2-substituted azole cell necrosis pathway inhibitor as well as preparation method and application thereof

Abstract

The invention provides a 2-substituted azole cell necrosis pathway inhibitor as well as a preparation method and application thereof. Specifically, the invention provides a compound with a structure as shown in a formula I, and each group is defined in the specification. The compound disclosed by the invention has very good inhibitory activity on RIPK3 and a cell necrosis pathway mediated by the RIPK3 at an enzyme level and a cell level. Therefore, the compound provided by the invention has a wide application prospect in the field of treatment or prevention of programmed cell necrosis and inflammation related diseases.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of 2-substituted azole cell necrosis pathway inhibitors, their preparation methods, and uses. Background Technology

[0002] Programmed cell death (PCD) is a regulated form of cell death discovered in recent years, closely related to the development of various diseases such as inflammation, infection, and neurodegenerative diseases. Unlike apoptosis, PCD cells exhibit necrosis-like characteristics such as cell swelling, cell membrane rupture, and release of cell contents. When necrosis stimuli such as tumor necrosis factor (TNF) are present, receptor-interacting protein kinase 1 (RIPK1) recruits and activates RIPK3 to form necrosomes, which further phosphorylate and activate downstream effector proteins, such as mixed lineage kinase domain-like proteins (MLKL), disrupting cell membrane integrity and executing the necrosis process. (Nat.Rev.Neurosci.,2019,20(1):19–33;Immunol.Rev.,2017,277(1):102-112)

[0003] Receptor-interacting protein kinase 3 (RIPK3) is a key regulatory protein in the programmed cell death pathway. Knockout or inactivation mutations of RIPK3 can effectively block the cell death pathway. In various disease models, including acute pancreatitis, acute liver injury, sepsis, ischemia-reperfusion injury, and heat shock, RIPK3 inhibition or knockout has shown significant alleviating effects. (Cell, 2009, 6: 1100-1111; Science, 2014, 343(6177): 1357-1360; Hepatology, 2013, 58(6): 2099-108; Immunity, 2011, 35(6): 908-18; Oxid.Med.Cell.Longevity, 2019, 2019: 2301903; Science, 2022, 376(6593): 609-615). Although RIPK3 is a potential therapeutic target for many diseases, the development of RIPK3 inhibitors has lagged behind, and no inhibitors have yet entered the clinical research stage. This is partly because some existing RIPK3 inhibitors have target-related pro-apoptotic side effects, promoting cell death at high concentrations (Mol.Cell,2014,56(4):481-495; Front.CellDev.Biol.,2020,8:606119), which reduces the safety and effectiveness of inhibitor application.

[0004] Therefore, developing novel RIPK3 inhibitors with high affinity, high selectivity, and the ability to avoid the side effects of pro-apoptosis is expected to overcome the limitations of existing inhibitors and provide a highly effective and low-toxicity treatment for necrosis and inflammatory diseases, with broad application prospects. Summary of the Invention

[0005] One object of the present invention is to provide a 2-substituted azole compound as shown in formula (I), its stereoisomers, tautomers, prodrugs or pharmaceutically acceptable salts thereof.

[0006] Another object of the present invention is to provide the use of a 2-substituted azole compound of formula (I), or a pharmaceutical composition comprising thereof, in the preparation of a RIPK3 inhibitor.

[0007] Another object of the present invention is to provide the use of a 2-substituted azole compound of formula (I), or a pharmaceutical composition comprising thereof, in the preparation of a medicament for the prevention, treatment or adjunctive treatment of diseases associated with abnormal RIPK3 activity or expression levels.

[0008] In a first aspect of the invention, a compound of formula (I) is provided, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotope derivative, or combination thereof;

[0009]

[0010] In the formula,

[0011] X1 is selected from the following group: S, O, CH, N, or NH;

[0012] X2 is selected from the following group: C, CH, or N;

[0013] U1, U2, and U3 are each independently selected from the following group: N or CH; wherein at most two of U1, U2, and U3 are N;

[0014] Ring B is selected from five-membered aromatic rings;

[0015] R1 is selected from the following group: halogen, deuterium, cyano, hydroxyl, -NRaRb, nitro, amino, straight-chain or branched C1-C. 10 Alkyl, straight-chain or branched C1-C 10 Alkyl group, straight-chain or branched C1-C 10 Alkylthio, C3-C 10 cycloalkyl, C3-C 10 Oxycyclic alkyl, C3-C 10 Thiocyclic alkyl, straight-chain or branched C2-C 10 Alkenyl, straight-chain or branched C2-C 10 alkynyl group, C3-C 10 Cycloalkenyl, -C(=O)-(C1-C 10 Alkyl), -S(O)2-(C1-C 10 Alkyl), -NH-C(O)-(C1-C 10 Alkyl), -C(O)-NH-(C1-C 10 Alkyl), C6-C 10 Aryl, 5-14 membered heteroaryl, 4-14 membered heterocyclic; wherein Ra and Rb are each independently selected from the following group: C1-C 10 Alkyl, C3-C 10 cycloalkyl, C6-C 10Aryl, 5-11 membered heteroaryl, or 4-11 membered heterocyclic group, or Ra and Rb and their commonly attached N atom form a 4-11 membered heterocycle or 5-11 membered heterocyclic ring containing 1-3 heteroatoms each independently selected from N, O, and S; said alkyl, alkoxy, alkylthio, cycloalkyl, oxocycloalkyl, thiocycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl, and heterocyclic group are optionally substituted by one or more groups selected from the group consisting of: halogen, deuterium, oxo (=O). , hydroxy, cyano, nitro, amino, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, benzyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic, -(halogenated or non-halogenated C1-C6 alkylene)-C3-C6 cycloalkyl, -(halogenated or non-halogenated C1-C6 alkylene)-phenyl, -(halogenated or non-halogenated C1-C6 alkylene)-5 -6-membered heteroaryl, -(halogenated or non-halogenated C1-C6 alkylene)-4-7-membered heterocyclic, -O-C3-C6 cycloalkyl, -O-phenyl, -O-5-6-membered heteroaryl, -O-(4-7-membered heterocyclic), -S-(C3-C6 cycloalkyl), -S-phenyl, -S-(5-6-membered heteroaryl), -S-(4-7-membered heterocyclic), -NH-(C3-C6 cycloalkyl), -NH-phenyl, -NH-(5-6-membered heteroaryl), -NH- (4-7-membered heterocyclic group), -NH-C(O)-(C3-C6 cycloalkyl), -C(O)-NH-(C3-C6 cycloalkyl), -(halogenated or non-halogenated C1-C6 alkylene)-O-C3-C6 cycloalkyl, -(halogenated or non-halogenated C1-C6 alkylene)-O-phenyl, -(halogenated or non-halogenated C1-C6 alkylene)-O-5-6-membered heteroaryl, -(halogenated or non-halogenated C1-C6 alkylene)-O-4-7-membered heterocyclic group;

[0016] Ring A is a 6-membered aromatic ring or a 6-membered heteroaromatic ring, and at any substituted site, ring A is substituted by 1-3 identical or different R2s.

[0017] R2 is selected from the following group: hydrogen, deuterium, halogen, oxo (=O), cyano, nitro, hydroxyl, amino, straight-chain or branched C1-C. 10 Alkyl, straight-chain or branched C1-C 10 Alkyl group, straight-chain or branched C2-C 10 Alkenyl, straight-chain or branched C2-C 10The alkyl, C3-C8 cycloalkyl, -(C1-C6 alkylene)-C3-C8 cycloalkyl, phenyl, benzyl, 4-9 membered heterocyclic or 5-9 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, phenyl, benzyl, heterocyclic and heteroaryl groups are optionally substituted by one or more (e.g. 2, 3, 4 or 5) groups selected from the group consisting of: halogen, cyano, hydroxy, nitro, oxo (=O), amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, benzyl, C3-C6 cycloalkyl, phenyl, 4-6 membered heterocyclic and 5-6 membered heteroaryl;

[0018] L represents a bond, -NH-, -O-, -N(R) x )-、-(CH2) m -、-(CHR x ) m -、-(C(R x )2) m -; m is 1, 2, 3, 4, 5, or 6;

[0019] Each R x Each is independently selected from the group consisting of: H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -S(O)2-(C1-C4 alkyl) or -C(=O)-(C1-C4 alkyl), wherein the alkyl and cycloalkyl groups are optionally substituted by one or more groups selected from the group consisting of: D, halogen, cyano, hydroxyl, oxo(=O), amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl;

[0020] Z has the structure shown in equation (II):

[0021]

[0022] in,

[0023] V1, V2, V3, V4 and V5 are each independently N, CH or C, of ​​which at most 3 of V1, V2, V3, V4 and V5 are N;

[0024] Y is either CH or N;

[0025] n is 0 or 1;

[0026] R9 is selected from the following group of substituted or unsubstituted groups: none, hydrogen, deuterium, halogen, nitro, amino, amide, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, 5-6 membered heteroaryl, phenyl, benzyl, wherein substitution refers to one or more hydrogen atoms on the group being replaced by halogen, deuterium, C1-C6 alkyl and C1-C6 alkoxy;

[0027] R3, R4, R5, and R6 are each independently selected from the following group: none, hydrogen, deuterium, hydroxyl, nitro, mercapto, halogen, amino, straight-chain or branched C1-C. 10 Alkyl, straight-chain or branched C1-C 10 Heteroalkyl, straight-chain or branched C1-C 10 Alkyl group, straight-chain or branched C2-C 10 Alkenyl, straight-chain or branched C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 Aryl, 4-11 membered heterocyclic, 5-11 membered heteroaryl, -S(O)2R7, -SOR7, -C(=O)OR7, -C(=O)R7, -C(=O)NHR7, -C(=O)NR7R8, -NHC(=O)R7, -NHC(=O)NHR7, -S(O)2NHR7, -S(O)2NR7R8, -NHS(O)2-R7, -(CH2) m R7, -CHR7R8, -NHR7, -NH-(C1-C6 alkylene)-R7, -NR7R8, -OR7, -O-(C1-C6 alkylene)-R7, -SR7, -O-(C1-C6 alkylene)-H2PO4 or R7 and R8 are each independently selected from the following group: hydrogen, straight-chain or branched C1-C 10 Alkyl, straight-chain or branched C1-C 10 Heteroalkyl, straight-chain or branched C1-C 10 Alkyl, straight-chain or branched C1-C 10 Hydroxyalkyl, C3-C 11 Cycloalkyl, 4-11 membered heterocyclic, C6-C 10 Aryl, 5-11 heteroaryl, -(C1-C6 alkylene)-C3-C 11 Cycloalkyl, -(C1-C6 alkylene)-4-11 heterocyclic, -(C1-C6 alkylene)-C6-C 10 aryl, -(C1-C6 alkylene)-5-11 heteroaryl, or, R7 and R8 and the atoms bonded to them together, form: C6-C 10 Aromatic rings, C3-C 11Carbon rings, 4-11 membered heterocycles, or 5-11 membered heteroaromatic rings;

[0028] or,

[0029] R4 and R7, R4 and R8, R3 and R6, R3 and R4, or R4 and R5, together with the atoms connected to them, form a ring structure selected from the following group: C6-C 10 Aromatic rings, saturated or unsaturated C3-C 11 Carbon rings, 4-11 membered heterocycles, or 5-11 membered heteroaromatic rings;

[0030] Wherein, the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, heterocyclic, heteroaryl, aromatic ring, and carbocyclic groups are optionally substituted by one or more groups selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, nitro, oxo (=O), amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, phenyl, 4-7 membered heterocyclic, 5-6 membered heteroaryl, -(halogenated or non-halogenated C1- -C6 alkylene)-C3-C7 cycloalkyl, -(halogenated or non-halogenated C1-C6 alkylene)-phenyl, -(halogenated or non-halogenated C1-C6 alkylene)-5-6 heteroaryl, -(halogenated or non-halogenated C1-C6 alkylene)-4-7 heterocyclic group; or any two substituents at the same or different sites on the heterocycle, heteroaromatic ring, aromatic ring and carbon ring and the atoms they are connected to form a spirocyclic, bridged, or fused ring structure.

[0031] In another preferred embodiment, at least one of X1 and X2 is C or CH.

[0032] In another preferred embodiment, at most two of V1, V2, V3, V4 and V5 are N.

[0033] In another preferred embodiment, the heteroaryl and heterocyclic groups refer to monocyclic or polycyclic (e.g., bicyclic and tricyclic) heterocyclic groups and heteroaryl groups containing 1-3 heteroatoms each independently selected from N, O and S.

[0034] In another preferred embodiment, the heteroaryl and heterocyclic groups can be monocyclic, or they can be polycyclic, spirocyclic, or bridged ring structures.

[0035] In another preferred embodiment, the compound has the structures shown in formulas IA, IB, IC, and ID:

[0036]

[0037] In the formula,

[0038] X1, X2, U1, U2, U3, R1, R2, Z, and R xAs described in the first aspect of the invention. In another preferred embodiment, ring A is a benzene ring.

[0039] In another preferred embodiment, Z has the following structure:

[0040]

[0041] in,

[0042] V2 and V4 are each independently N, C or CH;

[0043] Y is either CH or N;

[0044] R9, R3, R4, R5 and R6 are as described in the first aspect of the present invention.

[0045] In another preferred example, when n is 0, Z has the following structure:

[0046]

[0047]

[0048] When n is 1, Z has the following structure:

[0049]

[0050]

[0051] In the formula, R3, R4, R5, R6 and R9 are as described in the first aspect of the present invention.

[0052] In another preferred embodiment, Selected from the following group:

[0053] In another preferred embodiment, the compound has the structure shown in Formula I-A1:

[0054]

[0055] In the formula,

[0056] X1 is selected from S, O, CH, and N;

[0057] X2 is selected from C and N;

[0058] Y is selected from N or CH;

[0059] Cycle B is selected from 5-membered heteroaryl groups; and

[0060] R x R1, R2, R3, R4 and R9 are as described in the first aspect of the present invention.

[0061] In another preferred embodiment, R2 is selected from the group consisting of: hydrogen, deuterium, halogen, oxo (=O), cyano, nitro, hydroxyl, amino, amino, C1-C5 alkyl, C1-C5 alkoxy, C2-C5 alkenyl, C2-C5 alkynyl, C3-C6 cycloalkyl, -(C1-C4 alkylene)-C3-C6 cycloalkyl, phenyl, benzyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl The alkynyl, cycloalkyl, phenyl, benzyl, heterocyclic and heteroaryl groups are optionally substituted by one or more groups selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, nitro, oxo (=O), amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, benzyl, C3-C6 cycloalkyl, phenyl, 4-6 membered heterocyclic and 5-6 membered heteroaryl.

[0062] In another preferred embodiment, R2 is hydrogen, deuterium, halogen, or C1-C4 alkyl.

[0063] In another preferred embodiment, R9 is selected from the following group of substituted or unsubstituted groups: neutrophils, hydrogen, deuterium, halogen, nitro, amino, amide, cyano, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, 5-6 membered heteroaryl, phenyl, benzyl, wherein the substitution refers to one or more hydrogen atoms on the group being replaced by halogen, deuterium, C1-C4 alkyl, and C1-C4 alkoxy.

[0064] In another preferred embodiment, R x Selected from the following group: hydrogen, deuterium, C1-C4 alkyl.

[0065] In another preferred embodiment, R3 is selected from the group consisting of: none, hydrogen, deuterium, hydroxyl, nitro, mercapto, halogen, amino, C1-C6 alkyl, C1-C6 haloalkyl, -S(O)2R7, -SOR7, -C(=O)OR7, -C(=O)R7, -C(=O)NHR7, -C(=O)NR7R8, -NHC(=O)R7, -NHC(=O)NHR7, -S(O)2NHR7, -NHS(O)2-R7, -(CH2). m R7, -CHR7R8, -NHR7, -NR7R8, -OR7, -SR7;

[0066] R7 and R8 are each independently selected from the following group: hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, -(C1-C4 alkylene)-C3-C6 cycloalkyl, -(C1-C4 alkylene)-4-7 membered heterocyclic group;

[0067] The alkyl, alkylene, heteroalkyl, cycloalkyl, and heterocyclic groups are optionally substituted by one or more groups selected from the group consisting of: hydrogen, deuterium, halogen, amino, oxo (=O), hydroxyl, cyano, C l -C4 alkyl, C l -C4 haloalkyl, C l -C4 alkoxy group, C l -C4 haloalkoxy, C3-C5 cycloalkyl, -NH (C1-C3 alkyl), N (C1-C3 alkyl)2;

[0068] Alternatively, R7 or R8 can form 4-11 membered heterocycles, 5-11 membered heteroaromatic rings, benzene rings, or C3-C rings with R4 and the atoms they are connected to. 10 Carbon rings;

[0069] Alternatively, R3 and R4, along with their commonly bonded atoms, form: C6-C 10 Aromatic rings, C3-C 11 Carbon rings, 5-11 membered heterocycles, or 5-11 membered heteroaromatic rings;

[0070] The heterocycle, heteroaromatic ring, aromatic ring, and carbide ring are optionally substituted by one or more groups selected from the group consisting of: hydrogen, deuterium, halogen, amino, oxo (=O), hydroxyl, cyano, C. l -C3 alkyl, halo-C l -C3 alkyl, C l -C3 alkoxy, C3-C6 cycloalkyl, -NH(C1-C3 alkyl), N(C1-C3 alkyl)2, C2-C4 alkenyl, C2-C4 alkynyl, or any two substituents at the same or different sites on the ring and the atoms they are connected to form a spirocyclic, bridged, or fused ring structure.

[0071] In another preferred embodiment, R3 is selected from the group consisting of: none, H, -S(O)2R7 or -S(O)2NHR7;

[0072] R7 is selected from the following group: C1-C4 alkyl, C3-C5 cycloalkyl, 4-6 membered heterocyclic groups;

[0073] The alkyl, cycloalkyl, and heterocyclic groups are optionally substituted with one or more groups selected from the group consisting of: hydrogen, deuterium, halogen, amino, oxo (=O), hydroxyl, cyano, C l -C4 alkyl, halo-C l -C4 alkyl, C l -C4 alkoxy, C3-C5 cycloalkyl, -NH (C1-C3 alkyl), N (C1-C3 alkyl)2;

[0074] Alternatively, R7 and R4, along with the atoms bonded to them, form: C6-C 10 Aromatic rings, saturated or unsaturated C3-C11 Carbon rings, 5-9 membered heterocycles, or 5-9 membered heteroaromatic rings;

[0075] Alternatively, R3 and R4, along with their commonly bonded atoms, form: C6-C 10 Aromatic rings, C3-C 11 Carbon rings, 5-9 membered heterocycles, or 5-9 membered heteroaromatic rings;

[0076] The heterocycle, heteroaromatic ring, aromatic ring, and carbide ring are optionally substituted by one or more groups selected from the group consisting of: hydrogen, deuterium, halogen, amino, oxo (=O), hydroxyl, cyano, C. l -C4 alkyl, halo-C l -C4 alkyl, C l -C4 alkoxy group, C l -C4 haloalkoxy, C3-C5 cycloalkyl;

[0077] When R7 and R4, or R3 and R4 form a ring, the resulting heterocyclic and heteroaromatic rings can be monocyclic, bridged, spirocyclic, or fused.

[0078] In another preferred embodiment, R4 is selected from the group consisting of: none, H, deuterium, halogen, cyano, mercapto, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl, 5-6 membered heteroaryl, -O-(C1-C6 alkylene)-H2PO4. -C(O)NHR7, -S(O)2R7, -SO2NHR7, -OR7, -O-(C1-C6 alkylene)-R7, -SR7, -NHR7, -NH-(C1-C6 alkylene)-R7, -NHC(O)R7, -NR7R8 or -(C=O)R7-; wherein R7 and R8 are each independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-7 membered heterocyclic, phenyl or 5-6 membered heteroaryl; or, R7 and R8 together with the ring atom to which they are attached form a 4-7 membered heterocycle or a 5-6 membered heteroaryl ring;

[0079] Wherein, the alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, heterocyclic, and heteroaromatic groups are optionally substituted by one or more groups selected from the group consisting of: halogen, deuterium, halogen, oxo (=O), cyano, mercapto, nitro, hydroxyl, amino, C l -C4 alkyl, C l -C4 alkoxy, C3-C4 cycloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, C2-C4 alkenyl, C2-C4 alkynyl.

[0080] In another preferred embodiment, R4 is selected from the group consisting of: none, H, deuterium, halogen, cyano, mercapto, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 alkoxy, hydroxy-substituted C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, -O-(C1-C6 alkylene)-H2PO4. -C(O)NHR7, -SO2NHR7;

[0081] R7 is selected from the following group: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group.

[0082] In another preferred embodiment, when R1 is an alkoxy group, R4 is not a chlorine atom.

[0083] In another preferred embodiment, R5 and R6 are each independently selected from the group consisting of: none, H, deuterium, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, phenyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic or 5-6 membered heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, phenyl, cycloalkyl, heterocyclic and heteroaryl is optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, hydroxyl, nitro, oxo (=O), amino, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, phenyl, 4-6 membered heterocyclic and 5-6 membered heteroaryl.

[0084] In another preferred embodiment, R5 and R6 are each independently selected from the group consisting of: none, H, halogen, cyano, nitro, hydroxy, amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, halo-C1-C4 alkyl, halo-C1-C4 alkoxy, or C 3- C6 cycloalkyl.

[0085] In another preferred example, Z is selected from the following group:

[0086]

[0087] Preferably, Z is selected from the following group:

[0088]

[0089] In another preferred embodiment, R1 is selected from the group consisting of: halogen, deuterium, cyano, hydroxyl, -NR. a R bNitro, amino, straight-chain or branched C1-C6 alkyl, straight-chain or branched C1-C6 alkoxy, straight-chain or branched C1-C6 alkylthio, C3-C7 cycloalkyl, C3-C7 oxecycloalkyl, C3-C7 thionecycloalkyl, straight-chain or branched C2-C6 alkenyl, straight-chain or branched C2-C6 alkynyl, C3-C6 cycloalkenyl, -C(=O)-(C1-C6 alkyl), -S(O)2-(C1-C6 alkyl), -NH-C(O)-(C1-C6 alkyl), -C(O)-NH-(C1-C6 alkyl), C6-C 10 Aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclic; wherein Ra and Rb are each independently selected from the following group: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group, or Ra and Rb and their commonly attached N atom form a 4-9 membered heterocycle or 5-6 membered heterocyclic ring containing 1-3 heteroatoms each independently selected from N, O and S;

[0090] Wherein, the alkyl, alkoxy, alkylthio, cycloalkyl, oxetyl, thioheteroalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl, and heterocyclic groups are optionally substituted by one or more groups selected from the group consisting of: halogen, deuterium, oxo (=O), hydroxyl, cyano, nitro, amino, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C1-C6 hydroxyalkyl. C3-C6 cycloalkyl, benzyl, phenyl, 5-6-membered heteroaryl, 4-7-membered heterocyclic, -(halogenated or non-halogenated C1-C4 alkylene)-C3-C6 cycloalkyl, -(halogenated or non-halogenated C1-C4 alkylene)-phenyl, -(halogenated or non-halogenated C1-C4 alkylene)-5-6-membered heteroaryl, -(halogenated or non-halogenated C1-C4 alkylene)-4-7-membered heterocyclic, -O-C3 -C6 cycloalkyl, -O-phenyl, -O-5-6-membered heteroaryl, -O-(4-7-membered heterocyclic), -S-(C3-C6 cycloalkyl), -S-phenyl, -S-(5-6-membered heteroaryl), -S-(4-7-membered heterocyclic), -NH-(C3-C6 cycloalkyl), -NH-phenyl, -NH-(5-6-membered heteroaryl), -NH-(4-7-membered heterocyclic), -NH-C(O)- (C3-C6 cycloalkyl), -C(O)-NH-(C3-C6 cycloalkyl), -(halogenated or non-halogenated C1-C4 alkylene)-O-C3-C6 cycloalkyl, -(halogenated or non-halogenated C1-C4 alkylene)-O-phenyl, -(halogenated or non-halogenated C1-C4 alkylene)-O-5-6 heteroaryl, -(halogenated or non-halogenated C1-C4 alkylene)-O-4-7 heterocyclic;

[0091] Preferably, R1 is selected from the group consisting of: halogen, deuterium, cyano, -NRaRb, hydroxyl, nitro, amino, straight-chain or branched C1-C6 alkyl, straight-chain or branched C1-C6 alkoxy, C3-C6 cycloalkyl, straight-chain or branched C2-C6 alkenyl, straight-chain or branched C2-C6 alkynyl, -C(=O)-(C1-C6 alkyl), 4-7 membered heterocyclic or 5-6 membered heteroaryl; wherein Ra and Rb are each independently selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-7 membered heterocyclic, or Ra and Rb and the N atom they are connected to together form a 4-7 membered heterocycle or a 5-6 membered heteroaryl ring containing 1-3 heteroatoms each independently selected from N, O and S;

[0092] Wherein, the alkyl, alkoxy, alkylthio, cycloalkyl, oxocycloalkyl, thiocycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl, and heterocyclic groups are optionally substituted by one or more groups selected from the group consisting of: halogen, oxo (=O), hydroxyl, cyano, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 hydroxyalkyl, or C3-C6 cycloalkyl.

[0093] In another preferred embodiment, R1 is selected from the group consisting of: cyclopropyl, trifluoromethyl, -C(O)CH3, isopropyl, hydroxyethyl, methoxy, chlorine, ethoxy, cyclobutyl, hydroxybutyl, tert-butyl, ethynyl, hydroxypropyl, sec-butyl, cyano, cyclopentyl, methyl-substituted cyclopropyl, dimethyl-substituted cyclopropyl, butynyl, cyclohexyl,

[0094] In another preferred embodiment, R1 is selected from the following structures:

[0095] -CN、 -Cl, -OMe, -OEt, -CF3 Preferably, R1 is selected from the following structure: -OMe、 More preferably, R1 is selected from the following structure:

[0096] In another preferred embodiment, the compound is selected from the group consisting of:

[0097]

[0098]

[0099]

[0100] In another preferred embodiment, the compound is selected from the group consisting of:

[0101]

[0102] In another preferred embodiment, the compound is selected from the group consisting of:

[0103]

[0104] In a second aspect of the invention, a pharmaceutical composition is provided comprising one or more of the compounds described in the first aspect of the invention as active ingredients, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, prodrugs, isotope derivatives, or combinations thereof, and a pharmaceutically acceptable carrier.

[0105] In another preferred embodiment, the weight ratio of the active ingredient to a pharmaceutically acceptable carrier in the pharmaceutical composition is 0.001-100; preferably 0.001-10.

[0106] In a third aspect of the invention, the use of the compound described in the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotope derivative, or combination thereof, or the pharmaceutical composition described in the second aspect of the invention, in the preparation of a medicament for treating and / or preventing programmed cell necrosis and inflammation-related diseases is provided.

