CN114437063A

CN114437063A - Cyano derivative and application thereof in medicine

Info

Publication number: CN114437063A
Application number: CN202111252562.1A
Authority: CN
Inventors: 张晨; 王健民; 叶飞; 黄正刚; 李瑶; 倪佳; 严庞科
Original assignee: Haisco Pharmaceutical Group Co Ltd
Current assignee: Haisco Pharmaceutical Group Co Ltd
Priority date: 2020-11-03
Filing date: 2021-10-28
Publication date: 2022-05-06

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application thereof in preparation of medicines for treating JAK3 kinase activity or surfaceTo achieve the application in medicaments for treating related diseases.

Description

Cyano derivative and application thereof in medicine

Technical Field

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparing a medicament for treating diseases related to JAK3 kinase activity or expression quantity.

Background

Protein kinases are a class of intracellular messenger-dependent enzymes that catalyze phosphorylation of specific proteins and complete signaling processes, and mainly include tyrosine protein kinases such as JAKs, Src, Abl, EGFR, FGFR, TOGFR, and the like; serine/threonine protein kinases such as PKC, MAPK, Rho kinase, and the like; bispecific protein kinases such as MPKK and the like and phosphatidylinositol kinases such as PI 3K. Protein kinase phosphorylation/dephosphorylation processes are capable of regulating a variety of biological processes in different cells, such as metabolism, cell differentiation, cell survival, apoptosis, organ formation, angiogenesis, immune responses, etc. (Folia biol.2006,52, 81-100.).

The Janus family (JAKs) consists of four members, including JAK1, JAK2, JAK3, and TYK 2. Cytokines initiate receptor dimerization by binding to receptors in JAKs, causing phosphorylation of JAK kinase tyrosine residues, thereby enabling JAK activation. Phosphorylated JAKs kinases further bind to and phosphorylate a variety of stat (signal Transducers and Activators of transcription) proteins, inducing them to dimerize, lyse within the nucleus, directly regulate gene transcription and activate downstream disease signaling factors. Among innate immunity, inflammation and hematopoietic biological functions, JAKs form a vital signaling pathway; this pathway dysregulation is associated with immune diseases and cancer, and therefore JAKs are targets for the treatment of many disease indications (immunol. rev.2008,223, 132-142).

Tofacitinib, a pan-JAKs inhibitor from Pfizer, Inc., was approved by the FDA for the treatment of RA at 11 months 2012. However, Tofacitinib has side effects including causing decrease in the number of erythrocytes and leukocytes, increase in cholesterol levels, and the like, which is probably associated with its high JAK2 inhibitory activity (J.Med.chem.2012,55, 6176-6193). Thus, scientists at institutions such as large pharmaceutical companies have focused attention on the study and discovery of selective JAK inhibitors.

Unlike JAK1, JAK2 and TYK2, which are widely distributed in various tissue cells of the human body, JAK3 is mainly distributed in the bone marrow and lymphatic system, and JAK3 regulates cell signaling by binding to the gamma co-chain (γ c) in cytokine receptor complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, and the like. Based on the functional characteristics and special tissue distribution, JAK3 becomes an attractive drug target for diseases related to the immune system, and the inhibitor has important clinical application value in the treatment/prevention of Rheumatoid Arthritis (RA), inflammatory enteritis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, type I diabetes, psoriasis, allergic diseases, asthma, chronic obstructive pulmonary disease, leukemia, lymphoma, organ transplantation and other diseases (Trends Pharm Sci.2004,25, 558-562).

Disclosure of Invention

The invention aims to provide a compound capable of inhibiting JAK3 kinase, or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparation of medicines for treating diseases related to JAK3 activity or expression quantity.

The invention provides a compound shown in a general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, wherein

In certain embodiments, Y₁、Y₂、Y₃Each independently selected from CH or N;

in certain embodiments, Y₁、Y₂Is selected from CH, Y₃Is selected from N;

in certain embodiments, Y₁、Y₂、Y₃Is selected from CH;

in certain embodiments, Y₁、Y₂Is selected from N, Y₃Is selected from N;

in certain embodiments, Y₁Is selected from N, Y₂Is selected from CH, Y₃Is selected from CH;

in certain embodiments, Y₁Is selected from CH, Y₂Is selected from N, Y₃Is selected from CH;

in certain embodiments, Y₁Is selected from CH, Y₂Is selected from N, Y₃Is selected from N;

in certain embodiments, ring a is selected from a 5-to 6-membered heterocyclic or heteroaromatic ring optionally further substituted with 0, 1, 2, or 3R^aSubstituted with a substituent, said heterocycle or heteroaryl ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, N;

in some embodiments of the present invention, the substrate is,

is selected from

In some embodiments of the present invention, the substrate is,

is selected from

X₁Selected from N or CR^a；

In some embodiments of the present invention, the substrate is,

is selected from

In some embodiments of the present invention, the substrate is,

is selected from

In certain embodiments, R^aEach independently selected from H, ═ O, halogen, cyano, C_1-6Alkyl radical, C_1-6Alkoxy, - (CH)₂)_q-C(＝O)-NR^a1R^a2、-(CH₂)_q-NR^a1R^a2、-(CH₂)_qNR^a1C(＝O)-R^a2、-(CH₂)_q-C_3-10Carbocyclic ring or- (CH)₂)_q-3 to 12 membered heterocycle, said-CH₂-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;

in certain embodiments, R^aSelected from H, halogen, cyano, C_1-4Alkyl radical, C_1-4Alkoxy, - (CH)₂)_q-C(＝O)-NR^a1R^a2、-(CH₂)_q-NR^a1R^a2、-(CH₂)_qNR^a1C(＝O)-R^a2、-(CH₂)_q-C_3-6Carbocyclic ring or- (CH)₂)_q-3 to 6 membered heterocycle, said-CH₂-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Substitution of alkoxy groupsSubstituted with a group, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;

in certain embodiments, R^aSelected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, - (CH)₂)_q-C(＝O)-NR^a1R^a2、-(CH₂)_q-NR^a1R^a2、-(CH₂)_qNR^a1C(＝O)-R^a2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂-cyclopropyl, -CH₂-cyclobutyl, -CH₂-cyclopentyl or-CH₂-cyclohexyl radical, -CH₂-, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in certain embodiments, R^aSelected from H, F, Cl, cyano, NH₂、-NHCH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-C(O)NHCH₂CH₃、-C(O)N(CH₂CH₃)₂、-C(O)NHCH₂CH₂OCH₃-C (O) NH-cyclopropyl, -C (O) NH-cyclobutyl, -C (O) NH-cyclopentyl, -C (O) NH-cyclohexyl, -NHC (O) CH₃、-NHC(O)CH₂CH₃-NHC (O) -cyclopropyl, -NHC (O) -cyclobutyl, -NHC (O) -cyclopentyl, -NHC (O) -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂-cyclopropyl, -CH₂-cyclobutyl, -CH₂-cyclopentyl or-CH₂-a cyclohexyl group;

in certain embodiments, R^aIs selected from H;

in certain embodiments, ring B is selected from C_3-10A carbocyclic ring or a 3 to 10 membered heterocyclic ring, said carbocyclic or heterocyclic ring optionally further substituted by 0, 1, 2, 3 or 4R^bSubstituted, said heterocyclic ring containing 1, 2, 3 or 4A heteroatom selected from O, S, N;

in certain embodiments, ring B is selected from C_3-6Saturated or unsaturated monocyclic carbocyclic ring, C_5-10Saturated or unsaturated spirocyclic carbocyclic ring, C_5-10Saturated or unsaturated carbocyclic ring, C_5-10A saturated or unsaturated bridged carbocyclic ring, a 3-to 7-membered saturated or unsaturated monocyclic heterocyclic ring, a 5-to 10-membered saturated or unsaturated spiroheterocyclic ring, a 5-to 10-membered saturated or unsaturated fused heterocyclic ring, a 5-to 10-membered saturated or unsaturated bridged heterocyclic ring, said carbocyclic or heterocyclic ring optionally further substituted with 0, 1, 2, 3 or 4R^b(ii) substituted, said heterocycle containing 1, 2, 3, or 4 heteroatoms selected from O, S, N;

in certain embodiments, ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, bicyclo [1.1.1]Pentyl alkyl, bicyclo [2.2.1 ]]Heptaalkyl, cubic alkyl, bicyclo [3.1.0]Hexane radical, bicyclo [3.2.0 ]]Heptylalkyl, cyclopentacyclocyclopentyl, bicyclo [4.2.0]Octyl radical, bicyclo [2.2.2 ]]Octyl, cyclobutyl spirocyclobutyl, cyclobutyl spirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentyl spirohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, piperazinyl, morpholinyl, imidazolinyl, azetidinyl spiroazetidinyl, azetidinyl spirocyclobutyl, azetidinyl spiroazetidinyl, cyclopentyl spiroazetidinyl, azetidinyl spiroazacyclohexyl, cyclobutyl spiroazacyclohexyl, azetidinyl spirocyclohexyl, azetidinyl cyclopentacyclopentyl, azetidinyl azacyclopentyl, azetidinyl cyclopentacyclopentyl, cyclobutyl azacyclopentyl, azetidinyl azacyclopentyl, when substituted, are optionally further substituted by 0, 1, 2, 3 or 4R, optionally^bSubstitution;

in certain embodiments, ring B is selected from one of the following substituted or unsubstituted groups:

when substituted, is optionally further substituted with 0, 1, 2, 3 or 4R^bSubstitution, left side and L thereof₁Connecting;

in certain embodiments, ring B is selected from

Left side and L thereof₁Connecting;

in certain embodiments, when ring B is attached to X through an N atom, X is selected from a bond;

in certain embodiments, when ring B is attached to X through a C atom, X is selected from NH or N (C)_1-4Alkyl), said alkyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, substituted with a substituent;

in certain embodiments, when ring B is attached to X through a C atom, X is selected from NH, N (CH)₃)、N(CH₂CH₃)、N(CH₂-cyclopropyl), N (CH)₂-cyclobutyl), N (CH)₂-cyclopentyl), N (CH)₂-cyclohexyl);

