Isoindolinone derivatives, processes for their preparation and use thereof

Abstract

The present disclosure belongs to the technical field of biological medicine, and particularly relates to isoindolinone derivatives, a preparation method and application thereof. The present disclosure has the following advantages: the compound of formula (II) has a strong inhibitory effect on TLR7 activity.

Description

TECHNICAL FIELD

[0001] The present disclosure belongs to the technical field of biological medicine, and particularly relates to isoindolinone derivatives and a preparation method and application thereof. BACKGROUND

[0002] Toll-like receptors (TLRs) are important protein molecules involved in non-specific immunity (innate immunity) and are also a bridge connecting non-specific immunity and specific immunity. TLR7 (Toll-like receptor 7) in the TLR family is an important member of the Toll-like receptor (TLR) family, is a type I transmembrane protein, is located on the endosomal membrane, and can recognize single-stranded RNA (ssRNA) viruses (such as HIV, influenza virus) or self RNA (such as RNA from apoptotic cells). TLR7 activates NF-κB and IRF7 through a MyD88-dependent signaling pathway, induces the production of pro-inflammatory cytokines and type I interferons, and drives innate and adaptive immune responses. Excessive activation of TLR7 can lead to abnormal recognition of self RNA, trigger a pathological interferon response, promote the production of autoantibodies, and thus trigger the occurrence and progression of systemic lupus erythematosus (SLE), and an increase in the copy number of TLR7 genes is associated with the severity of SLE. TLR7 has important application prospects in the fields of anti-tumor therapy, autoimmune disease research, and the like.

[0003] Therefore, there is still a need to develop compounds having inhibitory effects on TLR7 activity and a preparation method thereof. SUMMARY

[0004] The present disclosure aims to propose isoindolinone derivatives and a preparation method and application thereof. The isoindolinone derivatives of the present disclosure have strong inhibitory effects on TLR7 activity.

[0005] To achieve the above technical purposes, the technical solution adopted by the present disclosure is as follows:

[0006] In one aspect, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer thereof,

[0007] (I)

[0008] wherein,

[0009] R1 is a five-membered unsaturated ring or a six-membered unsaturated ring to form a bicyclic fused ring structure;

[0010] R2 is selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl;

[0011] R3is selected from hydrogen, piperidine, pyridine, pyrazole, imidazole, pyrrole, pyridazine, pyrimidine, aziridine, azetidine, tetrahydropyrazole, tetrahydroimidazole, tetrahydropyrrole, piperazine, or hexahydropyrazine; the piperidine, pyridine, pyrazole, imidazole, pyrrole, pyridazine, pyrimidine, aziridine, azetidine, tetrahydropyrazole, tetrahydroimidazole, tetrahydropyrrole, piperazine, hexahydropyrazine is optionally substituted with one or more hydrogen, C 1-6 alkyl, -(CH2) 1-6 C(=O)NH2, -C(=O)NHC 1-6 alkyl, tetrahydrofuran, oxirane, oxetane, tetrahydropyran, dioxane, halogen, hydroxyl, cyano, C 1-6 alkoxy, C 1-6 haloalkyl, C 2-6 ester, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl.

[0012] In another aspect, the present disclosure provides a compound represented by Formula (II) or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, mixture of stereoisomers, or mixture of tautomers thereof,

[0013] (II)

[0014] wherein,

[0015] ring W is a six-membered unsaturated ring;

[0016] X is selected from one of C, CH, N, O, or S;

[0017] when X is selected from C or N, R 11 is a substituent at the X position;

[0018] R 11 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl;

[0019] Y is a substituent at a position other than the X position in ring W;

[0020] Y is selected from hydrogen, oxo, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy;

[0021] ring A is selected from absent, a five-membered unsaturated ring, or a six-membered unsaturated ring;

[0022] RA a substituent for a substitutable position on ring A;

[0023] R A selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl;

[0024] ring B is selected from the absence, a five-membered unsaturated ring, or a six- membered unsaturated ring;

[0025] R B a substituent for a substitutable position on ring B;

[0026] R B selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl;

[0027] R2is selected from hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy;

[0028] R3is selected from hydrogen, piperidine, pyridine, pyrazole, imidazole, pyrrole, pyridazine, pyrimidine, aziridine, azetidine, tetrahydropyrazole, tetrahydroimidazole, tetrahydropyrrole, piperazine, or hexahydropyrazine; the piperidine, pyridine, pyrazole, imidazole, pyrrole, pyridazine, pyrimidine, aziridine, azetidine, tetrahydropyrazole, tetrahydroimidazole, tetrahydropyrrole, piperazine, hexahydropyrazine is optionally substituted with one or more hydrogen, C 1-6 alkyl, -(CH2) 1-6 C(=O)NH2, -C(=O)NHC 1-6 alkyl, tetrahydrofuran, oxirane, oxetane, tetrahydropyran, dioxane;

[0029] when ring A is present, ring W forms a fused ring structure with ring A through a shared chemical bond;

[0030] when ring B is present, ring W forms a fused ring structure with ring B through a shared chemical bond.

[0031] In another aspect, the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, mixture of stereoisomers, or mixture of tautomers thereof,

[0032] (II)

[0033] wherein,

[0034] Ring W is a six-membered unsaturated ring;

[0035] X is selected from one of C, CH, N, O, or S;

[0036] R is a substituent at the X position; 11 is a substituent at the X position;

[0037] R is a substituent at the X position; 11 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl;

[0038] Y is a substituent at a position on ring W other than the X position;

[0039] Y is selected from hydrogen, oxo, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy;

[0040] Ring A is selected from absent, a five-membered unsaturated ring, or a six- membered unsaturated ring;

[0041] R is a substituent at a position on ring A; A is a substituent at a position on ring A;

[0042] R is a substituent at a position on ring A; A is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl;

[0043] Ring B is selected from absent, a five-membered unsaturated ring, or a six- membered unsaturated ring;

[0044] R is a substituent at a position on ring B; B is a substituent at a position on ring B;

[0045] R is a substituent at a position on ring B; B is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl;

[0046] R2is selected from hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy;

[0047] R3is selected from hydrogen, piperidine, pyridine, pyrazole, imidazole, pyrrole, pyridazine, pyrimidine, aziridine, azetidine, tetrahydropyrazole, tetrahydroimidazole, tetrahydropyrrole, piperazine, or hexahydropyrazine; said piperidine, pyridine, pyrazole, imidazole, pyrrole, pyridazine, pyrimidine, aziridine, azetidine, tetrahydropyrazole, tetrahydroimidazole, tetrahydropyrrole, piperazine, hexahydropyrazine is optionally substituted with one or more hydrogen, C 1-6 alkyl, -(CH2) 1-6 C(=O)NH2, -C(=O)NHC 1-6 alkyl, tetrahydrofuran, oxirane, oxetane, tetrahydropyran, dioxane;

[0048] when ring A is present, ring W forms a fused ring structure with ring A through a shared chemical bond;

[0049] when ring B is present, ring W forms a fused ring structure with ring B through a shared chemical bond;

[0050] only one of said ring A, ring B is present.

[0051] In some embodiments of the present disclosure, the compound has a structure represented by formula (III):

[0052] (III)

[0053] wherein,

[0054] X, X1, X2, X3are each independently selected from one of C, CH, or N;

[0055] when X is selected from C or N, R 11 is a substituent at the position of X;

[0056] Y is a substituent at one of the substitutable positions of ring W other than the position of X;

[0057] ring W is selected from a six-membered unsaturated aromatic ring or a six-membered unsaturated nitrogen heterocycle;

[0058] ring A is selected from none, a six-membered unsaturated aromatic ring, or a six-membered unsaturated nitrogen heterocycle;

[0059] ring B is selected from none, a five-membered unsaturated aromatic ring, a six-membered unsaturated aromatic ring, a five-membered unsaturated nitrogen heterocycle, or a six-membered unsaturated nitrogen heterocycle;

[0060] n is an integer from 0 to 3;

[0061] Y, R 11 , R A , R B , R2, R3are each defined as defined in formula (II);

[0062] “ represents a single or double bond.

[0063] In some embodiments of the present disclosure, the compound has a structure represented by Formula (III):

[0064] (III)

[0065] wherein,

[0066] X, X1, X2, X3are each independently selected from one of C, CH or N;

[0067] R is a substituent at the X position when X is selected from C or N; 11

[0068] Y is a substituent at a position in ring W other than the X position;

[0069] Ring W is selected from a six-membered unsaturated aromatic ring or a six-membered unsaturated nitrogen heterocycle;

[0070] Ring A is selected from absent, a six-membered unsaturated aromatic ring or a six-membered unsaturated nitrogen heterocycle;

[0071] Ring B is selected from absent, a five-membered unsaturated aromatic ring, a six-membered unsaturated aromatic ring, a five-membered unsaturated nitrogen heterocycle or a six-membered unsaturated nitrogen heterocycle;

[0072] There is and only one of the ring A, ring B;

[0073] n is an integer from 0 to 3;

[0074] Y, R 11 , R A , R B , R2, R3are each defined as defined in Formula (II);

[0075] represents a single or double bond.

[0076] In some embodiments of the present disclosure, the compound has a structure represented by Formula (IV):

[0077] (IV)

[0078] wherein,

[0079] X, X1, X2, X3are each independently selected from one of C, CH or N;

[0080] R is a substituent at the X position when X is selected from C or N; 11

[0081] Y is a substituent at a position in ring W other than the X position;​​​

[0082] Ring W is selected from a benzene ring or a pyridine ring;

[0083] Ring A is selected from the absence, a pyridine ring or a benzene ring;

[0084] Ring B is selected from the absence, a benzene ring, a pyridine ring, a triazole ring, a pyrazine ring, a pyrrole ring or an imidazole ring;

[0085] n is 0 or 1;

[0086] Y, R 11 , R A , R B , R2, R3 are each defined as defined in formula (II);

[0087] " " represents a single bond or a double bond. In some embodiments of the present disclosure, the compound has a structure shown in formula (IV):

[0088]

[0089] (IV) wherein,

[0090] X, X1, X2, X3 are each independently selected from one of C, CH or N;

[0091] R 11 is a substituent at the position of X;

[0092] Y is a substituent at a substitutable position other than the position of X in ring W;

[0093] Ring W is selected from a benzene ring or a pyridine ring;

[0094] Ring A is selected from the absence, a pyridine ring or a benzene ring;

[0095] Ring B is selected from the absence, a benzene ring, a pyridine ring, a triazole ring, a pyrazine ring, a pyrrole ring or an imidazole ring;

[0096] There is and only one of the ring A, ring B;

[0097] n is 0 or 1;

[0098] Y, R 11 , R A , R B , R2, R3 are each defined as defined in formula (II);

[0099] " " represents a single bond or a double bond.

[0100]

[0101] ​​In some embodiments of this disclosure, one and only one of ring A and ring B may exist.

[0102] In some embodiments of this disclosure, the compound has the structure shown in formula (V):

[0103] (V)

[0104] in,

[0105] X and X1 are each independently selected from C, CH or N;

[0106] When X is selected from C or N, R 11 The substituent is at the X position;

[0107] Y is a substituent at a position in ring W other than the X position that can be substituted;

[0108] Ring W is selected from a benzene ring or a pyridine ring;

[0109] Ring A is selected from a pyridine ring or a benzene ring;

[0110] Y, R 11 R A R1, R2, and R3 are defined as described in equation (II) above;

[0111] “ " indicates a single or double key.

[0112] In some embodiments of this disclosure, the compound has the structure shown in formula (VI):

[0113] (VI)

[0114] in,

[0115] X, X2, and X3 are each independently selected from C, CH, or N;

[0116] When X is selected from C or N, R 11 The substituent is at the X position;

[0117] Y is a substituent at a position in ring W other than the X position that can be substituted;

[0118] Ring W is selected from a benzene ring or a pyridine ring;

[0119] Ring B is selected from benzene ring, pyridine ring, triazole, pyrazine ring, pyrrole ring, or imidazole ring;

[0120] n is 0 or 1;

[0121] Y, R 11 R BR2, R3are each defined as defined previously in formula (II);

[0122] " represents a single or double bond. " represents a single or double bond.

[0123] In some embodiments of the present disclosure, R1is selected from , , , , , , , ; wherein, R 11 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl; Y is selected from hydrogen, oxo, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy.

[0124] In some embodiments of the present disclosure, R1is selected from , , , , , , , .

[0125] In some embodiments of the present disclosure, R2is selected from hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy.

[0126] In some embodiments of the present disclosure, R2is selected from hydrogen, C 1-6 haloalkyl, halogen, hydroxyl, cyano, C 1-6 alkyl.

[0127] In some embodiments of the present disclosure, R2is selected from hydrogen, C 1-6 haloalkyl, halogen, C 1-6 alkyl.

[0128] In some embodiments of the present disclosure, R2is selected from hydrogen, C 1-3 haloalkyl, halogen, C 1-3 alkyl.

[0129] In some embodiments of the present disclosure, R2is selected from hydrogen, C 1-3 haloalkyl, C 1-3 alkyl.

[0130] In some embodiments of the disclosure, R2is selected from hydrogen, C 1-3 haloalkyl.

[0131] In some embodiments of the disclosure, R2is selected from hydrogen, C 1-3 fluoroalkyl.

[0132] In some embodiments of the disclosure, R2is selected from hydrogen, C 1-2 fluoroalkyl.

[0133] In some embodiments of the disclosure, R2is selected from hydrogen, trifluoromethyl, difluoromethyl, monofluoromethyl.