[0107] In another preferred embodiment, the programmed cell necrosis and inflammation-related diseases are diseases caused by abnormal RIPK3 activity levels and / or expression levels.

[0108] In another preferred embodiment, the programmed cell necrosis and inflammation-related diseases refer to inflammatory, infectious, ischemic, autoimmune, allergic, or degenerative diseases or tissue damage caused by abnormal RIPK3 activity and / or expression levels.

[0109] In another preferred embodiment, the diseases caused by abnormal RIPK3 activity and / or expression levels are selected from the group consisting of: neurological diseases, ischemia-reperfusion injury, autoimmune diseases, acute liver injury, acute lung injury, acute kidney injury, hyperuricemia, gout, skin inflammation, chronic liver disease, atherosclerosis, Gaucher disease, pain, inflammation, retinal diseases, tumors, immunosenescence, viral infections, heatstroke, aging, platelet thrombosis, and graft-versus-host disease.

[0110] In another preferred embodiment, the neurological disease is selected from traumatic brain injury, ischemic brain injury, spinal cord injury, Huntington's disease, amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS).

[0111] In another preferred embodiment, the skin inflammation is psoriasis.

[0112] In another preferred embodiment, the pain is neuropathic pain.

[0113] In another preferred embodiment, the autoimmune disease is selected from systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, type I diabetes, autoimmune hemolytic anemia, and autoimmune thyroiditis.

[0114] In another preferred embodiment, the chronic liver disease is selected from fatty liver, alcoholic liver disease, and non-alcoholic liver disease.

[0115] In another preferred embodiment, the inflammation is selected from: systemic inflammatory response syndrome (SIRS), acute pancreatitis, ulcerative colitis, hepatitis, Crohn's disease, sepsis, mycoplasma pneumonia, sepsis, ankylosing spondylitis, and osteoarthritis.

[0116] In another preferred embodiment, the viral infection is SARS-CoV-2 infection, HSV infection, or influenza virus infection.

[0117] In another preferred embodiment, the retinal disease is selected from: diabetic retinopathy, glaucoma, age-related macular degeneration, and retinal detachment.

[0118] In another preferred embodiment, the tumor is selected from melanoma, glioma, colon cancer, glioma, lymphoma, T-cell leukemia, abdominal aortic aneurysm, and multiple myeloma.

[0119] In a fourth aspect of the invention, there is provided the use of the compound described in the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotope derivative, or combination thereof, or the pharmaceutical composition described in the second aspect of the invention, in the preparation of a RIPK3 inhibitor.

[0120] In another aspect of the invention, a method for inhibiting RIPK3 is provided, comprising contacting a therapeutically effective amount of a compound of the first aspect of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotope derivative, or combination thereof, or a pharmaceutical composition of the second aspect of the invention, with RIPK3 to inhibit RIPK3.

[0121] Another aspect of the present invention provides a method for preventing and / or treating procedural cell necrosis and inflammation-related diseases, comprising contacting a subject in need with a therapeutically effective amount of a compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotope derivative, or combination thereof, or a pharmaceutical composition of the second aspect of the present invention.

[0122] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0123] Figure 1 The results show the cleavage effects of compounds LK-16 and LK-18 of the present invention on caspase-3 and caspase-8 compared with the control compound GSK872.

[0124] Figure 2 The results show a comparison of the cleavage effects of compound LK-25 of the present invention and control compound DB-2 on caspase-3 and caspase-8.

[0125] Figure 3 The results show the comparison of the cleavage of caspase-3 and caspase-8 by compounds LK-48 and LK-49 of the present invention and control compound DB-3.

[0126] Figure 4 The effects of the compounds LK-28 and LK-34 of the present invention on inhibiting the ZBP-1-mediated cell necrosis pathway in mouse-ZBP1 stable transgenic MEF cells were demonstrated. Detailed Implementation

[0127] Through extensive and in-depth research, the inventors have, for the first time, provided a novel 2-substituted azole compound for the preparation of drugs to treat diseases associated with programmed cell necrosis related to RIPK3 abnormalities. The compound of this invention exhibits excellent inhibitory effects on RIPK3 while avoiding the apoptotic side effects caused by conventional RIPK3 inhibitors, significantly expanding the therapeutic window of the inhibitor and thus possessing broad application prospects. Based on this, the inventors completed this invention.

[0128] the term

[0129] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0130] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated components without excluding other components.

[0131] In this invention, the term "halogen" refers to F, Cl, Br, or I.

[0132] In this invention, "C" 1- C 10 "Alkyl" refers to a straight-chain or branched alkyl group comprising 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pterpentyl, or similar groups.

[0133] In this invention, "C" 1- C 10 "Heteroalkyl" refers to C 1- C 10 A group obtained by replacing the carbon atom in an alkyl group with 1-3 heteroatoms, each independently selected from N, O, and S, for example... Or similar groups.

[0134] As used herein, the term "alkylene" (also referred to herein as "alkylene chain") refers especially to those "alkylenes" located in the middle or not at the end of a molecule or group (such as "alkylenes" in Y, and L4) and as substituents (such as C3-C). 10 The "alkylene" in cycloalkyl-(C1-C6 alkylene)-O- refers to a linking group formed by removing a hydrogen atom from an alkyl or substituted alkyl group, used to connect two different atoms, or a group formed by removing a hydrogen atom from the atom containing the unsaturated bond of an alkyl or substituted alkyl group, such as methylene or methylene (-CH2-), ethylene, etc. Propionide Isopropylidene Butylene (e.g.) ), pentylene (e.g.) ), hexyl (such as) ), subheptagen (such as ), etc. Furthermore, the term also includes alkylene groups (such as C1-C...). 18 An alkylene group is formed by a methylene group (e.g., C3-C4) and a cycloalkyl group (e.g., C3-C4). 20 Replaced by (cycloalkylene), for example, "C1-C 18 Alkylene C3-C 20 "Cycloalkylene" or "C3-C" 20 Cycloalkyl C1-C 18"alkylene". In this invention, alkylene also includes substituted alkylene, and the substituents can be halogenated (-CHF- or -CF2-), hydroxyl, cyano, nitro, etc.

[0135] In this invention, the term "C" 2- C 10 "Alkenyl" refers to a straight-chain or branched alkenyl group with 2-10 carbon atoms and containing a double bond, including, without limitation, vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl.

[0136] In this invention, the term "C" 2- C 10 "Alynyl" refers to a straight-chain or branched alkynyl group with 2-10 carbon atoms and containing a triple bond, including, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentylyl, and hexynyl.

[0137] In this invention, the term "carbon ring" refers to a saturated or unsaturated cyclic structure having 3 to 11 ring atoms, and all ring atoms being carbon atoms, including cycloalkyl, cycloalkenyl, and cycloalkynyl groups, and can be monocyclic, polycyclic fused, polycyclic spirocyclic, and polycyclic bridged ring structures.

[0138] In this invention, the term "cycloalkyl" refers to a fully saturated or partially unsaturated (preferably fully saturated) cyclic hydrocarbon compound group comprising 1-4 rings, each ring containing 3-8 carbon atoms. The term "C3-C..." 20 "" refers to a cycloalkyl group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The cycloalkyl group is preferably C3-C. 14 Cycloalkyl, more preferably C3-C 10 Cycloalkyl groups, more preferably C3-C6 monocyclic cycloalkyl groups, C7-C 10 Bicyclic or tricyclic cycloalkyl. "Substituted cycloalkyl" refers to a cycloalkyl group in which one or more positions are substituted, particularly 1-4 substituents, which can be substituted at any position. In this invention, "cycloalkyl" includes substituted cycloalkyl groups, and typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl containing Cl3), nitrile, nitro, oxygen (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aromatic, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR eNR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e R appears here a It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, ynyl, heterocyclic, aryl, or heteroaryl, R b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c It can form heterocycles together with N atoms; R e The group can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, or heteroaryl. The typical substituents mentioned above can be optionally substituted. Typical substitutions also include spirocyclic, pyrimidine-fused, or fused-ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocyclic heterocyclic (excluding heteroaryl), pyrimidine-fused cycloalkyl, pyrimidine-fused cycloalkenyl, pyrimidine-fused cyclocyclic heterocyclic (excluding heteroaryl), fused-ring alkyl, fused-ring alkenyl, fused-ring heterocyclic, or fused-ring aromatic cycloalkyl, wherein the cycloalkyl, cycloalkenyl, heterocyclic, and heteroaryl groups can be optionally substituted. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl.

[0139] In this invention, the term "C"1- C 10 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1-10 carbon atoms, and includes, without limitation, methoxy, ethoxy, propoxy, isopropoxy, and butoxy. Preferably, it is C10. 1-4 Alkyl group.

[0140] In this invention, the term "heterocyclic group or heterocycle" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, 3-7 membered monocyclic, 4-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic or polycyclic systems), wherein at least one heteroatom is present in a ring with at least one carbon atom. The term "4-20 membered heterocyclic group" refers to a heterocyclic group containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. "Heterocyclic group" has the same meaning as "saturated or unsaturated heterocyclic group". The "heterocyclic group" is preferably a 4-14 membered heterocyclic group (including but not limited to 4-6 membered monocyclic, 7-10 membered bicyclic, or 8-14 membered tricyclic or polycyclic systems), more preferably a 4-12 membered heterocyclic group, even more preferably a 4-10 membered heterocyclic group, such as a 4-6 membered monocyclic heterocyclic group, a 7-11 membered bicyclic or tricyclic heterocyclic group, even more preferably a 4-8 membered heterocyclic group, and even more preferably a 4-6 membered heterocyclic group. Each heterocyclic group contains a heterocycle with 1, 2, 3, or 4 heteroatoms, each of which is independently selected from nitrogen, oxygen, or sulfur atoms, wherein the nitrogen or sulfur atom may be oxidized or quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of the ring or ring system molecule, preferably to an N or C atom of the ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, nitrogen-containing heterocyclic butyl, pyrrolyl, oxoheterocyclic butyl, pyrazolinyl, imidazolinyl, imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperylyl, hexahydroacoxaneyl, 4-piperidinoneyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxaneyl, and tetrahydro-1,1-dioxothiophene, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups; wherein the spirocyclic, fused-ring, and bridged-ring heterocyclic groups involved are optionally connected to other groups by single bonds, or further cyclically linked to other cycloalkyl, heterocyclic, aryl, and heteroaryl groups by any two or more atoms on the ring; the heterocyclic group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester groups.

[0141] The term "4-20 membered subheterocyclic group" refers to a group formed by removing two hydrogen atoms from a heterocyclic group, such as:

[0142] wait.

[0143] In this invention, the term "aryl or aromatic ring" refers to an aromatic cyclic hydrocarbon group having 1-5 rings, particularly monocyclic and bicyclic groups. Specifically, "C6-C..." 14 "Aryl" refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. The aryl group is preferably C6-C. 10 Aryl. Aryl groups include phenyl, biphenyl, or naphthyl. Any aryl group containing two or more aromatic rings (bicyclic, etc.) can have these rings linked by single bonds (e.g., biphenyl) or fused (e.g., naphthalene, anthracene, etc.). "Substituted aryl" refers to an aryl group where one or more positions are substituted, particularly 1-3 substituents, which can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: hydrogen, deuterium, halogens (e.g., monohalogen substituents or polyhalogen substituents, the latter such as trifluoromethyl or alkyl groups containing Cl3), cyano, nitro, oxo (e.g., =O), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, aryl, heteroaryl, OR a SR a S(=O)R e S(=O)2R e P(=O)2R e S(=O)2OR e P(=O)2OR e NR b R c NR b S(=O)2R e NR b P(=O)2R e S(=O)2NR b R c P(=O)2NR b R c C(=O)OR d C(=O)R a C(=O)NR b R c OC(=O)R a OC (=O)NR b R c NR b C(=O)OR e NR d C(=O)NR b Rc NR d S(=O)2NR b R c NR d P(=O)2NR b R c NR b C(=O)R a , or NR b P(=O)2R e R appears here a R can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. b R c and R d It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, or aromatic ring, or R. b and R c It can form heterocycles together with N atoms; R e It can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclic, or aryl. The above-mentioned typical substituents can be optionally substituted. Typical substitutions also include fused-ring substituents, especially fused-ring alkyl, fused-ring alkenyl, fused-ring heterocyclic, or fused-ring aryl groups, the above-mentioned cycloalkyl, cycloalkenyl, heterocyclic, and heterocyclic aryl groups can be optionally substituted.

[0144] The term "heteroaryl or heterocyclic" refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms, wherein the heteroatoms are selected from oxygen, nitrogen, and sulfur. Specifically, "5-14-membered heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms. The heteroaryl group is preferably a 5- to 10-membered ring, more preferably a 5- or 6-membered ring, such as pyrroleyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl. "Heteroaryl" can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, deuteralkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylic acid ester.

[0145] In this invention, the term "halogen" or "halogen" refers to chlorine, bromine, fluorine, and iodine.

[0146] In this invention, the term "halogenated" refers to being replaced by a halogen.

[0147] In this invention, the term "deuteration" refers to being replaced by deuterium.

[0148] In this invention, the term "hydroxyl group" refers to a group with the structure OH.

[0149] In this invention, the term "nitro" refers to a group containing the structure NO2.

[0150] In this invention, the term "cyano" refers to a group containing the structure CN.

[0151] In this invention, the term "ester group" refers to a group with the structure -COOR, where R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclic or substituted heterocyclic. The ester group is preferably -COO C1-C6 alkyl.

[0152] The term "amine" refers to a group with the structure -NR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, or R' and R" together with the nitrogen atom connected thereto form a substituted or unsubstituted heterocyclic group, as defined above. In one embodiment, R' or R" is each independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, or R' and R" together with the nitrogen atom connected thereto form a 4- to 7 membered heterocyclic group (preferably a saturated 4- to 7 membered heterocyclic group containing only one nitrogen heteroatom as a ring atom). In one embodiment, at least one of R' and R" is not H. R' and R" can be the same or different in the dialkylamine fragment. The amino group is preferably NH2, NHC1-C6 alkyl, or N(C1-C6 alkyl)2; more preferably NHC1-C6 alkyl or N(C1-C6 alkyl)2.

[0153] The term "amide group" refers to a group with the structure -CONR'R", where R' and R" can independently represent hydrogen, deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, or R' and R" together with the nitrogen atom attached thereto form a substituted or unsubstituted heterocyclic group, as defined above. In one embodiment, R' or R" is each independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, halo-C1-C6 alkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic group, or R' and R" together with the nitrogen atom attached thereto form a 4- to 7 membered heterocyclic group (preferably a saturated 4- to 7 membered heterocyclic group containing only one nitrogen heteroatom as a ring atom). R' and R" can be the same or different in the dialkylamine segment. The amide group is preferably -CONH2, -CONH (C1-C6 alkyl), or -CONH (C3-C6 cycloalkyl).

[0154] In this invention, the term "substitution" refers to the substitution of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is the substituent described accordingly above, or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are stable or chemically feasible combinations. Such substituents include, but are not limited to: halogens, hydroxyl groups, carboxyl groups (-COOH), C1-C6 alkyl groups, C2-C6 alkenyl groups, C2-C6 alkynyl groups, C3-C8 cycloalkyl groups, 3- to 12-membered heterocyclic groups, aryl groups, heteroaryl groups, C1-C8 aldehyde groups, C2-C10 acyl groups, C2-C10 ester groups, amino groups, C1-C6 alkoxy groups, C1-C10 sulfonyl groups, etc.

[0155] In this invention, the terms 1-6 refer to 1, 2, 3, 4, 5, or 6. Other similar terms each have a similar meaning independently. The term "multiple" refers to 2-6, such as 2, 3, 4, 5, or 6.

[0156] It should be understood that when a group exists simultaneously at multiple different positions in a compound, its definition at each position is independent and can be the same or different. That is, the term "selected from the following group:" and the term "each independently selected from the following group:" have the same meaning.

[0157] Active ingredients

[0158] This invention provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0159]

[0160] The groups are defined as described above.

[0161] In another preferred embodiment, in the compound, any one of X, Z, G, R1, R2 and ring A is independently the corresponding group in the specific compound.

[0162] In another preferred embodiment, the compound is preferably the compound prepared in the various embodiments.

[0163] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the compounds of the present invention with an acid or base that is suitable for use as a medicine. Pharmaceutically acceptable salts include both inorganic and organic salts. A preferred class of salts are those formed by the compounds of the present invention with an acid. Suitable acids for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, and naphthalenesulfonic acid; and amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.

[0164] Another preferred class of salts are salts formed by the compounds of the present invention with a base, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (such as lower alkanol ammonium salts and other pharmaceutically acceptable amine salts), such as methylamine salts, ethylamine salts, propylamine salts, dimethylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tert-butylamine salts, ethylenediamine salts, hydroxyethylamine salts, dihydroxyethylamine salts, trihydroxyethylamine salts, and amine salts formed from morpholine, piperazine, and lysine, respectively.

[0165] The compounds described in this invention may contain one or more asymmetric centers, and may thereby produce diastereomers and optical isomers. This invention includes all possible diastereomers and their racemic mixtures, their substantially pure enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts.

[0166] When the compound represented by formula (I) has tautomers, unless otherwise stated, the present invention includes any possible tautomers and their pharmaceutically acceptable salts, and mixtures thereof.

[0167] The present invention includes any possible solvates and polymorphs when the compound represented by formula (I) and its pharmaceutically acceptable salt are present in a solvate or polymorph. There are no particular limitations on the type of solvent forming the solvate, provided that the solvent is pharmacologically acceptable. For example, solvents such as water, ethanol, propanol, and acetone can be used.

[0168] The term "composition," as used herein, refers to a product comprising specified amounts of each of the specified ingredients, and any product produced directly or indirectly from a combination of specified amounts of the specified ingredients. Therefore, pharmaceutical compositions containing compounds of the present invention as active ingredients, and methods for preparing the compounds of the present invention, are also part of this invention. Furthermore, some crystalline forms of the compounds may exist in polymorphic forms, and such polymorphs are included in this invention. Additionally, some compounds may form solvates with water (i.e., hydrates) and common organic solvents, and such solvates also fall within the scope of this invention.

[0169] It should be understood that the compounds of the present invention can be prepared by the methods shown in the following examples, and can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations can be easily performed by those skilled in the art to which this invention pertains.

[0170] Pharmaceutical composition and administration

[0171] The pharmaceutical compositions of the present invention comprise, within a safe and effective range, the compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably, 5-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0172] "Pharmaceutically acceptable carriers" refers to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0173] The pharmaceutical composition is an injection, capsule, tablet, pill, powder, or granule.

[0174] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and local administration.

[0175] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0176] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0177] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0178] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0179] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0180] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0181] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0182] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0183] The treatment method of the present invention can be used alone or in combination with other treatment methods or drugs.

[0184] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment. The dosage administered is the pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 5–1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0185] Compared with the prior art, the main advantages of the present invention include:

[0186] (1) This invention provides a class of novel 2-substituted azole compounds, which are easy to synthesize.

[0187] (2) The compounds of the present invention have good inhibitory activity against RIPK3 and its mediated cell necrosis pathway at both the enzyme and cellular levels.

[0188] (3) The compounds of the present invention have excellent kinase selectivity and significantly reduced inhibitory activity against a variety of off-target kinases compared to positive compounds.

[0189] (4) The compounds of the present invention can avoid the side effects of apoptosis caused by common RIPK3 inhibitors and greatly improve the therapeutic window of the inhibitors. Therefore, they have broad application prospects in the treatment or prevention of programmed cell necrosis and inflammation-related diseases.

[0190] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0191] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0192] In the following examples, the compounds used are commercially available or can be synthesized using conventional methods employing commercially available raw materials and reagents. The reactions were monitored by thin-layer chromatography (TLC). In this invention, 1 H NMR and 13 C10 NMR spectra were obtained using a Bruker Avance 600 or Bruker Avance 500 NMR spectrometer, with TMS as an internal standard. High-resolution mass spectrometry (HRMS) was performed using an Agilent G6520 Q-TOF mass spectrometer. Low-resolution mass spectrometry (LRMS) was performed using a Thermo Fisher FINNIGAN LTQ linear ion trap mass spectrometer. All reactions were performed in air unless otherwise specified.

[0193] The following abbreviations were used in the examples:

[0194]

[0195] Example 1

[0196]

[0197] Synthesis of intermediate 4-chloro-6-(isopropylthio)quinoline (M1)

[0198] 6-Bromo-4-chloroquinoline (5 g, 20.60 mmol), Pd(PPh3)4 (714 mg, 0.62 mmol), and sodium carbonate (5.46 g, 51.60 mmol) were dissolved in 1,4-dioxane (50 mL). Isopropyl mercaptan (1.92 mL, 20.60 mmol) was added under N2 protection, and the mixture was heated to 70 °C and reacted for 48 hours. The organic phase was filtered, and the filtrate was evaporated to dryness, extracted with EA, and washed with saturated brine. The organic phase was evaporated to dryness, and purified by column chromatography (PE:EA = 4:1) to give 3.6 g of a pale yellow solid, which was intermediate M1, with a yield of 73%. 1 H NMR(600MHz,Chloroform-d)δ8.71(d,J=4.7Hz,1H),8.14(d,J=2.1Hz,1H),8.02(d,J=8.8Hz,1H),7 .71(dd,J=8.8,2.1Hz,1H),7.48(d,J=4.7Hz,1H),3.62(hept,J=6.7Hz,1H),1.40(d,J=6.7Hz,6H).

[0199] Synthesis of intermediate 4-chloro-6-(isopropylsulfonyl)quinoline (M2)

[0200] Intermediate M1 (1 g, 4.21 mmol) was dissolved in DCM (25 mL), and m-chloroperoxybenzoic acid (1.52 g, 8.83 mmol) was added in portions. The reaction was carried out at room temperature for 6 hours. After the reaction was complete, a white solid was filtered off. The pH of the filtrate was adjusted to 7–8, extracted with DCM, and washed with saturated brine. The organic phase was evaporated to dryness and purified by column chromatography (DCM:MeOH = 20:1) to give 650 mg of white solid, which was intermediate M2, with a yield of 57%. 1 H NMR (400MHz, DMSO-d6) δ9.07(d,J=4.7Hz,1H),8.68(d,J=2.0Hz,1H),8.37(d,J=8.8Hz,1H),8.25( dd,J=8.8,2.0Hz,1H),8.00(d,J=4.7Hz,1H),3.65(hept,J=7.3,6.8Hz,1H),1.22(d,J=6.8Hz,6H).

[0201] Synthesis of intermediate 2-cyclopropyl-5-nitrobenzo[d]thiazole (M3)

[0202] 5-Nitrobenzothiazole (500 mg, 2.77 mmol), silver p-toluenesulfonate (1.55 g, 5.54 mmol), and cyclopropaneformaldehyde (250 μL, 3.42 mmol) were added to water (15 mL). The mixture was heated to 100 °C under N2 protection and reacted for 12 hours. After the reaction was complete, the mixture was filtered through diatomaceous earth. The filtrate was extracted with EA and washed with saturated brine. The organic phase was evaporated and purified by column chromatography (PE:EA = 20:1) to give 15 mg of a yellow solid, which was intermediate M3, with a yield of 2%. 1 H NMR(400MHz,Chloroform-d)δ8.75(d,J=2.3Hz,1H),8.22(dd,J=8.8,2.2Hz,1H),7 .93(d,J=8.8Hz,1H),2.45(p,J=6.5Hz,1H),1.34–1.32(m,2H),1.30–1.26(m,2H).

[0203] Synthesis of intermediate 2-cyclopropylbenzo[d]thiazol-5-amine (M4)

[0204] Intermediate M3 (15 mg, 0.07 mmol) was dissolved in methanol (1 mL), and 5 mg of 10% palladium on carbon was added. The reaction was carried out under H2 atmosphere for 12 hours. After the reaction was completed, palladium on carbon was filtered out, and the organic phase was dried by rotary evaporation to obtain 12 mg of colorless solid, which was intermediate M4, with a yield of 93%. It was directly used for the next step of the reaction.

[0205] Compound 2-cyclopropyl-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-1) synthesis

[0206] Intermediate M1 (13 mg, 0.05 mmol) and intermediate M4 (9 mg, 0.05 mmol) were dissolved in ethanol (1 mL), and a catalytic amount of hydrochloric acid was added. The reaction was carried out at room temperature for 12 hours, and a yellow solid precipitated from the reaction solution. After filtration, 14 mg of the yellow solid was obtained, which was compound LK-1 in hydrochloride form, with a yield of 64%. 1H NMR (500MHz, DMSO-d6) δ15.03(brs,1H),11.68(s,1H),9.45(d,J=1.8Hz,1H),8.59(d,J=7. 1Hz,1H),8.39(dd,J=8.9,1.8Hz,1H),8.32(d,J=8.9Hz,1H),8.23(d,J=8.5Hz,1H),8.01(d ,J=2.0Hz,1H),7.51(dd,J=8.5,2.1Hz,1H),6.95(d,J=7.1Hz,1H),3.69(hept,J=6.8Hz,1H ),2.59(tt,J=8.2,4.8Hz,1H),1.31–1.27(m,2H),1.26(d,J=6.8Hz,6H),1.20–1.16(m,2H). 13 C NMR (126MHz, DMSO-d6) δ176.90,156.43,154.22,144.89,141.30,135.69,135.47,133.54,132.28,126 .92,123.89,122.33,118.78,117.40,101.94,54.86,40.10,15.62,15.35,12.50.ESI-MS:424.4[M+H] + .

[0207] Example 2

[0208]

[0209] Compound N-(6-(isopropylsulfonyl)quinoline-4-yl)-2-(trifluoromethyl)benzo[d]thiazol-5-amine (LK- 2) Synthesis

[0210] The synthesis of compound LK-2 was the same as that of compound LK-1, using 2-trifluoromethylbenzo[d]thiazol-5-amine and intermediate M2 as starting materials, yielding 42 mg of yellow solid in hydrochloride form, with a yield of 72%. 1H NMR(400MHz,DMSO-d6)δ14.62(brs,1H),11.53(s,1H),9.38(d,J=1.9Hz,1H), 8.65(d,J=6.9Hz,1H),8.57(d,J=8.8Hz,1H),8.44(d,J=2.1Hz,1H),8.38(dd,J =8.9,1.8Hz,1H),8.24(d,J=8.9Hz,1H),7.83(dd,J=8.7,2.1Hz,1H),7.07(d,J =6.9Hz,1H),3.63(p,J=6.8Hz,1H),1.26(d,J=6.8Hz,6H).ESI-MS:452.4[M+H] + .

