Compound for inhibiting TLR8 activity and use thereof

Abstract

The present application relates to a compound of formula (I) for inhibiting Toll-like receptor 8 (TLR8) activity, a stereoisomer thereof, an atropisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, a pharmaceutically acceptable salt of the atropisomer thereof or a pharmaceutically acceptable salt of the deuterated derivative thereof, and a method for preparing the compound, a composition thereof and the use thereof.

Description

A compound for inhibiting TLR8 activity and its use

[0001] This application claims priority to the prior application with international application number PCT / CN2024 / 070962 filed on January 5, 2024, and invention name “A compound for inhibiting TLR8 activity and its use”, the entire contents of which are incorporated by reference into this application. Technical Field

[0002] The present application belongs to the field of medicinal chemistry and relates to a compound having TLR8 inhibitory activity, as well as the compound, its preparation method and use. Background Art

[0003] The innate immune response is the first line of defense against pathogenic microorganisms and is also involved in autoimmune-mediated inflammatory diseases. This response is primarily triggered by Toll-like receptors (TLRs), which are activated by exogenous molecules or, in immune-mediated inflammatory diseases, by molecules released by damaged host cells.

[0004] Toll-like receptors (TLRs) are evolutionarily conserved type I transmembrane proteins of the innate immune system that recognize conserved molecular patterns (pathogen-associated molecular patterns, PAMPs) present in proteins, lipids, and nucleic acids of pathogens. Activation of the TLR pathway leads to host defense mechanisms such as the secretion of inflammatory cytokines, induction of the interferon pathway, and activation of B cells and neutrophils (Nature immunology 2010, 11(5), 373-84.) Endosome TLRs, TLR3, TLR7 / 8, and TLR9, recognize double-stranded RNA (dsDNA), GU-rich single-stranded RNA (ssRNA), and unmethylated single-stranded DNA (ssDNA), respectively. Aberrant activation of these nucleic acid-sensing endosomal TLRs is thought to be a key driver of systemic lupus erythematosus (SLE) and Sjögren's syndrome (SJS). syndrome) and other autoimmune diseases (Annual review of immunology 2007, 25, 419-41; Nature reviews. Immunology 2015, 15 (9), 529-44.). Genetic and functional evidence show that chronic overactivation of TLR7 / 8 caused by endogenous ssRNA is a driving factor for a variety of systemic autoimmune diseases. For example, TLR7 gain-of-function mutations have been found in children with severe autoimmune diseases, and expression of this mutant in mice can lead to fatal lupus-like diseases (Nature 2022, 605 (7909), 349-356). Overexpression of TLR7 (Immunity 2007, 27 (5), 801-10) or human TLR8 can also lead to this situation (Journal of experimental medicine 2013, 210 (13), 2903-19). Increased activation of TLR7 and TLR8 can drive a variety of cellular mechanisms of systemic autoimmune diseases. For example, RNA-containing immune complexes (ICs) between patient autoantibodies and ribonucleoproteins (RNPs) drive plasmacytoid dendritic cells (pDCs) to secrete type I interferon (IFN) (Journal of experimental medicine 2005, 202(8), 1131-9) and IFN (Journal of experimental medicine 2017, 214, 1547) in a TLR7-dependent manner, and elevated IFN-stimulated gene signatures are characteristic of SLE patients (Cell 2016, 165(3), 551). Neutrophils are activated through TLR8 (Nat. Commun. 2020, 11 (1), 105) Autoreactive B cells internalize RNA-containing autoantigens to activate TLR7 (Autoimmunity 2010, 43 (1), 76-83), and the complex RNA-containing autoantigens are phagocytosed by monocytes / DCs to activate TLR8 (Journal of experimental medicine 2009, 206 (9), 1983-94). In summary, TLR7 / 8 enhances the activation of autoreactive B cells, pDCs, and monocytes / DCs, increases the secretion of antinuclear antibodies (ANA), and maintains a self-sustaining feedback loop of inflammation and tissue damage. Based on gene polymorphism studies, TLR8 is associated with human inflammatory diseases, including rheumatoid arthritis (RA), antiphospholipid syndrome, and IBD. In addition, TLR8 signaling promotes RA in both human TLR8 transgenic mice and human patients.

[0005] Therefore, it is necessary to develop a small molecule TLR8 inhibitor with high bioavailability. Summary of the Invention

[0006] This application provides a novel compound for treating TLR8-mediated immune-related diseases and its uses. The details are as follows:

[0007] In a first aspect, the present application provides a compound of formula (I), its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers, or its acceptable salts of deuterated derivatives,

[0008] in,

[0009] R1 or R2 at each occurrence are independently selected from -C 1-6 Alkyl; said R1 or R2 are independently optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 deuterium or halogen;

[0010] Y1 is selected from -OH, -OS(=O)-R4 or -OS(=O)2-R4; preferably selected from -OS(=O)-R4 or -OS(=O)2-R4;

[0011] R4 is -N(R 41 )2; among them,

[0012] The R 41 independently selected at each occurrence from hydrogen, -C 1-6 Alkyl, -C 1-6 Alkenyl, -C 1-6 Alkynyl, -C 1-6 Haloalkyl, -C 1-6 Alkoxy, 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0013] The R 41 independently optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 atoms selected from deuterium, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, 6-12 membered aryl or 5-10 membered heteroaryl;

[0014] R S1 or R S2 is independently selected at each occurrence from deuterium, halogen, -C 1-6 Alkyl, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -S(=O)(OC 1-6alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 Alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), 3-10 membered carbocyclyl, 3-10 membered heterocyclyl, 6-12 membered aryl or 5-10 membered heteroaryl; the R S1 or R S2 independently optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms selected from deuterium, -C 1-3 Alkyl, -C 1-3 Alkenyl, -C 1-3 Alkynyl, -C 1-3 Haloalkyl, -C 1-3 Alkoxy, -CN, -NH2, -COOH, -NH(C 1-3 Alkyl), -N(C 1-3 Alkyl)2, -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -C(=O)(C 1-3 alkyl), -S(=O)(C 1-3 alkyl), -S(=O)2(C 1-3 alkyl), -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl)2, -NHC(=O)(C 1-3 Alkyl), -N(C 1-3 alkyl)C(=O)(C 1-3 alkyl), -C(=O)O(C 1-3 alkyl), -OC(=O)(C 1-3 alkyl), -S(=O)NH2, -S(=O)NH(C 1-3 alkyl), -S(=O)N(C 1-3 Alkyl)2, -NHS(=O)(C 1-3 Alkyl), -N(C 1-3 alkyl)S(=O)(C 1-3 alkyl), -S(=O)2NH2, -S(=O)2NH(C1-3 alkyl), -S(=O)2N(C 1-3 alkyl)2, -NHS(=O)2(C 1-3 Alkyl), -N(C 1-3 alkyl)S(=O)2(C 1-3 alkyl), 3-7 membered carbocyclyl, 3-7 membered heterocyclyl, phenyl or 5-10 membered heteroaryl;

[0015] n1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0016] n2 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0017] The heterocyclyl or heteroaryl group independently includes one or more heteroatoms selected from N, O or S at each occurrence.