in certain embodiments, Z is selected from the group consisting of a bond, -Y-4 to 12 membered nitrogen containing heterocycle-, -Y-C_4-12Carbocyclic ring-NRⁿ³-、-Y-(CRⁿ¹Rⁿ²)_rNRⁿ³-, when Z is chosen from-Y-4 to 12 membered nitrogen containing heterocycles-the nitrogen containing heterocycle or carbocycle is optionally further substituted by 0, 1, 2, 3 or 4 substituents chosen from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl radical)、-N(C_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

in certain embodiments, Z is selected from the group consisting of a bond, -Y-4 to 7 membered monocyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered fused cyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered spirocyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered bridged cyclic nitrogen-containing heterocycle-, -Y-C_3-6Monocyclic carbocyclic ring-NRⁿ³-、-Y-C_5-12And a cyclic carbocyclic ring, -NRⁿ³-、-Y-C_5-12Bridged carbocyclic ring-NRⁿ³-、-Y-(CRⁿ¹Rⁿ²)_rNRⁿ³-, when Z is selected from-Y-4 to 7 membered monocyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered fused cyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered spiro nitrogen-containing heterocycle-, -Y-5 to 12 membered bridged cyclic nitrogen-containing heterocycle-, the nitrogen-containing heterocycle or carbocycle is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

in certain embodiments, Z is selected from the group consisting of a bond, -Y-azetidinyl-, -Y-aziridinyl-, -Y-azacyclohexyl-, -Y-piperazinyl-, -Y-cyclobutyl-NRⁿ³-, -Y-cyclopentyl-NRⁿ³-, -Y-cyclohexyl-NRⁿ³-、-Y-CH₂NRⁿ³-、-Y-C(CH₃)₂NRⁿ³-、-Y-CH(CH₃)NRⁿ³-、-Y-CH₂CH₂NRⁿ³-、-Y-CH₂CH₂CH₂NRⁿ³-, when Z is selected from-Y-azetidinyl-, -Y-aziridinyl-, -Y-piperazinyl-, said azetidinyl, aziridinyl, azacyclohexyl, piperazinyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in certain embodiments, Z is selected from the group consisting of a bond, a,

In certain embodiments, Y is selected from the group consisting of a bond, C_1-4Alkylene, -C (O) -, -S (O) -, or-S (O)₂-；

In certain embodiments, Y is selected from-C (O) -, -S (O) -or-S (O)₂-；

In certain embodiments, Y is selected from-C (O) -or-CH₂-；

In certain embodiments, Y is selected from-C (O) -;

in certain embodiments, Rⁿ¹、Rⁿ²Each independently selected from H, halogen, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Carbocyclyl or 3 to 8 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

in certain embodiments, Rⁿ¹、Rⁿ²Each independently selected from H, halogen, cyano, C_1-4Alkyl radical, C_3-6Carbocyclyl or 3 to 7 membered heterocyclyl, said alkyl, alkenyl, carbocyclyl or heterocyclyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

in certain embodiments, Rⁿ¹、Rⁿ²Each independently selected from H, F, cyano, methyl, ethyl, propyl, ethynyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, ethynyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl groups being optionally further substituted by 0, 1, 2, 3 or 4 groups selected from H, F, Cl, Br, CF₃OH, cyano, COOH, NH₂Methyl, ethyl, isopropyl, propyl, methoxy, ethoxy or propoxy;

in certain embodiments, Rⁿ³Selected from H, C_1-6Alkyl radical, C_3-8Carbocyclyl, said alkyl, carbocyclyl optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, substituted with a substituent;

in certain embodiments, Rⁿ³Selected from H, C_1-4Alkyl radical, C_3-6Carbocyclyl, said alkyl, carbocyclyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl substituted with a substituent;

in certain embodiments, Rⁿ³Selected from H, methyl, ethyl, propyl, isopropyl or cyclopropyl, said methyl, ethyl, propyl, isopropyl or cyclopropyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, Cl, Br, CF₃OH, cyano, COOH, NH₂Methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

at a certain pointIn some embodiments, Rⁿ³Selected from H, methyl, ethyl, propyl, isopropyl, butyl, -CH₂-cyclopropyl, -CH₂-cyclobutyl, -CH₂-cyclopentyl, -CH₂-cyclohexyl;

in certain embodiments, Rⁿ¹And Rⁿ²Together with the atoms to which they are attached form C_3-8Carbocyclyl optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in certain embodiments, Rⁿ³And Rⁿ¹、Rⁿ³And Rⁿ²And the atoms to which they are attached, together form a 4-to 8-membered nitrogen-containing heterocyclic ring, said heterocyclic ring optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1, 2 or 3N atoms;

is selected from

In certain embodiments, R^bEach independently selected from H, halogen, cyano, C_1-6Alkyl or C_1-6Alkoxy, said alkyl or alkoxy being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from the group consisting of H, halogen, CF₃OH, cyano, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy or C_3-8Cycloalkyl, substituted with a substituent;

in certain embodiments, R^bEach independently selected from H, halogen, cyano, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy or C_3-8Cycloalkyl, substituted with a substituent;

in certain embodiments, R^bEach independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy being optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6Cycloalkyl, substituted with a substituent;

in certain embodiments, R^bEach independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy being optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, CF₃OH, cyano, NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂Methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or cyclopentyl;

in certain embodiments, R^bEach independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, CF₃OH, cyano, NH₂、-N(CH₃)₂、-N(CH₂CH₃)₂Methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl;

in certain embodiments, L₁Selected from-S (O)_n-、-NR^1a-、-CR^1bR^1c-、-O(CR^1bR^1c)_s-、-(CR^1bR^1c)_sO-、-NR^1aCR^1bR^1c-、-NR^1aS(O)_n-、-S(O)_nNR^1a-、-NR^1aC(O)-、-C(O)NR^1a-、-SCR^1bR^1c-or-CR^1bR^1cS-；

In certain embodiments, L₁Selected from-O-, -S (O)_n-、-NR^1a-、-CR^1bR^1c-、-OCR^1bR^1c-、-O(CR^1bR^1c)₂-、-CR^1bR^1cO-、-NR^1aCR^1bR^1c-、-SCR^1bR^1c-or-CR^1bR^1cS-；

In certain embodiments, L₁Selected from-O-, -S-, -NH-, -CH₂-、-S(O)₂-、-OCH₂-、-OCH(CH₃)-、-OC(CH₃)₂-、-OCH₂CH₂-、-CH₂O-、-NHCH₂-or-N (CH)₃)-；

In certain embodiments, L₁Selected from-O-, -NH-, -OCH₂-、-OC(CH₃)₂-、-CH₂O-or-NHCH₂-；

In certain embodiments, L₁Selected from-O-, -OCH₂-、-OC(CH₃)₂-or-CH₂O-；

In certain embodiments, L₁Selected from-O-, -OCH₂-、-OC(CH₃)₂-，L₁The right side is connected with the ring B;

in certain embodiments, R^1a、R^1bOr R^1cEach independentlySelected from H, C_1-4Alkyl or- (CH)₂)_p-C_3-6Carbocycle, said alkyl or carbocycle being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, CF₃Cyano, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in certain embodiments, R^1b、R^1cTogether with the carbon atom to which they are directly attached form a 3-membered carbocyclic ring;

in some embodiments of the present invention, the substrate is,

is selected from

X₁Selected from N or CR^a(ii) a Right side and L₁Direct connection;

in some embodiments of the present invention, the substrate is,

is selected from

X₁Is selected from N or CH; right side and L₁Direct connection;

in some embodiments of the present invention, the substrate is,

is selected from

Right side and L₁Direct connection;

in certain embodiments, ring C is selected from 5-6 membered heteroaryl or phenyl, optionally further substituted with 0, 1, 2, 3 or 4R^cSubstitution;

in certain embodiments, ring C is selected from pyridine, optionally further substituted with 0, 1, 2, or 3R^cSubstitution;

in some embodiments of the present invention, the substrate is,

is selected from

In some embodiments of the present invention, the substrate is,

is selected from

In certain embodiments, R^cEach independently selected from H, halogen, OH, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-C(＝O)R^3a、-(CH₂)_m-C(＝O)OR^3a、-(CH₂)_m-OC(＝O)R^3a、-(CH₂)_m-3 to 12 membered heterocyclyl or- (CH)₂)_m-C_3-10Carbocyclyl group of said-CH₂-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃O, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C_1-4Alkylene-hydroxy, C_3-6Carbocyclyl or 3 to 8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

in certain embodiments, R^cEach independently selected from R¹、R²、R³Or R⁴；

In certain embodiments, R¹、R²、R³、R⁴Each independently selected from H, halogen, OH, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-C(＝O)R^3a、-(CH₂)_m-C(＝O)OR^3a、-(CH₂)_m-OC(＝O)R^3a、-(CH₂)_m-3 to 12 membered heterocyclyl or- (CH)₂)_m-C_3-10Carbocyclyl group of said-CH₂-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃O, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C_1-4Alkylene-hydroxy, C_3-6Carbocyclyl or 3 to 8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

in certain embodiments, R¹、R²、R³、R⁴Each independently selected from H, halogen, OH, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-C(＝O)R^3a、-(CH₂)_m-C(＝O)OR^3a、-(CH₂)_m-OC(＝O)R^3a、-(CH₂)_m-3 to 10 membered heteroRing or- (CH)₂)_m-C_3-8Carbocyclic ring of said-CH₂-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃O, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C_1-4Alkylene-hydroxy, C_3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

in certain embodiments, R¹、R²、R³、R⁴Each independently selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, propenyl, ethynyl, propynyl, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-cyclopropyl, - (CH)₂)_m-cyclobutyl, - (CH)₂)_m-cyclopentyl, - (CH)₂)_m-cyclohexyl, - (CH)₂)_m-azetidinyl, - (CH)₂)_m-oxetanyl, - (CH)₂)_m-pyrrolidinyl, - (CH)₂)_m-tetrahydrofuranyl, - (CH)₂)_m-piperidinyl, - (CH)₂)_m-tetrahydropyranyl, - (CH)₂)_m-morpholinyl, - (CH)₂)_m-piperazinyl or- (CH)₂)_m-azepinyl, said-CH₂-, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepinyl optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃O, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C_1-4Alkylene-hydroxy, C_3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

in certain embodiments, R¹、R²、R³Each independently selected from H, F, Cl, Br, I, OH, cyano, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3bMethyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, or a pharmaceutically acceptable salt thereof₂-, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, CF₃OH, cyano, COOH, NH₂、-NHCH₃、-N(CH₃)₂Methyl, ethyl, isopropyl, propyl, ethynyl, methoxy, ethoxy, propoxy, -CH₂OH or-CH₂CH₂OH is substituted by a substituent;

