2-substituted azole cell necrosis pathway inhibitor, preparation method therefor and use thereof

Abstract

The present invention provides a 2-substituted azole cell necrosis pathway inhibitor, a preparation method therefor and a use thereof. Specifically, the present invention provides a compound having a structure represented by formula I, each group being as defined in the description. The compound of the present invention has strong inhibitory activity against RIPK3 and a RIPK3-mediated cell necrosis pathway at both enzyme level and cell level. Therefore, the compound provided by the present invention has broad application prospects in the field of treatment or prevention of programmed cell necrosis and inflammation-related diseases.

Description

2-substituted azole inhibitors of the necroptosis pathway and methods of making and using the same TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and in particular, relates to 2-substituted azole inhibitors of the necroptosis pathway and methods of making and using the same. BACKGROUND

[0002] Programmed necrosis is a regulated form of cell death discovered in recent years, which is closely related to the development of many diseases such as inflammation, infection and neurodegenerative diseases. Unlike apoptosis, cells undergoing programmed necrosis exhibit necrotic features such as cell swelling, cell membrane rupture, and release of cell contents. When cell necrosis stimulators such as tumor necrosis factor (TNF) appear, receptor interacting protein kinase 1 (RIPK1) recruits and activates RIPK3 to form a necrosome, further phosphorylates and activates downstream effector protein mixed lineage kinase domain-like protein (MLKL) to destroy cell membrane integrity, and execute the cell 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 cell programmed necrosis pathway. Knockout or inactivation mutation of RIPK3 can effectively block the cell necrosis pathway. In various disease models such as acute pancreatitis, acute liver injury, sepsis, ischemia-reperfusion injury, and heat shock, RIPK3 inhibition or knockout has a significant relief effect. (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 various diseases, the development of RIPK3 inhibitors has been relatively slow, and no inhibitors have entered the clinical research stage. One of the reasons is that some existing RIPK3 inhibitors have target-related pro-apoptotic side effects, which promote cell death at high concentrations, (Mol. Cell, 2014, 56(4): 481-495; Front. Cell Dev. Biol., 2020, 8: 606119), reducing the safety and effectiveness of the inhibitor application.

[0004] Therefore, the development of a new type of RIPK3 inhibitor with high affinity, high selectivity and the ability to avoid pro-apoptotic side effects is expected to overcome the limitations of existing inhibitors, provide an efficient and low-toxicity treatment for necrosis and inflammatory diseases, and has broad application prospects. SUMMARY

[0005] An object of the present application is to provide a 2-substituted azole compound as shown in formula (I), a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt thereof.

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

[0007] Still another object of the present application is to provide a use of a 2-substituted azole compound of formula (I) or a pharmaceutical composition comprising the same in the preparation of a medicament for preventing, treating or adjuvant therapy of a disease associated with abnormal activity level or expression level of RIPK3.

[0008] In a first aspect of the present application, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotopically enriched derivative, or combination thereof:

[0009] wherein,

[0010] X1is selected from the group consisting of S, O, CH, N, or NH;

[0011] X2is selected from the group consisting of C, CH, or N;

[0012] U1, U2, and U3are each independently selected from the group consisting of N or CH; wherein, at most two of U1, U2, and U3are N;

[0013] Ring B is selected from a five-membered heteroaromatic ring;

[0014] R1is selected from the group consisting of halogen, deuterium, cyano, hydroxyl, -NRaRb, nitro, amino, linear or branched C1-C 10 alkyl, linear or branched C1-C 10 alkoxy, linear or branched C2-C 10 alkenyl, C3-C 10 cycloalkyl, C3-C 10 oxacycloalkyl, C3-C 10 thiocycloalkyl, linear or branched C2-C 10 alkenyl, linear or branched C2-C 10 alkynyl, 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 heterocyclyl; wherein, Raand Rbare each independently selected from the group consisting of 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;

[0015] 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.

[0016] 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 10alkenyl, alkynyl, cycloalkyl, phenyl, benzyl, heterocyclyl, and heteroaryl are optionally substituted with one or more (e.g. 2, 3, 4, or 5) groups selected from the group consisting of halogen, cyano, hydroxyl, nitro, oxo (=0), amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, benzyl, C3-C6 cycloalkyl, phenyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl;

[0017] L is a bond, -NH-, -0-, -N(R x )-, -(CH2) m -, x -(CHR m )-, -(C(R x )2) m -; m is 1, 2, 3, 4, 5, or 6;

[0018] each R x is independently selected from the group consisting of H, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, -S(0)2-(C1-C4 alkyl), or -C(=0)-(C1-C4 alkyl), wherein said alkyl and cycloalkyl are optionally substituted with one or more groups selected from the group consisting of D, halogen, cyano, hydroxyl, oxo (=0), amino, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl;

[0019] Z has the structure shown in Formula (II):

[0020] wherein,

[0021] V1, V2, V3, V4, and V5 are each independently N, CH, or C, wherein no more than 3 of V1, V2, V3, V4, and V5 are N;

[0022] Y is CH or N;

[0023] n is 0 or 1;

[0024] R9 is selected from the group consisting of null, hydrogen, deuterium, halogen, nitro, amine, amide, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, benzyl, and substituted, wherein the substitution is one or more hydrogens on the group are replaced with halogen, deuterium, C1-C6 alkyl, and C1-C6 alkoxy;

[0025] R3, R4, R5, and R6 are each independently selected from the group consisting of null, hydrogen, deuterium, hydroxyl, nitro, thiol, 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 alkoxy, straight-chain or branched C2-C 10 alkenyl, straight-chain or branched C2-C 10 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 4-11 membered heterocyclyl, 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 wherein R7and R8are each independently selected from the group consisting of hydrogen, straight-chain or branched C1-C 10 alkyl, straight-chain or branched C1-C 10 heteroalkyl, straight-chain or branched C1-C 10 alkoxy, straight-chain or branched C1-C 10 hydroxyalkyl, C3-C 11 cycloalkyl, 4-11 membered heterocyclyl, C6-C 10 aryl, 5-11 membered heteroaryl, -(C1-C6 alkylene)-C3-C 11 cycloalkyl, -(C1-C6 alkylene)-4-11 membered heterocyclyl, -(C1-C6 alkylene)-C6-C 10 aryl, -(C1-C6 alkylene)-5-11 membered heteroaryl, or R7and R8, together with the atom to which they are both attached, form a C6-C 10 aromatic ring, C3-C 11 carbocyclic, 4-11 membered heterocyclic, or 5-11 membered heteroaromatic ring;

[0026] or,

[0027] R4and R7, R4and R8, R3and R6, R3and R4, or R4and R5, together with the atom to which they are attached, form a cyclic structure selected from the group consisting of C6-C 10 aromatic ring, saturated or unsaturated C3-C 11carbocycle, 4-11 membered heterocycle, or 5-11 membered heteroaromatic ring;

[0028] wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heterocycle, heteroaromatic ring, aromatic ring, and carbocycle are optionally substituted with one or more groups selected from deuterium, halogen, cyano, hydroxyl, nitro, oxo (=0), amino, C1-C6alkyl, C1-C6alkoxy, C3-C7cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, -(halogenated or non-halogenated C1-C6alkylene)-C3-C7cycloalkyl, -(halogenated or non-halogenated C1-C6alkylene)-phenyl, -(halogenated or non-halogenated C1-C6alkylene)-5-6 membered heteroaryl, -(halogenated or non-halogenated C1-C6alkylene)-4-7 membered heterocyclyl; or any two substituents on the same or different positions of the heterocycle, heteroaromatic ring, aromatic ring, and carbocycle form a spiro, bridged, or fused ring structure with the atoms to which they are commonly attached.

[0029] In another preferred embodiment, at least one of X1and X2is C or CH.

[0030] In another preferred embodiment, at most 2 of V1, V2, V3, V4, and V5are N.

[0031] In another preferred embodiment, the heteroaryl and heterocyclyl refer to monocyclic or polycyclic (e.g., bicyclic and tricyclic) heterocyclyl and heteroaryl containing 1-3 heteroatoms each independently selected from N, O, and S.

[0032] In another preferred embodiment, the heteroaryl and heterocyclyl can be monocyclic, or polycyclic fused, spiro, and bridged ring structures.

[0033] In another preferred embodiment, the compound has a structure represented by Formula I-A, Formula I-B, Formula I-C, and Formula I-D:

[0034] wherein,

[0035] X1, X2, U1, U2, U3, R1, R2, Z, and R x As described in the first aspect of the present application. In another preferred embodiment, ring A is a benzene ring.

[0036] In another preferred embodiment, Z has the following structure:

[0037] wherein,

[0038] V2and V4are each independently N, C, or CH;

[0039] Y is CH or N;

[0040] R9, R3, R4, R5, and R6are as described in the first aspect of the application.

[0041] In another preferred embodiment, when n is 0, Z has the following structure:

[0042] When n is 1, Z has the following structure:

[0043] wherein R3, R4, R5, R6, and R9are as described in the first aspect of the application.

[0044] In another preferred embodiment, is selected from the group consisting of:

[0045] In another preferred embodiment, the compound has the structure shown in Formula I-A1:

[0046] wherein,

[0047] X1is selected from S, O, CH, and N;

[0048] X2is selected from C and N;

[0049] Y is selected from N or CH;

[0050] Ring B is selected from 5-membered heteroaryl; and

[0051] R x , R1, R2, R3, R4, and R9are as described in the first aspect of the application.

[0052] In another preferred embodiment, R2is selected from the group consisting of hydrogen, deuterium, halogen, oxo (=0), cyano, nitro, hydroxyl, amino, amine, C1-C5alkyl, C1-C5alkoxy, C2-C5alkenyl, C2-C5alkynyl, C3-C6cycloalkyl, -(C1-C4alkylene)-C3-C6cycloalkyl, phenyl, benzyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, phenyl, benzyl, heterocyclyl, and heteroaryl are optionally substituted with one or more groups selected from deuterium, halogen, cyano, hydroxyl, nitro, oxo (=0), amino, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4haloalkoxy, benzyl, C3-C6cycloalkyl, phenyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl.

[0053] In another preferred embodiment, R2is hydrogen, deuterium, halogen, or C1-C4alkyl.

[0054] In another preferred embodiment, R9is selected from the group consisting of: nothing, hydrogen, deuterium, halogen, nitro, amine, amide, cyano, amino, C1-C4alkyl, C1-C4alkoxy, C1-C4hydroxyalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, benzyl, said substitution referring to one or more hydrogens on the group being replaced by halogen, deuterium, C1-C4alkyl and C1-C4alkoxy.

[0055] In another preferred embodiment, R x is selected from the group consisting of: hydrogen, deuterium, C1-C4alkyl.

[0056] In another preferred embodiment, R3is selected from the group consisting of: nothing, hydrogen, deuterium, hydroxyl, nitro, thiol, halogen, amino, C1-C6alkyl, C1-C6haloalkyl, -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;

[0057] R7and R8are each independently selected from the group consisting of: hydrogen, C1-C6alkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, -(C1-C4alkylene)-C3-C6cycloalkyl, -(C1-C4alkylene)-4-7 membered heterocyclyl;

[0058] wherein said alkyl, alkylene, heteroalkyl, cycloalkyl and heterocyclyl are optionally substituted with one or more groups selected from: hydrogen, deuterium, halogen, amino, oxo (=O), hydroxyl, cyano, C l -C4alkyl, C l -C4haloalkyl, C l -C4alkoxy, C l -C4haloalkoxy, C3-C5cycloalkyl, -NH(C1-C3alkyl), N(C1-C3alkyl)2;

[0059] or R7or R8and R4and the atoms to which they are both attached form: a 4-11 membered heterocyclic ring, a 5-11 membered heteroaromatic ring, a phenyl ring, a C3-C 10 carbocyclic ring;

[0060] or R3and R4and the atoms to which they are both attached form: a C6-C 10 aromatic ring, a C3-C 11 carbocyclic ring, a 5-11 membered heterocyclic ring or a 5-11 membered heteroaromatic ring;

[0061] wherein the heterocycle, heteroaromatic ring, aromatic ring, and carbocycle are optionally substituted with one or more groups selected from the group consisting of hydrogen, deuterium, halogen, amino, oxo (=0), hydroxyl, cyano, C l -C3alkyl, haloC l -C3alkyl, C l -C3alkyl, C3-C6cycloalkyl, -NH(C1-C3alkyl), N(C1-C3alkyl)2, C2-C4alkenyl, C2-C4alkynyl, or any two substituents on the ring at the same or different positions, together with the atom to which they are both attached, form a spiro, bridged, or fused ring structure.

[0062] In another preferred embodiment, R3is selected from the group consisting of null, H, -S(O)2R7, or -S(O)2NHR7;

[0063] wherein R7is selected from the group consisting of C1-C4alkyl, C3-C5cycloalkyl, 4-6 membered heterocyclyl;

[0064] The alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more groups selected from the group consisting of hydrogen, deuterium, halogen, amino, oxo (=0), hydroxyl, cyano, C l -C4alkyl, haloC l -C4alkyl, C l -C4alkyl, C3-C5cycloalkyl, -NH(C1-C3alkyl), N(C1-C3alkyl)2;

[0065] or R7and R4, together with the atom to which they are both attached, form: a C6-C 10 aromatic ring, saturated or unsaturated C3-C 11 carbocycle, 5-9 membered heterocycle, or 5-9 membered heteroaromatic ring;

[0066] or R3and R4, together with the atom to which they are both attached, form: a C6-C 10 aromatic ring, C3-C 11 carbocycle, 5-9 membered heterocycle, or 5-9 membered heteroaromatic ring;

[0067] wherein the heterocycle, heteroaromatic ring, aromatic ring, and carbocycle are optionally substituted with one or more groups selected from the group consisting of hydrogen, deuterium, halogen, amino, oxo (=0), hydroxyl, cyano, C l -C4alkyl, haloC l -C4alkyl, C l -C4alkyl, C3-C5cycloalkyl; l -C4haloalkoxy, C3-C5cycloalkyl;

[0068] When R7and R4, or R3and R4, are cyclized, the formed heterocycle and heteroaromatic ring can be monocyclic, bridged, spiro, or fused.

[0069] In another preferred embodiment, R4is selected from the group consisting of null, H, deuterium, halogen, cyano, thiol, nitro, hydroxyl, amino, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -0-(C1-C6alkylene)-H2PO4, -C(O)NHR7, -S(O)2R7, -SO2NHR7, -OR7, -O-(C1-C6alkylene)-R7, -SR7, -NHR7, -NH-(C1-C6alkylene)-R7, -NHC(O)R7, -NR7R8, or -(C=O)R7-; wherein R7and R8are each independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C3-C6cycloalkyl, 4-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or R7and R8together with the ring atoms to which they are both attached form a 4-7 membered heterocyclic or 5-6 membered heteroaromatic ring;

[0070] wherein said alkyl, heteroalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heterocyclic, and heteroaromatic rings are optionally substituted with one or more groups selected from halogen, deuterium, halogen, oxo (=O), cyano, thiol, nitro, hydroxyl, amino, C l -C4alkyl, C l -C4alkyl, C

[0071] In another preferred embodiment, R4is selected from the group consisting of null, H, deuterium, halogen, cyano, thiol, nitro, hydroxyl, amino, C1-C6alkyl, C1-C6alkoxy, hydroxyl-substituted C1-C6alkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, -O-(C1-C6alkylene)-H2PO4, -C(O)NHR7, -SO2NHR7;

[0072] wherein R7is selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl.

[0073] In another preferred embodiment, when R1is alkoxy, R4is not a chlorine atom.

[0074] In another preferred embodiment, R5and R6are each independently selected from the group consisting of null, H, deuterium, halogen, cyano, nitro, hydroxyl, amino, C1-C6alkyl, C1-C6heteroalkyl, C1-C6alkoxy, C1-C6hydroxyalkyl, C2-C6alkenyl, C2-C6alkynyl, phenyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein each alkyl, alkoxy, alkenyl, alkynyl, phenyl, cycloalkyl, heterocyclyl, and heteroaryl is optionally substituted with one or more groups selected from halogen, cyano, hydroxyl, nitro, oxo (=0), amino, C1-C4alkyl, C1-C4alkoxy, C3-C6cycloalkyl, phenyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl.

[0075] In another preferred embodiment, R5and R6are each independently selected from the group consisting of null, H, halogen, cyano, nitro, hydroxyl, amino, C1-C4alkyl, C1-C4alkoxy, C1-C4hydroxyalkyl, haloC1-C4alkyl, haloC1-C4alkoxy, or C 3- C6cycloalkyl.

[0076] In another preferred embodiment, Z is selected from the group consisting of:

[0077] Preferably, Z is selected from the group consisting of:

[0078] In another preferred embodiment, R1is selected from the group consisting of halogen, deuterium, cyano, hydroxyl, -NR a R b , nitro, amino, straight or branched chain C1-C6alkyl, straight or branched chain C1-C6alkoxy, straight or branched chain C1-C6alkylthio, C3-C7cycloalkyl, C3-C7oxacycloalkyl, C3-C7thiacycloalkyl, straight or branched chain C2-C6alkenyl, straight or branched chain C2-C6alkynyl, C3-C6cycloalkenyl, -C(=0)-(C1-C6alkyl), -S(O)2-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -C(O)-NH-(C1-C6alkyl), C6-C 10 aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl; wherein Raand Rbare each independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C6-C 10 aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, or, Raand Rb, together with the N atom to which they are both attached, form a 4-9 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms each independently selected from N, O, and S;

[0079] wherein said alkyl, alkoxy, alkylthio, cycloalkyl, oxacycloalkyl, thiacycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from halogen, deuterium, oxo (=0), hydroxyl, cyano, nitro, amino, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, benzyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, -(halo or non-halo C1-C4alkylene)-C3-C6cycloalkyl, -(halo or non-halo C1-C4alkylene)-phenyl, -(halo or non-halo C1-C4alkylene)-5-6 membered heteroaryl, -(halo or non-halo C1-C4alkylene)-4-7 membered heterocyclyl, -0-C3-C6cycloalkyl, -0-phenyl, -0-5-6 membered heteroaryl, -0-(4-7 membered heterocyclyl), -S-(C3-C6cycloalkyl), -S-phenyl, -S-(5-6 membered heteroaryl), -S-(4-7 membered heterocyclyl), -NH-(C3-C6cycloalkyl), -NH-phenyl, -NH-(5-6 membered heteroaryl), -NH-(4-7 membered heterocyclyl), -NH-C(O)-(C3-C6cycloalkyl), -C(O)-NH-(C3-C6cycloalkyl), -(halo or non-halo C1-C4alkylene)-0-C3-C6cycloalkyl, -(halo or non-halo C1-C4alkylene)-0-phenyl, -(halo or non-halo C1-C4alkylene)-0-5-6 membered heteroaryl, -(halo or non-halo C1-C4alkylene)-0-4-7 membered heterocyclyl;

[0080] Preferably, R1is selected from the group consisting of halogen, deuterium, cyano, -NRaRb, hydroxyl, nitro, amino, linear or branched C1-C6alkyl, linear or branched C1-C6alkoxy, C3-C6cycloalkyl, linear or branched C2-C6alkenyl, linear or branched C2-C6alkynyl, -C(=O)-(C1-C6alkyl), 4-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein Raand Rbare each independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl, or Raand Rb, together with the N atom to which they are both attached, form a 4-7 membered heterocyclic or 5-6 membered heteroaromatic ring containing from 1 to 3 heteroatoms each independently selected from N, O and S;

[0081] wherein said alkyl, alkoxy, alkylthio, cycloalkyl, oxacycloalkyl, thiacycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl are optionally substituted with one or more groups selected from halogen, oxo (=0), hydroxyl, cyano, nitro, C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C6hydroxyalkyl, or C3-C6cycloalkyl.

[0082] In another preferred embodiment, R1is selected from the group consisting of cyclopropyl, trifluoromethyl, -C(O)CH3, isopropyl, hydroxyethyl, methoxy, chloro, ethoxy, cyclobutyl, hydroxybutyl, t-butyl, ethynyl, hydroxypropyl, sec-butyl, cyano, cyclopentyl, methyl substituted cyclopropyl, dimethyl substituted cyclopropyl, butynyl, cyclohexyl,

[0083] In another preferred embodiment, R1is selected from the following structures:

[0084] - CN, - Cl, -OMe, -OEt, -CF3, Preferably, R1is selected from the following structures: - OMe, More preferably, R1is selected from the following structures:

[0085] In another preferred embodiment, the compound is selected from the group consisting of:

[0086] In another preferred embodiment, the compound is selected from the group consisting of:

[0087] In another preferred embodiment, the compound is selected from the group consisting of:

[0088] In a second aspect of the present application, there is provided a pharmaceutical composition comprising, as an active ingredient, one or more compounds of the first aspect of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotopically enriched derivative, or combination thereof, and a pharmaceutically acceptable carrier.

[0089] In another preferred embodiment, the weight ratio of the active ingredient to the pharmaceutically acceptable carrier in the pharmaceutical composition is 0.001-100; preferably 0.001-10.

[0090] In a third aspect of the present application, there is provided a use of a compound of the first aspect of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotopologue derivative, or a combination thereof, or a pharmaceutical composition of the second aspect of the present application, in the manufacture of a medicament for treating and / or preventing a necroptosis and inflammation related disease.

[0091] In another preferred embodiment, the necroptosis and inflammation related disease is a disease caused by abnormal level of activity and / or expression of RIPK3.

[0092] In another preferred embodiment, the necroptosis and inflammation related disease refers to an inflammatory, infectious, ischemic, autoimmune, allergic or degenerative related disease or tissue damage caused by abnormal level of activity and / or expression of RIPK3.

[0093] In another preferred embodiment, the disease caused by abnormal level of activity and / or expression of RIPK3 is selected from the group consisting of a nervous system disease, ischemia-reperfusion injury, autoimmune disease, acute liver injury, acute lung injury, acute kidney injury, hyperuricemia, gout, skin inflammation, chronic liver disease, atherosclerosis, Gaucher disease, pain, inflammation, retinal disease, tumor, immune senescence, viral infection, heat stroke, aging, platelet thrombosis, graft-versus-host disease.

[0094] In another preferred embodiment, the nervous system 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).

[0095] In another preferred embodiment, the skin inflammation is psoriasis.

[0096] In another preferred embodiment, the pain is neuropathic pain.

[0097] 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.

[0098] In another preferred embodiment, the chronic liver disease is selected from fatty liver, alcoholic liver disease and non-alcoholic liver disease.

[0099] In another preferred embodiment, the inflammation is selected from the group consisting of systemic inflammatory response syndrome (SIRS), acute pancreatitis, ulcerative colitis, hepatitis, Crohn's disease, sepsis, mycoplasma pneumonia, sepsis, ankylosing spondylitis, and osteoarthritis.

[0100] In another preferred embodiment, the viral infection is SARS-CoV-2 infection, HSV infection, influenza virus infection.

[0101] In another preferred embodiment, the retinal disease is selected from the group consisting of diabetic retinopathy, glaucoma, age-related retinal macular degeneration, and retinal detachment.