[0134] In some embodiments of the disclosure, R2is selected from hydrogen, trifluoromethyl.

[0135] In some embodiments of the disclosure, R2is trifluoromethyl.

[0136] In some embodiments of the disclosure, R3is selected from hydrogen, piperidine, pyridine, pyrazole, imidazole, pyrrole, pyridazine, pyrimidine, aziridine, azetidine, tetrahydropyrazole, tetrahydroimidazole, tetrahydropyrrole, piperazine, or hexahydropyrazine; the piperidine, pyridine, pyrazole, imidazole, pyrrole, pyridazine, pyrimidine, aziridine, azetidine, tetrahydropyrazole, tetrahydroimidazole, tetrahydropyrrole, piperazine, hexahydropyrazine is optionally substituted with one or more hydrogen, C 1-6 alkyl, -(CH2) 1-6 C(=0)NH2, -C(=0)NHC 1-6 alkyl, tetrahydrofuran, oxirane, oxetane, tetrahydropyran, dioxane.

[0137] In some embodiments of the disclosure, R3is selected from hydrogen, piperidine, pyridine, pyrazole; the piperidine, pyridine, pyrazole is optionally substituted with one hydrogen, C 1-6 alkyl, -(CH2) 1-6 C(=0)NH2, -C(=0)NHC 1-6 alkyl, tetrahydrofuran, oxirane, oxetane, tetrahydropyran, dioxane.

[0138] In some embodiments of the disclosure, R3is selected from hydrogen, piperidine, pyridine, pyrazole; the piperidine, pyridine, pyrazole is optionally substituted with one hydrogen, C 1-5 alkyl, -(CH2) 1-5 C(=0)NH2, -C(=0)NHC 1-5 alkyl, tetrahydrofuran, oxirane, oxetane, tetrahydropyran, dioxane.

[0139] In some embodiments of the disclosure, R3is selected from hydrogen, piperidine, pyridine, pyrazole; said piperidine, pyridine, pyrazole is optionally substituted with one hydrogen, C 1-3 alkyl, -(CH2) 1-3 C(=O)NH2, -C(=O)NHC 1-3 alkyl, tetrahydrofuran, oxirane, oxetane, tetrahydropyran, dioxane.

[0140] In some embodiments of the disclosure, R3is selected from hydrogen, piperidine, pyridine, pyrazole; said piperidine, pyridine, pyrazole is optionally substituted with one hydrogen, C 1-3 alkyl, -(CH2) 1-3 C(=O)NH2, -C(=O)NHC 1-3 alkyl, tetrahydrofuran.

[0141] In some embodiments of the disclosure, R3is selected from hydrogen, piperidine, pyridine, pyrazole; said piperidine, pyridine, pyrazole is optionally substituted with one hydrogen, C 1-2 alkyl, -(CH2) 1-2 C(=O)NH2, -C(=O)NHC 1-2 alkyl, tetrahydrofuran.

[0142] In some embodiments of the disclosure, R3is selected from hydrogen, piperidine, pyridine, pyrazole; said piperidine, pyridine, pyrazole is optionally substituted with one hydrogen, methyl, -(CH2)C(=O)NH2, -C(=O)NHCH3, substituted.

[0143] In some embodiments of the disclosure, R3is selected from hydrogen, , , , , .

[0144] In some embodiments of the disclosure, ring W is a six-membered unsaturated aromatic ring or a six-membered unsaturated heterocyclic ring.

[0145] In some embodiments of the disclosure, ring W is selected from one of benzene ring, pyridine ring, pyran ring, thiopyran ring.

[0146] In some embodiments of the disclosure, ring W is selected from one of benzene ring, pyridine ring.

[0147] In some embodiments of the disclosure, X is selected from C, CH or N.

[0148] In some embodiments of the disclosure, R 11 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl.

[0149] In some embodiments of the disclosure, R 11 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy.

[0150] In some embodiments of the disclosure, R 11 is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl.

[0151] In some embodiments of the disclosure, R 11 is selected from hydrogen, halogen, cyano, C 1-6 alkyl.

[0152] In some embodiments of the disclosure, R 11 is selected from hydrogen, halogen, cyano, C 1-3 alkyl.

[0153] In some embodiments of the disclosure, R 11 is selected from hydrogen, halogen, cyano, methyl, ethyl.

[0154] In some embodiments of the disclosure, R 11 is selected from hydrogen, F, Cl, Br, cyano, methyl, ethyl.

[0155] In some embodiments of the disclosure, R 11 is selected from hydrogen, F, Cl, cyano, methyl, ethyl.

[0156] In some embodiments of the disclosure, R 11 is selected from hydrogen, Cl, cyano, methyl, ethyl.

[0157] In some embodiments of the disclosure, R 11 is selected from hydrogen, Cl, cyano, methyl.

[0158] In some embodiments of the disclosure, ring A is a 5-6 membered unsaturated aromatic ring or a 5-6 membered unsaturated heterocyclic ring.

[0159] In some embodiments of the disclosure, ring A is selected from one of a pyridine ring, a triazole, a pyrazine ring, a pyrrole ring, a pyridazine ring, a pyrimidine ring, an imidazole ring, a pyrazole ring, a benzene ring, a pyran ring, a thiopyran ring, a furan ring, and a thiophene ring.

[0160] In some embodiments of the disclosure, Ring A is selected from one of a pyridine ring, a triazole, a pyrazine ring, a pyrrole ring, a pyridazine ring, a pyrimidine ring, an imidazole ring, a pyrazole ring, a benzene ring.

[0161] In some embodiments of the disclosure, Ring A is selected from one of a pyridine ring, a triazole, a pyrazine ring, a pyrrole ring, a pyridazine ring, a pyrimidine ring, an imidazole ring, a pyrazole ring, a benzene ring.

[0162] In some embodiments of the disclosure, Ring A is selected from one of a pyridine ring, a triazole, a pyrazine ring.

[0163] In some embodiments of the disclosure, Ring A is a pyridine ring.

[0164] In some embodiments of the disclosure, R A is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl.

[0165] In some embodiments of the disclosure, R A is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy.

[0166] In some embodiments of the disclosure, R A is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl.

[0167] In some embodiments of the disclosure, R A is selected from hydrogen, halogen, cyano, C 1-6 alkyl.

[0168] In some embodiments of the disclosure, R A is selected from hydrogen, halogen, cyano, C 1-3 alkyl.

[0169] In some embodiments of the disclosure, R A is selected from hydrogen, C 1-3 alkyl.

[0170] In some embodiments of the disclosure, R A is selected from hydrogen, methyl, ethyl.

[0171] In some embodiments of the disclosure, R A is selected from hydrogen, methyl.

[0172] In some embodiments of the disclosure, R A is hydrogen.

[0173] In some embodiments of the disclosure, ring B is a 5-6 membered unsaturated aromatic ring or a 5-6 membered unsaturated heterocyclic ring.

[0174] In some embodiments of the disclosure, ring B is selected from one of a pyridine ring, a triazole, a pyrazine ring, a pyrrole ring, a pyridazine ring, a pyrimidine ring, an imidazole ring, a pyrazole ring, a benzene ring, a pyran ring, a thiopyran ring, a furan ring, a thiophene ring.

[0175] In some embodiments of the disclosure, ring B is selected from one of a pyridine ring, a triazole, a pyrazine ring, a pyrrole ring, a pyridazine ring, a pyrimidine ring, an imidazole ring, a pyrazole ring, a benzene ring.

[0176] In some embodiments of the disclosure, ring B is selected from one of a pyridine ring, a triazole, a pyrazine ring, a pyrrole ring, a pyridazine ring, a pyrimidine ring, an imidazole ring, a pyrazole ring.

[0177] In some embodiments of the disclosure, ring B is selected from one of a pyridine ring, a triazole, a pyrazine ring.

[0178] In some embodiments of the disclosure, R B is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl.

[0179] In some embodiments of the disclosure, R B is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy.

[0180] In some embodiments of the disclosure, R B is selected from hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl.

[0181] In some embodiments of the disclosure, R B is selected from hydrogen, halogen, cyano, C 1-6 alkyl.

[0182] In some embodiments of the disclosure, R B is selected from hydrogen, halogen, cyano, C 1-3 alkyl.

[0183] In some embodiments of the disclosure, R B is selected from hydrogen, C 1-3 alkyl.

[0184] In some embodiments of the disclosure, RB selected from hydrogen, methyl, ethyl.

[0185] In some embodiments of the disclosure, R B is selected from hydrogen, methyl.

[0186] In some embodiments of the disclosure, R B is hydrogen.

[0187] In some embodiments of the disclosure, Y is selected from hydrogen, oxo, halo, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy.

[0188] In some embodiments of the disclosure, Y is selected from hydrogen, oxo, halo, cyano, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy.

[0189] In some embodiments of the disclosure, Y is selected from hydrogen, oxo, C 1-3 alkyl.

[0190] In some embodiments of the disclosure, Y is selected from hydrogen, oxo, methyl, ethyl.

[0191] In some embodiments of the disclosure, Y is selected from hydrogen, oxo, methyl.

[0192] In some embodiments of the disclosure, Y is selected from hydrogen, oxo.

[0193] In some embodiments of the disclosure, the compound is selected from the following compounds:

[0194] (compound 1), (compound 2), (compound 3), (compound 4), (compound 5), (compound 6), (compound 7), (compound 8), (compound 9), (compound 10), (compound 11), (compound 12), (compound 13), (compound 14), (compound 15), (compound 16), (compound 17), (Compound 18), (Compound 19), (Compound 20), (Compound 21), (Compound 22), (Compound 23), (Compound 24), (Compound 25), (Compound 26), (Compound 27).

[0195] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound as described previously, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer thereof, optionally comprising a pharmaceutically acceptable excipient.

[0196] In another aspect, the present disclosure provides use of a compound as described previously, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer thereof, or a pharmaceutical composition as described previously, in the manufacture of a medicament for treating a TLR7-related disease.

[0197] In some embodiments of the present disclosure, the medicament is prepared into a pharmaceutical preparation for treating a TLR7-related disease; the pharmaceutical preparation comprises the compound shown in formula (II) and / or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer thereof as the only active ingredient.

[0198] In some embodiments of the present disclosure, the medicament is prepared into a pharmaceutical preparation for treating a TLR7-related disease; the pharmaceutical preparation comprises the compound shown in formula (II) and / or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer thereof, and further comprises a pharmaceutically acceptable excipient.

[0199] In some embodiments of the present disclosure, the pharmaceutically acceptable excipient comprises one or more of a solvent, a solubilizer, a cosolvent, an emulsifier, a flavoring agent, an odorant, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, a pH regulator, a stabilizer, a surfactant, a preservative.

[0200] The filler, also known as diluent, examples of the filler include, but are not limited to, wheat starch, tapioca starch, corn starch, potato starch, dextrin, microcrystalline cellulose, lactose, etc. Examples of the flavoring agent include, but are not limited to, steviol glycoside, glycyrrhizin, mogroside, acesulfame potassium, aspartame, sucralose, isomaltulose, etc. Examples of the lubricant include, but are not limited to, magnesium stearate, talc, micronized silica, magnesium lauryl sulfate, etc.

[0201] In some embodiments of the present disclosure, the drug is prepared into a pharmaceutical preparation for treating a TLR7-related disease; the pharmaceutical preparation comprises the compound represented by formula (II) and / or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers thereof, and one or more other drugs for treating a TLR7-related disease.

[0202] In some embodiments of the present disclosure, the pharmaceutical preparation is a solid preparation, a semi-solid preparation, or a liquid preparation.

[0203] In some embodiments of the present disclosure, the solid preparation is a tablet, a capsule, a granule, or a pill.

[0204] In some embodiments of the present disclosure, the semi-solid preparation is a gel, a suppository, or a paste.

[0205] In some embodiments of the present disclosure, the liquid preparation is an emulsion, a mixture, a suspension, or a solution.

[0206] In some embodiments of the present disclosure, the drug is a tablet, a capsule, a granule, a dripping pill, an injection, a syrup, a powder, a chewable tablet, a gel, and a suppository.

[0207] In some embodiments of the present disclosure, the drug is administered by one or more of oral administration, sublingual administration, intravenous administration, transdermal administration, rectal administration, inhalation administration, intraperitoneal administration, or intramuscular administration.

[0208] In some embodiments of the present disclosure, the drug is administered by one or more of oral administration, sublingual administration, intravenous administration, transdermal administration, rectal administration.

[0209] In some embodiments of the present disclosure, the drug is administered by one or more of oral administration, sublingual administration, intravenous administration, transdermal administration.

[0210] The present disclosure has the following advantages:

[0211] The compound of formula (II) of the present disclosure has a strong inhibitory effect on TLR7 activity. DETAILED DESCRIPTION

[0212] Definitions and Explanations

[0213] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. In this disclosure, unless otherwise stated, the scientific and technical terms used herein have meanings commonly understood by those skilled in the art. Furthermore, the cell and tissue culture, microbiology-related terms, and laboratory procedures used herein are all widely used terms and routine procedures in their respective fields. Meanwhile, to better understand this disclosure, definitions and explanations of relevant terms are provided below. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, and variations thereof are certainly possible. It should also be understood that the terminology used in this application is for describing specific embodiments only and is not intended to be limiting.

[0214] Unless otherwise expressly stated, the terms “a,” “an,” and “the” as used in this specification and the appended claims cover one or more types.