in certain embodiments, R⁴Selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, propenyl, ethynyl, propynyl, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-cyclopropyl, - (CH)₂)_m-cyclobutyl, - (CH)₂)_m-cyclopentyl, - (CH)₂)_m-cyclohexyl, - (CH)₂)_m-azetidinyl, - (CH)₂)_m-oxetanyl, - (CH)₂)_m-pyrrolidinyl, - (CH)₂)_m-tetrahydrofuranyl, - (CH)₂)_m-piperidinyl, - (CH)₂)_m-tetrahydropyranyl, - (CH)₂)_m-morpholinyl, - (CH)₂)_m-piperazinyl or- (CH)₂)_m-azepinyl, said-CH₂-, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepinyl, optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, ═ O, OH, cyano, CF₃、COOH、NH₂、-NHCH₃、-N(CH₃)₂Methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, -CH₂OH、-CH₂CH₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl;

in certain embodiments, R¹、R²Each independently selected from H, F, Cl, OH, CF₃Cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy;

in certain embodiments, R³Selected from H, F, Cl, OH, CF₃、-CN、-CH₂CN、-CH₂CH₂CN、NH₂、-N(CH₃)₂、-N(CH₂CH₃)₂、-C(O)NH₂、-CH₂C(O)NH₂、-C(O)NHCH₃、-NHC(O)CH₃Methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy;

in certain embodiments, R⁴Selected from H, F, OH, CF₃、NH₂、-CN、-CH₂CN、-CH₂CH₂CN、-NHCH₃、-N(CH₃)₂、-C(O)-NH₂、-CH₂C(O)-NH₂、-CH₂CH₂C(O)-NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-NHC(O)CH₃Methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, -CH₂-cyclopropyl, cyclobutyl, -CH₂-cyclobutyl, cyclopentyl, -CH₂-cyclopentyl, cyclohexyl, -CH₂-cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl or piperazinyl;

in certain embodiments, R¹Selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

in certain embodiments, R²Selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

in certain embodiments, R³Selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

in certain embodiments, R⁴Selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

in certain embodiments, R^a1、R^a2、R^3a、R^3bEach independently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-12Carbocyclyl or 3 to 12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

in certain embodiments, R^a1、R^a2、R^3a、R^3bEach independently selected from H, C_1-4Alkyl radical, C_3-6Carbocyclyl or 3 to 6 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen,CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

in certain embodiments, R^a1、R^a2、R^3a、R^3bEach independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl groups being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

in certain embodiments, R^3a、R^3bEach independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl groups being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, CF₃OH, cyano, COOH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy or propoxy;

n and s are selected from 0, 1 or 2;

r, m, p, q are each independently selected from 0, 1, 2, 3 or 4.

As a first embodiment of the present invention, a compound represented by the above general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

Y₁、Y₂、Y₃each independently selected from CH or N;

ring A is selected from a 5-to 6-membered heterocyclic or heteroaromatic ringOptionally further substituted by 0 to 3R^aSubstituted with a substituent, said heterocycle or heteroaryl ring containing 1, 2, 3 or 4 heteroatoms selected from O, S, N;

R^aeach independently selected from H, ═ O, halogen, cyano, C_1-6Alkyl radical, C_1-6Alkoxy, - (CH)₂)_q-C(＝O)-NR^a1R^a2、-(CH₂)_q-NR^a1R^a2、-(CH₂)_qNR^a1C(＝O)-R^a2、-(CH₂)_q-C_3-10Carbocyclic ring or- (CH)₂)_q-3 to 12 membered heterocycle, said-CH₂-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;

ring B is selected from C_3-10A carbocycle or 3-to 10-membered heterocycle, said carbocycle or heterocycle optionally further substituted with 0, 1, 2, 3 or 4R^b(ii) substituted, said heterocycle containing 1, 2, 3, or 4 heteroatoms selected from O, S, N;

when ring B is attached to X through an N atom, X is selected from a bond;

when ring B is attached to X through a C atom, X is selected from NH or N (C)_1-4Alkyl), said alkyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, substituted with a substituent;

z is selected from the group consisting of a bond, -Y-4 to 12 membered nitrogen containing heterocycle-, -Y-C_4-12Carbocyclic ring-NRⁿ³-、-Y-(CRⁿ¹Rⁿ²)_rNRⁿ³-, when Z is chosen from-Y-4 to 12 membered nitrogen containing heterocycles-the nitrogen containing heterocycle or carbocycle is optionally further substituted by 0, 1, 2, 3 or 4 substituents chosen from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

y is selected from a bond, C_1-4Alkylene, -C (O) -, -S (O) -, or-S (O)₂-；

Rⁿ¹、Rⁿ²Each independently selected from H, halogen, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Carbocyclyl or 3 to 8 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

Rⁿ³selected from H, C_1-6Alkyl radical, C_3-8Carbocyclyl, said alkyl, carbocyclyl optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, substituted with a substituent;

alternatively, Rⁿ¹And Rⁿ²Together with the atoms to which they are attached form C_3-8Carbocyclyl optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

alternatively, Rⁿ³And Rⁿ¹、Rⁿ³And Rⁿ²And the atoms to which they are attached, together form a 4-to 8-membered nitrogen-containing heterocyclic ring, said heterocyclic ring optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl radicalOr C_1-4Alkoxy, said heterocycle containing 1, 2 or 3N atoms;

R^beach independently selected from H, halogen, cyano, C_1-6Alkyl or C_1-6Alkoxy, said alkyl or alkoxy being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy or C_3-8Cycloalkyl, substituted with a substituent;

L₁selected from-S (O)_n-、-NR^1a-、-CR^1bR^1c-、-O(CR^1bR^1c)_s-、-(CR^1bR^1c)_sO-、-NR^1aCR^1bR^1c-、-NR^1aS(O)_n-、-S(O)_nNR^1a-、-NR^1aC(O)-、-C(O)NR^1a-、-SCR^1bR^1c-or-CR^1bR^1cS-；

R^1a、R^1bOr R^1cEach independently selected from H, C_1-4Alkyl or- (CH)₂)_p-C_3-6Carbocycle, said alkyl or carbocycle being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, CF₃Cyano, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

alternatively, R^1b、R^1cTogether with the carbon atom to which they are directly attached form a 3-membered carbocyclic ring;

ring C is selected from 5-6 membered heteroaryl or phenyl, optionally further substituted with 0, 1, 2, 3 or 4R^cSubstitution;

R^ceach independently selected from H, halogen, OH, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-C(＝O)R^3a、-(CH₂)_m-C(＝O)OR^3a、-(CH₂)_m-OC(＝O)R^3a、-(CH₂)_m-3 to 12 membered heterocyclyl or- (CH)₂)_m-C_3-10Carbocyclyl group of said-CH₂-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃O, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C_1-4Alkylene-hydroxy, C_3-6Carbocyclyl or 3 to 8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

R^a1、R^a2、R^3a、R^3beach independently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-12Carbocyclyl or 3 to 12 membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1, 2, or 3 heteroatoms selected from O, S, N;

n and s are selected from 0, 1 or 2;

r, m, p, q are each independently selected from 0, 1, 2, 3 or 4.

As a second embodiment of the present invention, the compound represented by the above general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

is selected from

Right side and L₁Direct connection;

is selected from

X₁Selected from N or CR^a；

R^aSelected from H, halogen, cyano, C_1-4Alkyl radical, C_1-4Alkoxy, - (CH)₂)_q-C(＝O)-NR^a1R^a2、-(CH₂)_q-NR^a1R^a2、-(CH₂)_qNR^a1C(＝O)-R^a2、-(CH₂)_q-C_3-6Carbocyclic ring or- (CH)₂)_q-3 to 6 membered heterocycle, said-CH₂-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1, 2 or 3 heteroatoms selected from O, S, N;

ring B is selected from C_3-6Saturated or unsaturated monocyclic carbocyclic ring, C_5-10Saturated or unsaturated spirocyclic carbocyclic ring, C_5-10Saturated or unsaturated carbocyclic ring, C_5-10A saturated or unsaturated bridged carbocyclic ring, a 3-to 7-membered saturated or unsaturated monocyclic heterocyclic ring, a 5-to 10-membered saturated or unsaturated spiroheterocyclic ring, a 5-to 10-membered saturated or unsaturated fused heterocyclic ring, a 5-to 10-membered saturated or unsaturated bridged heterocyclic ring, said carbocyclic or heterocyclic ring optionally further substituted with 0, 1, 2, 3 or 4R^b(ii) substituted, said heterocycle containing 1, 2, 3, or 4 heteroatoms selected from O, S, N;

z is selected from the group consisting of a bond, -Y-4 to 7 membered monocyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered fused cyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered spirocyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered bridged cyclic nitrogen-containing heterocycle-, -Y-C_3-6Monocyclic carbocyclic ring-NRⁿ³-、-Y-C_5-12And a cyclic carbocyclic ring, -NRⁿ³-、-Y-C_5-12Bridged carbocyclic ring-NRⁿ³-、-Y-(CRⁿ¹Rⁿ²)_rNRⁿ³-, when Z is selected from-Y-4 to 7 membered monocyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered fused cyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered spiro nitrogen-containing heterocycle-, -Y-5 to 12 membered bridged cyclic nitrogen-containing heterocycle-, the nitrogen-containing heterocycle or carbocycle is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

y is selected from-C (O) -;

Rⁿ¹、Rⁿ²each independently selected from H, halogen, cyano, C_1-4Alkyl radical, C_3-6Carbocyclyl or 3 to 7 membered heterocyclyl, said alkyl, alkenyl, carbocyclyl or heterocyclyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

Rⁿ³selected from H, C_1-4Alkyl radical, C_3-6Carbocyclyl, said alkyl, carbocyclyl optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, substituted with a substituent;

alternatively, Rⁿ¹And Rⁿ²Together with the atom to which they are attached form C_3-8Carbocyclyl optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

alternatively, Rⁿ³And Rⁿ¹、Rⁿ³And Rⁿ²And the atoms to which they are attached, together form a 4-to 8-membered nitrogen-containing heterocyclic ring, said heterocyclic ring optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1, 2 or 3N atoms;

R^beach independently selected from H, halogen, cyano, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy or C_3-8Cycloalkyl, substituted with a substituent;

L₁selected from-O-, -S (O)_n-、-NR^1a-、-CR^1bR^1c-、-OCR^1bR^1c-、-O(CR^1bR^1c)₂-、-CR^1bR^1cO-、-NR^1aCR^1bR^1c-、-SCR^1bR^1c-or-CR^1bR^1cS-；

R¹、R²、R³、R⁴Each independently selected from H, halogen, OH, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-C(＝O)R^3a、-(CH₂)_m-C(＝O)OR^3a、-(CH₂)_m-OC(＝O)R^3a、-(CH₂)_m-3 to 10 membered heterocycle or- (CH)₂)_m-C_3-8Carbocyclic ring of said-CH₂-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃O, OH, cyano, COOH、NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C_1-4Alkylene-hydroxy, C_3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

R^a1、R^a2、R^3a、R^3beach independently selected from H, C_1-4Alkyl radical, C_3-6Carbocyclyl or 3 to 6 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

the remaining groups are as defined for the first embodiment.