[0102] In another preferred embodiment, the tumor is selected from the group consisting of melanoma, brain glioma, colon cancer, neuroglia, lymphoma, T-cell leukemia, abdominal aortic aneurysm, and multiple myeloma.

[0103] In a fourth aspect of the present application, there is provided use of a compound of the first aspect of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotopic derivative, or combination thereof, or a pharmaceutical composition of the second aspect of the present application, in the manufacture of a RIPK3 inhibitor.

[0104] In another aspect of the present application, there is provided a method of inhibiting RIPK3, comprising contacting a therapeutically effective amount of a compound of the first aspect of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotopic derivative, or combination thereof, or a pharmaceutical composition of the second aspect of the present application, with RIPK3, thereby inhibiting RIPK3.

[0105] In another aspect of the present application, there is provided a method of preventing and / or treating a disease associated with necroptosis and inflammation, comprising contacting a therapeutically effective amount of a compound of the first aspect of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotopic derivative, or combination thereof, or a pharmaceutical composition of the second aspect of the present application, with a subject in need thereof.

[0106] It should be understood that, within the scope of the present application, all combinations of the above-described technical features of the present application and the technical features specifically described hereinafter (e.g., in the examples) can be interchanged and combined to form new or preferred technical solutions. Due to the limited space, they are not listed one by one here. BRIEF DESCRIPTION OF DRAWINGS

[0107] Figure 1 shows the results of the comparison of the cleavage of caspase-3 and caspase-8 by the compounds LK-16 and LK-18 of the present application and the control compound GSK872.

[0108] Figure 2 shows the results of comparison of the cleavage of caspase-3 and caspase-8 by the compound LK-25 of the present application and the control compound DB-2.

[0109] Figure 3 shows the results of comparison of the cleavage of caspase-3 and caspase-8 by the compounds LK-48 and LK-49 of the present application and the control compound DB-3.

[0110] Figure 4 shows the effects of the compounds LK-28 and LK-34 of the present application on the inhibition of the ZBP-1 mediated cell necrosis pathway in mouse-ZBP1 stable cell line MEF cells. DETAILED DESCRIPTION

[0111] The inventors have made extensive and in-depth research and for the first time provided a novel 2-substituted azole compound for preparing a disease related to programmed cell necrosis associated with RIPK3 abnormality. The compound of the present application has a good inhibitory effect on RIPK3 and can avoid the apoptosis side effects caused by conventional RIPK3 inhibitors, greatly improving the therapeutic window of the inhibitor, and thus has a wide application prospect. Based on this, the inventors have completed the present application.

[0112] TERMS

[0113] In the present application, the terms used have the general meanings known to those skilled in the art, unless otherwise specified.

[0114] Unless otherwise explicitly indicated, throughout the specification and claims, the term "comprise" or its variants such as "comprises" or "comprising" will be understood to encompass the stated components, without excluding other components.

[0115] In the present application, the term "halogen" refers to F, Cl, Br or I.

[0116] In the present application, "C 1- C 10 "Alkyl" refers to a straight chain or branched alkyl group comprising 1-10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0117] In the present application, "C 1- C 10 "Heteroalkyl" refers to a group obtained by replacing one to three carbon atoms in an alkyl group with one to three heteroatoms each independently selected from N, O and S, such as 1- C 10 for example or the like.

[0118] As used herein, the term "alkylene" (also referred to herein as "alkylene chain"), especially those "alkylene" groups which are internal or non-terminal in a molecule or group (e.g., Y, and L4in the "alkylene" groups and as a substituent group (e.g., C3-C 10 As used herein, the term "alkylene" (also referred to herein as "alkylene chain"), especially those "alkylene" groups which are internal or non-terminal in a molecule or group (e.g., Y, and L4in the "alkylene" groups and as a substituent group (e.g., C3-C propylene isopropylene butylene (e.g., pentylene (e.g., hexylene (e.g., heptylene (e.g., , and the like. In addition, the term also includes alkylene groups (e.g., C1-C 18 alkylene) in which one methylene group has been replaced by a cycloalkylene group (e.g., C3-C 20 cycloalkylene), e.g., "C1-C 18 alkylene C3-C 20 cycloalkylene" or "C3-C 20 cycloalkylene C1-C 18 alkylene". In the present application, alkylene also includes substituted alkylene groups, which can be substituted with halo (-CHF- or -CF2-), hydroxy, cyano, nitro, and the like.

[0119] In the present application, the term "C 2- C 10 alkenyl" means a straight or branched chain alkenyl group having from 2 to 10 carbon atoms containing one double bond, including, without limitation, ethenyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl, and the like.

[0120] In the present application, the term "C 2- C 10 alkynyl" means a straight or branched chain alkynyl group having from 2 to 10 carbon atoms containing one triple bond, including, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, and hexynyl, and the like.

[0121] In the present application, the term "carbocyclic" means a cyclic structure having from 3 to 11 ring atoms which is saturated or unsaturated and all of which are carbon atoms, including cycloalkyl, cycloalkenyl, cycloalkynyl, which can be monocyclic, polycyclic fused, polycyclic bridged, polycyclic spirocyclic, and polycyclic bridged.

[0122] 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 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 R c NR d S(=O)2NR b Rc , NR d P(=O)2NR b R c , NR b C(=O)R a , or NR b P(=O)2R e wherein R a may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, aryl, or heteroaryl, R b , R c and R d may independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle, or aryl ring, or R b and R c together with the N atom can form a heterocyclic ring; and R e may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, aryl, or heteroaryl. The above typical substituents can be optionally substituted. Typical substitutions also include spirocyclic, pyrimidinocyclic, or fused ring substituents, especially spirocycloalkyl, spirocycloalkenyl, spirocycloheterocyclic (excluding heteroaromatic rings), pyrimidinocycloalkyl, pyrimidinocycloalkenyl, pyrimidinocycloheterocyclic (excluding heteroaromatic rings), fused cycloalkyl, fused cycloalkenyl, fused cycloheterocyclic, or fused aryl ring, which above cycloalkyl, cycloalkenyl, heterocyclyl, and heteroaryl can be optionally substituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.

[0123] In the present application, the term "C 1- C 10 alkoxy" refers to a straight chain or branched chain alkoxy group having 1 to 10 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy, and the like. Preferably, C 1-4 alkoxy.

[0124] In the present invention, the term "heterocyclyl or heterocycle" refers to a fully saturated or partially unsaturated cyclic group (including but not limited to, e.g., 3-7 membered monocyclic, 4-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic or polycyclic systems) in which at least one heteroatom is present in at least one carbon atom-containing ring. The term "4-20 membered heterocyclyl" refers to a heterocyclyl group comprising 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ring atoms. "Heterocyclyl" has the same meaning as "saturated or unsaturated heterocyclyl". "Heterocyclyl" is preferably 4-14 membered heterocyclyl (including but not limited to, e.g., 4-6 membered monocyclic, 7-10 membered bicyclic, or 8-14 membered tricyclic or polycyclic systems), more preferably 4-12 membered heterocyclyl, more preferably 4-10 membered heterocyclyl, such as 4-6 membered monocyclic heterocyclyl, 7-11 membered bicyclic or tricyclic heterocyclyl, more preferably 4-8 membered heterocyclyl, more preferably 4-6 membered heterocyclyl. The heterocycle containing heteroatoms of each heterocyclyl group can bear 1, 2, 3, or 4 heteroatoms each independently selected from a nitrogen atom, an oxygen atom, or a sulfur atom, wherein the nitrogen atom or the sulfur atom can be oxidized and the nitrogen atom can also be quaternized. The heterocyclyl group can be attached to the residue of any heteroatom or carbon atom of the ring or ring system, preferably to the N or C atom of the ring or ring system. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxanyl, and tetrahydro-l,l-dioxothiopyran, and the like. Polycyclic heterocyclyl groups include spiro, fused, and bridged ring heterocyclyl groups; wherein the spiro, fused, and bridged ring heterocyclyl groups are optionally connected to other groups by a single bond or further annulated to other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups through any two or more atoms of the ring; the heterocyclyl group can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxyl, thiol, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.

[0125] The term "4-20 membered heterocyclyl ene" refers to a group formed by removing two hydrogen atoms from a heterocyclyl group, such as:

[0126] and the like.

[0127] 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 R c NR d S(=O)2NR b R c NR d P(=O)2NR b R c NRb C(=O)R a , or NR b P(=O)2R e , wherein R a may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, or aryl, R b , R c , and R d may independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle, or aryl ring, or R b and R c together with the N atom can form a heterocyclic ring; and R e may independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocyclyl, or aryl. The above typical substituents can be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclyl, or fused ring aryl ring, the above cycloalkyl, cycloalkenyl, heterocyclyl, and heterocyclic aryl groups can be optionally substituted.

[0128] The term "heteroaryl or heteroaromatic ring" refers to an aromatic cyclic hydrocarbon group containing 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. Within this, "5-14 membered heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-14 ring atoms. Heteroaryl groups are preferably 5 to 10 membered rings, more preferably 5 or 6 membered, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, and tetrazolyl. "Heteroaryl" groups can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, thiol, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxy, and carboxylate.

[0129] In the present application, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.

[0130] In the present application, the term "halo" refers to substitution with halogen.

[0131] In the present application, the term "deuterated" refers to substitution with deuterium.

[0132] In the present application, the term "hydroxy" refers to a group with the structure OH.

[0133] In the present application, the term "nitro" refers to a group with the structure NO2.

[0134] In the present application, the term "cyano" refers to a group with the structure CN.

[0135] In the present application, the term "ester" refers to a group having the structure -COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle. Preferably, the ester is -COO C1-C6 alkyl.

[0136] The term "amine" refers to a group having the structure -NR'R", wherein 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 heterocyclyl, or R' and R" together with the nitrogen atom to which they are both attached form a substituted or unsubstituted heterocyclyl 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 heterocyclyl, or R' and R" together with the nitrogen atom to which they are both attached form a 4 to 7 membered heterocyclyl group (preferably a saturated 4 to 7 membered heterocyclyl group containing only one nitrogen heteroatom as a ring atom). In one embodiment, at least one of R' and R" is other than H. R' and R" can be the same or different in a dialkylamine moiety. Preferably, the amine is NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2; more preferably NHC1-C6 alkyl, N(C1-C6 alkyl)2.

[0137] The term "amide" refers to a group having the structure -CONR'R", wherein 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 heterocyclyl, or R' and R" together with the nitrogen atom to which they are both attached form a substituted or unsubstituted heterocyclyl 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 heterocyclyl, or R' and R" together with the nitrogen atom to which they are both attached form a 4 to 7 membered heterocyclyl group (preferably a saturated 4 to 7 membered heterocyclyl group containing only one nitrogen heteroatom as a ring atom). R' and R" can be the same or different in a dialkylamine moiety. Preferably, the amide is -CONH2, -CONH(C1-C6 alkyl), -CONH(C3-C6 cycloalkyl).

[0138] In the present application, the term "substituted" means that one or more hydrogen atoms on a specified group are replaced with a specified substituent. The specified substituents are those described in the foregoing, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group can have at any substitutable position one substituent selected from a specified group, which can be the same or different at each position. It will be understood by those skilled in the art that combinations of substituents contemplated by the present application are those stable or chemically feasible combinations. The substituents are, for example, but not limited to, halogen, hydroxy, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehydic, C2-C10 acyl, C2-C10 ester, amino, C1-C6 alkoxy, C1-C10 sulfonyl, and the like.

[0139] In the present application, the term 1-6 means 1, 2, 3, 4, 5, or 6. Other similar terms each independently have a similar meaning. The term "a plurality" means 2-6, such as 2, 3, 4, 5, or 6.

[0140] It will be understood that when a group is present simultaneously in a plurality of different positions of a compound, the definition thereof at each position is independent of the others, and can be the same or different. That is, the term "selected from the group consisting of" has the same meaning as the term "each independently selected from the group consisting of".

[0141] Active ingredient

[0142] The present application provides a compound represented by Formula I, or a pharmaceutically acceptable salt thereof,

[0143] wherein each group is as defined above.

[0144] In another preferred embodiment, in the compound, X, Z, G, R1, R2, and ring A are each independently the corresponding group in the specific compound.

[0145] In another preferred embodiment, the compound is preferably a compound prepared in each embodiment.

[0146] As used herein, the term "pharmaceutically acceptable salt" refers to those salts of the compounds of the present application which are suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts are those formed from the compounds of the present application and an acid. Suitable acids for salt formation include, but are not limited to, hydrochloric, hydrobromic, hydrofluoric, sulfuric, nitric, phosphoric, and the like inorganic acids; formic, acetic, trifluoroacetic, propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric, citric, picric, benzoic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic, naphthalenesulfonic, and the like organic acids; and amino acids such as proline, phenylalanine, aspartic acid, glutamic acid, and the like.

[0147] Another preferred class of salts are those formed from the compounds of the present application and a base, such as alkali metal salts (e.g., sodium or potassium), alkaline earth metal salts (e.g., magnesium or calcium), ammonium salts (e.g., lower alkylammonium salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, t-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, trihydroxyethylamine, and the like, and amine salts formed from morpholine, piperazine, lysine, respectively.

[0148] The compounds of the present application can contain one or more asymmetric centers and can thus give rise to diastereomers and optical isomers. The present application includes all possible diastereomers and optical isomers of the compounds of the present application and their racemic mixtures, substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

[0149] Where the compounds of Formula (I) exist in tautomeric forms, unless specifically stated otherwise, the present application includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof.

[0150] Where the compounds of Formula (I) and pharmaceutically acceptable salts thereof exist in solvated forms, the present application includes any possible solvates. The type of solvent that forms the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like similar solvents can be used.

[0151] The term "composition," as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Thus, pharmaceutical compositions containing a compound of the present application as an active ingredient, as well as methods of preparing compounds of the present application, are part of the present application. In addition, some of the crystalline forms of the compounds can exist as polymorphs and as such are intended to be included in the present application. In addition, some of the compounds can form solvates with water (i.e., hydrates) and common organic solvents, and such solvates are also intended to be encompassed within the scope of this application.

[0152] It is understood that the compounds of the present application can be prepared by the methods illustrated in the following examples, and also can be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combination being readily made by one skilled in the art to which the present application pertains.

[0153] Pharmaceutical compositions and modes of administration

[0154] The pharmaceutical composition of the present application comprises a safe and effective amount of the compound of the present application or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. The "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present application per dose, more preferably, 5-1000 mg of the compound of the present application per dose. Preferably, the "dose" is one capsule or tablet.

[0155] The "pharmacologically acceptable carrier" means one or more compatible solid or liquid filler or gel materials which are suitable for human use and must have sufficient purity and low toxicity. "Compatible" here means that the components of the composition are capable of being combined with the compound of the present application and with each other in the composition, without chemically interacting in a deleterious manner with the compound. Examples of the pharmacologically acceptable carrier include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g., lecithin), wetting agents (e.g., sodium dodecyl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0156] The pharmaceutical composition is an injection, a capsule, a tablet, a pill, a powder or a granule.

[0157] The mode of administration of the compound or the pharmaceutical composition of the present application is not particularly limited, and the representative modes of administration include (but are not limited to) oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0158] ​Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate or with such other ingredients as binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, and acacia; humectants, e.g., glycerol; disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; effervescing mixtures; attapulgus; waxes; and the like. The tablets, pills, capsules, and the like can also contain opacifying agents and can be of a composition that they release the active compound or compounds in a certain part of the digestive tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if desired, with one or more of the above-described excipients.

[0159] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art. They can contain opacifying agents, and can be of a composition that they release the active compound or compounds in a certain part of the digestive tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. If desired, the active compound(s) can also be in micro-encapsulated form, if desired, with one or more of the above-described excipients.

[0160] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and the like, either with or without the addition of such

[0161] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0162] Suspensions, in addition to the active compounds, can contain suspending agents, as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, and agar-agar, and the like.

[0163] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.

[0164] Dosage forms for topical administration of a compound of this application include ointments, powders, sprays, and inhalers. The active component is admixed with a carrier, which can be a sterile, physiologically acceptable carrier, and any buffers, preservatives, or propellants as can be required.

[0165] A compound of this application can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0166] The therapeutic methods of this application can be employed alone or in combination with other treatments or therapies.

[0167] In using the pharmaceutical compositions, therapeutically effective amounts of a compound of this application are administered to a mammal (e.g., human) in need of such treatment in dosages and using dosing regimens safe for such drug administration, and which will yield effective levels of the active compound. The dosage and dosing regimen will depend on the host, the particular compound of this application selected, the use for which it is intended, and other factors known to skilled practitioners. Generally, oral dosages in the range of 1-2000 mg, preferably 5-1000 mg, per day for a 60 kg individual are therapeutically effective. The specific dosage used, however, will vary with the particular compound of this application used, the host treated, the specific disease or disorder involved, the mode of administration and other factors known to skilled practitioners. The practitioner will ultimately determine appropriate dosages, dosing regimens and repetition rates.

[0168] The main advantages of the present application compared to the prior art include:

[0169] (1) The present application provides a class of structurally novel 2-substituted azole compounds, which are easy to synthesize.

[0170] (2) The compounds of the present application have good inhibitory activity on RIPK3 and the cell necrosis pathway mediated by RIPK3 at the enzyme level and cell level.

[0171] (3) The compounds of the present application have excellent selectivity of kinase spectrum, and the inhibitory activity of the compounds on various off-target kinases is significantly weakened compared to positive compounds.

[0172] (4) The compounds of the present application can avoid the side effect of apoptosis caused by common RIPK3 inhibitors, greatly improve the therapeutic window of the inhibitors, and therefore have broad application prospects in the treatment or prevention of programmed cell necrosis and inflammation-related diseases.

[0173] The application will be further described in conjunction with specific examples. It should be understood that these examples are intended to illustrate the application and are not intended to limit the scope of the application. The experimental procedures in the following examples, unless otherwise indicated, were carried out in accordance with conventional procedures, 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 indicated, percentages and parts are by weight.

[0174] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Also, any method and material similar or equivalent to those described herein can be used in the practice of the present application. The methods and materials described herein are illustrative only and not intended to be limiting.

[0175] In the following examples, the compounds used can be obtained commercially or can be synthesized by conventional methods using commercially available starting materials and reagents. Reactions were monitored by thin layer chromatography (TLC). In the present application, 1 H NMR and 13 C NMR spectra were determined using a Bruker Avance 600 or a Bruker Avance 500 NMR spectrometer using TMS as an internal standard. High resolution mass spectrometry (HRMS) was determined by an Agilent G6520 Q-TOF mass spectrometer. Low resolution mass spectrometry (LRMS) was determined by a Thermo Fisher FINNIGAN LTQ linear ion trap mass spectrometer. All reactions were carried out under an air atmosphere unless otherwise specified.

[0176] The following abbreviations were used in the examples: cataCXium A n-butylbis(1-adamantyl)phosphine DCM dichloromethane 1,4-Dioxane 1,4-dioxane DME ethylene glycol dimethyl ether DMF N,N-dimethylformamide EA ethyl acetate Na2CO3 sodium carbonate PE petroleum ether Pd(PPh3)4 tetrakis(triphenylphosphine)palladium TBAF tetrabutylammonium fluoride TEA triethylamine THF tetrahydrofuran

[0177] Example 1

[0178] Synthesis of intermediate 4-chloro-6-(isopropylthio)quinoline (M1)

[0179] 6-bromo-4-chloroquinoline (5 g, 20.60 mmol), Pd(PPh3)4(714 mg, 0.62 mmol), 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 N2protection, and the reaction was heated to 70 °C for 48 h. The organic phase was extracted by filtration, and the filtrate was rotary evaporated and extracted with EA, and washed with saturated brine. The organic phase was rotary evaporated and purified by column chromatography (PE:EA = 4:1) to obtain 3.6 g of yellow solid, which was intermediate M1, with a yield of 73%. 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 4.7 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.25 (dd, J = 8.8, 2.0 Hz, 1H), 8.00 (d, J = 4.7 Hz, 1H), 3.65 (hept, J = 7.3, 6.8 Hz, 1H), 1.22 (d, J = 6.8 Hz, 6H).

[0180] Synthesis of intermediate 4-chloro-6-(isopropylsulfonyl)quinoline (M2)

[0181] 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, and the reaction was carried out at room temperature for 6 h. After the reaction was completed, the white solid was filtered off, and the filtrate was adjusted to pH 7-8, extracted with DCM, and washed with saturated brine. The organic phase was rotary evaporated and purified by column chromatography (DCM:MeOH = 20:1) to obtain 650 mg of white solid, which was intermediate M2, with a yield of 57%. 1 H NMR (400 MHz, DMSO-d6) δ 9.07 (d, J = 4.7 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.25 (dd, J = 8.8, 2.0 Hz, 1H), 8.00 (d, J = 4.7 Hz, 1H), 3.65 (hept, J = 7.3, 6.8 Hz, 1H), 1.22 (d, J = 6.8 Hz, 6H).

[0182] Synthesis of intermediate 2-cyclopropyl-5-nitrobenzo[d]thiazole (M3)

[0183] Intermediate M3 was synthesized by adding 5-nitrobenzo[d]thiazole (500 mg, 2.77 mmol), p-toluenesulfonic acid silver (1.55 g, 5.54 mmol) and cyclopropanecarboxaldehyde (250 μL, 3.42 mmol) into water (15 mL), heating to 100 °C under N2protection for 12 h. After completion of the reaction, the reaction mixture was filtered through celite and the filtrate was extracted with EA and washed with saturated brine. The organic phase was dried and purified by column chromatography (PE:EA = 20:1) to give yellow solid 15 mg, which was intermediate M3 with a yield of 2%. 1 H NMR (400 MHz, Chloroform-d) δ 8.75 (d, J = 2.3 Hz, 1H), 8.22 (dd, J = 8.8, 2.2 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 2.45 (p, J = 6.5 Hz, 1H), 1.34 - 1.32 (m, 2H), 1.30 - 1.26 (m, 2H).

[0184] Synthesis of intermediate 2-cyclopropylbenzo[d]thiazol-5-amine (M4)

[0185] Intermediate M3 (15 mg, 0.07 mmol) was dissolved in methanol (1 mL) and 10% palladium on carbon (5 mg) was added. The reaction was carried out under H2atmosphere for 12 h. After completion of the reaction, the palladium on carbon was filtered off and the organic phase was dried to give colorless solid 12 mg, which was intermediate M4 with a yield of 93%. It was used directly in the next step.

[0186] Synthesis of compound 2-cyclopropyl-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5-amine (LK-1)

[0187] 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 h. Yellow solid was precipitated from the reaction solution. Filtration gave yellow solid 14 mg, which was compound LK-1 as a hydrochloride salt with a yield of 64%. 1H NMR (500 MHz, DMSO-d6) δ 15.03 (br s, 1H), 11.68 (s, 1H), 9.45 (d, J = 1.8 Hz, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.39 (dd, J = 8.9, 1.8 Hz, 1H), 8.32 (d, J = 8.9 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.5, 2.1 Hz, 1H), 6.95 (d, J = 7.1 Hz, 1H), 3.69 (hept, J = 6.8 Hz, 1H), 2.59 (tt, J = 8.2, 4.8 Hz, 1H), 1.31 - 1.27 (m, 2H), 1.26 (d, J = 6.8 Hz, 6H), 1.20 - 1.16 (m, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 176.90, 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] + .