[0215] As used herein, the terms “comprising” and “having”, and any variations thereof, are intended to cover non-exclusive inclusion. For example, a process, method, apparatus, product, or device that includes a series of steps is not limited to the steps or modules listed, but may optionally include steps not listed, or may optionally include other steps inherent to such process, method, product, or device.

[0216] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0217] The abbreviation EA stands for Ethyl Acetate.

[0218] The abbreviation PE stands for polyethylene.

[0219] The abbreviation DCM stands for dichloromethane.

[0220] The abbreviation MeOH refers to methanol.

[0221] The abbreviation HCl refers to hydrochloric acid.

[0222] The abbreviation DMF stands for dimethylformamide.

[0223] The abbreviation DMSO (Dimethyl Sulfoxide) refers to dimethyl sulfoxide.

[0224] EP tube refers to Eppendorf Tube.

[0225] As used herein, "eq." (equivalent) refers to equivalent, usually used to indicate the molar multiple relationship of a certain substance; for example, 1.2 eq. refers to 1.2 times the number of moles.

[0226] HEK-Blue-hTLR7 is a genetically engineered stable reporter cell line derived from human embryonic kidney cells (HEK293) for studying the activation of human Toll-like receptor 7 (TLR7) and its role in the NF-κB signaling pathway.

[0227] DMEM (Dulbecco's Modified Eagle Medium) is a widely used basic medium for cell culture.

[0228] Gardiquimod is an imidazoline compound, mainly used as an agonist of Toll-like receptor 7 (TLR7) and Toll-like receptor 8 (TLR8).

[0229] Quanti-Blue is a colorimetric enzyme assay reagent, mainly used for detecting alkaline phosphatase (AP) activity in biological samples (such as cell culture supernatant).

[0230] CCK-8 (Cell Counting Kit-8) is a WST-8-based kit widely used for rapid and high-sensitivity detection of cell proliferation and cytotoxicity.

[0231] IC50 (half maximal inhibitory concentration) refers to the concentration of an inhibitor required to reduce a certain biological activity (such as cell proliferation, etc.) to 50% of the original value under specific experimental conditions. IC50 is an important parameter for measuring drug efficacy, and the smaller the IC50 value, the stronger the inhibitory effect of the drug at a lower concentration. IC50 is calculated using conventional methods in the art.

[0232] Examples

[0233] In order to make the purpose, technical scheme and advantages of the embodiments of the present disclosure clearer, the technical scheme of the embodiments of the present disclosure will be described clearly and completely below in combination with the structural formula in the embodiments of the present disclosure. Obviously, the described embodiments are part of the embodiments of the present disclosure, rather than all the embodiments. The following is only a further description of the present disclosure, and the protection scope of the present disclosure is not limited thereto.

[0234] Example 1: Synthesis of Compound 1

[0235] (Compound 1)

[0236] Synthesis of methyl 2-methyl-3-(trifluoromethyl)benzoate:

[0237]

[0238] Into a 200ml single-necked flask was added 2-methyl-3-(trifluoromethyl)benzoic acid 25g (122.46mmol, 1eq), methanol 50ml, and concentrated sulfuric acid 30ml was slowly added at 0°C. The mixture was stirred at 70°C overnight. The reaction solution was cooled to room temperature and poured into 300ml water. The mixture was extracted with ethyl acetate (100ml*3) three times. The organic phase was washed with aqueous sodium carbonate solution twice and with water once. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to give 29.08g of yellow oil of intermediate 1 in a yield of 97.60%. The product was used in the next step without further purification.

[0239] Synthesis of methyl 5-bromo-2-methyl-3-(trifluoromethyl)benzoate:

[0240]

[0241] Into a 200ml single-necked flask was added 2-methyl-3-(trifluoromethyl)benzoic acid 25g (122.46mmol, 1eq), methanol 50ml, and concentrated sulfuric acid 30ml was slowly added at 0°C. The mixture was stirred at 70°C overnight. The reaction solution was cooled to room temperature and poured into 300ml water. The mixture was extracted with ethyl acetate (100ml*3) three times. The organic phase was washed with aqueous sodium carbonate solution twice and with water once. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to give 29.08g of yellow oil of intermediate 1 in a yield of 97.60%. The product was used in the next step without further purification.

[0242] Synthesis of methyl 5-bromo-2-(bromomethyl)-3-(trifluoromethyl)benzoate:

[0243]

[0244] A 500ml single-necked flask was charged with the above intermediate methyl 5-bromo-2-methyl-3-(trifluoromethyl)benzoate 28.55g (96.10mmol, 1.0 eq), 1,2-dichloroethane 300ml, dibenzoyl peroxide 4.66g (19.22mmol, 0.2 eq), N-bromosuccinimide 25.66g (144.16mmol, 1.5 eq), and heated to reflux under nitrogen overnight. Cooled to 0°C, solid precipitated, filtered; the filtrate was added to 50% sodium thiosulfate solution, extracted with dichloromethane three times (100ml*3), the organic phase was washed with water once, dried over anhydrous magnesium sulfate, filtered, and rotary evaporated; the residue was added to EA:PE=1:200, heated to dissolve, spread on silica gel, filtered, and the filtrate was rotary evaporated to give the intermediate 3 as a yellow oil 33.42g in 92.50% yield.

[0245] Synthesis of tert-butyl 4-[6-bromo-1-oxo-4-(trifluoromethyl)-2,3-dihydro-1H- isoindol-2-yl]piperidine-1-carboxylate:

[0246]

[0247] A 500ml single-necked flask was charged with the above intermediate 5-bromo-2-(bromomethyl)-3-(trifluoromethyl) 46.35g (123.26mmol, 1.0 eq), acetonitrile 500ml, N,N-diisopropylethylamine 31.87g (246.56mmol, 2.0 eq), 1-Boc-4-methylpiperidine 29.63g (147.94mmol, 1.2 eq), and heated to 90°C under nitrogen for 6h. Cooled to room temperature, rotary evaporated; dry loading, EA:PE=1:1 over the column, rotary evaporated; the residue was slurried with petroleum ether, filtered to give the intermediate 4 as a light yellow solid 47g in 82.28% yield.

[0248] Synthesis of tert-butyl 4-(1-oxo-6-(pinacolato-borano)-4-(trifluoromethyl)-2,3- dihydro-1H-isoindol-2-yl)piperidine-1-carboxylate:

[0249]

[0250] 100 ml single-mouth flask, add 4-[6-bromo-1-oxo-4-(trifluoromethyl)-2,3- dihydro-1H-isoindol-2-yl]piperidine-1-carboxylic acid tert-butyl ester 7.00 g (15.11 mmol, 1.0 eq), bis(pinacolato)diboron 4.6 g (18.13 mmol, 1.2 eq), potassium acetate 2.97 g (30.22 mmol, 2.0 eq), PdCl2(dppf)CH2Cl2 617 mg (0.76 mmol, 0.05 eq), DMSO 50 ml; under nitrogen protection, 90 °C overnight; the reaction solution is cooled to room temperature, and poured into 200 ml water; EA extraction three times (70 ml*3), the combined organic phase is washed twice with water, dried over anhydrous magnesium sulfate; filter and rotary evaporation, EA:PE = 1:5~1:3 over flash column; the residue is EA:PE = 1:10 slurried; get pink solid 3.78 g, yield 49.02%

[0251] Synthesis of 1-methyl-4-(3-oxo-2-(piperidin-4-yl)-7-(trifluoromethyl)isoindolin-5- yl)-1,8-naphthyridin-2(1H)-one hydrochloride:

[0252]

[0253] 100 ml single-mouth flask, add 4-(1-oxo-6-(bis(pinacolato)diboron-2-yl)-4- (trifluoromethyl)-2,3-dihydro-1H-isoindol-2-yl)piperidine-1-carboxylic acid tert-butyl ester 3.6 g (7.05 mmol, 1.0 eq), 4-bromo-1-methyl-1,8-naphthyridin-2(1H)-one 1.69 g (7.05 mmol, 1.0 eq), potassium carbonate 1.95 g (14.11 mol, 2.0 eq), PdCl2(dppf)CH2Cl2 288 mg (0.35 mmol, 0.05 eq), 1,4-dioxane 50 ml; add 2 ml water, 90 °C stirring overnight under nitrogen protection; the reaction solution is rotary evaporated, EA over flash column; the obtained oil, add 40 ml 3N HCl / MeOH solution, stirring at room temperature for 2 h; rotary evaporation, EA:PE = 1:10 slurried; get light yellow white solid 3.20 g, yield 88.03%

[0254] Synthesis of compound 1:

[0255] 100 ml single-mouth flask was added 1 -methyl-4-(3-oxo-2-(piperidin-4-yl)-7- (trifluoromethyl)isoindolin-5-yl)-1,8-naphthyridin-2(1 H)-one hydrochloride 1.2 g (2.33 mmol, 1.0 eq), dichloromethane 30 ml, triethylamine 942 mg (9.31 mmol, 4.0 eq), glacial acetic acid 280 mg (4.66 mmol, 2.0 eq), oxetan-3-one 671 mg (9.31 mmol, 4.0 eq); sodium triacetoxyborohydride 1.97 g (9.31 mmol, 4.0 eq) was added under stirring at room temperature, and 20 ml dichloromethane was added; stirring at room temperature overnight; reaction was completed, DCM:MeOH=50:1 over column; white solid 1.02 g was obtained, yield 86.15%

[0256] NMR data of compound 1:

[0257] 1H NMR (400 MHz, DMSO-D6) δ 8.67 (dd, J = 4.7, 1.7 Hz, 1H), 8.06 –7.97 (m, 2H), 7.73 (dd, J = 8.0, 1.8 Hz, 1H), 7.27 (dd, J = 8.0, 4.7 Hz, 1H),6.74 (s, 1H), 5.60 (d, J = 6.2 Hz, 2H), 4.74 (s, 2H), 4.69 – 4.48 (m, 7H),4.39 (t, J = 6.1 Hz, 2H), 4.31 (td, J = 5.5, 1.0 Hz, 3H), 3.71 (s, 3H).

[0258] Example 2: synthesis of compound 2

[0259] (Compound 2)

[0260] 50 ml single-mouth flask was added 1 -methyl-4-(3-oxo-2-(piperidin-4-yl)-7- (trifluoromethyl)isoindolin-5-yl)-1,8-naphthyridin-2(1 H)-one hydrochloride 1.2 g (2.33 mmol, 1.0 eq), dichloromethane 30 ml, triethylamine 942 mg (9.31 mmol, 4.0 eq), glacial acetic acid 280 mg (4.66 mmol, 2.0 eq), oxetan-3-one 671 mg (9.31 mmol, 4.0 eq); sodium triacetoxyborohydride 1.97 g (9.31 mmol, 4.0 eq) was added under stirring at room temperature, and 20 ml dichloromethane was added; stirring at room temperature overnight; reaction was completed, DCM:MeOH=50:1 over column; white solid 1.02 g was obtained, yield 86.15%

[0261] NMR data of compound 2:

[0262] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J = 4.7, 2.2 Hz, 1H), 8.21 (dd, J = 8.3, 2.0 Hz, 2H), 7.96 (dq, J = 2.5, 1.3 Hz, 1H), 7.34 (dd, J = 8.3, 4.8 Hz, 1H), 7.11 (s, 2H), 6.50 (s, 1H), 4.28 (s, 2H), 4.08 (p, J = 5.4 Hz, 1H), 3.33 (s, 2H), 2.94 (ddd, J = 12.2, 7.9, 5.1 Hz, 2H), 2.78 - 2.69 (m, 2H), 1.96 (ddt, J = 11.7, 7.9, 5.3 Hz, 2H), 1.70 (ddt, J = 11.7, 7.8, 5.3 Hz, 2H).

[0263] Example 3: Synthesis of compound 3

[0264] (Compound 3)

[0265] Synthesis of 8-cyano-5-pinacol boronate:

[0266]

[0267] Into a 100ml single necked flask was added 5-bromo-8-cyanoquinoline 1.07g (4.59mmol, 1.0 eq), potassium acetate 1.35g (13.77mmol, 3.0 eq), PdCl2(dppf)CH2Cl20.18g (0.23mmol, 5%mmol), pinacol diboronic acid 1.40g (5.51mmol, 1.2 eq), finally 1,4-dioxane 50ml, and stirred at 100°C under nitrogen overnight. The reaction solution was rotary evaporated, and dry loaded onto a DCM column to give a yellow solid 1.15g (yield: 90%), which was used directly for the next step without further purification.

[0268] Synthesis of tert-butyl 4-(5-(8-cyanoquinolin-5-yl)-3-oxo-1- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate:

[0269]

[0270] 100ml single neck flask, add tert-butyl 4-(5-(8-cyanoquinolin-5-yl)-3-oxo-1- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 1.5g (2.79mmol), 20ml 3N HCl / MeOH, stir at room temperature overnight, spin dry. 100ml single neck flask, add above reaction product 0.6g (1.18mmol, 1.0eq), dichloromethane 50ml, triethylamine 0.51g (5.07mmol, 4.0eq), glacial acetic acid 0.15g (2.54mmol, 2.0eq), finally add 3-oxetanone 0.37g (5.07mmol, 4.0eq), react at room temperature for 1h. Then add sodium triethoxyborohydride 1.07g (5.07mmol, 4.0eq), react at room temperature overnight under nitrogen protection. Add 30ml water to quench, extract with DCM three times (30ml*3), combine the organic phase, wash with saturated aqueous sodium bicarbonate solution twice, dry the organic phase with anhydrous magnesium sulfate, filter, pass through a column with DCM / MeOH=20:1, get colorless solid 358mg, yield 62%.