[0211] Example 3

[0212]

[0213] Synthesis of intermediate 1-(5-nitrobenzo[d]thiazolyl)ethane-1-one (M5)

[0214] The synthesis of intermediate M5 was the same as that of intermediate M3, using 5-nitrobenzo[d]thiazole and acetone aldehyde as starting materials, yielding 100 mg of yellow solid with a yield of 16%. 1 H NMR (400MHz, Chloroform-d) δ9.07 (d, J = 2.2Hz, 1H), 8.41 (dd, J = 8.9, 2.2Hz, 1H), 8.14 (d, J = 8.9Hz, 1H), 2.86 (s, 3H).

[0215] Synthesis of intermediate 1-(5-aminobenzo[d]thiazolyl)ethane-1-one (M6a)

[0216] Iron powder (251 mg, 4.50 mmol), ammonium chloride (24 mg, 0.45 mmol), and glacial acetic acid (51.6 μL, 0.90 mmol) were added to water (1 mL) at 50 °C. After reacting for 5 minutes, a solution of M5 (100 mg, 0.45 mmol) in ethanol (5 mL) was added, and the reaction was continued for another 30 minutes. After the reaction was complete, the mixture was filtered through diatomaceous earth and the reaction solution was concentrated. The organic phase was extracted with EA, washed with saturated brine, and evaporated to dryness to give 75 mg of a yellow oily substance, which was intermediate M6a, with a yield of 87%. 1 H NMR (400MHz, Chloroform-d) δ7.72(d,J=8.6Hz,1H),7.41(d,J=2.3Hz,1H),6.95(dd,J=8.6,2.3Hz,1H),3.93(s,2H),2.79(s,3H).

[0217] Compound 1-(5-((6-(isopropylsulfonyl)quinolin-4-yl)amino)benzo[d]thiazo-2-yl)ethane-1- Synthesis of ketone (LK-3)

[0218] The synthesis of compound LK-3 was the same as that of LK-1, using intermediates M6a and M2 as starting materials, yielding 36 mg of yellow solid in 70% yield. 1 H NMR (500MHz, DMSO-d6) δ11.80(s,1H),9.49(d,J=1.8Hz,1H),8.63(d,J=7.0Hz,1H),8.47(d,J=8.6Hz,1H),8.44–8.38(m,2H),8.3 5(d,J=8.9Hz,1H),7.78(dd,J=8.7,2.1Hz,1H),7.03(d,J=7.0Hz,1H),3.73(h,J=6.8Hz,1H),2.78(s,3H),1.25(d,J=6.8Hz,6H). 13 C NMR (126MHz, DMSO-d6) δ192.77,168.35,155.74,153.72,144.54,140.78,136.35,135.50,135.02 ,131.71,126.38,125.40,124.71,121.84,121.13,116.98,101.53,54.26,25.99,15.03.ESI-HRMS Calcd for C 21 H 20 N3O2S2[M+H] + :426.0941,found426.0940.

[0219] Example 4

[0220]

[0221] The synthesis of intermediates M7 to M8 is the same as that of intermediates M3 to M4.

[0222] 1H NMR spectrum of 2-isopropyl-5-nitrobenzo[d]thiazole (M7): 1 H NMR (400MHz, Chloroform-d) δ8.86(d,J=2.2Hz,1H),8.26(dd,J=8.8,2.2Hz,1H),8.00(d,J=8.7Hz,1H),3.49(hept,J=6.9Hz,1H),1.54(d,J=6.9Hz,6H).

[0223] 1H NMR spectrum of 2-isopropylbenzo[d]thiazol-5-amine (M8)

[0224] 1H NMR(500MHz,Chloroform-d)δ7.60(d,J=8.5Hz,1H),7.29(d,J=2.3Hz,1H),6.78(dd ,J=8.5,2.2Hz,1H),4.02(brs,2H),3.40(hept,J=6.9Hz,1H),1.47(d,J=6.9Hz,6H).

[0225] Compound 2-isopropyl-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-4) synthesis

[0226] The synthesis of compound LK-4 was the same as that of LK-1, using intermediates M8 and M2 as starting materials, yielding 12 mg of yellow solid in the form of hydrochloride, with a yield of 64%. 1 H NMR(500MHz,DMSO-d6)δ14.97(brs,1H),11.68(s,1H),9.45(d,J=1.8Hz,1H),8 .59(d,J=7.0Hz,1H),8.39(dd,J=8.9,1.8Hz,1H),8.34–8.26(m,2H),8.11(d,J =2.0Hz,1H),7.55(dd,J=8.5,2.1Hz,1H),6.96(d,J=7.1Hz,1H),3.69(hept,J= 6.7Hz, 1H), 3.48 (p, J = 6.8Hz, 1H), 1.45 (d, J = 6.9Hz, 6H), 1.26 (d, J = 6.8Hz, 6H). 13 C NMR(126MHz,DMSO-d6)δ179.72,155.38,153.03,143.99,140.37,134.64,134.42,133.02,131.23 ,125.87,123.11,121.77,121.42,118.37,116.39,100.95,53.84,32.85,21.96,14.59.ESI-HRMS Calcd for C 22 H 24 N3O2S2[M+H] + :426.1304, found 426.1307.

[0227] Example 5

[0228]

[0229] Synthesis of intermediate 1-(5-aminobenzo[d]thiazolyl)ethane-1-ol (M6b)

[0230] 7 mg of 10% palladium on carbon was added to a methanol (1 mL) solution of intermediate M5 (65 mg, 0.29 mmol), and the reaction was carried out under a hydrogen atmosphere for 16 hours. After the reaction was completed, the mixture was filtered, the filtrate was evaporated to dryness, and purified by column chromatography (DCM:MeOH = 10:1) to give 32 mg of a brown oily substance, which was intermediate M6b, with a yield of 56%. 1 H NMR (400MHz, DMSO-d6) δ7.62(d,J=8.5Hz,1H),7.04(d,J=2.1Hz,1H),6.71(dd,J=8.5,2 .2Hz,1H),6.14(d,J=5.1Hz,1H),5.20(s,2H),5.01–4.92(m,1H),1.48(d,J=6.5Hz,3H).

[0231] Compound 1-(5-((6-(isopropylsulfonyl)quinolin-4-yl)amino)benzo[d]thiazo-2-yl)ethane-1- Synthesis of alcohol (LK-5)

[0232] The synthesis of compound LK-5 was the same as that of LK-1, using intermediates M6b and M2 as starting materials, yielding 34 mg of yellow solid in the form of hydrochloride, with a yield of 66%. 1 H NMR(500MHz,DMSO-d6)δ14.88(brs,1H),11.65(s,1H),9.43(d,J=1.8Hz,1H),8.59 (d,J=7.0Hz,1H),8.39(dd,J=8.9,1.8Hz,1H),8.33–8.27(m,2H),8.09(d,J=2.0Hz ,1H),7.54(dd,J=8.5,2.1Hz,1H),6.96(d,J=7.1Hz,1H),6.47(s,1H),5.10(q,J=6 .5Hz,1H),3.67(hept,J=6.8Hz,1H),1.56(d,J=6.5Hz,3H),1.25(d,J=6.8Hz,6H). 13 C NMR(151MHz,DMSO-d6)δ182.10,155.87,154.01,144.40,140.76,134.94,134.88,133.67,131.72 ,126.31,123.71,122.10,121.83,118.93,116.81,101.37,66.98,54.30,23.74,15.04.ESI-HRMS Calcd for C 21 H 22 N3O3S2[M+H] + :428.1097,found 428.1099.

[0233] Example 6

[0234]

[0235] Synthesis of intermediate 1-iodo-2-isothiocyano-4-nitrobenzene (M7)

[0236] 2-Iodo-5-nitroaniline (300 mg, 1.14 mmol) and triethylamine (379 μL, 2.73 mmol) were added to tetrahydrofuran (5 mL), and phosgene (104 μL, 1.36 mmol) was slowly added dropwise at 0 °C. After reacting for 30 minutes, the mixture was brought to room temperature and the reaction was continued for 2 hours. After the reaction was complete, the solvent was evaporated, and the mixture was purified by rapid column chromatography to give 106 mg of a yellow solid, which was intermediate M7, with a yield of 30%. 1 H NMR (400MHz, Chloroform-d) δ8.09 (d, J = 2.6 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.82 (dd, J = 8.7, 2.5 Hz, 1H).

[0237] Synthesis of intermediate (2-iodo-5-nitrophenyl)aminothiocarbamate (M8)

[0238] Intermediate M7 (106 mg, 0.35 mmol) was dissolved in methanol (1 mL), and sodium methoxide (152 μL, 2.77 mmol, 1 mol / L in MeOH) was slowly added. The reaction was carried out at room temperature for 12 hours. After the reaction was completed, the solid was filtered to obtain 32 mg, which was intermediate M8, with a yield of 27%. 1 H NMR (400MHz, Chloroform-d) δ8.85 (s, 1H), 8.23 ​​(s, 1H), 8.06 (d, J = 8.7Hz, 1H), 7.79 (dd, J = 8.7, 2.6Hz, 1H), 4.19 (s, 3H).

[0239] Synthesis of intermediate 2-methoxy-5-nitrobenzo[d]thiazole (M9)

[0240] Intermediate M8 (30 mg, 0.09 mmol) and cesium carbonate (58 mg, 0.18 mmol) were added to 1,4-dioxane (1 mL), and the mixture was heated to 80 °C and reacted for 2 hours. After the reaction was complete, the reaction mixture was evaporated to dryness, and purified by column chromatography (PE:EA = 50:1) to give 16 mg of a pale yellow solid, which was intermediate M9, with a yield of 86%. 1 H NMR (400MHz, Chloroform-d) δ8.55(d,J=2.2Hz,1H),8.13(dd,J=8.7,2.3Hz,1H),7.77(d,J=8.7Hz,1H),4.26(s,3H).

[0241] Synthesis of intermediate 2-methoxybenzo[d]thiazol-5-amine (M10)

[0242] The synthesis of intermediate M10 was the same as that of intermediate M4, using intermediate M9 as the starting material, to obtain 14 mg of a colorless and transparent oil, which is intermediate M10, with a yield of 88%.

[0243] The compound N-(6-(isopropylsulfonyl)quinoline-4-yl)-2-methoxybenzo[d]thiazol-5-amine (LK-6) synthesis

[0244] The synthesis of compound LK-6 was the same as that of LK-1, using intermediates M2 and M10 as starting materials, yielding 28 mg of yellow solid in the form of hydrochloride, with a yield of 85%. 1 H NMR(400MHz,DMSO-d6)δ14.72(brs,1H),11.54(s,1H),9.40(d,J=1.8Hz,1H),8.6 0(d,J=7.0Hz,1H),8.38(dd,J=8.9,1.7Hz,1H),8.26(d,J=8.9Hz,1H),8.12(d,J=8 .4Hz,1H),7.84(d,J=2.0Hz,1H),7.42(dd,J=8.4,2.1Hz,1H),6.95(d,J=7.0Hz,1 H),4.21(s,3H),3.65(p,J=6.8Hz,1H),1.26(d,J=6.8Hz,6H).ESI-MS:414.3[M+H] + .

[0245] Example 7

[0246]

[0247] Synthesis of compound 2-chloro-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-7)

[0248] The synthesis of compound LK-7 was the same as that of LK-1, using 2-chloro-5-aminobenzothiazole and intermediate M2 as starting materials, yielding 31 mg of yellow solid in the form of hydrochloride, with a yield of 80%. 1H NMR(500MHz,DMSO-d6)δ14.81(brs,1H),11.60(s,1H),9.41(d,J=1.9Hz,1H), 8.64(d,J=7.0Hz,1H),8.40(dd,J=8.9,1.8Hz,1H),8.35(d,J=8.6Hz,1H),8.28 (d,J=8.9Hz,1H),8.16(d,J=2.1Hz,1H),7.67(dd,J=8.6,2.1Hz,1H),7.02(d,J =7.0Hz,1H),3.66(p,J=6.8Hz,1H),1.26(d,J=6.8Hz,6H).ESI-MS:418.4[M+H] + .

[0249] Example 8

[0250]

[0251] Synthesis of intermediate (2-iodo-5-nitrophenyl)aminothiocarbamate ethyl ester (M11)

[0252] The synthesis of intermediate M11 was the same as that of intermediate M8, using sodium ethoxide and intermediate M7 as starting materials, yielding 46 mg of yellow solid with a yield of 67%. 1 H NMR (400MHz, Chloroform-d) δ8.85(s,1H),8.22(s,1H),8.05(d,J=8.9Hz,1H),7.78(d,J=8.9Hz,1H),4.68(q,J=7.7,7.0Hz,2H),1.52–1.46(m,3H).

[0253] Synthesis of intermediate 2-ethoxy-5-nitrobenzo[d]thiazole (M12)

[0254] The synthesis of intermediate M12 was performed in accordance with the synthesis of intermediate M9, using intermediate M11 as the starting material, yielding 40 mg of yellow solid with a yield of 78%. 1 H NMR (400MHz, Chloroform-d) δ8.55(d,J=2.5Hz,1H),8.15(dd,J=8.3,2.7Hz,1H),7.78(dd,J=8.8,2.2Hz,1H),4.76–4.66(m,2H),1.56–1.51(m,3H).

[0255] Synthesis of intermediate 2-ethoxybenzo[d]thiazol-5-amine (M13)

[0256] The synthesis of intermediate M13 was similar to that of intermediate M4, using intermediate M12 as the starting material, yielding 22 mg of a colorless oil in 63% yield. This oil was used directly in the next reaction without purification.

[0257] Compound 2-ethoxy-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-8) synthesis

[0258] The synthesis of compound LK-8 was the same as that of LK-1, using intermediates M2 and M13 as starting materials, yielding 19 mg of yellow solid in the form of hydrochloride, with a yield of 36%. 1 H NMR (500MHz, DMSO-d6) δ14.76 (s, 1H), 11.58 (s, 1H), 9.41 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 7. 0Hz,1H),8.39(dd,J=8.9,1.8Hz,1H),8.27(d,J=8.9Hz,1H),8.12(d,J=8.4Hz,1H),7.83( d,J=2.1Hz,1H),7.42(dd,J=8.4,2.1Hz,1H),6.95(d,J=7.0Hz,1H),4.64(q,J=7.0Hz,2H) ,3.66(p,J=6.8Hz,1H),1.45(t,J=7.0Hz,3H),1.26(d,J=6.7Hz,6H).ESI-MS:428.3[M+H] + .

[0259] Example 9

[0260]

[0261] Synthesis of intermediate 5-nitro-2-((triisopropylsilyl)ethynyl)benzo[d]thiazole (M14)

[0262] Under N2 protection, 2-chloro-5-nitrobenzo[d]thiazole (100 mg, 0.47 mmol), triphenylphosphine (25 mg, 0.09 mmol), cuprous iodide (14 mg, 0.07 mmol), and palladium acetate (11 mg, 0.05 mmol) were added to a mixed solvent of TEA (0.9 mL) and THF (2.1 mL). Triisopropylsilylacetylene (167 μL, 0.75 mmol) was slowly added dropwise at 0 °C. After reacting for 2 hours, the mixture was brought to room temperature and reacted for another 16 hours. After the reaction was complete, the reaction solution was concentrated, extracted with ethyl acetate, washed with saturated brine, and purified by column chromatography (PE:EA = 5:1) to obtain 60 mg of a yellow solid, which was intermediate M14, with a yield of 54%. 1 H NMR(500MHz,Chloroform-d)δ8.93(d,J=2.3Hz,1H),8.36(dd,J=8.8,2.2Hz,1H),8.02(d,J=8.8Hz,1H),1.25–1.19(m,21H).

[0263] Synthesis of intermediate 2-((triisopropylsilyl)ethynyl)benzo[d]thiazol-5-amine (M15)

[0264] The synthesis of intermediate M15 followed the synthesis of M6a, using intermediate M14 as the starting material, yielding 28 mg of a brown oily substance in 51% yield. This unpurified substance was used directly in the next reaction step.

[0265] Intermediate N-(6-(isopropylsulfonyl)quinoline-4-yl)-2-((triisopropylsilyl)ethynyl)benzo[] Synthesis of [d]thiazol-5-amine (M16)

[0266] The synthesis of intermediate M16 was the same as that of LK-1, using intermediates M2 and M15 as starting materials, yielding 48 mg of yellow solid in the form of hydrochloride, with a yield of 76%. 1 H NMR(500MHz,DMSO-d6)δ14.91(brs,1H),11.63(s,1H),9.42(d,J=1.8Hz,1H),8.64(d ,J=7.0Hz,1H),8.40(dd,J=8.9,1.8Hz,1H),8.37(d,J=8.6Hz,1H),8.30(dd,J=8.8,2. 6Hz,1H),8.24(d,J=2.1Hz,1H),7.72(dd,J=8.7,2.1Hz,1H),7.03(d,J=7.0Hz,1H),3. 67(p,J=6.8Hz,1H),1.26(d,J=6.8Hz,6H),1.24–1.19(m,3H),1.15(d,J=6.8Hz,18H).

[0267] Compound 2-ethynyl-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-9) synthesis

[0268] Intermediate M16 (35 mg, 0.06 mmol) was dissolved in THF (2 mL), and TBAF (156 μL, 0.16 mmol) was slowly added dropwise at -40 °C for 1 hour. After reacting for 1 hour, the mixture was brought to room temperature and the reaction was continued for another hour. After the reaction was complete, the organic phase was evaporated to dryness, extracted with ethyl acetate, washed with saturated brine, concentrated, and separated by column chromatography (DCM:MeOH = 10:1) to give 18 mg of a pale yellow solid, with a yield of 71%. 1 H NMR(500MHz,DMSO-d6)δ9.78(brs,1H),9.07(s,1H),8.64(d,J=5.2Hz,1H),8.21(d,J=8.6Hz,1H),8.15–8.01(m,3H),7.6 6(d,J=8.8Hz,1H),7.14(d,J=5.3Hz,1H),5.23(s,1H),3.56(p,J=6.8Hz,1H),1.24(d,J=6.8Hz,6H).ESI-MS:408.3[M+H] + .

[0269] Example 10

[0270]

[0271] Synthesis of intermediate 2-(tert-butyl)-5-nitrobenzo[d]thiazole (M17)

[0272] The synthesis of intermediate M17 was the same as that of M3, using 5-nitrobenzothiazole and terpental as starting materials, yielding 31 mg of yellow solid in 10% yield. 1 H NMR (400MHz, Chloroform-d) δ8.79 (s, 1H), 8.16 (d, J = 8.8Hz, 1H), 7.90 (d, J = 8.8Hz, 1H), 1.48 (s, 9H).

[0273] Synthesis of intermediate 2-(tert-butyl)benzo[d]thiazol-5-amine (M18)

[0274] The synthesis of intermediate M18 followed the same procedure as that of M4, using intermediate M17 as the starting material, yielding 24 mg of a white solid in 85% yield. This solid was used directly in the next reaction without purification.

[0275] Compound 2-(tert-butyl)-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-10) Synthesis

[0276] The synthesis of compound LK-10 was the same as that of LK-1, using intermediates M2 and M18 as starting materials, yielding 27 mg of yellow solid in the form of hydrochloride, with a yield of 64%. 1 H NMR (500MHz, DMSO-d6) δ15.04(brs,1H),11.72(s,1H),9.47(d,J=1.8Hz,1H),8.60(d,J=7.1Hz,1H),8.40(dd,J=8.9,1.8Hz,1H),8.36–8.26(m ,2H),8.13(d,J=2.0Hz,1H),7.55(dd,J=8.5,2.1Hz,1H),6.97(d,J=7.1Hz,1H),3.71(hept,J=6.7Hz,1H),1.51(s,9H),1.26(d,J=6.8Hz,6H). 13 C NMR(126MHz,DMSO-d6)δ184.10,156.42,154.03,145.01,141.43,135.71,135.49,134.20,132.23 ,126.91,124.10,122.88,122.45,119.49,117.43,102.02,54.87,38.72,30.81,15.62.ESI-HRMS Calcd forC 23 H26 N3O2S2[M+H] + :440.1461,found 440.1464.

[0277] Example 11

[0278]

[0279] Synthesis of intermediate 2-methyl-1-(5-nitrobenzo[d]thiazolyl-2-yl)prop-1-ol (M19)

[0280] 5-Nitrobenzothiazole (150 mg, 0.83 mmol) was added to a glass dish containing isobutanol (1 mL) and acetonitrile (2 mL), followed by the addition of 12N concentrated hydrochloric acid (227 μL, 3.33 mmol). The mixture was stirred for 18 hours under an open container with an LED lamp irradiated at 390-400 nM. After the reaction was complete, the organic phase was concentrated, extracted with ethyl acetate, washed with saturated brine, and then separated by column chromatography (PE:EA = 5:1) to obtain 26 mg of a yellow solid, which was intermediate M19, with a yield of 12%. 1 H NMR(400MHz,Chloroform-d)δ8.87(s,1H),8.30(d,J=8.9Hz,1H),8.05(dd,J=8.7,2.3Hz,1H),5.07–4.96( m,1H),2.93(d,J=5.2Hz,1H),2.43–2.32(m,1H),1.13(dd,J=6.9,2.2Hz,3H),1.00(dd,J=6.9,2.2Hz,3H).

[0281] Synthesis of intermediate 1-(5-aminobenzo[d]thiazolyl)-2-methylprop-1-ol (M20)

[0282] The synthesis of intermediate M20 was performed following the same procedure as that of M4, using intermediate M19 as the starting material, yielding 9 mg of a pale yellow solid with a yield of 39%. 1 H NMR(400MHz,Chloroform-d)δ7.64(dd,J=8.5,2.5Hz,1H),7.28(s,1H),6.82(d,J=8.5Hz,1H),4.92–4.82(m,1H), 3.80(brs,2H),3.13–2.99(m,1H),2.26(h,J=6.8Hz,1H),1.10(dd,J=6.9,2.4Hz,3H),0.98(dd,J=6.8,2.4Hz,3H).

[0283] Compound 1-(5-((6-(isopropylsulfonyl)quinolin-4-yl)amino)benzo[d]thiazo-2-yl)-2-methyl Synthesis of propan-1-ol (LK-11)

[0284] The synthesis of compound LK-11 was the same as that of LK-1, using intermediates M2 and M20 as starting materials, yielding 12 mg of yellow solid in 65% yield. 1 H NMR(500MHz,DMSO-d6)δ14.88(brs,1H),11.64(s,1H),9.43(d,J=1.8Hz,1H),8.59(d,J=7.1Hz,1 H),8.39(dd,J=9.0,1.8Hz,1H),8.29(dd,J=8.7,3.6Hz,2H),8.09(d,J=2.0Hz,1H),7.54(dd,J=8. 5,2.1Hz,1H),6.97(d,J=7.0Hz,1H),6.44(s,1H),4.77(d,J=4.4Hz,1H),3.67(hept,J=6.8Hz,1H) ,2.23(pd,J=6.8,4.4Hz,1H),1.25(d,J=6.8Hz,6H),1.00(d,J=6.8Hz,3H),0.89(d,J=6.8Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ180.94,155.81,153.99,144.44,140.78,134.89,134.86,133.53,131.71,126.3 0,123.58,121.97,121.86,118.88,116.81,101.40,74.91,54.31,34.19,18.81,16.43,15.04.ESI-HRMS Calcd for C 23 H 26 N3O3S2[M+H] + :456.1410,found 456.1416.

[0285] Example 12

[0286]

[0287] Synthesis of intermediate 2-cyclobutyl-5-nitrobenzo[d]thiazole (M21)

[0288] 5-Nitrobenzothiazole (500 mg, 2.77 mmol), cyclobutylcarboxylic acid (531 μL, 5.55 mmol), potassium persulfate (3 g, 11.10 mmol), and silver nitrate (94 mg, 0.56 mmol) were added to dichloromethane (10 mL) and water (10 mL), and stirred vigorously for 12 hours. After the reaction was complete, the mixture was extracted with dichloromethane, washed with saturated brine, and the organic phase was concentrated and separated by column chromatography (PE:EA = 5:1) to give 250 mg of a yellow solid, with a yield of 39%. 1H NMR(400MHz,Chloroform-d)δ8.83(s,1H),8.24(d,J=8.9Hz,1H),7.97(dd,J=8.9,2.2H z,1H),4.00(p,J=8.6Hz,1H),2.64–2.43(m,4H),2.24–2.11(m,1H),2.11–1.99(m,1H).

[0289] Synthesis of intermediate 2-cyclobutylbenzo[d]thiazol-5-amine (M22)

[0290] The synthesis of intermediate M22 was performed following the same procedure as that of M6a, using intermediate M21 as the starting material, yielding 146 mg of a brown oily substance with a yield of 67%. 1 H NMR(400MHz,Chloroform-d)δ7.60(d,J=8.5Hz,1H),7.29(d,J=2.7Hz,1H),6.82–6.73( m,1H),3.94(p,J=8.6Hz,1H),2.60–2.40(m,4H),2.20–2.08(m,1H),2.07–1.94(m,1H).

[0291] The intermediate 2-cyclobutyl-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-12) synthesis

[0292] The synthesis of compound LK-12 was the same as that of LK-1, using intermediates M2 and M22 as starting materials, yielding 55 mg of yellow solid in the form of hydrochloride, with a yield of 70%. 1 H NMR(500MHz,DMSO-d6)δ14.65(brs,1H),11.58(s,1H),9.40(d,J=2.0Hz,1H),8.61(d,J=7.0Hz,1H) ,8.39(dd,J=8.9,1.8Hz,1H),8.29(d,J=8.5Hz,1H),8.25(dd,J=8.9,1.9Hz,1H),8.11(d,J=2.1Hz,1 H),7.54(dd,J=8.5,2.1Hz,1H),6.97(d,J=7.0Hz,1H),4.06(p,J=8.6Hz,1H),3.64(p,J=6.7Hz,1H) ,2.50–2.47(m,2H),2.46–2.35(m,2H),2.16–2.06(m,1H),2.02–1.92(m,1H),1.26(d,J=6.8Hz,6H). 13C NMR (126MHz, DMSO-d6) δ177.23,154.45,154.19,151.28,149.92,138.86,133.06,130.95,130.91,12 7.64,125.79,123.37,121.48,119.40,116.72,103.04,54.81,38.65,29.49,18.43,15.74.ESI-HRMS Calcd for C 23 H 24 N3O2S2[M+H] + :438.1304, found 438.1307.

[0293] Example 13

[0294]

[0295] Synthesis of intermediate 1-(5-nitrobenzo[d]thiazolyl)prop-1-ol (M23)

[0296] The synthesis of intermediate M23 was the same as that of M19, using 5-nitrobenzothiazole and n-butanol as starting materials, yielding 26 mg of yellow solid in 8% yield. 1 H NMR(400MHz,Chloroform-d)δ8.86(s,1H),8.29(d,J=8.8Hz,1H),8.05(d,J=8.7Hz,1H),5.17–5 .08(m,1H),2.97(d,J=5.0Hz,1H),2.23–2.11(m,1H),2.06–1.93(m,1H),1.12(t,J=7.5Hz,3H).