[0188] Example 2

[0189] Synthesis of compound N-(6-(isopropylsulfonyl)quinolin-4-yl)-2- (trifluoromethyl)benzo[d]thiazol-5-amine (LK-2)

[0190] Synthesis of compound LK-2 was performed according to the synthesis of compound LK-1, using 2-trifluoromethylbenzo[d]thiazol-5-amine and intermediate M2 as starting materials, to give 42 mg of yellow solid as hydrochloride salt, in 72% yield. 1H NMR (400 MHz, DMSO-d6) δ 14.62 (br s, 1H), 11.53 (s, 1H), 9.38 (d, J = 1.9 Hz, 1H), 8.65 (d, J = 6.9 Hz, 1H), 8.57 (d, J = 8.8 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 8.38 (dd, J = 8.9, 1.8 Hz, 1H), 8.24 (d, J = 8.9 Hz, 1H), 7.83 (dd, J = 8.7, 2.1 Hz, 1H), 7.07 (d, J = 6.9 Hz, 1H), 3.63 (p, J = 6.8 Hz, 1H), 1.26 (d, J = 6.8 Hz, 6H). ESI-MS: 452.4 [M+H] + .

[0191] Example 3

[0192] Synthesis of intermediate 1-(5-nitrobenzo[d]thiazol-2-yl)ethan-1-one (M5)

[0193] The synthesis of intermediate M5 was performed according to the synthesis of intermediate M3, using 5-nitrobenzo[d]thiazole and methylglyoxal as starting materials, to give yellow solid 100 mg in 16% yield. 1 H NMR (400 MHz, Chloroform-d) δ 9.07 (d, J = 2.2 Hz, 1H), 8.41 (dd, J = 8.9, 2.2 Hz, 1H), 8.14 (d, J = 8.9 Hz, 1H), 2.86 (s, 3H).

[0194] Synthesis of intermediate 1-(5-nitrobenzo[d]thiazol-2-yl)ethan-1-one (M5)

[0195] 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 5 minutes, a solution of M5 (100 mg, 0.45 mmol) in ethanol (5 mL) was added and the reaction was continued for 30 minutes. After completion of the reaction, the reaction mixture was filtered over celite and concentrated. The organic phase was extracted with EA, washed with saturated brine, and dried to give yellow oil 75 mg, which was intermediate M6a in 87% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.72 (d, J = 8.6 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 6.95 (dd, J = 8.6, 2.3 Hz, 1H), 3.93 (s, 2H), 2.79 (s, 3H).

[0196] Synthesis of compound 1-(5-((6-(isopropylsulfonyl)quinolin-4-yl)amino)benzo[d]thiazol-2-yl)ethan-1-one (LK-3)

[0197] The synthesis of compound LK-3 was performed according to the synthesis of LK-1, using intermediate M6a and intermediate M2 as starting materials, to give yellow solid 36 mg in 70% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.80 (s, 1H), 9.49 (d, J = 1.8 Hz, 1H), 8.63 (d, J = 7.0 Hz, 1H), 8.47 (d, J = 8.6 Hz, 1H), 8.44 - 8.38 (m, 2H), 8.35 (d, J = 8.9 Hz, 1H), 7.78 (dd, J = 8.7, 2.1 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 3.73 (h, J = 6.8 Hz, 1H), 2.78 (s, 3H), 1.25 (d, J = 6.8 Hz, 6H). 13 C NMR (126 MHz, DMSO-d6) δ 192.77, 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, found 426.0940.

[0198] Example 4

[0199] The synthesis of intermediates M7-M8 was performed according to the synthesis of intermediates M3-M4

[0200] Hydrogen spectrum of 2-isopropyl-5-nitrobenzo[d]thiazole (M7): 1 H NMR (400 MHz, Chloroform-d) δ 8.86 (d, J = 2.2 Hz, 1H), 8.26 (dd, J = 8.8, 2.2 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 3.49 (hept, J = 6.9 Hz, 1H), 1.54 (d, J = 6.9 Hz, 6H).

[0201] Hydrogen spectrum of 2-isopropylbenzo[d]thiazol-5-amine (M8)

[0202] 1 H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 6.78 (dd, J = 8.5, 2.2 Hz, 1H), 4.02 (br s, 2H), 3.40 (hept, J = 6.9 Hz, 1H), 1.47 (d, J = 6.9 Hz, 6H).

[0203] Synthesis of compound 2-isopropyl-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5-amine (LK-4)

[0204] Synthesis of compound LK-4 was performed according to the synthesis of LK-1, using intermediate M8 and intermediate M2 as starting materials, to give yellow solid 12 mg as hydrochloride salt, in 64% yield. 1 H NMR (500 MHz, DMSO-d6) δ 14.97 (br s, 1H), 11.68 (s, 1H), 9.45 (d, J = 1.8 Hz, 1H), 8.59 (d, J = 7.0 Hz, 1H), 8.39 (dd, J = 8.9, 1.8 Hz, 1H), 8.34 - 8.26 (m, 2H), 8.11 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.5, 2.1 Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 3.69 (hept, J = 6.7 Hz, 1H), 3.48 (p, J = 6.8 Hz, 1H), 1.45 (d, J = 6.9 Hz, 6H), 1.26 (d, J = 6.8 Hz, 6H). 13 C NMR (126 MHz, DMSO-d6) δ 179.72, 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.

[0205] Example 5

[0206] Synthesis of intermediate 1-(5-aminobenzo[d]thiazol-2-yl)ethan-1-ol (M6b)

[0207] To a solution of intermediate M5 (65 mg, 0.29 mmol) in methanol (1 mL) was added 10% palladium on carbon 7 mg, and the reaction was stirred under hydrogen atmosphere for 16 h. After completion of the reaction, the reaction mixture was filtered and the filtrate was evaporated to dryness and purified by column chromatography (DCM:MeOH = 10:1) to give 32 mg of intermediate M6b as a brown oil, yield 56%. 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 8.5 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.5, 2.2 Hz, 1H), 6.14 (d, J = 5.1 Hz, 1H), 5.20 (s, 2H), 5.01 - 4.92 (m, 1H), 1.48 (d, J = 6.5 Hz, 3H).

[0208] Synthesis of compound 1-(5-((6-(isopropylsulfonyl)quinolin-4-yl)amino)benzo[d]thiazol-2-yl)ethan-1-ol (LK-5)

[0209] Synthesis of compound LK-5 was performed according to the synthesis of LK-1, using intermediate M6b and intermediate M2 as starting materials, to give 34 mg of yellow solid as a hydrochloride salt, yield 66%. 1 H NMR (500 MHz, DMSO-d6) δ 14.88 (br s, 1H), 11.65 (s, 1H), 9.43 (d, J = 1.8 Hz, 1H), 8.59 (d, J = 7.0 Hz, 1H), 8.39 (dd, J = 8.9, 1.8 Hz, 1H), 8.33 - 8.27 (m, 2H), 8.09 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.5, 2.1 Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 6.47 (s, 1H), 5.10 (q, J = 6.5 Hz, 1H), 3.67 (hept, J = 6.8 Hz, 1H), 1.56 (d, J = 6.5 Hz, 3H), 1.25 (d, J = 6.8 Hz, 6H). 13 C NMR (151 MHz, DMSO-d6) δ 182.10, 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.

[0210] Example 6

[0211] Synthesis of intermediate 1-iodo-2-isothiocyanato-4-nitrobenzene (M7)

[0212] 2-Iodo-5-nitroaniline (300 mg, 1.14 mmol) and triethylamine (379 μL, 2.73 mmol) were added to tetrahydrofuran (5 mL), and thionyl chloride (104 μL, 1.36 mmol) was added dropwise slowly at 0 °C. The reaction was allowed to warm to room temperature and continue for 2 h. After completion of the reaction, the solvent was evaporated and purified by flash column chromatography to give 106 mg of yellow solid, which was intermediate M7 in 30% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 2.6 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.82 (dd, J = 8.7, 2.5 Hz, 1H).

[0213] Synthesis of intermediate methyl (2-iodo-5-nitrophenyl)aminothioformate (M8)

[0214] 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 added slowly. The reaction was allowed to proceed at room temperature for 12 h. After completion of the reaction, the solid was filtered to give 32 mg of intermediate M8 in 27% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.85 (s, 1H), 8.23 (s, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.79 (dd, J = 8.7, 2.6 Hz, 1H), 4.19 (s, 3H).

[0215] Synthesis of intermediate 2-methoxy-5-nitrobenzo[d]thiazole (M9)

[0216] 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 reaction was allowed to proceed at 80 °C for 2 h. After completion of the reaction, the reaction mixture was evaporated, and purified by column chromatography (PE:EA = 50:1) to give 16 mg of yellow solid, which was intermediate M9 in 86% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 8.7, 2.3 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 4.26 (s, 3H).

[0217] Synthesis of intermediate 2-methoxybenzo[d]thiazol-5-amine (M10)

[0218] The synthesis of intermediate M10 was performed according to the synthesis of intermediate M4, using intermediate M9 as starting material, to give 14 mg of colorless transparent oil, which was intermediate M10, in 88% yield.

[0219] Synthesis of compound N-(6-(isopropylsulfonyl)quinolin-4-yl)-2-methoxybenzo[d]thiazol-5-amine (LK-6)

[0220] The synthesis of compound LK-6 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M10 as starting materials, to give 28 mg of yellow solid as hydrochloride salt, in 85% yield. 1 H NMR (400 MHz, DMSO-d6) δ 14.72 (br s, 1H), 11.54 (s, 1H), 9.40 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 7.0 Hz, 1H), 8.38 (dd, J = 8.9, 1.7 Hz, 1H), 8.26 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.4, 2.1 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 4.21 (s, 3H), 3.65 (p, J = 6.8 Hz, 1H), 1.26 (d, J = 6.8 Hz, 6H). ESI-MS: 414.3 [M+H] + .

[0221] Example 7

[0222] Synthesis of compound 2-chloro-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5-amine (LK-7)

[0223] The synthesis of compound LK-7 was performed according to the synthesis of LK-1, using 2-chloro-5-amino-benzothiazole and intermediate M2 as starting materials, to give 31 mg of yellow solid as hydrochloride salt, in 80% yield. 1H NMR (500 MHz, DMSO-d6) δ 14.81 (br s, 1H), 11.60 (s, 1H), 9.41 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 7.0 Hz, 1H), 8.40 (dd, J = 8.9, 1.8 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.67 (dd, J = 8.6, 2.1 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 3.66 (p, J = 6.8 Hz, 1H), 1.26 (d, J = 6.8 Hz, 6H). ESI-MS: 418.4 [M+H] + .

[0224] Example 8

[0225] Synthesis of intermediate (2-iodo-5-nitrophenyl)aminothioformic acid ethyl ester (M11)

[0226] The synthesis of intermediate M11 was performed according to the synthesis of intermediate M8, using sodium ethoxide and intermediate M7 as starting materials, to give yellow solid 46 mg in 67% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 2.5 Hz, 1H), 8.15 (dd, J = 8.3, 2.7 Hz, 1H), 7.78 (dd, J = 8.8, 2.2 Hz, 1H), 4.76 - 4.66 (m, 2H), 1.56 - 1.51 (m, 3H).

[0227] Synthesis of intermediate 2-ethoxy-5-nitrobenzo[d]thiazole (M12)

[0228] The synthesis of intermediate M12 was performed according to the synthesis of intermediate M9, using intermediate M11 as starting material, to give yellow solid 40 mg in 78% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.55 (d, J = 2.5 Hz, 1H), 8.15 (dd, J = 8.3, 2.7 Hz, 1H), 7.78 (dd, J = 8.8, 2.2 Hz, 1H), 4.76 - 4.66 (m, 2H), 1.56 - 1.51 (m, 3H).

[0229] Synthesis of intermediate 2-ethoxybenzo[d]thiazol-5-amine (M13)

[0230] The synthesis of intermediate M13 was performed according to the synthesis of intermediate M4, using intermediate M12 as starting material, to give 22 mg of colorless oil in 63% yield. It was used directly in the next step without purification.

[0231] Synthesis of compound 2-ethoxy-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5- amine (LK-8)

[0232] The synthesis of compound LK-8 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M13 as starting materials, to give 19 mg of yellow solid as hydrochloride salt in 36% yield. 1 H NMR (500 MHz, DMSO-d6) δ 14.76 (s, 1H), 11.58 (s, 1H), 9.41 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 7.0 Hz, 1H), 8.39 (dd, J = 8.9, 1.8 Hz, 1H), 8.27 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 8.4, 2.1 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 4.64 (q, J = 7.0 Hz, 2H), 3.66 (p, J = 6.8 Hz, 1H), 1.45 (t, J = 7.0 Hz, 3H), 1.26 (d, J = 6.7 Hz, 6H). ESI-MS: 428.3 [M+H] + .

[0233] Example 9

[0234] Synthesis of intermediate 5-nitro-2-((triisopropylsilyl)ethynyl)benzo[d]thiazole (M14)

[0235] N2-protected 2-chloro-5-nitrobenzo[d]thiazole (100 mg, 0.47 mmol), triphenylphosphine (25 mg, 0.09 mmol), copper iodide (14 mg, 0.07 mmol) and palladium acetate (11 mg, 0.05 mmol) were added into a mixture of TEA (0.9 mL) and THF (2.1 mL). Triisopropylsilylacetylene (167 μL, 0.75 mmol) was added slowly dropwise at 0 °C. The reaction was continued at room temperature for 16 h after 2 h. After the reaction was completed, the reaction solution was concentrated, extracted with ethyl acetate, washed with saturated brine, and concentrated. The product was purified by column chromatography (PE:EA = 5:1) to give 60 mg of yellow solid, which was intermediate M14, in 54% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.93 (d, J = 2.3 Hz, 1H), 8.36 (dd, J = 8.8, 2.2 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 1.25 - 1.19 (m, 21H).

[0236] Synthesis of intermediate 2-((triisopropylsilyl)ethynyl)benzo[d]thiazol-5-amine (M15)

[0237] Synthesis of intermediate M15 was performed according to the synthesis of M6a, starting from intermediate M14 as a brown oil, 28 mg, 51% yield. It was used directly in the next step without purification.

[0238] Synthesis of intermediate N-(6-(isopropylsulfonyl)quinolin-4-yl)-2-((triisopropylsilyl)ethynyl)benzo[d]thiazol-5-amine (M16)

[0239] Synthesis of intermediate M16 was performed according to the synthesis of LK-1, starting from intermediate M2 and intermediate M15 as a yellow solid, 48 mg, 76% yield as a hydrochloride salt. 1 H NMR (500 MHz, DMSO-d6) δ 14.91 (br s, 1H), 11.63 (s, 1H), 9.42 (d, J = 1.8 Hz, 1H), 8.64 (d, J = 7.0 Hz, 1H), 8.40 (dd, J = 8.9, 1.8 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 8.30 (dd, J = 8.8, 2.6 Hz, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.7, 2.1 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 3.67 (p, J = 6.8 Hz, 1H), 1.26 (d, J = 6.8 Hz, 6H), 1.24 - 1.19 (m, 3H), 1.15 (d, J = 6.8 Hz, 18H).

[0240] Synthesis of compound 2-ethynyl-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5-amine (LK-9)

[0241] Intermediate M16 (35 mg, 0.06 mmol) was dissolved in THF (2 mL), TBAF (156 μL, 0.16 mmol) was added slowly dropwise at -40 °C, and the reaction was continued for 1 hour at room temperature. After the reaction was completed, the organic phase was spin-dried, extracted with ethyl acetate, washed with saturated brine, and concentrated. The product was separated by column chromatography (DCM:MeOH = 10:1) to obtain a yellow solid, 18 mg, 71% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 1.48 (s, 9H). + .

[0242] Example 10

[0243] Synthesis of intermediate 2-(tert-butyl)-5-nitrobenzo[d]thiazole (M17)

[0244] The synthesis of intermediate M17 was performed according to the synthesis of M3, using 5-nitrobenzothiazole and pivaldehyde as starting materials, to give yellow solid 31 mg in 10% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.79 (s, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 1.48 (s, 9H).

[0245] Synthesis of intermediate 2-(tert-butyl)benzo[d]thiazol-5-amine (M18)

[0246] The synthesis of intermediate M18 was performed according to the synthesis of M4, using intermediate M17 as starting material, to give white solid 24 mg in 85% yield. It was used directly in the next step without purification.

[0247] Synthesis of compound 2-(tert-butyl)-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5-amine (LK-10)

[0248] The synthesis of compound LK-10 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M18 as starting materials, to give yellow solid 27 mg as hydrochloride salt in 64% yield. 1H NMR (500 MHz, DMSO-d6) δ 15.04 (br s, 1H), 11.72 (s, 1H), 9.47 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 7.1 Hz, 1H), 8.40 (dd, J = 8.9, 1.8 Hz, 1H), 8.36 - 8.26 (m, 2H), 8.13 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 8.5, 2.1 Hz, 1H), 6.97 (d, J = 7.1 Hz, 1H), 3.71 (hept, J = 6.7 Hz, 1H), 1.51 (s, 9H), 1.26 (d, J = 6.8 Hz, 6H). 13 C NMR (126 MHz, DMSO-d6) δ 184.10, 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 for C 23 H 26 N3O2S2[M+H] + : 440.1461, found 440.1464.

[0249] Example 11

[0250] Synthesis of intermediate 2-methyl-l-(5-nitrobenzo[d]thiazol-2-yl)propan-l-ol (M19)

[0251] 5-nitrobenzothiazole (150 mg, 0.83 mmol) was added to a glass dish containing isobutanol (1 mL) and acetonitrile (2 mL), 12 N concentrated hydrochloric acid (227 μL, 3.33 mmol) was added and stirred open to a 390-400 nM LED light for 18 hours. After the reaction was completed, the organic phase was concentrated, extracted with ethyl acetate, washed with saturated brine, and the organic phase was concentrated and separated by column chromatography (PE:EA = 5: 1) to obtain 26 mg of yellow solid, which was intermediate M19, yield 12%. 1H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.30 (d, J = 8.9 Hz, 1H), 8.05 (dd, J = 8.7, 2.3 Hz, 1H), 5.07 - 4.96 (m, 1H), 2.93 (d, J = 5.2 Hz, 1H), 2.43 - 2.32 (m, 1H), 1.13 (dd, J = 6.9, 2.2 Hz, 3H), 1.00 (dd, J = 6.9, 2.2 Hz, 3H).

[0252] Synthesis of intermediate 1 -(5-aminobenzo[d]thiazol-2-yl)-2-methylpropan-1 -ol (M20)

[0253] The synthesis of intermediate M20 was performed according to the synthesis of M4, using intermediate M19 as starting material, to give 9 mg of a light yellow solid in 39% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (dd, J = 8.5, 2.5 Hz, 1H), 7.28 (s, 1H), 6.82 (d, J = 8.5 Hz, 1H), 4.92 - 4.82 (m, 1H), 3.80 (br s, 2H), 3.13 - 2.99 (m, 1H), 2.26 (h, J = 6.8 Hz, 1H), 1.10 (dd, J = 6.9, 2.4 Hz, 3H), 0.98 (dd, J = 6.8, 2.4 Hz, 3H).

[0254] Synthesis of compound 1 -(5-((6-(isopropylsulfonyl)quinolin-4-yl)amino)benzo[d]thiazol-2-yl)-2-methylpropan-1 -ol (LK-11)

[0255] The synthesis of compound LK-11 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M20 as starting materials, to give 12 mg of a yellow solid in 65% yield. 1H NMR (500 MHz, DMSO-d6) δ 14.88 (br s, 1 H), 11.64 (s, 1 H), 9.43 (d, J = 1.8 Hz, 1 H), 8.59 (d, J = 7.1 Hz, 1 H), 8.39 (dd, J = 9.0, 1.8 Hz, 1 H), 8.29 (dd, J = 8.7, 3.6 Hz, 2 H), 8.09 (d, J = 2.0 Hz, 1 H), 7.54 (dd, J = 8.5, 2.1 Hz, 1 H), 6.97 (d, J = 7.0 Hz, 1 H), 6.44 (s, 1 H), 4.77 (d, J = 4.4 Hz, 1 H), 3.67 (hept, J = 6.8 Hz, 1 H), 2.23 (pd, J = 6.8, 4.4 Hz, 1 H), 1.25 (d, J = 6.8 Hz, 6 H), 1.00 (d, J = 6.8 Hz, 3 H), 0.89 (d, J = 6.8 Hz, 3 H). 13 C NMR (126 MHz, DMSO-d6) δ 180.94, 155.81, 153.99, 144.44, 140.78, 134.89, 134.86, 133.53, 131.71, 126.30, 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.

[0256] Example 12

[0257] Synthesis of intermediate 2-cyclobutyl-5-nitrobenzo[d]thiazole (M21)

[0258] 5-nitrobenzo[d]thiazole (500 mg, 2.77 mmol), cyclobutylcarboxylic acid (531 μί, 5.55 mmol), potassium persulfate (3 g, 11.10 mmol) and silver nitrate (94 mg, 0.56 mmol) were added into dichloromethane (10 mL) and water (10 mL), stirred vigorously for 12 hours. After the reaction was completed, dichloromethane was extracted, washed with saturated brine, the organic phase was concentrated and separated by column chromatography (PE:EA = 5:1) to obtain 250 mg of yellow solid, yield 39%. 1H NMR (400 MHz, Chloroform-d) δ 8.83 (s, 1H), 8.24 (d, J = 8.9 Hz, 1H), 7.97 (dd, J = 8.9, 2.2 Hz, 1H), 4.00 (p, J = 8.6 Hz, 1H), 2.64 - 2.43 (m, 4H), 2.24 - 2.11 (m, 1H), 2.11 - 1.99 (m, 1H).

[0259] Synthesis of intermediate 2-cyclobutylbenzo[d]thiazol-5-amine (M22)

[0260] The synthesis of intermediate M22 was performed according to the synthesis of M6a, using intermediate M21 as starting material, to give 146 mg of brown oil in 67% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 2.7 Hz, 1H), 6.82 - 6.73 (m, 1H), 3.94 (p, J = 8.6 Hz, 1H), 2.60 - 2.40 (m, 4H), 2.20 - 2.08 (m, 1H), 2.07 - 1.94 (m, 1H).

[0261] Synthesis of intermediate 2-cyclobutyl-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5-amine (LK-12)

[0262] The synthesis of compound LK-12 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M22 as starting materials, to give 55 mg of yellow solid as hydrochloride salt in 70% yield. 1 H NMR (500 MHz, DMSO-d6) δ 14.65 (brs, 1H), 11.58 (s, 1H), 9.40 (d, J = 2.0 Hz, 1H), 8.61 (d, J = 7.0 Hz, 1H), 8.39 (dd, J = 8.9, 1.8 Hz, 1H), 8.29 (d, J = 8.5 Hz, 1H), 8.25 (dd, J = 8.9, 1.9 Hz, 1H), 8.11 (d, J = 2.1 Hz, 1H), 7.54 (dd, J = 8.5, 2.1 Hz, 1H), 6.97 (d, J = 7.0 Hz, 1H), 4.06 (p, J = 8.6 Hz, 1H), 3.64 (p, J = 6.7 Hz, 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 = 6.8 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 177.23, 154.45, 154.19, 151.28, 149.92, 138.86, 133.06, 130.95, 130.91, 127.64, 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.