[0018] Preferably, when Y1 is -OH, R2 is independently optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 deuteriums.

[0019] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer or its acceptable salt of its deuterated derivative,

[0020] Y1 is -OS(=O)2-R4; R4 is defined as in the first aspect of the present application.

[0021] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer or its acceptable salt of its deuterated derivative,

[0022] R4 is -N(R 41 )2; among them,

[0023] The R 41 independently selected at each occurrence from hydrogen, -C 1-3 Alkyl; the R 41 are independently optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 deuteriums.

[0024] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer or its acceptable salt of its deuterated derivative,

[0025] R4 is independently selected at each occurrence from -NH2, -NDH, -ND2, -NH(CH3), -N(CH3)2, -N(CD3)2, -NH(CH2CH3), -NH(CH2CH2CH3), - NH(CH(CH3)2), -NDH-(CH2D), -NDH-(CHD2), -NDH-(CD3), -NDH-(CH2CH3), -NDH-(CHD-CH3), -NDH-(C D2-CH3), -NDH-(CH2CDH2), -NDH-(CH2CHD2), -NDH-(CH2CD3), -NDH-(CHDCD3), -NDH-(CD2CD3), -ND H-(CH2CH2CD3), -NDH-(CH2CD2CD3), -NDH-(CD2CD2CD3), -NDH-(CH(CH3)2), -NDH-(CD(CH3)2), -NDH -(CD(CD3)(CH3)), -NDH-(CH(CD3)2), -NDH-(CD(CD3)2), -ND2-(CH2D), -ND2-(CHD2), -ND2-(CD3), -ND2-(CH2CH3), -ND2-(CHD-CH3), -ND2-(CD2-CH3), -ND2-(CH2CDH2), -ND2-(CH2CHD2), -ND2-(CH2C D3), ​​-ND2-(CHDCD3), -ND2-(CD2CD3), -ND2-(CH2CH2CD3), -ND2-(CH2CD2CD3), -ND2-(CD2CD2CD3), -ND2-(CH(CH3)2), -ND2-(CD(CH3)2), -ND2-(CD(CD3)(CH3)), -ND2-(CH(CD3)2), -ND2-(CD(CD3)2);

[0026] Preferably, R4 is independently selected at each occurrence from -NH2, -NDH, -ND2, -NH(CH3), -NH(CD3), -N(CH3)2, -N(CD3)2, -NH(CH2CH3), -NH(CH2CD3), -NH(CD2CD3), -NH(CH(CH3)2), -NH(CH(CD3)2), -NH(CH2CH2CH3), -NH(CH2CH2CD3) or -NH(CH2CD2CD3);

[0027] Preferably, R4 is independently selected at each occurrence from -NH2, -NDH, -ND2, -NH(CD3), -N(CH3)2, -N(CD3)2;

[0028] More preferably, R4 at each occurrence is independently selected from -NH2.

[0029] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer or its acceptable salt of its deuterated derivative,

[0030] Y1 is selected from -OS(=O)2-NH2, -OS(=O)2-NDH, -OS(=O)2-ND2, -OS(=O)2-NH(CD3), -OS(=O)2-N(CH3)2, -OS(=O)2-N(CD3)2, -OS(=O)2-NH(CH2CH3), -OS(=O)2-NH(CH2CH2CH3), -OS(=O)2-NH(CH(CH3)2), -OS(=O)2-NDH-(CH2D), -OS(=O)2-NDH-(CHD2), -OS(=O)2-NDH-(CD3), -OS(=O)2-NDH-(CH2CH3), -OS(=O)2-NDH-(CHD-CH3), -OS(=O)2-NDH-(CD2-CH3), -OS(=O)2-NDH-(CH2CDH2), -OS(=O)2-NDH-(CH2CHD2), -OS(=O)2-NDH-(CH2CD3), -OS(=O)2-NDH-(CHDCD3), -OS(=O)2-NDH-(CD2CD3), -OS(=O)2-NDH-(CH2CH2CD3), -OS(=O)2-NDH-(CH2CD2CD3), -OS(=O)2-NDH-(CD2CD2CD3), -OS(=O)2-NDH-(CH(CH3)2), -OS(=O)2-NDH-(CD(CH3)2), -OS(=O)2-NDH-(CD(CD3)(CH3)), -OS(=O)2-NDH-(CH(CD3)2), -OS(=O)2-NDH-(CD(CD3)2), -OS(=O)2-ND2-(CH2D), -OS(=O)2-ND2-(CHD2), -OS(=O)2-ND2-(CD3), -OS(=O)2-ND2-(CH2CH3), -OS(=O)2-ND2-(CHD-CH3), -OS(=O)2-ND2-(CD2-CH3), -OS(=O)2-ND2-(CH2CDH2), -OS(=O)2-ND2-(CH2CHD2), -OS(=O)2-ND2-(CH2CD3), -OS(=O)2-ND2-(CHDCD3), -OS(=O)2-ND2-(CD2CD3), -OS(=O)2-ND2-(CH2CH2CD3), -OS(=O)2-ND2-(CH2CD2CD3), -OS(=O)2-ND2-(CD2CD2CD3), -OS(=O)2-ND2-(CH(CH3)2), -OS(=O)2-ND2-(CD(CH3)2), -OS(=O)2-ND2-(CD(CD3)(CH3)),-OS(=O)2-ND2-(CH(CD3)2), -OS(=O)2-ND2-(CD(CD3)2);,

[0031] Preferably, Y1 is selected from -OS(=O)2-NH2, -OS(=O)2-NDH, -OS(=O)2-ND2, -OS(=O)2-NH(CD3), -OS(=O)2-N(CH3)2 or -OS(=O)2-N(CD3)2;

[0032] More preferably, Y1 is -OS(=O)2-NH2.

