TOLL-like receptor 7 (TLR7) specific antagonist and preparation method and application thereof

Abstract

The invention provides a TOLL-like receptor 7 (TLR7) specific antagonist as well as a preparation method and application of the TOLL-like receptor 7 (TLR7) specific antagonist. The TLR7 antagonist has a structure as shown in a formula (I) or a formula (II), has outstanding TLR7 antagonistic activity and selectivity, and is expected to be applied to prevention and treatment of related diseases.

Description

Technical Field

[0001] This invention relates to the field of medicine, specifically to a TOLL-like receptor 7 (TLR7) specific antagonist, and also to the preparation and application of said antagonist. Background Technology

[0002] Toll-like receptors (TLRs) are a typical class of pattern recognition receptors (PPRs) and type I transmembrane glycoproteins. TLRs can recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). In the innate immune system, TLRs can initiate antimicrobial host defense responses to suppress pathogen replication. To date, ten TLR subtypes (1-10) have been identified in mammals. They are expressed on various immune cells, including dendritic cells (DCs), macrophages, and B cells, as well as other cell types such as epithelial cells, endothelial cells, and fibroblasts.

[0003] Several intracellular TLRs that recognize nucleotides, including TLR3, TLR7, TLR8, and TLR9, are initially synthesized in the endoplasmic reticulum (ER) and eventually translocate to endosomes. TLR7 can be activated by viruses, bacteria, or endogenous guanylic acid and uracil-rich single-stranded RNAs (ssRNAs), as well as by some chemical ligands such as small heterocyclic molecules. When TLR7 recognizes its ligand, it homodimerizes, initiating a myeloid differentiation factor 88 (MyD88)-dependent signaling pathway. This pathway then initiates the expression of downstream genes via nuclear factor kappa-B (NF-κB) or interferon regulatory factor 3 / 7 (IRF3 / 7). Aberrant activation of TLR7 promotes the release of pro-inflammatory cytokines, chemokines, and type I interferon (IFN), leading to an inflammatory response.

[0004] In innate immunity, TLR7 is crucial for recognizing exogenous substances containing PAMPs; however, aberrant activation of TLR7 can also lead to autoimmune diseases, such as systemic lupus erythematosus. Therefore, the rational design of TLR7 antagonists is a major focus in the treatment of autoimmune diseases. Summary of the Invention

[0005] The purpose of this invention is to provide a TOLL-like receptor 7 (TLR7) specific antagonist.

[0006] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] R1 is selected from H, D, halogen, C1-C15 alkyl, halogenated C1-C15 alkyl, nitro, cyano, -C(O)OR a -OC(O)R a -C(O)NR a R a '、-NR a 'C(O)R a -S(O)2R a -OR a -SR a ;

[0010] R2, R3, R4, and R5 may be the same or different, and each may be independently selected from: H, D, halogen, hydroxyl, carboxyl, nitro, cyano, C1-C15 alkyl, halo-C1-C15 alkyl, C1-C15 alkoxy, halo-C1-C15 alkoxy, hydroxyl-substituted C1-C15 alkyl, and C1-C6 alkoxy-substituted C1-C15 alkyl.

[0011] Ar is selected from one of the following structures:

[0012]

[0013] X1 is selected from: N or CR 11 ;

[0014] X2 is selected from: N or CR 12 ;

[0015] X3 is selected from: N or CR 13 ;

[0016] X4 is selected from: N or CR 14 ;

[0017] X5 is selected from: N or CR 15 ;

[0018] R 11 R 12 R 13 R 14 R 15 The same or different, each independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -L1-R s -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c Or R 11 R 12 R 13 R 14 R 15 Any two adjacent connections in the loop form a substituted or unsubstituted ring;

[0019] R 16 R 17 R 18 R 19 The same or different, each independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -L1-Rs, -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c-L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c ;

[0020] n1 is selected from: 1, 2, 3 or 4;

[0021] n2 is selected from: 1, 2, or 3;

[0022] n3 is selected from: 1, 2, 3, 4, 5, or 6;

[0023] R is selected from: H, D, substituted or unsubstituted C1-C15 alkyl groups, -C(O)R b -C(O)OR b -S(O)2R b R c -S(O)2NR b R c -L1-R s ;

[0024] R 20 Selected from: H, D, substituted or unsubstituted C1-C6 alkyl groups, -C(O)R b -C(O)NR b R c ;

[0025] R a R a 'Identical or different, independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl;

[0026] R b R c Same or different, independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl, -L1-R s ;

[0027] L1 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups;

[0028] L2 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups;

[0029] Rs Selected from substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted 5-15 heterocyclic alkyl, and substituted or unsubstituted 5-20 heteroaryl.

[0030] In another aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0031]

[0032] Among them, R 17 Selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -L1-Rs, -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c ;

[0033] n2 is selected from: 1, 2, or 3;

[0034] R b R c Identical or different, independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl, -L1-R s ;

[0035] L1 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups;

[0036] L2 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups;

[0037] R sSelected from substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted 5-15 heterocyclic alkyl, and substituted or unsubstituted 5-20 heteroaryl;

[0038] Ar1 is selected from: substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted 5-15 heterocyclic alkyl, and substituted or unsubstituted 5-20 heteroaryl.

[0039] In another aspect, the present invention provides a pharmaceutical composition comprising at least one of the compounds of the present invention.

[0040] In another aspect, the present invention provides the use of the compounds of the present invention in the preparation of medicaments for treating TLR7-dependent immune responses.

[0041] In another aspect, the present invention provides a method for preparing the compounds of the present invention.

[0042] The beneficial effects of this invention are:

[0043] This invention provides a TLR7-specific antagonist, its preparation method, and its uses. The TLR7 antagonist of this invention exhibits outstanding TLR7 antagonistic activity and selectivity, and is expected to be applied to the prevention and treatment of related diseases. Attached Figure Description

[0044] Figure 1 Comparison of TLR7 / TLR8 selectivity for compound 90. Detailed Implementation

[0045] definition

[0046] Unless otherwise defined, the terminology used herein has the same meaning as commonly understood by one of ordinary skill in the art to which it belongs. The terminology used in this specification is for describing particular embodiments only and is not intended to limit the invention.

[0047] In this article, "*" indicates a connection site.

[0048] In this document, the term "alkyl" refers to a straight-chain, branched, fully saturated hydrocarbon group, preferably C1-15, more preferably C1-12, C1-6, or C1-4 alkyl. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl (e.g., n-pentyl), hexyl (e.g., n-hexyl), heptyl (e.g., n-heptyl), octyl (e.g., n-octyl), nonyl (e.g., n-nonyl), decyl (e.g., n-decyl), and so on. Alkyl groups may optionally be substituted.

[0049] In this document, the term "alkylene" refers to a group obtained by further removing a hydrogen atom from an alkyl group, which can be a C1-15, C1-12, C1-6, or C1-4 alkylene. Examples of alkylenes include methylene, ethylene (e.g., 1,2-ethylene), propylene (e.g., 1,3-propylene), butylene (e.g., 1,4-butylene), pentylene (e.g., 1,5-pentylene), hexylene (e.g., 1,6-hexylene), and so on. Alkylenes may optionally be substituted.

[0050] In this document, the term "cycloalkyl" refers to a C3-15 monocyclic or polycyclic alkyl group, preferably a C3-8 monocyclic or polycyclic alkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and the like. The cycloalkyl group may optionally be substituted.

[0051] In this document, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon double bond, preferably C2-15, more preferably C2-12, C2-6, or C2-4 alkenyl. Preferably, the alkenyl group is α-alkenyl. Examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, (Z)-2-pentenyl, (E)-1-pentenyl, (E)-2-pentenyl, (Z)-2-hexenyl, (E)-1-hexenyl, (Z)-1-hexenyl, (E)-2-hexenyl, (Z)-3-hexenyl, (E)-3-hexenyl, (E)-1,3-hexadienyl, 4-methyl-3-pentenyl, and so on. The alkenyl group may optionally be substituted.

[0052] In this document, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing at least one carbon-carbon triple bond, preferably C2-15, more preferably C2-12, C2-6, or C2-4 alkynyl. Preferably, the alkynyl group is α-alkynyl. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, etc. The alkynyl group may optionally be substituted.

[0053] In this document, the term "aryl" refers to an aromatic cyclic hydrocarbon group, which can be monocyclic or fused-ring, preferably C6-C30, more preferably C6-C25, C6-C15, or C6-C10 aryl. Examples of aryl groups include phenyl, naphthyl, anthracene, phenanthrene, etc. Aryl groups may optionally be substituted.

[0054] In this document, the term "heterocyclic alkyl" refers to a 5-18 member monocyclic or fused-ring cyclic group containing at least one (e.g., 1, 2, 3, 4, or 5) heteroatoms (e.g., N, O, S, or P), preferably 5-10 members, more preferably 5-7 members, or 5-6 members. Examples of heterocyclic alkyl groups include azirrobutyl, oxoheterobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, tetrahydropyranyl, dithiaalkyl, quininecycloyl, and the like. Heterocyclic alkyl groups may optionally be substituted.

[0055] In this document, the term "heteroaryl" refers to a 5-18 member monocyclic or fused-ring aromatic group containing at least one (e.g., 1, 2, 3, 4, or 5) heteroatoms (e.g., N, O, S, or P), preferably 5-10 member, more preferably 5-7 member, or 5-6 member aromatic group. Examples of heteroaryl groups include furanyl, thiopheneyl, pyrroleyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, or 5-pyrimidinyl), pyrazinyl, pyrazinyl, triazinyl, indoleyl, isoyindolyl, benzimidazolyl, and benzopyrazolyl. The groups include benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, carbazoleyl (including carbazole-9-yl), azacarbazoleyl (including azacarbazole-9-yl), quinolinyl, isoquinolinyl, indoleazinyl, azaindoleazinyl, dibenzofuranyl, dibenzothiophenyl, naphridinyl, quinolinyl, quinoxalinyl, quinazolinyl, etc.; furthermore, it also includes cases where one or more ring carbon atoms in the above groups are further replaced by nitrogen. The heteroaryl groups may optionally be substituted.

[0056] In this article, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0057] In this document, the terms “substituted or unsubstituted” or “optionally substituted” mean that a molecule / group may be unsubstituted or substituted by 1, 2, 3, 4, 5 or more substituents selected from the following: deuterium, oxo (=O), halogen, hydroxyl, thiol, carboxyl, cyano, nitro, amino, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylthio, substituted or unsubstituted aryl, substituted or unsubstituted aryloxy, substituted or unsubstituted arylthio, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, substituted or unsubstituted acyl, alkylamino, dialkylamino, substituted or unsubstituted amide, substituted or unsubstituted ester, etc. Preferably, the substituents can be: deuterium, halogen (preferably 1, 2 or 3 halogens), hydroxyl, thiol, carboxyl, cyano, nitro, C1-C10 alkyl (preferably C1-C6 alkyl), halo-C1-C6 alkyl (preferably CH2F, CHF2, CF3), C3-C7 cycloalkyl, C1-C6 alkoxy (preferably methoxy, ethoxy), haloalkoxy (preferably CF3O), C6-C10 aryloxy, C1-C6 Alkyl-S-, C6-C10 aryl-S-, C6-C10 aryl (especially phenyl and substituted phenyl, such as tolyl, trimethylphenyl, pentadeuterated phenyl), 5-7 membered heteroaryl, 5-7 membered heterocyclic, C1-C6 acyl, C1-C6 alkylamino, di(C1-C6 alkyl)amino, amide group optionally substituted with one or two C1-C6 alkyl groups, C1-C6 ester group, tri(C1-C6 alkyl)silyl, triphenylsilyl, etc. Preferably, the substituents can be: halogen, hydroxyl, carboxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, CH2F, CHF2, CF3, methoxy, ethoxy, CF3O-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, -COOMe, -COOEt, -COMe, -COEt, amino, methylamino, dimethylamino, ethylamino, diethylamino, -CONH2, -CONHMe, -CONHEt, -CON(Me)2, -CON(Et)2, trimethylsilyl, etc.

[0058] The term “nucleic acid” includes single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), single-stranded RNA (ssRNA) and double-stranded RNA (dsRNA), modified nucleotides, and polynucleotides, or combinations thereof.

[0059] The term "agonist" is used in the broadest sense and includes any molecule that activates signaling through a receptor. For example, TLR7 agonists bind to the TLR7 receptor and activate the TLR7 signaling pathway.

[0060] The term "antagonist" is used in the broadest sense and includes any molecule that blocks the biological activity of an agonist. For example, TLR7 antagonists inhibit the TLR7 signaling pathway.

[0061] The effect of a compound on a TLR7-dependent immune response can be determined in vitro by measuring the responses of immune cells (e.g., leukocytes, lymphocytes, monocytes, and dendritic cells) exposed to a TLR7 agonist, both in the presence and absence of the compound. As noted herein, TLR7 antagonists are defined in IC50 values ​​less than 500 nM. 50 Compounds that inhibit TLR-dependent immune responses at (half-maximal inhibitory concentration). 50 Compounds with a molecular weight less than 200 nM are considered highly active TLR antagonists. IC 50 Compounds with a concentration of 201-500 nM are considered moderately active TLR antagonists. IC 50 Compounds with a concentration greater than 500 mM are considered to be essentially inactive (e.g., not TLR antagonists).

[0062] Examples of measurable immune responses include, but are not limited to, antigen-specific antibody production, cytokine secretion, lymphocyte activation, and lymphocyte proliferation.

[0063] When compared to the same conditions other than the parameter of interest, or to another condition (e.g., an increase in TLR signaling in the presence of a TLR agonist compared to the absence of a TLR agonist), a “stimulation” of a response or parameter includes initiating and / or enhancing that response or parameter. For example, a “stimulation” of an immune response refers to an increase in the response, which can be caused by initiating and / or enhancing the response. Similarly, a “stimulation” of cytokine production (e.g., IL-1alpha, IL-1beta, IL-6, and / or TNF-alpha) or a “stimulation” of cell type (e.g., CTL) refers to an increase in the number or level of cytokines or cell types.

[0064] "Inhibition" or "suppression" of a response or parameter includes reducing its response or parameter when compared to the same conditions other than the parameter of interest, or to another condition (e.g., an increase in TLR signaling in the presence of both TLR agonists and TLR antagonists compared to the presence of TLR agonists in the absence of TLR antagonists).

[0065] The term "cell" as used herein should be understood not only to the specific test cell, but also to the progeny or potential progeny of that cell. Due to mutations or environmental influences, certain modifications may occur in the progeny, and such progeny may actually differ from the parent cell, but are still included within the scope of the terminology used herein.

[0066] The term "individual" refers to a mammal, including humans. Individuals include, but are not limited to, humans, cattle, horses, cats, dogs, rodents, or primates.

[0067] Dosing in combination with one or more other therapeutic agents includes administration in any order, simultaneously, and sequentially.

[0068] "Chronic" dosing refers to administration in a continuous pattern, the opposite of the acute pattern, in order to maintain the initial therapeutic effect (activity) over an extended period of time. "Intermittent" dosing refers to treatment that is discontinuous and / or continuous without interruption, and is essentially periodic.

[0069] The “effective amount” of the reagents disclosed herein is an amount sufficient to achieve the purpose specifically described. The “effective amount” can be determined empirically and conventionally with respect to the stated purpose.

[0070] The term "therapeutic effective dose" refers to the amount of an agent (e.g., a TLR antagonist) that effectively "treats" a disease or condition in a subject (e.g., a mammal, such as a human). In the case of autoimmune diseases, a therapeutically effective dose of the drug reduces the signs or symptoms of the autoimmune disease. For example, in relation to the treatment of rheumatoid arthritis, a therapeutically effective dose of an agent (e.g., a TLR7 inhibitor) reduces the signs or symptoms of rheumatoid arthritis in patients and may also reduce the rate of damage to bone and cartilage.

[0071] The terms "under treatment" or "treatment" refer to the implementation of a protocol that may include administering one or more medications to an individual (person or other) to alleviate the signs or symptoms of a disease. Therefore, "under treatment" or "treatment" does not require complete relief of signs or symptoms, does not require a cure, and specifically includes protocols that have only a marginal effect on the individual.

[0072] As used herein and as is well known in the art, “treatment” is a method for achieving a beneficial or desired outcome, including clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, relief or improvement of one or more symptoms, reduction of disease severity, stabilization of the disease state (i.e., no worsening), prevention of disease spread, delay or slowing of disease progression, improvement or relief of the disease state, and remission (whether partial or complete), whether detectable or undetectable. “Treatment” may also mean extended survival compared to expected survival without treatment.

[0073] References to the value or parameter “approximately” in this document include (and describe) variations of that value or parameter itself. For example, a description of “approximately X” includes a description of “X”.

[0074] As used herein and in the appended claims, unless the context clearly indicates otherwise, the singular forms “a,” “or,” and “the” include plural indicators.

[0075] It should be understood that the aspects described herein as "comprising" include "including" and / or "substantially consisting of aspects and embodiments".

[0076] Unless otherwise specified, the term "compound" means any particular compound disclosed herein and includes tautomers, regiomers, geometric isomers, and, where applicable, stereoisomers, including optical isomers (enantiomers) and other stereoisomers (diastereomers), as well as pharmaceutically acceptable salts and derivatives thereof (including prodrug forms). When used in the context, the term "compound" generally refers not only to a single compound but may include other compounds, such as stereoisomers, regiomers, and / or optical isomers (including racemic mixtures), and specific enantiomers or enantiomer-enriched mixtures of the disclosed compound. The term also refers in the context to a prodrug form of the compound that has been modified to facilitate the administration and delivery of the compound to the active site.

[0077] In this article, the term "pharmaceutically acceptable salt" refers to an addition salt formed by an active compound and a pharmaceutically acceptable inorganic or organic base or acid, which is relatively non-toxic to the patient and has no harmful activity, and whose side effects do not diminish the beneficial effects of the active compound.

[0078] The compounds of this invention include all tautomers and mixtures thereof in any proportion.

[0079] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0080]

[0081] in,

[0082] R1 is selected from H, D, halogen, C1-C15 alkyl, halogenated C1-C15 alkyl, nitro, cyano, -C(O)OR a -OC(O)R a -C(O)NR a R a '、-NR a 'C(O)R a -S(O)2R a -OR a -SR a ;

[0083] R2, R3, R4, and R5 may be the same or different, and each may be independently selected from: H, D, halogen, hydroxyl, carboxyl, nitro, cyano, C1-C15 alkyl, halo-C1-C15 alkyl, C1-C15 alkoxy, halo-C1-C15 alkoxy, hydroxyl-substituted C1-C15 alkyl, and C1-C6 alkoxy-substituted C1-C15 alkyl.

[0084] Ar is selected from one of the following structures:

[0085]

[0086] X1 is selected from: N or CR 11 ;

[0087] X2 is selected from: N or CR 12 ;

[0088] X3 is selected from: N or CR 13 ;

[0089] X4 is selected from: N or CR 14 ;

[0090] X5 is selected from: N or CR 15 ;

[0091] R 11 R 12 R 13 R 14 R 15 The same or different, each independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -L1-R s -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c-L2NR b S(O)2R c Or R 11 R 12 R 13 R 14 R 15 Any two adjacent connections in the loop form a substituted or unsubstituted ring;

[0092] R 16 R 17 R 18 R 19 The same or different, each independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -L1-Rs, -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c ;

[0093] n1 is selected from: 1, 2, 3 or 4;

[0094] n2 is selected from: 1, 2, or 3;

[0095] n3 is selected from: 1, 2, 3, 4, 5, or 6;

[0096] R is selected from: H, D, substituted or unsubstituted C1-C15 alkyl groups, -C(O)R b -C(O)OR b -S(O)2R b R c -S(O)2NR b R c -L1-Rs ;

[0097] R 20 Selected from: H, D, substituted or unsubstituted C1-C6 alkyl groups, -C(O)R b -C(O)NR b R c ;

[0098] R a R a 'Identical or different, independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl;

[0099] R b R c Identical or different, independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl, -L1-R s ;

[0100] L1 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups;

[0101] L2 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups;

[0102] R s Selected from substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted 5-15 heterocyclic alkyl, and substituted or unsubstituted 5-20 heteroaryl.

[0103] In a preferred embodiment, R a R a 'Same or different, independently selected from: H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, 2,2,2-trifluoroethyl.

[0104] In a preferred embodiment, R1 is selected from H, D, fluorine, chlorine, bromine, iodine, nitro, cyano, carboxyl, hydroxyl, -CHF2, -CF3, -C(O)OCH3, -C(O)OCH2CH3, -C(O)OCH2CH2CH3, -CONHCH3, -CONHCH2CH3, -CON(CH3)2, -CON(CH2CH3)2, -S(O)2CH3, -S(O)2CH2CH3, -S(O)2CH2CH2CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3.

[0105] In a preferred embodiment, R2, R3, R4, and R5 may be the same or different, and each is independently selected from: H, D, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, 2,2,2-trifluoroethyl, -OCH3, -OCH2CH3.

[0106] In a preferred embodiment, the Choose one of the following structures:

[0107]

[0108] In a preferred embodiment, R 11 R 12 R 13 R 14 R 15 Whether identical or different, each is independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C15 alkyl, halo-C1-C15 alkyl, hydroxy-substituted C1-C15 alkyl, C1-C4 alkoxy-substituted C1-C15 alkyl, -L1-R s -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c Or R 11 R 12 R 13 R 14 R 15 Any two adjacent connections in the loop form a substituted or unsubstituted ring.