[0297] Synthesis of intermediate 1-(5-aminobenzo[d]thiazolyl)prop-1-ol (M24)

[0298] The synthesis of intermediate M24 was the same as that of M4, using intermediate M23 as the starting material, to obtain 20 mg of brown oily substance with a yield of 88%. 1 H NMR(400MHz,Chloroform-d)δ7.64(d,J=9.0Hz,1H),7.30–7.28(m,1H),6.82(d,J=8.5Hz,1H), 5.06–4.99(m,1H),3.04–2.94(m,1H),2.10–2.05(m,1H),2.00–1.91(m,1H),1.11–1.05(m,3H).

[0299] Compound 1-(5-((6-(isopropylsulfonyl)quinolin-4-yl)amino)benzo[d]thiazolyl)prop-1-ol Synthesis of (LK-13)

[0300] The synthesis of compound LK-13 was the same as that of LK-1, using intermediates M2 and M23 as starting materials, yielding 10 mg of yellow solid in the form of hydrochloride, with a yield of 22%. 1 H NMR (500MHz, DMSO-d6) δ14.69(brs,1H),11.59(s,1H),9.40(s,1H),8.60(d,J=7.0Hz,1H),8.38(dd, J=8.9,1.7Hz,1H),8.30(d,J=8.4Hz,1H),8.28–8.22(m,1H),8.09(d,J=2.0Hz,1H),7.54(dd,J=8.5,2 .0Hz,1H),6.97(d,J=7.0Hz,1H),6.53–6.38(m,1H),4.90(t,J=6.0Hz,1H),3.64(p,J=6.8Hz,1H),2. 03–1.90(m,1H),1.88–1.76(m,1H),1.25(d,J=6.8Hz,6H),0.98(t,J=7.4Hz,3H).ESI-MS:442.3[M+H] + .

[0301] Example 14

[0302]

[0303] Synthesis of intermediate 2-(sec-butyl)-5-nitrobenzo[d]thiazole (M25)

[0304] The synthesis of intermediate M25 was the same as that of M3, using 5-nitrobenzothiazole and 2-methylbutyraldehyde as starting materials, yielding 33 mg of brown oily substance in 5% yield. 1 H NMR(400MHz,Chloroform-d)δ8.86(s,1H),8.26(d,J=8.9Hz,1H),8.00(dd,J=8.9,2.2Hz,1H),3.28 (q,J=6.8Hz,1H),2.03–1.91(m,1H),1.89–1.76(m,1H),1.50(d,J=7.0Hz,3H),1.02(t,J=7.4,3H).

[0305] Synthesis of intermediate 2-(sec-butyl)benzo[d]thiazol-5-amine (M26)

[0306] The synthesis of intermediate M25 was performed following the same procedure as that of M6a. Starting with intermediate M25, 29 mg of brown oily substance was obtained, with a yield of 99%. 1H NMR(400MHz,Chloroform-d)δ7.60(d,J=8.5Hz,1H),7.30(d,J=2.4Hz,1H),6.79(dd,J=8.5,2.7Hz,1H),4.26(brs,2H) ,3.18(h,J=7.1Hz,1H),1.90(dp,J=14.7,7.6Hz,1H),1.81–1.72(m,1H),1.44(d,J=6.9Hz,3H),0.98(t,J=7.4Hz,3H).

[0307] Compound 2-(sec-butyl)-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-14) Synthesis

[0308] The synthesis of compound LK-14 was the same as that of LK-1, using intermediates M2 and M26 as starting materials, yielding 23 mg of yellow solid in the form of hydrochloride, with a yield of 34%. 1 H NMR (500MHz, DMSO-d6) δ14.93(s,1H),11.64(s,1H),9.43(d,J=1.8Hz,1H),8.57(d,J=7.1Hz,1H),8.3 7(dd,J=8.9,1.8Hz,1H),8.28(dd,J=10.3,8.7Hz,2H),8.09(d,J=2.1Hz,1H),7.53(dd,J=8.5,2.1Hz, 1H),6.95(d,J=7.0Hz,1H),3.66(hept,J=6.8Hz,1H),3.25(p,J=6.9Hz,1H),1.86(dt,J=13.6,7.3Hz, 1H), 1.75 (dp, J=14.1, 7.2Hz, 1H), 1.40 (d, J=6.9Hz, 3H), 1.24 (d, J=6.8Hz, 6H), 0.92 (t, J=7.4Hz, 3H). 13 C NMR (126MHz, DMSO-d6) δ179.41,155.92,153.56,144.51,140.90,135.17,134.99,133.49,131.76,126.4 0,123.63,122.29,121.94,118.91,116.92,101.51,54.39,40.12,29.78,20.24,15.13,11.51.ESI-HRMS Calcd for C 23 H 26 N3O2S2[M+H] + :440.1461,found 440.1463.

[0309] Example 15

[0310]

[0311] Intermediate (R)-2-(sec-butyl)benzo[d]thiazol-5-amine (M26a) and intermediate (S)-2-(sec-butyl)benzo[d]thiazol-5-amine (M26b) were obtained from intermediate M26 by chiral separation.

[0312] Compound (R)-2-(sec-butyl)-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-15) and the compound (S)-2-(sec-butyl)-N-(6-(isopropylsulfonyl)quinoline-4-yl)

[0313] Synthesis of benzo[d]thiazol-5-amine (LK-16)

[0314] The synthesis of compounds LK-15 and LK-16 followed the synthesis of compound LK-1, and they were synthesized in hydrochloride form. The spectrum of compound LK-15 is shown below. 1 H NMR (500MHz, DMSO-d6) δ14.93(s,1H),11.64(s,1H),9.43(d,J=1.8Hz,1H),8.57(d,J=7.1Hz,1H),8.3 7(dd,J=8.9,1.8Hz,1H),8.28(dd,J=10.3,8.7Hz,2H),8.09(d,J=2.1Hz,1H),7.53(dd,J=8.5,2.1Hz, 1H),6.95(d,J=7.0Hz,1H),3.66(hept,J=6.8Hz,1H),3.25(p,J=6.9Hz,1H),1.86(dt,J=13.6,7.3Hz, 1H), 1.75 (dp, J=14.1, 7.2Hz, 1H), 1.40 (d, J=6.9Hz, 3H), 1.24 (d, J=6.8Hz, 6H), 0.92 (t, J=7.4Hz, 3H). 13 C NMR (126MHz, DMSO-d6) δ179.41,155.92,153.56,144.51,140.90,135.17,134.99,133.49,131.76,126.4 0,123.63,122.29,121.94,118.91,116.92,101.51,54.39,40.12,29.78,20.24,15.13,11.51.ESI-HRMS Calcd for C 23 H 26 N3O2S2[M+H] + :440.1461,found 440.1462.

[0315] Spectrum of compound LK-16: 1H NMR(500MHz,DMSO-d6)δ14.90(s,1H),11.64(s,1H),9.42(d,J=1.9Hz,1H),8.57(d,J=7.1Hz,1H),8 .37(dd,J=8.8,1.8Hz,1H),8.31–8.23(m,2H),8.09(d,J=2.1Hz,1H),7.53(dd,J=8.5,2.1Hz,1H),6 .95(d,J=7.0Hz,1H),3.66(hept,J=6.8Hz,1H),3.25(p,J=6.8Hz,1H),1.86(dp,J=14.6,7.3Hz,1H) ,1.74(dq,J=14.1,7.1Hz,1H),1.40(d,J=6.9Hz,3H),1.24(d,J=6.8Hz,6H),0.92(t,J=7.4Hz,3H). 13 C NMR (126MHz, DMSO-d6) δ179.41,155.92,153.56,144.53,140.90,135.16,134.98,133.49,131.77,126.3 9,123.64,122.29,121.96,118.91,116.92,101.51,54.39,40.12,29.79,20.24,15.13,11.51.ESI-HRMS Calcd for C 23 H 26 N3O2S2[M+H] + :440.1461,found 440.1466.

[0316]

[0317] Synthesis of intermediate 5-aminobenzo[d]thiazolyl-2-carboxynitrile (M27)

[0318] The synthesis of intermediate M27 was the same as that of M6a, starting with 5-nitrobenzo[d]thiazolyl-2-nitrile, yielding 37 mg of brown oily substance in 87% yield. 1 H NMR (400MHz, Chloroform-d) δ7.73(d,J=8.7Hz,1H),7.44(d,J=2.3Hz,1H),7.05(dd,J=8.7,2.3Hz,1H),4.03(brs,2H).

[0319] Compound 5-((6-(isopropylsulfonyl)quinoline-4-yl)amino)benzo[d]thiazolyl-2-carboxynitrile (LK-17) synthesis

[0320] The synthesis of compound LK-17 was the same as that of LK-1, using intermediates M2 and M27 as starting materials, yielding 35 mg of a pale yellow solid in the form of hydrochloride, with a yield of 71%.

[0321] Example 17

[0322]

[0323] Synthesis of intermediate 2-cyclopentyl-5-nitrobenzo[d]thiazole (M28)

[0324] The synthesis of intermediate M28 was the same as that of M21, using 5-nitrobenzothiazole and cyclopentylcarboxylic acid as starting materials, yielding 70 mg of yellow solid in 10% yield. 1 H NMR(500MHz,Chloroform-d)δ8.82(d,J=2.2Hz,1H),8.23(dd,J=8.8,2.2Hz,1H),7.96(d,J=8.8Hz,1H ),3.60(p,J=8.1Hz,1H),1.95–1.90(m,2H),1.87–1.81(m,2H),1.74–1.69(m,2H),1.62–1.57(m,2H).

[0325] Synthesis of intermediate 2-cyclopentylbenzo[d]thiazol-5-amine (M29)

[0326] The synthesis of intermediate M29 was the same as that of M6a, using intermediate M28 as the starting material, yielding 44 mg of brown oily substance in 71% yield. 1 H NMR(400MHz,Chloroform-d)δ7.59(d,J=8.5Hz,1H),7.28(s,1H),6.77(dd,J=8.5,2.3Hz,1H), 3.93(brs,2H),3.53(p,J=8.1Hz,1H),2.31–2.19(m,2H),1.97–1.85(m,4H),1.78–1.71(m,2H).

[0327] The compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-20) synthesis

[0328] The synthesis of compound LK-20 was the same as that of LK-1, using intermediates M2 and M27 as starting materials, yielding 40 mg of a pale yellow solid in the form of hydrochloride, with a yield of 60%. 1H NMR (500MHz, DMSO-d6) δ14.87(brs,1H),11.63(s,1H),9.42(d,J=1.9Hz,1H),8.56(d,J=7. 0Hz,1H),8.36(dd,J=8.9,1.8Hz,1H),8.28(d,J=8.9Hz,1H),8.24(d,J=8.5Hz,1H),8.06(d, J=2.0Hz,1H),7.51(dd,J=8.5,2.1Hz,1H),6.94(d,J=7.0Hz,1H),3.71–3.57(m,2H),2.24–2 .15(m,2H),1.94–1.85(m,2H),1.83–1.74(m,2H),1.73–1.65(m,2H),1.23(d,J=6.9Hz,6H). 13 C NMR(126MHz,DMSO-d6)δ178.73,155.94,153.61,144.47,140.86,135.14,134.98,133.69,131.77,12 6.39,123.56,122.23,121.92,118.82,116.91,101.48,54.40,43.98,33.38,25.11,15.12.ESI-HRMS Calcd forC 24 H 26 N3O2S2[M+H] + :452.1461,found 452.1463.

[0329] Example 18

[0330]

[0331] Synthesis of intermediate 2-(1-methylcyclopropyl)-5-nitrobenzo[d]thiazole (M30)

[0332] The synthesis of intermediate M30 was the same as that of M21, using 5-nitrobenzothiazole and 1-methylcyclopropane-1-carboxylic acid as starting materials, yielding 20 mg of yellow solid in 10% yield. 1 H NMR(500MHz,Chloroform-d)δ8.78(d,J=2.2Hz,1H),8.22(dd,J=8.8,2.2Hz,1H),7.95(d,J=8.7Hz,1H),1.71(s,3H),1.54–1.51(m,2H),1.19–1.15(m,2H).

[0333] Synthesis of intermediate 2-(1-methylcyclopropyl)benzo[d]thiazol-5-amine (M31)

[0334] The synthesis of intermediate M31 followed the synthesis of M6a, using intermediate M30 as the starting material, yielding 15 mg of a brown oily substance in 86% yield. This unpurified substance was used directly in the next reaction step.

[0335] Compound N-(6-(isopropylsulfonyl)quinoline-4-yl)-2-(1-methylcyclopropyl)benzo[d]thiazol-5-amine Synthesis

[0336] The synthesis of compound LK-19 was the same as that of LK-1, using intermediates M2 and M31 as starting materials, yielding 16 mg of yellow solid in the form of hydrochloride, with a yield of 40%. 1 H NMR(500MHz,DMSO-d6)δ14.92(brs,1H),11.65(s,1H),9.43(d,J=1.8Hz,1H),8.58(d,J =7.1Hz,1H),8.38(dd,J=8.9,1.7Hz,1H),8.29(d,J=8.9Hz,1H),8.24(d,J=8.4Hz,1H),8 .02(d,J=2.1Hz,1H),7.50(dd,J=8.5,2.1Hz,1H),6.94(d,J=7.0Hz,1H),3.67(p,J=6.8H z,1H),1.64(s,3H),1.36(q,J=4.0Hz,2H),1.25(d,J=6.8Hz,6H),1.18(q,J=4.1Hz,2H). 13 C NMR (126MHz, DMSO-d6) δ180.58,156.40,154.28,144.99,141.36,135.72,135.45,133.86,132.28,126.9 0,123.93,122.42,122.34,118.87,117.40,101.97,54.88,40.26,22.32,20.94,20.52,15.62.ESI-HRMS Calcd forC 23 H 24 N3O2S2[M+H] + :438.1304, found 438.1306.

[0337] Example 19

[0338]

[0339] Synthesis of intermediate 2,2-dimethylcyclopropylborate pinacol ester (M32)

[0340] Under N2 protection, diethylzinc (1.0 M in Toluene, 1.68 mL, 1.68 mmol) and diiodomethane (631.5 mg, 2.36 mmol) were sequentially added to pinacol 2-methyl-1-propenylboronic acid (338 μL, 1.68 mmol), and the mixture was heated to 50 °C and reacted for 10 hours. Then, diethylzinc (1.0 M in Toluene, 1.68 mL, 1.68 mmol) and diiodomethane (631.5 mg, 2.36 mmol) were added, and the reaction was continued for another 10 hours. After the reaction was complete, the mixture was quenched with 1N hydrochloric acid, and the white precipitate was filtered off. The filtrate was extracted with diethyl ether, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and separated by column chromatography (100% PE) to give 210 mg of a colorless oily substance (containing toluene solvent), which was intermediate M32. 1 H NMR (400MHz, Chloroform-d) δ1.23(d,J=8.9Hz,12H),1.15(s,3H),1.12(s,3H),0.64–0.55(m,2H),-0.23(dd,J=9.1,6.9Hz,1H).

[0341] Synthesis of intermediate potassium 2,2-dimethylcyclopropyltrifluoroborate (M33)

[0342] Dissolve potassium hydrogen fluoride (100 mg, 1.27 mmol) in water (0.5 mL), and add it to a tetrahydrofuran solution (1 mL) of intermediate M32 (130 mg, 0.63 mmol). Stir at room temperature for 12 hours. After the reaction is complete, evaporate the solvent to obtain intermediate M33, which can be used directly in the next reaction.

[0343] Synthesis of intermediate 2-(2,2-dimethylcyclopropyl)-5-nitrobenzo[d]thiazole (M34)

[0344] 2-Bromo-5-nitrobenzothiazole (60 mg, 0.23 mmol), intermediate M33 (81 mg, 0.46 mmol), palladium acetate (6 mg, 0.02 mmol), n-butylbis(1-adamantyl)phosphine (13 mg, 0.03 mmol), and cesium carbonate (226 mg, 0.70 mmol) were added to a mixed solvent of toluene (4 mL) and water (0.4 mL). The mixture was heated to 100 °C under N2 protection and reacted for 14 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and separated by preparative thin-layer chromatography (PTLC) to give 2 mg of yellow solid, which was intermediate M34, with a yield of 3%. 1H NMR(500MHz,Chloroform-d)δ8.79(d,J=2.2Hz,1H),8.23(dd,J=8.7,2.2Hz,1H),7.94(d,J=8.8Hz,1 H),2.28(dd,J=8.1,5.7Hz,1H),1.54(t,J=5.3Hz,1H),1.34(s,3H),1.28–1.22(m,1H),1.16(s,3H).

[0345] Synthesis of intermediate 2-(2,2-dimethylcyclopropyl)benzo[d]thiazol-5-amine (M35)

[0346] The synthesis of intermediate M35 was the same as that of M4. Starting with intermediate M34, 5 mg of yellow solid was obtained, with a yield of 41%.

[0347] Compound 2-(2,2-dimethylcyclopropyl)-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazole- Synthesis of 5-amine (LK-20)

[0348] The synthesis of compound LK-20 was the same as that of LK-1, using intermediates M2 and M35 as starting materials, yielding 3 mg of yellow solid in the form of hydrochloride, with a yield of 30%. 1 H NMR(500MHz,DMSO-d6)δ9.69(s,1H),9.07(d,J=1.9Hz,1H),8.59(d,J=5.4Hz,1H ),8.10–8.01(m,3H),7.87(d,J=2.1Hz,1H),7.44(dd,J=8.5,2.1Hz,1H),7.05(d, J=5.4Hz,1H),5.36–5.27(m,1H),3.55(p,J=6.8Hz,1H),2.40(dd,J=8.2,5.6Hz,1 H),2.05–1.94(m,1H),1.27(s,3H),1.23(d,J=2.8Hz,6H),1.09(s,3H).ESI-HRMS Calcd for C 24 H 26 N3O2S2[M+H] + :452.1361,found 452.1465.

[0349] Example 20

[0350]

[0351] Synthesis of intermediate 2-(2-methylprop-1-en-1-yl)-5-nitrobenzo[d]thiazole (M36)

[0352] 2-Chloro-5-nitrobenzothiazole (200 mg, 0.93 mmol), pinacol ester of 2-methyl-1-propenylboronic acid (189 μL, 1.68 mmol), and tetrakis(triphenylphosphine)palladium (54 mg, 0.05 mmol) were dissolved in 1,4-dioxane (3 mL), and a solution of potassium phosphate (500 mg, 2.33 mmol) in water (1 mL) was added. The mixture was heated to 100 °C under N2 protection and reacted for 12 hours. After the reaction was complete, the reaction solution was concentrated, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was then purified by column chromatography (PE:EA = 5:1) after rotary evaporation, yielding 150 mg of a white solid, which was intermediate M36, in 69% yield. 1 H NMR(500MHz,Chloroform-d)δ8.82(d,J=2.2Hz,1H),8.22(dd,J=8.8,2.2Hz,1H),7.96( d,J=8.8Hz,1H),6.59(hept,J=1.4Hz,1H),2.33(d,J=1.2Hz,3H),2.09(d,J=1.4Hz,3H).

[0353] Synthesis of intermediate 2-(2-methylprop-1-en-1-yl)benzo[d]thiazol-5-amine (M37)

[0354] The synthesis of intermediate M37 was the same as that of M6a, using intermediate M36 as the starting material, yielding 29 mg of yellow solid with a yield of 48%. 1 H NMR(400MHz,Chloroform-d)δ7.61(d,J=8.5Hz,1H),7.30(d,J=2.3Hz,1H),6.78(dd,J=8.5, 2.2Hz, 1H), 6.59 (p, J = 1.4Hz, 1H), 3.81 (s, 2H), 2.25 (d, J = 1.2Hz, 3H), 2.05 (d, J = 1.4Hz, 3H).

[0355] The compound N-(6-(isopropylsulfonyl)quinoline-4-yl)-2-(2-methylprop-1-en-1-yl)benzo[d]thia Synthesis of 5-azole amine

[0356] The synthesis of compound LK-21 was the same as that of LK-1, using intermediates M2 and M36 as starting materials, yielding 35 mg of yellow solid in 82% yield. 1H NMR(500MHz,DMSO-d6)δ9.71(s,1H),9.08(d,J=1.9Hz,1H),8.61(d,J=5.4Hz,1H),8.16–8.01(m,3H),7.93(d,J=2.1Hz,1H),7.48(dd ,J=8.6,2.1Hz,1H),7.09(d,J=5.4Hz,1H),6.70–6.60(m,1H),3.56(h,J=6.7Hz,1H),2.28(s,3H),2.04(s,3H),1.23(d,J=6.8Hz,6H). 13 C NMR (126MHz, DMSO) δ166.78,154.57,154.22,151.28,149.79,147.43,139.07,133.03,130.96,130.34, 127.65,125.82,123.07,121.39,119.41,119.19,116.42,103.10,54.80,27.82,21.36,15.74.ESI-HRMS Calcd for C 23 H 24 N3O2S2[M+H] + :438.1304,found 438.1405.

[0357] Example 21

[0358]

[0359] Synthesis of intermediate 2-cyclohexyl-5-nitrobenzo[d]thiazole (M38)

[0360] The synthesis of intermediate M38 was the same as that of M21, using 5-nitrobenzothiazole and cyclohexylcarboxylic acid as starting materials, yielding 400 mg of yellow oily substance in 55% yield. 1 H NMR(500MHz,Chloroform-d)δ8.85(d,J=2.2Hz,1H),8.26(dd,J=8.8,2.2Hz,1H),7.99(d,J=8.8Hz,1H),3.18(tt,J =11.5,3.6Hz,1H),2.29–2.22(m,2H),1.99–1.92(m,2H),1.84–1.77(m,2H),1.71–1.64(m,2H),1.51–1.25(m,2H).

[0361] Synthesis of intermediate 2-cyclohexylbenzo[d]thiazol-5-amine (M39)

[0362] The synthesis of intermediate M39 was the same as that of M6a, using intermediate M38 as the starting material, to obtain 98 mg of brown oily substance, with a yield of 44%. 1 H NMR(400MHz,Chloroform-d)δ7.60(d,J=8.5Hz,1H),7.30(s,1H),6.78(dd,J=8.4,2.1Hz,1H),3.14 –3.03(m,1H),2.20(d,J=12.8Hz,2H),1.90(d,J=13.1Hz,2H),1.69–1.55(m,4H),1.49–1.27(m,2H).

[0363] Compound 2-cyclohexyl-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK-22) synthesis

[0364] The synthesis of compound LK-22 was the same as that of LK-1, using intermediates M2 and M27 as starting materials, yielding 65 mg of a pale yellow solid in the form of hydrochloride, with a yield of 79%. 1 H NMR (500MHz, DMSO-d6) δ15.01(brs,1H),11.69(s,1H),9.45(d,J=1.8Hz,1H),8.59(d,J=7.0Hz,1H),8.39(dd,J=8.9, 1.8Hz,1H),8.30(dd,J=12.5,8.7Hz,2H),8.10(d,J=2.0Hz,1H),7.54(dd,J=8.4,2.1Hz,1H),6.95(d,J=7.0Hz,1H),3 .69(hept,J=6.7Hz,1H),3.17(tt,J=11.3,3.6Hz,1H),2.20–2.11(m,2H),1.83(dp,J=11.1,3.6Hz,2H),1.72(dt,J=1 2.8,3.6Hz,1H),1.61(qd,J=12.3,3.5Hz,2H),1.45(qt,J=12.7,3.5Hz,2H),1.35–1.26(m,1H),1.25(d,J=6.7Hz,6H). 13 C NMR (126MHz, DMSO) δ181.00,157.86,155.47,146.38,142.78,137.07,136.88,135.29,133.68,128.34 ,125.55,124.17,123.81,120.83,118.83,103.39,56.28,44.30,34.65,27.27,27.20,17.04.ESI-HRMS Calcd for C 25 H28 N3O2S2[M+H] + :466.1617,found 466.1616.

[0365] Example 22

[0366]

[0367] Intermediate 5-(((4-bromo-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6- Synthesis of diketone (M40)

[0368] Cycloisopropyl malonate (5 g, 34.69 mmol) was added to trimethyl orthoformate (15 mL, 150 mmol), and the mixture was heated to 105 °C and reacted for 1 hour. Then, 4-bromo-3-methoxyaniline (6.31 g, 31.22 mmol) was added, and the reaction continued for another 1.5 hours. After the reaction was complete, the mixture was cooled to room temperature, the precipitate was filtered off, washed with methanol, and dried to give 9.8 g of a yellow solid, which was intermediate M40, with a yield of 93%. 1 H NMR(500MHz,DMSO-d6)δ11.25(d,J=14.5Hz,1H),8.70–8.60(m,1H),7.60(d,J=8.5H z,1H),7.44(d,J=2.4Hz,1H),7.11(dd,J=8.6,2.5Hz,1H),3.91(s,3H),1.69(s,6H).

[0369] Synthesis of intermediate 6-bromo-7-methoxyquinoline-4-ol (M41)

[0370] The phenyl ether (50 mL) was heated to 220 °C, and intermediate M40 (16 g, 44.92 mmol) was added in batches and reacted for 1.5 hours. After the reaction was complete, the mixture was cooled to room temperature and then added to n-hexane (100 mL) with vigorous stirring, resulting in the precipitation of a brown solid. The precipitate was filtered off and then slurried with ethanol to give 8 g of a yellow solid, which was intermediate (M41), with a yield of 70%. 1 H NMR (500MHz, DMSO-d6) δ11.74(s,1H),8.18(d,J=3.8Hz,1H),7.88(dd,J=7.7,3.5Hz,1H),7.07(d,J=3.6Hz,1H),6.01(dd,J=7.5,3.6Hz,1H),3.95(s,3H).

[0371] Synthesis of intermediate 6-bromo-4-chloro-7-methoxyquinoline (M42)

[0372] Intermediate M41 (8 g, 32.49 mmol) was added to phosphorus oxychloride (20 mL), and the mixture was heated to 110 °C and reacted for 1 hour. After the reaction was complete, the phosphorus oxychloride was evaporated to dryness. The organic phase was extracted with ethyl acetate, washed with saturated brine, dried over colorless sodium sulfate, concentrated, and purified by column chromatography (DCM:MeOH = 100:1) to give 8.1 g of a yellow solid, which was intermediate M41, with a yield of 94%. 1 H NMR (500MHz, DMSO-d6) δ8.82(d,J=4.9Hz,1H),8.39(s,1H),7.67(d,J=5.0Hz,1H),7.62(s,1H),4.06(s,3H).

[0373] Synthesis of intermediate 4-chloro-6-(isopropylthio)-7-methoxyquinoline (M43)

[0374] The synthesis of intermediate M43 was the same as that of M1, using intermediate M42 and isopropyl mercaptan as starting materials, yielding 6.5 g of yellow solid with a yield of 83%.