[0033] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers, or its acceptable salts of deuterated derivatives, is selected from Formula (I-1A) or (I-1B):

[0034] in,

[0035] The R1, R2, R3, R4, R S1 、R S2 , n1 and n2 are defined as in the first aspect of this application.

[0036] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers, or its acceptable salts of deuterated derivatives, is selected from the following formula (I-2):

[0037] in,

[0038] R 41 is independently selected at each occurrence from hydrogen or -C 1-3 Alkyl; the R 41 independently optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 deuterium;

[0039] The R1, R2, R S1 、R S2 , n1 and n2 are defined as in the first aspect of this application.

[0040] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer or its acceptable salt of its deuterated derivative,

[0041] R1 or R2 at each occurrence are independently selected from H or -C 1-3 Alkyl; said R1 or R2 are independently optionally substituted by 1, 2, 3, 4, 5 or 6 substituents selected from deuterium or halogen;

[0042] Preferably, R1 or R2, at each occurrence, is independently selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2D, -CHD2, -CD3, -CH2CH3, -CHD-CH3, -CD2-CH3, -CH2CDH2, -CH2CHD2, -CH2CD3, -CHDCD3, -CD2CD3, -CH2CH2CD3, -CH2CD2CD3, -CD2CD2CD3, -CH(CH3)2, -CD(CH3)2, -CD(CD3)(CH3), -CH(CD3)2, or -CD(CD3)2;

[0043] More preferably, R1 or R2 at each occurrence is independently selected from CH3, -CH2D, -CHD2 or -CD3.

[0044] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer or its acceptable salt of its deuterated derivative,

[0045] R1 at each occurrence is independently selected from -CH3, -CH2D, -CHD2 or -CD3.

[0046] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer or its acceptable salt of its deuterated derivative,

[0047] R1 at each occurrence is independently selected from -CH3.

[0048] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer or its acceptable salt of its deuterated derivative,

[0049] R2 at each occurrence is independently selected from -CH3, -CH2D, -CHD2 or -CD3.

[0050] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer or its acceptable salt of its deuterated derivative,

[0051] R2 at each occurrence is independently selected from -CD3 or -CH3.

[0052] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers, or its acceptable salts of deuterated derivatives, the compound is selected from any one of the following formulae:

[0053] in,

[0054] The R4, R S1 、R S2 , n1 and n2 are defined as in the first aspect of this application.

[0055] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, its pharmaceutically acceptable salt of the atropisomer, or its acceptable salt of the deuterated derivative, wherein the compound is selected from any one of the following formulas:

[0056] in,

[0057] R 41 is independently selected at each occurrence from hydrogen or -C 1-3 Alkyl; the R 41 independently optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 deuterium;

[0058] The R S1 、R S2 , n1 and n2 are defined as in the first aspect of this application.

[0059] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomer, its atropisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its pharmaceutically acceptable salt of its atropisomer or its acceptable salt of its deuterated derivative,

[0060] R 41 Each occurrence is independently selected from H, D, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2D, -CHD2, -CD3, -CH2CH3, -CHD-CH3, -CD2-CH3, -CH2CDH2, -CH2CHD2, -CH2CD3, -CHDCD3, -CD2CD3, -CH2CH2CD3, -CH2CD2CD3, -CD2CD2CD3, -CH(CH3)2, -CD(CH3)2, -CD(CD3)(CH3), -CH(CD3)2, -CD(CD3)2;

[0061] Preferably, R 41 is independently selected at each occurrence from H, D, -CH3 or -CD3;

[0062] More preferably, R 41 is independently selected from H at each occurrence.

[0063] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers, or its acceptable salts of deuterated derivatives, the compound is selected from any one of the following formulae:

[0064] In some embodiments of the present application, the compound described in the first aspect of the present application, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers, or its acceptable salts of deuterated derivatives, the compound is selected from any one of the following formulae:

[0065] In a second aspect, the present application provides a pharmaceutical composition comprising the compound described in the first aspect of the present application, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers or acceptable salts of its deuterated derivatives; and at least one pharmaceutically acceptable excipient.

[0066] In a third aspect, the present application provides a compound described in the first aspect of the present application, a stereoisomer thereof, a transisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a transisomer thereof, or an acceptable salt of a deuterated derivative thereof; or the use of the pharmaceutical composition described in the second aspect of the present application in the preparation of a medicament for inhibiting a TLR8-dependent immune response; wherein the immune response is related to an autoimmune disease, and the autoimmune disease is related to increased expression of TLR8; the immune disease is selected from rheumatoid arthritis, pancreatitis, mixed tissue connective disease, systemic lupus erythematosus, antiphospholipid syndrome, irritable bowel disease, type 1 diabetes, and Sjögren's disease.

[0067] In a fourth aspect, the present application provides a method for treating a subject suffering from an autoimmune disease associated with increased expression of TLR8, the method comprising administering to the subject a therapeutically effective amount of the compound described in the first aspect of the present application, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of stereoisomers, its pharmaceutically acceptable salts of atropisomers, or an acceptable salt of its deuterated derivatives; or the pharmaceutical composition described in the second aspect of the present application; wherein the immune response is associated with an autoimmune disease, and the autoimmune disease is associated with increased expression of TLR8; the immune disease is selected from rheumatoid arthritis, pancreatitis, mixed tissue connective disease, systemic lupus erythematosus, antiphospholipid syndrome, irritable bowel disease, type 1 diabetes, and Sjögren's syndrome.

[0068] In a fifth aspect, the present application provides a compound described in the first aspect of the present application, a stereoisomer thereof, a transisomer thereof, a deuterated derivative thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a pharmaceutically acceptable salt of a transisomer thereof, or an acceptable salt of a deuterated derivative thereof; or the pharmaceutical composition described in the second aspect of the present application for use in treating autoimmune diseases associated with increased expression of TLR8; wherein the immune response is associated with an autoimmune disease, and the autoimmune disease is associated with increased expression of TLR8; the immune disease is selected from rheumatoid arthritis, pancreatitis, mixed tissue connective disease, systemic lupus erythematosus, antiphospholipid syndrome, irritable bowel disease, type 1 diabetes, and Sjögren's disease.