[0109] In a preferred embodiment, R b R cThe same or different, independently selected from: H, D, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C4 alkoxy-substituted C1-C6 alkyl, -L1-R s .

[0110] In a preferred embodiment, L1 is selected from single bonds, -(CR) n R m ) m -, R n R m Whether identical or different, each is independently selected from: H, D, C1-C4 alkyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Preferably, L1 is selected from single bonds, -(CH2). m -, m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0111] In a preferred embodiment, L2 is selected from single bonds, -(CR) p R q ) p -, R p R q Whether identical or different, each is independently selected from: H, D, C1-C4 alkyl; p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Preferably, L2 is selected from single bonds, -(CH2). p -, p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0112] In a preferred embodiment, R 11 R 12 R 13 R 14 R 15 The same or different, each independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, mercapto, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C4 alkoxy-substituted C1-C6 alkyl, -OC1-C6 alkyl, -SC1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)Ph, -C(O)OC1-C6 alkyl, -C(O)OPh, -NHC(O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -NHC(O)OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH2.

[0113] In a preferred embodiment, R 11 R 12 R 13 R 14 R15 The same or different, each independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, mercapto, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxyl-substituted C1-C4 alkyl, C1-C4 alkoxy-substituted C1-C4 alkyl, -OC1-C4 alkyl, -SC1-C4 alkyl, -C(O)C1-C4 alkyl, -OC(O)C1-C4 alkyl, -OC(O)Ph, -C(O)OC1-C4 alkyl, -C(O)OPh, -NHC(O)C1-C4 alkyl, -C(O)NHC1-C4 alkyl, -NHC(O)OC1-C4 alkyl, -NHC1-C4 alkyl, -N(C1-C4 alkyl)2, -S(O)2NH2.

[0114] In another preferred embodiment, R 11 R 12 R 13 R 14 R 15 One, two, three or more are selected from: -R s C1-C6 alkylene-R s -OR s -OC1-C6 alkylene-R s -C1-C6 alkylene-OR s -C1-C6 alkylene OC1-C6 alkylene-R s -SR s -SC1-C6 alkylene-R s -C1-C6 alkylene-SR s -C1-C6 alkylene SC1-C6 alkylene-R s -NH-R s -N(C1-C6 alkyl)-R s -NH-C1-C6 alkylene-R s -N(C1-C6 alkyl)-C1-C6 alkylene-R s -C1-C6 alkylene-NH-R s -C1-C6 alkylene-N(C1-C6 alkyl)-R s -C1-C6 alkylene-NH-C1-C6 alkylene-R s -C1-C6 alkylene-N(C1-C6 alkyl)-C1-C6 alkylene-R s -S(O)2-C1-C6 alkylene-R sThe remainder are independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, mercapto, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, -OC1-C6 alkyl, -SC1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)Ph, -C(O)OC1-C6 alkyl, -C(O)OPh, -NHC(O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -NHC(O)OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH2.

[0115] Preferred, R 11 R 12 R 13 R 14 R 15 At most one of them is selected from: -R s C1-C6 alkylene-R s -OR s -OC1-C6 alkylene-R s -C1-C6 alkylene-OR s -C1-C6 alkylene OC1-C6 alkylene-R s -SR s -SC1-C6 alkylene-R s -C1-C6 alkylene-SR s -C1-C6 alkylene SC1-C6 alkylene-R s -NH-R s -N(C1-C6 alkyl)-R s -NH-C1-C6 alkylene-R s -N(C1-C6 alkyl)-C1-C6 alkylene-R s -C1-C6 alkylene-NH-R s -C1-C6 alkylene-N(C1-C6 alkyl)-R s -C1-C6 alkylene-NH-R s -C1-C6 alkylene-N(C1-C6 alkyl)-C1-C6 alkylene-R s -S(O)2-C1-C6 alkylene-R sThe remainder are independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, mercapto, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, -OC1-C6 alkyl, -SC1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)Ph, -C(O)OC1-C6 alkyl, -C(O)OPh, -NHC(O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -NHC(O)OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH2.

[0116] More preferably, R 11 R 12 R 13 R 14 R 15 One of them is selected from: -R s C1-C6 alkylene-R s -OR s -OC1-C6 alkylene-R s -C1-C6 alkylene-OR s -C1-C6 alkylene OC1-C6 alkylene-R s -SR s -SC1-C6 alkylene-R s -C1-C6 alkylene-SR s -C1-C6 alkylene SC1-C6 alkylene-R s -NH-R s -N(C1-C6 alkyl)-R s -NH-C1-C6 alkylene-R s -N(C1-C6 alkyl)-C1-C6 alkylene-R s -C1-C6 alkylene-NH-R s -C1-C6 alkylene-N(C1-C6 alkyl)-R s -C1-C6 alkylene-NH-C1-C6 alkylene-R s -C1-C6 alkylene-N(C1-C6 alkyl)-C1-C6 alkylene-R s -S(O)2-C1-C6 alkylene-R s .

[0117] In a preferred embodiment, R sSelected from substituted or unsubstituted: phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, azacyclobutane, pyrrolidinyl, pyrazolyl, imidazolinyl, tetrahydrooxazolyl, tetrahydrothiazolinyl, tetrahydroisoxazolyl, tetrahydroisothiazolinyl, morpholinyl, thiomorpholinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxolinyl, quinazolinyl, triazolyl, pyrazolyl, pyrrolidinyl, imidazolinyl, furanyl, thiophenyl, oxazolyl, thiazolinyl, isoxazolyl, isothiazolyl, adamantyl, quininecycloyl.

[0118] The substituents in "substituted or unsubstituted" may be selected from: halogen, hydroxyl, carboxyl, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, oxo, -C(O)C1-C6 alkyl, -C(O)OC1-C6 alkyl, -C(O)NH2.

[0119] In a preferred embodiment, R s Selected from one of the following structures, substituted or unsubstituted:

[0120]

[0121]

[0122] R 21 R 22 Whether the elements are the same or different, they are each independently selected from: H, D, C1-C6 alkyl, -C(O)R d -C(O)NR d R e -S(O)2R d -S(O)2NR d R e ;

[0123] R d R e The same or different, independently selected from: H, D, substituted or unsubstituted C1-C6 alkyl.

[0124] Preferably, the substituents in the above structure that are "substituted or unsubstituted" are selected from: D, halogen, hydroxyl, C1-C4 alkyl, halo-C1-C4 alkyl, and C1-4 alkoxy. The number of substituents can be one, two, three, or more.

[0125] In a preferred embodiment, R 16 R 17 R 18 R 19 Selected from: H, D, halogen, hydroxyl, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-4 alkoxy.

[0126] In a preferred embodiment, R is selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, -C1-C6 alkylene-R. s R s .

[0127] In a preferred embodiment, R 20 Selected from: H, D, C1-C4 alkyl groups.

[0128] In a preferred embodiment, R 11 R 12 R 13 R 14 R 15 Any two adjacent carbon atoms in the ring form substituted or unsubstituted rings together with the carbon atoms they are attached to: imidazolidine-2-one ring, pyrazole ring, pyrrole ring, imidazolium ring, thiophene ring, furan ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring.

[0129] Preferably, the Choose one of the following structures:

[0130]

[0131] Among them, X1, X2, X5, R 21 R 22 As described in this article;

[0132] R 23 Whether the elements are the same or different, they are each independently selected from: H, D, C1-C6 alkyl, -C(O)R d -C(O)NR d R e -S(O)2R d -S(O)2NR d R e -L1-R s ;

[0133] R 31 The same or different, each independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -L1-R s -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR bR c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c ;

[0134] Among them, L1, L2, R b R c R d R e R s As described in this article.

[0135] For example, R b R c Identical or different, independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl, -L1-R s ;R d R e The same or different, independently selected from: H, D, substituted or unsubstituted C1-C6 alkyl;

[0136] L1 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups;

[0137] L2 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups;

[0138] R s Selected from substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted 5-15 heterocyclic alkyl, and substituted or unsubstituted 5-20 heteroaryl.

[0139] Preferably, X1, X2, and X5 are selected from CH.

[0140] Preferred, R 31 Whether identical or different, each is independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C15 alkyl, halo-C1-C15 alkyl, hydroxy-substituted C1-C15 alkyl, C1-C4 alkoxy-substituted C1-C15 alkyl, -L1-R s -OR b -SR b -C(O)Rb -C(O)OR b -OC(O)R b -C(O)NR b R c -NR b C(O)R c -NR b R c -S(O)2R b R c -S(O)2NR b R c .

[0141] Preferred, R 31 Whether identical or different, each is independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C4 alkoxy-substituted C1-C6 alkyl, -R s C1-C6 alkylene-R s -OR s -OC1-C6 alkylene-R s -C1-C6 alkylene-OR s -C1-C6 alkylene OC1-C6 alkylene-R s -SR s -SC1-C6 alkylene-R s -C1-C6 alkylene-SR s -C1-C6 alkylene SC1-C6 alkylene-R s -NH-R s -N(C1-C6 alkyl)-R s -NH-C1-C6 alkylene-R s -N(C1-C6 alkyl)-C1-C6 alkylene-R s -C1-C6 alkylene-NH-R s -C1-C6 alkylene-N(C1-C6 alkyl)-R s -C1-C6 alkylene-NH-C1-C6 alkylene-R s -C1-C6 alkylene-N(C1-C6 alkyl)-C1-C6 alkylene-R s .

[0142] In a preferred embodiment, Ar is selected from one of the following structures:

[0143]

[0144]

[0145] In another aspect, the present invention provides a compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0146]

[0147] Among them, R 17 n2, L1, R s The definition is as stated above;

[0148] Ar1 is selected from: substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted 5-15 heterocyclic alkyl, and substituted or unsubstituted 5-20 heteroaryl.

[0149] In a preferred embodiment, Ar1 is selected from substituted or unsubstituted: phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, aziridine, tetrahydropyrroleyl, tetrahydropyrazolyl, tetrahydroimidazolyl, morpholinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalolinyl, quinazolinyl, triazolyl, pyrazolyl, pyrroleyl, furanyl, thiophenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl.

[0150] Preferably, Ar1 is selected from substituted or unsubstituted: phenyl, naphthyl, pyridyl, pyrimidinyl, quinolinyl (e.g., quinolin-5-yl, quinolin-4-yl), quinoxalinyl, quinazolinyl.

[0151] Preferably, the substituents described in Ar1 as "substituted or unsubstituted" are selected from: D, nitro, cyano, -C(O)OR a -OC(O)R a -S(O)2R a Halogen, -OR a -SR a The number of substituents can be one, two, three, or more.

[0152] R a Selected from: H, D, substituted or unsubstituted C1-C15 alkyl groups.

[0153] In a preferred embodiment, L1 is selected from single bonds, -(CR) n R m ) m -, R n R m Whether identical or different, each is independently selected from: H, D, C1-C4 alkyl; m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Preferably, L1 is selected from -(CH2). m-, m is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0154] In a preferred embodiment, R s Selected from one of the following structures, substituted or unsubstituted:

[0155]

[0156] Among them, R 21 R 22 Whether identical or different, each is independently selected from: H, D, C1-C6 alkyl, -C(O)R d -C(O)NR d R e -S(O)2R d -S(O)2NR d R e ;

[0157] R d R e The same or different, independently selected from: H, D, substituted or unsubstituted C1-C6 alkyl.

[0158] In some embodiments, the compound of formula (I) of the present invention is selected from:

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165] In some embodiments, the compound of formula (II) of the present invention is selected from:

[0166]

[0167] The above lists some specific chemical structures of compounds of formula (I) or formula (II) of the present invention, but the present invention is not limited to these listed chemical structures. Any compound based on formula (I) or formula (II) with substituents as defined above should be included.

[0168] Another aspect of the present invention provides a pharmaceutical composition comprising at least one of the compounds of formula (I), formula (II), or pharmaceutically acceptable salts thereof.

[0169] In a preferred embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient, or stabilizer. Pharmaceutically acceptable carriers, excipients, or stabilizers are described herein and are well known in the art (see, for example, Remington: The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000). Examples of physiologically acceptable carriers, excipients, or stabilizers include, but are not limited to, buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid; low molecular weight peptides; proteins such as serum albumin, gelatin; or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants, such as… Polyethylene glycol (PEG) and

[0170] The pharmaceutical compositions of the present invention can be administered orally, parenterally, via inhalation spray, topically, rectally, via the nose, via the mouth, via the vagina, or via implantation.

[0171] In a preferred embodiment, the pharmaceutical composition further comprises at least one other bioactive agent.

[0172] Other bioactive agents include corticosteroids, such as glucocorticoids or mineral corticosteroids administered in combination. Corticosteroids include, but are not limited to, corticosterones and their derivatives, prodrugs, isomers and analogs, cortisones and their derivatives, prodrugs, isomers and analogs (i.e., Cortone), aldosterones and their derivatives, prodrugs, isomers and analogs, dexamethasones and their derivatives, prodrugs, isomers and analogs (e.g., Decadron), prednisones and their derivatives, prodrugs, isomers and analogs (e.g., Prelone), flucortisones and their derivatives, prodrugs, isomers and analogs, hydrocortisones and their derivatives, prodrugs, isomers and analogs (e.g., cortisol), hydroxycortisone, betamethasone, budesonide, methylprednisolone, prednisolone, triamcinolone, and any derivatives, prodrugs, isomers and analogs of these corticosteroids.

[0173] The TLR7 antagonist of the present invention can be administered concurrently with one or more other therapeutic agents, including but not limited to corticosteroids (concurrent administration). The TLR7 antagonist can also be administered sequentially with other therapeutic agents, including but not limited to corticosteroids (sequential administration). Sequential administration may include administering the TLR7 antagonist or other therapeutic agent at any subsequent time, approximately one minute, five minutes, 30 minutes, one hour, five hours, 24 hours, 48 ​​hours, or one week. The TLR7 antagonist can be administered via the same route of administration as other therapeutic agents. The TLR7 antagonist can also be administered via a different route of administration than other therapeutic agents. The other therapeutic agents can be administered parenterally (e.g., via central venous line, intra-arterial, intravenous, intramuscular, intraperitoneal, intradermal, or subcutaneous injection), orally, gastrointestinally, topically, or via nasopharyngeal and pulmonary administration (e.g., inhalation or intranasal administration).

[0174] Combining a TLR7 antagonist with one or more other therapeutic agents reduces the effective dose (including, but not limited to, dose volume, dose concentration, and / or total dose) and achieves the same effect when compared to the effective dose when the TLR7 antagonist or other therapeutic agent is administered alone. Alternatively or additionally, the combination of a TLR7 antagonist with a corticosteroid reduces the effective dose of the administered corticosteroid compared to administration of the corticosteroid alone. Combining a TLR7 antagonist with another therapeutic agent can reduce the frequency of administration of the therapeutic agent compared to administration of the other therapeutic agent alone. Alternatively or additionally, the combination of a TLR7 antagonist with another therapeutic agent reduces the total duration of treatment compared to administration of the other therapeutic agent alone. Combining a TLR7 antagonist with another therapeutic agent can reduce the side effects associated with administration of the other therapeutic agent alone. This other therapeutic agent may be a corticosteroid.

[0175] TLR7 antagonists can also be used as vaccine adjuvants, in combination with any substance that modulates humoral and / or cell-mediated immune responses, such as live viruses, bacteria, or parasite immunogens; inactivated viral, tumor-derived, protozoan, biological, fungal, or bacterial immunogens, toxoids, toxins; autoantigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; recombinant proteins; glycoproteins; peptides; etc. In some respects, combination therapies, including but not limited to those involving TLR7 antagonists and vaccines, are used to treat autoimmune diseases or inflammatory conditions. In some respects, combination therapies, including but not limited to those involving TLR7 antagonists and vaccines, are used to treat infectious diseases.

[0176] Combination therapy may include, but is not limited to, combinations of the TLR7 antagonists disclosed herein and corticosteroids used to treat autoimmune or inflammatory diseases. Autoimmune diseases may be selected from rheumatoid arthritis, systemic lupus erythematosus, autoimmune skin diseases, multiple sclerosis, pancreatitis, glomerulonephritis, pyelonephritis, sclerosing cholangitis, and type I diabetes or Sjogren's disease.

[0177] Another aspect of the present invention provides the use of the said compound and pharmaceutical composition in the preparation of a medicament for treating TLR7-dependent immune responses.

[0178] Another aspect of the present invention provides the use of the said compound or pharmaceutical composition in the preparation of a medicament for treating autoimmune diseases.

[0179] Another aspect of the present invention provides a method for treating TLR7-dependent immune responses, comprising providing the compound or pharmaceutical composition to an individual.

[0180] Another aspect of the present invention provides a method for treating autoimmune diseases, comprising providing the compound or pharmaceutical composition to an individual.

[0181] In a preferred embodiment, the compound or pharmaceutical composition is used in a human individual.

[0182] In a preferred embodiment, the immune response is associated with an autoimmune disease.

[0183] In a preferred embodiment, suppressing the immune response improves one or more symptoms of an autoimmune disease.

[0184] In a preferred embodiment, the autoimmune disease is selected from: arthritis caused by autoimmunity, autoimmune pancreatitis, mixed connective tissue disease, systemic lupus erythematosus, antiphospholipid syndrome, irritable bowel syndrome, type I diabetes, Sjögren's syndrome, scleroderma, multiple sclerosis, autoimmune hepatitis, Still's disease, Crohn's disease, ulcerative colitis, polymyositis, glomerulonephritis, sclerosing cholangitis, autoimmune dermatitis, uveitis, pernicious anemia, hypoparathyroidism, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, hypopituitarism, and cold disease.

[0185] Preferably, the arthritis is selected from rheumatoid arthritis, systemic arthritis, and osteoarthritis.

[0186] Preferably, the autoimmune skin disease is selected from psoriasis, vitiligo, pemphigus vulgaris, and pemphigus foliaceus.

[0187] In a preferred embodiment, the autoimmune disease is associated with RNA-containing immune complexes.

[0188] In a preferred embodiment, the immune response is associated with an inflammatory disease.

[0189] In a preferred embodiment, suppressing the immune response improves one or more symptoms of the inflammatory disease.

[0190] Preferably, the inflammatory disease is associated with elevated TLR7 expression.

[0191] This invention also provides a method for preparing compounds of formula (I) and formula (II), but the preparation method of this invention is not limited thereto. The core structure of compounds of formula (I) and formula (II) can be prepared by the reaction route shown below, the substituents can be bonded by methods known in the art, and the type and position or number of substituents can be changed according to techniques known in the art.

[0192] The preparation method described in this invention is, for example, as follows:

[0193] Method 1:

[0194]

[0195] Compound (A) reacts with compound (B) to produce compound (I);

[0196] Method 2:

[0197]

[0198] Compound (C) reacts with compound (D) to produce compound (I);

[0199] Method 3:

[0200]

[0201] Compound (E) reacts with compound (F) to produce compound (II);

[0202] Method 4:

[0203]

[0204] Compound (G) reacts with compound (H) to produce compound (II);

[0205] Xa is selected from halogens, preferably chlorine, bromine, or iodine;

[0206] M is selected from: -B(OH)2,

[0207] R1-R5, Ar, Ar1, R 17 L1, R s The definitions of n2 are as described in this article.

[0208] The following will describe preferred embodiments of the invention in detail. These embodiments are provided to better illustrate the invention and are not intended to limit the invention to these examples. Non-essential improvements and adjustments to the embodiments based on the invention's description still fall within the scope of the invention.

[0209] Unless otherwise specified, the experimental methods in the following embodiments are conventional methods. Where specific techniques or conditions are not specified in the embodiments, they should be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions.

[0210] The meanings of some of the raw material abbreviations are as follows:

[0211] DME: Dimethyl ethylene glycol; DCM: Dichloromethane; EA: Ethyl acetate; PE: Petroleum ether; DMF: N,N-Dimethylformamide; mCPBA: m-chloroperoxybenzoic acid; NBS: N-bromosuccinimide; AIBN: Azobisisobutyronitrile; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBt: 1-hydroxybenzotriazole; DIEA: N,N-diisopropylethylamine; DMA: N,N-dimethylacetamide.

[0212] I. Synthesis Examples

[0213] Example 1: Synthesis of TollB-7C-1

[0214] Add 250 mg (1.00 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 280 mg (1.20 mmol, 1.2 eq) of 3-methyl-4-hydroxyphenylboronic acid ester, 41 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 4 ml of DME to a 10 ml centrifuge tube; add 210 mg (2.00 mmol, 2.0 eq) of sodium carbonate and 1 ml of water to a 10 ml centrifuge tube, dissolve at room temperature, and then add to the reaction tube; react overnight at 80 °C under nitrogen protection; filter the reaction solution through diatomaceous earth, evaporate the filtrate to dryness, load the sample onto a dry column, and pass it through a DCM column to obtain 126 mg (42.8%) of yellow solid.

[0215] Example 2: Synthesis of TollB-7C-2

[0216] Add 250 mg (1.00 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 220 mg (1.20 mmol, 1.2 eq) of p-aminophenylboronic acid ester, 41 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 4 ml of DME to a 10 ml reaction tube; take a 10 ml centrifuge tube, add 210 mg (2.00 mmol, 2.0 eq) of sodium carbonate, 1 ml of water, dissolve at room temperature, and then add to the reaction tube; react overnight at 80 °C under nitrogen protection; filter the reaction solution through diatomaceous earth, evaporate the filtrate to dryness, load the sample dry, and pass it through a DCM column to obtain 78 mg of yellow solid, yield 29.4%.