[0375] Synthesis of intermediate 4-chloro-6-(isopropylsulfonyl)-7-methoxyquinoline 1-oxide (M44)

[0376] Intermediate M43 (9.3 g, 34.73 mmol) and potassium persulfate (32 g, 52.10 mmol) were added to a mixed solvent of ethyl acetate (20 mL) and water (20 mL), and reacted at room temperature for 16 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over colorless sodium sulfate. The organic phase was concentrated and purified by column chromatography (EA:MeOH = 10:1) to give 3.6 g of yellow solid, which was intermediate M43, in 33% yield. 1 H NMR(500MHz,DMSO-d6)δ8.73(d,J=6.7Hz,1H),8.63(s,1H),8.19(s,1H),7.7 2(d,J=6.6Hz,1H),4.15(s,3H),3.84(p,J=6.9Hz,1H),1.23(d,J=6.8Hz,6H).

[0377] Synthesis of intermediate 4-chloro-6-(isopropylsulfonyl)-7-methoxyquinoline (M45)

[0378] A solution of intermediate M44 (900 mg, 2.85 mmol) in dichloromethane (5 mL) was added dropwise to phosphorus trichloride (1.1 mL, 11.40 mol) at 0 °C, followed by a reaction at 45 °C for 1 hour. After the reaction was complete, the pH was adjusted to near neutral with saturated sodium bicarbonate. The organic phase was extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (PE:EA = 1:1) to give 80 mg of a white solid, which was intermediate M45, in a yield of 9%. 1H NMR (500MHz, Chloroform-d) δ8.96 (s, 1H), 8.85 (d, J = 4.7Hz, 1H), 7.74 (s, 1H), 7. 55(d,J=4.3Hz,1H),4.16(s,3H),3.86(hept,J=6.8Hz,1H),1.37(d,J=6.9Hz,6H).

[0379] Compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)-7-methoxyquinoline-4-yl)benzo[d]thiazol-5-amine Synthesis of (LK-23)

[0380] The synthesis of compound LK-23 was the same as that of LK-1, using intermediates M2 and M27 as starting materials, yielding 25 mg of a pale yellow solid in 78% yield. 1 H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.95(s,1H),8.50(d,J=5.4Hz,1H),8.06(d,J=8.5Hz ,1H),7.87(d,J=2.1Hz,1H),7.50(s,1H),7.43(dd,J=8.4,2.1Hz,1H),6.91(d,J=5.4Hz,1H ),4.05(s,3H),3.81(p,J=6.9Hz,1H),3.59(q,J=8.0Hz,1H),2.25–2.14(m,2H),1.96–1.8 6(m,2H),1.85–1.77(m,2H),1.75–1.66(m,2H),1.23(d,J=6.8Hz,6H).ESI-MS:482.3[M+H] + .

[0381] Example 23

[0382]

[0383] Synthesis of intermediate 3-bromo-5-nitrobenzo[b]thiophene (M46)

[0384] 5-Nitrobenzothiophene (3 g, 16.74 mmol) and NBS (3.28 g, 18.42 mmol) were added to DMF (45 mL), and the mixture was heated to 60 °C and reacted for 5 hours. After the reaction was complete, the DMF was evaporated to dryness, and ethyl acetate (15 mL) was added and stirred. The resulting solid was then stirred with water (20 mL), the solid precipitate was filtered, and dried to obtain 2.6 g of brown solid, which was intermediate M46, with a yield of 60%. 1 H NMR (500MHz, DMSO-d6) δ8.51(d,J=2.2Hz,1H),8.42(d,J=8.8Hz,1H),8.32(s,1H),8.30(dd,J=8.9,2.3Hz,1H). Synthesis of intermediate 3-bromo-5-nitrobenzo[b]thiophene 1,1-dioxide (M47) Intermediate M46 (2.60 g, 10.1 mmol) was dissolved in dichloromethane (30 mL) at 0 °C, and m-chloroperoxybenzoic acid (4.35 g, 25.2 mmol) was added. The mixture was then raised to room temperature and reacted for 12 hours. After the reaction was complete, the mixture was filtered, and the filtrate was adjusted to pH 7–8 with saturated sodium bicarbonate and washed with saturated brine. The organic phase was concentrated and slurried with ethanol to give 2.7 g of a yellow solid, which was intermediate M47, with a yield of 92%. 1 H NMR (500MHz, DMSO-d6) δ8.56(dd,J=8.3,2.0Hz,1H),8.34(s,1H),8.31(d,J=8.3Hz,1H),8.21(d,J=2.1Hz,1H).

[0385] Synthesis of intermediate 5-amino-3-bromobenzo[b]thiophene 1,1-dioxide (M48)

[0386] Ammonium chloride powder (2.51 g, 46.88 mmol) was added to a mixed solution of intermediate M47 (3.4 g, 11.72 mmol) in ethanol (45 mL) and water (15 mL). The mixture was then heated to 85 °C, and iron powder (2.62 g, 46.88 mmol) was added in portions, reacting for 2 hours. The reaction solution was filtered through diatomaceous earth, evaporated to dryness, and then slurried with water. The precipitate was filtered off and dried to obtain 2.4 g of brown solid, which was intermediate M48, with a yield of 79%. This was used directly in the next reaction.

[0387] Intermediate 5-(((3-bromo-1,1-dioxybenzo[b]thiophene-5-yl)amino)methylene)-2,2-dimethyl-1, Synthesis of 3-dioxane-4,6-dione (M49)

[0388] Intermediate M48 (500 mg, 1.92 mmol) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (537 mg, 2.88 mmol) were dissolved in ethanol (5 mL), stirred at room temperature for 5 hours, filtered, and the resulting solid was washed with ice-cold ethanol and dried to give 66 mg of a pale yellow solid, which was intermediate M49, with a yield of 83%. 1 H NMR (500MHz, DMSO-d6) δ11.42(d,J=14.0Hz,1H),8.69(d,J=14.2Hz,1H),8.13(s,1H),8.00(d,J=8.7Hz,1H),7.93–7.86(m,2H),1.70(s,6H).

[0389] Synthesis of intermediate 3-bromo-8-hydroxythiopheno[2,3-g]quinoline 1,1-dioxide (M50)

[0390] The phenyl ether (10 mL) was heated to 220 °C and stirred for 5 minutes. Intermediate M49 (250 mg, 0.60 mmol) was added in portions, and stirring continued for 15 minutes, followed by cooling to room temperature. Petroleum ether (7 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. A brown precipitate was filtered off. The precipitate was slurried with ethyl acetate to give 130 mg of a pale yellow solid, which was intermediate M50, with a yield of 69%. 1 H NMR (500MHz, DMSO-d6) δ12.29(s,1H),8.36(s,1H),8.26(s,1H),8.08(d,J=7.1Hz,1H),7.78(s,1H),6.23(d,J=7.5Hz,1H).

[0391] Synthesis of intermediate 3-bromo-8-chlorothiopheno[2,3-g]quinoline 1,1-dioxide (M51)

[0392] The synthesis of intermediate M51 was the same as that of M42, using intermediate M50 as the starting material, yielding 137 mg of yellow solid with a yield of 95%. 1 H NMR (500MHz, DMSO-d6) δ9.06(d,J=4.8Hz,1H),8.75(s,1H),8.37(s,1H),8.15(s,1H),8.01(d,J=4.8Hz,1H).

[0393] Intermediate 3-bromo-8-((2-cyclopentylbenzo[d]thiazolyl)amino)thieno[2,3-g]quinoline 1,1-di Synthesis of oxide (M52)

[0394] Intermediate M51 (137 mg, 0.42 mmol) and intermediate M29 (90 mg, 0.42 mmol) were added to ethanol (2 mL), followed by the addition of 6N HCl as a catalyst. The mixture was then heated to 85 °C and reacted for 1 hour. After the reaction was complete, the reaction mixture was directly evaporated to dryness and purified by column chromatography (DCM:MeOH = 10:1) to give 82 mg of a brown solid, which was intermediate M52, with a yield of 62%. 1 H NMR (500MHz, DMSO-d6) δ9.22(s,1H),8.61(d,J=6.1Hz,1H),8.37(s,1H),8.18(d,J=8.6Hz,1H),8.04(s,1H),7.98(s,1H),7.47(d,J =8.7Hz,1H),7.06(d,J=6.1Hz,1H),3.64–3.60(m,1H),2.27–2.14(m,2H),1.95–1.87(m,2H),1.85–1.77(m,2H),1.75–1.65(m,2H).

[0395] Compound 8-(2-cyclopentylbenzo[d]thiazolyl)amino)-2H-spirothiopheno[2,3-g]quinoline-3, Synthesis of 2'-[1,3]dioxolane]1,1-dioxide (LK-24)

[0396] Intermediate M52 (36 mg, 0.07 mmol) and cesium carbonate (62 mg, 0.19 mmol) were added to ethylene glycol (1 mL), and the mixture was heated to 60 °C and reacted for 12 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by preparative thin-layer chromatography (DCM:MeOH = 20:1) to give 10 mg of a yellow solid, which was compound LK-24, with a yield of 29%. 1 H NMR(500MHz,DMSO-d6)δ11.26(s,1H),9.38(s,1H),8.64(d,J=7.0Hz,1H),8.29–8 .24(m,2H),8.07(d,J=2.0Hz,1H),7.52(dd,J=8.5,2.1Hz,1H),6.99(d,J=7.0Hz,1 H),4.36–4.31(m,2H),4.28–4.22(m,2H),4.14(s,2H),3.63(p,J=8.1Hz,1H),2.2 5–2.17(m,2H),1.96–1.87(m,2H),1.85–1.77(m,2H),1.76–1.68(m,2H).ESI-HRMS Calcd forC 25 H 24 N3O4S2[M+H] + :494.1203,found 494.1202.

[0397] Example 24

[0398]

[0399] Synthesis of intermediate 3-cyclopropyl-5-nitrobenzo[b]thiophene 1,1-dioxide (M53)

[0400] Intermediate M47 (2.4 g, 8.27 mmol), cyclopropylboronic acid (853 mg, 9.93 mmol), palladium acetate (186 mg, 0.83 mmol), and tricyclohexylphosphine (464 mg, 1.65 mmol) were dissolved in toluene (70 mL). A solution of potassium phosphate (6.62 g, 24.82 mmol) in water (15 mL) was added, and the mixture was heated to 100 °C under N2 protection for 12 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:DCM = 3:7) to give 440 mg of a yellow solid, which was intermediate M53, with a yield of 21%. 1H NMR (500MHz, Chloroform-d) δ8.49–8.43(m,2H),7.93–7.89(m,1H),6.36(d,J=1.4Hz,1H),1.99–1.90(m,1H),1.31–1.27(m,2H),0.95–0.87(m,2H).

[0401] Synthesis of intermediate 5-amino-3-cyclopropylbenzo[b]thiophene 1,1-dioxide (M54)

[0402] The synthesis of intermediate M54 was the same as that of M48, using intermediate M53 as the starting material, to obtain 370 mg of yellow solid, with a yield of 95%. 1 H NMR(400MHz,Chloroform-d)δ7.45(d,J=8.2Hz,1H),6.81(d,J=2.1Hz,1H),6.67(dd,J=8.2,2.1Hz ,1H),6.11(d,J=1.2Hz,1H),4.18(s,2H),1.81–1.71(m,1H),1.16–1.06(m,2H),0.83–0.74(m,2H).

[0403] Intermediate 5-(((3-cyclopropyl-1,1-dioxane[b]thiophene-5-yl)amino)methylene)-2,2-dimethyl Synthesis of 1,3-dioxane-4,6-dione (M55)

[0404] The synthesis of intermediate M55 was the same as that of M49, using intermediate M54 as the starting material, to obtain 550 mg of yellow solid, with a yield of 72%. 1 H NMR (500MHz, DMSO-d6) δ11.40(d,J=14.3Hz,1H),8.79(d,J=14.3Hz,1H),8.17(d,J=2.1Hz,1H),7.86(d,J=8.2Hz,1H),7 .78(dd,J=8.2,2.0Hz,1H),6.98(s,1H),2.20(tt,J=8.3,4.1Hz,1H),1.70(s,6H),1.20–1.12(m,2H),0.93–0.85(m,2H).

[0405] Synthesis of intermediate 3-cyclopropyl-8-hydroxythiopheno[2,3-g]quinoline 1,1-dioxide (M56)

[0406] The synthesis of intermediate M56 was the same as that of M50, using intermediate M55 as the starting material, to obtain 400 mg of yellow solid, with a yield of 82%. 1H NMR(500MHz,DMSO-d6)δ12.20(s,1H),8.25(s,1H),8.03(dd,J=7.5,5.7Hz,1H),7.87(s,1H),7.17(s,1 H),6.19(d,J=7.4Hz,1H),2.05(tt,J=8.5,5.0Hz,1H),1.16(dq,J=6.7,4.1Hz,2H),0.97–0.84(m,2H).

[0407] Synthesis of intermediate 8-chloro-3-cyclopropylthiopheno[2,3-g]quinoline 1,1-dioxide (M57)

[0408] The synthesis of intermediate M57 was the same as that of M51, using intermediate M56 as the starting material, to obtain 220 mg of a light yellow solid, with a yield of 52%. 1 H NMR(500MHz,DMSO-d6)δ9.02(d,J=4.8Hz,1H),8.56(s,1H),8.52(s,1H),7.96(d,J=4.8 Hz,1H),7.23(d,J=0.8Hz,1H),2.40–2.31(m,1H),1.26–1.16(m,2H),0.99–0.90(m,2H).

[0409] Compound 8-(2-cyclopentylbenzo[d]thiazolyl-5-yl)amino)-3-cyclopropylthiopheno[2,3-g]quinoline 1,1- Synthesis of Dioxide (LK-25)

[0410] The synthesis of compound LK-25 was the same as that of LK-24, using intermediate M57 as the starting material and isopropanol as the solvent. The reaction was carried out at 95°C to give 46 mg of yellow solid in the form of hydrochloride, with a yield of 82%. 1 H NMR(600MHz,DMSO-d6)δ14.99(brs,1H),11.30(s,1H),9.34(s,1H),8.57(d,J=7.0Hz,1H),8.4 0(s,1H),8.26(d,J=8.5Hz,1H),8.07(d,J=2.1Hz,1H),7.52(dd,J=8.5,2.1Hz,1H),7.41(d,J=0 .9Hz,1H),6.98(d,J=7.0Hz,1H),3.62(p,J=8.1Hz,1H),2.25–2.18(m,2H),2.16–2.09(m,1H), 1.95–1.86(m,2H),1.84–1.77(m,2H),1.76–1.67(m,2H),1.27–1.21(m,2H),1.01–0.96(m,2H). 13CNMR(151MHz,DMSO)δ178.61,155.54,153.54,149.24,144.13,141.83,135.80,135.09,135.05,133.52,12 5.50,123.50,122.04,118.59,117.66,117.32,114.96,102.02,43.89,33.29,25.03,9.60,8.27.ESI-HRMS Calcd for C 26 H 24 N3O2S2[M+H] + :474.1304,found474.1305.

[0411] Example 25

[0412]

[0413] Compound 8-(2-cyclopentylbenzo[d]thiazolyl-5-yl)amino)-3-cyclopropyl-2,3-dihydrothiophene[2,3- Synthesis of quinoline 1,1-dioxide (LK-26)

[0414] The synthesis of compound LK-26 was performed following the same procedure as that of M4, using compound LK-25 as the starting material, yielding 8 mg of a yellow solid in 50% yield. 1 H NMR(500MHz,DMSO-d6)δ11.29(s,1H),9.30(d,J=2.3Hz,1H),8.59(dd,J=8.8,7.1Hz,1H),8.32–8.31(m,1H) ,8.30–8.26(m,1H),8.08(dd,J=3.6,2.1Hz,1H),7.52(dd,J=8.4,2.2Hz,1H),6.96(d,J=7.2Hz,1H),4.06(dd ,J=13.4,7.5Hz,1H),3.74–3.58(m,2H),3.23(q,J=8.0Hz,1H),2.26–2.17(m,2H),1.95–1.88(m,2H),1.85–1 .78(m,2H),1.77–1.68(m,3H),0.85–0.73(m,2H),0.65–0.58(m,1H),0.55–0.48(m,1H).ESI-MS:476.4[M+H] + .

[0415] Example 26

[0416]

[0417] Synthesis of intermediate 4-chloro-6-(isopropylthio)quinazoline (M58)

[0418] 4-Chloro-6-iodoquinazoline (5.0 g, 17.21 mmol), isopropanethiol (1.76 mL, 18.93 mmol), tetrakis(triphenylphosphine)palladium (596.71 mg, 0.52 mmol), and triethylamine (5.98 mL, 43.03 mmol) were dissolved in N,N-dimethylformamide (30 mL). The mixture was heated to 90 °C under N2 protection and reacted for 12 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:DCM = 3:7) to give 2.62 g of a yellow solid, which was intermediate M58, with a yield of 64%. 1 H NMR (400MHz, DMSO-d6) δ8.46(s,1H),8.01(d,J=2.2Hz,1H),7.84–7.82(m,1H),7.71(d,J=8.4Hz,1H),3.65(hept,J=6.6Hz,1H),1.29(d,J=6.6Hz,6H).

[0419] Synthesis of intermediate 2-cyclopentyl-N-(6-(isopropylthio)quinazolin-4-yl)benzo[d]thiazol-5-amine (M59)

[0420] Intermediate M58 (50.0 mg, 0.21 mmol), intermediate M29 (38.1 mg, 0.17 mmol), and triethylamine (121.3 μL, 0.87 mmol) were dissolved in isopropanol (5 mL), and the mixture was heated to 90 °C and reacted for 8 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (MeOH:DCM = 1:30) to give 61 mg of a yellow solid, which was intermediate M59, in 83% yield. 1 H NMR(500MHz,Chloroform-d)δ8.74(s,1H),8.47(d,J=2.1Hz,1H),7.95(s,1H),7.89(d,J=8.8Hz,1H),7.87–7.81(m,2H),7.63(dd,J=8 .5,2.1Hz,1H),3.61–3.52(m,2H),2.31–2.24(m,2H),2.02–1.94(m,2H),1.92–1.87(m,2H),1.79–1.73(m,2H),1.36(d,J=6.7Hz,6H).

[0421] Compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)quinazolin-4-yl)benzo[d]thiazol-5-amine (LK-27) Synthesis

[0422] Intermediate M59 (60 mg, 0.17 mmol) was dissolved in DCM (5 mL), and m-chloroperoxybenzoic acid (60.3 g, 0.35 mmol) was added in portions. The reaction was carried out at room temperature for 8 hours. After the reaction was complete, a white solid was filtered off. The filtrate was extracted with DCM, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness and purified by column chromatography (DCM:MeOH = 20:1) to give 35 mg of white solid, in 46% yield. 1 H NMR(500MHz,DMSO-d6)δ10.55(s,1H),9.25(d,J=2.0Hz,1H),8.74(s,1H),8.52(d ,J=2.1Hz,1H),8.21(dd,J=8.7,2.0Hz,1H),8.05(d,J=8.7Hz,1H),7.99(d,J=8.7H z,1H),7.78(dd,J=8.7,2.1Hz,1H),3.62–3.53(m,2H),2.23–2.15(m,2H),1.94–1 .86(m,2H),1.84–1.77(m,2H),1.75–1.67(m,2H),1.24(d,J=6.8Hz,6H).ESI-HRMS Calcd forC 23 H 25 N4O2S2[M+H] + :453.1413,found 453.1413.

[0423] Example 27

[0424]

[0425] Synthesis of intermediate 2-cyclopentyl-N-(6-iodo-7-methoxyquinazoline-4-yl)benzo[d]thiazol-5-amine (M60) become

[0426] 4-Chloro-6-iodo-7-methoxyquinazoline (250.0 mg, 0.78 mmol) and intermediate M29 (204.3 mg, 0.94 mmol) were dissolved in isopropanol (5 mL), and the mixture was heated to 90 °C and reacted for 1 hour. After the reaction was complete, the mixture was filtered and washed with a small amount of isopropanol to give 394 mg of a yellow solid, which was intermediate M60, with a yield of 101%. 1H NMR (500MHz, DMSO-d6) δ11.38(s,1H),9.36(s,1H),8.89(s,1H),8.36(d,J=2.0Hz,1H),8.12(d,J=8.6Hz,1H),7.70(dd,J=8.6,2.1H z,1H),7.31(s,1H),4.06(s,3H),3.59(p,J=8.0Hz,1H),2.23–2.16(m,2H),1.93–1.86(m,2H),1.83–1.77(m,2H),1.75–1.67(m,2H).

[0427] Intermediate 2-cyclopentyl-N-(6-(isopropylthio)-7-methoxyquinazoline-4-yl)benzo[d]thiazol-5-amine Synthesis of (M61)

[0428] Intermediate M60 (390 g, 0.78 mmol), isopropanethiol (72.1 μL, 0.78 mmol), tetrakis(triphenylphosphine)palladium (26.9 mg, 0.02 mmol), and triethylamine (269.8 μL, 1.94 mmol) were dissolved in N,N-dimethylformamide (10 mL). The mixture was heated to 90 °C for 4 hours under N2 protection. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (MeOH:DCM = 1:40) to give 186.5 g of a brown solid, which was intermediate M61, with a yield of 53%.

[0429] Intermediate 2-cyclopentyl-N-(6-(isopropylsulfinyl)-7-methoxyquinazoline-4-yl)benzo[d]thiazole- Synthesis of 5-amine (M62)

[0430] Intermediate M61 (186 mg, 0.39 mmol) was dissolved in DCM (5 mL), and m-chloroperoxybenzoic acid (336 mg, 1.07 mmol) was added in portions. The reaction was carried out at room temperature for 8 hours. After the reaction was complete, a white solid was filtered off, extracted with DCM, and washed with saturated brine. The organic phase was evaporated to dryness and purified by column chromatography (MeOH:DCM = 1:40) to give 120 mg of a yellow solid, in 64% yield. 1H NMR(500MHz,DMSO-d6)δ10.38(s,1H),8.75(s,1H),8.60(s,1H),8.49(d,J=2.1Hz,1 H),8.00(d,J=8.7Hz,1H),7.78(dd,J=8.7,2.1Hz,1H),7.33(s,1H),4.02(s,3H),3. 58(p,J=8.0Hz,1H),3.25(hept,J=6.9Hz,1H),2.22–2.16(m,2H),1.93–1.87(m,2H) ,1.83–1.77(m,2H),1.73–1.68(m,2H),1.37(d,J=7.0Hz,3H),0.93(d,J=6.8Hz,3H).

[0431] Compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)-7-methoxyquinazoline-4-yl)benzo[d]thiazol-5- Synthesis of amine (LK-28)

[0432] Intermediate M62 (32 mg, 0.39 mmol) was dissolved in tetrahydrofuran (3 mL), and an aqueous solution of potassium persulfate (336 mg, 1.07 mmol) (2 mL) was added. The reaction was carried out at room temperature for 8 hours. After the reaction was complete, a white solid was filtered off, extracted with DCM, and washed with saturated brine. The organic phase was evaporated to dryness and purified by column chromatography (MeOH:DCM = 1:20) to give 15 mg of a yellow solid, in 47% yield. 1 H NMR (500MHz, DMSO-d6) δ11.33(s,1H),9.22(s,1H),8.80(s,1H),8.36(d,J=2.0H z,1H),8.09(d,J=8.6Hz,1H),7.69(dd,J=8.6,2.1Hz,1H),7.45(s,1H),4.11(s,3 H),3.80(hept,J=6.8Hz,1H),3.59(p,J=8.0Hz,1H),2.23–2.16(m,2H),1.93–1. 86(m,2H),1.84–1.76(m,2H),1.75–1.67(m,2H),1.24(d,J=6.8Hz,6H).ESI-HRMS Calcd for C 24 H 27 N4O3S2[M+H] + :483.1519, found 483.1418.

[0433] Example 28

[0434]

[0435] Compound 4-((2-cyclopentylbenzo[d]thiazolyl-5-yl)amino)-6-(isopropylsulfonyl)quinazolin-7-ol Synthesis of (LK-29)

[0436] LK-28 (60.0 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (5 mL), and sodium isopropanethiolate (73.2 mg, 0.10 mmol) was added. The mixture was heated to 150 °C and reacted for 1 hour. After the reaction was complete, the solvent was evaporated, the pH was adjusted to 7-8 with hydrochloric acid (3N), and the mixture was filtered to give 55 mg of a pale yellow solid, with a yield of 94%. 1 H NMR (500MHz, DMSO-d6) δ11.47(s,1H),9.19(s,1H),8.77(s,1H),8.32(d,J=2.0Hz,1H),8.10(d,J=8.7Hz,1H),7.67(dd,J=8.6,2.1Hz,1H),7.28(s,1H ),3.89–3.86(m,1H),3.60–3.58(m,1H),2.22–2.17(m,2H),1.92–1.87(m, 2H),1.82–1.77(m,2H),1.73–1.69(m,2H),1.24(d,J=6.9Hz,6H).ESI-HRMS Calcd forC 23 H 25 N4O3S2[M+H] + :469.1363,found 469.1362.

[0437] Example 29

[0438]

[0439] Compound 2-((4-((2-cyclopentylbenzo[d]thiazolyl)amino)-6-(isopropylsulfonyl)quinazolin- Synthesis of 7-yl)oxy)ethanol (LK-30)

[0440] LK-29 (40 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (41.3 mg, 0.30 mmol) was added, and the mixture was stirred for 10 min. Then, 2-bromoethanol (24.2 μL, 0.34 mmol) was added, and the mixture was heated to 70 °C and reacted for 3 h. The reaction was then cooled to room temperature and stirred for another 16 h. After the reaction was complete, the solvent was evaporated, and the mixture was slurried using DCM / PE and filtered to obtain 40 mg of a pale yellow solid, with a yield of 91%. 1H NMR(500MHz,DMSO-d6)δ11.28(s,1H),9.22(s,1H),8.78(s,1H),8.37(d,J=2.1Hz,1H),8 .08(d,J=8.6Hz,1H),7.70(dd,J=8.6,2.1Hz,1H),7.44(s,1H),4.37(t,J=4.6Hz,2H),4. 04(hept,J=6.8Hz,1H),3.84(d,J=4.6Hz,2H),3.60(p,J=8.0Hz,1H),2.22–2.17(m,2H), 1.92–1.87(m,2H),1.82–1.77(m,2H),1.74–1.69(m,2H),1.23(d,J=6.8Hz,6H).ESI-HRMS Calcd for C 25 H 29 N4O4S2[M+H] + :513.1625,found 513.1627.