[0069] definition

[0070] Unless otherwise indicated, the term "halogen" is used interchangeably herein to refer to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0071] Unless otherwise indicated, the term "alkyl" as used herein includes saturated monovalent hydrocarbon groups having straight or branched chains. For example, alkyl includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl. Similarly, C 1-6 C in the alkyl group 1-6 It is defined to identify a group having a straight or branched chain arrangement of 1, 2, 3, 4, 5 or 6 carbon atoms.

[0072] Unless otherwise indicated, the term "haloalkyl" as used herein refers to an alkyl group substituted with one or more (1, 2, 3, 4, 5 or 6) halogens (-F, -Cl or -Br). In some embodiments, a haloalkyl group is an interchangeable -C 1-6 Halogenated alkyl or halogenated C 1-6 Alkyl, where -C 1-6 Halogenated alkyl or halogenated C 1-6 C in the alkyl group 1-6 In some embodiments, -C 1-6 Haloalkyl is -C 1-3 In some embodiments, -C 1-3 Haloalkyl is substituted by 1, 2, 3, 4, 5 or 6 -F (methyl, ethyl, propyl or isopropyl); preferably, -C 1-3 Haloalkyl is -CF3.

[0073] The term "alkylene" refers to a difunctional group obtained by removing an additional hydrogen atom from an alkyl group as defined above. For example, methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)- or -CH2-CH(CH3)-).

[0074] The term "alkenyl" refers to a straight or branched chain hydrocarbon group containing one or more double bonds, typically 2 to 20 carbon atoms in length.

[0075] For example, "-C 2-6 "Alkenyl" contains 2 to 6 carbon atoms. For example, alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

[0076] The term "alkynyl" refers to a straight or branched chain hydrocarbon group containing one or more triple bonds, typically 2 to 20 carbon atoms in length.

[0077] For example, "-C 2-6 An "alkynyl" group contains 2 to 6 carbon atoms. For example, representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

[0078] The term "alkoxy" refers to an oxygen ether formed from the aforementioned alkyl groups.

[0079] Unless otherwise indicated, the term "haloalkoxy" as used herein refers to an alkoxy group substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In certain embodiments, a haloalkoxy group is interchangeably -C 1-6 Haloalkoxy or halogenated C 1-6 Alkoxy, wherein -C 1-6 Halogenated alkoxy or halogenated C 1-6 C in alkoxy 1-6 Indicates that the total carbon atoms of the alkoxy group are 1 to 6. In certain embodiments, -C 1-6 Haloalkoxy is -C 1-3 In certain embodiments, -C 1-6 Haloalkoxy is substituted by 1, 2, 3, 4, 5 or 6 -F (methoxy, ethoxy, propoxy or isopropoxy), preferably -C 1-3 Haloalkoxy is -OCF3.

[0080] Unless otherwise indicated, the term "aryl" or "aromatic ring" as used herein refers to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing only carbon ring atoms. Preferred aryl groups are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryl groups.

[0081] Unless otherwise indicated, the term "heterocyclyl" or "heterocycle" as used herein refers to unsubstituted and substituted monocyclic or polycyclic non-aromatic ring systems containing one or more ring heteroatoms, including monocyclic heterocycles, bicyclic heterocycles, bridged heterocycles, fused heterocycles, and spirocyclic heterocycles. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably, the heterocycle is a three- to ten-membered ring that is fully saturated or has one or more degrees of unsaturation. The present definition of heterocycle includes multiple degrees of substitution (preferably one, two, or three degrees of substitution). Examples of such heterocyclic groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxazepanyl, azepanyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

[0082] Unless otherwise indicated, the term "heteroaryl" as used herein refers to an aromatic ring system containing carbon and at least one heteroatom. A heteroaryl or heteroaromatic ring can be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl can have 1 to 4 heteroatoms in its ring, while a polycyclic heteroaryl can contain 1 to 10 heteroatoms. Polycyclic heteroaryl rings can contain fused rings, spirocycles, or bridged rings. For example, a bicyclic heteroaryl is a polycyclic heteroaryl. A bicyclic heteroaryl ring can contain 8 to 12 atoms. A monocyclic heteroaryl ring can contain 5 to 8 atoms (carbon atoms and heteroatoms). Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl, or isoquinolinyl.

[0083] The term "carbocyclyl" refers to a substituted or unsubstituted monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring system containing only carbon atoms. Preferably, the ring is three to ten members and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two, or three, are included in this definition. Carbocyclyl includes, but is not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0084] The term "one or more" means one or more. In some embodiments, "one or more" means 1, 2, 3, 4, 5, or 6. In some embodiments, "one or more" means 1, 2, 3, or 4. In some embodiments, "one or more" means 1, 2, or 3. In some embodiments, "one or more" means 1 or 2. In some embodiments, "one or more" means 1. In some embodiments, "one or more" means 2. In some embodiments, "one or more" means 3. In some embodiments, "one or more" means 4. In some embodiments, "one or more" means 5. In some embodiments, "one or more" means 6.

[0085] In the present application, when a ring is substituted with one or more substituents, it means that each substituent can be substituted independently on each ring atom of the ring, including but not limited to a ring carbon atom or a ring nitrogen atom. In addition, when the ring is polycyclic, such as a fused ring, a bridged ring or a spiro ring, each substituent can be substituted independently on each ring atom of the polycyclic ring.

[0086] The term "oxo" refers to an oxygen atom and the carbon atom to which it is attached forming an group.

[0087] In the present application, the term "composition" is intended to encompass a product comprising a specific amount of a specific ingredient, as well as any product produced directly or indirectly by a combination of a specific amount of a specific ingredient. Therefore, pharmaceutical compositions containing the present application compound as an active ingredient and methods for preparing the present application compound are also part of the present application. Moreover, some crystalline forms of the compound may exist in the form of polymorphs and are therefore intended to be included in the present application. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the present application.

[0088] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compound of the present application is acidic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic bases and organic bases. When the compound of the present application is basic, its corresponding salt can be conveniently prepared from a pharmaceutically acceptable non-toxic acid, including inorganic acids and organic acids. Since the compounds in the present application are intended for pharmaceutical use, they are preferably provided in a substantially pure form, for example at least 60% pure, more suitably at least 75% pure, and especially at least 98% pure (% by weight).

[0089] The definition of any substituent or variable at a particular position in a molecule is intended to be independent of the definitions of substituents or variables at other positions in the molecule. It should be understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the present invention to provide chemically stable compounds that can be readily synthesized by techniques known in the art and the methods illustrated herein.