[0271] Synthesis of compound 3

[0272] 100ml single neck flask, add tert-butyl 4-(5-(8-cyanoquinolin-5-yl)-3-oxo-1- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 1.5g (2.79mmol), 20ml 3N HCl / MeOH, stir at room temperature overnight, spin dry. 100ml single neck flask, add above reaction product 0.6g (1.18mmol, 1.0eq), dichloromethane 50ml, triethylamine 0.51g (5.07mmol, 4.0eq), glacial acetic acid 0.15g (2.54mmol, 2.0eq), finally add 3-oxetanone 0.37g (5.07mmol, 4.0eq), react at room temperature for 1h. Then add sodium triethoxyborohydride 1.07g (5.07mmol, 4.0eq), react at room temperature overnight under nitrogen protection. Add 30ml water to quench, extract with DCM three times (30ml*3), combine the organic phase, wash with saturated aqueous sodium bicarbonate solution twice, dry the organic phase with anhydrous magnesium sulfate, filter, pass through a column with DCM / MeOH=20:1, get colorless solid 358mg, yield 62%.

[0273] NMR data of compound 3:

[0274] 1H NMR (400 MHz, DMSO) δ 9.15 (dd, J = 4.2, 1.6 Hz, 1H), 8.49 (d, J = 7.5 Hz, 1H), 8.24 (dd, J = 8.6, 1.6 Hz, 1H), 8.10 (d, J = 14.6 Hz, 2H), 7.83(d, J = 7.5 Hz, 1H), 7.74 (dd, J = 8.6, 4.2 Hz, 1H), 4.81 (s, 2H), 4.56 (t, J= 6.4 Hz, 2H), 4.44 (t, J = 6.1 Hz, 2H), 4.07 (q, J = 7.4 Hz, 1H), 3.45 (p, J= 6.1 Hz, 1H), 2.83 (d, J = 7.0 Hz, 2H), 1.95 (t, J = 9.9 Hz, 4H), 1.80 (q, J= 5.0 Hz, 2H).

[0275] Example 4: Synthesis of compound 4

[0276] (Compound 4)

[0277] 100 ml single neck flask, add tert-butyl 4-(5-(8-cyanoquinolin-5-yl)-3-oxo-1- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 1.5 g (2.79 mmol), 20 ml 3N HCl / MeOH, stir at room temperature overnight, spin dry. 100 ml single neck flask, add the above reaction product 0.36 g (0.71 mmol, 1.0 eq), dichloromethane 50 ml, triethylamine 0.29 g (2.88 mmol, 4.0 eq), bromoacetamide 0.12 g (0.85 mmol, 1.2 eq), react at room temperature overnight. Spin dry, column with DCM / MeOH = 20:1, get colorless solid 224 mg, yield 64%.

[0278] NMR data of compound 4:

[0279] 1H NMR (400 MHz, DMSO) δ 9.16 (dd, J = 4.2, 1.6 Hz, 1H), 8.49 (d, J = 7.5 Hz, 1H), 8.24 (dd, J = 8.7, 1.6 Hz, 1H), 8.10 (d, J = 13.1 Hz, 2H), 7.83(d, J = 7.5 Hz, 1H), 7.75 (dd, J = 8.6, 4.2 Hz, 1H), 7.18 (d, J = 3.3 Hz,1H), 4.78 (s, 2H), 4.06 (qt, J = 14.1, 5.6 Hz, 1H), 2.93 (d, J = 14.5 Hz,4H), 2.30 – 2.20 (m, 2H), 2.12 – 1.94 (m, 3H), 1.79 – 1.71 (m, 2H).

[0280] Example 5: Synthesis of compound 5

[0281] (Compound 5)

[0282] 100ml single neck flask, add tert-butyl 4-(5-(8-cyanoquinolin-5-yl)-3-oxo-1- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 1.5g (2.79mmol), 20ml 3N HCl / MeOH, stir at room temperature overnight, spin dry. 50ml single neck flask, add above reaction product 0.36g (0.72mmol, 1.0eq), dichloromethane 15ml, triethylamine 0.29g (2.88mmol, 4.0eq), stir to dissolve ready for use. Another 25ml single neck flask, add carbonyldiimidazole 0.14g (0.85mmol, 1.2eq), methylamine hydrochloride 53mg (0.79mmol, 1.1eq), DMF 2ml, acetonitrile 6ml, protect with nitrogen, react at room temperature for 2h, then add to the above ready for use liquid, protect with nitrogen, react at room temperature overnight. Spin dry, pass through a column with DCM / MeOH = 20:1, get colorless solid 184mg, yield 50%.

[0283] NMR data of compound 5:

[0284] 1H NMR (400 MHz, DMSO-D6) δ 9.15 (dt, J = 3.8, 1.8 Hz, 1H), 8.52 –8.45 (m, 1H), 8.47 (s, 1H), 8.27 – 8.18 (m, 2H), 8.09 (d, J = 10.7 Hz, 2H),7.82 (dd, J = 7.4, 1.6 Hz, 1H), 7.78 – 7.70 (m, 1H), 7.64 (t, J = 1.5 Hz,1H), 7.01 (d, J = 1.3 Hz, 1H), 6.50 (q, J = 4.4 Hz, 1H), 4.78 (s, 2H), 4.23(q, J = 7.8 Hz, 1H), 4.09 (d, J = 13.1 Hz, 2H), 2.80 (d, J = 4.5 Hz, 3H),2.59 (d, J = 4.3 Hz, 3H), 1.75 (s, 4H).

[0285] Example 6: Synthesis of compound 6

[0286] (Compound 6)

[0287] Synthesis of 8-methylquinoline-5-boronic acid pinacol ester:

[0288]

[0289] Into a 200ml single necked flask was added 5-bromo-8-methylquinoline 4g (18.01 mmol, 1.0 eq), 1,4-dioxane 100ml, pinacol diboronic acid 5.49g (21.61 mmol, 1.2 eq), potassium acetate 5.30g (54.03 mmol, 2.0 eq), Pd(dppf)Cl2.CH2Cl2 735mg (0.90 mmol, 0.05 eq), stirred at 90°C under nitrogen overnight. Cooled to room temperature, the reaction was rotary evaporated, dried loaded onto column, eluted with EA:PE = 1:20, rotary evaporated to get yellow solid; added petroleum ether to slurry, filtered to get white solid of intermediate 5 3.12g, yield 64.33%.

[0290] Synthesis of tert-butyl 4-[6-(8-methylquinolin-5-yl)-1-oxo-4-(trifluoromethyl)- 2,3-dihydro-1H-isoindol-2-yl]piperidine-1-carboxylate:

[0291]

[0292] A 200ml single-necked flask was charged with intermediate 5 8-methylquinoline-5- boronic acid pinacol ester 4.2g (9.07mmol, 1.0eq), intermediate 4 tert-butyl-4-[6-bromo-1- oxo-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-1-carboxylate 3.2g (11.79mmol, 1.3eq), potassium carbonate 2.5g (18.13mol, 2.0eq), Pd(dppf)Cl2.CH2Cl2 370mg (0.45mmol, 0.05eq), DMF 50ml, under nitrogen protection, 100°C for 2h. Cooled to room temperature, added 50ml water, extracted with dichloromethane three times (25ml*3), washed with saturated brine twice (25ml*2), dried with anhydrous magnesium sulfate, filtered; dry loading, DCM:MeOH=100:1 through the column, rotary evaporation, to obtain brown oil of intermediate 6 4g, yield 84.03%.

[0293] Synthesis of 6-(8-methylquinolin-5-yl)-2-(piperidin-4-yl)-4-(trifluoromethyl)-2,3- dihydro-1H-isoindol-1-one hydrochloride:

[0294]

[0295] A 200ml single-necked flask was charged with intermediate 5 8-methylquinoline-5- boronic acid pinacol ester 4.2g (9.07mmol, 1.0eq), intermediate 4 tert-butyl-4-[6-bromo-1- oxo-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-2-yl]piperidine-1-carboxylate 3.2g (11.79mmol, 1.3eq), potassium carbonate 2.5g (18.13mol, 2.0eq), Pd(dppf)Cl2.CH2Cl2 370mg (0.45mmol, 0.05eq), DMF 50ml, under nitrogen protection, 100°C for 2h. Cooled to room temperature, added 50ml water, extracted with dichloromethane three times (25ml*3), washed with saturated brine twice (25ml*2), dried with anhydrous magnesium sulfate, filtered; dry loading, DCM:MeOH=100:1 through the column, rotary evaporation, to obtain brown oil of intermediate 6 4g, yield 84.03%.

[0296] Synthesis of compound 6

[0297] 100 ml single-mouth bottle was added the above-mentioned intermediate 6-(8-methylquinolin-5-yl)-2-(piperidin-4-yl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one hydrochloride 1.2 g (2.41 mmol, 1.0 eq), dichloromethane 15 ml, triethylamine 975 mg (9.63 mmol, 4.0 eq), stirred at room temperature for 5 min; to the above-mentioned reaction solution, 3-oxetanone 347 mg (4.82 mmol, 2.0 eq), glacial acetic acid 289 mg (4.82 mmol, 2.0 eq), anhydrous magnesium sulfate 580 mg (4.82 mmol, 2.0 eq) were added, and stirred at room temperature for 30 min under nitrogen protection; to the above-mentioned reaction solution, sodium triacetylboration hydride 1.02 g (4.82 mmol, 2.0 eq) was added, and reacted at room temperature overnight under nitrogen protection. 10 ml of water was added, extracted with dichloromethane three times (10 ml*3), dried over anhydrous magnesium sulfate, filtered, and rotary evaporated; dry loading, DCM:MeOH=100:1, over column, rotary evaporation; the residue was slurried with PE:EA=10:1, filtered, to obtain compound 6 white solid 753 mg, yield 64.91%.

[0298] NMR data of compound 6:

[0299] 1H NMR (400 MHz, DMSO-D6) δ 8.96 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H),7.95 (d, J = 10.9 Hz, 2H), 7.70 (d, J = 7.4 Hz, 1H), 7.52 (d, J = 7.3 Hz,2H), 4.75 (s, 2H), 4.52 (s, 2H), 4.40 (s, 2H), 4.03 (s, 1H), 3.40 (s, 1H),2.76 (s, 4H), 1.89 (d, J = 9.6 Hz, 5H), 1.75 (s, 2H), 1.20 (s, 2H).

[0300] Example 7: synthesis of compound 7

[0301] (compound 7)

[0302] Into a 100ml single-necked flask, was added intermediate 6-(8-methylquinolin-5-yl)-2-(piperidin-4-yl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one hydrochloride 1.2g (2.41mmol, 1.0eq), dichloromethane 15ml, triethylamine 975mg (9.63mmol, 4.0eq), after the solution was clear, 2-bromoacetamide 399mg (2.89mmol, 1.2eq) was added, and the reaction was allowed to proceed at room temperature for 3h under nitrogen protection. 10ml of water was added, and the mixture was extracted with dichloromethane three times (10ml*3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was dried and loaded onto a column, and eluted with DCM:MeOH=100:1. The residue was slurried with PE:EA:MeOH=10:5:1, filtered, and dried to obtain compound 7 as a white solid 890mg, with a yield of 76.72%.

[0303] NMR data of compound 7:

[0304] 1H NMR (400 MHz, DMSO) δ 9.00 (dd, J = 4.1, 1.6 Hz, 1H), 8.11 (dd, J= 8.6, 1.7 Hz, 1H), 7.99 (d, J = 7.2 Hz, 2H), 7.73 (d, J = 7.3 Hz, 1H), 7.60– 7.52 (m, 2H), 7.30 – 7.25 (m, 1H), 7.22 – 7.17 (m, 1H), 4.76 (s, 2H), 4.14– 3.99 (m, 2H), 2.93 (d, J = 14.0 Hz, 4H), 2.80 (s, 3H), 2.30 – 2.20 (m, 2H),2.11 – 1.95 (m, 2H), 2.00 (s, 1H), 1.75 (dd, J = 12.2, 4.2 Hz, 2H), 1.18 (t,J = 7.1 Hz, 2H).

[0305] Example 8: Synthesis of compound 8

[0306] (compound 8)

[0307] Into a 50 ml single-necked flask, add N,N'-carbonyldiimidazole 468 mg (2.89 mmol, 1.2 eq), methylamine hydrochloride 179 mg (2.65 mmol, 1.1 eq), acetonitrile 6 ml, DMF 2 ml, stir for 2 h at room temperature under nitrogen protection. Into another 50 ml single-necked flask, add intermediate 6-(8-methylquinolin-5-yl)-2-(piperidin-4-yl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one hydrochloride 1.2 g (2.41 mmol, 1.0 eq), dichloromethane 15 ml, triethylamine 975 mg (9.63 mmol, 4.0 eq), add the reaction solution to the above reaction flask after dissolving, and react overnight at room temperature under nitrogen protection. Add 10 ml of water, extract three times with dichloromethane (10 ml*3), dry over anhydrous magnesium sulfate, filter, and rotary evaporate; dry loading, DCM:MeOH=100:1, pass through the column, and rotary evaporate; the residue is slurried with PE:EA:MeOH=10:5:1, filtered, and T0llB-7C-329 white solid 525 mg is obtained with a yield of 45.26%.