[0263] Example 13

[0264] Synthesis of intermediate 1-(5-nitrobenzo[d]thiazol-2-yl)propan-1-ol (M23)

[0265] Synthesis of intermediate M23 was performed according to the synthesis of M19, using 5-nitrobenzothiazole and n-butanol as starting materials, to give 26 mg of yellow solid in 8% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 5.17 - 5.08 (m, 1H), 2.97 (d, J = 5.0 Hz, 1H), 2.23 - 2.11 (m, 1H), 2.06 - 1.93 (m, 1H), 1.12 (t, J = 7.5 Hz, 3H).

[0266] Synthesis of intermediate 1-(5-nitrobenzo[d]thiazol-2-yl)propan-1-ol (M23)

[0267] Synthesis of intermediate M24 was performed according to the synthesis of M4, using intermediate M23 as starting material, to give 20 mg of brown oil in 88% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J = 9.0 Hz, 1H), 7.30 - 7.28 (m, 1H), 6.82 (d, J = 8.5 Hz, 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).

[0268] Synthesis of compound 1-(5-((6-(isopropylsulfonyl)quinolin-4-yl)amino)benzo[d]thiazol-2-yl)propan-1-ol (LK-13)

[0269] The synthesis of compound LK-13 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M23 as starting materials, to give 10 mg of yellow solid as hydrochloride salt, in 22% yield. 1 H NMR (500 MHz, DMSO-d6) δ 14.69 (br s, 1H), 11.59 (s, 1H), 9.40 (s, 1H), 8.60 (d, J = 7.0 Hz, 1H), 8.38 (dd, J = 8.9, 1.7 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 8.28 - 8.22 (m, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.5, 2.0 Hz, 1H), 6.97 (d, J = 7.0 Hz, 1H), 6.53 - 6.38 (m, 1H), 4.90 (t, J = 6.0 Hz, 1H), 3.64 (p, J = 6.8 Hz, 1H), 2.03 - 1.90 (m, 1H), 1.88 - 1.76 (m, 1H), 1.25 (d, J = 6.8 Hz, 6H), 0.98 (t, J = 7.4 Hz, 3H). ESI-MS: 442.3 [M+H] + .

[0270] Example 14

[0271] Synthesis of intermediate 2-(sec-butyl)-5-nitrobenzo[d]thiazole (M25)

[0272] The synthesis of intermediate M25 was performed according to the synthesis of M3, using 5-nitrobenzo thiazole and 2-methylbutanal as starting materials, to give 33 mg of brown oil in 5% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.86 (s, 1H), 8.26 (d, J = 8.9 Hz, 1H), 8.00 (dd, J = 8.9, 2.2 Hz, 1H), 3.28 (q, J = 6.8 Hz, 1H), 2.03 - 1.91 (m, 1H), 1.89 - 1.76 (m, 1H), 1.50 (d, J = 7.0 Hz, 3H), 1.02 (t, J = 7.4, 3H).

[0273] Synthesis of intermediate 2-(sec-butyl)benzo[d]thiazol-5-amine (M26)

[0274] The synthesis of intermediate M25 was performed according to the synthesis of M6a, using intermediate M25 as starting material, to give 29 mg of brown oil in 99% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 8.5, 2.7 Hz, 1H), 4.26 (br s, 2H), 3.18 (h, J = 7.1 Hz, 1H), 1.90 (dp, J = 14.7, 7.6 Hz, 1H), 1.81 - 1.72 (m, 1H), 1.44 (d, J = 6.9 Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H).

[0275] Synthesis of compound 2-(sec-butyl)-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5-amine (LK-14)

[0276] The synthesis of compound LK-14 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M26 as starting materials, to give 23 mg of yellow solid as hydrochloride salt in 34% yield. 1 H NMR (500 MHz, DMSO-d6) δ 14.93 (s, 1H), 11.64 (s, 1H), 9.43 (d, J = 1.8 Hz, 1H), 8.57 (d, J = 7.1 Hz, 1H), 8.37 (dd, J = 8.9, 1.8 Hz, 1H), 8.28 (dd, J = 10.3, 8.7 Hz, 2H), 8.09 (d, J = 2.1 Hz, 1H), 7.53 (dd, J = 8.5, 2.1 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 3.66 (hept, J = 6.8 Hz, 1H), 3.25 (p, J = 6.9 Hz, 1H), 1.86 (dt, J = 13.6, 7.3 Hz, 1H), 1.75 (dp, J = 14.1, 7.2 Hz, 1H), 1.40 (d, J = 6.9 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 179.41, 155.92, 153.56, 144.51, 140.90, 135.17, 134.99, 133.49, 131.76, 126.40, 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 H26 N3O2S2[M+H] + : 440.1461, found 440.1463.

[0277] Example 15

[0278] Intermediate (R)-2-(sec-butyl)benzo[d]thiazol-5-amine (M26a) and Intermediate (S)-2-(sec-butyl)benzo[d]thiazol-5-amine (M26b) were prepared from Intermediate M26 by chiral separation.

[0279] Synthesis of compound (R)-2-(sec-butyl)-N-(6-(isopropylsulfonyl)quinolin-4- yl)benzo[d]thiazol-5-amine (LK-15) and compound (S)-2-(sec-butyl)-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5-amine (LK-16)

[0280] Synthesis of compound LK-15 and compound LK-16 followed the synthesis of compound LK-1 as a hydrochloride salt. Spectra of compound LK-15: 1 H NMR (500 MHz, DMSO-d6) δ 14.93 (s, 1H), 11.64 (s, 1H), 9.43 (d, J = 1.8 Hz, 1H), 8.57 (d, J = 7.1 Hz, 1H), 8.37 (dd, J = 8.9, 1.8 Hz, 1H), 8.28 (dd, J = 10.3, 8.7 Hz, 2H), 8.09 (d, J = 2.1 Hz, 1H), 7.53 (dd, J = 8.5, 2.1 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 3.66 (hept, J = 6.8 Hz, 1H), 3.25 (p, J = 6.9 Hz, 1H), 1.86 (dt, J = 13.6, 7.3 Hz, 1H), 1.75 (dp, J = 14.1, 7.2 Hz, 1H), 1.40 (d, J = 6.9 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 179.41, 155.92, 153.56, 144.51, 140.90, 135.17, 134.99, 133.49, 131.76, 126.40, 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 H26 N3O2S2[M+H] + : 440.1461, found 440.1462.

[0281] Spectrum of compound LK-16: 1 H NMR (500 MHz, DMSO-d6) δ 14.90 (s, 1H), 11.64 (s, 1H), 9.42 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 7.1 Hz, 1H), 8.37 (dd, J = 8.8, 1.8 Hz, 1H), 8.31 - 8.23 (m, 2H), 8.09 (d, J = 2.1 Hz, 1H), 7.53 (dd, J = 8.5, 2.1 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 3.66 (hept, J = 6.8 Hz, 1H), 3.25 (p, J = 6.8 Hz, 1H), 1.86 (dp, J = 14.6, 7.3 Hz, 1H), 1.74 (dq, J = 14.1, 7.1 Hz, 1H), 1.40 (d, J = 6.9 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H), 0.92 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 179.41, 155.92, 153.56, 144.53, 140.90, 135.16, 134.98, 133.49, 131.77, 126.39, 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.

[0282] Example 16

[0283] Synthesis of intermediate 5-amino-benzo[d]thiazole-2-carbonitrile (M27)

[0284] The synthesis of intermediate M27 was performed according to the synthesis of M6a, using 5-nitro-benzo[d]thiazole-2-carbonitrile as starting material, to give 37 mg of brown oil in 87% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.73 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 8.7, 2.3 Hz, 1H), 4.03 (br s, 2H).

[0285] Synthesis of compound 5-((6-(isopropylsulfonyl)quinolin-4-yl)amino)benzo[d]thiazole-2- carbonitrile (LK-17)

[0286] Synthesis of compound LK-17 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M27 as starting materials, to give 35 mg of yellowish solid as hydrochloride salt in 71% yield.

[0287] Example 17

[0288] Synthesis of intermediate 2-cyclopentyl-5-nitrobenzo[d]thiazole (M28)

[0289] Synthesis of intermediate M28 was performed according to the synthesis of M21, using 5- nitrobenzothiazole and cyclopentylcarboxylic acid as starting materials, to give 70 mg of yellow solid in 10% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 8.5 Hz, 1H), 7.28 (s, 1H), 6.77 (dd, J = 8.5, 2.3 Hz, 1H), 3.93 (br s, 2H), 3.53 (p, J = 8.1 Hz, 1H), 2.31 - 2.19 (m, 2H), 1.97 - 1.85 (m, 4H), 1.78 - 1.71 (m, 2H).

[0290] Synthesis of intermediate 2-cyclopentylbenzo[d]thiazol-5-amine (M29)

[0291] Synthesis of intermediate M29 was performed according to the synthesis of M6a, using intermediate M28 as starting material, to give 44 mg of brown oil in 71% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 8.5 Hz, 1H), 7.28 (s, 1H), 6.77 (dd, J = 8.5, 2.3 Hz, 1H), 3.93 (br s, 2H), 3.53 (p, J = 8.1 Hz, 1H), 2.31 - 2.19 (m, 2H), 1.97 - 1.85 (m, 4H), 1.78 - 1.71 (m, 2H).

[0292] Synthesis of compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)quinolin-4- yl)benzo[d]thiazol-5-amine (LK-20)

[0293] Synthesis of compound LK-20 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M27 as starting materials, to give 40 mg of yellowish solid as hydrochloride salt, in 60% yield. 1 H NMR (500 MHz, DMSO-d6) δ 14.87 (br s, 1H), 11.63 (s, 1H), 9.42 (d, J = 1.9 Hz, 1H), 8.56 (d, J = 7.0 Hz, 1H), 8.36 (dd, J = 8.9, 1.8 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.5, 2.1 Hz, 1H), 6.94 (d, J = 7.0 Hz, 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 = 6.9 Hz, 6H). 13 C NMR (126 MHz, DMSO-d6) δ 178.73, 155.94, 153.61, 144.47, 140.86, 135.14, 134.98, 133.69, 131.77, 126.39, 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 for C 24 H 26 N3O2S2[M+H] + : 452.1461, found 452.1463.

[0294] Example 18

[0295] Synthesis of intermediate 2-(1-methylcyclopropyl)-5-nitrobenzo[d]thiazole (M30)

[0296] Synthesis of intermediate M30 was performed according to the synthesis of M21, using 5-nitrobenzo thiazole and 1-methylcyclopropane-1-carboxylic acid as starting materials, to give 20 mg of yellow solid, in 10% yield. 1H NMR (500 MHz, Chloroform-d) δ 8.78 (d, J = 2.2 Hz, 1H), 8.22 (dd, J = 8.8, 2.2 Hz, 1H), 7.95 (d, J = 8.7 Hz, 1H), 1.71 (s, 3H), 1.54 - 1.51 (m, 2H), 1.19 - 1.15 (m, 2H).

[0297] Synthesis of intermediate 2-(1-methylcyclopropyl)benzo[d]thiazol-5-amine (M31)

[0298] The synthesis of intermediate M31 was performed according to the synthesis of M6a, using intermediate M30 as starting material, to give 15 mg of brown oil in 86% yield. It was used directly in the next reaction without purification.

[0299] Synthesis of compound N-(6-(isopropylsulfonyl)quinolin-4-yl)-2-(1- methylcyclopropyl)benzo[d]thiazol-5-amine

[0300] The synthesis of compound LK-19 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M31 as starting materials, to give 16 mg of yellow solid as hydrochloride salt in 40% yield. 1 H NMR (500 MHz, DMSO-d6) δ 14.92 (brs, 1H), 11.65 (s, 1H), 9.43 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 7.1 Hz, 1H), 8.38 (dd, J = 8.9, 1.7 Hz, 1H), 8.29 (d, J = 8.9 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.5, 2.1 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 3.67 (p, J = 6.8 Hz, 1H), 1.64 (s, 3H), 1.36 (q, J = 4.0 Hz, 2H), 1.25 (d, J = 6.8 Hz, 6H), 1.18 (q, J = 4.1 Hz, 2H). 13 C NMR (126 MHz, DMSO-d6) δ 180.58, 156.40, 154.28, 144.99, 141.36, 135.72, 135.45, 133.86, 132.28, 126.90, 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 for C 23 H 24 N3O2S2[M+H]+ : 438.1304, found 438.1306.

[0301] Example 19

[0302] Synthesis of intermediate 2,2-dimethylcyclopropylboronic acid pinacol ester (M32)

[0303] To a solution of intermediate M31 (100 mg, 0.42 mmol) in THF (2 mL) was added potassium fluoride (100 mg, 1.27 mmol) in water (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The solvent was removed by rotary evaporation. The residue was used directly in the next step without further purification. 1 H NMR (400 MHz, Chloroform-d) δ 1.23 (d, J = 8.9 Hz, 12 H), 1.15 (s, 3 H), 1.12 (s, 3 H), 0.64 - 0.55 (m, 2 H), -0.23 (dd, J = 9.1, 6.9 Hz, 1 H).

[0304] Synthesis of intermediate potassium 2,2-dimethylcyclopropyltrifluoroborate (M33)

[0305] To a solution of intermediate M32 (130 mg, 0.63 mmol) in THF (1 mL) was added potassium fluoride (100 mg, 1.27 mmol) in water (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. The solvent was removed by rotary evaporation. The residue was used directly in the next step without further purification.

[0306] Synthesis of intermediate 2-(2,2-dimethylcyclopropyl)-5-nitrobenzo[d]thiazole (M34)

[0307] Intermediate M34 was synthesized by the same procedure as described in the synthesis of Intermediate M4, using 2-bromo-5-nitrobenzo[d]thiazole (60 mg, 0.23 mmol), Intermediate M33 (81 mg, 0.46 mmol), palladium acetate (6 mg, 0.02 mmol), n-butyl bis(1-adamantyl)phosphine (13 mg, 0.03 mmol), and cesium carbonate (226 mg, 0.70 mmol) in toluene (4 mL) and water (0.4 mL) at 100 °C for 14 h. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was concentrated, and the residue was separated by preparative thin-layer chromatography (PTLC) to give 2 mg of yellow solid, Intermediate M34, in 3% yield. 1 H NMR (500 MHz, Chloroform-d) δ 8.79 (d, J = 2.2 Hz, 1H), 8.23 (dd, J = 8.7, 2.2 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 2.28 (dd, J = 8.1, 5.7 Hz, 1H), 1.54 (t, J = 5.3 Hz, 1H), 1.34 (s, 3H), 1.28 - 1.22 (m, 1H), 1.16 (s, 3H).

[0308] Synthesis of intermediate 2-(2,2-dimethylcyclopropyl)benzo[d]thiazol-5-amine (M35)

[0309] Intermediate M35 was synthesized by the same procedure as described in the synthesis of Intermediate M4, using Intermediate M34 as the starting material, to give 5 mg of yellow solid in 41% yield.

[0310] Synthesis of compound 2-(2,2-dimethylcyclopropyl)-N-(6-(isopropylsulfonyl)quinolin-4- yl)benzo[d]thiazol-5-amine (LK-20)

[0311] Intermediate M35 was synthesized by the same procedure as described in the synthesis of Intermediate M4, using Intermediate M34 as the starting material, to give 5 mg of yellow solid in 41% yield. 1H NMR (500 MHz, DMSO-d6) δ 9.69 (s, 1H), 9.07 (d, J = 1.9 Hz, 1H), 8.59 (d, J = 5.4 Hz, 1H), 8.10 - 8.01 (m, 3H), 7.87 (d, J = 2.1 Hz, 1H), 7.44 (dd, J = 8.5, 2.1 Hz, 1H), 7.05 (d, J = 5.4 Hz, 1H), 5.36 - 5.27 (m, 1H), 3.55 (p, J = 6.8 Hz, 1H), 2.40 (dd, J = 8.2, 5.6 Hz, 1H), 2.05 - 1.94 (m, 1H), 1.27 (s, 3H), 1.23 (d, J = 2.8 Hz, 6H), 1.09 (s, 3H). ESI-HRMS calcd for C 24 H 26 N3O2S2[M+H] + : 452.1361, found 452.1465.

[0312] Example 20

[0313] Synthesis of intermediate 2-(2-methylprop-1-en-1-yl)-5-nitrobenzo[d]thiazole (M36)

[0314] Dissolve 2-chloro-5-nitrobenzo thiazole (200 mg, 0.93 mmol), 2-methyl-1-propenyl boronic acid pinacol ester (189 μL, 1.68 mmol), tetrakis(triphenylphosphine)palladium (54 mg, 0.05 mmol) in 1,4-dioxane (3 mL), add potassium phosphate (500 mg, 2.33 mmol) in water (1 mL), heat to 100 °C under N2protection for 12 h. Concentrate the reaction mixture after completion of the reaction, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate. Dry the organic phase by rotary evaporation, then purify by column chromatography (PE:EA = 5:1) to give 150 mg of white solid, which is intermediate M36, in 69% yield. 1 H NMR (500 MHz, Chloroform-d) δ 8.82 (d, J = 2.2 Hz, 1H), 8.22 (dd, J = 8.8, 2.2 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 6.59 (hept, J = 1.4 Hz, 1H), 2.33 (d, J = 1.2 Hz, 3H), 2.09 (d, J = 1.4 Hz, 3H).

[0315] Synthesis of intermediate 2-(2-methylprop-1-en-1-yl)benzo[d]thiazol-5-amine (M37)

[0316] The synthesis of intermediate M37 was performed according to the synthesis of M6a, using intermediate M36 as starting material, to give 29 mg of yellow solid in 48% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1H), 6.78 (dd, J = 8.5, 2.2 Hz, 1H), 6.59 (p, J = 1.4 Hz, 1H), 3.81 (s, 2H), 2.25 (d, J = 1.2 Hz, 3H), 2.05 (d, J = 1.4 Hz, 3H).

[0317] Synthesis of compound N-(6-(isopropylsulfonyl)quinolin-4-yl)-2-(2-methylprop-1-en-1-yl)benzo[d]thiazol-5-amine

[0318] The synthesis of compound LK-21 was performed according to the synthesis of LK-1, using intermediate M2 and intermediate M36 as starting materials, to give 35 mg of yellow solid in 82% yield. 1 H NMR (500 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.08 (d, J = 1.9 Hz, 1H), 8.61 (d, J = 5.4 Hz, 1H), 8.16 - 8.01 (m, 3H), 7.93 (d, J = 2.1 Hz, 1H), 7.48 (dd, J = 8.6, 2.1 Hz, 1H), 7.09 (d, J = 5.4 Hz, 1H), 6.70 - 6.60 (m, 1H), 3.56 (h, J = 6.7 Hz, 1H), 2.28 (s, 3H), 2.04 (s, 3H), 1.23 (d, J = 6.8 Hz, 6H). 13 C NMR (126 MHz, DMSO) δ 166.78, 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.

[0319] Example 21

[0320] Synthesis of intermediate 2-cyclohexyl-5-nitrobenzo[d]thiazole (M38)

[0321] The synthesis of intermediate M38 was performed according to the synthesis of M21 using 5-nitrobenzo[d]thiazole and cyclohexanecarboxylic acid as starting materials to give 400 mg of yellow oil in 55% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 8.5 Hz, 1H), 7.30 (s, 1H), 6.78 (dd, J = 8.4, 2.1 Hz, 1H), 3.14 - 3.03 (m, 1H), 2.20 (d, J = 12.8 Hz, 2H), 1.90 (d, J = 13.1 Hz, 2H), 1.69 - 1.55 (m, 4H), 1.49 - 1.27 (m, 2H).

[0322] Synthesis of intermediate 2-cyclohexylbenzo[d]thiazol-5-amine (M39)

[0323] The synthesis of intermediate M39 was performed according to the synthesis of M6a using intermediate M38 as starting material to give 98 mg of brown oil in 44% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 8.5 Hz, 1H), 7.30 (s, 1H), 6.78 (dd, J = 8.4, 2.1 Hz, 1H), 3.14 - 3.03 (m, 1H), 2.20 (d, J = 12.8 Hz, 2H), 1.90 (d, J = 13.1 Hz, 2H), 1.69 - 1.55 (m, 4H), 1.49 - 1.27 (m, 2H).

[0324] Synthesis of compound 2-cyclohexyl-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]thiazol-5-amine (LK-22)

[0325] The synthesis of compound LK-22 was performed according to the synthesis of LK-1 using intermediate M2 and intermediate M27 as starting materials to give 65 mg of pale yellow solid as hydrochloride salt in 79% yield. 1H NMR (500 MHz, DMSO-d6) δ 15.01 (br s, 1H), 11.69 (s, 1H), 9.45 (d, J = 1.8 Hz, 1H), 8.59 (d, J = 7.0 Hz, 1H), 8.39 (dd, J = 8.9, 1.8 Hz, 1H), 8.30 (dd, J = 12.5, 8.7 Hz, 2H), 8.10 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 8.4, 2.1 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 3.69 (hept, J = 6.7 Hz, 1H), 3.17 (tt, J = 11.3, 3.6 Hz, 1H), 2.20 - 2.11 (m, 2H), 1.83 (dp, J = 11.1, 3.6 Hz, 2H), 1.72 (dt, J = 12.8, 3.6 Hz, 1H), 1.61 (qd, J = 12.3, 3.5 Hz, 2H), 1.45 (qt, J = 12.7, 3.5 Hz, 2H), 1.35 - 1.26 (m, 1H), 1.25 (d, J = 6.7 Hz, 6H). 13 C NMR (126 MHz, DMSO) δ 181.00, 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 H 28 N3O2S2[M+H] + : 466.1617, found 466.1616.

[0326] Example 22

[0327] Synthesis of intermediate 5-(((4-bromo-3-methoxyphenyl)amino)methylene)- 2,2-dimethyl-1,3-dioxane-4,6-dione (M40)

[0328] Propiolactone (5 g, 34.69 mmol) was added to trimethyl orthoformate (15 mL, 150 mmol) and warmed to 105 °C for 1 hour, then 4-bromo-3-methoxyaniline (6.31 g, 31.22 mmol) was added and the reaction was continued for 1.5 hours. After completion of the reaction, it was cooled to room temperature, the precipitate was filtered off, washed with methanol and dried to get yellow solid 9.8 g, which was intermediate M40 in 93% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.25 (d, J = 14.5 Hz, 1H), 8.70 - 8.60 (m, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.6, 2.5 Hz, 1H), 3.91 (s, 3H), 1.69 (s, 6H).