[0090] The compounds described herein may contain one or more asymmetric centers and may therefore produce diastereomers and optical isomers. The present application includes all such possible diastereomers and racemic mixtures thereof, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

[0091] This application includes all stereoisomers of the compounds and pharmaceutically acceptable salts thereof. In addition, mixtures of stereoisomers and isolated specific stereoisomers are also included. In the process of synthetic steps used to prepare these compounds, or in the process of using racemization or epimerization methods known to those skilled in the art, the products of these steps may be mixtures of stereoisomers.

[0092] The term "stereoisomer" as used herein refers to isomers resulting from differences in spatial arrangement of atoms or groups of atoms in a molecule in the same order of interconnection. This includes configurational isomers and conformational isomers. Configurational isomers further include geometric isomers and optical isomers. Optical isomers primarily include enantiomers and diastereomers. This application encompasses all possible stereoisomers of the compound.

[0093] Certain compounds provided herein may exist as atropisomers, which are conformational stereoisomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule. The compounds provided herein include all atropisomers, including pure individual atropisomers, enriched atropisomers of each, or nonspecific mixtures of each. If the barrier to rotation about a single bond is high enough and the interconversion between conformations is slow enough, separation of atropisomers may be permitted.

[0094] This application is intended to include all isotopes of atoms present in the compounds of this application. Isotopes are atoms having the same atomic number but different mass numbers. As a general example and not limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen can be represented by 1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). They are also commonly represented as D (deuterium) and T (tritium). In this application, CD3 represents a methyl group in which all hydrogen atoms are deuterium. Carbon isotopes include 13 C and 14C. Isotopically labeled compounds of the present application can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described herein, using an appropriate isotopically labeled reagent instead of a non-labeled reagent.

[0095] Unless otherwise indicated, the term "deuterated derivative" as used herein refers to a compound having the same chemical structure as a reference compound, but in which one or more hydrogen atoms are replaced by a deuterium atom ("D"). It will be appreciated that some variation in the natural isotopic abundance will occur in the synthetic compound depending on the source of the chemical materials used in the synthesis. The concentration of the naturally abundant stable hydrogen isotope, although such variation is small and insignificant, will be compared to the degree of stable isotopic substitution of the deuterated derivatives described herein.

[0096] When the compounds of the present application exist in tautomers, the present application includes any possible tautomers and pharmaceutically acceptable salts and mixtures thereof, unless otherwise specifically stated.

[0097] The pharmaceutical composition of the present application comprises a compound of the present application (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optional other therapeutic ingredients or adjuvants. Although the most suitable approach in any given case will depend on the specific host, and the nature and severity of the disease (the active ingredient is being applied for the treatment of the disease), the composition includes compositions suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular and intravenous) administration. The pharmaceutical composition can be conveniently present in unit dosage form and prepared by any method well known in the pharmaceutical field.

[0098] In practice, according to conventional drug formulation techniques, the compound of the present application or its pharmaceutically acceptable salt can be combined as an active ingredient with a drug carrier and a drug carrier to form a close mixture. Depending on the formulation form required for the route of administration, for example, the carrier can take a variety of forms, such as oral or parenteral (including intravenous) routes of administration. Therefore, the pharmaceutical composition of the present application can exist as discrete units suitable for oral administration, such as capsules, cachets or tablets, each containing a predetermined amount of active ingredient. In addition, the composition can exist as a powder form, a granular form, a solution form, a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or an oil-in-water emulsion. In addition to the above-mentioned common dosage forms, the compound represented by Formula I or its pharmaceutically acceptable salt can also be administered by controlled release and / or a delivery device. The composition can be prepared by any pharmaceutical method. Typically, such methods include the step of combining the active ingredient with a carrier constituting one or more essential ingredients. Typically, the composition is prepared by uniformly and closely mixing the active ingredient with a liquid carrier or a finely divided solid carrier or both. The product can then be conveniently formed into the desired style.

[0099] Therefore, the pharmaceutical composition of the present application may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt. The compound of the present application or a pharmaceutically acceptable salt thereof may also be included in a pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0100] The pharmaceutical carrier used can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing compositions for oral dosage forms, any convenient pharmaceutical medium can be used. For example, water, ethylene glycol, oil, alcohol, flavorings, preservatives, colorants, etc. can be used to form oral liquid preparations such as suspensions, elixirs, and solutions; while carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc. can be used to form oral solid preparations such as powders, capsules, and tablets. Tablets and capsules are preferred oral dosage units due to their ease of administration, which utilize solid pharmaceutical carriers. Alternatively, tablets can be coated using standard aqueous or non-aqueous techniques.

[0101] Tablets containing the compositions of the present application can be prepared by compression or molding, optionally containing one or more auxiliary ingredients or adjuvants. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form, such as a powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, surfactant, or dispersant. Molded tablets can be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient, and each cachet or capsule preferably contains from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation for oral administration to humans may contain from about 0.5 mg to about 5 g of the active agent mixed with an appropriate and convenient amount of carrier material, which may comprise from about 0.05 to about 95% of the total composition. Dosage unit forms typically contain from about 0.01 mg to about 2 g of active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1500 mg or 2000 mg.

[0102] The pharmaceutical compositions of the present application suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. Suitable surfactants, such as hydroxypropylcellulose, can be included. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oils. In addition, preservatives can be included to prevent the harmful growth of microorganisms.

[0103] The pharmaceutical compositions of the present application suitable for injection include sterile aqueous solutions or dispersions. In addition, the compositions may be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for ease of injection. The pharmaceutical composition must be stable under the conditions of manufacture and storage; therefore, it is best to preserve it to prevent contamination by microorganisms such as bacteria and fungi. The carrier may be, for example, a solvent or dispersion medium containing water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), a vegetable oil, and suitable mixtures thereof.

[0104] The pharmaceutical composition of the present application can be in a form suitable for topical use, such as an aerosol, cream, ointment, lotion, dusting powder, etc. In addition, the composition can be in a form suitable for transdermal devices. Utilizing the compound shown in the present application formula (I) or a pharmaceutically acceptable salt thereof, these preparations can be prepared by conventional processing methods. For example, a cream or ointment can be prepared by mixing a hydrophilic material and water with about 0.05wt% to about 10wt% of the compound to produce a cream or ointment with the desired consistency.