[0217] Example 3: Synthesis of TollB-7C-3

[0218] 250 mg (1.00 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 280 mg (1.20 mmol, 1.2 eq) of 4-methoxyphenylboronic acid ester, 41 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 4 ml of DME were added to a 10 ml centrifuge tube. 210 mg (2.00 mmol, 2.0 eq) of sodium carbonate and 1 ml of water were added to a centrifuge tube and dissolved at room temperature before being added to the reaction tube. The reaction was carried out overnight at 80 °C under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filtrate was evaporated to dryness, and the sample was loaded onto a dry column. The solution was passed through a DCM column to obtain 110 mg of a yellow solid, with a yield of 39.2%.

[0219] Example 4: Synthesis of TollB-7C-4

[0220] Add 250 mg (1.00 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 290 mg (1.20 mmol, 1.2 eq) of pinacol ester of 3-acrylonitrile-4-hydroxyphenylboronic acid, 41 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 4 ml of DME to a 10 ml centrifuge tube; add 210 mg (2.00 mmol, 2.0 eq) of sodium carbonate and 1 ml of water to a 10 ml centrifuge tube, dissolve at room temperature, and then add to the reaction tube; react overnight at 80 °C under nitrogen protection; filter the reaction solution through diatomaceous earth, evaporate the filtrate to dryness, load the sample onto a dry column, and pass it through a DCM column to obtain 120 mg of yellow solid, yield 41.2%.

[0221] Example 5: Synthesis of TollB-7C-5

[0222] 250 mg (1.00 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 290 mg (1.20 mmol, 1.2 eq) of 3-fluoro-4-hydroxyboronic acid ester, 41 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 4 ml of DME were added to a 10 ml centrifuge tube. 210 mg (2.00 mmol, 2.0 eq) of sodium carbonate and 1 ml of water were added to the centrifuge tube and dissolved at room temperature before being added to the reaction tube. The reaction was carried out overnight at 80 °C under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filtrate was evaporated to dryness, and the sample was loaded onto a dry column. The solution was passed through a DCM column to obtain 136 mg of a yellow solid, with a yield of 46.7%.

[0223] Example 6: Synthesis of TollB-7C-6

[0224] 250 mg (1.00 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 300 mg (1.20 mmol, 1.2 eq) of 3-chloro-4-hydroxyphenylboronic acid ester, 41 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 4 ml of DME were added to a 10 ml centrifuge tube. 210 mg (2.00 mmol, 2.0 eq) of sodium carbonate and 1 ml of water were added to the centrifuge tube and dissolved at room temperature before being added to the reaction tube. The reaction was carried out overnight at 80 °C under nitrogen protection. The reaction solution was filtered through diatomaceous earth, the filtrate was evaporated to dryness, and the sample was loaded onto a dry column. The solution was passed through a DCM column to obtain 112 mg of a yellow solid, with a yield of 37.2%.

[0225] Example 7: Synthesis of TollB-7C-7

[0226] Add 250 mg (1.00 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 150 mg (1.20 mmol, 1.2 eq) of phenylboronic acid, 41 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 4 ml of DME to a 10 ml reaction tube; take a 10 ml centrifuge tube, add 210 mg (2.00 mmol, 2.0 eq) of sodium carbonate and 1 ml of water, dissolve at room temperature, and then add to the reaction tube; react overnight at 80 °C under nitrogen protection; filter the reaction solution through diatomaceous earth, evaporate the filtrate to dryness, load the sample by dry method, and pass it through a DCM column to obtain 87 mg of yellow solid, with a yield of 34.8%.

[0227] Example 8: Synthesis of TollB-7C-8

[0228] Add 250 mg (1.00 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 180 mg (1.20 mmol, 1.2 eq) of 4-mercaptophenylboronic acid ester, 41 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 4 ml of DME to a 10 ml centrifuge tube; add 210 mg (2.00 mmol, 2.0 eq) of sodium carbonate and 1 ml of water to a 10 ml centrifuge tube, dissolve at room temperature, and then add to the reaction tube; react overnight at 80 °C under nitrogen protection; filter the reaction solution through diatomaceous earth, evaporate the filtrate to dryness, load the sample onto a dry column, and pass it through a DCM column to obtain 113 mg of yellow solid, yield 40.0%.

[0229] Example 9: Synthesis of TollB-7C-9

[0230] Add 250 mg (1.00 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 200 mg (1.20 mmol, 1.2 eq) of 4-acetylphenylboronic acid ester, 41 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 4 ml of DME to a 10 ml centrifuge tube; add 210 mg (2.00 mmol, 2.0 eq) of sodium carbonate and 1 ml of water to a 10 ml centrifuge tube, dissolve at room temperature, and then add to the reaction tube; react overnight at 80 °C under nitrogen protection; filter the reaction solution through diatomaceous earth, evaporate the filtrate to dryness, load the sample onto a dry column, and pass it through a DCM column to obtain 110 mg of yellow solid, yield 36.7%.

[0231] Example 10: Synthesis of TollB-7C-10

[0232] Add 190 mg (0.75 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 250 mg (0.90 mmol, 1.2 eq) of 2-oxo-2,3-dihydro-1H-benzimidazole-5-boronic acid pinacol ester, 33 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, 160 mg (1.50 mmol, 2.0 eq) of sodium carbonate, 4 mL of DME, and 1 mL of water to a 10 mL reaction tube; react overnight at 80 °C under nitrogen protection; filter the reaction solution through diatomaceous earth, wash with a large amount of methanol, evaporate the filtrate to dryness, add 40 mL of methanol and 2 g of activated carbon, stir at 50 °C for 2 h, filter, evaporate the filtrate to dryness, add 15 mL of DCM to the residual solid, stir at room temperature for 1 h, filter, wash the filter cake with dichloromethane, and dry in a vacuum drying oven at room temperature overnight to obtain 0.28 g of brownish-yellow solid powder.

[0233] Example 11: Synthesis of TollB-7C-11

[0234] 300 mg (1.20 mmol, 1.2 eq) of 5-bromo-8-nitroquinoline, 140 mg (1.00 mmol, 1.0 eq) of K2CO3, 100 mg (1.00 mmol, 1.0 eq) of 4-pyridone, 10 mg (0.05 mmol, 5% mmol) of cuprous iodide, and 5 ml of DMSO were added sequentially to a 10 ml reaction tube. The tube was sealed at 120 °C and reacted overnight. The reaction solution was cooled to room temperature and poured into 200 ml of water. The solution was extracted four times with EA (60 ml * 4). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. 5 ml of ethyl acetate was added to the crude product, and the mixture was stirred at room temperature for 1 h. The mixture was filtered, and the solid was washed twice with EA. The solid was dried under vacuum at room temperature to obtain 120 mg of yellow solid.

[0235] Example 12: Synthesis of TollB-7C-12

[0236] In a 50 ml reaction flask, add 930 mg (3.50 mmol, 1.0 eq) of methyl 5-bromo-8-carboxylate quinoline, 140 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 25 ml of 1,4-dioxane. Take a 10 ml EP tube, add 740 mg (7.00 mmol, 2.00 eq) of sodium carbonate, dissolve in 5 ml of drinking water, cool to room temperature, and add to the reaction flask. Under nitrogen protection, stir overnight at 80°C. Filter with diatomaceous earth, wash with ethyl acetate, evaporate the filtrate to dryness, and dry-load the sample onto a column (DCM / MeOH = 100:1) to obtain 0.70 g of a pale white-yellow solid. Yield: 71%.

[0237] Example 13: Synthesis of TollB-7C-13

[0238] In a 50 ml reaction flask, add 280 mg (1.00 mmol, 1.0 eq) of Toll B-7c-12 and 10 ml of methanol, and cool to 0 °C. Take a 10 ml EP tube, add 320 mg (8.00 mmol, 8.00 eq) of sodium hydroxide, dissolve in 1.5 ml of water, and cool to room temperature. Add the solution dropwise to the reaction flask, transfer to room temperature, and stir overnight. Add 460 g (8.00 mmol, 8.00 eq) of glacial acetic acid to the reaction solution, stir at room temperature for 10 minutes, evaporate to dryness, add silica gel, and pass through a column in a dichloromethane / methanol ratio of 4:1 to obtain 0.23 g of a yellow solid, yield: 86%.

[0239] Example 14: Synthesis of TollB-7C-14

[0240] 270 mg (1.00 mmol, 1.0 eq) of Toll B-7C, 25 mL of dichloromethane, and 0.42 mL (3.00 mmol, 3.0 eq) of triethylamine were added sequentially to a 50 mL reaction flask. The mixture was cooled to approximately 0 °C, and 0.15 mL (1.20 mmol, 1.2 eq) of tert-butyl chloride was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature overnight. The reaction solution was directly evaporated to dryness by TLC (EA / PE = 1:2), and then passed through a column chromatography (DCM / MeOH = 100:1) to obtain 0.3 g of a pale yellow solid. The yield was 85.6%.

[0241] Example 15: Synthesis of TollB-7C-15

[0242] 270 mg (1.00 mmol, 1.0 eq) of Toll B-7C, 25 mL of dichloromethane, and 0.42 mL (3.00 mmol, 3.0 eq) of triethylamine were added sequentially to a 50 mL reaction flask. The mixture was cooled to approximately 0 °C, and 0.11 mL (1.20 mmol, 1.2 eq) of acetyl chloride was added dropwise. After the addition was complete, the reaction mixture was allowed to react at room temperature overnight. The reaction solution was directly evaporated to dryness by TLC (EA / PE = 1:2), and then subjected to column chromatography (DCM / MeOH = 100:1) to obtain 0.28 g of a pale yellow solid, yield: 90.8%.

[0243] Example 16: Synthesis of TollB-7C-16

[0244] 270 mg (1.00 mmol, 1.0 eq) of Toll B-7C, 25 mL of dichloromethane, and 0.42 mL (3.00 mmol, 3.0 eq) of triethylamine were added sequentially to a 50 mL reaction flask. The mixture was cooled to approximately 0 °C, and 0.14 mL (1.20 mmol, 1.2 eq) of benzoyl chloride was added dropwise. After the addition was complete, the reaction mixture was allowed to react at room temperature overnight. The reaction solution was directly evaporated to dryness by TLC (EA / PE = 1:2), and then subjected to column chromatography (DCM / MeOH = 100:1) to obtain 0.34 g of a pale yellow solid, yield: 91.8%.

[0245] Example 17: Synthesis of TollB-7C-17

[0246] TollB-7C-2 106 mg (0.40 mmol, 1.0 eq), dichloromethane 25 mL, and triethylamine 121 mg (1.20 mmol, 3.0 eq) were added sequentially to a 50 mL reaction flask. The mixture was cooled to approximately 0 °C, and acetyl chloride 37.7 mg (0.48 mmol, 1.2 eq) was added dropwise. After the addition was complete, the reaction mixture was allowed to react at room temperature overnight. The reaction solution was directly evaporated to dryness by TLC (EA / PE = 1:2), and then subjected to column chromatography with DCM / MeOH = 100:1 to obtain 98 mg of a pale yellow solid. Yield: 79.6%.

[0247] Example 18: Synthesis of TollB-7C-18

[0248] TollB-7C-2 106 mg (0.40 mmol, 1.0 eq), dichloromethane 25 mL, and triethylamine 121 mg (1.20 mmol, 3.0 eq) were added sequentially to a 50 mL reaction flask. The mixture was cooled to approximately 0 °C, and tert-butyryl chloride 58 mg (0.48 mmol, 1.2 eq) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature overnight. The reaction solution was directly evaporated to dryness by TLC (EA / PE = 1:2), and then subjected to column chromatography with DCM / MeOH = 100:1 to obtain 110 mg of a pale yellow solid. Yield: 78.5%.

[0249] Example 19: Synthesis of TollB-7C-19

[0250] Add 750 mg (3.00 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 800 mg (3.60 mmol, 1.2 eq) of p-fluorophenylboronic acid ester, 123 mg (0.15 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 30 ml of DME to a 10 ml centrifuge tube; add 630 mg (6.00 mmol, 2.0 eq) of sodium carbonate and 2 ml of water to a 10 ml centrifuge tube, dissolve at room temperature, and then add to the reaction tube; react overnight at 80 °C under nitrogen protection; filter the reaction solution through diatomaceous earth, evaporate the filtrate to dryness, load the sample dry, and pass it through a DCM column to obtain 560 mg of yellow solid (70.0%).

[0251] Example 20: Synthesis of TollB-7C-20

[0252] Toll B-7C-19 134 mg (0.50 mmol, 1.0 eq), potassium carbonate 1.38 g (1.00 mmol, 2.0 eq), methylamine hydrochloride 510 mg (0.75 mmol, 1.5 eq), and DMSO 4 ml were added sequentially to a 10 ml reaction tube. The tube was sealed at 85 °C and stirred overnight. TLC was used for detection. The reaction solution was poured into water, and EA was added for extraction three times (15 ml * 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The solution was passed through a column chromatography at a DCM / MeOH ratio of 100:1 to give 16 mg of a brownish-yellow solid, with a yield of 12%.

[0253] Example 21: Synthesis of TollB-7C-21

[0254] 86 mg (0.34 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 100 mg (0.41 mmol, 1.2 eq) of 1H-indazole-6-boronic acid pinacol ester, 14 mg (0.02 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, 72 mg (0.68 mmol, 2.0 eq) of sodium carbonate, 2.5 ml of DME, and 0.5 ml of water were added to a 10 ml reaction tube. The reaction mixture was reacted overnight at 80 °C under nitrogen protection. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was evaporated to dryness. The solution was loaded onto a dry column and passed through a DCM column to obtain 38 mg of a yellow solid, with a yield of 38.2%.

[0255] Example 22: Synthesis of TollB-7C-22

[0256] Add 91 mg (0.36 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 110 mg (0.43 mmol, 1.2 eq) of 2-methyl-2H-indazole-6-boronic acid pinacol, 15 mg (0.02 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, 76 mg (0.72 mmol, 2.0 eq) of sodium carbonate, 2.5 ml of DME, and 0.5 ml of water to a 10 ml reaction tube; react overnight at 80 °C under nitrogen protection; filter the reaction solution through diatomaceous earth, wash with ethyl acetate, evaporate the filtrate to dryness, load the sample onto a dry column, and pass the DCM / MeOH mixture at a ratio of 200:1 to obtain 62 mg of a yellow solid, yield 55.6%.

[0257] Example 23: Synthesis of TollB-7C-23

[0258] 86 mg (0.34 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 100 mg (0.41 mmol, 1.2 eq) of pinacol ester of 3-cyano-4-aminophenylboronic acid, 14 mg (0.02 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, 72 mg (0.68 mmol, 2.0 eq) of sodium carbonate, 2.5 ml of DME, and 0.5 ml of water were added to a 10 ml reaction tube. The reaction mixture was reacted overnight at 85 °C under nitrogen protection. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was evaporated to dryness. The solution was loaded onto a dry column and passed through a DCM column to obtain 54 mg of a yellow solid, with a yield of 55.9%.

[0259] Example 24: Synthesis of TollB-7C-24

[0260] Synthesis of 2-trifluoromethylaniline-4-phenylboronic acid pinacol ester

[0261]

[0262] 1.00 g (4.17 mmol, 1.0 eq) of 5-bromo-2-aminotrifluorotoluene, 1.27 g (5.00 mmol, 1.2 eq) of pinacol diboronate, 170 mg (0.21 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, 1.64 g (16.67 mmol, 4.0 eq) of potassium acetate, and 25 ml of 1,4-dioxane were added to a 50 ml reaction flask. The reaction mixture was reacted overnight at 85 °C under nitrogen protection. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was evaporated to dryness. The solution was loaded onto a dry column and passed through a DCM column to obtain 810 mg of a white solid, with a yield of 55.9%.

[0263] Synthesis of TollB-7C-24

[0264] 100 mg (0.40 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 136 mg (0.47 mmol, 1.2 eq) of 2-trifluoromethylaniline-4-phenylboronic acid pinacol ester, 16 mg (0.02 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, 72 mg (0.68 mmol, 2.0 eq) of sodium carbonate, 2.5 ml of DME, and 0.5 ml of water were added to a 10 ml reaction tube. The reaction mixture was reacted overnight at 85 °C under nitrogen protection. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was evaporated to dryness. The solution was loaded onto a dry column and passed through a DCM column to obtain 62 mg of a yellow solid, with a yield of 45.0%.

[0265] Example 25: Synthesis of TollB-7C-25

[0266] Synthesis of 8-nitroquinoline-5-boronic acid pinacol ester

[0267]

[0268] In a 50 mL single-necked flask, add 1.0 g (3.95 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 1.55 g (15.81 mmol, 4.0 eq) of potassium acetate, 160 mg (0.2 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 1.2 g (4.74 mmol, 1.2 eq) of pinacol diboronate. Finally, add 25 mL of 1,4-dioxane. Stir overnight at 70 °C under nitrogen protection. Filter the reaction solution through diatomaceous earth, wash with ethyl acetate, evaporate the filtrate to dryness, and dry-load the solution onto a DCM column to obtain 1.02 g of a white solid (yield: 86.1%). No further purification is required; it can be used directly in the next synthesis.

[0269] Synthesis of TollB-7C-25

[0270] 400 mg (1.33 mmol, 1.2 eq) of 8-nitroquinoline-5-phenanthoxyboronate, 314 mg (1.11 mmol, 1.0 eq) of p-bromoiodobenzene, 57 mg (0.07 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, 235 mg (2.22 mmol, 2.0 eq) of sodium carbonate, 2.5 ml of DME, and 0.5 ml of water were added to a 10 ml reaction tube. The reaction mixture was reacted overnight at 85 °C under nitrogen protection. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, and the filtrate was evaporated to dryness. The solution was loaded onto a dry column and passed through a DCM column to obtain 200 mg of a yellow solid, with a yield of 55.0%.

[0271] Example 26: TollB-7C-29

[0272] Synthesis of 5-nitro-8-methylthioquinoline

[0273]

[0274] 3 g (3.95 mmol, 1.0 eq) of 5-nitro-8-bromoquinoline and 30 ml of acetonitrile were added to a 100 ml single-necked flask. 1.26 g (5.93 mmol, 1.5 eq) of sodium methanethiol was added with stirring at room temperature. The mixture was heated to 40 °C and stirred for 2 h. 0.84 g (3.95 mmol, 1.0 eq) of sodium methanethiol was added, and stirring was continued at 40 °C for another 2 h. The reaction mixture was poured into water and extracted three times with EA (25 ml * 3). The organic phases were combined and washed once with water. The solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. 10 g of silica gel was placed in a funnel. The crude product was dissolved in a small amount of DCM, and the DCM was rapidly passed through a column. The solution was evaporated to dryness to give 2.7 g of a yellow solid. Synthesis of 5-nitro-8-methanesulfonylquinoline

[0275]

[0276] Add 2.7 g (12.3 mmol, 1.0 eq) of 5-nitro-8-methylthioquinoline and 30 ml of dichloromethane to a 100 ml single-necked flask. Add 6.4 g (36.9 mmol, 3.0 eq) of mCPBA in portions while stirring at room temperature. After the addition is complete, stir at room temperature for 3 h.

[0277] Add 30 ml of 2N sodium thiosulfate solution to the reaction solution; stir at room temperature for 30 min, then add 20 ml of 4N sodium hydroxide solution, continue stirring at room temperature for another 30 min, then separate the liquid and extract the aqueous phase twice with DCM (20 ml * 2), combine the organic phases, wash once with 20% sodium hydroxide solution and once with water, dry the organic phase with anhydrous magnesium sulfate, filter, and evaporate to dryness to obtain 2.8 g of light yellow solid, yield 90.6%, no further purification is required, and it can be used directly in the next reaction.

[0278] Synthesis of 5-amino-8-methanesulfonylquinoline

[0279]

[0280] 6.31 g (11.1 mmol, 1.0 eq) of stannous chloride and 15 ml of 95% ethanol were added to a 50 ml Erlenmeyer flask and dissolved by sonication at room temperature. 2.8 g of 5-nitro-8-methanesulfonylquinoline and 30 ml of ethanol were added to a 200 ml single-necked flask and stirred at room temperature until evenly dispersed. Then, the alcoholic solution of stannous chloride was added, and the mixture was stirred at room temperature for 2 hours. The solution was analyzed by LC-MS. 6.14 g of potassium carbonate was added directly to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. 45 ml of DCM was added, and the reaction mixture was filtered (using filter cloth and diatomaceous earth). The reaction mixture was evaporated to dryness, and the residue was slurried with methanol. The solid was filtered to obtain 2 g of a yellow solid, with a yield of 81%. Synthesis of 5-iodo-8-methanesulfonylquinoline.

[0281]

[0282] Add 2.0 g (9.0 mmol, 1.0 eq) of 5-amino-8-methanesulfonylquinoline, 40 ml of water, and 5 ml (36 mmol, 4.0 eq) of concentrated hydrochloric acid to a 100 ml three-necked flask and reflux for 1 h. First, allow it to cool naturally to room temperature, then cool it to 0-5 °C. Take a 2.5 ml EP tube, add 745 mg (10.8 mmol, 1.2 eq) of sodium nitrite dissolved in 1 ml of water, and slowly add it to the reaction flask, controlling the temperature to be less than or equal to 5 °C. After the addition is complete, keep it at 0-5 °C and stir for 1 h.