[0441] Example 30

[0442]

[0443] Synthesis of intermediate 4-chloro-N-methylquinoline-7-carboxamide (M63)

[0444] 4-Chloroquinoline-7-carboxylic acid (130 mg, 0.58 mmol) was dissolved in oxalyl chloride (1 mL), and 1 drop of DMF was added. The reaction was carried out at room temperature for 4 hours, and then the reaction solution was evaporated to dryness to obtain the corresponding crude acyl chloride product. Methylamine hydrochloride (39 mg, 0.58 mmol) and triethylamine (160 μL, 1.15 mmol) were dissolved in DMF (2 mL) at 0 °C, and the crude acyl chloride product in DMF (1 mL) was added dropwise. The reaction was then slowly brought to room temperature and carried out for 12 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (DCM:MeOH = 20:1) after concentration of the organic phase, yielding 40 mg of a white solid, which was intermediate M63, with a yield of 31%.

[0445] The compound 4-(2-cyclopentylbenzo[d]thiazolyl-5-yl)amino)-N-methylquinoline-7-carboxamide (LK-31) synthesis

[0446] The synthesis of compound LK-31 was the same as that of LK-1, using M-63 and M-29 as starting materials, yielding 28 mg of yellow solid in 70% yield. 1H NMR(500MHz,DMSO-d6)δ9.28(s,1H),8.75(q,J=3.4,2.5Hz,1H),8.59–8.46(m,2H),8.39 (d,J=1.8Hz,1H),8.06(d,J=8.5Hz,1H),7.97(dd,J=8.7,1.9Hz,1H),7.89(d,J=2.0Hz,1H ),7.44(dd,J=8.5,2.1Hz,1H),7.01(d,J=5.3Hz,1H),3.58(p,J=8.1Hz,1H),2.86(d,J=4. 4Hz, 3H), 2.19 (h, J = 6.7Hz, 2H), 1.95–1.85 (m, 2H), 1.84–1.75 (m, 2H), 1.75–1.64 (m, 2H).

[0447] Example 31

[0448]

[0449] Synthesis of intermediate 4-chloro-N-cyclopropylquinoline-7-carboxamide (M-64)

[0450] The synthesis of compound M64 was the same as that of M63, using 4-chloroquinoline-7-carboxylic acid and cyclopropylamine as starting materials, yielding 50 mg of white solid in 35% yield. 1 H NMR(500MHz,Chloroform-d)δ8.86(d,J=4.7Hz,1H),8.39(d,J=1.7Hz,1H),8.33(dd,J=8.7,0.6Hz,1H),8.12(dd,J=8 .7,1.8Hz,1H),7.59(d,J=4.7Hz,1H),6.50(s,1H),3.01(qt,J=7.1,3.6Hz,1H),1.02–0.91(m,2H),0.78–0.66(m,2H).

[0451] Compound 4-(2-cyclopentylbenzo[d]thiazolyl-5-yl)amino)-N-cyclopropylquinoline-7-carboxamide (LK-32) Synthesis

[0452] The synthesis of compound LK-31 was the same as that of LK-1, using M-63 and M-29 as starting materials, yielding 26 mg of yellow solid in the form of hydrochloride, with a yield of 68%. 1H NMR (500MHz, DMSO-d6) δ14.45(s,1H),11.17(s,1H),8.98(d,J=4.3Hz,1H),8.88(d,J=8.9Hz,1H),8.56(d,J=7.0H z,1H),8.43(d,J=1.7Hz,1H),8.26(d,J=8.4Hz,1H),8.19(dd,J=8.7,1.7Hz,1H),8.08(d,J=2.0Hz,1H),7.53(dd, J=8.5,2.0Hz,1H),6.90(d,J=6.9Hz,1H),3.63(p,J=8.1Hz,1H),2.96(tq,J=7.7,4.0Hz,1H),2.28–2.17(m,2H),1 .98–1.87(m,2H),1.85–1.77(m,2H),1.77–1.66(m,2H),0.82–0.75(m,2H),0.70–0.63(m,2H).ESI-MS:429.4[M+H] + .

[0453] Example 32

[0454]

[0455] Compound 4-(2-cyclopentylbenzo[d]thiazolyl-5-yl)amino)-6-(isopropylsulfonyl)quinoline-7-ol (LK- 33) Synthetic intermediate

[0456] Compound LK-23 (86 mg, 0.16 mmol) was dissolved in DCM (2 mL), cooled to 0 °C under N2 protection, and boron tribromide (1 M in DCM, 1.66 mL, 1.66 mmol) was slowly added dropwise. The reaction was carried out at 0 °C for 16 hours. After the reaction was complete, the mixture was extracted with a dichloromethane-n-butanol mixture (v / v = 3:1), washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness and purified by preparative thin-layer chromatography (DCM:MeOH = 10:1) to give 66 mg of a yellow solid, which was compound LK-33, in 79% yield. ESI-MS: 468.3 [M+H] + .

[0457] Example 33

[0458]

[0459] Compound 2-((4-((2-cyclopentylbenzo[d]thiazolyl-5-yl)amino)-6-(isopropylsulfonyl)quinoline-7- Synthesis of alkyl(oxy)ethane-1-ol (LK-34)

[0460] The synthesis of compound LK-34 was the same as that of LK-30, using LK-33 as the starting material, yielding 28 mg of yellow solid in 64% yield. 1H NMR (500MHz, DMSO-d6) δ11.52(s,1H),9.26(s,1H),8.47(d,J=7.2Hz,1H),8.25(d,J=8.4Hz,1H),8.0 5(d,J=2.0Hz,1H),7.59(s,1H),7.49(dd,J=8.5,2.1Hz,1H),6.81(d,J=7.2Hz,1H),4.37(t,J=4.7Hz, 2H),4.05(hept,J=6.7Hz,1H),3.87(dd,J=5.2,4.1Hz,2H),3.62(p,J=8.1Hz,1H),2.26–2.16(m,2H) ,1.97–1.86(m,2H),1.85–1.76(m,2H),1.76–1.68(m,2H),1.24(d,J=6.7Hz,6H).ESI-MS:512.4[M+H] +

[0461] Example 34

[0462]

[0463] Synthesis of intermediate N-(2-chloro-4-fluoro-5-nitrophenyl)formamide (M65)

[0464] 1.2 g (6.30 mmol) of 2-chloro-4-fluoro-5-nitroaniline was dissolved in 4 mL of formic acid, and the mixture was heated to 105 °C and reacted for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was directly evaporated to dryness. The solution was purified by column chromatography (PE:EA = 3:1) to give 1.16 g of a yellow solid, which was intermediate M65, with a yield of 84%. 1 H NMR (500MHz, Chloroform-d) δ9.24(d,J=7.5Hz,1H),8.55(s,1H),7.68(s,1H),7.41(d,J=9.7Hz,1H).

[0465] Synthesis of intermediate 6-fluoro-5-nitrobenzo[d]thiazole (M66)

[0466] Intermediate M65 (1.16 g, 5.31 mmol) was dissolved in ethanol (15 mL), heated to 90 °C and refluxed. Sodium sulfide nonahydrate (1.53 g, 6.37 mmol) was added in portions. After reacting for 40 minutes, heating was stopped, and the mixture was cooled to room temperature. The pH was adjusted to 2–3 with 1 N hydrochloric acid. The reaction solution was concentrated and extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (PE:EA = 3:1) to give 300 mg of a yellow solid, which was intermediate M66, with a yield of 29%. 1H NMR (500MHz, Chloroform-d) δ9.16 (s, 1H), 8.86 (d, J = 6.6Hz, 1H), 7.90 (d, J = 9.9Hz, 1H).

[0467] Synthesis of intermediate 2-cyclopentyl-6-fluoro-5-nitrobenzo[d]thiazole (M67)

[0468] The synthesis of intermediate M67 was the same as that of M28, using M66 as the starting material, yielding 25 mg of yellow solid in 12% yield. 1 H NMR(500MHz,Chloroform-d)δ8.63(d,J=6.6Hz,1H),7.72(d,J=10.1Hz,1H),3.56(p,J= 8.1Hz,1H),2.31–2.22(m,2H),2.00–1.93(m,2H),1.92–1.84(m,2H),1.81–1.73(m,2H).

[0469] Synthesis of intermediate 2-cyclopentyl-6-fluorobenzo[d]thiazol-5-amine (M68)

[0470] The synthesis of intermediate M68 was the same as that of M29, using M67 as the starting material, yielding 16 mg of white solid in 67% yield. 1 H NMR(500MHz,Chloroform-d)δ7.43(d,J=10.2Hz,1H),7.36(d,J=8.0Hz,1H),3 .51(p,J=8.1Hz,1H),2.31–2.21(m,2H),1.99–1.83(m,4H),1.82–1.70(m,2H).

[0471] Compound 2-cyclopentyl-6-fluoro-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]thiazol-5-amine (LK- Synthesis of 35)

[0472] The synthesis of compound LK-35 was the same as that of LK-1, using M68 and M29 as starting materials, yielding 23 mg of yellow solid in the form of hydrochloride, with a yield of 67%. 1H NMR(500MHz,DMSO-d6)δ15.08(brs,1H),11.56(s,1H),9.44(d,J=1.8Hz,1H),8 .65(d,J=7.0Hz,1H),8.41(dd,J=9.0,1.8Hz,1H),8.38–8.28(m,2H),8.19(d,J= 7.0Hz,1H),6.77(dd,J=7.0,2.1Hz,1H),3.72–3.58(m,2H),2.25–2.16(m,2H), 1.95–1.86(m,2H),1.85–1.77(m,2H),1.76–1.66(m,2H),1.26(d,J=6.8Hz,6H). 13 C NMR (126MHz, DMSO-d6) δ178.32,156.18,155.02,153.05,149.75,144.92,140.80,135.13(d,J=11.2Hz),131.76,126.20,1 23.36(d,J=15.5Hz),122.20,121.29,116.60,110.18(d,J=25.3Hz),101.92,54.32,43.81,33.26,25.01,15.05.ESI-HRMS Calcd for C 24 H 25 FN3O2S2[M+H] + :470.1367,found 470.1370.

[0473] Example 35

[0474]

[0475] Synthesis of intermediate 5-nitro-2-(thiazolyl-2-yl)benzo[d]thiazole (M69)

[0476] 5-Nitrobenzothiazole (200 mg, 1.11 mmol), thiazole (142 mg, 1.66 mmol), palladium acetate (25 mg, 0.11 mmol), copper acetate (101 mg, 0.55 mmol), potassium fluoride (194 mg, 3.33 mmol), and silver nitrate (283 mg, 1.66 mmol) were added to DMF (4 mL), and the mixture was heated to 120 °C in an open container for 12 hours. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and separated by column chromatography (PE:EA = 3:1) to give 15 mg of a yellow solid, which was intermediate M69, with a yield of 5%. 1H NMR (500MHz, Chloroform-d) δ8.97(d,J=2.2Hz,1H),8.35(dd,J=8.8,2.2Hz,1H),8.11(d,J=8.8Hz,1H),8.06(d,J=3.1Hz,1H),7.67(d,J=3.1Hz,1H).

[0477] Synthesis of intermediate 2-(thiazol-2-yl)benzo[d]thiazol-5-amine (M70)

[0478] The synthesis of intermediate M70 was the same as that of M4, using M69 as the starting material, to obtain 10 mg of white solid, with a yield of 66%. 1 H NMR(500MHz,Chloroform-d)δ7.98(d,J=3.2Hz,1H),7.71(d,J=8.5Hz,1H),7.54(d ,J=3.2Hz,1H),7.39(d,J=2.3Hz,1H),6.89(dd,J=8.5,2.3Hz,1H),3.83(brs,2H).

[0479] Compound N-(6-(isopropylsulfonyl)quinoline-4-yl)-2-(thiazolyl-2-yl)benzo[d]thiazolyl-5-amine (LK- Synthesis of 36)

[0480] The synthesis of compound LK-36 was the same as that of LK-1, using M70 and M2 as starting materials, yielding 16 mg of yellow solid in the form of hydrochloride, with a yield of 74%. 1 H NMR (500MHz, DMSO-d6) δ14.95(brs,1H),11.68(s,1H),9.45(d,J=1.9Hz,1H),8.62(d,J=7.1Hz,1H),8.48–8.36(m,2H),8.35–8.2 5(m,2H),8.20–8.11(m,2H),7.68(dd,J=8.6,2.1Hz,1H),7.06(d,J=7.1Hz,1H),3.68(hept,J=6.8Hz,1H),1.26(d,J=6.9Hz,6H). 13 C NMR(126MHz,DMSO-d6)δ163.00,160.08,155.68,153.73,144.80,144.68,140.92,136.07,134.94,133 .67,131.69,126.30,124.82,124.21,123.85,122.02,119.49,116.94,101.59,54.31,15.05.ESI-HRMS Calcd for C 22 H 19 N4O2S3[M+H]+ :467.0665,found 467.0663.

[0481] Example 36

[0482]

[0483] Synthesis of intermediate 5-nitro-2-(oxazol-2-yl)benzo[d]thiazole (M71)

[0484] The synthesis of intermediate M71 was the same as that of M69, using 5-nitrobenzothiazole and oxazole as starting materials, yielding 19 mg of white solid in 6% yield. 1 H NMR (500MHz, Chloroform-d) δ9.05(d,J=2.2Hz,1H),8.40(dd,J=8.9,2.2Hz,1H),8.14(d,J=8.8Hz,1H),7.97(d,J=0.8Hz,1H),7.47(d,J=0.8Hz,1H).

[0485] Synthesis of intermediate 2-(thiazol-2-yl)benzo[d]oxazol-5-amine (M72)

[0486] The synthesis of intermediate M72 was performed following the same procedure as M4, using M71 as the starting material, yielding 14 mg of a white solid in 73% yield.

[0487] Compound N-(6-(isopropylsulfonyl)quinoline-4-yl)-2-(thiazolyl-2-yl)benzo[d]oxazol-5-amine (LK- Synthesis of 37)

[0488] The synthesis of compound LK-37 was the same as that of LK-1, using M72 and M2 as starting materials, yielding 11 mg of yellow solid in the form of hydrochloride, with a yield of 69%. 1 H NMR (500MHz, DMSO-d6) δ14.94(brs,1H),11.68(s,1H),9.44(d,J=2.0Hz,1H),8.64(d,J=7.1Hz,1H),8.52(s,1H),8.46(d,J=8.6Hz,1H),8.40(dd,J =8.9,1.8Hz,1H),8.36–8.26(m,2H),7.72(dd,J=8.6,2.1Hz,1H),7.65(s ,1H),7.05(d,J=7.0Hz,1H),3.67(p,J=6.8Hz,1H),1.26(d,J=6.9Hz,6H). 13C NMR(126MHz,DMSO-d6)δ155.90,155.69,155.38,153.88,144.70,142.60,140.89,136.20,134.94,133.70 ,131.71,129.63,126.29,124.21,124.18,122.01,120.05,116.94,101.55,54.32,15.05.ESI-HRMSCalcd for C 22 H 19 N4O3S2[M+H] + :451.0893,found 451.0893.

[0489] Example 37

[0490]

[0491] Synthesis of intermediate N-(2-bromo-5-nitrophenyl)cyclopentanamide (M73)

[0492] The synthesis of intermediate M73 was the same as that of M63, using 2-bromo-5-nitroaniline and cyclopentanecarboxylic acid as starting materials and pyridine as base, to give 230 mg of yellow solid, with a yield of 32%. 1 H NMR(500MHz,Chloroform-d)δ9.35(d,J=2.7Hz,1H),7.85(dd,J=8.8,2.7Hz,1H),7.81(s,1H),7.74(d,J=8. 8Hz,1H),2.85(p,J=8.0Hz,1H),2.11–2.01(m,2H),2.01–1.93(m,2H),1.89–1.80(m,2H),1.74–1.66(m,2H).

[0493] Synthesis of intermediate 2-cyclopentyl-5-nitrobenzo[d]oxazole (M74)

[0494] Intermediate M74 (100 mg, 0.32 mmol), cuprous iodide (4 mg, 0.02 mmol), 1,10-phenanthroline (6 mg, 0.03 mmol), and cesium carbonate (157 mg, 0.48 mmol) were added to ethylene glycol dimethyl ether (4 mL). The mixture was heated to 95 °C for 24 hours under N2 protection. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, and dried over colorless sodium sulfate. The organic phase was purified by column chromatography (PE:EA = 4:1) after rotary evaporation, yielding 37 mg of a yellow solid, which was intermediate M74, in 50% yield. 1H NMR(600MHz,Chloroform-d)δ8.56(d,J=2.3Hz,1H),8.27(dd,J=8.9,2.3Hz,1H),7.57(d,J=8.9Hz,1H ),3.43(p,J=8.1Hz,1H),2.27–2.16(m,2H),2.11–2.00(m,2H),1.95–1.84(m,2H),1.81–1.71(m,2H).

[0495] Synthesis of intermediate 2-cyclopentylbenzo[d]oxazol-5-amine (M75)

[0496] The synthesis of intermediate (M75) was the same as that of M6a, using M74 as the starting material, yielding 27 mg of brown oily substance in 77% yield. 1 H NMR(400MHz,Chloroform-d)δ7.23(d,J=8.6Hz,1H),6.96(d,J=2.3Hz,1H),6.64(dd,J=8.6,2.3Hz,1H ),3.32(p,J=8.1Hz,1H),2.20–2.07(m,2H),2.07–1.95(m,2H),1.88–1.79(m,2H),1.74–1.67(m,2H).

[0497] Compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]oxazol-5-amine (LK-38) synthesis

[0498] The synthesis of compound LK-38 was the same as that of LK-1, using M74 and M2 as starting materials, yielding 20 mg of yellow solid in the form of hydrochloride, with a yield of 50%. 1 H NMR(500MHz,DMSO-d6)δ14.86(s,1H),11.59(s,1H),9.41(d,J=1.9Hz,1H),8.57(d,J=7.1Hz ,1H),8.38(dd,J=8.9,1.8Hz,1H),8.28(d,J=8.9Hz,1H),7.96–7.82(m,2H),7.47(dd,J=8.6 ,2.1Hz,1H),6.83(d,J=7.1Hz,1H),3.65(hept,J=6.7Hz,1H),3.49(p,J=8.0Hz,1H),2.20–2 .09(m,2H),2.03–1.92(m,2H),1.82–1.74(m,2H),1.73–1.65(m,2H),1.25(d,J=6.8Hz,6H). 13C NMR (126MHz, DMSO) δ171.72,156.19,149.38,144.34,141.90,140.75,134.83,133.04,131.71, 126.27,122.51,121.83,116.67,111.77,101.20,54.31,37.97,30.71,25.13,15.05.ESI-HRMS Calcd for C 24 H 26 N3O3S[M+H] + :436.1689,found436.1690.

[0499] Example 38

[0500]

[0501] Compound 8-(benzo[d]thiazol-5-ylamino)-3-cyclopropylthiopheno[2,3-g]quinoline 1,1-dioxide Synthesis of (DB-2)

[0502] The synthesis of compound DB-2 was based on that of compound LK-25, using M57 and 5-aminobenzothiazole as starting materials, yielding 40 mg of yellow solid in 91% yield. 1 H NMR(600MHz,DMSO-d6)δ14.75(brs,1H),11.24(s,1H),9.51(s,1H),9.28(s ,1H),8.56(d,J=7.0Hz,1H),8.37(d,J=8.5Hz,1H),8.33(s,1H),8.21(d,J=2 .1Hz,1H),7.59(dd,J=8.5,2.1Hz,1H),7.38(d,J=0.9Hz,1H),6.98(d,J=7. 0Hz,1H),2.11(qd,J=8.7,4.9Hz,1H),1.24–1.18(m,2H),0.97–0.92(m,2H). 13 C NMR(151MHz,DMSO-d6)δ158.41,155.50,153.87,149.26,144.34,141.87,135.81,135.23,135.12 ,132.73,125.52,123.98,122.77,119.33,117.57,117.37,115.09,102.04,9.56,8.27.ESI-HRMS Calcd for C 21 H 16 N3O2S2[M+H] + :406.0678,found 406.0678.

[0503] Example 39

[0504]

[0505] Synthesis of intermediate 1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (M76)

[0506] 5-Amino-1-(tert-butyl)-1H-pyrazole-4-onitrile (350 mg, 2.13 mmol) was dissolved in formamide (3 mL), and the mixture was heated to 180 °C and reacted for 9 hours. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by column chromatography (PE:EA = 1:1) to give 250 mg of a yellow solid, which was intermediate M76, with a yield of 61%. 1 H NMR (400MHz, DMSO-d6) δ8.15(s,1H),8.03(s,1H),7.58(brs,2H),1.70(s,9H).

[0507] Synthesis of intermediate 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (M77)

[0508] N-bromosuccinimide (209 mg, 1.18 mmol) was added to 2 mL of an acetonitrile solution of intermediate M76 (150 mg, 0.78 mmol). The reaction mixture was heated to 100 °C and reacted for 2 hours. After the reaction mixture was evaporated to dryness, it was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 3:2) to give 168 mg of orange solid, which was intermediate M77, with a yield of 79%. 1 H NMR (400MHz, DMSO-d6) δ8.24 (s, 1H), 1.69 (s, 9H).

[0509] Synthesis of intermediate 5-bromo-2-(sec-butyl)benzo[d]thiazole (M78)

[0510] To a 20 mL / 20 mL mixture of 5-bromobenzo[d]thiazole (3 g, 14.01 mmol) and dichloromethane / water, 2-methylbutyric acid (3.03 mL, 28.03 mmol), silver nitrate (476 mg, 2.80 mmol), and potassium persulfate (15.15 g, 56.05 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was extracted with dichloromethane, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (PE:EA = 10:1) to give 1.66 g of a brown oily substance, which was intermediate M78, with a yield of 44%.

[0511] Intermediate 2-(sec-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]thiazole Synthesis of (M79)

[0512] To a solution of intermediate M78 (200 mg, 0.74 mmol) and pinacol diborate (207 mg, 0.81 mmol) in 1,4-dioxane (3 mL) and water (1 mL), PdCl2 (dppf) (61 mg, 0.07 mmol) and potassium acetate (255 mg, 2.59 mmol) were added. The reaction mixture was heated to 100 °C for 12 hours under N2 protection. After the reaction was complete, the reaction solution was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by column chromatography (PE:EA = 10:1) to give 165 mg of a colorless oil, which was intermediate M79, with a yield of 70%. 1 H NMR(400MHz,Chloroform-d)δ8.43(t,J=0.9Hz,1H),7.85(dd,J=8.0,0.7Hz,1H),7.74(dd,J=7.9,1.1Hz,1H),3.21 (h,J=6.9Hz,1H),1.96–1.86(m,1H),1.83–1.72(m,1H),1.44(d,J=6.9Hz,3H),1.36(s,12H),0.96(t,J=7.4Hz,3H).

[0513] Compound 1-(tert-butyl)-3-(2-(sec-butyl)benzo[d]thiazolyl-5-yl)-1H-pyrazolo[3,4-d]pyrimidine- Synthesis of 4-amine (LK-48)

[0514] Intermediate M79 (52 mg, 0.17 mmol), intermediate M77 (30 mg, 0.11 mmol), PdCl2 (dppf) (5 mg, 0.006 mmol), and potassium carbonate (31 mg, 0.22 mmol) were dissolved in a mixed solvent of 1,4-dioxane (2.5 mL) and water (0.5 mL). The reaction mixture was heated to 100 °C for 12 hours under N2 protection. After the reaction was complete, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. The crude product was concentrated and purified by preparative thin-layer chromatography to give 36 mg of a white solid, which was compound LK-48, in 85% yield. 1 H NMR(500MHz,Chloroform-d)δ8.36(s,1H),8.30(d,J=1.7Hz,1H),7.99(d,J=8.2Hz,1H),7.71(dd,J=8.1,1.7Hz,1H),5 .59(s,2H),3.25(h,J=7.0Hz,1H),1.99–1.90(m,1H),1.85–1.77(m,1H),1.48(d,J=7.0Hz,3H),1.00(t,J=7.4Hz,3H). 13C NMR(126MHz,Chloroform-d)δ179.43,157.76,154.46,154.34,153.72,141.66,135.25,13 1.76,125.04,122.47,122.43,99.74,60.57,41.20,30.61,29.22,20.66,11.80.ESI-HRMS Calcd for C 24 H 26 N3O2S2[M+H] + :381.1856,found 381.1859.

[0515] Example 40

[0516]

[0517] Synthesis of intermediate 5-bromo-2-cyclopentylbenzo[d]thiazole (M80)

[0518] The synthesis of intermediate M80 was the same as that of intermediate M78, using 5-bromobenzo[d]thiazole and cyclopentanecarboxylic acid as starting materials, yielding 345 mg of brown oily substance in 26% yield. 1 H NMR(400MHz,Chloroform-d)δ8.10(d,J=1.9Hz,1H),7.68(d,J=8.5Hz,1H),7.44(dd,J=8.5, 1.9Hz,1H),3.54(p,J=8.0Hz,1H),2.34–2.20(m,2H),2.01–1.83(m,4H),1.81–1.70(m,2H).

[0519] Intermediate 2-cyclopentyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)benzo[d]thiazole Synthesis of (M81)

[0520] The synthesis of intermediate M81 was performed following the same procedure as intermediate M79, using intermediate M80 as the starting material, yielding 180 mg of a colorless oily substance in 77% yield. 1 H NMR(500MHz,Chloroform-d)δ8.41(s,1H),7.83(d,J=8.0Hz,1H),7.74(dd,J=8.0,1.1Hz,1H),3.55(p,J =8.2Hz,1H),2.29–2.20(m,2H),2.01–1.91(m,2H),1.91–1.82(m,2H),1.79–1.69(m,2H),1.36(s,12H).

[0521] Compound 1-(tert-butyl)-3-(2-cyclopentylbenzo[d]thiazolyl-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4- Synthesis of amine (LK-49)

[0522] The synthesis of compound LK-49 was performed with reference to the synthesis of compound LK-48, using intermediates M77 and M81 as starting materials, yielding 30 mg of white solid in 69% yield.

[0523] 1 H NMR(500MHz,Chloroform-d)δ8.37(s,1H),8.28(d,J=1.5Hz,1H),7.98(d,J=8.2Hz,1H),7.70(dd,J=8.2,1.6Hz,1H),5.5 4(s,2H),3.59(p,J=8.1Hz,1H),2.32–2.25(m,2H),2.02–1.95(m,2H),1.92–1.88(m,2H),1.85(s,9H),1.80–1.74(m,2H). 13 C NMR (126MHz, CDCl3) δ178.67,157.74,154.47,154.34,153.85,141.67,135.40,1 31.76,125.00,122.35(2C),99.75,60.56,44.91,34.08,29.22,25.62.ESI-HRMS Calcd forC 24 H 26 N3O2S2[M+H] + :393.1856,found393.1861.