[0105] The pharmaceutical composition of the present application can be a form suitable for rectal administration, wherein the carrier is a solid. Preferably, the mixture forms a unit dose suppository. Suitable carriers include cocoa butter and other materials commonly used in this area. Suppositories can be formed easily by first mixing the composition with a softening or melting carrier, then cooling and molding in a mold.

[0106] In addition to the above-mentioned carrier components, the above-mentioned pharmaceutical preparations may suitably include one or more additional carrier components, such as diluents, buffers, flavorings, adhesives, surfactants, thickeners, lubricants, preservatives (including antioxidants), etc. In addition, other adjuvants may be included to make the preparation isotonic with the blood of the intended recipient. Compositions containing the compound or its pharmaceutically acceptable salt may also be prepared in the form of powders or liquid concentrates.

[0107] Generally, dosage levels of about 0.001 mg / kg to about 150 mg / kg of body weight per day are useful for treating the above-mentioned conditions, or about 0.05 mg to about 7 g per patient per day. For example, about 0.001 to 50 mg of the compound per kg of body weight per patient per day, or about 0.05 mg to about 3.5 g of the compound per kg of body weight per patient per day, may be effective for treating inflammation, cancer, psoriasis, allergies / asthma, immune system diseases and disorders, and central nervous system (CNS) diseases and disorders.

[0108] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors including age, weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular condition being treated.

[0109] Unless the context indicates otherwise, when a value is expressed as "about" X or "approximately X," the specified value of X will be understood to be accurate to ±10%, preferably ±5%, ±2%.

[0110] These and other aspects will become apparent from the following written description of the application. DETAILED DESCRIPTION

[0111] The compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples outlining specific synthetic routes are intended to provide guidance to synthetic chemists skilled in the art, who will readily understand that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, times, temperatures, etc. can be modified as needed within the skill and judgment of those skilled in the art.

[0112] Example

[0113] The following examples are provided to better illustrate the present application. Unless otherwise specified, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

[0114] Synthesis method of compound A:

[0115] Compound A of the present application (2-methyl-4-(7-methoxy-4-quinolyl)-phenol) Refer to the following steps for synthesis:

[0116] Under a nitrogen atmosphere, a mixture of 4-chloro-7-methoxy-quinolone (80 mg, 0.42 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenol (97 mg, 0.42 mmol), K2CO3 (158 mg, 1.1 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) was heated at 100°C overnight with a complex of dichloromethane (18 mg, 0.01 mmol) in dioxane (5 mL) and H2O (1 mL). The reaction was then quenched with water and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (eluent: dichloromethane / methanol, 0-10%) to give Compound A (77 mg, 85% yield) as a white solid. ESI-MS m / z:266.1181[M+H]+ ; Purity: 99.0%.

[0117] 1 HNMR (400MHz, DMSO-d6) δ=9.69(s,1H),8.79(d,J=4.5Hz,1H),7.85(d,J=9.3Hz,1H),7.44(d,J=2 .6Hz,1H),7.26-7.20(m,3H),7.20-7.16(m,1H),6.95(d,J=8.2Hz,1H),3.93(s,3H),2.21(s,3H);

[0118] 13 CNMR(101MHz,DMSO)δ=159.84,155.98,150.27,150.14,147.57,131.66,127.96, 127.90,126.93,124.32,121.13,119.20,119.12,114.71,107.77,55.46,16.03.

[0119] Example 1

[0120] Compound 1-1 (64 mg, 0.55 mmol) was added to a solution of compound A (100 mg, 0.37 mmol) in DMA (1 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to obtain a residue. The resulting residue was purified by high-performance liquid chromatography (C18, eluent: acetonitrile and water) to obtain compound 1 (80.2 mg, yield: 61%) as a white solid. LCMS: m / z = 345.6 [M+H] + .

[0121] 1 H NMR (400MHz, DMSO-d6) δ = 8.86 (d, J = 4.5Hz, 1H), 8.16 (s, 2H), 7.77 (d, J = 9.3Hz, 1H), 7.51 -7.47(m,3H),7.43(dd,J=8.3,2.2Hz,1H),7.31-7.25(m,2H),3.94(s,3H),2.39(s,3H).

[0122] Example 2

[0123] K2CO3 (4.93 g, 35.7 mmol) was added to a DMF (30 mL) solution of compound 2-1 (3 g, 17.8 mmol) and deuterated iodomethane (CD3I) (3.88 g, 26.8 mmol). The reaction mixture was stirred at room temperature for 3 hours, quenched by adding water (30 mL), and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (using V 石油醚 / V 乙酸乙酯 =10 / 1-10 / 3 elution) to obtain white solid compound 2-2 (1.5 g, yield 42.2%). LCMS: m / z=197[M+1] + .

[0124] Compound 2-2 (150 mg, 0.76 mmol), compound 2-3 (174 mg, 1.14 mmol) and potassium carbonate (157 mg, 1.14 mmol) were dispersed in a mixed solvent of 1,4-dioxane (1.2 mL) and water (0.3 mL). The resulting mixture was purged with N2 and maintained under N2 atmosphere, and Pd(dppf)Cl2 (55.6 mg, 0.076 mmol) was added. After the reaction mixture was stirred at 80°C for 5 hours, it was cooled to room temperature, water (2 mL) was added and extracted with EA (3×3 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain white solid compound 2-4 (59.8 mg, yield 28.9%). LCMS: m / z = 269.5 [M+1] + .

[0125] 1 H NMR (400MHz, DMSO-d6) δ = 9.68 (s, 1H), 8.78 (d, J = 4.6Hz, 1H), 7.85 (d, J = 9.2Hz, 1H), 7.43 (d, J=2.6Hz,1H),7.26-7.20(m,3H),7.18(d,J=8.1Hz,1H),6.95(d,J=8.2Hz,1H),2.21(s,3H).

[0126] Following a similar synthesis and purification method as in Example 1, compound 2-4 (100 mg, 0.37 mmol), compound 1-1 (47 mg, 0.41 mmol), and DMA (1 mL) were used as reactants and purified by high-performance liquid chromatography (C18, eluents: acetonitrile and water) to obtain compound 2 (51.6 mg, yield 39.5%) as a white solid. LCMS: m / z = 348.5 [M+1] + .