[0283] In a separate 200ml single-necked flask, add 3.0g of potassium iodide (18.0mmol, 2.0eq) and 15ml of water. Add the diazonium salt solution (in batches, slowly, followed by a large release of gas) while stirring at room temperature. After the addition is complete, stir at room temperature for 3 hours. Adjust the pH of the reaction solution to approximately 8 using sodium bicarbonate. Extract three times with EA (25ml x 3), combine the organic phases, wash twice with 2N sodium thiosulfate, wash once with water, dry the organic phase with anhydrous magnesium sulfate, filter, evaporate to dryness, and load the residue onto a dry sample and pass it through a rapid column under reduced pressure to obtain 2.1g of a pale yellow solid, with a yield of 70%.

[0284] Synthesis of TollB-7C-29

[0285] Add 0.5 g (1.5 mmol, 1.0 eq) of 5-iodo-8-methanesulfonylquinoline, 0.25 g (1.8 mmol, 1.2 eq) of p-hydroxyphenylboronic acid, 61 mg (0.075 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 300 ml of ethylene glycol dimethyl ether to a 50 ml single-necked flask; take a 10 ml centrifuge tube, add 0.32 g (3.00 mmol, 2.0 eq) of sodium carbonate, 4 ml of water, dissolve at room temperature, and then add to the reaction flask; react overnight at 100 °C under nitrogen protection; filter the reaction solution, dry-load the sample, and pass it through a fast column with DCM / MeOH = 100:1. Add 10 ml of EA to the solid obtained from the column chromatography, stir at room temperature for 1 h, and filter the solid; 243 mg of beige solid was obtained, with a yield of 60.75%.

[0286] Example 27: Synthesis of TollB-7C-30

[0287] Add 0.12 g (0.45 mmol, 1.0 eq) of Toll B-7C-2, 0.15 g (0.68 mmol, 1.5 eq) of Boc anhydride, 0.12 g (0.90 mmol, 1.0 eq) of potassium carbonate, and 15 ml of DMF to a 50 ml single-necked flask in sequence; stir overnight at room temperature; pour the reaction solution into water and add 15 ml of EA, stir thoroughly, and separate the layers. Extract the aqueous phase three times with EA (10 ml * 3), combine the organic phases, wash once each with saturated brine and water, dry the organic phase with anhydrous magnesium sulfate, filter, evaporate the filtrate to dryness, and pass it through a column with DCM / MeOH = 200:1 to obtain 78 mg of yellow-brown solid.

[0288] Example 28: Synthesis of TollB-7C-31

[0289] Add Toll B-7C (500 mg, 1.88 mmol, 1.0 eq), 1-BOC-4-bromomethylpiperidine (627 mg, 2.25 mmol, 1.2 eq), potassium carbonate (519 mg, 3.76 mmol, 2.0 eq), and 15 ml of DMF to a 50 ml single-necked flask, and stir overnight at 100 °C. Pour the reaction solution into 70 ml of water, extract four times with EA (15 ml * 4), and combine the organic phases. Wash the organic phase once with 15% sodium hydroxide solution, then wash once with water, dry with anhydrous magnesium sulfate, filter, evaporate to dryness, and add the residue to 3N hydrochloric acid methanol solution and stir overnight at room temperature.

[0290] The reaction solution was evaporated to dryness, and the pH was adjusted to 8-9 by adding sodium carbonate aqueous solution. The solution was extracted three times with DCM (15ml*3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and the crude product was filtered through a column with DCM / MeOH / Et3N = 100:1:1 to obtain 120mg of a yellow-brown oily substance.

[0291] Example 29: Synthesis of TollB-7C-32

[0292] Synthesis of tert-butyl 4-((5-bromo-2-pyridone-1(2H)-yl)methyl)piperidine-1-carboxylate

[0293]

[0294] Add 0.25 g (1.44 mmol, 1.0 eq) of 2-hydroxy-5-bromopyridine, 0.69 g (2.16 mmol, 1.5 eq) of 1-BOC-4-bromomethylpiperidine, 0.33 g (2.16 mmol, 1.5 eq) of potassium carbonate, and 25.0 ml of acetonitrile to a 50 ml single-necked flask in sequence; stir overnight at 110 °C; pour the reaction solution into water and add 15 ml of EA, stir thoroughly, and then extract the aqueous phase three times with EA (15 ml * 3). Combine the organic phases and wash once each with saturated brine and water. Dry the organic phase with anhydrous magnesium sulfate and filter.

[0295] The solution of EA / PE / Et3N = 1:8:0.1 was passed through a column to obtain 376 mg of a yellow oily liquid, with a yield of 70.5%.

[0296] Synthesis of TollB-7C-32

[0297] In another 50ml single-necked flask, add 0.35g (0.94mmol, 12eq) of 4-((5-bromo-2-pyridone-1(2H)-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester, 0.24g (0.79mmol, 1.0eq) of 8-nitroquinoline-5-piphenate borate, 33mg (33mg, 5% mmol) of PdCl2(dppf)CH2Cl2, and finally add 25ml of ethylene glycol dimethyl ether. Take a 10ml EP tube, weigh 0.17g (1.57mmol, 2.0eq) of sodium carbonate, add 5ml of water, dissolve and cool to room temperature, then add to the aforementioned single-necked flask. React overnight at 80℃ under nitrogen protection.

[0298] The reaction solution was filtered, evaporated to dryness, and passed through a column chromatography (DCM / MeOH = 100:1) to obtain 0.14 g of a yellow oil (yield 39%). The oil was placed in a 50 ml single-necked flask, and 20 ml of 3N HCl / MeOH was added and stirred overnight at room temperature. The solution was evaporated to dryness, and potassium carbonate and acetonitrile were added and stirred at room temperature for 6 h. The solution was then filtered directly, and the filtrate was evaporated to dryness to obtain 0.92 g of a colorless oil (yield 84.4%).

[0299] Example 30: Synthesis of TollB-7C-33

[0300] Add 89 mg (0.35 mmol, 1.0 eq) of 5-bromo-8-nitroquinoline, 100 mg (0.43 mmol, 1.2 eq) of 1-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyridin-2(1H)-one, 17 mg (0.018 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, 75 mg (0.70 mmol, 2.0 eq) of sodium carbonate, 2.5 ml of DME, and 0.5 ml of water to a 10 ml reaction tube; react overnight at 100 °C under nitrogen protection; filter the reaction solution through diatomaceous earth, wash with ethyl acetate, evaporate the filtrate to dryness, load the sample onto a dry column, and pass the DCM / MeOH column at a ratio of 150:1 to obtain 21 mg of a pale yellow solid, yield 21.1%.

[0301] Example 31: Synthesis of TollB-7C-34

[0302] In a 50 ml single-necked flask, 8-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline (250 mg, 0.83 mmol, 1.0 eq), 5-bromobenzofuran (250 mg, 1.33 mmol, 1.2 eq), tripotassium phosphate (330 mg, 1.67 mmol, 2.0 eq), PdCl2(dppf)CH2Cl2 (33 mg, 0.04 mmol, 5%), and 15 ml of DMF were added. The mixture was stirred overnight at 110 °C under nitrogen protection. The reaction solution was poured into 20 ml of water and extracted four times with 15 ml of EA (15 ml * 5). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography using DCM to give 140 mg of a yellowish-white solid, with a yield of 73.7%.

[0303] Example 32: Synthesis of TollB-7C-35

[0304] Add 8-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline (150 mg, 0.5 mmol, 1.0 eq), 5-bromo-1-methyl-1H-benzimidazole (130 mg, 0.6 mmol, 1.2 eq), tripotassium phosphate (210 mg, 1.0 mmol, 2.0 eq), PdCl2(dppf)CH2Cl2 (20.4 mg, 0.025 mmol, 5%), and 2.5 ml of DMF to a 15 ml reaction tube; stir overnight at 100 °C under nitrogen protection; filter the reaction solution and load the sample dry; pass the crude product through a column chromatography with DCM / MeOH = 150:1 to obtain 66 mg of a yellow solid, yield 43.4%.

[0305] Example 33: Synthesis of TollB-7C-36

[0306] Following the synthesis of 7C-35, a yellow solid of 47 mg was obtained, with a yield of 30.9%.

[0307] Example 34: Synthesis of TollB-7C-37

[0308] Following the synthesis of 7C-35, 66 mg of a yellow solid was obtained, with a yield of 44%.

[0309] Example 35: Synthesis of TollB-7C-38

[0310] Following the synthesis of 7C-35, 66 mg of a yellow solid was obtained, with a yield of 21.7%.

[0311] Example 36: Synthesis of TollB-7C-39

[0312] 5-Bromo-8-nitroquinoline (150 mg, 0.59 mmol, 1.0 eq), 5-bromobenzothiophene (98 mg, 0.71 mmol, 1.2 eq), cesium carbonate (386 mg, 1.19 mmol, 2.0 eq), and 2.5 ml of DMF were added to a 15 ml reaction tube; the mixture was stirred at 100 °C for 18 h, the reaction solution was poured into water, and the mixture was extracted three times with EA (15 ml * 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and loaded onto the sample using the dry method; the crude product was filtered through a column with DCM / MeOH = 50:1 to obtain 21 mg of yellow solid.

[0313] Example 37: Synthesis of TollB-7C-41

[0314] Add 4-(8-nitroquinoline-5-yl)phenol (150 mg, 0.56 mmol, 1.0 eq), cyclopropyl methyl bromide (114 mg, 0.85 mmol, 1.2 eq), potassium carbonate (156 mg, 1.13 mmol, 2.0 eq), and 2.5 ml of DMF to a 10 ml reaction tube; stir overnight at 100 °C; pour the reaction solution into water; extract four times with EA (15 ml * 4); wash the organic phase twice with 15% sodium hydroxide solution, then wash once with water; dry the organic phase with anhydrous magnesium sulfate, filter, evaporate to dryness, and load the sample by dry method; pass the crude product through a DCM column to obtain 103 mg of a yellow-brown oily substance, yield 57%.

[0315] Example 38: Synthesis of TollB-7C-42

[0316] Following the synthesis of TollB-7C-41, 114 mg of yellow crystals were obtained, with a yield of 55.9%.

[0317] Example 39: Synthesis of TollB-7C-43

[0318] Following the synthesis of TollB-7C-41, 108 mg of yellow crystals were obtained, with a yield of 52.7%.

[0319] Example 40: Synthesis of TollB-7C-44

[0320] Following the synthesis of Toll B-7C-31, 89 mg of a yellowish-brown solid was obtained, with a yield of 36.3%.

[0321] Example 41: Synthesis of TollB-7C-45

[0322] Synthesis of 1-BOC-4-(4-bromophenylthiomethyl)piperidine

[0323] Add tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (250 mg, 0.9 mmol, 1.0 eq), 4-bromobenzylthiol (187 mg, 1.08 mmol, 1.2 eq), potassium carbonate (248 mg, 1.8 mmol, 2.0 eq), and 15 ml of DMF to a 50 ml single-necked flask; stir overnight at 100 °C; pour the reaction solution into a 250 ml Erlenmeyer flask containing 50 ml of water, extract three times with EA (20 ml * 3), wash the organic phase twice with 15% sodium hydroxide solution, then wash once with water, dry the organic phase with anhydrous magnesium sulfate, filter, evaporate to dryness, and load the sample by dry method; pass the crude product through a column with DCM / MeOH = 100:1; obtain 300 mg of a pale yellow-white solid, yield 86.4%.

[0324] Synthesis of 1-BOC-4-(4-bromobenzenesulfonylmethyl)piperidine

[0325]

[0326] Add 1-BOC-4-(4-bromophenylthiomethyl)piperidine (150 mg, 0.39 mmol, 1.0 eq) and 25 ml of DCM to a 50 ml single-necked flask; after dissolving, cool to about 0 °C; add m-chloroperoxybenzoic acid (213 mg, 1.36 mmol, 3.5 eq) in small batches (in small amounts multiple times to prevent spillage), and after the addition is complete, transfer to room temperature and stir for 2 h; pour the reaction solution into a 250 ml Erlenmeyer flask containing 5 M sodium thiosulfate solution, and stir at room temperature for 30 min to quench excess m-chloroperoxybenzoic acid;

[0327] The liquid-liquid phase was extracted twice with DCM (15 ml * 2), the organic phases were combined, and washed once with 15% sodium hydroxide solution and once with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to dryness. The solution was then passed through a column chromatography system with a DCM / MeOH ratio of 100:1 to give 115 mg of a grayish-white solid, with a yield of 71%. Synthesis of TollB-7C-45

[0328] Add 8-nitroquinoline-5-borate pinacol ester (90 mg, 0.3 mmol, 1.0 eq), 1-BOC-4-(4-bromobenzenesulfonylmethyl)piperidine (100 mg, 0.24 mmol, 0.8 eq), potassium carbonate (82.9 mg, 0.6 mmol, 2.0 eq), PdCl2(dppf)CH2Cl2 (12 mg, 0.015 mmol, 5%), and 2.5 ml of DME to a 10 ml reaction tube; react overnight at 100 °C under nitrogen protection; filter the reaction solution, dry-load the sample, and pass the crude product through a column with DCM / MeOH = 80:1 to obtain a yellow oily substance;

[0329] The yellow oily substance was placed in a 50 ml single-necked flask, and 15 ml of 3 M HCl / MeOH was added. The mixture was stirred overnight at room temperature. The reaction solution was evaporated to dryness, and potassium carbonate and methanol were added. The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was evaporated to dryness to obtain 16 mg of grayish-white solid, with a yield of 12.5%.

[0330] Example 42: Synthesis of TollB-7C-46

[0331] Add 150 mg (0.5 mmol, 1.0 eq) of 8-nitroquinoline-5-borate pinacol ester, 4-bromobenzenesulfonamide (94 mg, 0.4 mmol, 0.8 eq), potassium carbonate (212 mg, 1.0 mmol, 1.0 eq), PdCl2(dppf)CH2Cl2 (20 mg, 0.025 mmol, 5%), and 2.5 ml of DME to a 10 ml reaction tube; react overnight at 100 °C under nitrogen protection; filter the reaction solution, dry-load the sample, and pass the crude product through a column with a DCM / MeOH ratio of 80:1, yielding 35 mg of yellow solid, with a yield of 21.2%.

[0332] Example 43: Synthesis of TollB-7C-48

[0333] Following the synthesis of TollB-7C-32, 370 mg of a pale yellow solid was obtained.

[0334] Example 44: Synthesis of TollB-7C-49

[0335] Synthesis of 4-(quinoline-5-yl)phenol

[0336]

[0337] 5-Bromoquinoline (500 mg, 2.4 mmol, 1.0 eq), (4-hydroxyphenyl)boronic acid (398 mg, 2.9 mmol, 1.2 eq), and PdCl2(dppf)CH2Cl2 (98 mg, 0.1 mmol, 5%) were dissolved in 10 ml of Diox solution in a 50 ml single-necked flask. An aqueous solution of potassium carbonate (996 mg, 7.2 mmol, 3.0 eq) was then added to the Diox solution of the substrate. The reaction was carried out overnight at 90 °C under nitrogen protection. After the reaction was completed, DCM and H2O were added to the reaction solution, and the mixture was extracted three times (15 ml * 3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated. The sample was loaded onto a dry column, and the crude product was passed through a column to obtain 500 mg of an orange-yellow solid.

[0338] Synthesis of TollB-7C-49

[0339] Following the synthesis method of TollB-7C-31, 130 mg of a white solid was obtained.

[0340] Example 45: Synthesis of TollB-7C-50

[0341] Add Toll B-7C-31 (100 mg, 0.25 mmol, 1.0 eq), potassium carbonate (138 mg, 1 mmol, 4.0 eq), methyl iodoform (106 mg, 0.75 mmol, 3.0 eq), and acetonitrile 2.5 ml to a 10 ml reaction tube and react overnight at 70 °C. Pour the reaction solution into water, extract three times with EA (15 ml * 3), wash the organic phase once with water, dry the organic phase with anhydrous magnesium sulfate, filter, evaporate to dryness, and load the sample by dry method. Pass the crude product through a column with DCM / MeOH / Et3N = 100:1:1, and dry the product under vacuum at 45 °C to give 89 mg of yellow solid, yield 85.7%.

[0342] Example 46: Synthesis of TollB-7C-51

[0343] Synthesis of 4-(4-bromophenyl)morpholine

[0344]

[0345] Add p-bromophenylethyl bromide (300 mg, 1.14 mmol, 1.0 eq), morpholine (198 mg, 1.98 mmol, 2.0 eq), potassium carbonate (471 mg, 3.42 mmol, 3.0 eq), and 20 ml of acetonitrile to a 50 ml single-necked flask. Stir overnight at 70 °C. Pour the reaction solution into water and extract three times with EA (15 ml * 3). Combine the organic phases, wash once with water, dry the organic phase with anhydrous magnesium sulfate, filter, evaporate to dryness, and load the sample by dry method. Pass the crude product through a column with DCM / MeOH = 50:1 to obtain 270 mg of yellow liquid intermediate 1, yield 87.9%.

[0346] Synthesis of TollB-7C-51

[0347] Intermediate 1 (270 mg, 1 mmol, 1.0 eq), 8-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)quinoline (395 mg, 1.2 mmol, 1.2 eq), tripotassium phosphate (424 mg, 2 mmol, 2.0 eq), PdCl2(dppf)CH2Cl2 (41 mg, 0.05 mmol, 5%), and 20 ml of DME were added to a 50 ml single-necked flask. The reaction mixture was reacted overnight at 100 °C under nitrogen protection. The reaction solution was filtered and loaded onto the sample using a dry method. The crude product was filtered through a column chromatography of DCM / MeOH / Et3N = 80:1:0.5. The product was an orange oily liquid, yielding 270 mg, with a yield of 74.5%.

[0348] Example 47: Synthesis of TollB-7C-52

[0349] Synthesis of 4-(4-bromophenylethyl)piperazine-1-carboxylic acid tert-butyl ester

[0350]

[0351] Add 1.0 g (3.8 mmol, 1.0 eq) of p-bromophenylethyl bromide, 0.56 g (3.05 mmol, 0.8 eq) of N-Boc piperazine, 1.05 g (7.6 mmol, 2.0 eq) of potassium carbonate, and 25 ml of acetonitrile to a 50 ml single-necked flask; stir overnight at 70 °C, filter the reaction solution, evaporate to dryness, and pass the crude product (DCM / MeOH / Et3N = 70:1:1) through a column to obtain 540 mg of a pale yellow liquid (which turned into a solid after standing overnight).

[0352] Synthesis of TollB-7C-52

[0353] Add 10 ml of tert-butyl 4-(4-bromophenylethyl)piperazine-1-carboxylate (113 mg, 0.31 mmol, 1.0 eq), 8-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)quinoline (110 mg, 0.37 mmol, 1.2 eq), tripotassium phosphate (130 mg, 0.61 mmol, 2.0 eq), and 3 ml of DME to a 10 ml reaction tube. React overnight at 100 °C under nitrogen protection. Filter the reaction solution, evaporate to dryness, and pass it through a column at a DCM / MeOH ratio of 100:1 to obtain 63 mg of intermediate 2.

[0354] Intermediate 2 was placed in a 50ml single-necked flask, and 20ml of 3M HCl / MeOH solution was added. The mixture was stirred at room temperature for 3 hours. The reaction solution was evaporated to dryness, and 10ml of ethyl acetate was added and stirred at room temperature for 2 hours. The solid was filtered and dried to obtain 21mg of yellow solid.

[0355] Example 48: Synthesis of TollB-7C-53

[0356] 4-(4-bromophenylethyl)piperazin-2-one

[0357]

[0358] In a 50 ml single-necked flask, p-bromophenylethyl bromide (200 mg, 0.76 mmol, 1.0 eq), piperazine-2-one (91 mg, 0.91 mmol, 1.2 eq), potassium carbonate (209 mg, 1.52 mmol, 2.0 eq), and acetonitrile (2.5 ml) were added sequentially. The mixture was stirred overnight at 70 °C. The reaction solution was filtered, evaporated to dryness, and loaded onto the sample using the dry method. The crude product was filtered through a column (DCM / MeOH = 50:1) to obtain 116 mg of a white solid, intermediate 1, with a yield of 51.6%.

[0359] Synthesis of TollB-7C-53

[0360] Add 4-(4-bromophenylethyl)piperazin-2-one (116 mg, 0.4 mmol, 0.8 eq), 8-nitroquinoline-5-boronic acid pinacol ester (150 mg, 0.5 mmol, 1.0 eq), tripotassium phosphate (212 mg, 1.0 mmol, 2.0 eq), PdCl2(dppf)CH2Cl2 (20 mg, 0.025 mmol, 5%) and 20 ml of DME to a 50 ml single-necked flask. React overnight at 100 °C under nitrogen protection. Filter the reaction solution and load the sample dry. Pass the crude product through a column chromatography of DCM / MeOH / Et3N = 80:1:0.5 to obtain 98 mg of white solid.