As a third embodiment of the present invention, there is provided a compound represented by the general formula (I) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

L₁selected from-O-, -S-, -NH-, -CH₂-、-S(O)₂-、-OCH₂-、-OCH(CH₃)-、-OC(CH₃)₂-、-OCH₂CH₂-、-CH₂O-、-NHCH₂-or-N (CH)₃)-；

The ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, bicyclo [1.1.1]Pentyl alkyl, bicyclo [2.2.1 ]]Heptaalkyl, cubic alkyl, bicyclo [3.1.0]Hexane radical, bicyclo [3.2.0 ]]Heptylalkyl, cyclopentacyclocyclopentyl, bicyclo [4.2.0]Octyl, bicyclo [2.2.2]Octyl, cyclobutyl spirocyclobutyl, cyclobutyl spirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentyl spirohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, piperazinyl, morpholinyl, imidazolinyl, azetidinyl, and azetidinyl(iii) a group, azacyclopentyl spiroazetidinyl, azetidinyl spiroazacyclohexyl, cyclobutyl spiroazacyclohexyl, azetidinyl spirocyclohexyl, azepino cyclopentyl, azepino-cyclopentyl, azetidino-cyclopentyl, cyclobutylazacyclopentyl, azetidino-cyclopentyl, when substituted, optionally further substituted with 0, 1, 2, 3 or 4R^bSubstitution;

when ring B is attached to X through an N atom, X is selected from a bond;

z is selected from the group consisting of a bond, -Y-azetidinyl-, -Y-aziridinyl-, -Y-azacyclohexyl-, -Y-piperazinyl-, -Y-cyclobutyl-NRⁿ³-, -Y-cyclopentyl-NRⁿ³-, -Y-cyclohexyl-NRⁿ³-、-Y-CH₂NRⁿ³-、-Y-C(CH₃)₂NRⁿ³-、-Y-CH(CH₃)NRⁿ³-、-Y-CH₂CH₂NRⁿ³-、-Y-CH₂CH₂CH₂NRⁿ³-, when Z is selected from-Y-azetidinyl-, -Y-aziridinyl-, -Y-piperazinyl-, said azetidinyl, aziridinyl, azacyclohexyl, piperazinyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, OH, cyano, C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

y is selected from-C (O) -;

Rⁿ³selected from H, methyl, ethyl, propyl, isopropyl, butyl, -CH₂-cyclopropyl, -CH₂-cyclobutyl, -CH₂-cyclopentyl, -CH₂-cyclohexyl;

when ring B is linked to X through a C atom, X is selected from NH, N (CH)₃)、N(CH₂CH₃)、N(CH₂-cyclopropyl), N (CH)₂-cyclobutyl), N (CH)₂-cyclopentyl), N (CH)₂-cyclohexyl);

R^beach independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propylOxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy being optionally further substituted by 0, 1, 2, 3 or 4 groups selected from H, halogen, CF₃OH, cyano, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6Cycloalkyl, substituted with a substituent;

R^aselected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, - (CH)₂)_q-C(＝O)-NR^a1R^a2、-(CH₂)_q-NR^a1R^a2、-(CH₂)_qNR^a1C(＝O)-R^a2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂-cyclopropyl, -CH₂-cyclobutyl, -CH₂-cyclopentyl or-CH₂-cyclohexyl, said-CH₂-, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R¹、R²、R³、R⁴each independently selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, propenyl, ethynyl, propynyl, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-cyclopropyl, - (CH)₂)_m-cyclobutyl, - (CH)₂)_m-cyclopentyl, - (CH)₂)_m-cyclohexyl, - (CH)₂)_m-azetidinyl, - (CH)₂)_m-oxetanyl, - (CH)₂)_m-pyrrolidinyl, - (CH)₂)_m-tetrahydrofuranFuryl, - (CH)₂)_m-piperidinyl, - (CH)₂)_m-tetrahydropyranyl, - (CH)₂)_m-morpholinyl, - (CH)₂)_m-piperazinyl or- (CH)₂)_m-azepinyl, said-CH₂-, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepinyl optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃O, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C_1-4Alkylene-hydroxy, C_3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said heterocyclyl containing 1, 2 or 3 heteroatoms selected from O, S, N;

R^a1、R^a2、R^3a、R^3beach independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl groups being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

the remaining groups are defined in accordance with any one of the first or second embodiments of the invention.

As a fourth embodiment of the present invention, there is provided a compound represented by the general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

ring B is selected from one of the following substituted or unsubstituted groups:

R^beach independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy being optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, CF₃OH, cyano, NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂Methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or cyclopentyl;

R^aselected from H, F, Cl, cyano, NH₂、-NHCH₃、-N(CH₃)₂、-C(O)NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-C(O)NHCH₂CH₃、-C(O)N(CH₂CH₃)₂、-C(O)NHCH₂CH₂OCH₃-C (O) NH-cyclopropyl, -C (O) NH-cyclobutyl, -C (O) NH-cyclopentyl, -C (O) NH-cyclohexyl, -NHC (O) CH₃、-NHC(O)CH₂CH₃-NHC (O) -cyclopropyl, -NHC (O) -cyclobutyl, -NHC (O) -cyclopentyl, -NHC (O) -cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂-cyclopropyl, -CH₂-cyclobutyl, -CH₂-cyclopentyl or-CH₂-a cyclohexyl group;

R¹、R²、R³each independently selected from H, F, Cl, Br, I, OH, cyano, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3bMethyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said-CH₂-, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, CF₃OH, cyano, COOH, NH₂、-NHCH₃、-N(CH₃)₂Methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, -CH₂OH or-CH₂CH₂OH is substituted by a substituent;

R^3a、R^3beach independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl groups being optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, CF₃OH, cyano, COOH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy or propoxy;

R⁴selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, propenyl, ethynyl, propynyl, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-cyclopropyl, - (CH)₂)_m-cyclobutyl, - (CH)₂)_m-cyclopentyl, - (CH)₂)_m-cyclohexyl, - (CH)₂)_m-azetidinyl, - (CH)₂)_m-oxetanyl, - (CH)₂)_m-pyrrolidinyl, - (CH)₂)_m-tetrahydrofuranyl, - (CH)₂)_m-piperidinyl, - (CH)₂)_m-tetrahydropyranyl, - (CH)₂)_m-morpholinyl, - (CH)₂)_m-piperazinyl or- (CH)₂)_m-azepinyl, said-CH₂-, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepinyl, optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H, F, ═ O, OH, cyano, CF₃、COOH、NH₂、-NHCH₃、-N(CH₃)₂Methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, -CH₂OH、-CH₂CH₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepanyl;

the remaining groups are defined in accordance with the second or third embodiment of the invention.

As a fifth embodiment of the present invention, there is provided a compound represented by the general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

L₁selected from-O-, -NH-, -OCH₂-、-OC(CH₃)₂-、-CH₂O-or-NHCH₂-；

Z is selected from a bond,

R^bEach independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy being optionally further substituted by 0, 1, 2, 3 or 4 groups selected from H, F, CF₃OH, cyano, NH₂、-N(CH₃)₂、-N(CH₂CH₃)₂Methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl;

X₁is selected from N or CH;

R¹、R²each independently selected from H, F, Cl, OH, CF₃Cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy;

R³selected from H, F, Cl, OH, CF₃、-CN、-CH₂CN、-CH₂CH₂CN、NH₂、-N(CH₃)₂、-N(CH₂CH₃)₂、-C(O)NH₂、-CH₂C(O)NH₂、-C(O)NHCH₃、-NHC(O)CH₃Methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy;

R⁴selected from H, F, OH, CF₃、NH₂、-CN、-CH₂CN、-CH₂CH₂CN、-NHCH₃、-N(CH₃)₂、-C(O)-NH₂、-CH₂C(O)-NH₂、-CH₂CH₂C(O)-NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-NHC(O)CH₃Methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, -CH₂-cyclopropyl, cyclobutyl, -CH₂-cyclobutyl, cyclopentyl, -CH₂-cyclopentyl, cyclohexyl, -CH₂-cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl or piperazinyl;

the remaining groups are defined in accordance with any of the second, third or fourth embodiments of the invention. .

As a sixth embodiment of the present invention, there is provided a compound represented by the general formula (I) or a stereoisomer, a deuteride, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

L₁selected from-O-, -OCH₂-、-OC(CH₃)₂-，L₁The right side is connected with the ring B;

is selected from

Is selected from

Right side and L₁Direct connection;

is selected from

R¹Selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

R²selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

R³selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

R⁴selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

the remaining groups are defined in accordance with any of the second, third, fourth or fifth embodiments of the invention.

As a seventh embodiment of the present invention, a compound represented by the following general formula (Ia) or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof,

each group is defined in accordance with any one of the second, third, fourth, fifth or sixth embodiments of the invention.

The invention provides a compound shown as the following or a stereoisomer, a deutero-compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof,

the invention relates to a pharmaceutical composition, which comprises any of the compounds or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a eutectic crystal thereof, and a pharmaceutically acceptable carrier.

The invention relates to application of any compound or stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic crystal thereof in preparing a medicament for treating diseases related to JAK3 kinase activity or expression, preferably, the diseases are selected from immune system related diseases.