[0308] NMR data of compound 8:

[0309] 1H NMR (400 MHz, DMSO) δ 9.00 (d, J = 4.1 Hz, 1H), 8.11 (d, J = 8.5Hz, 1H), 7.99 (d, J = 5.3 Hz, 2H), 7.73 (d, J = 7.3 Hz, 1H), 7.56 (dd, J =9.2, 5.3 Hz, 2H), 6.50 (d, J = 4.8 Hz, 1H), 4.77 (s, 2H), 4.25 (p, J = 8.3Hz, 1H), 4.11 (d, J = 13.1 Hz, 2H), 2.80 (s, 5H), 2.60 (d, J = 4.2 Hz, 3H),1.76 (d, J = 8.4 Hz, 4H).

[0310] Example 9: synthesis of compound 9

[0311] (compound 9)

[0312] Synthesis of tert-butyl 4-(1-oxo-6-(quinolin-5-yl)-4-(trifluoromethyl)isoindolin-2- yl)piperidine-1-carboxylate:

[0313] 100 ml single-mouth flask was added 4-(6-bromo-1-oxo-4-(trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate tert-butyl ester 1 g (2.16 mmol, 1.0 eq), 5-quinoline boronic acid pinacol ester 661 mg (2.59 mmol, 1.2 eq), sodium carbonate 458 mg (4.32 mmol, 2.0 eq) aqueous solution, Pd(dppf)Cl2.CH2Cl2 88 mg (0.11 mmol, 5% mmol), finally 20 ml 1,4-dioxane, 95°C reaction overnight under nitrogen protection; the reaction solution was rotary dried, dried and loaded, DCM / MeOH=50:1 column, to get yellow oily intermediate 1 850 mg, yield 77.3%.

[0314] Synthesis of hydrochloride of 2-(piperidin-4-yl)-6-(quinolin-5-yl)-4- (trifluoromethyl)isoindolin-1-one:

[0315] 100 ml single-mouth flask was added 4-(6-bromo-1-oxo-4-(trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate tert-butyl ester 1 g (2.16 mmol, 1.0 eq), 5-quinoline boronic acid pinacol ester 661 mg (2.59 mmol, 1.2 eq), sodium carbonate 458 mg (4.32 mmol, 2.0 eq) aqueous solution, Pd(dppf)Cl2.CH2Cl2 88 mg (0.11 mmol, 5% mmol), finally 20 ml 1,4-dioxane, 95°C reaction overnight under nitrogen protection; the reaction solution was rotary dried, dried and loaded, DCM / MeOH=50:1 column, to get yellow oily intermediate 1 850 mg, yield 77.3%.

[0316] Synthesis of compound 9

[0317] 50 ml single-mouth flask was added 4-(6-bromo-1-oxo-4-(trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate tert-butyl ester 1 g (2.16 mmol, 1.0 eq), 5-quinoline boronic acid pinacol ester 661 mg (2.59 mmol, 1.2 eq), sodium carbonate 458 mg (4.32 mmol, 2.0 eq) aqueous solution, Pd(dppf)Cl2.CH2Cl2 88 mg (0.11 mmol, 5% mmol), finally 20 ml 1,4-dioxane, 95°C reaction overnight under nitrogen protection; the reaction solution was rotary dried, dried and loaded, DCM / MeOH=50:1 column, to get yellow oily intermediate 1 850 mg, yield 77.3%.

[0318] NMR data of compound 9:

[0319] 1H NMR (400 MHz, DMSO) δ 8.98 (dd, J = 4.2, 1.6 Hz, 1H), 8.13 (t, J = 8.6 Hz, 2H), 8.02 (d, J = 12.6 Hz, 2H), 7.88 (dd, J = 8.5, 7.1 Hz, 1H), 7.67(dd, J = 7.2, 1.1 Hz, 1H), 7.56 (dd, J = 8.6, 4.2 Hz, 1H), 4.79 (s, 2H), 4.56(t, J = 6.5 Hz, 2H), 4.44 (t, J = 6.1 Hz, 2H), 4.07 (s, 1H), 3.45 (p, J = 6.4Hz, 1H), 2.83 (d, J = 7.2 Hz, 2H), 2.04 – 1.87 (m, 4H), 1.80 (q, J = 6.3 Hz,2H).

[0320] Example 10: Synthesis of compound 10

[0321] (Compound 10)

[0322] Into a 50ml single neck flask was added intermediate 2-(piperidin-4-yl)-6-(quinolin-5- yl)-4-(trifluoromethyl)isoindolin-l-one hydrochloride 200mg (0.41mmol, 1.0 eq), triethylamine 5ml, 25ml of 1,2-dichloroethane was added, after the solution was clear, 2-bromoacetamide 63mg (0.45mmol, 1.1 eq) was added, and the reaction was carried out at room temperature for 3h; dry loading, column chromatography with EA / MeOH = 10:1, to obtain TollB-7C-331 white solid 113mg, yield 58%.

[0323] NMR data of compound 10:

[0324] 1H NMR (400 MHz, DMSO-D6) δ 8.93 (d, J = 4.2 Hz, 1H), 8.09 (t, J = 8.1 Hz, 2H), 7.98 (d, J = 13.0 Hz, 2H), 7.83 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 7.1 Hz, 1H), 7.52 (dd, J = 8.7, 4.2 Hz, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 4.72 (s, 2H), 4.04 (s, 1H), 2.89 (d, J = 13.0 Hz, 4H), 2.21 (t, J = 11.7 Hz, 2H), 2.05 - 1.98 (m, 1H), 1.98 - 1.93 (m, 1H), 1.70 (q, J = 4.2 Hz, 2H).

[0325] Example 11: Synthesis of compound 11

[0326] (Compound 11)

[0327] Into a 25ml single neck flask was added N,N'-carbonyldiimidazole 190mg (1.17mmol, 1.2eq), methylamine hydrochloride 72mg (1.07mmol, 1.1eq), and acetonitrile 6ml, DMF 2ml, stirred at room temperature for 2h. Into another 50ml flask was added intermediate 2-(piperidin-4-yl)-6-(quinolin-5-yl)-4-(trifluoromethyl)isoindolin-l-one hydrochloride 472mg (0.97mmol, 1.0eq), triethylamine 8ml, added 10ml of dichloroethane, after the solution was clear, the reaction solution from the 25ml flask was added, and reacted at room temperature overnight; dry loading, DCM / MeOH=25:1 passed through the column TollB-7C-332 white solid 400mg, yield 87.6%.

[0328] NMR data of compound 11:

[0329] 1H NMR (400 MHz, DMSO) δ 8.98 (dd, J = 4.1, 1.6 Hz, 1H), 8.18 – 8.09(m, 2H), 8.02 (d, J = 8.7 Hz, 2H), 7.88 (dd, J = 8.5, 7.1 Hz, 1H), 7.71 –7.64 (m, 1H), 7.57 (dd, J = 8.6, 4.2 Hz, 1H), 6.56 (q, J = 4.3 Hz, 1H), 4.78(s, 2H), 4.25 (p, J = 8.3 Hz, 1H), 4.13 (d, J = 13.2 Hz, 2H), 2.80 (p, J =6.0 Hz, 3H), 2.60 (d, J = 4.2 Hz, 3H), 1.77 (dd, J = 8.5, 3.4 Hz, 4H).

[0330] Example 12: Synthesis of compound 12

[0331] (Compound 12)

[0332] Synthesis of tert-butyl 4-(3-oxo-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l- (trifluoromethyl)isoindolin-2-yl)piperidine-l-carboxylate:

[0333] Into a 100ml single neck flask was added tert-butyl 4-(5-bromo-3-oxo-l- (trifluoromethyl)isoindolin-2-yl)piperidine-l-carboxylate 1.0g (2.16mmol, 1.0 eq), bis(pinacolato)diboron 0.66g (2.59mmol, 1.2 eq), potassium acetate 0.42g (4.32mmol, 2.0 eq), Pd(dppf)Cl2.CH2Cl2 88mg (0.11mmol, 5%mmol) and finally 35ml DMSO, under nitrogen protection, 90°C overnight. The reaction solution was poured into 100ml water, extracted with EA three times (30ml*3), the organic phase was combined, washed with water twice, the organic phase was dried over anhydrous magnesium sulfate, filtered, and columned with EA / PE=1:3 to obtain the off-white solid of intermediate 1 1.02g in a yield of 93%.

[0334] Tert-butyl 4-(5-(l-methyl-2-oxo-l,2-dihydro-l,8-naphthyridin-4-yl)-3-oxo-l- (trifluoromethyl)isoindolin-2-yl)piperidine-l-carboxylate:

[0335] 100ml single-necked flask, add tert-butyl 4-(5-(1-methyl-2-oxo-1,2-dihydro-1,8- naphthyridin-4-yl)-3-oxo-1-(trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 0.78g (1.42mmol), 20ml 3N HCl / MeOH, stir overnight at room temperature, spin dry. 50ml single-necked flask, add the above reaction product 0.64g (1.25mmol, 1.0eq), dichloromethane 15ml, triethylamine 0.64g (6.25mmol, 4.0eq), stir to dissolve and reserve. Another 25ml single-necked flask, add carbonyldiimidazole 0.24g (1.50mmol, 1.2eq), methylamine hydrochloride 0.10g (1.40mmol, 1.1eq), DMF 2ml, acetonitrile 6ml, react at room temperature for 2h under nitrogen protection, then add to the above reserved solution, react overnight at room temperature under nitrogen protection. Spin dry, DCM / MeOH=20:1, column chromatography, get light yellow solid 290mg, yield 47%.

[0336] Synthesis of compound 12

[0337] 100ml single-necked flask, add tert-butyl 4-(5-(1-methyl-2-oxo-1,2-dihydro-1,8- naphthyridin-4-yl)-3-oxo-1-(trifluoromethyl)isoindolin-2yl)piperidine-1-carboxylate 0.78g (1.42mmol), 20ml 3N HCl / MeOH, stir overnight at room temperature, spin dry. 50ml single-necked flask, add the above reaction product 0.64g (1.25mmol, 1.0eq), dichloromethane 15ml, triethylamine 0.64g (6.25mmol, 4.0eq), stir to dissolve and reserve. Another 25ml single-necked flask, add carbonyldiimidazole 0.24g (1.50mmol, 1.2eq), methylamine hydrochloride 0.10g (1.40mmol, 1.1eq), DMF 2ml, acetonitrile 6ml, react at room temperature for 2h under nitrogen protection, then add to the above reserved solution, react overnight at room temperature under nitrogen protection. Spin dry, DCM / MeOH=20:1, column chromatography, get light yellow solid 290mg, yield 47%.

[0338] NMR data of compound 12:

[0339] 1H NMR (400 MHz, DMSO-D6) δ 8.66 (dd, J = 4.7, 1.8 Hz, 1H), 8.01 (d, J = 11.3 Hz, 2H), 7.73 (dd, J = 7.9, 1.8 Hz, 1H), 7.26 (dd, J = 8.0, 4.7 Hz, 1H), 6.73 (s, 1H), 6.46 (q, J = 4.3 Hz, 1H), 4.72 (s, 2H), 4.19 (h, J = 7.5 Hz, 1H), 4.05 (d, J = 13.1 Hz, 2H), 3.70 (s, 3H), 2.81 - 2.70 (m, 2H), 2.55 (d, J = 4.2 Hz, 3H), 1.69 (h, J = 4.3 Hz, 4H), 1.18 (s, 1H).

[0340] Example 13: Synthesis of compound 13

[0341] (Compound 13)

[0342] Synthesis of (E)-N-(3-bromo-6-methylpyridin-2-yl)-N,N-dimethylformamidine:

[0343] Into a 200ml single necked flask was added 2-amino-3-bromo-6-methylpyridine 5.3g (28.34mmol, 1.0 eq), toluene 30ml, substrate N,N-dimethylformamide dimethyl acetal 16.9g (141.68mmol, 5.0 eq); refluxed overnight under nitrogen protection; the reaction solution was rotary dried to give white solid 6.45g, yield 94.1%;

[0344] Synthesis of 8-bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridine:

[0345] Into a 200ml single-necked flask was added (E) -N -(3 -bromo-6- methylpyridine 2-yl) N,N dimethylformamidine 6.45g (26.64mmol, 1.0 eq), isopropanol 30ml, N,N-dimethylformamide dimethyl acetal 1.59g (13.32mmol, 0.5 eq); the reaction mixture was heated to 50°C, and hydroxylamine sulfonic acid 4.52g (39.96mmol, 1.5 eq) was added in portions. After the addition was completed, the reaction mixture was stirred at 50°C overnight. The reaction mixture was rotary evaporated, and saturated sodium carbonate aqueous solution 150ml was added. The reaction mixture was stirred at room temperature for 30min. The reaction mixture was extracted with dichloromethane three times (80ml*3), and the combined organic phase was washed with saturated sodium carbonate solution once and water twice. The organic phase was dried over anhydrous magnesium sulfate, filtered over silica gel, and rotary evaporated to give a white solid 5.12g in 90.64% yield.

[0346] Synthesis of 6-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-2-(piperidin-4-yl)-4- (trifluoromethyl)isoindolin-1-one hydrochloride:

[0347] Into a 100ml single-necked flask was added tert-butyl 4-(1-oxo-6-(pinacolato- boronate-2-yl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-2-yl)piperidine-1-carboxylate 2.5g (4.9mmol, 1.0 eq), 8-bromo-5-methyl[1,2,4]triazolo[1,5-a]pyridine 1.25g (5.88mmol, 1.2 eq), sodium carbonate 1.04g (9.80mol, 2.0 eq), Pd(dppf)Cl2.CH2Cl2200mg (0.24mmol, 0.05 eq), 1,4-dioxane 50ml; 2ml water was added, and the reaction mixture was stirred at 90°C overnight under nitrogen protection. The reaction mixture was rotary evaporated, and the residue was purified by flash column chromatography with EA. The obtained oil was added to 40ml 3N HCl / MeOH solution, and the reaction mixture was stirred at room temperature for 3h. The reaction mixture was rotary evaporated, and the residue was slurried with EA:PE=1:10 to give a light yellow white solid 2.4g in 93.36% yield.