[0524] Example 41

[0525]

[0526] Synthesis of intermediate 2-cyclopentyl-6-nitro-2H-indazole (M82)

[0527] 2-Amino-4-nitrobenzaldehyde (2.55 mmol, 500 mg) and cyclopentanamine (3.06 mmol, 302 μL) were added to ethanol (5 mL) and the mixture was heated to 50 °C for 30 minutes. The solvent was then evaporated by rotary evaporation, and trimethyl phosphate (3 mL) was added. The mixture was heated to 110 °C and reacted for 1 hour. After the reaction was complete, the reaction solution was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE:EA = 3:1) to give 370 mg of a brown oily substance, with a yield of 63%. 1H NMR(400MHz,Chloroform-d)δ8.72(dt,J=1.9,0.8Hz,1H),8.08(d,J=1.0Hz,1H),7.89(dd,J=9.1,2.0Hz,1H),7.74(dd,J=9.1 ,0.7Hz,1H),5.01(ddd,J=14.2,7.7,6.5Hz,1H),2.44–2.30(m,2H),2.27–2.14(m,2H),2.10–1.93(m,2H),1.91–1.73(m,2H).

[0528] Synthesis of intermediate 2-cyclopentyl-2H-indazole-6-amine (M83)

[0529] The synthesis of intermediate M83 was the same as that of M4, using intermediate M82 as the starting material, to obtain 290 mg of brown oily substance, with a yield of 90%. 1 H NMR(500MHz,Chloroform-d)δ7.82(d,J=1.0Hz,1H),7.47(dd,J=8.8,0.8Hz,1H),6.86(dt,J=1.9,0.9Hz,1H),6.61(dd ,J=8.8,1.9Hz,1H),4.88(p,J=7.3Hz,1H),2.35–2.25(m,2H),2.23–2.13(m,2H),2.02–1.92(m,2H),1.85–1.73(m,2H).

[0530] The synthesis of compound N-(2-cyclopentyl-2H-indazol-6-yl)-6-(isopropylsulfonyl)quinoline-4-amine (LK-47) become

[0531] The synthesis of compound LK-47 was performed with reference to the synthesis of compound LK-1, using intermediates M2 and M83 as starting materials, yielding 62 mg of yellow solid in the form of hydrochloride, with a yield of 70%. 1H NMR (500MHz, DMSO-d6) δ14.74(brs,1H),11.57(s,1H),9.41(d,J=1.8Hz,1H),8.64–8.50(m,2H),8.37(dd,J= 9.0,1.8Hz,1H),8.26(d,J=8.9Hz,1H),7.91(d,J=8.8Hz,1H),7.76(s,1H),7.11(dd,J=8.7,1.8Hz,1H),6.92( d,J=7.0Hz,1H),5.08(p,J=7.1Hz,1H),3.65(hept,J=6.7Hz,1H),2.24(dq,J=13.0,7.0Hz,2H),2.11(ddt,J= 13.0,8.5,6.2Hz,2H),1.97–1.84(m,2H),1.74(dtd,J=12.3,7.8,3.5Hz,2H),1.25(d,J=6.8Hz,6H).ESI-HRMS Calcd for C 24 H 27 N4O2S[M+H] + :435.1849,found435.1846.

[0532] Example 42

[0533]

[0534] Synthesis of intermediate 2-fluoro-4,6-dinitrophenol (M84)

[0535] 2-Fluorophenol (71.4 mmol, 8 g) was added to dichloromethane (30 mL), and 63% nitric acid (178.4 mmol, 8.12 mL) was added dropwise at 0 °C, followed by slow warming to room temperature for 2 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate and washed with saturated brine. The organic phase was concentrated, and petroleum ether (30 mL) was added to precipitate a solid. The solid was filtered, dried, and yielded 6 g of a yellow solid, with a yield of 42%. 1 H NMR (500MHz, Chloroform-d) δ10.97 (s, 1H), 8.91 (t, J = 2.3Hz, 1H), 8.32 (dd, J = 9.2, 2.7Hz, 1H).

[0536] Synthesis of intermediate 2-amino-6-fluoro-4-nitrophenol (M85)

[0537] Intermediate M84 (15.6 mmol, 3.15 g) was dissolved in ethanol (25 mL), heated to 80 °C, and then stannous chloride (23.3 mmol, 4.4 g) was added and the reaction was carried out for 2 hours. After the reaction was completed, the pH was adjusted to 5-6 with 10% sodium hydroxide solution. The reaction solution was extracted with ethyl acetate, washed with saturated brine, and the organic phase was concentrated and separated by column chromatography (PE:EA = 1:1) to give 1.66 g of brown oil, with a yield of 62%. 1 H NMR (500MHz, DMSO-d6) δ7.37 (s, 1H), 7.31 (dd, J = 10.5, 3.1Hz, 1H).

[0538] Synthesis of intermediate N-(3-fluoro-2-hydroxy-5-nitrophenyl)cyclopentanecarboxamide (M86)

[0539] At 0 °C, intermediate M85 (2.32 mmol, 400 mg) and pyridine (4.65 mmol, 380 μL) were dissolved in dichloromethane (5 mL), and cyclopentylformyl chloride (2.44 mmol, 294 μL) was added dropwise. The mixture was then slowly raised to room temperature and reacted for 12 hours. After the reaction was complete, the mixture was extracted with dichloromethane, washed with saturated brine, and the organic phase was concentrated and separated by column chromatography (PE:EA = 2:1) to give 230 mg of a yellow solid, with a yield of 37%.

[0540] Synthesis of intermediate 2-cyclopentyl-7-fluoro-5-nitrobenzo[d]oxazole (M87)

[0541] At 0 °C, intermediate M86 (0.41 mmol, 110 mg) and triphenylphosphine (0.90 mmol, 237 mg) were dissolved in tetrahydrofuran (2 mL), and diethyl azodicarbonate (0.90 mmol, 142 μL) was added dropwise. The mixture was then slowly raised to room temperature and reacted for 12 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, and the organic phase was concentrated and separated by column chromatography (PE:EA = 3:1) to give 25 mg of a yellow oil, with a yield of 24%. 1 H NMR(500MHz,Chloroform-d)δ8.42(d,J=2.0Hz,1H),8.07(dd,J=9.6,2.0Hz,1H),3.47(p, J=8.1Hz,1H),2.31–2.20(m,2H),2.15–2.05(m,2H),1.98–1.87(m,2H),1.85–1.75(m,2H).

[0542] Synthesis of 2-cyclopentyl-7-fluorobenzo[d]oxazol-5-amine (M88)

[0543] The synthesis of intermediate M88 was the same as that of M4, using intermediate M82 as the starting material, to obtain 16 mg of brown oily substance, with a yield of 73%. 1H NMR(500MHz,Chloroform-d)δ6.73(d,J=2.0Hz,1H),6.42(dd,J=11.4,2.0Hz,1H),3.33(p, J=8.2Hz,1H),2.24–2.10(m,2H),2.09–1.96(m,2H),1.93–1.80(m,3H),1.78–1.65(m,3H).

[0544] Compound 2-cyclopentyl-7-fluoro-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]oxazol-5-amine Synthesis of (LK50)

[0545] The synthesis of compound LK-50 followed that of compound LK-1, using intermediates M2 and M88 as starting materials, yielding 16 mg of a yellow solid in 65% yield. Further purification by reversed-phase HPLC (column: Waters Sunfire C18, 19 x 150 mm, 5 μm; mobile phase A: H2O containing 0.1% trifluoroacetic acid; mobile phase B: MeCN containing 0.1% trifluoroacetic acid; gradient: 10%-50% B - 15 min, 50%-65% B - 10 min; 65%-100% B - 7 min; flow rate: 10 mL / min) yielded pure LK-50 in the form of trifluoroacetate. 1 H NMR(500MHz,DMSO-d6)δ14.56(brs,1H),11.50(s,1H),9.33(d,J=1.8Hz,1H),8.64(d,J=7.0Hz ,1H),8.39(dd,J=8.8,1.8Hz,1H),8.21(d,J=8.9Hz,1H),7.74(d,J=1.7Hz,1H),7.53(dd,J=10. 8,1.8Hz,1H),6.96(d,J=7.1Hz,1H),3.60(p,J=6.7Hz,1H),3.53(p,J=7.9Hz,1H),2.24–2.12(m ,2H),2.08–1.91(m,2H),1.85–1.76(m,2H),1.74–1.65(m,2H),1.25(d,J=6.7Hz,6H).ESI-HRMS Calcd for C 24 H 25 FN3O3S[M+H] + :454.1595,found 454.1599.

[0546] Example 42

[0547]

[0548] Synthesis of intermediate N-(2-bromo-3-methyl-5-nitrophenyl)cyclopentanecarboxamide (M89)

[0549] The synthesis of intermediate M89 was the same as that of M86, using 2-bromo-3-methyl-5-nitroaniline and cyclopentylformyl chloride as starting materials, and triethylamine as base, to give 120 mg of pale yellow solid, with a yield of 85%. 1 H NMR(500MHz,Chloroform-d)δ9.18(d,J=2.8Hz,1H),7.93(s,1H),7.90–7.84(m,1H),2.85(p,J=8. 1Hz,1H),2.56(s,3H),2.11–2.01(m,2H),2.00–1.92(m,2H),1.90–1.79(m,2H),1.75–1.65(m,2H).

[0550] Synthesis of intermediate 2-cyclopentyl-7-methyl-5-nitrobenzo[d]oxazole (M90)

[0551] The synthesis of intermediate M90 ​​was the same as that of M74, using intermediate M89 as the starting material, to obtain 56 mg of pale yellow solid, with a yield of 62%. 1 H NMR(400MHz,Chloroform-d)δ8.40(dd,J=2.3,0.7Hz,1H),8.10(dq,J=1.7,0.8Hz,1H),3.44(p,J=8 .1Hz,1H),2.61(s,3H),2.29–2.18(m,2H),2.14–2.02(m,2H),2.01–1.86(m,2H),1.85–1.69(m,2H).

[0552] Synthesis of intermediate 2-cyclopentyl-7-methylbenzo[d]oxazol-5-amine (M91)

[0553] The synthesis of intermediate M91 was similar to that of M4, using intermediate M91 as the starting material. It was used directly in the next reaction without purification.

[0554] Compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)quinoline-4-yl)-7-methylbenzo[d]oxazol-5-amine Synthesis of (LK52)

[0555] The synthesis of compound LK-52 followed the method for compound LK-1, using intermediates M2 and M91 as starting materials, yielding 30 mg of a yellow solid in 56% yield. (ESI-HRMS Calcd for C) 25 H 28 N3O3S[M+H] + :450.1846,found450.1847.

[0556] Example 43

[0557]

[0558] Synthesis of intermediate N-(3-fluoro-2-hydroxy-5-nitrophenyl)tetrahydrofuran-2-carboxamide (M92)

[0559] Tetrahydrofuran-2-carboxylic acid (2.79 mmol, 268 μL) was added to oxalyl chloride (1 mL), followed by the catalytic amount of N,N-dimethylformamide, and the reaction was carried out at room temperature for 2 hours. After the reaction was complete, the acyl chloride was concentrated and diluted with dichloromethane (1 mL). Intermediate M85 (2.32 mmol, 400 mg) and pyridine (6.97 mmol, 380 μL) were dissolved in dichloromethane (5 mL) at 0 °C, and the acyl chloride solution was added dropwise. The mixture was slowly heated to room temperature and reacted for 12 hours. After the reaction was complete, the mixture was extracted with dichloromethane and washed with saturated brine. The organic phase was concentrated and separated by column chromatography (PE:EA = 3:1) to give 480 mg of a pale yellow solid, with a yield of 76%.

[0560] The synthesis of intermediates M93-M94 is the same as that of intermediates M87-M88.

[0561] The proton spectrum of intermediate M93: 1 H NMR(500MHz,Chloroform-d)δ8.47(dd,J=2.0,0.7Hz,1H),8.12(dd,J=9.5,2.0Hz,1H),5.29(dd,J=7.9,5.5Hz,1H),4.23–4.13(m,1 H),4.08(ddd,J=8.4,7.3,6.1Hz,1H),2.51(dtd,J=12.7,8.1,6.7Hz,1H),2.47–2.39(m,1H),2.29–2.19(m,1H),2.19–2.10(m,1H).

[0562] Compound 7-fluoro-N-(6-(isopropylsulfonyl)quinolin-4-yl)-2-(tetrahydrofuran-2-yl)benzo[d]ox Synthesis of 5-azole-amine (LK53)

[0563] The synthesis of compound LK-53 was performed following the same procedure as that of compound LK-1, using intermediates M2 and M91 as starting materials, yielding 43 mg of a pale yellow solid in the form of hydrochloride, with a yield of 61%. 1H NMR (500MHz, DMSO-d6) δ11.55(s,1H),9.38(d,J=1.9Hz,1H),8.64(d,J=7.0Hz,1H),8.39(dd,J=8. 9,1.8Hz,1H),8.28(d,J=8.9Hz,1H),7.78(d,J=1.8Hz,1H),7.57(dd,J=10.8,1.8Hz,1H),6.95(d, J=7.0Hz,1H),4.12(dd,J=8.7,7.7Hz,1H),4.07(dd,J=8.7,5.4Hz,1H),3.99–3.90(m,2H),3.85(t d,J=8.0,6.6Hz,1H),3.65(hept,J=6.8Hz,1H),2.47–2.30(m,2H),1.25(d,J=6.8Hz,6H).ESI-HRMS Calcdfor C 23 H 23 FN3O4S[M+H] + :456.1388,found 456.1389.

[0564] Example 44

[0565]

[0566] The synthesis of intermediates M95 to M97 is the same as that of intermediates M92 to M94.

[0567] Compound 7-fluoro-N-(6-(isopropylsulfonyl)quinolin-4-yl)-2-(tetrahydrofuran-3-yl)benzo[d]ox Synthesis of 5-azole-amine (LK54)

[0568] The synthesis of compound LK-53 was performed with reference to the synthesis of compound LK-1, using intermediates M2 and M91 as starting materials, yielding 47 mg of a pale yellow solid in the form of hydrochloride, with a yield of 85%. 1H NMR (500MHz, DMSO-d6) δ11.55(s,1H),9.38(d,J=1.9Hz,1H),8.64(d,J=7.0Hz,1H),8.39(dd,J= 8.9,1.8Hz,1H),8.28(d,J=8.9Hz,1H),7.78(d,J=1.8Hz,1H),7.57(dd,J=10.8,1.8Hz,1H),6.9 5(d,J=7.0Hz,1H),4.12(dd,J=8.7,7.7Hz,1H),4.07(dd,J=8.7,5.4Hz,1H),3.99–3.90(m,2H), 3.89–3.81(m,1H),3.65(hept,J=6.8Hz,1H),2.47–2.30(m,2H),1.25(d,J=6.8Hz,6H).ESI-HRMS Calcd forC 23 H 23 FN3O4S[M+H] + :456.1388, found 456.1385.

[0569] Example 45

[0570]

[0571] Compound 2-cyclopentyl-7-fluoro-N-(6-(isopropylsulfonyl)-7-methoxyquinoline-4-yl)benzo[d]ox Synthesis of 5-azole-amine (LK-55)

[0572] The synthesis of compound LK-55 was based on that of compound LK-1, using intermediates M88 and M45 as starting materials. After the reaction was complete, the reaction solution was evaporated to dryness and purified by thin-layer chromatography (DCM:MeOH = 20:1) to give 9 mg of a pale yellow solid, with a yield of 24%. Further purification by reversed-phase HPLC (column: Waters Sunfire C18, 19 x 150 mm, 5 μm; mobile phase A: H2O containing 0.1% trifluoroacetic acid; mobile phase B: MeCN containing 0.1% trifluoroacetic acid; gradient: 10%-50% B - 15 min, 50%-65% B - 10 min; 65%-100% B - 7 min; flow rate: 10 mL / min) yielded pure LK-55 in the form of trifluoroacetate. 1H NMR (500MHz, DMSO-d6) δ11.49(s,1H),9.23(s,1H),8.52(d,J=7.2Hz,1H),7.71(d,J=1.8Hz,1H),7.64(s,1H),7.51(dd,J=10.9,1.8Hz,1H),6.85–6 .75(m,2H),4.12(s,3H),3.86–3.80(m,1H),3.52(p,J=8.0Hz,1H),2.23– 2.10(m,2H),2.04–1.95(m,2H),1.82–1.68(m,4H),1.24(d,J=6.8Hz,6H). 13 C NMR (126MHz, DMSO-d6) δ172.19,159.25,155.93,146.79,144.70(d,J=24.7Hz),144.22,143.18,136.19(d,J=10.7Hz),133.79(d,J=8.3Hz),128 .42,126.66,113.25(d,J=4.1Hz),110.46,109.96(d,J=18.6Hz),101.67 ,100.75,57.21,52.99,37.85,30.75,25.14,14.63.ESI-MS:484.1[M+H] + .

[0573] Example 46

[0574]

[0575] Synthesis of compound 2-cyclopentyl-N-(6,7-dimethoxyquinoline-4-yl)benzo[d]thiazol-5-amine (LK56)

[0576] The synthesis of compound LK-56 was based on the synthesis of compound LK-1, using intermediate M29 and 4-chloro-6,7-dimethoxyquinoline as starting materials, yielding 32 mg of yellow solid in hydrochloride form, with a yield of 67%. 1H NMR(500MHz,DMSO-d6)δ14.14(s,1H),10.80(s,1H),8.34(d,J=7.0Hz,1H),8.24 (d,J=8.4Hz,1H),8.17(s,1H),8.04(d,J=2.0Hz,1H),7.50(dd,J=8.4,2.1Hz,1H) ,7.44(s,1H),6.78(d,J=6.9Hz,1H),4.03(s,3H),4.00(s,3H),3.62(p,J=8.0Hz, 1H),2.28–2.16(m,2H),1.98–1.87(m,2H),1.86–1.77(m,2H),1.77–1.67(m,2H). 13 C NMR (126MHz, DMSO-d6) δ178.40,154.59,153.58,153.37,149.41,139.88,135.70,135.18,132.94,123.3 1,122.48,118.84,111.51,102.50,99.81,99.21,56.58,56.11,43.90,33.29,25.03.ESI-MS:406.1[M+H] + .

[0577] Example 47

[0578]

[0579] Compound 2-cyclopentyl-N-(6-methoxy-7-(3-morpholinopropoxy)quinoline-4-yl)benzo[d]thiazol-5- Synthesis of amine (LK-57)

[0580] The synthesis of compound LK-56 was based on that of compound LK-1, using intermediate M29 and 4-(3-((4-chloro-6-methoxyquinoline-7-yl)oxy)propyl)morpholine as starting materials. The reaction was carried out in a sealed tube at 100°C for 12 hours. After the reaction was completed, LK-57 was purified by reversed-phase HPLC (column: Waters Sunfire C18, 19 x 150 mm, 5 μm; mobile phase A: H2O containing 0.1% trifluoroacetic acid; mobile phase B: MeCN containing 0.1% trifluoroacetic acid; gradient: 10%-50% B - 15 min, 50%-65% B - 10 min; 65%-100% B - 7 min; flow rate: 10 mL / min) to obtain 23 mg of pure white solid in the form of trifluoroacetate, with a yield of 56%. 1H NMR (500MHz, DMSO-d6) δ14.19(s,1H),10.66(s,1H),9.99(s,1H),8.37(d,J=7.0Hz,1H),8.25(d,J=8.5Hz,1H),8.0 8(s,1H),8.03(d,J=2.1Hz,1H),7.48(dd,J=8.5,2.1Hz,1H),7.46(s,1H),6.79(d,J=7.0Hz,1H),4.29(t,J=5.8Hz,2 H),4.10–3.97(m,5H),3.69(t,J=12.1Hz,2H),3.62(t,J=8.0Hz,1H),3.55(d,J=12.3Hz,2H),3.35(t,J=7.6Hz,2H) ,3.22–3.09(m,2H),2.34–2.26(m,2H),2.26–2.18(m,2H),1.96–1.86(m,2H),1.85–1.77(m,2H),1.76–1.68(m,2H). 13 C NMR (126MHz, DMSO-d6) δ 178.54, 158.08 (q, J = 32.6Hz), 153.63, 153.50, 153.43, 149.38, 140.22, 135.58, 135.08, 133.11, 123.45, 122.47, 118. 84,116.68(q,J=297.6Hz),111.59,102.28,100.71,99.32,66.33,63.3 7,56.47,53.62,51.23,43.91,33.31,25.04,22.80.ESI-MS:519.1[M+H] + .

[0581] Example 48

[0582]

[0583] The synthesis of intermediates M98 to M100 is the same as that of intermediates M95 to M97.

[0584] The proton spectrum of intermediate M99: 1 H NMR (500MHz, Chloroform-d) δ8.44 (dd, J=2.1, 0.6Hz, 1H), 8.10 (dd, J=9.5, 2.0Hz, 1H), 3.79–3.66 (m, 1H), 3.23–3.11 (m, 4H).

[0585] Synthesis of compound 2-(3,3-difluorocyclobutyl)-7-fluoro-N-(6-(isopropylsulfonyl)quinoline-4-yl)benzo[d]oxazol-5-amine (LK58)

[0586] The synthesis of compound LK-58 was performed with reference to the synthesis of compound LK-1, using intermediates M2 and M100 as starting materials, yielding 45 mg of yellow solid in the form of hydrochloride, with a yield of 85%. 1 H NMR(500MHz,DMSO-d6)δ11.60(s,1H),9.39(d,J=2.0Hz,1H),8.64(d,J=7.0Hz,1H) ,8.39(dd,J=8.9,1.8Hz,1H),8.30(d,J=8.9Hz,1H),7.81(d,J=1.8Hz,1H),7.60(dd ,J=10.8,1.8Hz,1H),6.94(d,J=7.0Hz,1H),3.97–3.84(m,J=6.0,4.5Hz,1H),3.66 (hept,J=6.9Hz,1H),3.29–3.08(m,4H),1.25(d,J=6.8Hz,6H).ESI-MS:476.1[M+H] + .

[0587] Example 49

[0588]

[0589] Compound 2-(3,3-difluorocyclobutyl)-7-fluoro-N-(6-(isopropylsulfonyl)-7-methoxyquinoline-4-yl) Synthesis of benzo[d]oxazol-5-amine (LK59)

[0590] The synthesis of compound LK-59 was performed with reference to the synthesis of compound LK-1, using intermediates M45 and M100 as starting materials, yielding 50 mg of white solid in the form of hydrochloride, with a yield of 89%. 1 H NMR (500MHz, DMSO-d6) δ14.59(brs,1H),11.50(s,1H),9.24(s,1H),8.53(d,J=7.0Hz,1H),7.78(d,J=1.8Hz,1H),7.71(s,1H),7.57(dd,J=10 .9,1.8Hz,1H),6.79(d,J=7.1Hz,1H),4.12(s,3H),3.95–3.86(m,1H),3.85–3.77(m,1H),3.27–3.06(m,4H),1.25(d,J=6.9Hz,6H).ESI-HRMS Calcd for C 24 H 23 F3N3O4S[M+H] +:506.1356,found506.1355.

[0591] Example 50

[0592]

[0593] Compound 3-cyclopropyl-8-((2-(3,3-difluorocyclobutyl)-7-fluorobenzo[d]oxazol-5-yl)amino)thiophene Synthesis of [2,3-g]quinoline-1,1-dioxide (LK-60)

[0594] Intermediate M57 (0.189 mmol, 55 mg) and intermediate M100 (0.189 mmol, 46 mg) were added to isopropanol (3 mL), and the mixture was heated to 95 °C and reacted for 9 hours. After the reaction was complete, the mixture was cooled to room temperature, and the solvent was evaporated to dryness. The mixture was then purified by column chromatography (DCM:MeOH = 15:1) to give 72 mg of a white solid, with a yield of 77%. 1 H NMR (500MHz, DMSO-d6) δ10.04(brs,1H),9.03(s,1H),8.61(d,J=6.0Hz,1H),8.28(s,1H),7.67(d,J=1.8Hz,1H),7.46(dd,J=11.3,1.8Hz,1H),7.22(s ,1H),7.02(d,J=6.0Hz,1H),3.93–3.80(m,1H),3.25–3.05(m,4H),2.26(dd d,J=13.2,8.2,4.9Hz,1H),1.25–1.19(m,2H),0.98–0.93(m,2H).ESI-HRMS Calcd forC 25 H 19 F3N3O3S[M+H] + :498.1094,found 498.1095.

[0595] Example 51

[0596]

[0597] Synthesis of intermediate 4-chloro-6-(isopropylsulfonyl)quinoline-7-ol (M101)

[0598] Intermediate M45 (0.90 mmol, 270 mg) and lithium iodide (0.90 mmol, 121 mg) were dissolved in 2,4,6-trimethylpyridine (2 mL), and the mixture was heated to 100 °C and reacted for 4 hours. After the reaction was complete, the pH was adjusted to 2–3 with 3N HCl, and the mixture was extracted with a 3:1 dichloromethane-n-butanol mixture and washed with saturated brine. The organic phase was concentrated and purified by column chromatography (DCM:MeOH = 20:1) to give 210 mg of a yellow oil, with a yield of 82%. 1H NMR(500MHz,DMSO-d6)δ8.85(d,J=4.8Hz,1H),8.61(s,1H),7.67(d,J=4.7Hz,1 H),7.57(s,1H),6.86(s,1H),3.91(hept,J=6.8Hz,1H),1.22(d,J=6.9Hz,6H).

[0599] Intermediate 7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chloro-6-(isopropylsulfonyl) Synthesis of quinoline (M102)

[0600] Intermediate M101 (0.28 mmol, 80 mg), tert-butyl-(2-iodoethoxy)dimethylsilane (0.29 mmol, 31 μL), and potassium carbonate (0.70 mmol, 200 mg) were dissolved in N,N-dimethylformamide (1 mL), and the mixture was heated to 50 °C and reacted for 3 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, washed with saturated brine, concentrated the organic phase, and purified by column chromatography (PE:EA = 1:1) to give 62 mg of a colorless, transparent oil, with a yield of 50%.

[0601] Intermediate N-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-(isopropylsulfonyl)quinoline Synthesis of lin-4-yl)-2-(3,3-difluorocyclobutyl)-7-fluorobenzo[d]oxazol-5-amine (M103)

[0602] Intermediate M102 (0.068 mmol, 30 mg) and intermediate M100 (0.068 mol, 17 mg) were dissolved in ethanol (1 mL), and 6N HCl was added as a catalyst. The mixture was then heated to 60 °C and reacted for 3 hours. After the reaction was complete, the mixture was purified by thin-layer chromatography (DCM:MeOH = 20:1) to give 15 mg of a yellow solid, with a yield of 34%. 1 H NMR(500MHz,Chloroform-d)δ8.69(s,1H),8.56(d,J=5.6Hz,1H),7.57(s,1H),7.50(d,J=1.9Hz,1H),7.15(dd,J=10.5,1.9Hz,1H),6.85(d,J=5. 5Hz,1H),4.39–4.30(m,2H),4.16–4.03(m,3H),3.72(qd,J=8.9,2.6Hz, 1H),3.27–3.07(m,4H),1.35(d,J=6.8Hz,6H),0.93(s,9H),0.13(s,6H).