[0361] Example 49: Synthesis of TollB-7C-54

[0362] Add 200 mg (0.75 mmol, 1.0 eq) of 4-(8-nitroquinoline-5-yl)phenol, 173 mg (0.9 mmol, 1.2 eq) of 4-(bromomethyl)piperidin-2-one, 208 mg (1.5 mmol, 2.0 eq) of potassium carbonate and 25 mL of acetonitrile to a 50 mL single-necked flask. Reflux overnight at 100 °C. Filter the reaction solution, evaporate to dryness, and load the sample using the dry method. Pass the crude product through a column chromatography system with DCM / MeOH = 200:1 to obtain 120 mg of a pale yellow oily liquid, yield 42.3%.

[0363] Example 50: Synthesis of TollB-7C-55

[0364] Add Toll B-7C-31 (148 mg, 0.41 mmol, 1.0 eq) and 15 ml of glacial acetic acid to a 50 ml single-necked flask and stir until dissolved at room temperature. Take a 50 ml EP tube, add potassium cyanide and 15 ml of water and dissolve until dissolved. Add the potassium cyanide (66 mg, 0.81 mmol, 2.0 eq) aqueous solution to the single-necked flask and stir overnight at room temperature.

[0365] The reaction solution was poured into a 250ml Erlenmeyer flask, the pH was adjusted to 8-9 with sodium hydroxide aqueous solution, and the mixture was extracted three times with ethyl acetate (15ml*3). The organic phases were combined, washed once with water, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and loaded onto the sample using the dry method. The crude product was filtered through a column chromatography system with DCM / MeOH / ammonia water = 100:1:1 to obtain 86mg of yellowish-white solid, yield 52%.

[0366] Example 51: Synthesis of TollB-7C-56

[0367] 4-(8-nitroquinoline-5-yl)phenol (100 mg, 0.38 mmol, 1.0 eq), 4-(bromomethyl)piperidin-2-one (90 mg, 0.3 mmol, 0.8 eq), potassium carbonate (209 mg, 0.75 mmol, 2.0 eq) and DMF 2.5 ml were added sequentially to a 10 ml reaction tube and stirred overnight at 90 °C.

[0368] The reaction solution was poured into a 250ml Erlenmeyer flask, 20ml of water was added, and the mixture was extracted four times with DCM (15ml*4). The organic phases were combined, and the organic phase was washed four times with concentrated sodium hydroxide solution (until the aqueous phase was colorless). The organic phase was washed once with water, dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and loaded onto the sample using the dry method. The crude product was passed through a column with a DCM / MeOH ratio of 200:1 to obtain 109mg of yellow solid, with a yield of 81.2%.

[0369] Example 52: Synthesis of TollB-7C-57

[0370] Synthesis of 1-(4-bromophenylethyl)-1H-1,2,4-triazole

[0371]

[0372] Add p-bromophenylethyl bromide (200 mg, 0.76 mmol, 1.0 eq), 4H-1,2,4-triazole (68 mg, 0.99 mmol, 1.3 eq), potassium carbonate (260 mg, 1.52 mmol, 2.0 eq), and 15 ml of DMF to a 50 ml single-necked flask, and stir overnight at 100 °C. Pour the reaction solution into water, extract three or four times with EA (15 ml * 3), wash the organic phase three times with water, dry the organic phase with anhydrous magnesium sulfate, filter, evaporate to dryness, and load the sample by dry method. Pass the crude product through a column with DCM = 50:1 to obtain 130 mg of light yellow solid intermediate 1, with a yield of 68.1%.

[0373] Synthesis of TollB-7C-57

[0374] The synthesis of 1-(4-bromophenylethyl)-1H-1,2,4-triazole (130 mg, 0.52 mmol, 1.0 eq), 8-nitroquinoline-5-borate pinacol ester (123.8 mg, 0.41 mmol, 0.8 eq), tripotassium phosphate (424 mg, 1.02 mmol, 2.0 eq), PdCl2(dppf)CH2Cl2 (21 mg, 0.026 mmol, 5%), and 20 mL of DME were added to a 50 mL single-necked flask. The mixture was reacted overnight at 100 °C under nitrogen protection. The reaction solution was filtered and loaded onto a dry column. The crude product was filtered through a column chromatography system with a DCM / MeOH ratio of 100:1 to give 80 mg of a pale yellow solid, with a yield of 44.9%.

[0375] Example 53: Synthesis of TollB-7C-58

[0376] Synthesis of 1-BOC-4-(hydroxymethyl)pyrazole

[0377]

[0378] 1H-pyrazole-4-methanol (1 g, 10.19 mmol, 1.0 eq), potassium carbonate (2.82 g, 20.39 mmol, 2.0 eq), and 30 ml of methanol were added sequentially to a 100 ml reaction flask. The mixture was cooled to approximately 0 °C, and di-tert-butyl malonate (2.2 g, 10.19 mmol, 1.0 eq) was slowly added dropwise. After the addition was complete, the mixture was transferred to room temperature and reacted for 3 h. The reaction solution was filtered, evaporated to dryness, and loaded onto a dry column. The crude product was filtered through a column with a DCM / MeOH ratio of 100:1 to obtain 670 mg of a yellow liquid.

[0379] Synthesis of TollB-7C-58

[0380] In a 100 ml three-necked flask, 1-BOC-4-(hydroxymethyl)pyrazole (265 mg, 1.34 mmol, 1.0 eq), 4-(8-nitroquinoline-5-yl)phenol (356 mg, 1.34 mmol, 1.0 eq), triphenylphosphine (421 mg, 1.6 mmol, 1.2 eq), and 50 ml of dichloromethane were added sequentially. The mixture was cooled to approximately 0 °C, and a dichloromethane solution of diethyl azodicarbonate (279 mg, 1.6 mmol, 1.2 eq) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature overnight. TLC was used to detect the complete reaction of 4-(8-nitroquinoline-5-yl)phenol. The reaction solution was filtered, evaporated to dryness, and the residue was loaded onto a column using a dry method with an EA / PE ratio of 1:6 to obtain 276 mg of a light yellow oily product.

[0381] The above product was placed in a 50 ml single-necked flask, and 3N hydrochloric acid methanol solution was added. The mixture was stirred overnight at room temperature, and the reaction solution was evaporated to dryness. The residual solid was added to methanol and sodium carbonate, stirred at room temperature for 3 hours, filtered, evaporated to dryness, and the crude product was filtered through a column with DCM / MeOH = 100:1 to obtain 120 mg of gray solid.

[0382] Example 54: Synthesis of TollB-7C-59

[0383] Synthesis of 2-bromo-5-(pyridin-4-ylmethoxy)pyrimidine

[0384]

[0385] 2-Bromopyrimidin-5-ol (200 mg, 1.14 mmol, 1.0 eq), 4-(bromomethyl)pyridine (177 mg, 1.03 mmol, 0.9 eq), potassium carbonate (158 mg, 2.29 mmol, 2.0 eq), and 15 ml of DMF were added sequentially to a 50 ml reaction flask. The reaction mixture was reacted at 90 °C for 2 h. The reaction solution was poured into a 250 ml Erlenmeyer flask, 40 ml of drinking water was added, and the mixture was extracted three times with EA (15 ml * 3). The organic phases were combined, washed twice with 10% sodium hydroxide solution, and then washed twice with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. 280 mg of yellow solid intermediate 1 was obtained, with a yield of 92%. No further purification was required, and the mixture was directly added to the next reaction step.

[0386] Synthesis of TollB-7C-59

[0387] Intermediate 1 (280 mg, 1.05 mmol), 8-nitroquinoline-5-borate pinacol ester (379 mg, 1.26 mmol, 1.2 eq), PdCl2(dppf)CH2Cl2 (42 mg, 0.052 mmol, 5%), and 20 ml of DME were added to a 50 ml single-necked flask. Sodium carbonate (223 mg, 2.1 mmol, 2.0 eq) and 4 ml of water were added to a 10 ml centrifuge tube. After dissolving at room temperature, the solution was added to a reaction flask. The reaction was carried out overnight at 100 °C under nitrogen protection. The reaction solution was filtered, and the sample was loaded onto a dry column. The crude product was filtered through a column with a DCM / MeOH ratio of 100:1. 230 mg of a light yellow solid was obtained, with a yield of 60.8%.

[0388] Example 55: Synthesis of TollB-7C-61

[0389] Synthesis of (S)-1-(4-bromophenylethyl)piperidine-3-ol

[0390]

[0391] In a 50 mL reaction flask, p-bromophenylethyl bromide (150 mg, 0.57 mmol, 1.0 eq), (S)-piperidin-3-ol (69 mg, 0.68 mmol, 1.2 eq), potassium carbonate (393 mg, 2.84 mmol, 2.0 eq), and 15 mL of DMF were added sequentially. The reaction mixture was reacted overnight at 90 °C. The reaction solution was poured into a 250 mL Erlenmeyer flask, 40 mL of drinking water was added, and the mixture was extracted three times with EA (15 mL * 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by column chromatography with a DCM / MeOH ratio of 70:1. Intermediate 1 was a yellow liquid, 114 mg, with a yield of 67.9%.

[0392] Synthesis of TollB-7C-61

[0393] Intermediate 1 (114 mg, 0.4 mmol, 0.8 eq), 8-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)quinoline (150 mg, 0.5 mmol, 1.0 eq), PdCl2(dppf)CH2Cl2 (20 mg, 0.025 mmol, 5%), and 20 ml of DME were added to a 50 ml single-necked flask. Sodium carbonate (106 mg, 1.06 mmol, 2.0 eq) and 4 ml of water were added to a 10 ml centrifuge tube. After dissolving at room temperature, the solution was added to a reaction flask. The reaction was carried out overnight at 100 °C under nitrogen protection. The reaction solution was filtered, and the sample was loaded dry. The crude product was filtered through a column with a DCM / MeOH ratio of 100:1 to obtain 68 mg of a yellow oily substance, with a yield of 44%.

[0394] Example 56: Synthesis of TollB-7C-62

[0395] Following the synthesis of TollB-7C-61, 62 mg of a yellow oily substance was obtained, with a yield of 46%.

[0396] Example 57: Synthesis of TollB-7C-63

[0397] Following the synthesis of TollB-7C-61, a yellow oily substance of 39 mg was obtained in 38% yield.

[0398] Example 58: Synthesis of TollB-7C-64

[0399] Following the synthesis of TollB-7C-61, 82 mg of a yellow-brown oily substance was obtained, with a yield of 58%.

[0400] Example 59: Synthesis of TollB-7C-65

[0401] Add 250 mg (0.99 mmol, 1.0 eq) of 8-nitro-5-bromoquinoline, 243 mg (1.19 mmol, 1.2 eq) of pyridine-4-pinacol boronic acid ester, 41 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 20 ml of DME to a 50 ml single-necked flask; take a 10 ml centrifuge tube, add 209 mg of sodium carbonate and 4 ml of water, dissolve at room temperature, and then add to the reaction flask; react overnight at 100 °C under nitrogen protection; filter the reaction solution, dry-load the sample, and pass it through a column with DCM / MeOH = 100:1 to obtain 200 mg of a light yellow solid, yield 80.6%.

[0402] Example 60: Synthesis of TollB-7C-67

[0403] Following the synthesis of TollB-7C-55, 232 mg of TollB-7C-67 was obtained, with a yield of 50%.

[0404] Example 61: Synthesis of TollB-7C-68

[0405] Synthesis of 2-(8-nitroquinoline-5-yl)phenol

[0406]

[0407] Following the synthesis of TollB-7C-1, 820 mg of the product was obtained as a yellow powder solid, with a yield of 78%.

[0408] Synthesis of TollB-7C-68

[0409] Following the synthesis method of TollB-7C-55, 360 mg of a yellow powder solid was obtained, with a yield of 75%.

[0410] Example 62: Synthesis of TollB-7C-69

[0411] Synthesis of methyl 3-bromo-4-(pyridin-4-ylmethoxy)benzoate

[0412]

[0413] In a 50 ml single-necked flask, 1 g (4.33 mol, 1.0 eq) of methyl 3-bromo-4-hydroxybenzoate, 1.64 g (6.50 mmol, 1.5 eq) of 4-bromomethylpyridine, and 5.7 g (17.32 mmol, 4.0 eq) of cesium carbonate were added, followed by 25 ml of DMF and stirring overnight at room temperature. The reaction mixture was poured into 100 ml of water and extracted three times with EA (30 ml x 3). The organic phases were combined, washed twice with water, dried over anhydrous magnesium sulfate, filtered, and column filtered. The EA / PE ratio was 1:20 to obtain 1.36 g of a colorless solid, intermediate 1, in 97% yield.

[0414] Synthesis of (3-bromo-4-(pyridin-4-ylmethoxy)phenyl)methanol

[0415]

[0416] Weigh 0.21 g of lithium aluminum hydride (5.46 mmol, 2.0 eq) into a three-necked flask. Under nitrogen protection, add anhydrous tetrahydrofuran and cool to about 0 °C. Add dropwise a tetrahydrofuran solution of 0.88 g (2.73 mmol, 1.0 eq) of the above intermediate methyl 3-bromo-4-(pyridin-4-ylmethoxy)benzoate, maintaining the temperature at about 0 °C. After the addition is complete, stir overnight at room temperature. Add 2 ml of drinking water to the reaction solution, then add 20 ml of ethyl acetate. While stirring at room temperature, slowly add anhydrous magnesium sulfate and dry. Filter, evaporate to dryness, and pass the crude product through a column chromatography at a DCM / MeOH ratio of 100:1 to obtain 757 mg of colorless solid intermediate 2, with a yield of 94%.

[0417] Synthesis of 4-((2-bromo-4-(methoxymethyl)phenoxy)methyl)pyridine

[0418]

[0419] Take a 50ml three-necked flask, add 124mg of sodium hydride (5.2mmol, 2.0eq) and 5ml of anhydrous tetrahydrofuran, cool to about 0℃, add 757mg of (3-bromo-4-(pyridin-4-ylmethoxy)phenyl)methanol (2.57mmol, 1.0eq) in tetrahydrofuran solution, control the temperature at about 0-5℃, stir at 0℃ for 1h after the addition, then add 323mg of iodomethane (5.2mmol, 2.0eq), after the addition, transfer to room temperature and stir overnight. Pour the reaction solution into crushed ice, extract three times with EA (15ml*3), combine the organic phases, dry to anhydrous magnesium sulfate, filter and evaporate to dryness, pass the crude product through DCM column to obtain 30mg of colorless oily intermediate 3, yield 3%.

[0420] Synthesis of TollB-7C-69

[0421] Add 36 mg (0.38 mmol, 1.2 eq) of 8-nitroquinoline-5-borate pinacol ester, 30 mg (0.32 mmol, 1.02 eq) of 4-((2-bromo-4-(methoxymethyl)phenoxy)methyl)pyridine, 8 mg (0.01 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, 55 mg of potassium carbonate (1.28 mmol, 4.0 eq), 1.6 ml of DME and 0.4 ml of water to a 15 ml sealed tube. React overnight at 80 °C under nitrogen protection. Filter the reaction solution, load the sample dry, and pass it through a column with DCM / MeOH = 100:1 to obtain 17 mg of a colorless oily liquid (Toll B-7c-69), yield 14%.

[0422] Example 63: Synthesis of TollB-7C-70

[0423] Following the synthesis of TollB-7C-32, 100 mg of a yellow solid of TollB-7C-70 was obtained, with a yield of 67%.

[0424] Example 64: Synthesis of TollB-7C-71

[0425] Synthesis of 8-fluoroquinoline-5-boronic acid pinacol ester

[0426]

[0427] In a 50 mL single-necked flask, add 266 mg (1 mmol, 1.0 eq) of 5-bromo-8-fluoroquinoline, 294 mg (3 mmol, 3.0 eq) of potassium acetate, 40 mg (0.05 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 273 mg (1.1 mmol, 1.1 eq) of pinacol diboronate. Finally, add 25 mL of 1,4-dioxane. Stir overnight at 70 °C under nitrogen protection. Filter the reaction solution through diatomaceous earth, wash with ethyl acetate, evaporate the filtrate to dryness, and dry-load the solution onto a DCM column to obtain 223 mg of a white solid (yield: 82%). No further purification is required; it can be used directly in the next synthesis.

[0428] Synthesis of tert-butyl 4-(((2-bromopyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylate

[0429]

[0430] In a 50 ml single-necked flask, 500 mg (2.9 mmol, 1.0 eq) of 2-bromo-5-pyrimidinol, 1.2 g (4.3 mmol, 1.5 eq) of 4-bromomethyl-N-Boc piperazine, 794 mg (5.7 mmol, 2.0 eq) of potassium carbonate, and 30 ml of DMF were added. The mixture was reacted overnight at 100 °C. The reaction solution was cooled to room temperature and poured into 100 ml of water. The mixture was extracted three times with EA (30 ml each time). The organic layers were washed twice with sodium hydroxide solution and twice with water. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue (PE:EA = 15:1) was column-sected to give 1.0 g of intermediate 1, a gray solid, with a yield of 94%. Synthesis of TollB-7C-71

[0431] In a 50 ml single-necked flask, 365 mg (0.98 mmol, 1.2 eq) of 4-(((2-bromopyrimidin-5-yl)oxy)methyl)piperidine-1-carboxylic acid tert-butyl ester, 223 mg (0.82 mmol, 1.0 eq) of 8-fluoroquinoline-5-pinacol boronic acid ester, and 32 mg (0.04 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2 were added sequentially. Finally, 25 ml of ethylene glycol dimethyl ether was added. In a 10 ml EP tube, 0.45 g (3.3 mmol, 4.0 eq) of potassium carbonate was weighed and dissolved in 5 ml of water. The solution was cooled to room temperature and then added to the aforementioned single-necked flask. The reaction was carried out overnight at 80 °C under nitrogen protection.

[0432] The reaction solution was filtered, evaporated to dryness, and passed through a column chromatography at a DCM / MeOH ratio of 200:1 to obtain 450 mg of a reddish-brown oil. The oil was placed in a 50 ml single-necked flask, and 20 ml of 3N HCl / MeOH was added. The mixture was stirred overnight at room temperature and evaporated to dryness. The solid was placed in a 50 ml single-necked flask, and 10 ml of water and 2 ml of methanol were added. Then, 340 mg of potassium cyanate solid (4.0 mmol, 5.0 eq) was added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into 30 ml of ice water and stirred at room temperature for 30 min. The solid was filtered, and the filter cake was passed through a column chromatography at a DCM / MeOH ratio of 50:1 to obtain 114 mg of TollB-7C-71, with a yield of 50%.

[0433] Example 65: Synthesis of TollB-7C-72

[0434] Synthesis of 8-methoxyquinoline-5-piphenanol borate

[0435]

[0436] Following the synthesis of 8-nitroquinoline-5-boronic acid pinacol ester, 450 mg of a yellow oily product was obtained in 89% yield. No further purification was required, and it was directly used for the synthesis of TollB-7C-72.

[0437] Synthesis of TollB-7C-72

[0438] Following the synthesis of TollB-7C-71, 60 mg of a yellow solid product was obtained, with a yield of 32%.

[0439] Example 66: Synthesis of TollB-7C-73

[0440] Following the synthesis of TollB-7C-71, 78 mg of a yellow solid product was obtained, with a yield of 45%.

[0441] Example 67: Synthesis of TollB-7C-76

[0442] Following the synthetic route of TollB-7C-68 and the synthetic method of TollB-7C-67, 54 mg of a yellowish-white solid was obtained, with a yield of 60.9%.

[0443] Example 68: Synthesis of TollB-7C-77

[0444] 200 mg (0.7 mmol, 1.0 eq) of Toll B-7C-70 was placed in a 50 ml single-necked flask, 10 ml of water and 2 ml of methanol were added, and then 320 mg (4.2 mmol, 6.0 eq) of potassium cyanate solid was added. The mixture was stirred overnight at room temperature. The reaction solution was poured into 30 ml of ice water and stirred at room temperature for 30 min. The solid was filtered, and the filter cake was passed through a column with a DCM / MeOH ratio of 25:1 to obtain 120 mg of yellow solid Toll B-7C-77, with a yield of 60%.

[0445] Example 69: Synthesis of TollB-7C-80

[0446] Synthesis of mesylate quinoline-5-boronic acid phenazol ester

[0447]

[0448] Add 2.3 g (10.35 mmol, 1.0 eq) of 5-amino-8-methanesulfonylquinoline and 40 ml of methanol / water (V / V = 1:6) to a 100 ml three-necked flask. While stirring at room temperature, add 4.31 ml (51.74 mmol, 4.0 eq) of concentrated hydrochloric acid and heat appropriately until dissolved. Then cool to about 0 °C. Weigh 785 mg (11.38 mmol, 1.1 eq) of sodium nitrite into a 10 ml centrifuge tube, add 1 ml of water to dissolve it, and add the sodium nitrite solution dropwise into the reaction flask, keeping the temperature below 5°C. After the addition is complete, maintain the temperature at 0–5°C and stir for 1 h until the solution is clear and transparent. In a separate 250 ml single-necked flask, add 3.15 g (12.42 mmol, 1.2 eq) of pinacol diboronate and 10 ml of methanol, and stir at room temperature until the solid is evenly dispersed. Add the diazonium salt solution to the reaction flask while stirring at room temperature (add slowly, and prevent bubbling). After the addition is complete, stir at room temperature for 1.5 h. Extract three times with DCM (30 ml * 3), combine the organic phases, dry with anhydrous magnesium sulfate, filter, evaporate to dryness, load the residual solid dry, and pass DCM through a rapid reduced pressure column to obtain 3.1 g of white solid, yield 89.9%.