[0348] Synthesis of compound 13:

[0349] 100 ml single-necked flask, add 6-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-2- (piperidin-4-yl)-4-(trifluoromethyl)isoindolin-1-one hydrochloride 0.7 g (1.33 mmol, 1.0 eq), dichloromethane 30 ml, triethylamine 540 mg (5.33 mmol, 4.0 eq), glacial acetic acid 160 mg (2.67 mmol, 2.0 eq), oxetanone 38 mg (5.3 mmol, 4.0 eq); add sodium triacetoxyborohydride 1.13 g (5.3 mmol, 4.0 eq) under stirring at room temperature, and supplement 20 ml of dichloromethane; stir at room temperature overnight; after the reaction is completed, pass through a column with DCM:MeOH=50:1; obtain 0.32 g of white solid, yield 50.88%

[0350] NMR data of compound 13:

[0351] 1H NMR (400 MHz, DMSO-D6) δ 8.81 (s, 1H), 8.76 (s, 1H), 8.64 (s, 1H),8.21 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 4.72 (s, 2H), 4.52 (t, J= 6.5 Hz, 2H), 4.40 (t, J = 6.2 Hz, 2H), 4.03 (s, 1H), 3.44 – 3.36 (m, 1H),2.77 (s, 5H), 1.88 (s, 5H), 1.75 (s, 2H), 1.19 (s, 3H).

[0352] Example 14: Synthesis of compound 14

[0353] (Compound 14)

[0354] 50 ml single-necked flask, add 6-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-2- (piperidin-4-yl)-4-(trifluoromethyl)isoindolin-1-one hydrochloride 0.7 g (1.33 mmol, 1.0 eq), 1,2-dichloroethane 25 ml, then add DBU 1.02 g (6.67 mmol, 5.0 eq) and bromoacetamide 276 mg (2.00 mmol, 1.5 eq), stir at 40°C overnight; after the reaction is completed, spin dry, pass through a column with DCM:MeOH=50:1; obtain 0.29 g of white solid, yield 46.02%

[0355] NMR data of compound 14:

[0356] 1H NMR (400 MHz, DMSO-D6) δ 8.80 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H),8.19 (d, J = 7.5 Hz, 1H), 7.22 (d, J = 7.1 Hz, 2H), 7.15 (s, 1H), 4.68 (s,2H), 4.08 – 3.97 (m, 1H), 2.88 (d, J = 12.7 Hz, 4H), 2.76 (s, 3H), 2.20 (t, J= 11.4 Hz, 2H), 2.02 – 1.88 (m, 2H), 1.74 – 1.65 (m, 2H).

[0357] Example 15: Synthesis of compound 15

[0358] (Compound 15)

[0359] 50ml single neck flask was added 6-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-2- (piperidin-4-yl)-4-(trifluoromethyl)isoindolin-1-one hydrochloride 0.7g (1.33mmol, 1.0 eq), DCM 25ml, then DIEA 862mg (6.67mmol, 5, 0 eq) and substrate N- methyl-1-imidazolecarboxamide 250mg (2.00mmol, 1.5 eq) were added, stirred at room temperature overnight; after the reaction was completed, it was rotary evaporated, and DCM:MeOH=50:1 was passed through the column; 0.33g of white solid was obtained, with a yield of 52.36%

[0360] NMR data of compound 15:

[0361] 1H NMR (400 MHz, DMSO-D6) δ 8.73 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H),8.12 (s, 1H), 7.16 (s, 1H), 6.41 (s, 1H), 4.62 (s, 2H), 4.15 (s, 1H), 4.00(d, J = 13.1 Hz, 2H), 2.71 (s, 5H), 2.41 (s, 3H), 1.99 (s, 1H), 1.64 (s, 4H).

[0362] Example 16: Synthesis of compound 16

[0363] (Compound 16)

[0364] Synthesis of 5-bromo-8-methylquinoxaline:

[0365] Into a 200ml single-necked flask was placed 5-methylquinoxaline 10g (69.36mmol, 1.0eq), N-bromosuccinimide 28.39g (159.53mmol, 2.3eq), acetonitrile 70ml, stirred at 60°C overnight. The reaction solution was rotary evaporated, added 500ml ethyl acetate, stirred at room temperature to dissolve, filtered out the insoluble, the filtrate was concentrated, the concentrated filtrate was extracted with saturated brine three times (30ml*3), then extracted with saturated ammonium chloride once (30ml*1), dried and loaded onto a column with PE / EA=4:1, to obtain intermediate 1 light yellow solid 10.82g, yield: 70%.

[0366] Synthesis of (8-methylquinoxalin-5-yl)boronic acid:

[0367] Into a 200ml single-necked flask was placed 5-bromo-8-methylquinoxaline 3g (13.45mmol, 1.0eq), potassium acetate 2.64g (26.9mmol, 2.0eq), PdCl2(dppf)CH2Cl2 549mg (0.67mmol, 5%mmol), bis(pinacolato)diboron 4.1g (16.14mmol, 1.2eq), finally added 1,4-dioxane 60ml, stirred at 100°C overnight under nitrogen protection. The reaction solution was rotary evaporated, dried and loaded onto a column with PE / EA=4:1, to obtain intermediate 2 brown oil 2.03g, yield: 55.8%, without further purification, directly used in the next step synthesis.

[0368] Synthesis of tert-butyl 4-(6-(8-methylquinoxalin-5-yl)-1-oxo-4- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate:

[0369] Into a 50ml single-necked flask was placed tert-butyl 4-(6-bromo-1-oxo-4- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 2g (4.32mmol, 1.0eq), (8-methylquinoxalin-5-yl)boronic acid 1.22mg (6.48mmol, 1.5eq), sodium carbonate 915mg (8.63mmol, 2.0eq) aqueous solution, Pd(dppf)Cl2.CH2Cl2 176mg (0.22mmol, 5%mmol), finally added 30ml 1,4-dioxane, reacted at 95°C overnight under nitrogen protection; the reaction solution was rotary evaporated, dried and loaded onto a column with PE / EA=1:1, to obtain intermediate 3 yellow oil 1.82g, yield 80.2%.

[0370] Synthesis of hydrochloride salt of 6-(8-methylquinoxalin-5-yl)-2-(piperidin-4-yl)-4- (trifluoromethyl)isoindolin-1-one:

[0371] 50ml single neck flask was charged with intermediate tert-butyl 4-(6-(8-methylquinoxalin-5-yl)-1-oxo-4-(trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 1.82g (3.46mmol, 1.0eq), 30ml of 3N HC1 / MeOH, stirred at room temperature for 30min; the reaction solution was directly rotary evaporated to get intermediate 4 as yellow solid 1.47g, yield 100%.

[0372] Synthesis of compound 16:

[0373] 50ml single neck flask was charged with intermediate 6-(8-methylquinoxalin-5-yl)-2-(piperidin-4-yl)-4-(trifluoromethyl)isoindolin-1-one hydrochloride 700mg (1.4mmol, 1.0eq), triethylamine 10ml, 30ml of 1,2-dichloroethane, after the solution was clear, 3-oxetanone 404mg (5.61mmol, 4.0eq) and glacial acetic acid 8ml were added, the ph was adjusted to weakly acidic, stirred at room temperature for 30min, then sodium triacetoxyborohydride 1.19g (5.61mmol, 4.0eq) was added, after the addition, stirred at room temperature under nitrogen overnight. The reaction solution was poured into saturated aqueous sodium carbonate solution to quench, extracted with DCM three times (15ml*3), the organic phase was combined, dried over anhydrous magnesium sulfate, dried by loading, the column was eluted with DCM / MeOH=25:1, to get TollB-7C-337 as yellowish solid 331mg, yield 46%.

[0374] NMR data of compound 16:

[0375] 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.98 (s, 1H), 8.17 (d, J = 8.7Hz, 2H), 7.94 (d, J = 7.3 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 4.75 (s, 2H),4.56 (t, J = 6.4 Hz, 2H), 4.44 (t, J = 6.1 Hz, 2H), 4.07 (s, 1H), 3.44 (p, J= 6.4 Hz, 1H), 2.81 (d, J = 11.6 Hz, 4H), 2.09 (s, 2H), 1.92 (d, J = 8.1 Hz,4H), 1.80 (d, J = 7.9 Hz, 2H).

[0376] Example 17: Synthesis of compound 17

[0377] (Compound 17)

[0378] 50ml single-necked flask was added intermediate 6-(8-methylquinoxalin-5-yl)-2- (piperidin-4-yl)-4-(trifluoromethyl)isoindolin-l-one hydrochloride 600mg (1.2mmol, 1.0 eq), triethylamine 8ml, 30ml of 1,2-dichloroethane was added, after the solution was added 2-bromoacetamide 183mg (1.32mmol, 1.1 eq), room temperature reaction for 4h; dry loading, EA / MeOH=10:1 column to get TollB-7C-338 yellowish solid 341mg, yield 58.7%.

[0379] NMR data of compound 17:

[0380] 1H NMR (400 MHz, DMSO-D6) δ 9.01 - 8.90 (m, 2H), 8.13 (d, J = 8.3 Hz, 2H), 7.89 (dd, J = 7.4, 1.5 Hz, 1H), 7.79 (dq, J = 7.4, 1.1 Hz, 1H), 7.24 (s, 1H), 7.15 (s, 1H), 4.68 (s, 2H), 4.01 (dtd, J = 12.1, 7.8, 4.2 Hz, 1H), 2.88 (d, J = 13.5 Hz, 4H), 2.75 (s, 3H), 2.25 - 2.14 (m, 2H), 2.03 - 1.89 (m, 2H), 1.73 - 1.65 (m, 2H).

[0381] Example 18: Synthesis of compound 18

[0382] (Compound 18)

[0383] Into a 25 ml single neck flask was added N,N'-carbonyldiimidazole 234 mg (1.44 mmol, 1.2 eq), methylamine hydrochloride 89 mg (1.32 mmol, 1.1 eq), and acetonitrile 6 ml, DMF 2 ml, stirred at room temperature for 2 h. Into another 50 ml flask was added intermediate 6-(8-methylquinoxalin-5-yl)-2-(piperidin-4-yl)-4- (trifluoromethyl)isoindolin-l-one hydrochloride 600 mg (1.2 mmol, 1.0 eq), triethylamine 10 ml, added 15 ml of dichloroethane, after the solution was clear, the reaction solution was added to the 25 ml flask, and reacted at room temperature overnight; dry loading, DCM / MeOH = 15: 1 column, TollB-7C-339 white solid 270 mg, yield 46.5%.

[0384] NMR data of compound 18:

[0385] 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.98 (s, 1H), 8.17 (d, J = 12.2 Hz, 2H), 7.94 (d, J = 7.1 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 6.51 (s, 1H), 4.74 (s, 2H), 4.25 (s, 1H), 4.11 (d, J = 13.2 Hz, 2H), 2.82 (d, J = 13.1 Hz, 5H), 2.61 (s, 3H), 1.74 (t, J = 9.9 Hz, 4H), 1.24 (s, 2H), 0.86 (s, 1H).

[0386] Example 19: Synthesis of compound 19

[0387] (Compound 19)

[0388] Synthesis of tert-butyl-4-[6-bromo-4-(trifluoromethyl)-2H-indazol-2-yl]piperidine-l- carboxylate:

[0389]

[0390] 100 ml single-mouth flask, add 6-bromo-4-(trifluoromethyl)-1H-indazole 2.7 g (10.19 mmol, 1.0 eq), 1-Boc-4-methanesulfonyloxy piperidine 3.3 g (11.82 mmol, 1.16 eq), potassium carbonate 2.82 g (20.37 mmol, 2.0 eq), finally add DMF 30 ml, protect under nitrogen, 100 ℃ reaction overnight. Add 30 ml water, extract with dichloromethane three times (30 ml*3), wash the organic phase with saturated brine twice (20 ml*2), dry over anhydrous magnesium sulfate, filter, rotary evaporation; dry loading, PE:EA=10:1 over the column, rotary evaporation to get yellow solid 1.8 g of intermediate 1, yield 39.39%.

[0391] Synthesis of tert-butyl-4-[6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-2H-indazol-2-yl]piperidine-1-carboxylate:

[0392]

[0393] 100 ml single-mouth flask, add 6-bromo-4-(trifluoromethyl)-1H-indazole 2.7 g (10.19 mmol, 1.0 eq), 1-Boc-4-methanesulfonyloxy piperidine 3.3 g (11.82 mmol, 1.16 eq), potassium carbonate 2.82 g (20.37 mmol, 2.0 eq), finally add DMF 30 ml, protect under nitrogen, 100 ℃ reaction overnight. Add 30 ml water, extract with dichloromethane three times (30 ml*3), wash the organic phase with saturated brine twice (20 ml*2), dry over anhydrous magnesium sulfate, filter, rotary evaporation; dry loading, PE:EA=10:1 over the column, rotary evaporation to get yellow solid 1.8 g of intermediate 1, yield 39.39%.