[0329] Synthesis of intermediate 6-bromo-7-methoxyquinolin-4-ol (M41)

[0330] Phenyl ether (50 mL) was warmed to 220 °C, intermediate M40 (16 g, 44.92 mmol) was added in batches and reacted for 1.5 hours. After the reaction was completed, it was cooled to room temperature, added into n-hexane (100 mL) and stirred vigorously, a brown solid was precipitated. After the precipitate was filtered, it was slurried with ethanol to obtain a yellow solid 8 g, which was intermediate (M41) with a yield of 70%. 1 H NMR (500 MHz, DMSO-d6) δ 11.74 (s, 1H), 8.18 (d, J = 3.8 Hz, 1H), 7.88 (dd, J = 7.7, 3.5 Hz, 1H), 7.07 (d, J = 3.6 Hz, 1H), 6.01 (dd, J = 7.5, 3.6 Hz, 1H), 3.95 (s, 3H).

[0331] Synthesis of intermediate 6-bromo-4-chloro-7-methoxyquinoline (M42)

[0332] Intermediate M41 (8 g, 32.49 mmol) was added into phosphorus oxychloride (20 mL) and warmed to 110 °C for 1 hour. After the reaction was completed, the phosphorus oxychloride was rotary evaporated. The organic phase was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (DCM:MeOH = 100:1) gave a yellow solid 8.1 g, which was intermediate M41 with a yield of 94%. 1 H NMR (500 MHz, DMSO-d6) δ 8.82 (d, J = 4.9 Hz, 1H), 8.39 (s, 1H), 7.67 (d, J = 5.0 Hz, 1H), 7.62 (s, 1H), 4.06 (s, 3H).

[0333] Synthesis of intermediate 4-chloro-6-(isopropylthio)-7-methoxyquinoline (M43)

[0334] The synthesis of intermediate M43 was performed according to the synthesis of M1, using intermediate M42 and isopropyl mercaptan as starting materials, to give a yellow solid 6.5 g with a yield of 83%.

[0335] Synthesis of intermediate 4-chloro-6-(isopropylsulfonyl)-7-methoxyquinoline 1-oxide (M44)

[0336] Intermediate M43 (9.3 g, 34.73 mmol) and oxone (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 completed, ethyl acetate was extracted, washed with saturated brine, and dried over anhydrous sodium sulfate. After the organic phase was concentrated, it was purified by column chromatography (EA:MeOH = 10:1) to obtain 3.6 g of a yellow solid, which was intermediate M43, at a yield of 33%. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J = 6.7 Hz, 1H), 8.63 (s, 1H), 8.19 (s, 1H), 7.72 (d, J = 6.6 Hz, 1H), 4.15 (s, 3H), 3.84 (p, J = 6.9 Hz, 1H), 1.23 (d, J = 6.8 Hz, 6H).

[0337] Synthesis of intermediate 4-chloro-6-(isopropylsulfonyl)-7-methoxyquinoline (M45)

[0338] 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, and then the temperature was increased to 45°C and reacted for 1 hour. After the reaction was completed, 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 obtain 80 mg of a white solid, which was intermediate M45, at a yield of 9%. 1 H NMR (500 MHz, Chloroform-d) δ 8.96 (s, 1H), 8.85 (d, J = 4.7 Hz, 1H), 7.74 (s, 1H), 7.55 (d, J = 4.3 Hz, 1H), 4.16 (s, 3H), 3.86 (hept, J = 6.8 Hz, 1H), 1.37 (d, J = 6.9 Hz, 6H).

[0339] Synthesis of compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)-7-methoxyquinolin-4- yl)benzo[d]thiazol-5-amine (LK-23)

[0340] The synthesis of compound LK-23 was performed by referring to the synthesis of LK-1, using intermediate M2 and intermediate M27 as starting materials, to obtain 25 mg of a light yellow solid at a yield of 78%. 1H NMR (500 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.95 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.87 (d, J = 2.1 Hz, 1H), 7.50 (s, 1H), 7.43 (dd, J = 8.4, 2.1 Hz, 1H), 6.91 (d, J = 5.4 Hz, 1H), 4.05 (s, 3H), 3.81 (p, J = 6.9 Hz, 1H), 3.59 (q, J = 8.0 Hz, 1H), 2.25 - 2.14 (m, 2H), 1.96 - 1.86 (m, 2H), 1.85 - 1.77 (m, 2H), 1.75 - 1.66 (m, 2H), 1.23 (d, J = 6.8 Hz, 6H). ESI-MS: 482.3 [M+H] + .

[0341] Example 23

[0342] Synthesis of intermediate 3-bromo-5-nitrobenzo[b]thiophene (M46)

[0343] 5-nitrobenzothiophene (3 g, 16.74 mmol) and NBS (3.28 g, 18.42 mmol) were added into DMF (45 mL) and warmed to 60 °C for 5 hours. After completion of the reaction, DMF was evaporated, and the residue was slurried with ethyl acetate (15 mL), and the resulting solid was slurried with water (20 mL), and the solid precipitate was filtered and dried to give 2.6 g of brown solid as intermediate M46 in 60% yield. 1 H NMR (500 MHz, DMSO-d6) δ 8.51 (d, J = 2.2 Hz, 1H), 8.42 (d, J = 8.8 Hz, 1H), 8.32 (s, 1H), 8.30 (dd, J = 8.9, 2.3 Hz, 1H). Synthesis of intermediate 3-bromo-5-nitrobenzo[b]thiophene 1,1-dioxide (M47) 1 H NMR (500 MHz, DMSO-d6) δ 8.56 (dd, J = 8.3, 2.0 Hz, 1H), 8.34 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.21 (d, J = 2.1 Hz, 1H).

[0344] Synthesis of intermediate 5-amino-3-bromobenzo[b]thiophene 1,1-dioxide (M48)

[0345] To a mixture of intermediate M47 (3.4 g, 11.72 mmol) in ethanol (45 mL) and water (15 mL) was added ammonium chloride (2.51 g, 46.88 mmol) powder, followed by iron powder (2.62 g, 46.88 mmol) in portions and the reaction was heated to 85 °C for 2 h. The reaction was filtered through celite and the filtrate was washed with water, the precipitate was filtered and dried to give 2.4 g of intermediate M48 as a brown solid in 79% yield. It was used directly in the next step.

[0346] Synthesis of intermediate 5-(((3-bromo-1,1-dioxido-benzo[b]thiophen-5-yl)amino)methylene)- 2,2-dimethyl-1,3-dioxane-4,6-dione (M49)

[0347] 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) and stirred at room temperature for 5 h. The solid was filtered and washed with ethanol to give 66 mg of intermediate M49 as a light yellow solid in 83% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.42 (d, J = 14.0 Hz, 1H), 8.69 (d, J = 14.2 Hz, 1H), 8.13 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.93 - 7.86 (m, 2H), 1.70 (s, 6H).

[0348] Synthesis of intermediate 3-bromo-8-hydroxythieno[2,3-g]quinoline 1,1-dioxide (M50)

[0349] Phenyl ether (10 mL) was heated to 220 °C and stirred for 5 min before intermediate M49 (250 mg, 0.60 mmol) was added in portions. The reaction was stirred for another 15 min before it was cooled to room temperature. Petroleum ether (7 mL) was added to the reaction and stirred for 30 min. The brown precipitate was filtered and washed with ethyl acetate to give 130 mg of intermediate M50 as a light yellow solid in 69% yield. 1 H NMR (500 MHz, DMSO-d6) δ 12.29 (s, 1H), 8.36 (s, 1H), 8.26 (s, 1H), 8.08 (d, J = 7.1 Hz, 1H), 7.78 (s, 1H), 6.23 (d, J = 7.5 Hz, 1H).

[0350] Synthesis of intermediate 3-bromo-8-chlorothieno[2,3-g]quinoline 1,1-dioxide (M51)

[0351] The synthesis of intermediate M51 was performed according to the synthesis of M42, using intermediate M50 as starting material, to give yellow solid 137 mg in 95% yield. 1 H NMR (500 MHz, DMSO-d6) δ 9.06 (d, J = 4.8 Hz, 1H), 8.75 (s, 1H), 8.37 (s, 1H), 8.15 (s, 1H), 8.01 (d, J = 4.8 Hz, 1H).

[0352] Synthesis of intermediate 3-bromo-8-((2-cyclopentylbenzo[d]thiazol-5-yl)amino)thieno[2,3-g]quinoline 1,1-dioxide (M52)

[0353] Intermediate M51 (137 mg, 0.42 mmol) and intermediate M29 (90 mg, 0.42 mmol) were added into ethanol (2 mL) with catalytic amount of 6N HC1, then heated to 85 °C for 1 hour. After the reaction was completed, the reaction solution was directly spin dried, purified by column chromatography (DCM:MeOH = 10:1) to give brown solid 82 mg, which was intermediate M52 in 62% yield. 1 H NMR (500 MHz, DMSO-d6) δ 9.06 (d, J = 4.8 Hz, 1H), 8.75 (s, 1H), 8.37 (s, 1H), 8.15 (s, 1H), 8.01 (d, J = 4.8 Hz, 1H).

[0354] Synthesis of compound 8-(2-cyclopentylbenzo[d]thiazol-5-yl)amino)-2H-spirothieno[2,3-g]quinoline-3,2'-[1,3]dioxolane] 1,1-dioxide (LK-24)

[0355] Intermediate M52 (36 mg, 0.07 mmol) and cesium carbonate (62 mg, 0.19 mmol) were added into ethylene glycol (1 mL) and heated to 60 °C for 12 hours. After the reaction was completed, it was extracted with ethyl acetate and washed with saturated brine, dried over anhydrous sodium sulfate. The organic phase was concentrated and purified by preparative thin layer chromatography (DCM:MeOH = 20:1) to give yellow solid 10 mg, which was compound LK-24 in 29% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.26 (s, 1H), 9.38 (s, 1H), 8.64 (d, J = 7.0 Hz, 1H), 8.29 - 8.24 (m, 2H), 8.07 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.5, 2.1 Hz, 1H), 6.99 (d, J = 7.0 Hz, 1H), 4.36 - 4.31 (m, 2H), 4.28 - 4.22 (m, 2H), 4.14 (s, 2H), 3.63 (p, J = 8.1 Hz, 1H), 2.25 - 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 for C 25 H 24 N3O4S2[M+H] + : 494.1203, found 494.1202.

[0356] Example 24

[0357] Synthesis of intermediate 3-cyclopropyl-5-nitrobenzo[b]thiophene 1,1-dioxide (M53)

[0358] Intermediate M47 (2.4 g, 8.27 mmol), cyclopropylboronic acid (853 mg, 9.93 mmol), palladium acetate (186 mg, 0.83 mmol), 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 reaction was heated to 100 °C under N2protection for 12 h. After the reaction was completed, the reaction solution was filtered with celite, 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 yellow solid, which was intermediate M53, in 21% yield. 1 H NMR (500 MHz, Chloroform-d) δ 8.49 - 8.43 (m, 2H), 7.93 - 7.89 (m, 1H), 6.36 (d, J = 1.4 Hz, 1H), 1.99 - 1.90 (m, 1H), 1.31 - 1.27 (m, 2H), 0.95 - 0.87 (m, 2H).

[0359] Synthesis of intermediate 5-amino-3-cyclopropylbenzo[b]thiophene 1,1-dioxide (M54)

[0360] The synthesis of intermediate M54 was performed according to the synthesis of M48, using intermediate M53 as starting material, to give 370 mg of yellow solid in 95% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.45 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.2, 2.1 Hz, 1H), 6.11 (d, J = 1.2 Hz, 1H), 4.18 (s, 2H), 1.81 - 1.71 (m, 1H), 1.16 - 1.06 (m, 2H), 0.83 - 0.74 (m, 2H).

[0361] Synthesis of intermediate 5-(((3-cyclopropyl-l,l-dioxido-benzo[b]thiophen-5-yl)amino)methylene)-2,2-dimethyl-l,3-dioxane-4,6-dione (M55)

[0362] The synthesis of intermediate M55 was performed according to the synthesis of M49, using intermediate M54 as starting material, to give 550 mg of yellow solid in 72% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.40 (d, J = 14.3 Hz, 1H), 8.79 (d, J = 14.3 Hz, 1H), 8.17 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.78 (dd, J = 8.2, 2.0 Hz, 1H), 6.98 (s, 1H), 2.20 (tt, J = 8.3, 4.1 Hz, 1H), 1.70 (s, 6H), 1.20 - 1.12 (m, 2H), 0.93 - 0.85 (m, 2H).

[0363] Synthesis of intermediate 3-cyclopropyl-8-hydroxy-thieno[2,3-g]quinoline 1,1-dioxide (M56)

[0364] The synthesis of intermediate M56 was performed according to the synthesis of M50, using intermediate M55 as starting material, to give 400 mg of yellow solid in 82% yield. 1 H NMR (500 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.25 (s, 1H), 8.03 (dd, J = 7.5, 5.7 Hz, 1H), 7.87 (s, 1H), 7.17 (s, 1H), 6.19 (d, J = 7.4 Hz, 1H), 2.05 (tt, J = 8.5, 5.0 Hz, 1H), 1.16 (dq, J = 6.7, 4.1 Hz, 2H), 0.97 - 0.84 (m, 2H).

[0365] Synthesis of intermediate 8-chloro-3-cyclopropylthieno[2,3-g]quinoline 1,1-dioxide (M57)

[0366] The synthesis of intermediate M57 was performed according to the synthesis of M51, starting from intermediate M56, to give a yellow solid 220 mg, 52% yield. 1 H NMR (500 MHz, DMSO-d6) δ 9.02 (d, J = 4.8 Hz, 1H), 8.56 (s, 1H), 8.52 (s, 1H), 7.96 (d, J = 4.8 Hz, 1H), 7.23 (d, J = 0.8 Hz, 1H), 2.40 - 2.31 (m, 1H), 1.26 - 1.16 (m, 2H), 0.99 - 0.90 (m, 2H).

[0367] Synthesis of compound 8-(2-cyclopentylbenzo[d]thiazol-5-yl)amino)-3- cyclopropylthieno[2,3-g]quinoline 1,1-dioxide (LK-25)

[0368] The synthesis of compound LK-25 was performed according to the synthesis of LK-24, starting from intermediate M57, in isopropanol as solvent, heating to 95 °C, to give a yellow solid 46 mg as hydrochloride salt, 82% yield. 1 H NMR (600 MHz, DMSO-d6) δ 14.99 (br s, 1H), 11.30 (s, 1H), 9.34 (s, 1H), 8.57 (d, J = 7.0 Hz, 1H), 8.40 (s, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 2.1 Hz, 1H), 7.52 (dd, J = 8.5, 2.1 Hz, 1H), 7.41 (d, J = 0.9 Hz, 1H), 6.98 (d, J = 7.0 Hz, 1H), 3.62 (p, J = 8.1 Hz, 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 (151 MHz, DMSO) δ 178.61, 155.54, 153.54, 149.24, 144.13, 141.83, 135.80, 135.09, 135.05, 133.52, 125.50, 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, found 474.1305.

[0369] Example 25

[0370] Synthesis of compound 8-(2-cyclopentylbenzo[d]thiazol-5-ylamino)-3- cyclopropyl-2,3-dihydrothieno[2,3-g]quinoline 1,1-dioxide (LK-26)

[0371] Synthesis of compound LK-26 was performed according to the procedure described for the synthesis of M4, using compound LK-25 as starting material, to give yellow solid 8 mg, 50% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.29 (s, 1H), 9.30 (d, J = 2.3 Hz, 1H), 8.59 (dd, J = 8.8, 7.1 Hz, 1H), 8.32 - 8.31 (m, 1H), 8.30 - 8.26 (m, 1H), 8.08 (dd, J = 3.6, 2.1 Hz, 1H), 7.52 (dd, J = 8.4, 2.2 Hz, 1H), 6.96 (d, J = 7.2 Hz, 1H), 4.06 (dd, J = 13.4, 7.5 Hz, 1H), 3.74 - 3.58 (m, 2H), 3.23 (q, J = 8.0 Hz, 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] + .

[0372] Example 26

[0373] Synthesis of intermediate 4-chloro-6-(isopropylthio)quinazoline (M58)

[0374] Intermediate M58 (50.0 mg, 0.21 mmol), intermediate M29 (38.1 mg, 0.17 mmol), triethylamine (121.3 μL, 0.87 mmol) were dissolved in isopropanol (5 mL) and heated to 90 °C for 8 h. After completion of the reaction, the reaction 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 yellow solid, which was intermediate M59 with 83% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.84 - 7.82 (m, 1H), 7.71 (d, J = 8.4 Hz, 1H), 3.65 (hept, J = 6.6 Hz, 1H), 1.29 (d, J = 6.6 Hz, 6H).

[0375] Synthesis of intermediate 2-cyclopentyl-N-(6-(isopropylsulfonyl)quinazolin-4-yl)benzo[d]thiazol-5-amine (M59)

[0376] Intermediate M58 (50.0 mg, 0.21 mmol), intermediate M29 (38.1 mg, 0.17 mmol), triethylamine (121.3 μL, 0.87 mmol) were dissolved in isopropanol (5 mL) and heated to 90 °C for 8 h. After completion of the reaction, the reaction 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 yellow solid, which was intermediate M59 with 83% yield. 1 H NMR (500 MHz, Chloroform-d) δ 8.74 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 7.95 (s, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.63 (dd, J = 8.5, 2.1 Hz, 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 = 6.7 Hz, 6H).

[0377] Synthesis of compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)quinazolin-4-yl)benzo[d]thiazol-5-amine (LK-27)

[0378] Intermediate M59 (60 mg, 0.17 mmol) was dissolved in DCM (5 mL), m-chloroperoxybenzoic acid (60.3 g, 0.35 mmol) was added portionwise, and the reaction was stirred at room temperature for 8 h. After completion of the reaction, the 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, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 35 mg of a white solid in 46% yield. 1 H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 9.25 (d, J = 2.0 Hz, 1H), 8.74 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.21 (dd, J = 8.7, 2.0 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 8.7, 2.1 Hz, 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 = 6.8 Hz, 6H). ESI-HRMS calcd for C 23 H 25 N4O2S2[M+H] + : 453.1413, found 453.1413.

[0379] Example 27

[0380] Synthesis of intermediate 2-cyclopentyl-N-(6-iodo-7-methoxyquinazolin-4-yl)benzo[d]thiazol-5-amine (M60)

[0381] Intermediate M59 (60 mg, 0.17 mmol) was dissolved in DCM (5 mL), m-chloroperoxybenzoic acid (60.3 g, 0.35 mmol) was added portionwise, and the reaction was stirred at room temperature for 8 h. After completion of the reaction, the 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, and the residue was purified by column chromatography (DCM:MeOH = 20:1) to give 35 mg of a white solid in 46% yield. 1H NMR (500 MHz, DMSO-d6) δ 11.38 (s, 1H), 9.36 (s, 1H), 8.89 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.70 (dd, J = 8.6, 2.1 Hz, 1H), 7.31 (s, 1H), 4.06 (s, 3H), 3.59 (p, J = 8.0 Hz, 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).

[0382] Synthesis of intermediate 2-cyclopentyl-N-(6-(isopropylsulfinyl)-7- methoxyquinazolin-4-yl)benzo[d]thiazol-5-amine (M62)

[0383] Intermediate M60 (390 g, 0.78 mmol), isopropylthiol (72.1 μL, 0.78 mmol), tetrakis(triphenylphosphine)palladium (26.9 mg, 0.02 mmol), triethylamine (269.8 μL, 1.94 mmol) were dissolved in N,N-dimethylformamide (10 mL), and the reaction was heated to 90 °C under N2protection for 4 hours. After the reaction was completed, the reaction solution was filtered with celite, 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 obtain 186.5 g of brown solid, which was intermediate M61, with a yield of 53%.

[0384] Synthesis of intermediate 2-cyclopentyl-N-(6-(isopropylsulfinyl)-7- methoxyquinazolin-4-yl)benzo[d]thiazol-5-amine (M62)

[0385] Intermediate M61 (186 mg, 0.39 mmol) was dissolved in DCM (5 mL), and m-chloroperoxybenzoic acid (336 mg, 1.07 mmol) was added portionwise, and the reaction was allowed to proceed at room temperature for 8 hours. After the reaction was completed, the white solid was filtered off, extracted with DCM, and washed with saturated brine. The organic phase was dried in vacuo and purified by column chromatography (MeOH:DCM = 1:40) to obtain 120 mg of yellow solid, with a yield of 64%. 1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.75 (s, 1H), 8.60 (s, 1H), 8.49 (d, J = 2.1 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.78 (dd, J = 8.7, 2.1 Hz, 1H), 7.33 (s, 1H), 4.02 (s, 3H), 3.58 (p, J = 8.0 Hz, 1H), 3.25 (hept, J = 6.9 Hz, 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 = 7.0 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H).

[0386] Synthesis of compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)-7- methoxyquinazolin-4-yl)benzo[d]thiazol-5-amine (LK-28)

[0387] Intermediate M62 (32 mg, 0.39 mmol) was dissolved in tetrahydrofuran (3 mL), and an aqueous solution of oxone (336 mg, 1.07 mmol) (2 mL) was added, and the reaction was allowed to proceed at room temperature for 8 hours. After the reaction was completed, the white solid was filtered off, extracted with DCM, and washed with saturated brine. The organic phase was dried and purified by column chromatography (MeOH:DCM = 1:20) to obtain 15 mg of a yellow solid with a yield of 47%. 1 H NMR (500 MHz, DMSO-d6) δ 11.33 (s, 1H), 9.22 (s, 1H), 8.80 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.1 Hz, 1H), 7.45 (s, 1H), 4.11 (s, 3H), 3.80 (hept, J = 6.8 Hz, 1H), 3.59 (p, J = 8.0 Hz, 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 = 6.8 Hz, 6H). ESI-HRMS calcd for C 24 H 27 N4O3S2[M+H] + :483.1519, found 483.1418.

[0388] Example 28

[0389] Synthesis of compound 4-((2-cyclopentylbenzo[d]thiazol-5-yl)amino)-6- (isopropylsulfonyl)quinazolin-7-ol (LK-29)

[0390] LK-28 (60.0 mg, 0.12 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium isopropyl mercaptane (73.2 mg, 0.10 mmol) was added, and the temperature was raised to 150 °C for 1 h. After the reaction was completed, the solvent was evaporated, and the pH was adjusted to 7-8 with hydrochloric acid (3 N) and then filtered under suction to obtain a light yellow solid (55 mg, 94% yield). 1 H NMR (500 MHz, DMSO-d6) δ 11.47 (s, 1H), 9.19 (s, 1H), 8.77 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 8.7 Hz, 1H), 7.67 (dd, J = 8.6, 2.1 Hz, 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 = 6.9 Hz, 6H). ESI-HRMS Calcd for C 23 H 25 N4O3S2[M+H] + : 469.1363, found 469.1362.

[0391] Example 29

[0392] Synthesis of compound 2-((4-((2-cyclopentylbenzo[d]thiazol-5-yl)amino)-6- (isopropylsulfonyl)quinazolin-7-yl)oxy)ethanol (LK-30)

[0393] 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 stirred for 10 min, followed by the addition of 2-bromoethanol (24.2 μL, 0.34 mmol) and the temperature was raised to 70 °C for 3 h, and then the reaction was cooled to room temperature and stirred for 16 h. After the reaction was completed, the solvent was evaporated, and the slurry was filtered under suction with DCM / PE to obtain a light yellow solid (40 mg, 91% yield). 1H NMR (500 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.22 (s, 1H), 8.78 (s, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.70 (dd, J = 8.6, 2.1 Hz, 1H), 7.44 (s, 1H), 4.37 (t, J = 4.6 Hz, 2H), 4.04 (hept, J = 6.8 Hz, 1H), 3.84 (d, J = 4.6 Hz, 2H), 3.60 (p, J = 8.0 Hz, 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 = 6.8 Hz, 6H). ESI-HRMS calcd for C 25 H 29 N4O4S2[M+H] + : 513.1625, found 513.1627.

