^3b , R ^5a are each independently selected from deuterium, halogen, CN, OH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -C _0-4 alkylene-C _3-10 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl or -OC _3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R ^k ; R ^k is each independently selected from deuterium, halogen, OH, ＝O, CN, NH ₂ , COOH, -C(＝O)NH ₂ , 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 carbocycle _, -NH-3 to 7 membered heterocycle, -C _0-4 alkylene-C _3-6 carbocycle, -C _0-4 alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, ＝O, CN, OH, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy; Provided that: when ring A is selected from ^R5 is selected from one of the following groups optionally substituted by 1 to 4 ^R5a : phenyl, 5 to 6 membered heteroaryl, benzo _C5-6 carbocyclyl, 6 membered heteroaryl and _C5-6 carbocyclyl, 6 membered heteroaryl and 5 to 6 membered oxygen-containing heterocyclyl, benzo 5 to 6 membered oxygen-containing heterocyclyl, when the _C5-6 carbocyclyl or 5 to 6 membered oxygen-containing heterocyclyl is a partially saturated ring, ^R3 is selected from ^R3A . The compound according to claim 1 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R ⁵ is selected from C _3-7 monocyclic carbocycle, C _6-12 cyclic carbocycle, C _6-12 spirocyclic carbocycle, C _5-12 bridged carbocycle, 4-7 membered monocyclic heterocycle, 6-12 membered cyclic heterocycle, 6-12 membered spirocyclic heterocycle, 6-12 membered bridged heterocycle, 8 to 10 membered cyclic heteroaryl, wherein said R ⁵ is optionally substituted by 1 to 4 R ^5a ; R ^3B is selected from phenyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, benzo C _4-6 carbocyclyl, benzo 4-6 membered heterocyclyl, C _3-7 monocyclic cycloalkyl, C _3-6 monocyclic cycloalkenyl, C _6-12 cycloalkyl, C _6-12 spirocycloalkyl, C _5-9 bridged ring cycloalkyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered heterocycloalkenyl, 6-12 membered cycloheterocycloalkyl, 6-12 membered cycloheterocycloalkenyl, 6-12 membered spirocycloheterocycloalkyl, 6-9 membered bridged ring heterocycloalkyl, said R ^3B is optionally substituted by 1 to 4 R ^3b ; R ¹ is selected from C _1-4 alkyl, said alkyl being optionally substituted with 1 to 4 R ^k ; R ⁴ is selected from H, deuterium, halogen, CN, OH, CN, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-2 alkylene-C _3-6 cycloalkyl or -OC _3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy and cycloalkyl are optionally substituted by 1 to 4 R ^k ; R ^a , R ^3a , R ^3b , R ^5a are each independently selected from deuterium, halogen, CN, OH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -C _0-2 alkylene-C _3-6 carbocyclyl, -C _0-2 alkylene-4 to 7 membered heterocyclyl or -OC _3-6 cycloalkyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, cycloalkyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R ^k ; R ^k is each independently selected from deuterium, halogen, OH, =O, CN, NH ₂ , COOH, -C(=O)NH ₂ , 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 carbocycle _, -NH-3 to 7 membered heterocycle, -C _0-2 alkylene-C _3-6 carbocycle, -C _0-2 alkylene-4 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 substituents selected from deuterium, halogen, =O, CN, OH, NH ₂ , C _1-4 alkyl, C _1-4 alkoxy; The remaining groups are defined in accordance with those described in claim 1. The compound according to claim 2 or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R ^3A is selected from The R ^3A is optionally substituted by 1 to 4 R ^3a ; R ^3B is selected from phenyl, 5-6 membered heteroaryl, 8 to 10 membered heteroaryl, benzo C _4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, The R ^3B is optionally substituted by 1 to 4 R ^3b ; s1, s3, s5, s8 are each independently selected from 0, 1 or 2; s2 and s4 are each independently selected from 0 or 1; s6 is selected from 0, 1, 2 or 3; s7 is selected from 1, 2 or 3; 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, wherein the ring A is optionally substituted with 1 to 4 ^Ra ; R ⁴ is selected from NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, -C _0-2 alkylene-C _3-6 cycloalkyl, wherein the alkyl, alkylene and cycloalkyl are optionally substituted by 1 to 4 R ^k ; R ⁵ is selected from phenyl, 5- to 6-membered heteroaryl, benzoC _4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 8- to 10-membered heterocyclyl, The R ⁵ is optionally substituted by 1 to 4 R ^5a . 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, and the methyl, ethyl, propyl, isopropyl is optionally substituted by 1 to 4 R ^k ; R ² is selected from -C(=O)NH ₂ ; R ⁴ is selected from NH ₂ , methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted with 1 to 4 R ^k ; R ^3A is selected from The R ^3A is optionally substituted by 1 to 4 R ^3a ; ^R3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, benzothienyl, benzothiazolyl, benzofuranyl, benzoxazolyl, benzopyrrolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrazolyl, pyrroloimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, pyrrolopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyrazinyl, pyrazolopyridazinyl, imidazopyridinyl, imidazopyrimidinyl, imidazopyrazinyl, imidazopyrazinyl, imidazopyridazinyl, The R ^3B is optionally substituted by 1 to 4 R ^3b ; R 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 is optionally substituted by 1 to 4 R ^5a ; ^Ra , ^R3a , ^R3b , and ^R5a are each independently selected from deuterium, F, Cl, Br, I, OH, CN, _NH2 , _NHCH3 , N( _CH3 ) ₂ , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, _-CH2 -cyclopropyl, _{-CH2-cyclobutyl, -CH2} -cyclopentyl, _-CH2 -cyclohexyl, _-CH2 -oxetanyl, _-CH2 -oxolanyl, _-CH2 -oxhexyl, _-CH2 -azetidinyl, _-CH2 -pyrrolidinyl, _{-CH2 -} piperidinyl, _-CH2- -piperazinyl, -CH ₂ -morpholinyl, -O-cyclopropyl, the CH ₂ , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxadiazole Butyl, oxolanyl, oxacyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted with 1 to 4 R ^k ; R ^k is each independently selected from deuterium, F, Cl, Br, I, OH, =O, CN, NH ₂ , COOH, CONH ₂ , NHCH ₃ , N(CH ₃ ) 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 deuterium, F, Cl, Br, I, =O, CN, OH, NH ₂ , C _1-4 alkyl ... The moiety is substituted by _{1 to 4} alkoxy substituents. According to claim 1, 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),
R ¹ is selected from CF ₃ , CHF ₂ , CH ₂ F, methyl, ethyl, -CH ₂ -cyclopropyl; R ⁴ is selected from NH ₂ , methyl, CF ₃ , CHF ₂ or CH ₂ F; Selected from R ⁵ is selected from phenyl, pyridyl, pyrimidinyl, thienyl, The R ⁵ is optionally substituted by 1 to 4 R ^5a ; R ^5A is selected from The R ^5A is optionally substituted by 1 to 4 R ^5a ; R ^5a is each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl, ethyl; R ^3A is selected from The R ^3A is optionally substituted by 1 to 4 R ^3a ; ^R3B is selected from phenyl, naphthyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, The R ^3B is optionally substituted by 1 to 4 R ^3b ; R ^3a and R ^3b are each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl and cyclobutyl, and the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl and cyclobutyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, methyl and ethyl. The compound according to claim 5 or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, R ^3A is selected from R ^3B is selected from 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. 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 comprises 1 to 1500 mg of 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. 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 the preparation of a medicament for treating diseases associated with abnormal DGKζ kinase. The use according to claim 9 is characterized in that the disease is selected from cancer, autoimmune disease, and preferably solid tumor. 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.