[0394] Synthesis of tert-butyl-4-[6-(1-methyl-2-oxo-1,2-dihydro-1,8-naphtho[4,5-b]pyridin-4-yl)-4-(trifluoromethyl)-2H-indazol-2-yl]piperidine-1-carboxylate:

[0395]

[0396] 100ml single-mouth flask, add 4-bromo-1-methyl-1,8-naphthyridin-2-one 800mg (3.35mmol, 1.0eq), the above intermediate tert-butyl-4-[6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-2H-indazol-2-yl]piperidine-1-carboxylate 1.8g (3.68mmol, 1.1eq), Pd(dppf)Cl2.CH2Cl2 1340mg (0.17mmol, 0.05eq), add 1,4-dioxane 20ml; after adding sodium carbonate 710mg (18.13mol, 2.0eq) dissolved in 2ml water to the above reaction solution, react overnight under nitrogen protection at 100℃. Cool to room temperature, add 20ml water, extract with ethyl acetate three times (20ml*3), dry over anhydrous magnesium sulfate, filter; dry loading, column chromatography with EA:PE=1:2, rotary evaporation, to get the yellow solid of intermediate 3 1.4g, yield 79.10%.

[0397] Synthesis of 1-methyl-4-[2-(piperidin-4-yl)-4-(trifluoromethyl)-2H-indazol-6-yl]-1,2-dihydro-1,8-naphthalene-2-ketone hydrochloride:

[0398]

[0399] 100ml single-mouth flask, add the above intermediate tert-butyl-4-[6-(1-methyl-2-oxo-1,2-dihydro-1,8-naphtho[4,5-b]pyridin-4-yl)-4-(trifluoromethyl)-2H-indazol-2-yl]piperidine-1-carboxylate 1.4g (2.65mmol, 1.0eq), 3M hydrochloric acid methanol solution 10ml, stir at room temperature for 30min. Rotary evaporation, acetonitrile twice; ethyl acetate slurry, filter to get the yellow solid of intermediate 4 1.2g, yield 90.22%, without further purification, directly used for the next step synthesis.

[0400] Synthesis of compound 19:

[0401] 100 ml single-mouth bottle was added 400 mg (0.97 mmol, 1.0 eq) of the above-mentioned intermediate 1-methyl-4-[2-(piperidin-4-yl)-4-(trifluoromethyl)-2H-indazol-6-yl]-1,2- dihydro-1,8-naphtho-2-ketone hydrochloride, 10 ml of dichloromethane, 392 mg (3.88 mmol, 4.0 eq) of triethylamine, and stirred at room temperature for 5 min; 140 mg (1.94 mmol, 2.0 eq) of 3-oxetanone, 116 mg (1.94 mmol, 2.0 eq) of glacial acetic acid, and 234 mg (1.94 mmol, 2.0 eq) of anhydrous magnesium sulfate were added to the above reaction solution, and stirred at room temperature for 30 min under nitrogen protection; 411 mg (1.94 mmol, 2.0 eq) of sodium triacetylboration hydride was added to the above reaction solution, and reacted at room temperature overnight under nitrogen protection. 10 ml of water was added, extracted with dichloromethane three times (10 ml*3), dried over anhydrous magnesium sulfate, filtered, and rotary evaporated; dry loading, DCM:MeOH=75:1, over column, rotary evaporation; the residue was slurried with PE:EA=10:1, filtered, to obtain 298 mg of white solid of TollB-7C-340, with a yield of 63.55% and a purity of 100%.

[0402] NMR data of compound 19:

[0403] 1H NMR (400 MHz, DMSO-D6) δ 8.67 (d, J = 4.7 Hz, 1H), 8.31 (d, J =16.5 Hz, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.60 (s, 1H), 7.28 (dd, J = 8.0, 4.6Hz, 1H), 6.80 (s, 1H), 4.84 (t, J = 11.3 Hz, 1H), 4.51 (t, J = 6.5 Hz, 2H),4.41 (t, J = 6.1 Hz, 2H), 3.72 (s, 3H), 3.40 (p, J = 6.4 Hz, 1H), 2.80 (d, J= 10.7 Hz, 2H), 2.13 (q, J = 12.4 Hz, 2H), 1.96 (d, J = 12.1 Hz, 4H).

[0404] Example 20: Synthesis of compound 20

[0405] (Compound 20)

[0406] 100 ml single-mouth bottle was added 400 mg of the above intermediate 1-methyl-4-[2-(piperidin-4-yl)-4-(trifluoromethyl)-2H-indazol-6-yl]-1,2-dihydro-1,8-naphtho-2-ketone hydrochloride (0.97 mmol, 1.0 eq), 10 ml of dichloromethane, 392 mg of triethylamine (3.88 mmol, 4.0 eq), after the reaction solution was dissolved, 161 mg of 2-bromoacetamide (1.16 mmol, 1.2 eq) was added, and the reaction was carried out at room temperature under nitrogen protection overnight. 10 ml of water was added, extracted with dichloromethane three times (10 ml*3), dried over anhydrous magnesium sulfate, filtered, and rotary evaporated; dry loading, EA:MeOH=75:1, column, rotary evaporated; the residue was slurried with PE:EA=10:1, filtered, to obtain 254 mg of TollB-7C-341 white solid, yield 53.84%, purity 100%.

[0407] NMR data of compound 20:

[0408] 1H NMR (400 MHz, DMSO-D6) δ 8.67 (dd, J = 4.7, 1.7 Hz, 1H), 8.34 (s,1H), 8.27 (d, J = 1.9 Hz, 1H), 7.84 (dd, J = 8.0, 1.8 Hz, 1H), 7.59 (s, 1H),7.28 (dd, J = 8.0, 4.7 Hz, 1H), 7.24 (s, 1H), 6.80 (s, 1H), 4.87 – 4.77 (m,1H), 3.72 (s, 3H), 2.89 (d, J = 7.1 Hz, 4H), 2.35 – 2.15 (m, 4H), 1.97 – 1.85(m, 3H).

[0409] Example 21: Synthesis of compound 21

[0410] (Compound 21)

[0411] Into a 50 ml single-necked flask, N,N'-carbonyldiimidazole 188 mg (1.16 mmol, 1.2 eq), methylamine hydrochloride 72 mg (1.07 mmol, 1.1 eq), acetonitrile 1 ml, DMF 0.3 ml, stirring at room temperature for 2 h under nitrogen protection. Into another 50 ml single-necked flask, add the above-mentioned intermediate 1-methyl-4-[2-(piperidin-4-yl)-4-(trifluoromethyl)-2H-indazol-6-yl]-1,2-dihydro-1,8-naphthridin-2-one hydrochloride 400 mg (0.97 mmol, 1.0 eq), dichloromethane 10 ml, triethylamine 392 mg (3.88 mmol, 4.0 eq), after the reaction solution is clear, add to the above reaction flask, and react overnight at room temperature under nitrogen protection. Add 10 ml of water, extract with dichloromethane three times (10 ml*3), dry over anhydrous magnesium sulfate, filter, and rotary evaporate; dry loading, DCM:MeOH=50:1 through the column, rotary evaporate; the residue is slurried with PE:EA:MeOH=10:5:1, filtered, to obtain white solid 200 mg of TollB-7C-342, with a yield of 42.56% and a purity of 90%.

[0412] NMR data of compound 21:

[0413] 1H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H),8.21 (s, 1H), 7.93 – 7.87 (m, 1H), 7.65 (s, 1H), 7.33 (s, 1H), 7.26 (s, 1H),6.86 (s, 1H), 6.54 (s, 1H), 5.07 (s, 1H), 4.11 (d, J = 12.2 Hz, 2H), 3.78 (s,3H), 2.96 – 2.78 (m, 3H), 2.60 (s, 3H), 1.97 (s, 4H), 1.45 – 1.15 (m, 2H).

[0414] Example 22: Synthesis of compound 22

[0415] (Compound 22)

[0416] Synthesis of tert-butyl 4-(5-(8-chloroquinolin-5-yl)-3-oxo-1-(trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate

[0417] 100ml single-necked flask, add tert-butyl 4-(5-(8-chloroquinolin-5-yl)-3-oxo-1- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 1.0g (1.83mmol), 20ml 3N HCl / MeOH, stir at room temperature overnight, spin dry. 100ml single-necked flask, add the above reaction product 0.5g (0.95mmol, 1.0eq), dichloromethane 50ml, triethylamine 0.39g (3.84mmol, 4.0eq), glacial acetic acid 0.12g (1.92mmol, 2.0eq), finally add 3-oxetanone 0.27g (3.84mmol, 4.0eq), react at room temperature for 1h. Add sodium triethoxyborohydride 0.81g (5.07mmol, 4.0eq), react at room temperature overnight under nitrogen protection. Add 30ml water to quench, extract with DCM three times (30ml*3), combine the organic phase, wash twice with saturated aqueous sodium bicarbonate solution, dry the organic phase over anhydrous magnesium sulfate, filter, pass through a column with DCM / MeOH=20:1, obtain colorless solid 262mg, yield 54%.

[0418] Synthesis of compound 22:

[0419] 100ml single-necked flask, add tert-butyl 4-(5-(8-chloroquinolin-5-yl)-3-oxo-1- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 1.0g (1.83mmol), 20ml 3N HCl / MeOH, stir at room temperature overnight, spin dry. 100ml single-necked flask, add the above reaction product 0.5g (0.95mmol, 1.0eq), dichloromethane 50ml, triethylamine 0.39g (3.84mmol, 4.0eq), glacial acetic acid 0.12g (1.92mmol, 2.0eq), finally add 3-oxetanone 0.27g (3.84mmol, 4.0eq), react at room temperature for 1h. Add sodium triethoxyborohydride 0.81g (5.07mmol, 4.0eq), react at room temperature overnight under nitrogen protection. Add 30ml water to quench, extract with DCM three times (30ml*3), combine the organic phase, wash twice with saturated aqueous sodium bicarbonate solution, dry the organic phase over anhydrous magnesium sulfate, filter, pass through a column with DCM / MeOH=20:1, obtain colorless solid 262mg, yield 54%.

[0420] NMR data of compound 22:

[0421] 1H NMR (400 MHz, DMSO) δ 9.09 (dd, J = 4.1, 1.6 Hz, 1H), 8.17 (dd, J= 8.6, 1.6 Hz, 1H), 8.11 - 8.00 (m, 3H), 7.71 - 7.62 (m, 2H), 4.79 (s, 2H),4.56 (t, J = 6.5 Hz, 2H), 4.44 (t, J = 6.1 Hz, 2H), 3.45 (p, J = 6.3 Hz, 1H),2.82 (d, J = 7.1 Hz, 2H), 1.94 (dq, J = 12.8, 9.8 Hz, 4H), 1.80 (d, J = 9.2Hz, 2H), 1.24 (d, J = 7.0 Hz, 2H).

[0422] Example 23: Synthesis of compound 23

[0423] (Compound 23)

[0424] 100ml single neck flask, add tert-butyl 4-(5-(8-chloroquinolin-5-yl)-3-oxo-1- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 1.0g (1.83mmol), 20ml 3N HCl / MeOH, stir at room temperature overnight, spin dry. 100ml single neck flask, add above reaction product 0.5g (0.95mmol, 1.0eq), dichloromethane 50ml, triethylamine 0.39g (3.84mmol, 4.0eq), bromoacetamide 0.16g (1.16mmol, 1.2eq), react at room temperature overnight. Spin dry, column with DCM / MeOH=20:1, get colorless solid 287mg, yield 60%.

[0425] NMR data of compound 23:

[0426] 1H NMR (400 MHz, DMSO) δ 9.09 (dd, J = 4.1, 1.6 Hz, 1H), 8.17 (dd, J= 8.6, 1.6 Hz, 1H), 8.05 (t, J = 9.1 Hz, 3H), 7.71 - 7.62 (m, 2H), 7.31 -7.25 (m, 1H), 7.20 (d, J = 3.3 Hz, 1H), 4.77 (s, 2H), 4.14 - 3.99 (m, 2H),2.94 (d, J = 13.9 Hz, 4H), 2.31 - 2.20 (m, 2H), 2.06 (dd, J = 12.1, 3.8 Hz,1H), 2.01 (d, J = 6.3 Hz, 2H), 1.75 (dd, J = 12.2, 4.1 Hz, 2H), 1.18 (t, J =7.1 Hz, 1H).

[0427] Example 24: Synthesis of compound 24

[0428] (Compound 24)

[0429] 100ml single neck flask, add tert-butyl 4-(5-(8-chloroquinolin-5-yl)-3-oxo-1- (trifluoromethyl)isoindolin-2-yl)piperidine-1-carboxylate 1.0g (1.83mmol), 20ml 3N HCl / MeOH, stir at room temperature overnight, spin dry. 50ml single neck flask, add above reaction product 0.89g (1.71mmol, 1.0eq), dichloromethane 15ml, triethylamine 0.69g (6.84mmol, 4.0eq), stir to dissolve, ready for use. Another 25ml single neck flask, add carbonyldiimidazole 0.34g (2.05mmol, 1.2eq), methylamine hydrochloride 0.13g (1.89mmol, 1.1eq), DMF 2ml, acetonitrile 6ml, protect with nitrogen, react at room temperature for 2h, then add to the above ready for use solution, protect with nitrogen, react at room temperature overnight. Spin dry, pass through a column with DCM / MeOH=20:1, get colorless solid 664mg, yield 77%.