[0127] 1 H NMR (400MHz, DMSO-d6) δ = 8.86 (d, J = 4.5Hz, 1H), 8.16 (s, 2H), 7.77 (d, J = 9.3Hz, 1H ),7.52-7.47(m,3H),7.43(dd,J=8.3,2.2Hz,1H),7.31-7.25(m,2H),2.39(s,3H).

[0128] Example 3

[0129] DMF (30 mL) was added to a 100 mL round-bottom flask containing compound 2-1 (3 g, 17.8 mmol) and deuterated iodomethane (CD3I) (3.88 g, 26.8 mmol), followed by the addition of K2CO3 (4.93 g, 35.7 mmol). The reaction mixture was stirred at room temperature for 3 hours, quenched with water (30 mL), and extracted with ethyl acetate (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 10 / 3) to afford compound 2-2 (1.5 g, yield: 42.2%) as a white solid. LC / MS: m / z = 197 [M+H] + .

[0130] 1,4-Dioxane (1.2 mL) and purified water (0.3 mL) were added to a 38 mL reaction tube containing compound 2-2 (150 mg, 0.76 mmol), compound 2-3 (174 mg, 1.14 mmol), and potassium carbonate (157 mg, 1.14 mmol). The reaction solution was sparged with nitrogen for 5 minutes, followed by the addition of Pd(dppf)Cl2 (55.6 mg, 0.076 mmol). The reaction solution was heated to 80°C and stirred for 5 hours before being cooled to room temperature. Water (2 mL) was added and the mixture was extracted with ethyl acetate (3×3 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to afford compound 3 (59.8 mg, yield: 28.9%) as a white solid. LC / MS: m / z = 269.51 [M+H]+ .

[0131] 1 H NMR (400MHz, DMSO-d6) δ9.68(s,1H),8.78(d,J=4.6Hz,1H),7.85(d,J=9.2Hz,1H),7.43(d, J=2.6Hz,1H),7.26-7.20(m,3H),7.18(d,J=8.1Hz,1H),6.95(d,J=8.2Hz,1H),2.21(s,3H).

[0132] Pharmacological experiments

[0133] Reference compound 1 is: The control compound 2 is:

[0134] The control compound 3 is:

[0135] 1. TLR8 / TLR7 cell activity test

[0136] HEK-Blue-HTLR8 cells (or HEK-Blue-HTLR7 cells) with a survival rate greater than 98% that have been cultured in advance are digested and collected by centrifugation and resuspended in DMEM (11995065, Gibco) cell culture medium containing 10% FBS (#76294-180, Avantar). The density of the resuspended cells is counted using a cell counter. An appropriate amount of cell suspension is removed from the centrifuge tube to prepare a system of 5000 cells / 40 μL. 40 μL of HEK-Blue was plated in each well of a 384-well plate (#3764, Corning). TM -HTLR8 cells (or HEK-Blue TM -HTLR7 cell suspension, with 5000 cells per well. The 384-well plate with cells was placed in a CO2 incubator (CLM-240B-8-TC, ESCO) at 5% CO2 and 37°C for incubation. The assay was performed 24 hours later.

[0137] All test compounds were dissolved in DMSO to a 10 mM stock solution, and the 10 mM stock solution was further diluted with DMSO to a final concentration of 3.33 mM, 1.11 mM, 0.37 mM, 0.12 mM, 0.04 mM, 0.01 mM, 0.004 mM, and 0.001 mM. The diluted test compounds were dispensed onto the corresponding cell wells of a 384-well plate using an Echo 650 Series acoustic pipetting workstation (Echo 650, Beckman Coulter), and the 384-well plate with the test compound was returned to a carbon dioxide incubator for incubation. After 0.5 hours, 10 ng / mL R848 (TLRL-R848, Invivogen) was added to the well plate using an Echo 650 Series acoustic pipetting workstation. The 384-well plate was then placed in a cell incubator and incubated for 24 hours. After 24 hours, 18 μL of prepared Quanti-Blue™ solution (rep-qbs3, InvivoGen) was added to each well of a new 384-well plate. 2 μL of supernatant from the 384-well plate with test compounds was transferred to the plate with Quanti-Blue™ solution. TM The solution was placed in a 384-well plate and incubated at room temperature for 120 minutes. The absorbance data were read at 620-655 nm using a microplate reader in 384-well absorbance mode (PHERAstar FSX, BMG). Data were analyzed, curve-fitted, and reported using the dose-response one-site 205 model of IDBS XLfit. The test results are shown in Table 1 below.

[0138] Table 1 TLR8 / TLR7 cell activity data

[0139] As shown in Table 1, compound 1 of the present application has good inhibitory activity and selectivity against TLR8.

[0140] 2. Pharmacokinetic Study in Mice

[0141] The purpose of this study is to evaluate the pharmacokinetic properties of the compound in ICR mice (male) after single-dose administration (20 mg / kg, PO). Three mice are required for each compound, with a total of one group. Mice are treated with a single 20 mg / kg dose of the compound (oral). For each mouse, blood samples are collected at 0.25, 0.5, 1, 4 and 8 hours after administration. The whole blood sample is placed in a test tube containing EDTA-K2, turned upside down several times, and then centrifuged at 6000 rpm and 4 ° C for 15 minutes to obtain plasma. The plasma samples are stored at -75 ± 15 ° C until analysis. The concentration of the compound in the plasma sample is determined using the LC-MS / MS method. The results are shown in Table 2 below.

[0142] Table 2 Pharmacokinetic parameters

[0143] As can be seen from Table 2, the C max and AUC last They were 2647 ng / mL and 4329 h×ng / mL, respectively, with higher in vivo plasma exposure.

[0144] 3. In vitro liver microsome metabolic stability test

[0145] The purpose of this study is to evaluate the metabolic stability of compounds in different species of liver microsomes in vitro. The test compounds were incubated in parallel with phosphate buffer systems of different species of liver microsomes with or without coenzyme factors for 60 minutes. Sampling was terminated at 0.5 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes and 60 minutes, and the samples were analyzed by UPLC-MS / MS to determine the concentration of the test compound and calculate the percentage of the compound at 60 minutes, the in vitro intrinsic clearance (CL) int ) and half-life (T 1 / 2 ), the specific data results are shown in Table 3.

[0146] Table 3 Percentage, intrinsic clearance and half-life at 60 min

[0147] As shown in Table 3, compound 1 of the present application has good stability in the human body.

[0148] It should be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication is part of the common general knowledge in the art in any country.