References and monographs in this field detail the synthesis of reactants useful in the preparation of the compounds described herein, or provide articles describing the preparation for reference. These references and monographs include: "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; sandler et al, "Organic Functional Group precursors," 2nd ed, Academic Press, New York, 1983; h.o.house, "Modern Synthetic Reactions", 2nd ed., w.a.benjamin, inc.menlo Park, calif.1972; gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; march, "Advanced Organic Chemistry: Reactions, mechanics and Structure", 4th Ed., Wiley-Interscience, New York, 1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: hubs, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-; hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-; march, J. "Advanced Organic Chemistry: Reactions, mechanics, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-; otera, J. (editor) "Modern carbon Chemistry" (2000) Wiley-VCH, ISBN: 3-527-; patai, S. "Patai's 1992Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-; solomons, T.W.G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-; stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73volumes.

Specific and similar reactants can be selectively identified by an index of known chemicals prepared by the chemical abstracts society of america, which is available in most public and university libraries and online. Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which standard chemical supply plants (e.g., those listed above) provide custom synthesis services. References to the preparation and selection of pharmaceutically acceptable Salts of the compounds described herein are P.H.Stahl & C.G.Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich,2002.

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

Where carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I are involved in the radicals and compounds of the invention, including their isotopes, and where carbon, hydrogen, oxygen, sulfur or nitrogen are involved in the radicals and compounds of the invention, optionally further substituted with one or more of their corresponding isotopes, where isotopes of carbon include¹²C、¹³C and¹⁴c, isotopes of hydrogen including protium (H), deuterium (D, also called deuterium), tritium (T, also called deuterium), isotopes of oxygen including¹⁶O、¹⁷O and¹⁸isotopes of O, sulfur including³²S、³³S、³⁴S and³⁶isotopes of S, nitrogen include¹⁴N and¹⁵isotopes of N, F include¹⁷F and¹⁹isotopes of F, chlorine including³⁵Cl and³⁷cl, isotopes of bromine including⁷⁹Br and⁸¹Br。

"halogen" means F, Cl, Br or I.

"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and further preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; the alkyl group may be optionally further substituted with 0 to 6 groups selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, C_1-6Alkyl radical, C_1-6Hydroxyalkyl radical, C_1-6Alkoxy, 3-to 8-membered carbocyclyl, 3-to 8-membered heterocyclyl, 3-to 8-membered carbocyclyloxy, 3-to 8-membered heterocyclyloxy, carboxy, or carboxylate, wherein alkyl is as defined herein.

"alkylene" refers to a straight and branched chain divalent saturated hydrocarbon radical, including- (CH)₂)_v- (v is an integer of 1 to 10), examples of alkylene include, but are not limited to, methylene, ethylene, propylene, butylene, and the like; the alkylene group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkylene groups, as used herein, are defined in accordance with the present definition.

"cycloalkyl" refers to a monovalent saturated carbocyclic hydrocarbon group, typically of 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the like. The cycloalkyl group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Cycloalkyl as found herein, is as defined above.

"alkenyl" means a straight and branched chain monovalent unsaturated hydrocarbon group having at least 1, and usually 1, 2 or 3 carbon double bonds, and the main chain includes 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the main chain, examples of alkenyl 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-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-hexenyl, and the like, 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-hexadiene, and the like; the alkenyl group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkenyl groups are present herein, the definition of which is consistent with the present definition.

"alkynyl" refers to straight and branched chain monovalent unsaturated hydrocarbon radicals having at least 1, and typically 1, 2 or 3 carbon-carbon triple bonds, and a backbone containing 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms in the backbone, with examples of alkynyl including, but not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 2-butynyl, 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 optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkynyl groups are presented herein, and their definitions are consistent with this definition.

"alkoxy" means-O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy. The alkoxy group may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy, or carboxylate. Alkoxy groups, as used herein, are defined in accordance with the present definition.

"carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic, or 10 to 15 membered tricyclic ring system, the carbocyclyl may be attached to the aromatic or non-aromatic ring, which is optionally monocyclic, bridged or spiro. 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, and mixtures thereof,

The carbocycle may be optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, ═ O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. Carbocyclic or carbocyclic groups, as used herein, are defined in accordance with the present definition.

"Heterocyclyl" or "heteroRing "means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring system and contains 1 to 3 heteroatoms selected from N, O or S, preferably a 3 to 8 membered heterocyclic group, the optionally substituted N, S in the ring of which may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, the heterocyclic group may be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples of which include oxiranyl, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolanyl, 1, 4-dioxolanyl, 1, 3-dioxanyl, azepinyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithiayl, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, dihydropyranyl, spirocyclo-pyridyl, spiro-pyridyl, spirocyclo-pyridyl, oxacycloheptyl, azanyl, pyridyl, oxathianyl, thianyl, thienyl, pyridyl, etc, Benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuranyl, benzopyrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo [3.2.1]Octyl, azabicyclo [5.2.0 ] s]Nonoalkyl oxatricyclo [5.3.1.1 ]]Dodecyl, azaadamantyl, oxaspiro [3.3 ]]A heptylalkyl group,

Said heterocyclic group may be optionally further substituted by 0 to 5 groups selected from F, Cl, Br, I, ═ O, hydroxyl, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxylAlkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxyl, or carboxylate. Heterocyclyl groups, as found herein, are defined in accordance with this definition.

"spiro" refers to a 5 to 20 membered polycyclic group sharing one atom (called spiro atom) between substituted or unsubstituted monocyclic rings, which may contain 0 to 5 double bonds, and may contain 0 to 5 substituents selected from N, O or S (═ O)_nWherein n is 0, 1, 2. Preferably 6 to 14, more preferably 6 to 12, more preferably 6 to 10, non-limiting examples of which include:

when substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate₂)_m-C(＝O)-R^a、-O-(CH₂)_m-C(＝O)-R^a、-(CH₂)_m-C(＝O)-NR^bR^c、-(CH₂)_mS(＝O)_nR^a、-(CH₂)_m-alkenyl-R^a、OR^dOr- (CH)₂)_m-alkynyl-R^a(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cEtc. wherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heteroCyclic, carbonyl, ester, bridged, spiro, or fused groups. Spiro rings appear herein, and their definition is consistent with this definition.

"fused" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more of the rings may contain 0 or more double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 atoms selected from N, S (═ O)_nOr a heteroatom of O (wherein n is 0, 1, 2). Preferably 5 to 20, more preferably 5 to 14, more preferably 5 to 12, and even more preferably 5 to 10 yuan. Non-limiting examples include:

when substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate₂)_m-C(＝O)-R^a、-O-(CH₂)_m-C(＝O)-R^a、-(CH₂)_m-C(＝O)-NR^bR^c、-(CH₂)_mS(＝O)_nR^a、-(CH₂)_m-alkenyl-R^a、OR^dOr- (CH)₂)_m-alkynyl-R^a(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cEtc. wherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. Book (I)The definition of fused rings appearing herein is consistent with this definition.

"bridged ring" means any two polycyclic group of atoms not directly linked, which may contain 0 or more double bonds and may be substituted or unsubstituted, and any ring in the ring system may contain 0 to 5 heteroatoms or groups selected from N, S (═ O) n or O (where n is 0, 1, 2). The ring atoms contain 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12, and further preferably 5 to 10. Non-limiting examples include

And adamantane. When substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate₂)_m-C(＝O)-R^a、-O-(CH₂)_m-C(＝O)-R^a、-(CH₂)_m-C(＝O)-NR^bR^c、-(CH₂)_mS(＝O)_nR^a、-(CH₂)_m-alkenyl-R^a、OR^dOr- (CH)₂)_m-alkynyl-R^a(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cEtc. wherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. The definition of bridged ring, as found herein, is consistent with this definition.

"carbocyclyl", "spirocarbocyclyl" or "carbospirocyclic" refers to a "spiro" ring whose ring system consists of only carbon atoms. The definition of "carbospiro", "spirocyclic carbocyclyl", "spirocarbocyclyl" or "carbospiro" group, as used herein, is consistent with the present definition. "carbocyclic", "fused carbocyclic", or "carbocyclic" refers to "fused rings" in which the ring system consists of only carbon atoms. The definition of "carbocyclic", "fused carbocyclic", or "fused carbocyclic" appearing herein is consistent with the present definition.

"Carbobridged ring", "bridged carbocyclyl" or "carbocyclyl" refers to a "bridged ring" in which the ring system consists of only carbon atoms. The definition of "carbocycle", "carbocyclyl", "bridged carbocyclyl", or "carbocyclyl" as used herein is consistent with the present definition.

"Heteromonocyclic", "monocyclic heterocyclyl" or "heteromonocyclic" refers to "heterocyclyl" or "heterocycle" of a monocyclic ring system, and the definition of heterocyclyl, "monocyclic heterocyclyl" or "heteromonocyclic" as found herein is consistent with the present definition.

"Heterocyclo", "heterocyclocyclyl" or "heterocyclocyclyl" means a "fused ring" containing heteroatoms. A hetero-cyclic, "hetero-cyclic" or "hetero-cyclic" group, as used herein, is defined consistent with this definition.

"Heterospirocyclic", "heterospirocyclic", "spiroheterocyclic" or "heterospirocyclic" refers to "spirocyclic" containing heteroatoms. The definition of heterospirocyclic, "heterospirocyclic", "spiroheterocyclic" or "heterospirocyclic" as used herein is consistent with the present definition.

"heterobridged ring," "heterobridged ring group," "bridged heterocyclic group," or "heterobridged ring group" refers to a "bridged ring" containing a heteroatom. The definition of heterobridged ring, "heterobridged ring group," "bridged heterocyclic group," or "heterobridged ring group," as used herein, is consistent with this definition.

The "aryl" or "aromatic ring" isRefers to a monovalent aromatic hydrocarbon group having a single ring or fused rings, typically 6 to 12 carbon atoms, and which may be substituted or unsubstituted. When substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate₂)_m-C(＝O)-R^a、-O-(CH₂)_m-C(＝O)-R^a、-(CH₂)_m-C(＝O)-NR^bR^c、-(CH₂)_mS(＝O)_nR^a、-(CH₂)_m-alkenyl-R^a、OR^dOr- (CH)₂)_m-alkynyl-R^a(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cEtc. wherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. Aryl or aromatic rings are present herein, and the definition is consistent with the present definition.