[0394] Example 30

[0395] Synthesis of intermediate 4-chloro-N-methylquinoline-7-carboxamide (M63)

[0396] Dissolve 4-chloroquinoline-7-carboxylic acid (130 mg, 0.58 mmol) in oxalyl chloride (1 mL), add 1 drop of DMF, react at room temperature for 4 hours, then spin dry the reaction solution to obtain the corresponding acyl chloride crude product. Dissolve methylamine hydrochloride (39 mg, 0.58 mmol) and triethylamine (160 μL, 1.15 mmol) in DMF (2 mL) at 0 °C, add the acyl chloride crude product in DMF (1 mL) dropwise, then slowly raise the temperature to room temperature and react for 12 hours. After the reaction is completed, extract with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate the organic phase, and purify by column chromatography (DCM:MeOH = 20:1) to obtain 40 mg of white solid, which is intermediate M63, with a yield of 31%.

[0397] Synthesis of compound 4-(2-cyclopentylbenzo[d]thiazol-5-yl)amino)-N- methylquinoline-7-carboxamide (LK-31)

[0398] Synthesis of compound LK-31 refers to the synthesis of LK-1, using M-63 and M-29 as starting materials, to obtain 28 mg of yellow solid, with a yield of 70%. 1H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.75 (q, J = 3.4, 2.5 Hz, 1H), 8.59 - 8.46 (m, 2H), 8.39 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.97 (dd, J = 8.7, 1.9 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.5, 2.1 Hz, 1H), 7.01 (d, J = 5.3 Hz, 1H), 3.58 (p, J = 8.1 Hz, 1H), 2.86 (d, J = 4.4 Hz, 3H), 2.19 (h, J = 6.7 Hz, 2H), 1.95 - 1.85 (m, 2H), 1.84 - 1.75 (m, 2H), 1.75 - 1.64 (m, 2H).

[0399] Example 31

[0400] Synthesis of intermediate 4-chloro-N-cyclopropylquinoline-7-carboxamide (M-64)

[0401] The synthesis of compound M64 was performed according to the synthesis of M63, using 4-chloroquinoline-7-carboxylic acid and cyclopropylamine as starting materials, to give 50 mg of white solid in 35% yield. 1 H NMR (500 MHz, Chloroform-d) δ 8.86 (d, J = 4.7 Hz, 1H), 8.39 (d, J = 1.7 Hz, 1H), 8.33 (dd, J = 8.7, 0.6 Hz, 1H), 8.12 (dd, J = 8.7, 1.8 Hz, 1H), 7.59 (d, J = 4.7 Hz, 1H), 6.50 (s, 1H), 3.01 (qt, J = 7.1, 3.6 Hz, 1H), 1.02 - 0.91 (m, 2H), 0.78 - 0.66 (m, 2H).

[0402] Synthesis of compound 4-(2-cyclopentylbenzo[d]thiazol-5-yl)amino)-N- cyclopropylquinoline-7-carboxamide (LK-32)

[0403] The synthesis of compound LK-31 was performed according to the synthesis of LK-1, using M-63 and M-29 as starting materials, to give 26 mg of yellow solid as hydrochloride salt in 68% yield. 1H NMR (500 MHz, DMSO-d6) δ 14.45 (s, 1H), 11.17 (s, 1H), 8.98 (d, J = 4.3 Hz, 1H), 8.88 (d, J = 8.9 Hz, 1H), 8.56 (d, J = 7.0 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.19 (dd, J = 8.7, 1.7 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.53 (dd, J = 8.5, 2.0 Hz, 1H), 6.90 (d, J = 6.9 Hz, 1H), 3.63 (p, J = 8.1 Hz, 1H), 2.96 (tq, J = 7.7, 4.0 Hz, 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] + .

[0404] Example 32

[0405] Synthesis of intermediate compound for compound 4-(2-cyclopentylbenzo[d]thiazol-5-yl)amino)-6-(isopropylsulfonyl)quinolin-7-ol (LK-33)

[0406] Compound LK-23 (86 mg, 0.16 mmol) was dissolved in DCM (2 mL), and under N2protection, it was cooled to 0 °C, and then boron tribromide (1 M in DCM, 1.66 mL, 1.66 mmol) was added dropwise slowly. The reaction was carried out at 0 °C for 16 h, and after the reaction was completed, it was extracted with dichloromethane / n-butanol (v / v = 3:1) mixed solution, washed with saturated brine, and dried over anhydrous sodium sulfate. After the organic phase was rotary evaporated, thin layer preparative chromatography purification (DCM:MeOH = 10:1) was performed, and 66 mg of yellow solid was obtained, which was compound LK-33, with a yield of 79%. ESI-MS: 468.3 [M+H] + .

[0407] Example 33

[0408] Synthesis of compound 2-((4-((2-cyclopentylbenzo[d]thiazol-5-yl)amino)-6- (isopropylsulfonyl)quinolin-7-yl)oxy)ethan-1-ol (LK-34)

[0409] The synthesis of compound LK-34 was performed with reference to the synthesis of LK-30, using LK-33 as the starting material, and 28 mg of yellow solid was obtained, with a yield of 64%.1 H NMR (500 MHz, DMSO-d6) δ 11.52 (s, 1H), 9.26 (s, 1H), 8.47 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.59 (s, 1H), 7.49 (dd, J = 8.5, 2.1 Hz, 1H), 6.81 (d, J = 7.2 Hz, 1H), 4.37 (t, J = 4.7 Hz, 2H), 4.05 (hept, J = 6.7 Hz, 1H), 3.87 (dd, J = 5.2, 4.1 Hz, 2H), 3.62 (p, J = 8.1 Hz, 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 = 6.7 Hz, 6H). ESI-MS: 512.4 [M+H] +

[0410] Example 34

[0411] Synthesis of intermediate N-(2-chloro-4-fluoro-5-nitrophenyl)formamide (M65)

[0412] Dissolve 2-chloro-4-fluoro-5-nitroaniline (1.2 g, 6.30 mmol) in formic acid (4 mL), and heat to 105 °C for 16 h. After the reaction is completed, cool to room temperature, and directly spin dry the reaction solution. Purify by column chromatography (PE:EA = 3:1) to obtain yellow solid 1.16 g, which is intermediate M65, with a yield of 84%. 1 H NMR (500 MHz, Chloroform-d) δ 9.24 (d, J = 7.5 Hz, 1H), 8.55 (s, 1H), 7.68 (s, 1H), 7.41 (d, J = 9.7 Hz, 1H).

[0413] Synthesis of intermediate 6-fluoro-5-nitrobenzo[d]thiazole (M66)

[0414] Dissolve intermediate M65 (1.16 g, 5.31 mmol) in ethanol (15 mL), and heat to 90 °C for 40 min. After the reaction is completed, cool to room temperature, and adjust the pH to 2-3 with 1 N hydrochloric acid. Concentrate the reaction solution, extract with ethyl acetate, wash with saturated brine, and dry over anhydrous sodium sulfate. Concentrate the organic phase, and purify by column chromatography (PE:EA = 3:1) to obtain yellow solid 300 mg, which is intermediate M66, with a yield of 29%. 1H NMR (500 MHz, Chloroform-d) δ 9.16 (s, 1H), 8.86 (d, J = 6.6 Hz, 1H), 7.90 (d, J = 9.9 Hz, 1H).

[0415] Synthesis of intermediate 2-cyclopentyl-6-fluoro-5-nitrobenzo[d]thiazole (M67)

[0416] The synthesis of intermediate M67 was performed according to the synthesis of M28, using M66 as starting material, to give a yellow solid 25 mg, 12% yield. 1 H NMR (500 MHz, Chloroform-d) δ 8.63 (d, J = 6.6 Hz, 1H), 7.72 (d, J = 10.1 Hz, 1H), 3.56 (p, J = 8.1 Hz, 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).

[0417] Synthesis of intermediate 2-cyclopentyl-6-fluorobenzo[d]thiazol-5-amine (M68)

[0418] The synthesis of intermediate M68 was performed according to the synthesis of M29, using M67 as starting material, to give a white solid 16 mg, 67% yield. 1 H NMR (500 MHz, Chloroform-d) δ 7.43 (d, J = 10.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 3.51 (p, J = 8.1 Hz, 1H), 2.31 - 2.21 (m, 2H), 1.99 - 1.83 (m, 4H), 1.82 - 1.70 (m, 2H).

[0419] Synthesis of compound 2-cyclopentyl-6-fluoro-N-(6-(isopropylsulfonyl)quinolin-4- yl)benzo[d]thiazol-5-amine (LK-35)

[0420] The synthesis of compound LK-35 was performed according to the synthesis of LK-1, using M68 and M29 as starting materials, to give a yellow solid 23 mg, as hydrochloride salt, 67% yield. 1H NMR (500 MHz, DMSO-d6) δ 15.08 (br s, 1H), 11.56 (s, 1H), 9.44 (d, J = 1.8 Hz, 1H), 8.65 (d, J = 7.0 Hz, 1H), 8.41 (dd, J = 9.0, 1.8 Hz, 1H), 8.38 - 8.28 (m, 2H), 8.19 (d, J = 7.0 Hz, 1H), 6.77 (dd, J = 7.0, 2.1 Hz, 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 = 6.8 Hz, 6H). 13 C NMR (126 MHz, DMSO-d6) δ 178.32, 156.18, 155.02, 153.05, 149.75, 144.92, 140.80, 135.13 (d, J = 11.2 Hz), 131.76, 126.20, 123.36 (d, J = 15.5 Hz), 122.20, 121.29, 116.60, 110.18 (d, J = 25.3 Hz), 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.

[0421] Example 35

[0422] Synthesis of intermediate 5-nitro-2-(thiazol-2-yl)benzo[d]thiazole (M69)

[0423] 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 into DMF (4 mL) and heated to 120 °C open for 12 hours. After the reaction was completed, the reaction solution was filtered with celite, 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 obtain 15 mg of yellow solid, which was intermediate M69, with a yield of 5%. 1H NMR (500 MHz, Chloroform-d) δ 8.97 (d, J = 2.2 Hz, 1H), 8.35 (dd, J = 8.8, 2.2 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 3.1 Hz, 1H), 7.67 (d, J = 3.1 Hz, 1H).

[0424] Synthesis of intermediate 2-(thiazol-2-yl)benzo[d]thiazol-5-amine (M70)

[0425] The synthesis of intermediate M70 was performed according to the synthesis of M4, using M69 as starting material, to give 10 mg of white solid in 66% yield. 1 H NMR (500 MHz, Chloroform-d) δ 7.98 (d, J = 3.2 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 3.2 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.5, 2.3 Hz, 1H), 3.83 (br s, 2H).

[0426] Synthesis of compound N-(6-(isopropylsulfonyl)quinolin-4-yl)-2-(thiazol-2-yl)benzo[d]thiazol-5-amine (LK-36)

[0427] The synthesis of compound LK-36 was performed according to the synthesis of LK-1, using M70 and M2 as starting materials, to give 16 mg of yellow solid as hydrochloride salt in 74% yield. 1 H NMR (500 MHz, DMSO-d6) δ 14.95 (br s, 1H), 11.68 (s, 1H), 9.45 (d, J = 1.9 Hz, 1H), 8.62 (d, J = 7.1 Hz, 1H), 8.48 - 8.36 (m, 2H), 8.35 - 8.25 (m, 2H), 8.20 - 8.11 (m, 2H), 7.68 (dd, J = 8.6, 2.1 Hz, 1H), 7.06 (d, J = 7.1 Hz, 1H), 3.68 (hept, J = 6.8 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H). 13C NMR (126 MHz, DMSO-d6) δ 163.00, 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.

[0428] Example 36

[0429] Synthesis of intermediate 5-nitro-2-(oxazol-2-yl)benzo[d]thiazole (M71)

[0430] The synthesis of intermediate M71 was performed according to the synthesis of M69, using 5-nitrobenzothiazole and oxazole as starting materials, to give 19 mg of white solid in 6% yield. 1 H NMR (500 MHz, Chloroform-d) δ 9.05 (d, J = 2.2 Hz, 1H), 8.40 (dd, J = 8.9, 2.2 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.47 (d, J = 0.8 Hz, 1H).

[0431] Synthesis of intermediate 2-(thiazol-2-yl)benzo[d]oxazol-5-amine (M72)

[0432] The synthesis of intermediate M72 was performed according to the synthesis of M4, using M71 as starting material, to give 14 mg of white solid in 73% yield.

[0433] Synthesis of compound N-(6-(isopropylsulfonyl)quinolin-4-yl)-2-(thiazol-2- yl)benzo[d]oxazol-5-amine (LK-37)

[0434] The synthesis of compound LK-37 was performed according to the synthesis of LK-1, using M72 and M2 as starting materials, to give 11 mg of yellow solid as hydrochloride salt in 69% yield. 1H NMR (500 MHz, DMSO-d6) δ 14.94 (brs, 1 H), 11.68 (s, 1 H), 9.44 (d, J = 2.0 Hz, 1 H), 8.64 (d, J = 7.1 Hz, 1 H), 8.52 (s, 1 H), 8.46 (d, J = 8.6 Hz, 1 H), 8.40 (dd, J = 8.9, 1.8 Hz, 1 H), 8.36 - 8.26 (m, 2 H), 7.72 (dd, J = 8.6, 2.1 Hz, 1 H), 7.65 (s, 1 H), 7.05 (d, J = 7.0 Hz, 1 H), 3.67 (p, J = 6.8 Hz, 1 H), 1.26 (d, J = 6.9 Hz, 6 H). 13 C NMR (126 MHz, DMSO-d6) δ 155.90, 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-HRMS Calcd for C 22 H 19 N4O3S2[M+H] + : 451.0893, found 451.0893.

[0435] Example 37

[0436] Synthesis of intermediate N-(2-bromo-5-nitrophenyl)cyclopentanecarboxamide (M73)

[0437] The synthesis of intermediate M73 was performed according to the synthesis of M63, using 2-bromo-5-nitroaniline and cyclopentanecarboxylic acid as starting materials, pyridine as base, to give yellow solid 230 mg, 32% yield. 1 H NMR (500 MHz, Chloroform-d) δ 9.35 (d, J = 2.7 Hz, 1 H), 7.85 (dd, J = 8.8, 2.7 Hz, 1 H), 7.81 (s, 1 H), 7.74 (d, J = 8.8 Hz, 1 H), 2.85 (p, J = 8.0 Hz, 1 H), 2.11 - 2.01 (m, 2 H), 2.01 - 1.93 (m, 2 H), 1.89 - 1.80 (m, 2 H), 1.74 - 1.66 (m, 2 H).

[0438] Synthesis of intermediate 2-cyclopentyl-5-nitrobenzo[d]oxazole (M74)

[0439] 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 into ethylene glycol dimethyl ether (4 mL) and heated to 95 °C for 24 h under N2protection. After the reaction was completed, the reaction solution was filtered through celite, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The organic phase was rotary evaporated and purified by column chromatography (PE:EA = 4:1) to give 37 mg of yellow solid, which was intermediate M74, with a yield of 50%. 1 H NMR (400 MHz, Chloroform-d) δ 7.23 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.64 (dd, J = 8.6, 2.3 Hz, 1H), 3.32 (p, J = 8.1 Hz, 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).

[0440] Synthesis of intermediate 2-cyclopentylbenzo[d]oxazol-5-amine (M75)

[0441] The synthesis of intermediate (M75) was performed according to the synthesis of M6a, using M74 as the starting material, to give 27 mg of brown oil with a yield of 77%. 1 H NMR (400 MHz, Chloroform-d) δ 7.23 (d, J = 8.6 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.64 (dd, J = 8.6, 2.3 Hz, 1H), 3.32 (p, J = 8.1 Hz, 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).

[0442] Synthesis of compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]oxazol-5-amine (LK-38)

[0443] The synthesis of compound LK-38 was performed according to the synthesis of LK-1, using M74 and M2 as the starting materials, to give 20 mg of yellow solid as a hydrochloride salt with a yield of 50%. 1H NMR (500 MHz, DMSO-d6) δ 14.86 (s, 1H), 11.59 (s, 1H), 9.41 (d, J = 1.9 Hz, 1H), 8.57 (d, J = 7.1 Hz, 1H), 8.38 (dd, J = 8.9, 1.8 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 7.96 - 7.82 (m, 2H), 7.47 (dd, J = 8.6, 2.1 Hz, 1H), 6.83 (d, J = 7.1 Hz, 1H), 3.65 (hept, J = 6.7 Hz, 1H), 3.49 (p, J = 8.0 Hz, 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 = 6.8 Hz, 6H). 13 C NMR (126 MHz, DMSO) δ 171.72, 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, found 436.1690.

[0444] Example 38

[0445] Synthesis of compound 8-(benzo[d]thiazol-5-ylamino)-3-cyclopropylthieno[2,3- g]quinoline 1,1-dioxide (DB-2)

[0446] The synthesis of compound DB-2 was performed according to the synthesis of reference compound LK-25, using M57 and 5-amino benzothiazole as starting materials, to give 40 mg of yellow solid in 91% yield. 1H NMR (600 MHz, DMSO-d6) δ 14.75 (br s, 1H), 11.24 (s, 1H), 9.51 (s, 1H), 9.28 (s, 1H), 8.56 (d, J = 7.0 Hz, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.33 (s, 1H), 8.21 (d, J = 2.1 Hz, 1H), 7.59 (dd, J = 8.5, 2.1 Hz, 1H), 7.38 (d, J = 0.9 Hz, 1H), 6.98 (d, J = 7.0 Hz, 1H), 2.11 (qd, J = 8.7, 4.9 Hz, 1H), 1.24 - 1.18 (m, 2H), 0.97 - 0.92 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 158.41, 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.

[0447] Example 39

[0448] Synthesis of intermediate 1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (M76)

[0449] Dissolve 5-amino-1-(tert-butyl)-1H-pyrazole-4-carbonitrile (350 mg, 2.13 mmol) in formamide (3 mL), and warm to 180 °C for 9 hours. After the reaction is completed, dilute the reaction with water, and extract with ethyl acetate. Combine the organic layers, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate. Purify the crude product by column chromatography (PE:EA = 1:1) to give 250 mg of yellow solid, which is intermediate M76, in 61% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.03 (s, 1H), 7.58 (br s, 2H), 1.70 (s, 9H).

[0450] Synthesis of intermediate 3-bromo-1-(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (M77)

[0451] To a solution of intermediate M76 (150 mg, 0.78 mmol) in acetonitrile (2 mL) was added N-bromosuccinimide (209 mg, 1.18 mmol). The reaction was heated to 100 °C for 2 h. After the reaction was concentrated, 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 orange solid 168 mg, which was intermediate M77, in 79% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 1.69 (s, 9H).

[0452] Synthesis of intermediate 5-bromo-2-(sec-butyl)benzo[d]thiazole (M78)

[0453] To a solution of 5-bromo-benzo[d]thiazole (3 g, 14.01 mmol) in dichloromethane / water (20 mL / 20 mL) was added 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). The reaction was stirred at room temperature for 16 h. After the reaction was completed, it was extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography (PE:EA = 10:1) to give brown oil 1.66 g, which was intermediate M78, in 44% yield.

[0454] Synthesis of intermediate 2-(sec-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzo[d]thiazole (M79)

[0455] To a solution of intermediate M78 (200 mg, 0.74 mmol) and pinacol diboronic acid (207 mg, 0.81 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was added PdCl2(dppf) (61 mg, 0.07 mmol) and potassium acetate (255 mg, 2.59 mmol). The reaction was heated to 100 °C for 12 h under N2. After the reaction was completed, it 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 colorless oil 165 mg, which was intermediate M79, in 70% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.43 (t, J = 0.9 Hz, 1H), 7.85 (dd, J = 8.0, 0.7 Hz, 1H), 7.74 (dd, J = 7.9, 1.1 Hz, 1H), 3.21 (h, J = 6.9 Hz, 1H), 1.96 - 1.86 (m, 1H), 1.83 - 1.72 (m, 1H), 1.44 (d, J = 6.9 Hz, 3H), 1.36 (s, 12H), 0.96 (t, J = 7.4 Hz, 3H).

[0456] Synthesis of compound 1-(tert-butyl)-3-(2-(tert-butyl)-benzo[d]thiazol-5-yl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine (LK-47)

[0457] 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). After the reaction was completed under N2protection at 100 °C for 12 h, the reaction solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. After the crude product was concentrated, 36 mg of white solid was obtained by thin layer preparative chromatography, which was compound LK-48, with a yield of 85%. 1 H NMR (500 MHz, Chloroform-d) δ 8.36 (s, 1H), 8.30 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.71 (dd, J = 8.1, 1.7 Hz, 1H), 5.59 (s, 2H), 3.25 (h, J = 7.0 Hz, 1H), 1.99 - 1.90 (m, 1H), 1.85 - 1.77 (m, 1H), 1.48 (d, J = 7.0 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 179.43, 157.76, 154.46, 154.34, 153.72, 141.66, 135.25, 131.76, 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.

[0458] Example 40

[0459] Synthesis of intermediate 5-bromo-2-cyclopentylbenzo[d]thiazole (M80)

[0460] The synthesis of intermediate M80 was performed according to the synthesis of intermediate M78, using 5-bromo-benzo[d]thiazole and cyclopentanecarboxylic acid as starting materials, to give 345 mg of brown oil in 26% yield. 1 H NMR (400 MHz, Chloroform-d) δ 8.10 (d, J = 1.9 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 8.5, 1.9 Hz, 1H), 3.54 (p, J = 8.0 Hz, 1H), 2.34 - 2.20 (m, 2H), 2.01 - 1.83 (m, 4H), 1.81 - 1.70 (m, 2H).

[0461] Synthesis of intermediate 2-cyclopentyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[d]thiazole (M81)

[0462] The synthesis of intermediate M81 was performed according to the synthesis of intermediate M79, using intermediate M80 as starting material, to give 180 mg of colorless oil in 77% yield. 1 H NMR (500 MHz, Chloroform-d) δ 8.41 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 8.0, 1.1 Hz, 1H), 3.55 (p, J = 8.2 Hz, 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).

[0463] Synthesis of compound l-(tert-butyl)-3-(2-cyclopentylbenzo[d]thiazol-5-yl)-lH-pyrazolo[3,4-d]pyrimidin-4-amine (LK-49)

[0464] The synthesis of compound LK-49 was performed according to the synthesis of compound LK-48, using intermediates M77 and M81 as starting materials, to give 30 mg of white solid in 69% yield.