[0449] Synthesis of TollB-7C-80

[0450] Add 500 mg (1.35 mmol, 1.0 eq) of 4-(4-bromophenylethyl)piperazine-1-carboxylic acid tert-butyl ester, 541 mg (1.628 mmol, 1.2 eq) of 8-methanesulfonylquinoline-5-boronic acid pinacol ester, 55 mg (0.068 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2 and 30 ml of DME to a 50 ml single-necked bottle;

[0451] Take a 10 ml centrifuge tube, add 287 mg (2.71 mmol, 2.0 eq) of sodium carbonate and 5 ml of water, dissolve at room temperature, and then add to a reaction flask; react overnight at 100 °C under nitrogen protection; filter the reaction solution, load the sample by dry method, and pass it through a column with DCM / MeOH = 100:1. Concentrate the product obtained by column chromatography, add 20 ml of 3N HCl / MeOH, and stir overnight at room temperature; evaporate to dryness, add 1 g of potassium carbonate and 20 ml of methanol to the solid, stir at room temperature for 3 h, filter the solid; evaporate to dryness, and 370 mg of a light yellow oil is obtained, with a yield of 69.09%.

[0452] Example 70: Synthesis of TollB-7C-78

[0453] 10 mg (0.28 mmol, 1.1 eq) of Toll B-7C-801, 20 ml of water, and 5 ml of ethanol were added to a 50 ml single-necked flask and stirred until dissolved at room temperature. 90 mg (1.1 eq, 4.0 eq) of potassium cyanate solid was added to the reaction flask and stirred overnight at room temperature. The reaction solution was filtered, and the solid was subjected to column chromatography with crude DCM / MeOH / ammonia solution in a ratio of 100:1:1 to obtain 86 mg of a yellowish-white solid, yielding 70.5%.

[0454] Example 71: Synthesis of TollB-7C-79

[0455] Synthesis of 5-(4-bromophenylethyl)-N-methylpiperazine-1-carboxamide

[0456]

[0457] Add 6.0 g (17.54 mmol, 1.0 eq) of (4-bromophenylethyl)piperazine-1-carboxylic acid tert-butyl ester and 30 mL of 3N HCl / MeOH solution to a 100 mL reaction flask, and stir at room temperature for 2 h; evaporate to dryness, add a small amount of methanol to the solid and slurry, filter the solid, and dry to obtain 6 g of white solid.

[0458] The solid was placed in a 100 ml single-necked flask, and 30 ml of dichloromethane was added. 7.31 ml of triethylamine (52.62 mmol, 3.0 eq) was added with stirring at room temperature, followed by 2.41 g of N-methylimidazolium carboxamide (19.29 mmol, 1.1 eq). After the addition was complete, the mixture was stirred at room temperature overnight. The reaction solution was evaporated to dryness, and methanol was added twice. The residue was then added to 10 ml of methanol, stirred at room temperature to disperse evenly, and then 100 ml of water was added to crystallize. After the addition was complete, the mixture was stirred at room temperature for 1 h. The solid was filtered and rinsed with a large amount of water, then dried under vacuum at 40 °C overnight to obtain 5.72 g of white solid.

[0459] Synthesis of TollB-7C-79

[0460] Add 500 mg (1.53 mmol, 1.0 eq) of 5-(4-bromophenylethyl)-N-methylpiperazine-1-carboxamide, 613 mg (1.84 mmol, 1.2 eq) of 8-methanesulfonylquinoline-5-boronic acid pinacol ester, 62 mg (0.077 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 30 ml of DME to a 50 ml single-necked bottle;

[0461] Take a 10 ml centrifuge tube, add 325 mg (3.07 mmol, 2.0 eq) of sodium carbonate and 5 ml of water, dissolve at room temperature and then add to a reaction flask; react overnight at 100 °C under nitrogen protection; filter the reaction solution, load the sample by dry method, and pass it through a column with DCM / MeOH = 25:1. The white solid obtained by column chromatography is 463 mg, yield 66.75%.

[0462] Example 72: Synthesis of TollB-7C-81

[0463] Synthesis of 4-(8-nitroquinoline-5-yl)phenol

[0464]

[0465] Following the synthesis of TollB-7C-1, 40 mg of a yellow powder solid was obtained, with a yield of 8%.

[0466] Synthesis of TollB-7C-81

[0467] Following the synthesis of TollB-7C-55, 30 mg of a white solid was obtained, with a yield of 72%.

[0468] Example 73: Synthesis of TollB-7C-82

[0469] Following the synthesis of TollB-7C-32, 50 mg of a milky white solid was obtained, with a yield of 41.2%.

[0470] Example 74: Synthesis of TollB-7C-83

[0471] Following the synthesis of TollB-7C-77, 127 mg of a white solid was obtained, with a yield of 78%.

[0472] Example 75: Synthesis of TollB-7C-84

[0473] Synthesis of ethyl 4-((4-bromophenyl)amino)piperidine-1-carboxylate

[0474]

[0475] In a 50 ml single-necked flask, 1.0 g (5.81 mmol, 1.0 eq) of p-bromoaniline, 1.04 g (5.23 mmol, 0.9 eq) of N-Boc-4-piperidinone, and 25 ml of dichloromethane were added sequentially. After stirring at room temperature for 30 min, 524 mg (8.72 mmol, 1.5 eq) of glacial acetic acid and 1.85 g (8.72 mmol, 1.5 eq) of sodium triacetoxyborohydride were added. The mixture was stirred at room temperature for 3 h. The reaction solution was poured into 50 ml of 1 N sodium hydroxide aqueous solution (slowly added in batches), separated, and extracted twice with dichloromethane (20 ml * 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The solution was then passed through a column chromatography of ethyl acetate / petroleum ether at a ratio of 1:8 to give 1.42 g of a pale white solid, with a yield of 68.6%.

[0476] Synthesis of TollB-7C-84

[0477] Add 500 mg (1.41 mmol, 1.0 eq) of ethyl 4-((4-bromophenyl)amino)piperidine-1-carboxylate, 563 mg (1.69 mmol, 1.2 eq) of pinacol 8-methanesulfonylquinoline-5-boronic acid pinacol ester, 60 mg (0.0715 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 20 ml of DME to a 50 ml single-necked flask; take a 10 ml centrifuge tube, add 298 mg (2.81 mmol, 2.0 eq) of sodium carbonate, 4 ml of water, dissolve at room temperature, and then add to the reaction flask; react overnight at 70 °C under nitrogen protection; filter the reaction solution, dry-load the sample, pass through a column with DCM / MeOH = 200:1, concentrate the product obtained by column chromatography (intermediate 2), and add 20 ml of 3N HCl / MeOH, stirred overnight at room temperature; evaporate to dryness, add 1g potassium carbonate and 20ml methanol to the solid, stir at room temperature for 3h, filter the solid; evaporate to dryness, DCM / MeOH / Et3N = 20:1:0.5, and rapidly evaporate to dryness to obtain 189mg of yellow solid, yield 35.2%.

[0478] Example 76: Synthesis of TollB-7C-85

[0479] Synthesis of tert-butyl 4-(((4-bromophenyl)amino)methyl)piperidine-1-carboxylate

[0480]

[0481] In a 50 ml single-necked flask, 1.0 g (5.81 mmol, 1.0 eq) of p-bromoaniline, 1.12 g (5.23 mmol, 0.9 eq) of N-Boc piperidine-4-carboxaldehyde, and 25 ml of dichloromethane were added sequentially. After stirring at room temperature for 30 min, 524 mg (8.72 mmol, 1.5 eq) of glacial acetic acid and 1.85 g (8.72 mmol, 1.5 eq) of sodium triacetoxyborohydride were added. The mixture was stirred at room temperature for 3 h. The reaction solution was poured into 50 ml of 1 N sodium hydroxide aqueous solution (slowly added in batches), separated, and extracted twice with dichloromethane (20 ml * 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The solution was then passed through a column chromatography of ethyl acetate / petroleum ether at a ratio of 1:8 to give 1.04 g of white solid, with a yield of 48.4%.

[0482] Synthesis of TollB-7C-85

[0483] Add 500 mg (1.35 mmol, 1.0 eq) of 4-(((4-bromophenyl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester, 541 mg (1.62 mmol, 1.2 eq) of 8-methanesulfonylquinoline-5-boronic acid pinacol ester, 56 mg (0.0715 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 20 ml of DME to a 50 ml single-necked flask; take a 10 ml centrifuge tube, add 297 mg (2.71 mmol, 2.0 eq) of sodium carbonate, 4 ml of water, dissolve at room temperature, and then add to the reaction flask; react overnight at 70 °C under nitrogen protection; filter the reaction solution, dry-load the sample, and pass it through a column with DCM / MeOH = 200:1. Concentrate the product obtained from the column (intermediate 2), and add 20 ml of 3N. HCl / MeOH was stirred overnight at room temperature; the mixture was evaporated to dryness, and 1 g of potassium carbonate and 20 ml of methanol were added to the solid. The mixture was stirred at room temperature for 3 h, and the solid was filtered. The filtrate was evaporated to dryness, and DCM / MeOH / Et3N = 10:1:0.5 was passed through a column to give 88 mg of yellow solid, with a yield of 16.4%.

[0484] Example 77: Synthesis of TollB-7C-86

[0485] Following the synthesis of TollB-7C-84, 210 mg of bright yellow solid was obtained in 53.3% yield.

[0486] Example 78: Synthesis of TollB-7C-87

[0487] Add 200 mg (0.63 mmol, 1.0 eq) of Toll B-7C-80, 206 mg (1.25 mmol, 2.0 eq) of potassium carbonate, 20 mL of acetonitrile, and 212 mg (1.25 mmol, 2.0 eq) of iodomethane to a 50 mL single-necked flask; reflux the reaction overnight; filter, evaporate to dryness, and pass through a column chromatography (DCM / MeOH = 50:1) to give 103 mg of a pale yellow oily product, yield 48.9%.

[0488] Example 79: Synthesis of TollB-7C-88

[0489] Synthesis of 5-bromo-8-aldehyde quinoline intermediate

[0490]

[0491] Add 1 g (4.5 mmol, 1.0 eq) of 5-bromo-8-methylquinoline, 2.4 g (13.51 mmol, 3.0 eq) of NBS, 63 mg (0.38 mmol, 0.085 eq) of AIBN, and 15 ml of 1,2-dichloroethane to a 50 ml single-necked flask; reflux overnight, cool the reaction solution to room temperature, pour into a 250 ml Erlenmeyer flask, add water, and extract three times with dichloromethane (20 ml * 3); combine the organic phases, wash three times with 10% sodium hydroxide solution, wash once with water, dry with anhydrous magnesium sulfate, filter, evaporate to dryness, and place the residual solid in a 50 ml single-necked flask with 15 ml of tap water, reflux overnight under nitrogen protection.

[0492] The reaction was cooled to room temperature, and the product was extracted four times with DCM (10 ml * 4). The organic phases were combined and dried over anhydrous magnesium sulfate. The mixture was filtered and evaporated to dryness. The crude solid DCM was passed through a column to give 0.45 g of white solid, with a yield of 42.5%.

[0493] Synthesis of 5-bromoquinoline-8-carboxaldehyde oxime

[0494]

[0495] 450 mg (1.91 mmol, 1.0 eq) of 5-bromo-8-aldehydequinoline, 530 mg (7.62 mmol, 4.0 eq) of hydroxylamine hydrochloride, 20 ml of acetonitrile, and 772 mg (7.62 mmol, 4.0 eq) of triethylamine were added to a 50 ml single-necked flask. The mixture was refluxed for 5 h. The reaction solution was evaporated to dryness, and 10 g of silica gel was placed in a 100 ml funnel. The residue was added to ethyl acetate, filtered, and washed with plenty of ethyl acetate. The filtrate was evaporated to dryness to give 300 mg of white solid, with a yield of 62.7%.

[0496] Synthesis of 5-bromo-8-cyanoquinoline

[0497]

[0498] 0.3 g (1.19 mmol, 1.0 eq) of 5-bromoquinoline-8-carboxaldehyde oxime, 11 mg (0.06 mmol, 5% mmol) of copper acetate, and 25 mL of acetonitrile were added to a 50 mL reaction flask; the mixture was refluxed and stirred for 24 h. The reaction solution was evaporated to dryness, loaded onto a dry column under reduced pressure (DCM), and passed through a high-pressure column chromatography (DCM) to obtain 230 mg of a white solid, yield 82.7%.

[0499] Synthesis of TollB-7C-88

[0500] Following the synthesis of TollB-7C-31, 70 mg of a yellow solid was obtained, with a yield of 23%.

[0501] Example 80: Synthesis of TollB-7C-89

[0502] Following the synthesis of TollB-7C-79, 120 mg of a yellow solid was obtained, with a yield of 30%.

[0503] Example 81: Synthesis of TollB-7C-90

[0504] Following the synthesis of Toll B-7C-84, a yellow solid of 185 mg was obtained in 72.5% yield.

[0505] Example 82: Synthesis of TollB-7C-91

[0506] Synthesis of 4-hydroxy-8-methylthioquinoline

[0507]

[0508] Add 5.0 g (35.92 mmol, 1.0 eq) of 2-methylthioaniline, 6.21 g (43.10 mmol, 1.2 eq) of cyclo(isopropyl)malonate, and 40 ml of anhydrous acetonitrile to a 100 ml single-necked flask. Add 2.71 g (46.69 mmol, 1.3 eq) of trimethyl orthoformate while stirring at room temperature. Reflux for 3 h, then cool to room temperature, evaporate to dryness, add 15 ml of methanol to the residue, stir at room temperature for about 3 h, filter the solid, and dry for later use.

[0509] Take a 100ml three-necked flask, add 10ml of diphenyl ether, heat to 220℃, and add the above white solid under a nitrogen atmosphere, adding slowly while controlling the temperature at around 200℃; after the addition is complete, maintain 220℃ for 5 minutes, then slowly cool to room temperature, add 60ml of petroleum ether, and stir overnight at room temperature; discard the supernatant, dissolve the solid on the flask wall with dichloromethane, load the sample dry, and pass it through a DCM column to obtain 2.3g of white solid, yield 33.48%.

[0510] Synthesis of 5-bromo-8-methanesulfonylquinoline

[0511]

[0512] Add 2.3 g (12.03 mmol, 1.0 eq) of 4-hydroxy-8-methylthioquinoline and 40 ml of DMF to a 100 ml three-necked flask and cool to about 0 °C. Add 6.51 g (24.05 mmol, 2.0 eq) of phosphorus tribromide dropwise, keeping the temperature below 5 °C. Transfer to room temperature and stir overnight. Pour the reaction solution into an aqueous solution of crushed ice, adjust the pH to 12 with sodium hydroxide, and filter the solid. Dissolve the solid in dichloromethane, dry with anhydrous magnesium sulfate, filter, and evaporate to dryness. The resulting crude 4-bromo-8-methylthioquinoline solid (1.4 g) is used directly for oxidation.

[0513] 1.4 g (5.51 mmol, 1.0 eq) of crude 4-bromo-8-methylthioquinoline solid and 25 ml of dichloromethane were added to a 50 ml single-necked flask. 3.8 g (22.03 mmol, 4.0 eq) of mCPBA was added in portions while stirring. The mixture was stirred at room temperature for 1 h. 30 ml of 3N sodium thiosulfate solution was added to a 250 ml Erlenmeyer flask. The reaction mixture was poured into the flask and stirred at room temperature for 30 min. Then, 40% sodium hydroxide solution was added and stirred at room temperature for 10 min. The mixture was separated, and the aqueous phase was extracted twice with DCM (20 ml x 2). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue (EA / PE = 1:10) was passed through a column to give 720 mg of a white solid, yield 50%.

[0514] Synthesis of borate intermediates

[0515]

[0516] Refer to the synthesis of 8-nitroquinoline-5-boronic acid phenazol ester.

[0517] Synthesis of TollB-7C-91

[0518] Following the synthesis of TollB-7C-84, 243 mg of a yellow solid was obtained, with a yield of 64.875%.

[0519] Example 83: Synthesis of TollB-7C-93

[0520] Following the synthesis of TollB-7C-79, 160 mg of a pale yellow solid was obtained, with a yield of 40%.

[0521] Example 84: Synthesis of TollB-7C-94

[0522] Synthesis of bromo-2-(piperidin-4-yl)benzoxazole

[0523]

[0524] Add 1 g (5.32 mmol, 1.0 eq) of 2-amino-4-bromophenol, 0.69 g (5.32 mmol, 1.0 eq) of 4-piperidinic acid, and 10 ml of polyphosphoric acid to a 50 ml single-necked flask; heat to 180 °C and stir for 2 h; pour the reaction solution into water while hot, adjust the pH to about 12 with sodium hydroxide aqueous solution, extract three times with dichloromethane (20 ml * 3), combine the organic phases, dry with anhydrous magnesium sulfate, filter and evaporate to dryness, and slurry the residual solid acetonitrile at 0 °C to obtain 710 mg of gray solid, yield 47.48%.

[0525] Synthesis of TollB-7C-94

[0526] Add 200 mg (0.71 mmol, 1.0 eq) of bromo-2-(piperidin-4-yl)benzoxazole, 308 mg (0.92 mmol, 1.3 eq) of 8-methanesulfonylquinoline-5-boronic acid pinacol ester, 32 mg (0.04 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 20 ml of DME to a 50 ml single-necked flask; take a 10 ml centrifuge tube, add 1518 mg (1.42 mmol, 2.0 eq) of sodium carbonate, 4 ml of water, dissolve at room temperature, and then add to the reaction flask; react overnight at 90 °C under nitrogen protection; filter the reaction solution, dry-load the sample, and pass it through a column with DCM / MeOH = 10:1 to obtain 13 mg of grayish-white solid.

[0527] Example 85: Synthesis of TollB-7C-95

[0528] Based on Toll B-7C-79 and synthesis, 50 mg of grayish-white solid was obtained in 23% yield.

[0529] Example 86: Synthesis of TollB-7C-96

[0530] Synthesis of tert-butyl-4-((4-bromophenylmethyl)oxo)piperidine-1-carboxylic acid ester

[0531]

[0532] Add 119 mg of sodium hydride (4.97 mmol, 2.0 eq) to a 50 ml three-necked flask. Under nitrogen protection, add 5 ml of ultra-dry tetrahydrofuran. Cool to about 0 °C and add a tetrahydrofuran solution of 500 mg (2.48 mmol, 1.0 eq) of N-Boc-4-hydroxypiperidine. After the addition is complete, stir at about 0 °C for 1 h. Then add 807 mg (3.23 mmol, 1.3 eq) of p-bromobenzyl bromide. After the addition is complete, transfer to room temperature and stir overnight.

[0533] After the reaction was complete, the reaction solution was poured into ice water and extracted three times with EA (30 ml * 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to obtain 710 mg of a pale yellow oil, with a yield of 77.18%. No further purification was required, and it was directly used for the synthesis of TollB-7C-96. Synthesis of TollB-7C-96

[0534] In a 50 ml single-necked flask, 200 mg (0.5 mmol, 1.0 eq) of tert-butyl-4-((4-bromophenylmethyl)oxo)piperidine-1-carboxylic acid ester, 220 mg (0.7 mmol, 1.2 eq) of 8-methanesulfonylquinoline-5-boronic acid pinacol ester, 224 mg (1.5 mmol, 3.0 eq) of potassium carbonate, and 222 mg (0.025 mmol, 5% mmol) of PdCl2(dppf)CHCl2 were added sequentially in dioxane / H2O. The mixture was substituted with N2 three times and reacted at 90 °C for 12 h. DCM was added to the reaction mixture, and the mixture was extracted with water, dried over anhydrous MgSO4, filtered, concentrated under reduced pressure, and the residue (DCM:MeOH = 1000:1) was subjected to column chromatography to obtain 180 mg of a pale yellow oil, with a yield of 67%.

[0535] The above oily substance was placed in a 50 ml single-necked flask, and 25 ml of 3N HCl / MeOH solution was added. The mixture was reacted at 25 °C for 2 h. The reaction solution was concentrated, and saturated sodium bicarbonate solution was slowly added dropwise under ice bath to adjust the pH to 7-8. The mixture was extracted twice with DCM (25 ml * 2), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was filtered through a column at a DCM:MeOH ratio of 15:1 to give 180 mg of white solid, with a yield of 45.9%.

[0536] Example 87: Synthesis of TollB-7C-74

[0537] Synthesis of 2-(8-(methanesulfonyl)quinoline-5-yl)phenol:

[0538]

[0539] Following the synthesis method of TollB-7C-1, 220 mg of a pale yellow solid was obtained, with a yield of 78.5%.

[0540] Synthesis of TollB-7C-74:

[0541] Following the synthesis method of TollB-7C-32, 140 mg of a white solid was obtained, with a yield of 55.7%.