"heteroaryl" refers to a substituted or unsubstituted 5 to 15 membered aromatic ring and contains 1 to 5 heteroatoms or groups selected from N, O or S (═ O) n (where n is 0, 1, 2), preferably 5 to 10 membered heteroaromatic rings, more preferably 5 to 6 membered aromatic rings. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring joined together to the parent structure is a heteroaryl ring, non-limiting examples of which include

When substituted, the substituents may be 1 to 5 substituents selected from F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro ring, fused ring, hydroxyalkyl, ═ O, carbonyl, aldehyde, carboxylic acid, formate, - (CH), carbonyl, carboxylate, or carboxylate₂)_m-C(＝O)-R^a、-O-(CH₂)_m-C(＝O)-R^a、-(CH₂)_m-C(＝O)-NR^bR^c、-(CH₂)_mS(＝O)_nR^a、-(CH₂)_m-alkenyl-R^a、OR^dOr- (CH)₂)_m-alkynyl-R^a(wherein m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or-NR^bR^cEtc. wherein R is^bAnd R^cIndependently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R^bAnd R^cFive or six membered cycloalkyl or heterocyclyl groups may be formed. R^aAnd R^dEach independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring, or fused ring. Heteroaryl, as used herein, is defined in accordance with the present definition.

"contains 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.

"substituted with 0 to X substituents" means substituted with 0, 1, 2, 3 … X substituents, X being selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0, 1, 2, 3, or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0, 1, 2, 3, 4, or 5 substituents. By "heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the heterobridged ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F.

"0 to X substituents selected from …" means substituted with 0, 1, 2, 3 … X substituents selected from …, X being selected from any integer between 1 and 10. If "substituted with 0 to 4 substituents selected from …" is intended to mean substituted with 0, 1, 2, 3, or 4 substituents selected from …. If "substituted with 0 to 5 substituents selected from …" is meant substituted with 0, 1, 2, 3, 4, or 5 substituents selected from …. By "heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the heterobridged ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F.

The ring of X-Y element (X is selected from the integer less than or equal to Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) includes the ring of X +1, X +2, X +3, X +4 … Y element. Rings include heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterospirocyclic, or heterobridged rings. For example, "4-7 membered heteromonocyclic" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterobicyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterobicyclic ring.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. Such as: "alkyl optionally substituted with F" means that the alkyl group may, but need not, be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base obtained by reaction with a non-toxic inorganic or organic base, and the free base obtained by reaction with a non-toxic inorganic or organic acid.

"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.

By "carrier" is meant a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.

By "prodrug" is meant a compound of the invention that is metabolically convertible in vivo to a biologically active compound. Prodrugs of the invention are prepared by modifying an amino or carboxyl group in a compound of the invention, which modification may be removed by routine manipulation or in vivo, to yield the parent compound. When a prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"cocrystal" refers to a crystal of an Active Pharmaceutical Ingredient (API) and a cocrystal former (CCF) bound by hydrogen bonding or other non-covalent bonds, wherein the API and CCF are both solid in their pure state at room temperature and a fixed stoichiometric ratio exists between the components. A co-crystal is a multi-component crystal that contains both a binary co-crystal formed between two neutral solids and a multicomponent co-crystal formed between a neutral solid and a salt or solvate.

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

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, and conformers.

"optional" or "optionally" or "selective" or "selectively" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group, and the case where the heterocyclic group is not substituted with an alkyl group.

Detailed Description

The following examples illustrate the technical solutions of the present invention in detail, but the scope of the present invention includes but is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS);

MS measurement (Agilent 6120B (ESI)) and Agilent 6120B (APCI));

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. mu.M);

the thin layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5 mm;

the column chromatography generally uses 200-mesh and 300-mesh silica gel of the Tibet yellow sea silica gel as a 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 Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical industry, Shaoshanghi chemical technology, and Bailingwei technology;

SEM:

THP:

boc: a tert-butoxycarbonyl group; ms:

TBS:

MTBE methyl tert-butyl ether; b, Bn:

example 1:

4- ((((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy) methyl) piperidine-1-carbonitrile (Compound 1)

4-(((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)methyl)piperidine-1-carbonitrile

The first step is as follows: ((5-bromo-3-fluoropyridin-2-yl) methyl) carbamic acid tert-butyl ester (1B)

tert-butyl((5-bromo-3-fluoropyridin-2-yl)methyl)carbamate

To a 250mL reaction flask, 5-bromo-3-fluoro-2-pyridinecarbonitrile (1A) (10.0g, 50mmol), raney nickel (10g), methanol (100mL), BOC anhydride (21.8g, 100mmol) were added in this order, and then replaced with hydrogen three times, and the mixture was stirred at room temperature for 48 hours under a hydrogen atmosphere, filtered with celite, concentrated under reduced pressure, and purified with a silica gel column (petroleum ether/ethyl acetate (v/v) ═ 10:1) to give the title compound tert-butyl ((5-bromo-3-fluoropyridin-2-yl) methyl) carbamate (1B), a yellow oil (9.1g, yield 60%)

LCMS m/z＝249.0/251.0[M-55]⁺

The second step is that: hydrochloride of (5-bromo-3-fluoropyridin-2-yl) methylamine (1C)

(5-bromo-3-fluoropyridin-2-yl)methanamine；hydrochloric acid

Tert-butyl ((5-bromo-3-fluoropyridin-2-yl) methyl) carbamate (1B) (9.1g, 30mmol) was dissolved in 2.5M hydrochloric acid/ethyl acetate solution (100mL) and reacted at room temperature for 1 hour. The reaction was directly concentrated to give the title compound (5-bromo-3-fluoropyridin-2-yl) methylamine hydrochloride ((1C) crude, yellow oil (6.8g, used directly in the next reaction).

The third step: n- ((5-bromo-3-fluoropyridin-2-yl) methyl) carboxamide (1D)

N-((5-bromo-3-fluoropyridin-2-yl)methyl)formamide

The crude hydrochloride of (5-bromo-3-fluoropyridin-2-yl) methylamine from the previous step (1C) (6.8g) was dissolved in 100mL of water, then ammonia (10mL) was added to make it free to basic (pH 10-11), then dichloromethane (100mL x 3) was used for extraction, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give a residue which was added to 125mL of a reaction pressure-resistant tube, ethyl formate (60mL) was added thereto, stirred at 50 ℃ for 2h and concentrated under reduced pressure to give the crude title compound N- ((5-bromo-3-fluoropyridin-2-yl) methyl) carboxamide (1D) as a brown solid (5.8g) which was used directly in the next step.

The fourth step: 6-bromo-8-fluoroimidazo [1,5-a ] pyridine (1E)

6-bromo-8-fluoroimidazo[1,5-a]pyridine

Under the protection of nitrogen, the crude N- ((5-bromo-3-fluoropyridin-2-yl) methyl) formamide (1D) (5.8g) in the previous step, phosphorus oxychloride (6mL) and toluene (60mL) were added in sequence in a 250mL reaction flask, and after the addition, the mixture was stirred at 80 ℃ for 2 hours. Concentrated under reduced pressure, quenched with saturated sodium bicarbonate solution (80mL), extracted with dichloromethane (100mL x 3), the organic layers combined, dried over anhydrous sodium sulfate, filtered, the filtrate concentrated under reduced pressure, and purified on silica gel (petroleum ether/ethyl acetate (v/v) ═ 2:1) to give the title compound 6-bromo-8-fluoroimidazo [1,5-a ] pyridine (1E) as a gray solid (5g, 47% yield over three steps)

LCMS m/z＝215.0/217.0[M+1]⁺

The fifth step: 4- ((((6-bromoimidazo [1,5-a ] pyridin-8-yl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (1F)

tert-butyl4-(((6-bromoimidazo[1,5-a]pyridin-8-yl)oxy)methyl)piperidine-1-carboxylate

N-Boc-4-piperidinemethanol (375mg, 1.74mmol) and DMF (10mL) were added to a reaction flask under nitrogen, sodium hydrogen (140mg, 3.49mmol) was added with cooling in an ice water bath, and after the addition was complete, the reaction was allowed to warm to room temperature and stirred for 30 min. After cooling in an ice-water bath, a solution of 6-bromo-8-fluoroimidazo [1,5-a ] pyridine (1E) (250mg, 1.16mmol) in DMF (5mL) was added dropwise, and the mixture was stirred at room temperature for 3 hours. TLC monitored the reaction for completion, added ethyl acetate (100mL) and water (10mL), separated layers and extracted the aqueous phase once with ethyl acetate (100m), combined organic layers, washed with saturated sodium chloride solution (100mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography of the residue (PE/EA ═ 5/1) to give 4- (((6-bromoimidazo [1,5-a ] pyridin-8-yl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (1F) as a white solid (472mg, 99% yield).

LCMS m/z＝410.1/412.1[M+1]⁺

And a sixth step: 4- ((((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy) methyl) piperidine-1-carboxylic acid tert-butyl ester (1G)

tert-butyl4-(((6-(2-ethyl-5-fluoro-4-hydroxyphenyl)imidazo[1,5-a]pyridin-8-yl)oxy)methyl)piperidine-1-carboxylate

5-Ethyl-2-fluoro-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol (371mg, 1.40mmol), potassium phosphate heptahydrate (1.12g, 3.30mmol), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (0.09g, 0.11mmol) were added to a solution of tert-butyl 4- ((((((6-bromoimidazo [1,5-a ] pyridin-8-yl) oxy) methyl) piperidine-1-carboxylate (1F) (452mg, 1.10mmol) in 1, 4-dioxane (20mL) and water (5mL), respectively, stirred at 110 ℃ for 1h, a saturated sodium bicarbonate solution (20mL) was quenched, ethyl acetate (20mL 3) was extracted, the combined organic layers were dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate (v/v) ═ 2:1) to give the title compound tert-butyl 4- ((((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy) methyl) piperidine-1-carboxylate (1G), a tan solid (386mg, 75% yield)

LCMS m/z＝470.2[M+1]⁺

The seventh step: 5-Ethyl-2-fluoro-4- (8- (piperidin-4-ylmethoxy) imidazo [1,5-a ] pyridin-6-yl) phenol (1H)

5-ethyl-2-fluoro-4-(8-(piperidin-4-ylmethoxy)imidazo[1,5-a]pyridin-6-yl)phenol

Tert-butyl 4- (((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy) methyl) piperidine-1-carboxylate (1G) (340mg, 0.72mmol) was dissolved in dichloromethane (20mL) and trifluoroacetic acid (10mL) was added to react at room temperature for 1 hour, the reaction was directly concentrated, the residue was dissolved in dichloromethane, 30mL of a saturated sodium bicarbonate solution was added, a mixed solvent of dichloromethane/methanol (v/v ═ 8/1) was used for extraction (40mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 5-ethyl-2-fluoro-4- (8- (piperidin-4-ylmethoxy) imidazo [1,5-a ] pyridin-6-yl) phenol (1H), a white solid (267mg), was used directly in the next step.