[0465] 1H NMR (500 MHz, Chloroform-d) δ 8.37 (s, 1H), 8.28 (d, J = 1.5 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.70 (dd, J = 8.2, 1.6 Hz, 1H), 5.54 (s, 2H), 3.59 (p, J = 8.1 Hz, 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 (126 MHz, CDC13) δ 178.67, 157.74, 154.47, 154.34, 153.85, 141.67, 135.40, 131.76, 125.00, 122.35 (2C), 99.75, 60.56, 44.91, 34.08, 29.22, 25.62. ESI-HRMS calcd for C 24 H 26 N3O2S2[M+H] + : 393.1856, found 393.1861.

[0466] Example 41

[0467] Synthesis of intermediate 2-cyclopentyl-6-nitro-2H-indazole (M82)

[0468] 2-amino-4-nitrobenzaldehyde (2.55 mmol, 500 mg) and cyclopentylamine (3.06 mmol, 302 μL) were added into ethanol (5 mL), heated to 50 °C for 30 min. Then the solvent was rotary evaporated, trimethyl phosphate (3 mL) was added, heated to 110 °C for 1 h. After the reaction was completed, 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 brown oil, yield 63%. 1 H NMR (400 MHz, Chloroform-d) δ 8.72 (dt, J = 1.9, 0.8 Hz, 1H), 8.08 (d, J = 1.0 Hz, 1H), 7.89 (dd, J = 9.1, 2.0 Hz, 1H), 7.74 (dd, J = 9.1, 0.7 Hz, 1H), 5.01 (ddd, J = 14.2, 7.7, 6.5 Hz, 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).

[0469] Synthesis of intermediate 2-cyclopentyl-2H-indazol-6-amine (M83)

[0470] The synthesis of intermediate M83 was performed according to the synthesis of M4, using intermediate M82 as starting material, to give 290 mg of brown oil in 90% yield. 1 H NMR (500 MHz, Chloroform-d) δ 7.82 (d, J = 1.0 Hz, 1H), 7.47 (dd, J = 8.8, 0.8 Hz, 1H), 6.86 (dt, J = 1.9, 0.9 Hz, 1H), 6.61 (dd, J = 8.8, 1.9 Hz, 1H), 4.88 (p, J = 7.3 Hz, 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).

[0471] Synthesis of compound N-(2-cyclopentyl-2H-indazol-6-yl)-6-(isopropylsulfonyl)quinolin-4- amine (LK-47)

[0472] The synthesis of compound LK-47 was performed according to the synthesis of compound LK-1, using intermediates M2 and M83 as starting materials, to give 62 mg of yellow solid as hydrochloride salt in 70% yield. 1 H NMR (500 MHz, DMSO-d6) δ 14.74 (br s, 1H), 11.57 (s, 1H), 9.41 (d, J = 1.8 Hz, 1H), 8.64 - 8.50 (m, 2H), 8.37 (dd, J = 9.0, 1.8 Hz, 1H), 8.26 (d, J = 8.9 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.11 (dd, J = 8.7, 1.8 Hz, 1H), 6.92 (d, J = 7.0 Hz, 1H), 5.08 (p, J = 7.1 Hz, 1H), 3.65 (hept, J = 6.7 Hz, 1H), 2.24 (dq, J = 13.0, 7.0 Hz, 2H), 2.11 (ddt, J = 13.0, 8.5, 6.2 Hz, 2H), 1.97 - 1.84 (m, 2H), 1.74 (dtd, J = 12.3, 7.8, 3.5 Hz, 2H), 1.25 (d, J = 6.8 Hz, 6H). ESI-HRMS calcd for C 24 H 27 N4O2S [M+H] + : 435.1849, found 435.1846.

[0473] Example 42

[0474] Synthesis of intermediate 2-fluoro-4,6-dinitrophenol (M84)

[0475] 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, then slowly warmed to room temperature for 2 hours. The reaction was complete, the reaction was extracted with ethyl acetate and washed with saturated brine. The organic phase was concentrated and petroleum ether (30 mL) was added to precipitate the solid. The solid was filtered and dried to give a yellow solid 6 g in 42% yield. 1 H NMR (500 MHz, Chloroform-d) δ 10.97 (s, 1H), 8.91 (t, J = 2.3 Hz, 1H), 8.32 (dd, J = 9.2, 2.7 Hz, 1H).

[0476] Synthesis of intermediate 2-amino-6-fluoro-4-nitrophenol (M85)

[0477] Intermediate M84 (15.6 mmol, 3.15 g) was dissolved in ethanol (25 mL) and heated to 80 °C, then stannous chloride (23.3 mmol, 4.4 g) was added and the reaction was stirred for 2 hours. The reaction was complete, the reaction was adjusted to pH 5-6 with 10% sodium hydroxide solution, extracted with ethyl acetate and washed with saturated brine. The organic phase was concentrated and purified by column chromatography (PE:EA = 1:1) to give a brown oil 1.66 g in 62% yield. 1 H NMR (500 MHz, DMSO-d6) δ 7.37 (s, 1H), 7.31 (dd, J = 10.5, 3.1 Hz, 1H).

[0478] Synthesis of intermediate N-(3-fluoro-2-hydroxy-5-nitrophenyl)cyclopentanecarboxamide (M86)

[0479] Intermediate M85 (2.32 mmol, 400 mg) and pyridine (4.65 mmol, 380 μί) were dissolved in dichloromethane (5 mL) at 0 °C, then cyclopentylcarbonyl chloride (2.44 mmol, 294 μί) was added dropwise, then slowly warmed to room temperature for 12 hours. The reaction was complete, extracted with dichloromethane and washed with saturated brine. The organic phase was concentrated and purified by column chromatography (PE:EA = 2:1) to give a yellow solid 230 mg in 37% yield.

[0480] Synthesis of intermediate 2-cyclopentyl-7-fluoro-5-nitrobenzo[d]oxazole (M87)

[0481] Intermediate M86 (0.41 mmol, 110 mg) and triphenylphosphine (0.90 mmol, 237 mg) were dissolved in tetrahydrofuran (2 mL) at 0 °C, diethyl azodicarboxylate (0.90 mmol, 142 μί) was added dropwise, and the reaction was slowly warmed to room temperature for 12 h. After the reaction was completed, ethyl acetate extraction, saturated brine washing, and column chromatography separation (PE:EA = 3:1) of the concentrated organic phase yielded 25 mg of yellow oil, with a yield of 24%. 1 H NMR (500 MHz, Chloroform-d) δ 8.42 (d, J = 2.0 Hz, 1H), 8.07 (dd, J = 9.6, 2.0 Hz, 1H), 3.47 (p, J = 8.1 Hz, 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).

[0482] Synthesis of 2-cyclopentyl-7-fluorobenzo[d]oxazol-5-amine (M88)

[0483] Synthesis of intermediate M88 was performed according to the synthesis of M4, using intermediate M82 as the starting material, to yield 16 mg of brown oil, with a yield of 73%. 1 H NMR (500 MHz, Chloroform-d) δ 6.73 (d, J = 2.0 Hz, 1H), 6.42 (dd, J = 11.4, 2.0 Hz, 1H), 3.33 (p, J = 8.2 Hz, 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).

[0484] Synthesis of compound 2-cyclopentyl-7-fluoro-N-(6-(isopropylsulfonyl)quinolin-4- yl)benzo[d]oxazol-5-amine (LK50)

[0485] Synthesis of compound LK-50 was performed according to the synthesis of compound LK-1, using intermediate M2 and M88 as the starting material, to yield 16 mg of yellow solid, with a yield of 65%. Further purification by reverse phase HPLC (column type: Waters Sunfire C18, 19 x 150 mm, 5 μm; mobile phase A: H20 with 0.1% trifluoroacetic acid; mobile phase B: MeCN with 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 LK-50 as a trifluoroacetate salt. 1H NMR (500 MHz, DMSO-d6) δ 14.56 (br s, 1H), 11.50 (s, 1H), 9.33 (d, J = 1.8 Hz, 1H), 8.64 (d, J = 7.0 Hz, 1H), 8.39 (dd, J = 8.8, 1.8 Hz, 1H), 8.21 (d, J = 8.9 Hz, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.53 (dd, J = 10.8, 1.8 Hz, 1H), 6.96 (d, J = 7.1 Hz, 1H), 3.60 (p, J = 6.7 Hz, 1H), 3.53 (p, J = 7.9 Hz, 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 = 6.7 Hz, 6H). ESI-HRMS calcd for C 24 H 25 FN3O3S [M+H] + : 454.1595, found 454.1599.

[0486] Example 42

[0487] Synthesis of intermediate N-(2-bromo-3-methyl-5-nitrophenyl)cyclopentanecarboxamide (M89)

[0488] The synthesis of intermediate M89 was performed following the procedure described for the synthesis of M86, using 2-bromo-3-methyl-5-nitroaniline and cyclopentanecarbonyl chloride as starting materials, and triethylamine as base, to give a yellowish solid 120 mg in 85% yield. 1 H NMR (500 MHz, Chloroform-d) δ 9.18 (d, J = 2.8 Hz, 1H), 7.93 (s, 1H), 7.90 - 7.84 (m, 1H), 2.85 (p, J = 8.1 Hz, 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).

[0489] Synthesis of intermediate 2-cyclopentyl-7-methyl-5-nitrobenzo[d]oxazole (M90)

[0490] The synthesis of intermediate M90 was performed following the procedure described for the synthesis of M74, using intermediate M89 as starting material, to give a yellowish solid 56 mg in 62% yield. 1H NMR (400 MHz, Chloroform-d) δ 8.40 (dd, J = 2.3, 0.7 Hz, 1H), 8.10 (dq, J = 1.7, 0.8 Hz, 1H), 3.44 (p, J = 8.1 Hz, 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).

[0491] Synthesis of intermediate 2-cyclopentyl-7-methylbenzo[d]oxazol-5-amine (M91)

[0492] The synthesis of intermediate M91 was performed according to the synthesis of M4, using intermediate M91 as starting material. It was used directly in the next step without purification.

[0493] Synthesis of compound 2-cyclopentyl-N-(6-(isopropylsulfonyl)quinolin-4-yl)-7- methylbenzo[d]oxazol-5-amine (LK52)

[0494] The synthesis of compound LK-52 was performed according to the synthesis of compound LK-1, using intermediates M2 and M91 as starting materials, which gave yellow solid 30 mg in 56% yield. ESI-HRMS calcd for C 25 H 28 N3O3S [M+H] + : 450.1846, found 450.1847.

[0495] Example 43

[0496] Synthesis of intermediate N-(3-fluoro-2-hydroxy-5-nitrophenyl)tetrahydrofuran-2- carboxamide (M92)

[0497] Tetrahydrofuran-2-carboxylic acid (2.79 mmol, 268 μί) was added to oxalyl chloride (1 mL) with a catalytic amount of N,N-dimethylformamide and reacted at room temperature for 2 hours. After the reaction was completed, the oxalyl chloride was concentrated and diluted with dichloromethane (1 mL). Intermediate M85 (2.32 mmol, 400 mg) and pyridine (6.97 mmol, 380 μί) were dissolved in dichloromethane (5 mL) at 0 °C, and the oxalyl chloride solution was added dropwise. After slowly increasing the temperature to room temperature, the reaction was allowed to proceed for 12 hours. After the reaction was completed, it was extracted with dichloromethane and washed with saturated brine. After the organic phase was concentrated, it was separated by column chromatography (PE:EA = 3: 1) to give a light yellow solid 480 mg in 76% yield.

[0498] The synthesis of intermediates M93~M94 was performed according to the synthesis of intermediates M87~M88.

[0499] Hydrogen spectrum of intermediate M93: 1 H NMR (500 MHz, Chloroform-d) δ 8.47 (dd, J = 2.0, 0.7 Hz, 1H), 8.12 (dd, J = 9.5, 2.0 Hz, 1H), 5.29 (dd, J = 7.9, 5.5 Hz, 1H), 4.23 - 4.13 (m, 1H), 4.08 (ddd, J = 8.4, 7.3, 6.1 Hz, 1H), 2.51 (dtd, J = 12.7, 8.1, 6.7 Hz, 1H), 2.47 - 2.39 (m, 1H), 2.29 - 2.19 (m, 1H), 2.19 - 2.10 (m, 1H).

[0500] Synthesis of compound 7-fluoro-N-(6-(isopropylsulfonyl)quinolin-4-yl)-2- (tetrahydrofuran-2-yl)benzo[d]oxazol-5-amine (LK53)

[0501] Synthesis of compound LK-53 was performed according to the synthesis of compound LK-1, using intermediates M2 and M91 as starting materials, to give 43 mg of a yellowish solid as a hydrochloride salt in 61% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.38 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 7.0 Hz, 1H), 8.39 (dd, J = 8.9, 1.8 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.57 (dd, J = 10.8, 1.8 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 4.12 (dd, J = 8.7, 7.7 Hz, 1H), 4.07 (dd, J = 8.7, 5.4 Hz, 1H), 3.99 - 3.90 (m, 2H), 3.85 (td, J = 8.0, 6.6 Hz, 1H), 3.65 (hept, J = 6.8 Hz, 1H), 2.47 - 2.30 (m, 2H), 1.25 (d, J = 6.8 Hz, 6H). ESI-HRMS Calcd for C 23 H 23 FN3O4S [M+H] + : 456.1388, found 456.1389.

[0502] Example 44

[0503] Synthesis of intermediates M95 to M97 was performed according to the synthesis of intermediates M92 to M94

[0504] Synthesis of compound 7-fluoro-N-(6-(isopropylsulfonyl)quinolin-4-yl)-2- (tetrahydrofuran-3-yl)benzo[d]oxazol-5-amine (LK54)

[0505] Synthesis of compound LK-53 was performed according to the synthesis of compound LK-1, using intermediates M2 and M91 as starting materials. The reaction was completed after 24 hours. The reaction solution was concentrated under reduced pressure and purified by thin layer chromatography (DCM:MeOH = 20:1) to give a light yellow solid 47 mg as hydrochloride salt in 85% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.38 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 7.0 Hz, 1H), 8.39 (dd, J = 8.9, 1.8 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.57 (dd, J = 10.8, 1.8 Hz, 1H), 6.95 (d, J = 7.0 Hz, 1H), 4.12 (dd, J = 8.7, 7.7 Hz, 1H), 4.07 (dd, J = 8.7, 5.4 Hz, 1H), 3.99 - 3.90 (m, 2H), 3.89 - 3.81 (m, 1H), 3.65 (hept, J = 6.8 Hz, 1H), 2.47 - 2.30 (m, 2H), 1.25 (d, J = 6.8 Hz, 6H). ESI-HRMS calcd for C 23 H 23 FN3O4S [M+H] + : 456.1388, found 456.1385.

[0506] Example 45

[0507] Synthesis of compound 2-cyclopentyl-7-fluoro-N-(6-(isopropylsulfonyl)-7- methoxyquinolin-4-yl)benzo[d]oxazol-5-amine (LK-55)

[0508] Synthesis of compound LK-55 was performed according to the synthesis of compound LK-1, using intermediates M88 and M45 as starting materials. The reaction was completed after 24 hours. The reaction solution was concentrated under reduced pressure and purified by thin layer chromatography (DCM:MeOH = 20:1) to give a light yellow solid 9 mg in 24% yield. Further purification by reverse phase HPLC (column type: 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 minutes, 50%-65% B-10 minutes; 65%-100% B-7 minutes; flow rate: 10 mL / minute) to give LK-55 as trifluoroacetate salt. 1H NMR (500 MHz, DMSO-d6) δ 11.49 (s, 1H), 9.23 (s, 1H), 8.52 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.64 (s, 1H), 7.51 (dd, J = 10.9, 1.8 Hz, 1H), 6.85 - 6.75 (m, 2H), 4.12 (s, 3H), 3.86 - 3.80 (m, 1H), 3.52 (p, J = 8.0 Hz, 1H), 2.23 - 2.10 (m, 2H), 2.04 - 1.95 (m, 2H), 1.82 - 1.68 (m, 4H), 1.24 (d, J = 6.8 Hz, 6H). 13 C NMR (126 MHz, DMSO-d6) δ 172.19, 159.25, 155.93, 146.79, 144.70 (d, J = 24.7 Hz), 144.22, 143.18, 136.19 (d, J = 10.7 Hz), 133.79 (d, J = 8.3 Hz), 128.42, 126.66, 113.25 (d, J = 4.1 Hz), 110.46, 109.96 (d, J = 18.6 Hz), 101.67, 100.75, 57.21, 52.99, 37.85, 30.75, 25.14, 14.63. ESI-MS: 484.1 [M+H] + .

[0509] Example 46

[0510] Synthesis of compound 2-cyclopentyl-N-(6,7-dimethoxyquinolin-4-yl)benzo[d]thiazol-5- amine (LK56)

[0511] Synthesis of compound LK-56 was performed according to the synthesis of compound LK-1, using intermediate M29 and 4-chloro-6,7-dimethoxyquinoline as starting materials, to give 32 mg of yellow solid as hydrochloride salt in 67% yield. 1H NMR (500 MHz, DMSO-d6) δ 14.14 (s, 1H), 10.80 (s, 1H), 8.34 (d, J = 7.0 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz, 1H), 7.44 (s, 1H), 6.78 (d, J = 6.9 Hz, 1H), 4.03 (s, 3H), 4.00 (s, 3H), 3.62 (p, J = 8.0 Hz, 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 (126 MHz, DMSO-d6) δ 178.40, 154.59, 153.58, 153.37, 149.41, 139.88, 135.70, 135.18, 132.94, 123.31, 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] + .

[0512] Example 47

[0513] Synthesis of compound 2-cyclopentyl-N-(6-methoxy-7-(3- morpholinopropoxy)quinolin-4-yl)benzo[d]thiazol-5-amine (LK-57)

[0514] The synthesis of compound LK-56 was performed according to the procedure for synthesis of compound LK-1, using intermediate M29 and 4-(3-((4-chloro-6-methoxyquinolin-7- yl)oxy)propyl)morpholine as starting material, in a sealed tube, heating to 100 °C for 12 h. After completion of the reaction, purification by reverse phase HPLC (column type: Waters Sunfire C18, 19 x 150 mm, 5 μm; mobile phase A: H20 with 0.1% trifluoroacetic acid; mobile phase B: MeCN with 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) afforded LK-57 as a white solid, 23 mg, 56% yield, as trifluoroacetate salt. 1H NMR (500 MHz, DMSO-d6) δ 14.19 (s, 1H), 10.66 (s, 1H), 9.99 (s, 1H), 8.37 (d, J = 7.0 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.08 (s, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.48 (dd, J = 8.5, 2.1 Hz, 1H), 7.46 (s, 1H), 6.79 (d, J = 7.0 Hz, 1H), 4.29 (t, J = 5.8 Hz, 2H), 4.10 - 3.97 (m, 5H), 3.69 (t, J = 12.1 Hz, 2H), 3.62 (t, J = 8.0 Hz, 1H), 3.55 (d, J = 12.3 Hz, 2H), 3.35 (t, J = 7.6 Hz, 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 (126 MHz, DMSO-d6) δ 178.54, 158.08 (q, J = 32.6 Hz), 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 = 297.6 Hz), 111.59, 102.28, 100.71, 99.32, 66.33, 63.37, 56.47, 53.62, 51.23, 43.91, 33.31, 25.04, 22.80. ESI-MS: 519.1 [M+H] + .

[0515] Example 48

[0516] Synthesis of intermediates M98-M100 was performed according to the synthesis of intermediates M95-M97

[0517] Hydrogen spectrum of intermediate M99: 1 H NMR (500 MHz, Chloroform-d) δ 8.44 (dd, J = 2.1, 0.6 Hz, 1H), 8.10 (dd, J = 9.5, 2.0 Hz, 1H), 3.79 - 3.66 (m, 1H), 3.23 - 3.11 (m, 4H).

[0518] Synthesis of compound 2-(3,3-difluorocyclobutyl)-7-fluoro-N-(6-(isopropylsulfonyl)quinolin-4-yl)benzo[d]oxazole-5-amine (LK58)

[0519] The synthesis of compound LK-58 was performed according to the synthesis of compound LK-1, using intermediates M2 and M100 as starting materials, to give yellow solid 45 mg as hydrochloride salt, in 85% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.60 (s, 1H), 9.39 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 7.0 Hz, 1H), 8.39 (dd, J = 8.9, 1.8 Hz, 1H), 8.30 (d, J = 8.9 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.60 (dd, J = 10.8, 1.8 Hz, 1H), 6.94 (d, J = 7.0 Hz, 1H), 3.97 - 3.84 (m, J = 6.0, 4.5 Hz, 1H), 3.66 (hept, J = 6.9 Hz, 1H), 3.29 - 3.08 (m, 4H), 1.25 (d, J = 6.8 Hz, 6H). ESI-MS: 476.1 [M+H] + .

[0520] Example 49

[0521] Synthesis of compound 2-(3,3-difluorocyclobutyl)-7-fluoro-N-(6-(isopropylsulfonyl)-7- methoxyquinolin-4-yl)benzo[d]oxazole-5-amine (LK59)

[0522] The synthesis of compound LK-59 was performed according to the synthesis of compound LK-1, using intermediates M45 and M100 as starting materials, to give white solid 50 mg as hydrochloride salt, in 89% yield. 1 H NMR (500 MHz, DMSO-d6) δ 14.59 (br s, 1H), 11.50 (s, 1H), 9.24 (s, 1H), 8.53 (d, J = 7.0 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.71 (s, 1H), 7.57 (dd, J = 10.9, 1.8 Hz, 1H), 6.79 (d, J = 7.1 Hz, 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 = 6.9 Hz, 6H). ESI-HRMS Calcd for C 24 H 23 F3N3O4S [M+H] + : 506.1356, found 506.1355.

[0523] Example 50

[0524] Synthesis of compound 3-cyclopropyl-8-((2-(3,3-difluorocyclobutyl)-7- fluorobenzo[d]oxazol-5-yl)amino)thieno[2,3-g]quinoline 1,1-dioxide (LK-60)

[0525] Intermediate M57 (0.189 mmol, 55 mg) and intermediate M100 (0.189 mmol, 46 mg) were added into isopropanol (3 mL) and warmed to 95 °C for 9 h. After the reaction was completed, it was cooled to room temperature and purified by column chromatography (DCM:MeOH = 15:1) after solvent evaporation to give 72 mg of white solid in 77% yield. 1 H NMR (500 MHz, DMSO-d6) δ 10.04 (br s, 1H), 9.03 (s, 1H), 8.61 (d, J = 6.0 Hz, 1H), 8.28 (s, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.46 (dd, J = 11.3, 1.8 Hz, 1H), 7.22 (s, 1H), 7.02 (d, J = 6.0 Hz, 1H), 3.93 - 3.80 (m, 1H), 3.25 - 3.05 (m, 4H), 2.26 (ddd, J = 13.2, 8.2, 4.9 Hz, 1H), 1.25 - 1.19 (m, 2H), 0.98 - 0.93 (m, 2H). ESI-HRMS calcd for C 25 H 19 F3N3O3S [M+H] + :498.1094, found 498.1095.