[0542] Example 88: Synthesis of TollB-7C-G

[0543] Synthesis of TollB-7C intermediate:

[0544]

[0545] Following the synthetic method of Toll B-7C-1, 2.23 g of a pale yellow solid was obtained, with a yield of 69.3%. Synthesis of glucuronic acid intermediate: Synthesis of glucuronic acid intermediate:

[0546]

[0547] Add TollB-7C sequentially to 50ml single-necked bottles. 1.33 g (5 mmol, 1.0 eq), 4.63 g (20 mmol, 4.0 eq) of silver oxide, 5 g of 4A molecular sieve (ground into powder and dried under vacuum at 150 °C for 6 h), 15 ml of quinoline, cooled to about 0 °C and stirred for 1 h, then 3.97 g (10 mmol, 2.0 eq) of α-D-glucuronide methyl ester was added. After the addition was complete, the mixture was stirred overnight at room temperature (25 °C) under nitrogen protection. TLC detection (ethyl acetate / petroleum ether = 1:2) showed that the reaction was complete. The reaction solution was filtered through diatomaceous earth, rinsed with ethyl acetate, and the ethyl acetate was removed by rotary evaporation. The residual liquid was wet-loaded and passed through a reduced-pressure column (first removing quinoline with ethyl acetate / petroleum ether = 1:8, then rinsing with pure ethyl acetate to remove the remaining organic matter). The quinoline-free solution was evaporated to dryness, and the residue was dry-loaded and passed through a column (ethyl acetate / petroleum ether = 1:4 to 1:3) to obtain 1.56 g of brown solid (yield 54.6%). Synthesis of TollB-7C-G:

[0548] 1.56 g (2.7 mmol, 1.0 eq) of intermediate methyl glucuronide and 20 ml of methanol were added sequentially to a 50 ml single-necked flask; the mixture was cooled to approximately 0 °C. In a 10 ml EP tube, 0.86 g of sodium hydroxide (21.6 mmol, 8.0 eq) and 2 ml of water were added, dissolved, and cooled to room temperature. The sodium hydroxide aqueous solution was added dropwise to a 50 ml reaction flask, and after the addition was complete, the mixture was transferred to room temperature and stirred overnight. TLC analysis was performed (ethyl acetate / petroleum ether = 1:2, DCM / MeOH = 3:1). After the reaction was complete, 1.6 g of glacial acetic acid (27 mmol, 10 eq) was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The solution was then evaporated to dryness, mixed with silica gel, and passed through a column chromatography with dichloromethane / methanol at a ratio of 4:1 to obtain 1.12 g of a yellow solid (yield: 92.6%).

[0549] Example 89: Synthesis of TollB-7C-98

[0550] Synthesis of 5-bromo-8-(difluoromethyl)quinoline

[0551] 314 mg (1.33 mmol, 1.0 eq) of 5-bromo-8-quinoline carbaldehyde and dichloromethane were added to a 50 mL single-necked flask. Under nitrogen protection, 715 mg (3.99 mmol, 3.0 eq) of diethylaminotrifluoride was slowly added. After stirring at low temperature for 20 min, the mixture was transferred to room temperature and reacted overnight. The reaction solution was slowly poured into ice water, and saturated sodium bicarbonate solution was added with stirring to adjust the pH to approximately 8. The mixture was extracted three times with dichloromethane (20 mL x 3), and the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The sample was loaded onto a dry column using a DCM / PE ratio of 1:2 for rapid column chromatography, yielding 340 mg of a white solid (99% yield).

[0552] Synthesis of TollB-7C-98

[0553] 143 mg (0.55 mmol, 1.0 eq) of 5-bromo-8-(difluoromethyl)quinoline, 162 mg (0.66 mmol, 1.2 eq) of 2-(benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, 117 mg (1.11 mmol, 2.0 eq) of anhydrous sodium carbonate, 20.27 mg (27.71 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 4 ml of ethylene glycol dimethyl ether, and 1 ml of water were added to a sealed tube. The reaction was carried out overnight at 80 °C under nitrogen protection. The sample was loaded dry and filtered through a column using DCM / PE = 2:5 to obtain 97 mg of a white oily product, with a yield of 59.3%.

[0554] Example 90: Synthesis of TollB-7C-99:

[0555] 114 mg (489.13 μmol, 1.0 eq) of 5-bromoquinoline-8-onitrile, 143 mg (586.95 μmol, 1.2 eq) of 2-(benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, 104 mg (978.26 μmol, 2.0 eq) of anhydrous sodium carbonate, 18 mg (24.46 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 4 ml of ethylene glycol dimethyl ether, and 1 ml of water were added to a 15 ml sealed tube. The reaction was carried out overnight at 80 °C under nitrogen protection. The sample was loaded onto a dry column and filtered through a PE / EA column at a ratio of 9:1 to obtain 99 mg of a white solid product, with a yield of 74.9%.

[0556] Example 91: Synthesis of TollB-7C-100:

[0557] Synthesis of 5-bromo-N-methylquinoline-8-carboxamide

[0558] 200 mg (0.79 mmol, 1.0 eq) of 5-bromoquinoline-8-carboxylic acid and 5 ml of DCM were added to a 50 ml single-necked flask and dissolved until dissolved. The flask was then transferred to an ice bath. 182 mg (0.95 mmol, 1.2 eq) of EDCI, 128 mg (0.95 mmol, 1.2 eq) of HOBt, and 410 mg (3.17 mmol, 4.0 eq) of DIEA were added at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 1 h. Then, 80 mg (1.18 mmol, 1.5 eq) of methylamine hydrochloride was added, and the mixture was reacted overnight at room temperature under nitrogen protection. Water was added to the reaction solution, and the mixture was extracted three times (15 ml * 3) with dichloromethane. The organic phases were combined and washed with sodium bicarbonate solution. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The solution was loaded onto a column using a dry loading method, with a DCM:MeOH ratio of 500:1 → 300:1, yielding 110 mg of a white solid (55% yield).

[0559] Synthesis of TollB-7C-100

[0560] Add 110 mg (0.41 mmol, 1.0 eq) of 5-bromo-N-methylquinoline-8-carboxamide, 121 mg (0.50 mmol, 1.2 eq) of 2-(benzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane, 15 mg (0.02 mmol, 0.05 eq) of PdCl2(dppf)CH2Cl2, and 3 ml of 1,4-dioxane to a 10 ml sealed tube. Take a 5 ml centrifuge tube, add 132 mg (1.25 mmol, 3.0 eq) of Na2CO3 and 0.6 ml of water, dissolve the solution at room temperature, and then add the solution to the sealed tube. React overnight at 80°C under nitrogen protection. Filter the reaction solution, and load the filtrate onto a dry column using a DCM:MeOH ratio of 500:1 to obtain 120 mg of an orange-yellow solid, with a yield of 95%.

[0561] Example 92: Synthesis of TollB-7C-101

[0562] Synthesis of 8-difluoromethylquinoline-5-boronic acid pinacol ester

[0563] 224 mg (868 μmol, 1.0 eq) of 5-bromo-8-(difluoromethyl)quinoline, 265 mg (1.04 mmol, 1.2 eq) of pinacol diboronate, 170 mg (1.74 mmol, 2.0 eq) of potassium acetate, 31.76 mg (43.4 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, and 20 mL of 1,4-dioxane were added to a 50 mL three-necked flask. The mixture was reacted overnight at 80 °C under nitrogen protection. The sample was loaded onto a dry column and filtered through a PE / EA column at a ratio of 50:1 to obtain 50 mg of a white solid, with a yield of 18.87%.

[0564] Synthesis of N-(4-bromophenyl)-1-methylpiperidine-4-amine

[0565] 1.5 g (8.72 mmol, 1.2 eq) of 4-bromoaniline, 839 mg (7.27 mmol, 1.0 eq) of 1-methylpiperidin-4-one, and 20 ml of dichloromethane were added to a 50 ml reaction flask and stirred at room temperature for 30 min. 2.31 g (10.9 mmol, 1.5 eq) of sodium triacetoxyborohydride and 654.54 mg (10.99 mmol, 1.5 eq) of acetic acid were added, and the reaction was carried out under nitrogen protection for 4 h. NaOH solution was added at low temperature to neutralize the acetic acid. The sample was loaded dry and passed through a column using DCM / MeOH = 10:1 to obtain 440 mg of white solid.

[0566] Synthesis of TollB-7C-101

[0567] 36 mg (133.74 μmol, 1.0 eq) of N-(4-bromophenyl)-1-methylpiperidin-4-amine, 50 mg (160.48 μmol, 1.2 eq) of 8-difluoromethylquinoline-5-borate pinacol ester, 28 mg (267.47 μmol, 2.0 eq) of anhydrous sodium carbonate, 5 mg (6.69 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 5 ml of 1,4-dioxane, and 1 ml of water were added to a 10 ml sealed tube. The reaction was carried out overnight at 90 °C under nitrogen protection. The sample was loaded dry and filtered through a column with DCM / MeOH = 50:1 to obtain 13 mg of orange-red solid, with a yield of 26.46%.

[0568] Example 93: Synthesis of TollB-7C-102:

[0569] Add 75 mg (0.29 mmol, 1.0 eq) of N-(4-bromophenyl)-1-methylpiperidin-4-amine, 105 mg (0.34 mmol, 1.2 eq) of N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline-8-carboxamide, 10 mg (0.01 mmol, 0.05 eq) of PdCl2(dppf)CH2Cl2, and 3.5 ml of 1,4-dioxane to a 10 ml sealed tube. Take a 5 ml centrifuge tube, add 89 mg (0.84 mmol, 3.0 eq) of Na2CO3 and 0.7 ml of water, dissolve the solution at room temperature, and add it to the sealed tube. Then, replace the solution with N2 three times and react overnight at 80°C. Filter the reaction solution, load the filtrate onto a dry column using a DCM:MeOH ratio of 15:1, and pass it through a column to obtain 30 mg of a yellow solid.

[0570] Example 94: Synthesis of TollB-7C-103:

[0571] Synthesis of 5-bromo-N,N-dimethylquinoline-8-carboxamide

[0572] In a 50 ml single-necked flask, 200 mg (0.79 mmol, 1.0 eq) of 5-bromoquinoline-8-carboxylic acid and 25 ml of DCM were added and dissolved until dissolved. The flask was then placed in an ice bath. At 0°C, 182 mg (0.95 mmol, 1.2 eq) of EDCI, 128 mg (0.95 mmol, 1.2 eq) of HOBt, and 410 mg (3.17 mmol, 4.0 eq) of DIEA were added. After the addition was complete, the flask was brought to room temperature and stirred for 1 h. Then, 97 mg (1.19 mmol, 1.5 eq) of dimethylaminohydrochloride was added, and the mixture was reacted overnight at room temperature under nitrogen protection. The reaction solution was poured into water and extracted three times with dichloromethane (15 ml * 3). The organic phases were combined and washed with sodium bicarbonate solution. The mixture was dried over anhydrous sodium sulfate, filtered, concentrated, and evaporated to dryness. The solution was loaded onto a dry column with DCM:MeOH = 200:1 to obtain 150 mg of a white solid, yield 67.7%.

[0573] Synthesis of N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)quinoline-8-carboxamide

[0574] Add 150 mg (0.54 mmol, 1.0 eq) of 5-bromo-N,N-dimethylquinoline-8-carboxamide, 164 mg (0.65 mmol, 1.2 eq) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane), 20 mg (0.02 mmol, 0.05 eq) of PdCl2(dppf)CH2Cl2, 158 mg (1.61 mmol, 3.0 eq) of potassium acetate, and 3 ml of 1,4-dioxane to a 10 ml sealed tube. React overnight at 100 °C under nitrogen protection. Filter the reaction solution, load the filtrate dry onto a column, and pass it through a DCM:MeOH column at a ratio of 100:1 to obtain 100 mg of an orange solid, yield 57%.

[0575] Synthesis of TollB-7C-103

[0576] Add 70 mg (0.26 mmol, 1.0 eq) of N-(4-bromophenyl)-1-methylpiperidin-4-amine, 100 mg (0.31 mmol, 1.2 eq) of N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline-8-carboxamide, 10 mg (0.01 mmol, 0.05 eq) of PdCl2(dppf)CH2Cl2, and 3.5 ml of 1,4-dioxane to a 10 ml sealed tube. Dissolve 83 mg (0.78 mmol, 3.0 eq) of Na2CO3 and 0.7 ml of water in a 5 ml centrifuge tube at room temperature, then add the dissolved solution to the sealed tube. React overnight at 80°C under nitrogen protection. Filter the reaction solution, and load the filtrate onto a dry column using a DCM:MeOH ratio of 15:1 to obtain 50 mg of a yellow solid.

[0577] Example 95: Synthesis of TollB-7C-104:

[0578] 362 mg (1.47 mmol) of 5-(4-hydroxyphenyl)-8-cyanoquinoline, 1.76 mmol of N-methyl-4-piperidinol, and 501 mg (1.91 mmol) of triphenylphosphine were added to a 50 ml single-necked flask, followed by 20 ml of tetrahydrofuran. The mixture was cooled to approximately 0 °C under nitrogen protection. 333 mg (1.91 mmol) of diethyl azodicarbonate was dissolved in 5 ml of tetrahydrofuran and added to the above reaction flask under nitrogen protection, maintaining the temperature below 5 °C. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction solution was evaporated to dryness and purified by column chromatography (DCM / MeOH / Et3N = 40:1:1). 180 mg of a yellowish-white solid was obtained, with a yield of 35.66%.

[0579] Example 96: Synthesis of TollB-7C-115:

[0580] Synthesis of 8-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline

[0581] Add 200 mg (0.88 mmol, 1.0 eq) of 5-bromo-8-fluoroquinoline, 270 mg (1.06 mmol, 1.2 eq) of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) and 32 mg (0.04 mmol, 0.05 eq) of PdCl2(dppf)CH2Cl2, 260 mg (2.65 mmol, 3.0 eq) of potassium acetate and 3.5 ml of 1,4-dioxane to a 10 ml sealed tube. React overnight at 90 °C under nitrogen protection. Filter the reaction solution, load the filtrate dry onto a column, and pass it through a column with DCM:MeOH = 600:1 to obtain 227 mg of a white solid, yield 94%.

[0582] Synthesis of TollB-7C-115

[0583] Add 180 mg (0.67 mmol, 1.0 eq) of N-(4-bromophenyl)-1-methylpiperidin-4-amine, 220 mg (0.81 mmol, 1.2 eq) of 8-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline, 25 mg (0.03 mmol, 0.05 eq) of PdCl2(dppf)CH2Cl2, and 3.5 ml of 1,4-dioxane to a 10 ml sealed tube. Take a 5 ml centrifuge tube, add 212 mg (2.00 mmol, 3.0 eq) of sodium carbonate and 0.7 ml of water to dissolve the solution at room temperature, and then add the solution to the sealed tube. React overnight at 80°C under nitrogen protection. Filter the reaction solution, load the filtrate dry onto a column using a DCM:MeOH ratio of 15:1, and pass it through a column to obtain 70 mg of a brown solid, yield 31%.

[0584] Example 97: Synthesis of TollB-7C-121:

[0585] Synthesis of tert-butyl 4-(5-bromo-1H-indazol-2-yl)piperidine-1-carboxylate

[0586] In a 100 ml single-necked flask, add 2 g (10.18 mmol, 1.0 eq) of 5-bromo-1H-indazole, 40 ml of DMA to dissolve, 1.37 g (12.2 mmol, 1.2 eq) of potassium tert-butoxide, and 3.40 g (12.2 mmol, 1.2 eq) of tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate; heat to 150 °C and react overnight; pour the reaction solution into ice water, extract three times with ethyl acetate (50 ml * 3), combine the organic layers, dry to anhydrous magnesium sulfate, filter, load the filtrate by dry method, and separate by PE / EA = 10:1 column chromatography to obtain 1.1 g of yellow solid, yield 28.4%.

[0587] Synthesis of tert-butyl 4-(5-(8-(methylsulfonyl)quinoline-5-yl)-1H-indazol-2-yl)piperidine-1-carboxylic acid

[0588] 380 mg (1.0 mmol, 1.0 eq) of 4-(5-bromo-1H-indazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester, 436 mg (1.3 mmol, 1.3 eq) of 8-methanesulfonylquinoline-5-boronic acid pinacol, 36 mg (0.05 mmol, 5% mmol) of PdCl2 (dppf), and 8 ml of DME were added to a 10 ml centrifuge tube. 212 mg (2.0 mmol, 2.0 eq) of sodium carbonate and 2 ml of water were added and dissolved at room temperature before being added to the reaction flask. The reaction mixture was reacted overnight at 90 °C under nitrogen protection. The reaction solution was filtered, loaded dry, and column-sected at a DCM / MeOH ratio of 100:1 to obtain 380 mg of a pale yellow solid, yield 75%. Synthesis of TollB-7C-121

[0589] 380 mg (0.75 mmol, 1.0 eq) of 4-(5-(8-(methanesulfonyl)quinoline-5-yl)-1H-indazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester and 6 ml of 3N HCl / MeOH solution were added to a 50 ml single-necked flask; the reaction was carried out at room temperature for 3 h; the solvent was removed by rotary evaporation, 5 ml of methanol was added, and the pH was adjusted to 9 with saturated sodium bicarbonate solution at 0 °C. The sample was loaded onto a dry column with DCM / MeOH = 10:1 to obtain 183 mg of colorless solid, yield 60.09%.

[0590] Example 98: Synthesis of TollB-7C-122:

[0591] Synthesis of 6-bromo-N-(1-methylpiperidin-4-yl)-1H-indazole-3-amine

[0592] 1 g (4.72 mmol, 1.2 eq) of 6-bromo-1H-indazole-3-amine, 456.98 mmol (3.93 mmol, 1.0 eq) of 1-methylpiperidin-4-one, 1.89 g (15.72 mmol, 4 eq) of anhydrous magnesium sulfate, and 15 ml of DCM were added to a 100 ml reaction flask. After stirring at room temperature for 30 min, 1.25 g (5.89 mmol, 1.5 eq) of sodium triacetylborohydride and 338.83 mmol (5.89 mmol, 1.5 eq) of acetic acid were added. The reaction was carried out overnight under nitrogen protection. After filtration, the solution was evaporated to dryness, and the solution was loaded onto a dry column. The solution was rapidly passed through a column with a DCM / MeOH ratio of 15:1 to obtain 983 mg of a pink oil, with a yield of 80.6%. Synthesis of TollB-7C-122

[0593] In a 50 mL reaction flask, 267 mg (863.49 μmol, 1.0 eq) of 6-bromo-N-(1-methylpiperidin-4-yl)-1H-indazole-3-amine, 345 mg (1.04 mmol, 1.2 eq) of 8-(methanesulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline, 183 mg (1.73 mmol, 2.0 eq) of anhydrous sodium carbonate, 32 mg (43.17 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 20 mL of 1,4-dioxane, and 4 mL of H2O were added. The reaction was carried out overnight at 85 °C under nitrogen protection. The sample was loaded dry and filtered through a column using DCM / MeOH = 15:1 to give 290 mg of a yellow solid product, with a yield of 77.1%.

[0594] Example 99: Synthesis of TollB-7C-125:

[0595] Synthesis of 5-(4,4,5-trimethyl-1,3,2-dioxaborane-2-yl)quinoline

[0596] 2.0 g (9.6 mmol, 1.0 eq) of 5-bromoquinoline, 2.93 g (11.5 mmol, 1.2 eq) of pinacol diboronate, 1.96 g (19.2 mmol, 2.0 eq) of potassium acetate, 0.36 g (0.50 mmol, 5% mmol) of PdCl2 (dppf) and 40 ml of dioxane were added to a 100 ml single-necked flask. The reaction was carried out at 90 °C for 6 h under nitrogen protection. The reaction solution was filtered, and the filtrate was loaded onto a dry plate. The resulting oily petroleum ether was separated by rapid column chromatography and slurryed to give 1.52 mg of colorless solid, with a yield of 62.09%.

[0597] Synthesis of TollB-7C-125

[0598] 162 mg (523 μmol, 1.0 eq) of 6-bromo-N-(1-methylpiperidin-4-yl)-1H-indazole-3-amine, 160.4 mg (628.7 mmol, 1.2 eq) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline, 111.06 mg (1.05 mmol, 2.0 eq) of anhydrous sodium sulfate, 19.17 mg (26.2 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 4 mL of 1,4-dioxane, and 1 mL of H2O were added to a sealed tube. The reaction was carried out overnight at 85 °C under nitrogen protection. The sample was loaded dry and filtered through a column with EA / Et3N = 3:1 to obtain 62 mg of a brownish-yellow solid product, with a yield of 33%.

[0599] Example 100: Synthesis of TollB-7C-127:

[0600] Synthesis of 5-bromo-N-(1-methylpiperidin-4-yl)-1H-indazole-3-amine

[0601] 1 g (4.72 mmol, 1.2 eq) of 5-bromo-1H-indazole-3-amine, 454 mg (4.01 mmol, 1.0 eq) of 1-methylpiperidin-4-one, 1.89 g (15.70 mmol, 4.0 eq) of anhydrous magnesium sulfate, and 25 ml of dichloromethane were added to a 50 ml single-necked flask. The mixture was stirred at room temperature for 30 min, followed by the addition of 356 mg (5.93 mmol, 1.5 eq) of glacial acetic acid and 1.25 g (5.90 mmol, 1.5 eq) of sodium triacetoxyborohydride. The mixture was stirred overnight at room temperature. The pH was adjusted to 7 with 10% NaOH solution, and the mixture was filtered off the solid and concentrated to dryness. The sample was then subjected to a dry mixing process and passed through a column with a DCM:MeOH ratio of 50:1 to 10:1. The mixture was then concentrated to dryness, and a small amount of dichloromethane was added and stirred for 10 min. The mixture was then filtered off the solid. 960 mg of a white product was obtained, with a yield of 77%.