[0430] NMR data of compound 24:

[0431] 1H NMR (400 MHz, DMSO) δ 9.09 (d, J = 4.1 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.06 (dd, J = 12.6, 8.1 Hz, 3H), 7.66 (t, J = 7.3 Hz, 2H), 6.50 (q, J = 4.3 Hz, 1H), 4.77 (s, 2H), 4.25 (p, J = 8.2 Hz, 1H), 4.10 (d, J = 13.0 Hz, 2H), 2.81 (p, J = 7.1 Hz, 2H), 2.60 (d, J = 4.2 Hz, 3H), 1.76 (d, J = 8.4 Hz, 4H).

[0432] Example 25: Synthesis of compound 25

[0433] (Compound 25)

[0434] Synthesis of 6-bromo-4-(trifluoromethyl)isoindolin-1-one:

[0435]

[0436] Into a 250ml three-necked flask was added 5-bromo-2-(bromomethyl)-3- (trifluoromethyl)benzoic acid methyl ester 12g (31.92mmol, 1.0 eq), dichloromethane 150ml; 7M methylamine methanol solution 60ml was added slowly under stirring at 0°C, and stirred at room temperature overnight. After rotary evaporation, 60ml water was added, and the mixture was extracted with ethyl acetate three times (60ml*3), dried over anhydrous magnesium sulfate, filtered over silica gel, and the filtrate was rotary evaporated; the residue was slurried with petroleum ether to obtain yellow solid 6.9g of intermediate 1, with a yield of 77.18%.

[0437] Synthesis of 6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-2,3- dihydro-1H-isoindol-1-one:

[0438]

[0439] Into a 200ml single-necked flask was placed the above intermediate 6-bromo-4- (trifluoromethyl) isoindolin-1-one 6.9g (24.64mmol, 1.0 eq), 1,4-dioxane 100ml, bis(pinacolato)diboron 7.51g (29.57mmol, 1.2 eq), potassium acetate 4.84g (49.28mmol, 2.0 eq), Pd(dppf)Cl2.CH2Cl2 1.01g (1.23mmol, 0.05 eq), and stirred at 90°C under nitrogen protection for 4h. After cooling to room temperature, the reaction solution was rotary evaporated, dried loaded, and columned with DCM. The residue was slurried with petroleum ether, and filtered to give the intermediate 2 as brown solid 6.9g in 85.61% yield.

[0440] Synthesis of compound 25:

[0441] Into a 200ml single-necked flask was placed 4-bromo-1-methyl-1,8-naphthyridin-2- one 3g (12.55mmol, 1.0 eq), the above intermediate 6-(tetramethyl-1,3,2-dioxaborolan-2-yl)- 4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 4.93g (15.06mmol, 1.3 eq), Pd(dppf)Cl2.CH2Cl2 512mg (0.63mmol, 0.05 eq), and 1,4-dioxane 50ml. Sodium carbonate 2.66g (25.10mol, 2.0 eq) dissolved in 5ml water was added to the above reaction solution, and stirred at 95°C under nitrogen protection overnight. After cooling to room temperature, 30ml water was added, and extracted with dichloromethane three times (30ml*3), dried over anhydrous magnesium sulfate, and filtered. The residue was dried loaded, columned with DCM:MeOH=50:1, and rotary evaporated. The residue was slurried with PE:EA:MeOH=10:1:1, and filtered to give TollB-7C-346 as off-white solid 2.66g in 58.98% yield.

[0442] NMR data of compound 25:

[0443] 1H NMR (400 MHz, DMSO) δ 9.07 (s, 1H), 8.71 (s, 1H), 8.07 (s, 1H),8.02 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.31 (s, 1H), 6.80 (s, 1H), 4.67(s, 2H), 3.76 (s, 3H), 1.24 (s, 2H).

[0444] Example 26: Synthesis of compound 26

[0445] (compound 26)

[0446] 50ml three-necked flask was added cuprous iodide 79.51mg (0.42mmol, 0.3eq), potassium phosphate tribasic 886.14mg (4.17mmol, 3.0eq), DMF 2ml, stirred for 5min under nitrogen protection at room temperature; to the above reaction solution was added trans-1,2-cyclohexanediamine 47.67mg (0.42mmol, 0.3eq), stirred for 30min under nitrogen protection at room temperature; TollB-7C-346 500mg (1.39mmol, 1.0eq) and 4-iodopyridine 342mg (1.67mmol, 1.2eq) were dissolved in 5ml DMF and added to the above reaction solution, reacted overnight under nitrogen protection at 110°C. Cooled to room temperature, the reaction solution was poured into ice water, a solid was precipitated, filtered; the solid was dissolved in DCM:MeOH=50:1, dried with anhydrous magnesium sulfate, filtered on silica gel, the filtrate was rotary evaporated; the residue was slurried with PE:EA:DCM:MeOH=5:1:1:1, filtered to get light yellow solid 200mg, yield 32.93%, purity 94%.

[0447] NMR data of compound 26:

[0448] 1H NMR (400 MHz, DMSO-d6) δ 8.51 – 8.45 (m, 2H), 8.33 (dd, J = 4.7,2.2 Hz, 1H), 8.28 – 8.18 (m, 2H), 7.92 (dq, J = 2.6, 1.3 Hz, 1H), 7.34 (dd, J= 8.3, 4.8 Hz, 1H), 7.17 – 7.11 (m, 2H), 6.50 (s, 1H), 5.07 (s, 2H).

[0449] Example 27: Synthesis of compound 27

[0450] (Compound 27)

[0451] Into a 50ml flask, add cuprous iodide 79.51mg (0.42mmol, 0.3eq), potassium phosphate tribasic 886.14mg (4.17mmol, 3.0eq), DMF 2ml, stir for 5min under nitrogen protection at room temperature; add trans-1,2-cyclohexanediamine 47.67mg (0.42mmol, 0.3eq) into the above reaction solution, stir for 30min under nitrogen protection at room temperature; dissolve TollB-7C-346 500mg (1.39mmol, 1.0eq) and 1-methyl-4-iodopyrazole 347mg (1.67mmol, 1.2eq) in 5ml DMF and add into the above reaction solution, react overnight under nitrogen protection at 110°C. Cool to room temperature, pour the reaction solution into ice water, solid precipitates, filter; dissolve the solid in DCM:MeOH=50:1, dry with anhydrous magnesium sulfate, filter through silica gel, spin dry the filtrate; slurry the residue with PE:EA:MeOH=5:1:1, filter to get purple solid 60mg, yield 9.8%, purity 95%.

[0452] NMR data of compound 27:

[0453] 1H NMR (400 MHz, DMSO-d6) δ 8.33 (dd, J = 4.7, 2.2 Hz, 1H), 8.28 –8.18 (m, 2H), 7.92 (dq, J = 2.6, 1.3 Hz, 1H), 7.34 (dd, J = 8.3, 4.8 Hz, 1H),7.27 (s, 1H), 7.21 (s, 1H), 6.50 (s, 1H), 5.18 (s, 2H), 3.75 (s, 3H).

[0454] Experimental Example 1: Activity determination of the compounds of the present application

[0455] (1) Remove the original culture medium in the HEK-blue-hTLR7 cell culture dish, blow and count the cells in DMEM. Uniformly distribute the cells in a 96-well plate, with a cell number of 50,000 cells per well.

[0456] (2) Add the activator Gardiquimod to a final concentration of 3 μg / mL. Add different concentrations of the test molecules.

[0457] (3) After 24 hours of incubation in the incubator, take 50 μL of supernatant to a new 96-well plate, and then add 50 μL of Quanti-Blue (chromogenic agent). After the negative control well turns blue, test its absorbance at 620 nm (use skanIt software to measure wavelength).

[0458] (4) Add 5 μL / well of CCK-8 to the remaining cell-containing plates, and after the untreated cell wells turn yellow to a certain level, test the absorbance at 450 nm.

[0459] (5) Data analysis. (The readings of cells treated only with Gardiquimod were normalized to 100% activation, while the untreated cells were 0% activation; the readings of untreated cells were normalized to 100% survival.)

[0460] The IC50 of compounds 1-27 is shown in the following table. It can be seen that the compounds 1-27 provided by the present application have strong inhibitory effect on TLR7.

[0461] Table 1. TLR7 inhibitory activity (IC50 value) of compounds 1-27

[0462]

[0463] For the IC50 value, "+" means that the IC50 value is greater than 1 μM, "++" means that the IC50 value is greater than 500 nM and less than or equal to 1 μM, "+++" means that the IC50 value is greater than 100 nM and less than or equal to 500 nM; "++++" means that the IC50 value is greater than 20 nM and less than or equal to 100 nM; "+++++" means that the IC50 value is less than or equal to 20 nM.

[0464] It is found by the above experimental examples that the compound of formula (II) of the present application has strong inhibitory effect on TLR7 activity.

[0465] The foregoing description of specific exemplary embodiments of the disclosure is intended to be illustrative only and is not intended to limit the disclosure to the precise forms described. Many modifications and variations are possible in light of the above teachings without departing from the spirit or essential characteristics of the disclosure. The exemplary embodiments were chosen and described in order to explain the principles of the disclosure and its practical application and to allow others skilled in the art to understand the various exemplary embodiments and various modifications as are suited to the particular use contemplated. The scope of the disclosure is intended to be defined by the claims and their equivalents.

Claims

1. A compound represented by formula (IV) or a pharmaceutically acceptable salt, tautomer, stereoisomer thereof, wherein, X, X2, X3are each independently selected from one of C, CH or N; X1is N; Y is a substituent at a substitutable position of ring W except the position of X; ring W is selected from a benzene ring or a pyridine ring; ring A is selected from nothing or a pyridine ring; ring B is selected from nothing, a pyridine ring or a pyrazine ring; there is and only one of the ring A, ring B; n is 1; R2is trifluoromethyl; the compound has a structure represented by formula (V): wherein, X is selected from one of C, CH or N; X1is N; Y is a substituent at a substitutable position of ring W except the position of X; ring W is selected from a benzene ring or a pyridine ring; ring A is a pyridine ring; the compound has a structure represented by formula (VI): wherein, X, X2, X3are each independently selected from one of C, CH or N; Y is a substituent at a substitutable position of ring W except the position of X; ring W is selected from a benzene ring or a pyridine ring; ring B is selected from a pyridine ring or a pyrazine ring; n is 1; Y is selected from hydrogen, oxo. (Ⅳ) 11. The following compound or a pharmaceutically acceptable salt, tautomer, stereoisomer thereof: .

12. A pharmaceutical composition comprising the compound of any one of claims 1-11 or a pharmaceutically acceptable salt, tautomer, stereoisomer thereof, optionally comprising a pharmaceutically acceptable excipient.

13. Use of the compound of any one of claims 1-11 or a pharmaceutically acceptable salt, tautomer, stereoisomer thereof, or the pharmaceutical composition of claim 12 in the manufacture of a medicament for treating a TLR7 related disease. When X is selected from C or N, R 11 The substituent is at the X position; ​ ​ ​ ​ ​ ​ Y is selected from hydrogen, oxo, C 1-3 alkyl; R 11 selected from hydrogen, halogen, cyano, C 1-3 alkyl; R A selected from hydrogen, C 1-3 alkyl; R B selected from hydrogen, C 1-3 alkyl; ​ R3is selected from piperidine; said piperidine is optionally substituted with one -(CH2)C(=0)NH2, -C(=0)NHCH3, substituted; "represents a single or double bond.​ 2. The compound or pharmaceutically acceptable salt, tautomer, stereoisomer thereof according to claim 1, characterized in that, ​ (Ⅴ) ​ ​ ​ When X is selected from C or N, R 11 The substituent is at the X position; ​ ​ ​ Y, R 11 Y, R A R2, R3 are each defined as in formula (IV) in claim 1; "represents a single or double bond.​ 3. The compound of claim 1, or a pharmaceutically acceptable salt, tautomer, stereoisomer thereof, wherein ​ (Ⅵ) ​ ​ When X is selected from C or N, R 11 The substituent is at the X position; ​ ​ ​ ​ Y, R 11 , R B , R2, R3 are each defined as in formula (IV) in claim 1 ; "represents a single or double bond.​ 4. The compound or pharmaceutically acceptable salt, tautomer, stereoisomer thereof according to claim 1, characterized in that, selected from , , ; wherein Y, R 11 are as defined in formula (IV) in claim 1.

5. The compound or pharmaceutically acceptable salt, tautomer, stereoisomer thereof according to claim 4, characterized in that, selected from , , , , , .

6. The compound or pharmaceutically acceptable salt, tautomer, stereoisomer thereof according to any one of claims 1-4, characterized in that, ​ 7. The compound or pharmaceutically acceptable salt, tautomer, stereoisomer thereof according to any one of claims 1-4, characterized in that, R 11 selected from hydrogen, Cl, cyano, methyl, ethyl.

8. The compound or pharmaceutically acceptable salt, tautomer, stereoisomer thereof according to any one of claims 1-3, characterized in that, R A is hydrogen.

9. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, tautomer, stereoisomer thereof, wherein, R B is hydrogen.

10. The compound or pharmaceutically acceptable salt, tautomer, stereoisomer thereof according to any one of claims 1-5, characterized in that, R3is selected from , , . ​ (compound 1), (compound 2), (compound 3), (compound 4), (compound 5), (compound 6), (compound 7), (compound 8), (compound 9), (compound 10), (compound 11), (compound 12), (compound 16), (compound 17), (compound 18), (compound 22), (compound 23), (compound 24). ​ ​

Images