[0603] Compound 2-(4-((2-(3,3-difluorocyclobutyl)-7-fluorobenzo[d]oxazol-5-yl)amino)-6-(isopropyl) Synthesis of sulfonyl)quinoline-7-yl)oxy)eth-1-ol (LK-61)

[0604] Intermediate M103 (0.023 mmol, 15 mg) was dissolved in tetrahydrofuran (1 mL), and 1 M tetrabutylammonium fluoride (0.062 mmol, 62 μL) was added dropwise at 0 °C, followed by reaction at room temperature for 2 hours. After the reaction was complete, the organic phase was concentrated and purified by reversed-phase HPLC (column: Waters Sunfire C18, 19 x 150 mm, 5 μm; mobile phase A: H2O containing 0.1% trifluoroacetic acid; mobile phase B: MeCN containing 0.1% trifluoroacetic acid; gradient: 10%-50% B - 15 min, 50%-65% B - 10 min; 65%-100% B - 7 min; flow rate: 10 mL / min) to obtain pure LK-61, yielding 2 mg of white solid in the form of trifluoroacetate, with a yield of 16%. 1 H NMR (500MHz, DMSO-d6) δ11.50(s,1H),9.24(s,1H),8.51(dd,J=11.9,7.2Hz,1H),7.63–7.50(m,2H),6.79(dd,J=7.2,5.1Hz,1H),4.37(q, J=4.0,3.4Hz,2H),4.05(dq,J=13.8,6.8Hz,1H),3.92–3.84(m,3H),3.29–3.17(m,2H),3.17–3.06(m,2H),1.24(d,J=6.6Hz,6H).ESI-HRMS Calcd for C 25 H 25 F3N3O5S[M+H] + :536.1462,found 536.1462.

[0605] Pharmacological Experiment Section

[0606] Test Example 1: Inhibitory activity of the compound of this application against RIPK3 enzyme levels

[0607] In this embodiment, a human RIPK3 kinase domain (2-328) sequence with a 6×His and TEV tag at the N-terminus and a 10×His tag at the C-terminus was cloned into the pFastBacHT B vector (Invitrogen). Bacmid was generated in DH10Bac cells using the Bac-to-Bac system, and then produced and amplified in Sf-9 insect cells to obtain baculovirus. Sf-9 insect cells were collected 72 hours after baculovirus infection and lysed in lysis buffer containing 25 mM Tris (pH 7.8), 500 mM NaCl, 5% glycerol, 5 mM β-mercaptoethanol, and a protease inhibitor. The lysis buffer was incubated with Ni-NTA beads (GE Healthcare) on ice for 30 minutes, followed by centrifugation at 1000 rpm for 5-10 minutes to obtain a resin precipitate containing the binding protein. The precipitate was then washed twice with lysis buffer containing 20 mM and 50 mM imidazole, respectively. Finally, the target protein was eluted with lysis buffer containing 300 mM imidazole. The target protein was further obtained by size exclusion chromatography (purity >95%) and used for subsequent experiments.

[0608] 1. Determination of the inhibitory rate of the compound on RIPK3 at specific concentrations

[0609] Specific method: Set up the prephosphorylation reaction system as follows:

[0610] Comparison 1 Comparison 2 compound buffer solution 30μL 10μL 0μL compound 0μL 0μL 10μL protein 0 20μL 20μL ATP 20μL 20μL 20μL Total volume 50μL 50μL 50μL

[0611] Compounds were used at fixed concentrations (1 μM, 100 nM, 10 nM). After adding ATP, the mixture was incubated at room temperature for 40 minutes. Subsequently, 5 μL of the pre-incubation mixture and 5 μL of ADP-Glo ​​Reagent were added to each well of a 384-well plate, and the plate was incubated at room temperature for 1 hour with shaking. Then, 10 μL of Kinase Detection Reagent was added to each well, and the plate was incubated at room temperature for 40 minutes with shaking, and the fluorescence values ​​were read.

[0612] 2. Compound inhibits the IC50 of RIPK3 50 Value determination

[0613] Specific method: Set up the prephosphorylation reaction system as follows:

[0614] Comparison 1 Comparison 2 compound buffer solution 30μL 10μL 0μL compound 0μL 0μL 10μL protein 0 20μL 20μL ATP 20μL 20μL 20μL Total volume 50μL 50μL 50μL

[0615] Compound concentration gradients were set (10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 0.1 nM, 0.01 nM). After adding ATP, the mixture was incubated at room temperature for 40 minutes. Subsequently, 5 μL of the pre-incubation mixture and 5 μL of ADP-Glo ​​Reagent were added to each well of a 384-well plate, and the plate was incubated at room temperature for 1 hour with shaking. Then, 10 μL of Kinase Detection Reagent was added to each well, and the plate was incubated at room temperature for 40 minutes with shaking, and the fluorescence values ​​were read.

[0616] The experimental results are shown in Table 1. The compounds provided by this invention can effectively inhibit the kinase activity of RIPK3, with the inhibitory activity generally reaching the sub-micromolar level. The inhibitory activity of some compounds is comparable to that of the positive compound GSK872. (IC) 50 The values ​​are represented by A, B, and C, where 0 is M. <A<100nM;100nM<B<1μM;1μM<C<10μM)

[0617] Table 1. Inhibitory activity of the compounds in this application against RIPK3 enzyme levels.

[0618]

[0619] Test Example 2: Determination of the anti-programmed cell necrosis activity of the compound of this application in cells.

[0620] In this test case, the anti-programmed cell necrosis activity of the compound was evaluated in HT29 (human colon cancer cells) and L929 (mouse fibroblasts).

[0621] Test method: HT29 and L929 cells derived from ATCC were seeded into 96-well plates at a density of 100,000 cells / mL, with 100 μL per well. The next day, Z-VAD-FMK (concentrations of 20 μM and 10 μM on HT29 and L929 cells, respectively) was added and pre-incubated with the compound for 1 hour. The model drug was added to induce cell necrosis (induction conditions for HT29 cells were 100 nM SM164 + 40 μg / mL h-TNF-α, and for L929 cells, the induction conditions were 20 μg / mL m-TNF-α). After 16-18 hours, CCK8 detection solution was added, and the cells were incubated at 37 degrees Celsius for 1 hour. The absorbance was then measured at 450 nm.

[0622] The experimental results are shown in Table 2. The compounds provided in this application exhibit good anti-necrosis activity in both HT29 and L929 cells. Some compounds achieved cell activity comparable to or even better than the positive control compound GSK872. (EC) 50 The values ​​are represented by A, B, and C, where 0 is M. <A<1μM;1μM<B<10μM;10μM<C<25μM;D> 25μM; ND, not detected)

[0623] Table 2. Determination of the anti-programmed cell necrosis activity of the compounds in this application.

[0624]

[0625] Test Example 3: Effects of the Compounds in this Application on the Apoptosis Signaling Pathway

[0626] The compounds designed for this test case are as follows:

[0627]

[0628] The structures of the compounds for comparison are as follows:

[0629]

[0630] Assay method: L929 cells derived from ATCC were seeded in 12-well plates at a density of 40W cells / mL, with 1 mL per well. The compound was added every other day, with groups defined as 10 μM, 20 μM, and 20 Mm+z-VAD-FMK. The control group received an equal concentration of DMSO. After incubation for 3 hours, cells were lysed for sample preparation. Western blotting was used to examine the protein expression levels of caspase-3 and caspase-8 lysates.

[0631] Experimental results are as follows Figures 1 to 3 As shown, in the absence of the caspase inhibitor z-VAD, the DB group compounds (DB-1, DB-2, DB-3) significantly promoted the cleavage of caspase-3 and caspase-8, indicating activation of the apoptosis pathway. In contrast, the representative compounds provided in this invention (LK-16, LK-18, LK-25, LK-48, LK-49) did not significantly promote caspase activation at different concentrations, demonstrating that this series of compounds has the advantage of avoiding apoptosis-related side effects compared to common RIPK3 inhibitors.

[0632] Test Example 4:

[0633] Test method: EC50 of the compound on L929 cells 50 The testing method is the same as in Test Example 2.

[0634] Cytotoxic CC 50 Assay method: L929 cells derived from ATCC were seeded in 96-well plates at a density of 100,000 cells / mL, 100 μL per well. The test compound was added every other day (compound concentration gradient: 50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.56 μM, 0.78 μM, 0.39 μM, 0.195 μM). Simultaneously, a z-VAD group (20 μM on L929 cells) was incubated with the compound (compound concentration gradient set as before). After 16-18 hours, CCK8 assay solution was added, and the cells were incubated at 37°C for 1 hour. The absorbance was measured at 450 nm. Cell viability was calculated as: inhibitor reading / control reading * 100%. The cell CCK8 assay was fitted based on the cell viability. 50 value.

[0635] The experimental results are shown in Table 3. DB-1 and DB-2, due to inducing apoptosis at high concentrations, generally exhibited high cytotoxicity. In contrast, the compounds LK-18 and LK-25 of this invention did not activate the apoptosis pathway. 50 The values ​​were all greater than 10 μM, which greatly improved the therapeutic window. 50 / EC 50 The ratio is more than 25 times.

[0636] Table 3 EC50 and CC50 values ​​of the compounds in this application and the positive control compounds.

[0637]

[0638] Test Example 5: Effect of the compound of this application on Caspase 3 activity

[0639] Test Method: ATCC-derived L929 cells were seeded in 12-well plates at a density of 400,000 cells / mL. After 24 hours, the compounds were administered: GSK872 at 10 μM and all other compounds at 20 μM. Cell samples were collected three hours after administration. Cells were first digested with trypsin and then transferred to a prepared cell culture medium. Cells were collected by centrifugation at 600g, 4°C for 5 minutes. The supernatant was carefully aspirated, and the cells were washed once with PBS. After aspirating the supernatant as before, lysis buffer was added at a ratio of 100 μL per 2 million cells. The pellet was resuspended and lysed on ice for 15 minutes. The reaction system was set up as follows:

[0640]

[0641] After adding Ac-DEVD-pNA and mixing well, incubate overnight at 37°C, and measure the absorbance at 405 nm the next day.

[0642] The experimental results are shown in Table 4. The DB group compounds (DB-1, DB-2) can significantly induce caspase 3 activation, indicating that the inhibitors have the side effect of activating apoptosis. In contrast, the series of compounds provided by this invention hardly induces caspase 3 activation, indicating that this series of compounds has the unique advantage of avoiding the side effect of apoptosis.

[0643] Table 4. Effects of the compounds in this application on Caspase-3 activity.

[0644]

[0645]

[0646] Test Example 5: Evaluation of the antinecrosis activity of compounds against non-classical necrosis pathways in viral infections and inflammatory diseases such as enteritis.

[0647] Assay Methods: Mouse-ZBP1 stable transgenic MEF cells, constructed using conventional methods, were seeded in 12-well plates at a density of 400,000 cells / mL, with 1 mL per well. Every other day, the compound (10 μM) and z-VAD (10 μM) were added and co-incubated for one hour. The control group received an equal concentration of DMSO. Following this, the inducing agent CBL0137 (CAS No.: 1197397-89-9, 5 μM) was added and incubated for 4-6 hours. Cells were then lysed for sample preparation. Western blotting was used to examine the phosphorylation of MLKL and the expression levels of its caspase-3 cleaved form.

[0648] Experimental results are as follows Figure 4 As shown, the compounds of this application significantly inhibit the phosphorylation of MLKL, indicating that the compounds of this application can inhibit the activation of the ZBP-1 (sensor that recognizes viral Z-DNA) mediated necrosis pathway, suggesting that the compounds of this invention have a protective effect in antiviral defense and inflammatory diseases.

[0649] Test Example 6: Evaluation of the survival rate of compounds in mouse lung epithelial cells necrotic due to influenza virus

[0650] Assay method: THP-1PMA cells were infected with influenza A virus PR8 strain (MOI=2) for 1 hour using serum-free culture medium. After infection, the virus solution was removed, cells were washed, and fresh culture medium containing different inhibitors (the compounds of this invention, 1 μM) was used. The control group was incubated with an equal concentration of DMSO for 3 hours, followed by cell lysis and sample preparation. The phosphorylation level of RIPK3 was assessed using Western blotting.

[0651] Experimental results show that the compounds of this application (such as LK-34 and LK-60) can significantly inhibit the phosphorylation of RIPK3 at a concentration of 1 μM, suggesting that the compounds of this invention have a significant protective effect against virus infection-induced cell necrosis.

[0652] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotope derivative, or combination thereof; In the formula, X1 is selected from the following group: S, O, CH, N, or NH; X2 is selected from the following group: C, CH, or N; U1, U2, and U3 are each independently selected from the following group: N or CH; where, At most two of U1, U2 and U3 are N; Ring B is selected from five-membered aromatic rings; R1 is selected from the following group: halogen, deuterium, cyano, hydroxyl, -NRaRb, nitro, amino, straight-chain or branched C1-C. 10 Alkyl, straight-chain or branched C1-C 10 Alkyl group, straight-chain or branched C1-C 10 Alkylthio, C3-C 10 cycloalkyl, C3-C 10 Oxycyclic alkyl, C3-C 10 Thiocyclic alkyl, straight-chain or branched C2-C 10 Alkenyl, straight-chain or branched C2-C 10 alkynyl group, C3-C 10 Cycloalkenyl, -C(=O)-(C1-C 10 Alkyl), -S(O)2-(C1-C 10 Alkyl), -NH-C(O)-(C1-C 10 Alkyl), -C(O)-NH-(C1-C 10 Alkyl), C6-C 10 Aryl, 5-14 membered heteroaryl, 4-14 membered heterocyclic; wherein Ra and Rb are each independently selected from the following group: C1-C 10 Alkyl, C3-C 10 cycloalkyl, C6-C 10 Aryl, 5-11 membered heteroaryl, or 4-11 membered heterocyclic group, or Ra and Rb and their commonly attached N atom form a 4-11 membered heterocycle or 5-11 membered heterocyclic ring containing 1-3 heteroatoms each independently selected from N, O, and S; said alkyl, alkoxy, alkylthio, cycloalkyl, oxocycloalkyl, thiocycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl, and heterocyclic group are optionally substituted by one or more groups selected from the group consisting of: halogen, deuterium, oxo (=O). , hydroxy, cyano, nitro, amino, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, benzyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclic, -(halogenated or non-halogenated C1-C6 alkylene)-C3-C6 cycloalkyl, -(halogenated or non-halogenated C1-C6 alkylene)-phenyl, -(halogenated or non-halogenated C1-C6 alkylene)-5 -6-membered heteroaryl, -(halogenated or non-halogenated C1-C6 alkylene)-4-7-membered heterocyclic, -O-C3-C6 cycloalkyl, -O-phenyl, -O-5-6-membered heteroaryl, -O-(4-7-membered heterocyclic), -S-(C3-C6 cycloalkyl), -S-phenyl, -S-(5-6-membered heteroaryl), -S-(4-7-membered heterocyclic), -NH-(C3-C6 cycloalkyl), -NH-phenyl, -NH-(5-6-membered heteroaryl), -NH- (4-7-membered heterocyclic group), -NH-C(O)-(C3-C6 cycloalkyl), -C(O)-NH-(C3-C6 cycloalkyl), -(halogenated or non-halogenated C1-C6 alkylene)-O-C3-C6 cycloalkyl, -(halogenated or non-halogenated C1-C6 alkylene)-O-phenyl, -(halogenated or non-halogenated C1-C6 alkylene)-O-5-6-membered heteroaryl, -(halogenated or non-halogenated C1-C6 alkylene)-O-4-7-membered heterocyclic group; Ring A is a 6-membered aromatic ring or a 6-membered heteroaromatic ring, and at any substituted site, ring A is substituted by 1-3 identical or different R2s. R2 is selected from the following group: hydrogen, deuterium, halogen, oxo (=O), cyano, nitro, hydroxyl, amino, straight-chain or branched C1-C. 10 Alkyl, straight-chain or branched C1-C 10 Alkyl group, straight-chain or branched C2-C 10 Alkenyl, straight-chain or branched C2-C 10 The alkyl, C3-C8 cycloalkyl, -(C1-C6 alkylene)-C3-C8 cycloalkyl, phenyl, benzyl, 4-9 membered heterocyclic or 5-9 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, phenyl, benzyl, heterocyclic and heteroaryl groups are optionally substituted by one or more (e.g. 2, 3, 4 or 5) groups selected from the group consisting of: halogen, cyano, hydroxy, nitro, oxo (=O), amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, benzyl, C3-C6 cycloalkyl, phenyl, 4-6 membered heterocyclic and 5-6 membered heteroaryl; L represents a bond, -NH-, -O-, -N(R) x )-、-(CH2) m -、-(CHR x ) m -、-(C(R x )2) m -; m is 1, 2, 3, 4, 5, or 6; Each R x Each is independently selected from the group consisting of: H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -S(O)2-(C1-C4 alkyl) or -C(=O)-(C1-C4 alkyl), wherein the alkyl and cycloalkyl groups are optionally substituted by one or more groups selected from the group consisting of: D, halogen, cyano, hydroxyl, oxo(=O), amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl; Z has the structure shown in equation (II): in, V1, V2, V3, V4 and V5 are each independently N, CH or C, of ​​which at most 3 of V1, V2, V3, V4 and V5 are N; Y is either CH or N; n is 0 or 1; R9 is selected from the following group of substituted or unsubstituted groups: none, hydrogen, deuterium, halogen, nitro, amino, amide, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclic, 5-6 membered heteroaryl, phenyl, benzyl, wherein substitution refers to one or more hydrogen atoms on the group being replaced by halogen, deuterium, C1-C6 alkyl and C1-C6 alkoxy; R3, R4, R5, and R6 are each independently selected from the following group: none, hydrogen, deuterium, hydroxyl, nitro, mercapto, halogen, amino, straight-chain or branched C1-C. 10 Alkyl, straight-chain or branched C1-C 10 Heteroalkyl, straight-chain or branched C1-C 10 Alkyl group, straight-chain or branched C2-C 10 Alkenyl, straight-chain or branched C2-C 10 alkynyl group, C3-C 10 cycloalkyl, C6-C 10 Aryl, 4-11 membered heterocyclic, 5-11 membered heteroaryl, -S(O)2R7, -SOR7, -C(=O)OR7, -C(=O)R7, -C(=O)NHR7, -C(=O)NR7R8, -NHC(=O)R7, -NHC(=O)NHR7, -S(O)2NHR7, -S(O)2NR7R8, -NHS(O)2-R7, -(CH2) m R7, -CHR7R8, -NHR7, -NH-(C1-C6 alkylene)-R7, -NR7R8, -OR7, -O-(C1-C6 alkylene)-R7, -SR7, -O-(C1-C6 alkylene)-H2PO4 or R7 and R8 are each independently selected from the following group: hydrogen, straight-chain or branched C1-C 10 Alkyl, straight-chain or branched C1-C 10 Heteroalkyl, straight-chain or branched C1-C 10 Alkyl, straight-chain or branched C1-C 10 Hydroxyalkyl, C3-C 11 Cycloalkyl, 4-11 membered heterocyclic, C6-C 10 Aryl, 5-11 heteroaryl, -(C1-C6 alkylene)-C3-C 11 Cycloalkyl, -(C1-C6 alkylene)-4-11 heterocyclic, -(C1-C6 alkylene)-C6-C 10 aryl, -(C1-C6 alkylene)-5-11 heteroaryl, or, R7 and R8 and the atoms bonded to them together, form: C6-C 10 Aromatic rings, C3-C 11 Carbon rings, 4-11 membered heterocycles, or 5-11 membered heteroaromatic rings; or, R4 and R7, R4 and R8, R3 and R6, R3 and R4, or R4 and R5, together with the atoms connected to them, form a ring structure selected from the following group: C6-C 10 Aromatic rings, saturated or unsaturated C3-C 11 Carbon rings, 4-11 membered heterocycles, or 5-11 membered heteroaromatic rings; Wherein, the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic, heteroaryl, heterocyclic, heteroaryl, aromatic ring, and carbocyclic groups are optionally substituted by one or more groups selected from the group consisting of: deuterium, halogen, cyano, hydroxyl, nitro, oxo (=O), amino, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, phenyl, 4-7 membered heterocyclic, 5-6 membered heteroaryl, -(halogenated or non-halogenated C1- -C6 alkylene)-C3-C7 cycloalkyl, -(halogenated or non-halogenated C1-C6 alkylene)-phenyl, -(halogenated or non-halogenated C1-C6 alkylene)-5-6 heteroaryl, -(halogenated or non-halogenated C1-C6 alkylene)-4-7 heterocyclic group; or any two substituents at the same or different sites on the heterocycle, heteroaromatic ring, aromatic ring and carbon ring and the atoms they are connected to form a spirocyclic, bridged, or fused ring structure.

2. The compound according to claim 1, characterized in that, The compounds described above have the structures shown in formulas IA, IB, IC, and ID: In the formula, X1, X2, U1, U2, U3, R1, R2, Z, and R x As described in claim 1.

3. The compound according to claim 1, characterized in that, When n is 0, Z has the following structure: When n is 1, Z has the following structure: In the formula, R3, R4, R5, R6 and R9 are as described in claim 1.

4. The compound according to claim 1, characterized in that, The compound has the structure shown in Formula I-A1: In the formula, X1 is selected from S, O, CH, and N; X2 is selected from C and N; Y is selected from N or CH; Cycle B is selected from 5-membered heteroaryl groups; and R x R1, R2, R3, R4 and R9 are as described in claim 1.

5. The compound according to claim 1, characterized in that, R1 is selected from the following group: halogen, deuterium, cyano, hydroxyl, -NR a R b Nitro, amino, straight-chain or branched C1-C6 alkyl, straight-chain or branched C1-C6 alkoxy, straight-chain or branched C1-C6 alkylthio, C3-C7 cycloalkyl, C3-C7 oxecycloalkyl, C3-C7 thionecycloalkyl, straight-chain or branched C2-C6 alkenyl, straight-chain or branched C2-C6 alkynyl, C3-C6 cycloalkenyl, -C(=O)-(C1-C6 alkyl), -S(O)2-(C1-C6 alkyl), -NH-C(O)-(C1-C6 alkyl), -C(O)-NH-(C1-C6 alkyl), C6-C 10 Aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclic; wherein Ra and Rb are each independently selected from the following group: C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, 5-6 membered heteroaryl or 4-7 membered heterocyclic group, or Ra and Rb and their commonly attached N atom form a 4-9 membered heterocycle or 5-6 membered heterocyclic ring containing 1-3 heteroatoms each independently selected from N, O and S; Wherein, the alkyl, alkoxy, alkylthio, cycloalkyl, oxetyl, thioheteroalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl, and heterocyclic groups are optionally substituted by one or more groups selected from the group consisting of: halogen, deuterium, oxo (=O), hydroxyl, cyano, nitro, amino, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C1-C6 hydroxyalkyl. C3-C6 cycloalkyl, benzyl, phenyl, 5-6-membered heteroaryl, 4-7-membered heterocyclic, -(halogenated or non-halogenated C1-C4 alkylene)-C3-C6 cycloalkyl, -(halogenated or non-halogenated C1-C4 alkylene)-phenyl, -(halogenated or non-halogenated C1-C4 alkylene)-5-6-membered heteroaryl, -(halogenated or non-halogenated C1-C4 alkylene)-4-7-membered heterocyclic, -O-C3 -C6 cycloalkyl, -O-phenyl, -O-5-6-membered heteroaryl, -O-(4-7-membered heterocyclic), -S-(C3-C6 cycloalkyl), -S-phenyl, -S-(5-6-membered heteroaryl), -S-(4-7-membered heterocyclic), -NH-(C3-C6 cycloalkyl), -NH-phenyl, -NH-(5-6-membered heteroaryl), -NH-(4-7-membered heterocyclic), -NH-C(O)- (C3-C6 cycloalkyl), -C(O)-NH-(C3-C6 cycloalkyl), -(halogenated or non-halogenated C1-C4 alkylene)-O-C3-C6 cycloalkyl, -(halogenated or non-halogenated C1-C4 alkylene)-O-phenyl, -(halogenated or non-halogenated C1-C4 alkylene)-O-5-6 heteroaryl, -(halogenated or non-halogenated C1-C4 alkylene)-O-4-7 heterocyclic; Preferably, R1 is selected from the group consisting of: halogen, deuterium, cyano, -NRaRb, hydroxyl, nitro, amino, straight-chain or branched C1-C6 alkyl, straight-chain or branched C1-C6 alkoxy, C3-C6 cycloalkyl, straight-chain or branched C2-C6 alkenyl, straight-chain or branched C2-C6 alkynyl, -C(=O)-(C1-C6 alkyl), 4-7 membered heterocyclic or 5-6 membered heteroaryl; wherein Ra and Rb are each independently selected from the group consisting of: C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-7 membered heterocyclic, or Ra and Rb and the N atom they are connected to together form a 4-7 membered heterocycle or a 5-6 membered heteroaryl ring containing 1-3 heteroatoms each independently selected from N, O and S; Wherein, the alkyl, alkoxy, alkylthio, cycloalkyl, oxocycloalkyl, thiocycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl, and heterocyclic groups are optionally substituted by one or more groups selected from the group consisting of: halogen, oxo (=O), hydroxyl, cyano, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C1-C6 hydroxyalkyl, or C3-C6 cycloalkyl.

6. The compound according to claim 1, characterized in that, The compounds are selected from the following group:

7. A pharmaceutical composition, characterized in that, The active ingredient comprises one or more of the compounds of claim 1, or pharmaceutically acceptable salts, stereoisomers, tautomers, solvates, hydrates, prodrugs, isotope derivatives, or combinations thereof, and a pharmaceutically acceptable carrier.

8. Use of a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotope derivative, or combination thereof, or a pharmaceutical composition of claim 7, in the preparation of a medicament for treating and / or preventing programmed cell necrosis and inflammation-related diseases.

9. The use as described in claim 8, characterized in that, The programmed cell necrosis and inflammation-related diseases mentioned above are diseases caused by abnormal RIPK3 activity levels and / or expression levels; preferably, the diseases caused by abnormal RIPK3 activity levels and / or expression levels are selected from the following group: nervous system diseases, ischemia-reperfusion injury, autoimmune diseases, acute liver injury, acute lung injury, acute kidney injury, hyperuricemia, gout, skin inflammation, chronic liver disease, atherosclerosis, Gaucher disease, pain, inflammation, retinal diseases, tumors, immunosenescence, viral infection, heatstroke, aging, platelet thrombosis, and graft-versus-host disease.

10. Use of a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotope derivative, or combination thereof, or the pharmaceutical composition of claim 7, in the preparation of a RIPK3 inhibitor.

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