[0526] Example 51

[0527] Synthesis of intermediate 4-chloro-6-(isopropylsulfonyl)quinolin-7-ol (M101)

[0528] 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 warmed to 100 °C for 4 h. After the reaction was completed, the pH was adjusted to 2-3 with 3N HCl and extracted with dichloromethane / n-butanol (3:1) mixed solvent and washed with saturated brine. The organic phase was concentrated and purified by column chromatography (DCM:MeOH = 20:1) to give 210 mg of yellow oil in 82% yield. 1H NMR (500 MHz, DMSO-d6) δ 8.85 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H), 7.67 (d, J = 4.7 Hz, 1H), 7.57 (s, 1H), 6.86 (s, 1H), 3.91 (hept, J = 6.8 Hz, 1H), 1.22 (d, J = 6.9 Hz, 6H).

[0529] Synthesis of intermediate 7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4- chloro-6-(isopropylsulfonyl)quinoline (M102)

[0530] 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 warmed to 50 °C for 3 hours. After completion of the reaction, ethyl acetate was extracted, washed with saturated brine and the organic phase was concentrated and purified by column chromatography (PE:EA = 1 : 1) to give 62 mg of colorless transparent oil with a yield of 50%.

[0531] Synthesis of intermediate N-(7-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6- (isopropylsulfonyl)quinolin-4-yl)-2-(3,3-difluorocyclobutyl)-7-fluorobenzo[d]oxazol-5- amine (M103)

[0532] Intermediate M102 (0.068 mmol, 30 mg) and intermediate M100 (0.068 mol, 17 mg) were dissolved in ethanol (1 mL), a catalytic amount of 6N HC1 was added and then warmed to 60 °C for 3 hours. After completion of the reaction, thin layer chromatography (DCM:MeOH = 20: 1) was used for purification to give 15 mg of yellow solid with a yield of 34%. 1 H NMR (500 MHz, Chloroform-d) δ 8.69 (s, 1H), 8.56 (d, J = 5.6 Hz, 1H), 7.57 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.15 (dd, J = 10.5, 1.9 Hz, 1H), 6.85 (d, J = 5.5 Hz, 1H), 4.39 - 4.30 (m, 2H), 4.16 - 4.03 (m, 3H), 3.72 (qd, J = 8.9, 2.6 Hz, 1H), 3.27 - 3.07 (m, 4H), 1.35 (d, J = 6.8 Hz, 6H), 0.93 (s, 9H), 0.13 (s, 6H).

[0533] Synthesis of compound 2-(4-((2-(3,3-difluorocyclobutyl)-7-fluorobenzo[d]oxazol-5-yl)amino)-6- (isopropylsulfonyl)quinolin-7-yl)oxy)ethan-1-ol (LK-61)

[0534] Intermediate M103 (0.023 mmol, 15 mg) was dissolved in tetrahydrofuran (1 mL), 1M tetrabutylammonium fluoride (0.062 mmol, 62 μL) was added dropwise at 0 °C, then the reaction was allowed to warm to room temperature for 2 hours. After the reaction was completed, the organic phase was concentrated, and purified by reverse phase HPLC (column type: 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 minutes, 50% - 65% B - 10 minutes; 65% - 100% B - 7 minutes; flow rate: 10 mL / minute) to give LK-61 as a white solid 2 mg as trifluoroacetate salt in 16% yield. 1 H NMR (500 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.24 (s, 1H), 8.51 (dd, J = 11.9, 7.2 Hz, 1H), 7.63 - 7.50 (m, 2H), 6.79 (dd, J = 7.2, 5.1 Hz, 1H), 4.37 (q, J = 4.0, 3.4 Hz, 2H), 4.05 (dq, J = 13.8, 6.8 Hz, 1H), 3.92 - 3.84 (m, 3H), 3.29 - 3.17 (m, 2H), 3.17 - 3.06 (m, 2H), 1.24 (d, J = 6.6 Hz, 6H). ESI-HRMS calcd for C 25 H 25 F3N3O5S [M+H] + : 536.1462, found 536.1462.

[0535] Pharmacology Experimental Section

[0536] Test Example 1: Inhibition activity of the compounds of the present application on the level of RIPK3 enzyme

[0537] In this example, the sequence of human RIPK3 kinase domain (2-328) with 6xHis and TEV tag at N-terminus and 10xHis tag at C-terminus was cloned into pFastBacHT B vector (Invitrogen). Bacmid was generated in DH10Bac cells using Bac-to-Bac system, and then baculovirus was produced and amplified in Sf-9 insect cells. Sf-9 insect cells were collected 72 hours after infection with baculovirus and lysed in lysis buffer containing 25 mM Tris (pH 7.8), 500 mM NaCl, 5% glycerol, 5 mM β-mercaptoethanol and protease inhibitors. The lysate was incubated with Ni-NTA beads (GE Healthcare) on ice for 30 minutes, and then centrifuged at 1000 rpm for 5-10 minutes to obtain the precipitate as the resin of bound protein. Then it was 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. Further molecular exclusion chromatography was used to obtain high-purity target protein (purity > 95%) for subsequent experiments.

[0538] 1. Determination of the inhibition rate of a compound on RIPK3 at a specific concentration

[0539] Specific method: The pre-phosphorylation reaction system was set as follows:

[0540] The compound was set at a fixed concentration (1 μM, 100 nM, 10 nM). After the addition of ATP, incubate at room temperature for 40 minutes. Then add 5 μL of pre-incubation system and 5 μL of ADP-Glo Reagent to each well of the 384-well plate and incubate at room temperature for 1 hour. Add 10 μL of Kinase Detection Reagent to each well and incubate at room temperature for 40 minutes, and then read the fluorescence value.

[0541] 2. Determination of the IC of a compound inhibiting RIPK3 50

[0542] Specific method: The pre-phosphorylation reaction system was set as follows:

[0543] The compound was set at a concentration gradient (10 μM, 1 μM, 100 nM, 10 nM, 1 nM, 0.1 nM, 0.01 nM). After the addition of ATP, incubate at room temperature for 40 minutes. Then add 5 μL of pre-incubation system and 5 μL of ADP-Glo Reagent to each well of the 384-well plate and incubate at room temperature for 1 hour. Add 10 μL of Kinase Detection Reagent to each well and incubate at room temperature for 40 minutes, and then read the fluorescence value.

[0544] ​The experimental results are shown in Table 1. The compound provided by the application can effectively inhibit the kinase activity of RIPK3, and the inhibition activity of some compounds is comparable to that of the positive compound GSK872. (IC 50 Values are represented by A, B, C, wherein, 0nM < A < 100nM; 100nM < B < 1 μM; 1 μM < C < 10 μM

[0545] Table 1 Inhibition activity of the compound of the application on RIPK3 enzyme level

[0546] Test Example 2: Anti-programmed cell necrosis activity determination of the compound of the application in cells

[0547] In this test example, the anti-programmed cell necrosis activity of the compound was evaluated in HT29 (human colon cancer cells) and L929 cells (mouse fibroblasts).

[0548] Test method: HT29 and L929 cells from ATCC were used, and 96-well plates were plated at a density of 100,000 cells / mL, 100 μL per well. Z-VAD-FMK (20 μM and 10 μM for HT29 cells and L929 cells, respectively) and the compound were pre-incubated for 1 hour every other day, and model drugs were added to induce cell necrosis (HT29 cells were induced at 100 nM SM164 + 40 μg / mL h-TNF-α, and L929 cells were induced at 20 μg / mL m-TNF-α). After 16-18 hours, CCK8 detection solution was added, and the absorbance was detected at 450 nm after incubation at 37°C for 1 hour.

[0549] The experimental results are shown in Table 2. The compound provided by the application has good anti-necrosis activity in HT29 cells and L929 cells. Some compounds have cell activity comparable to or even better than the positive compound GSK872. (EC 50 Values are represented by A, B, C, wherein, 0nM < A < 1 μM; 1 μM < B < 10 μM; 10 μM < C < 25 μM; D > 25 μM; ND, not detected

[0550] Table 2 Anti-programmed cell necrosis activity determination of the compound of the application

[0551] Test Example 3: Effect of the compound of the application on the apoptosis signaling pathway

[0552] The compounds designed in this test example are as follows:

[0553] The structures of the comparative compounds are as follows:

[0554] Test method: L929 cells from ATCC were used, 40,000 cells / mL were plated in 12-well plates, 1 mL per well, and compounds were added every other day. The group was set to 10 μM, 20 μM, 20 μM + z-VAD-FMK. The control group was added with the same concentration of DMSO. After 3 hours of incubation, the cells were lysed to prepare samples. Western Blot experiment was used to investigate the expression of caspase-3 and caspase-8 cleavage form proteins.

[0555] The experimental results are shown in Figures 1 to 3. Without caspase inhibitor z-VAD, the compounds in the DB group (DB-1, DB-2, DB-3) can significantly promote the cleavage of caspase-3 and caspase-8, showing the activation of the apoptosis pathway. The representative compounds (LK-16, LK-18, LK-25, LK-48, LK-49) provided by the present application do not significantly promote the activation of caspase at different concentrations, showing that the present series of compounds have the advantage of avoiding the side effect of apoptosis compared with common RIPK3 inhibitors.

[0556] Test Example 4:

[0557] Test method: EC of compounds on L929 cells 50 The test method is referred to Test Example 2.

[0558] Cytotoxicity CC 50 Test method: L929 cells from ATCC were used, 100,000 cells / mL were plated in 96-well plates, 100 μL per well, and the test compounds were 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), and z-VAD group (L929 cells with a concentration of 20 μM) was set to incubate with the compounds at the same time (compound concentration gradient is set as before). After 16-18 hours, CCK8 detection solution was added, and after 1 hour of incubation at 37 degrees Celsius, the absorbance was detected at 450 nm. Cell survival rate = inhibitor reading value / control group reading value*100%, and the cell CC 50 value was fitted according to the cell survival rate.

[0559] The experimental results are shown in Table 3. DB-1 and DB-2 caused apoptosis at high concentrations, resulting in generally larger cytotoxicity. The compounds LK-18 and LK-25 of the present application do not cause the activation of the apoptosis pathway, and the CC 50 values are all greater than 10 μM, thereby greatly improving the treatment window, and the CC 50 / EC 50 ratio reaches more than 25 times.

[0560] Table 3 EC50, CC50values of the compounds of the application and positive compounds

[0561] Test Example 5: Effect of the compounds of the application on Caspase 3 activity

[0562] Test method: L929 cells from ATCC were used, 12-well plates were plated at a density of 40W cells / mL, and 24h later the compounds were given, GSK872 at a concentration of 10 μΜ, and the rest of the compounds at a concentration of 20 μΜ. Three hours after administration, the cell samples were collected, first digested with trypsin and collected in a prepared cell culture medium, centrifuged at 600 g, 4°C for 5 minutes to collect the cells, the supernatant was carefully aspirated, and washed once with PBS. After aspirating the supernatant as before, the lysis buffer was added at a ratio of 100 μL of lysis buffer per 2 million cells, the pellet was resuspended, and lysed for 15 minutes on ice. The reaction system was set up as follows:

[0563] After adding Ac-DEVD-pNA, incubate overnight at 37°C, and the next day measure the absorbance at 405 nm.

[0564] The experimental results are shown in Table 4, the compounds in the DB group (DB-1, DB-2) can significantly cause activation of caspase 3, showing that the inhibitors have the side effect of activating apoptosis, while the series of compounds provided by the application hardly cause activation of caspase 3 in cells, indicating that the series of compounds have the unique advantage of avoiding the side effect of apoptosis.

[0565] Table 4 Effect of the compounds of the application on Caspase-3 activity

[0566] Test Example 5: Evaluation of the anti-necrosis activity of the compounds on the non-canonical necrosis pathway of viral infection and inflammatory diseases such as enteritis

[0567] Test method: mouse-ZBP1 stable MEF cells constructed by a conventional method were used, 12-well plates were plated at a density of 400,000 cells / mL, 1 mL per well, and the compounds (10 μΜ) and z-VAD (10 μΜ) were added every other day for one hour of co-incubation, the control group was added with the same concentration of DMSO, and then the inducer CBL0137 (CAS No: 1197397-89-9, 5 μΜ) was added for 4-6 hours of incubation, and the cells were lysed to prepare samples. The phosphorylation of MLKL and the expression amount of the caspase-3 cleavage form of protein were investigated by Western Blot experiment.

[0568] The experimental results are shown in Figure 4. The compounds of the present application significantly inhibit the phosphorylation of MLKL, indicating that the compounds of the present application can inhibit the activation of the necrosis pathway mediated by ZBP-1 (a sensor that recognizes viral Z-DNA), suggesting that the compounds of the present application have a protective effect in antiviral defense and inflammatory diseases.

[0569] Test Example 6: Evaluation of the effect of the compounds on the survival rate of mouse lung epithelial cells necrosis caused by influenza virus

[0570] Test method: THP-1 PMA cells were inoculated with influenza A virus PR8 strain (MOI = 2) for 1 hour, and serum-free medium was used during the infection process. After the infection was completed, the virus solution was removed, the cells were washed, and fresh medium containing different inhibitors (compounds of the present application, 1 μM) was replaced. The control group was added with the same concentration of DMSO, and after 3 hours of incubation, the cells were lysed for sample preparation. The degree of phosphorylation of RIPK3 was investigated by Western Blot experiment.

[0571] The experimental results show that the compounds of the present application (such as LK-34 and LK-60, etc.) can significantly inhibit the phosphorylation of RIPK3 at a concentration of 1 μM, suggesting that the compounds of the present application have a significant protective effect on cell necrosis induced by viral infection.

[0572] All the documents mentioned in the present application are cited as references in the present application, just as each document is cited as a reference individually. In addition, it should be understood that those skilled in the art can make various modifications or changes to the present application after reading the above teachings of the present application, and these equivalent forms also fall within the scope defined by the claims attached to the present application.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotope derivative, or combination thereof; wherein, X1is selected from the group consisting of S, O, CH, N or NH; X2is selected from the group consisting of C, CH or N; U1, U2and U3are each independently selected from the group consisting of N or CH; wherein, at most two of U1, U2and U3are N; Ring B is selected from a five-membered heteroaromatic ring; R1is selected from the group consisting of halogen, deuterium, cyano, hydroxyl, -NRaRb, nitro, amino, linear or branched C1-C 10 alkyl, linear or branched C1-C 10 alkoxy, linear or branched C1-C 10 alkylthio, C3-C 10 cycloalkyl, C3-C 10 oxacycloalkyl, C3-C 10 thiocycloalkyl, linear or branched C2-C 10 alkenyl, linear or branched C2-C 10 alkynyl, 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 heterocyclyl; wherein Raand Rbare each independently selected from the group consisting of C1-C 10 alkyl, C3-C 10 cycloalkyl, C6-C 10 Rais selected from the group consisting of hydrogen, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, benzyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, -(halo or non-halo substituted C1-C6alkylene)-C3-C6cycloalkyl, -(halo or non-halo substituted C1-C6alkylene)-phenyl, -(halo or non-halo substituted C1-C6alkylene)-5-6 membered heteroaryl, -(halo or non-halo substituted C1-C6alkylene)-4-7 membered heterocyclyl, -O-C3-C6cycloalkyl, -O-phenyl, -O-5-6 membered heteroaryl, -O-(4-7 membered heterocyclyl), -S-(C3-C6cycloalkyl), -S-phenyl, -S-(5-6 membered heteroaryl), -S-(4-7 membered heterocyclyl), -NH-(C3-C6cycloalkyl), -NH-phenyl, -NH-(5-6 membered heteroaryl), -NH-(4-7 membered heterocyclyl), -NH-C(O)-(C3-C6cycloalkyl), -C(O)-NH-(C3-C6cycloalkyl), -(halo or non-halo substituted C1-C6alkylene)-O-C3-C6cycloalkyl, -(halo or non-halo substituted C1-C6alkylene)-O-phenyl, -(halo or non-halo substituted C1-C6alkylene)-O-5-6 membered heteroaryl, -(halo or non-halo substituted C1-C6alkylene)-O-4-7 membered heterocyclyl; Ring A is a 6-membered aromatic or heteroaromatic ring, and at any substitutable position, Ring A is substituted with 1-3 R2which are the same or different; 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 is a bond, -NH-, -0-, -N(R x )-, -(CH2) m -, x -(CHR m )-, -(C(R x )2) m -; m is 1, 2, 3, 4, 5 or 6; each R x each independently is selected from the group consisting of H, halogen, C1-C6alkyl, C3-C6cycloalkyl, -S(O)2-(C1-C4alkyl), or -C(=O)-(C1-C4alkyl), wherein said alkyl and cycloalkyl are optionally substituted with one or more groups selected from the group consisting of D, halogen, cyano, hydroxy, oxo(=O), amino, C1-C4alkyl, C1-C4alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, C3-C6cycloalkyl; Z has the structure shown in Formula (II): wherein, V1, V2, V3, V4and V5are each independently N, CH or C, wherein at most 3 of V1, V2, V3, V4and V5are N; Y is CH or N; n is 0 or 1; R9is selected from the group consisting of null, hydrogen, deuterium, halogen, nitro, amine, amide, cyano, amino, C1-C6alkyl, C1-C6alkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, benzyl, and substituted with one or more of halogen, deuterium, C1-C6alkyl and C1-C6alkoxy; 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, R4and R7, R4and R8, R3and R6, R3and R4, or R4and R5, and the atoms to which they are attached, collectively form a cyclic structure selected from the group consisting of C6-Ci0aryl, C3-Ci0cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl; 10 C3-Ci0cycloalkyl, 4-10 membered heterocycloalkyl, and 5-10 membered heteroaryl; 11 carbocyclic, 4-11 membered heterocyclic, or 5-11 membered heteroaromatic ring; wherein, the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heterocyclic ring, heteroaromatic ring, aromatic ring and carbocyclic ring are optionally substituted with one or more groups selected from deuterium, halogen, cyano, hydroxyl, nitro, oxo (=0), amino, C1-C6alkyl, C1-C6alkoxy, C3-C7cycloalkyl, phenyl, 4-7 membered heterocyclyl, 5-6 membered heteroaryl, -(halogenated or non-halogenated C1-C6alkylene)-C3-C7cycloalkyl, -(halogenated or non-halogenated C1-C6alkylene)-phenyl, -(halogenated or non-halogenated C1-C6alkylene)-5-6 membered heteroaryl, -(halogenated or non-halogenated C1-C6alkylene)-4-7 membered heterocyclyl; or any two substituents on the same or different positions of the heterocyclic ring, heteroaromatic ring, aromatic ring and carbocyclic ring form a spiro, bridged or fused ring structure with the atoms to which they are commonly attached.

2. The compound of claim 1, wherein The compounds have structures according to Formula I-A, Formula I-B, Formula I-C, and Formula I-D: wherein, X1, X2, U1, U2, U3, R1, R2, Z and R x As in claim 1.

3. The compound of claim 1, wherein When n is 0, Z has the following structure: When n is 1, Z has the following structure: wherein, R3, R4, R5, R6and R9are as described in claim 1.

4. The compound of claim 1, wherein The compounds have a structure according to Formula I-A1 : wherein, X1is selected from S, O, CH and N; X2is selected from C and N; Y is selected from N or CH; Ring B is selected from 5-membered heteroaryl; and R x , R1, R2, R3, R4, and R9 are as described in claim 1.

5. The compound of claim 1, wherein R1is selected from the group consisting of halogen, deuterium, cyano, hydroxyl, -NR a R b , nitro, amino, linear or branched C1-C6alkyl, linear or branched C1-C6alkoxy, linear or branched C1-C6alkylthio, C3-C7cycloalkyl, C3-C7oxacycloalkyl, C3-C7thiacycloalkyl, linear or branched C2-C6alkenyl, linear or branched C2-C6alkynyl, C3-C6cycloalkenyl, -C(=O)-(C1-C6alkyl), -S(O)2-(C1-C6alkyl), -NH-C(O)-(C1-C6alkyl), -C(O)-NH-(C1-C6alkyl), C6-C 10 aryl, 5-11 membered heteroaryl, 4-11 membered heterocyclyl; wherein Raand Rbare each independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C6-C 10 aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, or Raand Rb, together with the N atom to which they are both attached, form a 4-9 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing from 1 to 3 heteroatoms each independently selected from N, O and S; wherein said alkyl, alkoxy, alkylthio, cycloalkyl, oxacycloalkyl, thiacycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from halogen, deuterium, oxo (=0), hydroxyl, cyano, nitro, amino, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C6hydroxyalkyl, C3-C6cycloalkyl, benzyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl, -(halo or non-halo C1-C4alkylene)-C3-C6cycloalkyl, -(halo or non-halo C1-C4alkylene)-phenyl, -(halo or non-halo C1-C4alkylene)-5-6 membered heteroaryl, -(halo or non-halo C1-C4alkylene)-4-7 membered heterocyclyl, -0-C3-C6cycloalkyl, -0-phenyl, -0-5-6 membered heteroaryl, -0-(4-7 membered heterocyclyl), -S-(C3-C6cycloalkyl), -S-phenyl, -S-(5-6 membered heteroaryl), -S-(4-7 membered heterocyclyl), -NH-(C3-C6cycloalkyl), -NH-phenyl, -NH-(5-6 membered heteroaryl), -NH-(4-7 membered heterocyclyl), -NH-C(O)-(C3-C6cycloalkyl), -C(O)-NH-(C3-C6cycloalkyl), -(halo or non-halo C1-C4alkylene)-0-C3-C6cycloalkyl, -(halo or non-halo C1-C4alkylene)-0-phenyl, -(halo or non-halo C1-C4alkylene)-0-5-6 membered heteroaryl, -(halo or non-halo C1-C4alkylene)-0-4-7 membered heterocyclyl; Preferably, R1is selected from the group consisting of halogen, deuterium, cyano, -NRaRb, hydroxyl, nitro, amino, linear or branched C1-C6alkyl, linear or branched C1-C6alkoxy, C3-C6cycloalkyl, linear or branched C2-C6alkenyl, linear or branched C2-C6alkynyl, -C(=0)-(C1-C6alkyl), 4-7 membered heterocyclyl or 5-6 membered heteroaryl; wherein Raand Rbare each independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, phenyl, 5-6 membered heteroaryl or 4-7 membered heterocyclyl, or Raand Rb, together with the N atom to which they are both attached, form a 4-7 membered heterocyclic ring or a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms each independently selected from N, O and S; wherein said alkyl, alkoxy, alkylthio, cycloalkyl, oxacycloalkyl, thiacycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups selected from halogen, deuterium, oxo (=0), hydroxyl, cyano, nitro, C1-C6alkyl, haloC1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C6hydroxyalkyl or C3-C6cycloalkyl.

6. The compound of claim 1, wherein The compound is selected from the group consisting of:

7. A pharmaceutical composition, characterized by, A pharmaceutical composition comprising, as an active ingredient, one or more compounds of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, hydrate, prodrug, isotope derivative, or combination 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 manufacture of a medicament for treating and / or preventing a necroptosis and inflammation related disease.

9. The use according to claim 8, characterized in that, The necroptosis and inflammation related disease is preferably a disease caused by abnormal RIPK3 activity level and / or expression level; more preferably, the disease caused by abnormal RIPK3 activity level and / or expression level is selected from the group consisting of 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 disease, tumor, immune aging, viral infection, heat stroke, aging, platelet thrombosis, 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 a pharmaceutical composition of claim 7, in the manufacture of a RIPK3 inhibitor.

Images