Eighth step: 4- ((((6- (2-ethyl-5-fluoro-4-hydroxyphenyl) imidazo [1,5-a ] pyridin-8-yl) oxy) methyl) piperidine-1-carbonitrile (Compound 1)

The crude 5-ethyl-2-fluoro-4- (8- (piperidin-4-ylmethoxy) imidazo [1,5-a ] pyridin-6-yl) phenol (267mg) from the previous step was dissolved in a 100mL single neck round bottom flask with 20mL acetonitrile, triethylamine (0.36g,3.6mmol) was added, the temperature was reduced to 0-5 ℃ with an ice water bath, cyanogen bromide (76mg,0.72mmol) was weighed into the reaction flask, warmed to room temperature and stirred for half an hour, TLC monitored complete consumption of starting material. The reaction was quenched with 25mL of water, extracted with mixed solvent dichloromethane/methanol (v/v ═ 10/1) (30mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue, which was isolated and purified by column chromatography on silica gel to give a white solid (50mg, 18% yield in two steps).

LCMS m/z＝395.1[M+1]⁺

¹H NMR(400MHz,CD₃OD)δ8.28(d,1H),7.77(s,1H),7.42(s,1H),6.96(d,1H),6.88(d,1H),6.10(s,1H),4.02(d,2H),3.53-3.42(m,2H),3.15(td,2H),2.57(q,2H),2.14-2.00(m,1H),1.96–1.88(m,2H),1.65-1.47(m,2H),1.12(t,3H).

Biological test example

Test example 1: inhibitory Activity against JAK1, JAK2, JAK3, TYK2 kinase

The detection is carried out by adopting HTRF KinEASE-TKkit (Cat number: 62TK0PEC) of Cisbio company, and the specific method is as follows:

diluting the compound with 1 × kinase buffer to 2.5 times the final concentration; the enzymes JAK1, JAK2, JAK3 and Tyk2 (Carna; 08-144, 08-045, 08-046 and 08-147) were diluted to 15. mu.g/mL, 0.185. mu.g/mL, 1.665. mu.g/mL and 5. mu.g/mL, respectively; ATP was diluted to 19.6. mu.M (JAK1), 19.8. mu.M (JAK2), 7.15. mu.M (JAK3) and 25.3. mu.M (Tyk2), respectively; TK Substrate-biotin stock was diluted to 10. mu.M.

10 μ L of kinase reaction was performed with 1 × kinase buffer: test Compound or Positive 4. mu.L + TK Substrate-biotin 2. mu.L + enzyme 2. mu.L + ATP 2. mu.L, mix wellAnd incubated at room temperature for 2 hours (JAK1), 30 minutes (JAK2 with JAK3) or 50 minutes (Tyk2), followed by the addition of 5. mu.L of Streptavidin-XL665(500nM) and 5. mu.L of TK Antibody-cryptate (1X), and continued incubation at room temperature for 1 hour. The fluorescence values at 665nm and 620nm were measured with a microplate reader (PHERAstar FSX). Signal Ratio is calculated according to equation (1), IC is calculated and analyzed using origin 9.2₅₀。

Ratio＝[Signal 665]/[Signal 620]×10⁴(formula 1)

The inhibitory activity of the compounds of the present invention, JAK1, JAK2, JAK3 and Tyk2 kinase, was determined by the above experiment.

Table 1 results of testing the inhibitory activity of the compound JAK3 kinase

Compound numbering	JAK3 IC50(nM)
		Compound 1	<10

And (4) conclusion: the compound has selective inhibition effect on JAK kinase family and has good inhibition effect on JAK3 kinase.

Claims

1. A compound or its stereoisomer, deuteron, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic is selected from the compounds shown in the general formula (I), wherein

Y₁、Y₂、Y₃Each independently selected from CH or N;

ring A is selected from a 5-to 6-membered heterocyclic or heteroaromatic ring optionally further substituted with 0 to 3R^aSubstituted with a substituent, said heterocycle or heteroaryl ring containing 1 to 4 heteroatoms selected from O, S, N;

R^aeach independently selected from H, ═ O, halogen, cyano, C_1-6Alkyl radical, C_1-6Alkoxy, - (CH)₂)_q-C(＝O)-NR^a1R^a2、-(CH₂)_q-NR^a1R^a2、-(CH₂)_qNR^a1C(＝O)-R^a2、-(CH₂)_q-C_3-10Carbocyclic ring or- (CH)₂)_q-3 to 12 membered heterocycle, said-CH₂-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;

ring B is selected from C_3-10A carbocyclic ring or a 3 to 10 membered heterocyclic ring, said carbocyclic or heterocyclic ring optionally further substituted with 0 to 4R^b(ii) substituted, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

when ring B is attached to X through an N atom, X is selected from a bond;

when ring B is attached to X through a C atom, X is selected from NH or N (C)_1-4Alkyl), optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, substituted with a substituent;

z is selected from the group consisting of a bond, -Y-4 to 12 membered nitrogen containing heterocycle-, -Y-C_4-12Carbocyclic ring-NRⁿ³-、-Y-(CRⁿ¹Rⁿ²)_rNRⁿ³-, when Z is chosen from-Y-4 to 12 membered nitrogen containing heterocycles-the nitrogen containing heterocycle or carbocycle is optionally further substituted by 0 to 4 substituents chosen from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

y is selected from a bond, C_1-4Alkylene, -C (O) -, -S (O) -, or-S (O)₂-；

Rⁿ¹、Rⁿ²Each independently selected from H, halogen, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-8Carbocyclyl or 3-to 8-membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;

Rⁿ³selected from H, C_1-6Alkyl radical, C_3-8Carbocyclyl, said alkyl, carbocyclyl optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, substituted with a substituent;

alternatively, Rⁿ¹And Rⁿ²Together with the atoms to which they are attached form C_3-8Carbocyclyl optionally further substituted with 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

alternatively, Rⁿ³And Rⁿ¹、Rⁿ³And Rⁿ²And the atoms to which they are attached, together form a 4-to 8-membered nitrogen-containing heterocyclic ring, said heterocyclic ring optionally further substituted with 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Substituent of alkoxy(ii) substituted, said heterocyclic ring containing 1 to 3N atoms;

R^beach independently selected from H, halogen, cyano, C_1-6Alkyl or C_1-6Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy or C_3-8Cycloalkyl, substituted with a substituent;

R^1a、R^1bOr R^1cEach independently selected from H, C_1-4Alkyl or- (CH)₂)_p-C_3-6Carbocycle, said alkyl or carbocycle being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, CF₃Cyano, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

ring C is selected from 5-6 membered heteroaryl or phenyl optionally further substituted with 0 to 4R^cSubstitution;

R^ceach independently selected from H, halogen, OH, cyano, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-C(＝O)R^3a、-(CH₂)_m-C(＝O)OR^3a、-(CH₂)_m-OC(＝O)R^3a、-(CH₂)_m-3 to 12 membered heterocyclyl or- (CH)₂)_m-C_3-10Carbocyclyl group of said-CH₂-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 groups selected from H, halogen, CF₃O, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C_1-4Alkylene-hydroxy, C_3-6Carbocyclyl or 3-to 8-membered heterocyclyl, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;

R^a1、R^a2、R^3a、R^3beach independently selected from H, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkoxy radical, C_3-12Carbocyclyl or 3-to 12-membered heterocyclyl, said alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;

n and s are selected from 0, 1 or 2;

r, m, p, q are each independently selected from 0, 1, 2, 3 or 4.

2. The compound of claim 1, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof,

is selected from

Right side and L₁Direct connection;

is selected from

X₁Selected from N or CR^a；

R^aSelected from H, halogen, cyano, C_1-4Alkyl radical, C_1-4Alkoxy, - (CH)₂)_q-C(＝O)-NR^a1R^a2、-(CH₂)_q-NR^a1R^a2、-(CH₂)_qNR^a1C(＝O)-R^a2、-(CH₂)_q-C_3-6Carbocyclic ring or- (CH)₂)_q-3 to 6 membered heterocycle, said-CH₂-, alkyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;

ring B is selected from C_3-6Saturated or unsaturated monocyclic carbocyclic ring, C_5-10Saturated or unsaturated spirocyclic carbocyclic ring, C_5-10Saturated or unsaturated carbocyclic ring, C_5-10A saturated or unsaturated bridged carbocyclic ring, a 3-to 7-membered saturated or unsaturated monocyclic heterocyclic ring, a 5-to 10-membered saturated or unsaturated spiroheterocyclic ring, a 5-to 10-membered saturated or unsaturated fused heterocyclic ring, a 5-to 10-membered saturated or unsaturated bridged heterocyclic ring, said carbocyclic or heterocyclic ring optionally further substituted with 0 to 4R^b(ii) substituted, said heterocycle containing 1 to 4 heteroatoms selected from O, S, N;

z is selected from the group consisting of a bond, -Y-4 to 7 membered monocyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered fused cyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered spirocyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered bridged cyclic nitrogen-containing heterocycle-, -Y-C_3-6Monocyclic carbocyclic ring-NRⁿ³-、-Y-C_5-12And a cyclic carbocyclic ring, -NRⁿ³-、-Y-C_5-12Bridged carbocyclic ring-NRⁿ³-、-Y-(CRⁿ¹Rⁿ²)_rNRⁿ³When Z is selected from-Y-4 to 7 membered monocyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered fused cyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered spiro cyclic nitrogen-containing heterocycle-, -Y-5 to 12 membered bridged cyclic nitrogen-containing heterocycle-optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, COOH, NH, attached to CN through the N atom₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

y is selected from-C (O) -;