[0149] Although the foregoing invention has been described in considerable detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain subtle changes and modifications may be implemented. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. A compound of formula (I), its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its atropisomers or acceptable salts of its deuterated derivatives, Wherein, Each occurrence of R1 or R2 is independently selected from -C 1-6 alkyl; each occurrence of R1 or R2 is independently optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 deuteriums or halogens; Y1 is selected from -OH, -O-S(=O)-R4 or -O-S(=O)2-R4; R4 is -N(R 41 )2; wherein, Said R 41 is independently selected from hydrogen, -C 1-6 alkyl, -C 1-6 alkenyl, -C 1-6 alkynyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, 3- to 10-membered carbocyclic group, 3- to 10-membered heterocyclic group, 6- to 10-membered aryl group or 5- to 10-membered heteroaryl group each time it appears; The R 41 is independently optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 substituents selected from deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), a 3- to 10-membered carbocyclic group, a 3- to 10-membered heterocyclic group, a 6- to 12-membered aryl group or a 5- to 10-membered heteroaryl group; R S1 or R S2 is independently selected, at each occurrence, from deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), a 3- to 10-membered carbocyclic group, a 3- to 10-membered heterocyclic group, a 6- to 12-membered aryl group or a 5- to 10-membered heteroaryl group; said R S1 or R S2 is independently optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substituents selected from deuterium, -C 1-3 alkyl, -C 1-3 alkenyl, -C 1-3 alkynyl, -C 1-3 haloalkyl, -C 1-3 alkoxy, -CN, -NH2, -COOH, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -O(C 1-3 (alkyl), -SH, -S(C 1-3 (alkyl), -C(=O)(C 1-3 (alkyl), -S(=O)(C 1-3 (alkyl), -S(=O)2(C 1-3 (alkyl), -C(=O)NH2, -C(=O)NH(C 1-3 (alkyl), -C(=O)N(C 1-3 (alkyl)2, -NHC(=O)(C 1-3 (alkyl), -N(C 1-3 (alkyl)C(=O)(C 1-3 (alkyl), -C(=O)O(C 1-3 (alkyl), -O-C(=O)(C 1-3 (alkyl), -S(=O)NH2, -S(=O)NH(C 1-3 (alkyl), -S(=O)N(C 1-3 (alkyl)2, -NHS(=O)(C 1-3 (alkyl), -N(C 1-3 (alkyl)S(=O)(C 1-3 (alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-3 (alkyl), -S(=O)2N(C 1-3 (alkyl)2, -NHS(=O)2(C 1-3 (alkyl), -N(C 1-3 (alkyl)S(=O)2(C 1-3 (alkyl), substituted by substituents of 3- to 7-membered carbocyclic group, 3- to 7-membered heterocyclic group, phenyl or 5- to 10-membered heteroaryl; n1 is selected from 0, 1, 2, 3, 4, 5 or 6; n2 is selected from 0, 1, 2, 3, 4, 5 or 6; The heterocyclic group or heteroaryl group independently includes one or more heteroatoms selected from N, O or S each time it appears; When Y1 is -OH, R2 is independently optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 deuteriums.

2. The compound according to claim 1, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of its stereoisomers, its pharmaceutically acceptable salts of its atropisomers or its acceptable salts of its deuterated derivatives, characterized in that, Y1 is selected from -O-S(=O)2-R4; the definition of R4 is the same as in claim 1.

3. The compound according to claim 1 or 2, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of its stereoisomers, its pharmaceutically acceptable salts of its atropisomers or its acceptable salts of its deuterated derivatives, characterized in that, R4 is -N(R 41 )2; Said R 41 is independently selected from hydrogen or -C 1-3 alkyl each time it appears; said R 41 is independently optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8 or 9 deuteriums.

4. The compound according to any one of claims 1 to 3, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of its stereoisomers, its pharmaceutically acceptable salts of its atropisomers or its acceptable salts of its deuterated derivatives, characterized in that, R4 independently is selected from -NH2, -NDH, -ND2, -NH(CH3), -NH(CD3), -N(CH3)2, -N(CD3)2, -NH(CH2CH3), -NH(CH2CD3), -NH(CD2CD3), -NH(CH(CH3)2), -NH(CH(CD3)2), -NH(CH2CH2CH3), -NH(CH2CH2CD3) or -NH(CH2CD2CD3) each time it appears.

5. The compound according to any one of claims 1 to 4, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, its pharmaceutically acceptable salts of its stereoisomers, its pharmaceutically acceptable salts of its atropisomers or its acceptable salts of its deuterated derivatives, characterized in that, R1 or R2 independently is selected from -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2D, -CHD2, -CD3, -CH2CH3, -CHD-CH3, -CD2-CH3, -CH2CDH2, -CH2CHD2, -CH2CD3, -CHDCD3, -CD2CD3, -CH2CH2CD3, -CH2CD2CD3, -CD2CD2CD3, -CH(CH3)2, -CD(CH3)2, -CD(CD3)(CH3), -CH(CD3)2 or -CD(CD3)2 each time it appears; Preferably, each occurrence of R1 is independently selected from -CH3, -CH2D, -CHD2 or -CD3, and each occurrence of R2 is independently selected from -CH3, -CH2D, -CHD2 or -CD3.

6. A compound, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its atropisomers or acceptable salts of its deuterated derivatives, characterized in that, The compound is selected from any one of the following formulas:

7. A pharmaceutical composition, characterized in that, A compound according to any one of claims 1 to 6, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its atropisomers or acceptable salts of its deuterated derivatives; and at least one pharmaceutically acceptable excipient.

8. Use of a compound according to any one of claims 1 to 6, its stereoisomers, its atropisomers, its deuterated derivatives, its pharmaceutically acceptable salts, pharmaceutically acceptable salts of its stereoisomers, pharmaceutically acceptable salts of its atropisomers or acceptable salts of its deuterated derivatives; or the pharmaceutical composition according to claim 7 in the preparation of a medicament for inhibiting TLR8-dependent immune responses.

9. The use according to claim 8, characterized in that, The immune response is related to an autoimmune disease, and the autoimmune disease is related to an elevated expression of TLR8.

10. The use according to claim 9, wherein, The immune disease is selected from rheumatoid arthritis, pancreatitis, mixed tissue connective disease, systemic lupus erythematosus, antiphospholipid syndrome, irritable bowel disease, type I diabetes, Sjogren's syndrome.

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