Rⁿ¹、Rⁿ²each independently selected from H, halogen, cyano, C_1-4Alkyl radical, C_3-6Carbocyclyl or 3-to 7-membered heterocyclyl, said alkyl, alkenyl, carbocyclyl or heterocyclyl being optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;

Rⁿ³selected from H, C_1-4Alkyl radical, C_3-6Carbocyclyl, said alkyl, carbocyclyl optionally further substituted with 0 to 4 substituents selected from H, halogen, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl, halogen substituted C_1-4Alkyl radical, C_1-4Alkoxy radical, C_3-6Cycloalkyl, substituted with a substituent;

alternatively, Rⁿ³And Rⁿ¹、Rⁿ³And Rⁿ²And the atoms to which they are attached, together form a 4-to 8-membered nitrogen-containing heterocyclic ring, said heterocyclic ring optionally further substituted with 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocycle containing 1 to 3N atoms;

R^beach independently selected from H, halogen, cyano, C_1-4Alkyl or C_1-4Alkoxy, said alkyl or alkoxy being optionally further substituted by 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy or C_3-8Cycloalkyl, substituted with a substituent;

R¹、R²、R³、R⁴Each independently selected from H, halogen, OH, cyano, C_1-4Alkyl radical, C_2-4Alkenyl radical, C_2-4Alkynyl, C_1-4Alkoxy, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-C(＝O)R^3a、-(CH₂)_m-C(＝O)OR^3a、-(CH₂)_m-OC(＝O)R^3a、-(CH₂)_m-3 to 10 membered heterocycle or- (CH)₂)_m-C_3-8Carbocyclic ring of said-CH₂-, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle are optionally further substituted by 0 to 4 groups selected from H, halogen, CF₃O, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C_1-4Alkylene-hydroxy, C_3-6Cycloalkyl or 3 to 8 membered(ii) heterocyclyl, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;

R^a1、R^a2、R^3a、R^3beach independently selected from H, C_1-4Alkyl radical, C_3-6Carbocyclyl or 3-to 6-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally further substituted with 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Alkoxy, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N.

3. The compound of claim 2, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

The ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, bicyclo [1.1.1]Pentyl alkyl, bicyclo [2.2.1 ]]Heptaalkyl, cubic alkyl, bicyclo [3.1.0]Hexane radical, bicyclo [3.2.0 ]]Heptylalkyl, cyclopentacyclocyclopentyl, bicyclo [4.2.0]Octyl, bicyclo [2.2.2]Octyl, cyclobutyl spirocyclobutyl, cyclobutyl spirocyclopentyl, cyclobutyl spirocyclohexyl, cyclopentyl spirohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, piperazinyl, morpholinyl, imidazolinyl, azetidinyl spiroazetidinyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, cyclopentyl spiroazetidinyl, azetidinyl spiroazacyclohexyl, cyclobutyl spiroazacyclohexyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclopentyl, azetidinylcyclopentyl, azetidinopentyl, azetidinocyclocyclopentyl, when substituted byWhen substituted, is optionally further substituted with 0 to 4R^bSubstitution;

when ring B is attached to X through an N atom, X is selected from a bond;

z is selected from the group consisting of a bond, -Y-azetidinyl-, -Y-aziridinyl-, -Y-azacyclohexyl-, -Y-piperazinyl-, -Y-cyclobutyl-NRⁿ³-, -Y-cyclopentyl-NRⁿ³-, -Y-cyclohexyl-NRⁿ³-、-Y-CH₂NRⁿ³-、-Y-C(CH₃)₂NRⁿ³-、-Y-CH(CH₃)NRⁿ³-、-Y-CH₂CH₂NRⁿ³-、-Y-CH₂CH₂CH₂NRⁿ³-, when Z is selected from-Y-azetidinyl-, -Y-aziridinyl-, -Y-piperazinyl-, said azetidinyl, aziridinyl, azacyclohexyl, piperazinyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further substituted by 0 to 4 substituents selected from H, halogen, OH, cyano, C_1-4Alkyl, halogen substituted C_1-4Alkyl or C_1-4Substituted with a substituent of alkoxy;

y is selected from-C (O) -;

R^beach independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy being optionally further substituted with 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy or C_3-6Preparation of cycloalkyl radicalsSubstituted by substituent groups;

R^aselected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, - (CH)₂)_q-C(＝O)-NR^a1R^a2、-(CH₂)_q-NR^a1R^a2、-(CH₂)_qNR^a1C(＝O)-R^a2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH₂-cyclopropyl, -CH₂-cyclobutyl, -CH₂-cyclopentyl or-CH₂-cyclohexyl radical, -CH₂-, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl or cyclopentyl optionally further substituted by 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, NH₂、C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy;

R¹、R²、R³、R⁴each independently selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, propenyl, ethynyl, propynyl, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-cyclopropyl, - (CH)₂)_m-cyclobutyl, - (CH)₂)_m-cyclopentyl, - (CH)₂)_m-cyclohexyl, - (CH)₂)_m-azetidinyl, - (CH)₂)_m-oxetanyl, - (CH)₂)_m-pyrrolidinyl, - (CH)₂)_m-tetrahydrofuranyl, - (CH)₂)_m-piperidinyl, - (CH)₂)_m-tetrahydropyranyl, - (CH)₂)_m-morpholinyl, - (CH)₂)_m-piperazinyl or- (CH)₂)_m-azepinyl, said-CH₂-, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, vinyl, propylAlkenyl, ethynyl, propynyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepinyl optionally further substituted by 0 to 4 substituents selected from H, halogen, CF₃O, OH, cyano, COOH, NH₂、-NH(C_1-4Alkyl), -N (C)_1-4Alkyl radical)₂、C_1-4Alkyl radical, C_1-4Alkoxy, -C_1-4Alkylene-hydroxy, C_3-6Cycloalkyl or 3 to 8 membered heterocyclyl, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;

R^a1、R^a2、R^3a、R^3beach independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl groups being optionally further substituted by 0 to 4 substituents selected from H, halogen, CF₃OH, cyano, COOH, C_1-4Alkyl or C_1-4Substituted by a substituent of alkoxy.

4. The compound of claim 3, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

when substituted, is optionally further substituted with 0 to 4R^bSubstitution, left side and L thereof₁Connecting;

R^beach independently selected from H, F, Cl, Br, I, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, said methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy optionally further substituted with 0 to 4 substituents selected from H, F, CF₃OH, cyano, NH₂、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂Methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, or cyclopentyl;

R¹、R²、R³each independently selected from H, F, Cl, Br, I, OH, cyano, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3bMethyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy or propoxy, or a pharmaceutically acceptable salt thereof₂-, methyl, ethyl, isopropyl, propylButyl, methoxy, ethoxy or propoxy optionally further substituted with 0 to 4 substituents selected from H, F, CF₃OH, cyano, COOH, NH₂、-NHCH₃、-N(CH₃)₂Methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, -CH₂OH or-CH₂CH₂OH is substituted by a substituent;

R^3a、R^3beach independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl, said methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl or piperidinyl groups optionally further substituted with 0 to 4 substituents selected from H, F, CF₃OH, cyano, COOH, methyl, ethyl, isopropyl, propyl, methoxy, ethoxy or propoxy;

R⁴selected from H, F, Cl, Br, I, OH, cyano, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, ethenyl, propenyl, ethynyl, propynyl, - (CH)₂)_m-C(＝O)-NR^3aR^3b、-(CH₂)_m-NR^3aR^3b、-(CH₂)_mNR^3aC(＝O)-R^3b、-(CH₂)_m-cyclopropyl, - (CH)₂)_m-cyclobutyl, - (CH)₂)_m-cyclopentyl, - (CH)₂)_m-cyclohexyl, - (CH)₂)_m-azetidinyl, - (CH)₂)_m-oxetanyl, - (CH)₂)_m-pyrrolidinyl, - (CH)₂)_m-tetrahydrofuranyl, - (CH)₂)_m-piperidinyl, - (CH)₂)_m-tetrahydropyranyl, - (CH)₂)_m-morpholinyl, - (CH)₂)_m-piperazinyl or- (CH)₂)_m-azepinyl, said-CH₂-, methyl, ethyl, isopropyl, propyl, butyl, methoxy, ethoxy, propoxy, cyclopropylOptionally further substituted by 0 to 4 substituents selected from H, F, ═ O, OH, cyano, CF, and optionally substituted by one or more substituents selected from the group consisting of aryl, heteroaryl, alkynyl, cyclopropyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl, and azepinyl₃、COOH、NH₂、-NHCH₃、-N(CH₃)₂Methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, -CH₂OH、-CH₂CH₂OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl, piperazinyl or azepinyl.

5. The compound of claim 4, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

L₁Selected from-O-, -NH-, -OCH₂-、-OC(CH₃)₂-、-CH₂O-or-NHCH₂-；

Z is selected from a bond,

R^bEach independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally further substituted by 0 to 4 groups selected from H, F, CF₃OH, cyano, NH₂、-N(CH₃)₂、-N(CH₂CH₃)₂Methyl, ethyl, isopropyl, propyl, cyclopropyl or cyclobutyl;

X₁is selected from N or CH;

R⁴selected from H, F, OH, CF₃、NH₂、-CN、-CH₂CN、-CH₂CH₂CN、-NHCH₃、-N(CH₃)₂、-C(O)-NH₂、-CH₂C(O)-NH₂、-CH₂CH₂C(O)-NH₂、-C(O)NHCH₃、-C(O)N(CH₃)₂、-NHC(O)CH₃Methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, -CH₂-cyclopropyl, cyclobutyl, -CH₂-cyclobutyl, cyclopentyl, -CH₂-cyclopentyl, cyclohexyl, -CH₂-cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, morpholinyl or piperazinyl.

6. The compound of claim 5, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein

is selected from

Is selected from

Right side and L₁Direct connection;

is selected from

R¹Selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

R²selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

R³selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy;

R⁴selected from H, F, Cl, cyano, CF₃Methyl, ethyl or methoxy.

7. The compound of claim 1, or a stereoisomer, deutero-compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:

8. a pharmaceutical composition comprising a compound of any one of claims 1-7, or a stereoisomer, deuteride, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier.

9. Use of a compound according to any one of claims 1-7, or a stereoisomer, a deuterode, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with JAK3 kinase activity or expression.

10. The use according to claim 9, wherein the disease is selected from immune system related diseases.