[0602] Synthesis of N-TollB-7C-127

[0603] 120 mg (388.08 μmol, 1.0 eq) of 5-bromo-N-(1-methylpiperidin-4-yl)-1H-indazole-3-amine, 149 mg (582.13 mmol, 1.2 eq) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline, 82.26 mg (776.17 μmol, 2.0 eq) of anhydrous sodium sulfate, 14.2 mg (19.4 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 5 ml of 1,4-dioxane, and 1 ml of water were added to a 15 ml sealed tube. The reaction was carried out overnight at 85 °C under nitrogen protection. The sample was loaded dry and filtered through a column with EA / Et3N = 3:1 to obtain 86 mg of yellow solid product, with a yield of 62%.

[0604] Example 101: Synthesis of TollB-7C-133:

[0605] Synthesis of 6-bromo-5-methyl-1H-indazole-3-amine

[0606] 500 mg (2.34 mmol, 1.0 eq) of 4-bromo-2-fluoro-5-methylbenzonitrile, 5 ml of ethanol and 4 ml of hydrazine hydrate were added to a 50 ml single-necked flask; the mixture was heated to 90 °C and reacted overnight; the reaction solution was poured into water, stirred at 0 °C for 1 h, filtered, the filter cake was washed with water and dried under vacuum overnight to give 287 mg of colorless solid, yield 54.3%.

[0607] 6-Bromo-5-methyl-N-(1-methylpiperidin-4-yl)-1H-indazole-3-amine

[0608] 287 mg (1.27 mmol, 1.0 eq) of 6-bromo-5-methyl-1H-indazole-3-amine, 287 mg (2.54 mmol, 2.0 eq) of 1-methylpiperidin-4-one, and 5 ml of DMF were added to a 100 ml single-necked flask and stirred at room temperature for 30 min. 807 mg (3.81 mmol, 3.0 eq) of sodium triacetylborohydride and 114 mg (1.90 mmol, 1.5 eq) of glacial acetic acid were added. The reaction mixture was reacted overnight under nitrogen protection. EA was added to the reaction solution, and the mixture was washed three times with saturated brine (10 ml * 3). The organic phase was dried over anhydrous magnesium sulfate, filtered, and the filtrate was loaded onto a dry column. The solution was filtered through a column with DCM / MeOH / TEA = 20:1:0.5% to obtain 87 mg of a yellow solid, yield 21.20%.

[0609] Synthesis of TollB-7C-133

[0610] 87 mg (0.267 mmol, 1.0 eq) of 6-bromo-5-methyl-1H-indazole-3-amine, 82 mg (0.324 mmol, 1.2 eq) of quinoline 5-boronic acid pinacol ester, 7.0 mg (0.01 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 5 ml of dioxane were added to a 10 ml centrifuge tube. 56 mg (0.534 mmol, 2.0 eq) of sodium carbonate and 1 ml of water were added to the tube and dissolved at room temperature before being added to the reaction flask. The reaction mixture was reacted overnight at 90 °C under nitrogen protection. The reaction solution was loaded onto a column using a dry method, and DCM / MeOH / TEA = 20:1:0.5% was passed through the column to obtain 88 mg of a gray solid, with a yield of 88.83%.

[0611] Example 102: Synthesis of TollB-7C-134:

[0612] Synthesis of (1s,3R,5S,7s)-4-((6-bromo-1H-indazol-3-yl)amino)adamantane-1-ol

[0613] In a 50 mL single-necked flask, 250 mg (1.50 mmol, 1.0 eq) of (1R,3S,5S,7S)-5-hydroxyadamantane-2-one, 383 mg (1.81 mmol, 1.2 eq) of 6-bromo-1H-indazole-3-amine, 362 mg (3.01 mmol, 2.0 eq) of anhydrous magnesium sulfate, and 10 mL of dichloromethane were added. The mixture was stirred at room temperature for 30 min, followed by the addition of 135 mg (2.25 mmol, 1.5 eq) of glacial acetic acid and 478 mg (2.26 mmol, 1.5 eq) of sodium triacetoxyborohydride. The mixture was reacted at room temperature for 3 h. The pH was adjusted to 7 by adding 10% NaOH solution. The solid was then filtered, concentrated, and evaporated to dryness. The sample was then subjected to a dry mixing process and passed through a column chromatography (DCM:MeOH = 100:1) to obtain 80 mg of a white solid, with a yield of 15%.

[0614] Synthesis of TollB-7C-134

[0615] Add 80 mg (0.22 mmol, 1.0 eq) of (1s,3R,5S,7s)-4-((6-bromo-1H-indazol-3-yl)amino)adamantane-1-ol, 85 mg (0.33 mmol, 1.5 eq) of 5-(4,4,5-trimethyl-1,3,2-dioxaboran-2-yl)quinoline, 8 mg (0.01 mmol, 0.05 eq) of PdCl2(dppf)CH2Cl2, and 4 ml of 1,4-dioxane to a 10 ml sealed tube. Add 70 mg (0.66 mmol, 3.0 eq) of sodium carbonate and 1 ml of water to a 5 ml centrifuge tube, dissolve the solution at room temperature, and then add the solution to the sealed tube. React overnight at 85°C under nitrogen protection. Filter the reaction solution, and load the filtrate onto a dry column using a DCM:MeOH ratio of 50:1 to obtain 70 mg of a yellow solid, yield 77%.

[0616] Example 103: Synthesis of TollB-7C-135:

[0617] Synthesis of 6-bromo-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-1H-indazole-3-amine

[0618] In a 50 mL single-necked flask, 220 mg (1.30 mmol, 1.0 eq) of 1,2,2,6,6-pentamethylpiperidin-4-one, 303 mg (1.43 mmol, 1.1 eq) of 6-bromo-1H-indazole-3-amine, 312 mg (2.59 mmol, 2.0 eq) of anhydrous magnesium sulfate, and 10 mL of dichloromethane were added. The mixture was stirred at room temperature for 30 min, followed by the addition of 117 mg (1.95 mmol, 1.5 eq) of glacial acetic acid and 413 mg (1.95 mmol, 1.5 eq) of sodium triacetoxyborohydride. The reaction mixture was then allowed to react at room temperature for 3 h. The pH was adjusted to approximately 7 by adding 10% NaOH solution. The mixture was filtered through a solid filter, concentrated, and evaporated to dryness. The sample was then subjected to a dry-mixing process and column chromatography (DCM:MeOH = 5:1) to obtain 100 mg of a yellow oil, with a yield of 21%.

[0619] Synthesis of TollB-7C-135

[0620] Add 100 mg (0.27 mmol, 1.0 eq) of 6-bromo-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-1H-indazole-3-amine alcohol, 84 mg (0.33 mmol, 1.2 eq) of 5-(4,4,5-trimethyl-1,3,2-dioxaborane-2-yl)quinoline, 10 mg (0.01 mmol, 0.05 eq) of PdCl2(dppf)CH2Cl2, and 4 ml of 1,4-dioxane to a 10 ml reaction tube. Dissolve 87 mg (0.82 mmol, 3.0 eq) of sodium carbonate and 1 ml of water in a 5 ml centrifuge tube at room temperature. Seal the tube and react overnight at 85°C under nitrogen protection. Filter the reaction solution, load the filtrate dry onto a column using a DCM:MeOH ratio of 20:1, and pass through a column to obtain 30 mg of a yellow solid, yield 26.5%.

[0621] Example 104: Synthesis of TollB-7C-136:

[0622] Synthesis of N-(6-bromo-1H-indazol-3-yl)quinine-3-amine

[0623] 300 mg (1.41 mmol, 1.0 eq) of 6-bromo-1H-indole-3-amine, 274 mg (1.70 mmol, 1.2 eq) of 3-quininecycloone hydrochloride, and 5 mL of dichloromethane were added to a 100 mL single-necked flask and stirred at room temperature for 30 min. 127 mg (2.12 mmol, 1.5 eq) of glacial acetic acid and 450 mg (2.12 mmol, 1.5 eq) of sodium triacetylborohydride were added. The reaction was carried out under nitrogen protection for 3 h. The reaction solution was loaded onto a dry column and filtered through a column with DCM / MeOH / TEA = 20:1:0.5%, yielding 176 mg of a pink solid, with a yield of 38.7%.

[0624] Synthesis of TollB-7C-136

[0625] 176 mg (0.58 mmol, 1.0 eq) of N-(6-bromo-1H-indazol-3-yl)quinine-3-amine, 180 mg (0.71 mmol, 1.2 eq) of pinacol 5-borate, 20 mg (0.027 mmol, 5% mmol) of PdCl2 (dppf) and 10 ml of dioxane were added to a 50 ml single-necked flask. 116 mg (1.10 mmol, 2.0 eq) of sodium carbonate and 2 ml of water were added to a 10 ml centrifuge tube and dissolved at room temperature before being added to the reaction flask. The reaction mixture was reacted overnight at 80 °C under nitrogen protection. The reaction solution was loaded onto a column using a dry method, and DCM / MeOH / TEA = 10:1:0.5% was passed through the column to obtain 126 mg of a gray solid, with a yield of 63.3%.

[0626] Example 105: Synthesis of TollB-7C-137:

[0627] Synthesis of 6-bromo-N-(quinoline-4-ylmethyl)-1H-indazole-3-amine

[0628] 300 mg (1.41 mmol, 1.0 eq) of 6-bromo-1H-indole 3-amine, 267 mg (1.70 mmol, 1.2 eq) of 4-quinoline benzaldehyde, and 5 mL of dichloromethane were added to a 100 mL single-necked flask and stirred at room temperature for 30 min. 127 mg (2.12 mmol, 1.5 eq) of glacial acetic acid and 450 mg (2.12 mmol, 1.5 eq) of sodium triacetylborohydride were added. The reaction was carried out under nitrogen protection for 3 h. The reaction solution was loaded onto a dry column and filtered through a column with DCM / MeOH / TEA = 20:1:0.5%, yielding 176 mg of a pink solid, with a yield of 38.7%.

[0629] Synthesis of TollB-7C-137

[0630] 143 mg (0.406 mmol, 1.0 eq) of 6-bromo-N-(quinolin-4-ylmethyl)-1H-indazole-3-amine, 124 mg (0.48 mmol, 1.2 eq) of pinacol 5-borate, 15 mg (0.02 mmol, 5% mmol) of PdCl2 (dppf) and 6 ml of dioxane were added to a 50 ml single-necked flask. 86 mg (0.812 mmol, 2.0 eq) of sodium carbonate and 1.5 ml of water were added to a 10 ml centrifuge tube and dissolved at room temperature before being added to the reaction flask. The reaction mixture was reacted overnight at 80 °C under nitrogen protection. The reaction solution was loaded onto a column using a dry method, and DCM / MeOH / TEA = 20:1:0.5% was passed through the column to obtain 48 mg of a red solid, with a yield of 29.6%.

[0631] Example 106: Synthesis of TollB-7C-139:

[0632] 92 mg (297.53 μmol, 1.0 eq) of 6-bromo-N-(1-methylpiperidin-4-yl)-1H-indazole-3-amine, 100 mg (357.04 μmol, 1.2 eq) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)quinoline-8-onitrile, 63 mg (595.06 μmol, 2.0 eq) of anhydrous sodium sulfate, 12 mg (14.88 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 4 mL of 1,4-dioxane, and 1 mL of water were added to a sealed tube. The reaction was carried out overnight at 85 °C under nitrogen protection. The sample was loaded dry and filtered through a column using EA:Et3N = 3:1 to obtain 32 mg of a yellow solid product, with a yield of 28%.

[0633] Example 107: Synthesis of TollB-7C-140:

[0634] 92 mg (297.53 μmol, 1.0 eq) of 6-bromo-N-(1-methylpiperidin-4-yl)-1H-indazole-3-amine, 109 mg (357.04 μmol, 1.2 eq) of 8-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline, 63.07 mg (595.06 μmol, 2.0 eq) of anhydrous sodium sulfate, 12 mg (14.88 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 5 mL of 1,4-dioxane, and 1 mL of water were added to a sealed tube. The reaction was carried out overnight at 85 °C under nitrogen protection. The sample was loaded dry and filtered through a column using EA:Et3N = 4:1 to obtain 69 mg of a yellow solid product, with a yield of 57%.

[0635] Example 108: Synthesis of TollB-7C-144:

[0636] 113 mg (0.50 mmol, 1.0 eq) of 5-bromo-8-fluoroquinoline, 178 mg (0.5 mmol, 1.0 eq) of N-(1-methylpiperidin-4-yl-6-(4,4,5,5,5-methyl-2-methyl-2-methyl)-1H-pyrazole-2-amine, 20 mg (0.025 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 6 ml of dioxane were added to a 50 ml single-necked flask. 106 mg (1.0 mmol, 2.0 eq) of sodium carbonate and 1.5 ml of water were added to a 10 ml centrifuge tube and dissolved at room temperature before being added to the reaction flask. The reaction mixture was reacted overnight at 85 °C under nitrogen protection. The reaction solution was loaded onto a column using a dry method, and DCM / MeOH / TEA ratio of 10:1:0.5% was passed through the column to obtain 165 mg of a gray solid, with a yield of 88.23%.

[0637] Example 109: Synthesis of TollB-7C-145:

[0638] Synthesis of tert-butyl 4-(5-(8-cyanoquinoline-5-yl)-2H-indazol-2-yl)piperidine-1-carboxylate

[0639] 150 mg (0.38 mmol, 1.0 eq) of 4-(5-bromo-1H-indazole-2-yl)piperidine-1-carboxylic acid tert-butyl ester, 130 mg (0.46 mmol, 1.0 eq) of 5-boronic acid pinacol ester-8-cyanoquinoline, 15 mg (0.019 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 6 ml of dioxane were added to a 50 ml single-necked flask. 80 mg (1.0 mmol, 2.0 eq) of sodium carbonate and 1.5 ml of water were added to a 10 ml centrifuge tube and dissolved at room temperature before being added to the reaction flask. The reaction mixture was reacted overnight at 80 °C under nitrogen protection. The reaction solution was loaded onto a column using a dry method, and the PE / EA ratio was 1:1 to obtain 150 mg of a colorless solid, with a yield of 87.2%.

[0640] Synthesis of TollB-7C-145

[0641] 150 mg (0.34 mmol, 1.0 eq) of 4-(5-(8-cyanoquinoline-5-yl)-2H-indazole-2-yl)piperidine-1-carboxylic acid tert-butyl ester and 6 ml of 3N HCl / MeOH solution were added to a 50 ml single-necked flask; the reaction was carried out at room temperature for 3 h; the solvent was removed by rotary evaporation, 5 ml of methanol was added, the pH was adjusted to 9 with saturated sodium bicarbonate solution, and the sample was loaded onto a dry column with DCM / MeOH = 10:1 to obtain 64 mg of colorless solid, yield 53.3%.

[0642] Example 110: Synthesis of TollB-7C-147:

[0643] Synthesis of tert-butyl 4-(6-(8-(difluoromethyl)quinolin-5-yl)-2H-indazol-2-yl)piperidine-1-carboxylate

[0644] 100 mg (262.96 μmol, 1 eq) of 4-(6-bromo-2H-indazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester, 96.28 mg (315.55 μmol, 1.2 eq) of 8-(difluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline, 55.74 mg (525.92 μmol, 2.0 eq) of anhydrous sodium sulfate, 10.74 mg (13.15 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 5 mL of 1,4-dioxane, and 1 mL of water were added to a sealed tube. The reaction was carried out overnight at 85 °C under nitrogen protection. The sample was loaded dry and filtered through a column with PE / EA = 4:1 to obtain 96 mg of a colorless oil, yield 76.3%. Synthesis of TollB-7C-147

[0645] 96 mg (200.61 μmol, 1 eq) of 4-(6-(8-(difluoromethyl)quinolin-5-yl)-2H-indazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester and 7 ml of 3N HCl / MeOH were added to a 50 ml reaction flask and stirred at room temperature for 1 h. Saturated NaHCO3 was added at low temperature to adjust the pH to about 7-8. The mixture was extracted three times with EA (20 ml * 3), separated, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to give 44 mg of white solid product, with a yield of 58%.

[0646] Example 111: Synthesis of TollB-7C-148:

[0647] Add 250 mg (1.04 mmol, 1.0 eq) of 4-bromo-2-(trifluoromethyl)aniline, 319 mg (1.25 mmol, 1.2 eq) of 5-(4,4,5-trimethyl-1,3,2-dioxaborane-2-yl)quinoline, 43 mg (0.05 mmol, 0.05 eq) of PdCl2(dppf)CH2Cl2, and 4 ml of dioxane to a 10 ml sealed tube; add 331 mg (3.12 mmol, 3.0 eq) of sodium carbonate and 1 ml of water to a 5 ml centrifuge tube, and react overnight at 85 °C under nitrogen protection. Filter the reaction solution, and load the filtrate onto a column using the dry method. Pass the solution through a column with a DCM:MeOH ratio of 50:1 → 20:1 to obtain 230 mg of a yellow solid, yielding 76.6%.

[0648] Example 112: Synthesis of TollB-7C-150:

[0649] 250 mg (0.943 mmol, 1.0 eq) of 5-bromo-7-(trifluoromethyl)-1H-indazole, 288 mg (1.132 mmol, 1.2 eq) of pinacol 5-borate, 40 mg (0.047 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 6 ml of dioxane were added to a 50 ml single-necked flask. 212 mg (2.0 mmol, 2.0 eq) of sodium carbonate and 1.5 ml of water were added to a 10 ml centrifuge tube and dissolved at room temperature before being added to the reaction flask. The reaction mixture was reacted overnight at 80 °C under nitrogen protection. The reaction solution was loaded onto a column using a dry method, and the PE / EA ratio was 1:1. 256 mg of a colorless solid was obtained, with a yield of 72.31%.

[0650] Example 113: Synthesis of TollB-7C-151:

[0651] Synthesis of 4-(quinolin-5-yl)-2-(trifluoromethyl)benzaldehyde

[0652] 150 mg (592.84 μmol, 1.0 eq) of 4-bromo-2-(trifluoromethyl)benzaldehyde, 182 mg (711.41 μmol, 1.2 eq) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline, 126 mg (1.19 mmol, 2.0 eq) of anhydrous sodium carbonate, 24 mg (29.64 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 4 mL of 1,4-dioxane, and 1 mL of water were added to a sealed tube. The reaction was carried out overnight at 85 °C under nitrogen protection. The sample was loaded dry and filtered through a column with EA / PE = 1:4 to obtain 178 mg of a yellow oil, with a yield of 99.6%.

[0653] Synthesis of TollB-7C-151

[0654] 178 mg (590.84 μmol, 1.0 eq) of 4-(quinolin-5-yl)-2-(trifluoromethyl)benzaldehyde, 81 mg (709 μmol, 1.2 eq) of 1-methylpiperidin-4-amine, 284 mg (2.36 mol, 4.0 eq) of anhydrous magnesium sulfate, and 20 mL of dichloromethane were added to a 50 mL reaction flask. After stirring at room temperature for 30 min, 188 mg (886.25 μmol, 1.5 eq) of sodium triacetylborohydride and 53.22 mg (886.25 μmol, 1.5 eq) of acetic acid were added. The reaction was carried out overnight under nitrogen protection. The pH was adjusted to neutral by adding sodium hydroxide aqueous solution. The sample was loaded dry and filtered through a column with PE / EA = 4:1 to obtain 73 mg of white solid product, with a yield of 30.6%.

[0655] Example 114: Synthesis of TollB-7C-152:

[0656] Synthesis of tert-butyl 4-(((4-(quinolin-5-yl)-2-(trifluoromethyl)phenyl)amino)methyl)piperidine-1-carboxylate

[0657] 177 mg (0.83 mmol, 1.2 eq) of 4-formylpiperidin-1-carboxylic acid tert-butyl ester, 200 mg (0.69 mmol, 1.0 eq) of Toll B-7C-148, 334 mg (2.77 mmol, 4.0 eq) of anhydrous magnesium sulfate, and 10 ml of dichloromethane were added to a 50 ml single-necked flask. The mixture was stirred at room temperature for 30 min, followed by the addition of 62 mg (1.03 mmol, 1.5 eq) of glacial acetic acid and 220 mg (1.04 mmol, 1.5 eq) of sodium triacetoxyborohydride. The mixture was reacted at room temperature for 6 h after the addition was complete. The pH was adjusted to 7 by adding 10% NaOH solution, followed by solid filtration and concentrated to dryness. The sample was then subjected to dry mixing and column chromatography (PE:EA = 8:1) to obtain 100 mg of a yellow oil, with a yield of 30%.

[0658] Synthesis of TollB-7C-152

[0659] 100 mg (0.21 mmol, 1.0 eq) of 4-(5-(1,4-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-2H-indazol-2-yl)piperidin-1-carboxylic acid tert-butyl ester and 10 mL of 3N HCl / MeOH were added to a 50 mL single-necked flask and reacted at room temperature for 1.5 h. The system was concentrated and evaporated to dryness, then dissolved in MeOH, and the pH was adjusted to alkaline by adding saturated NaHCO3 solution. The solution was then concentrated and evaporated to dryness. The sample was mixed dry and passed through a column in a DCM:MeOH ratio of 10:1 to obtain 50 mg of a milky white solid, with a yield of 43.5%.

[0660] Example 115: Synthesis of TollB-7C-153:

[0661] 100 mg (0.474 mmol, 1.0 eq) of 5-bromo-7-methyl-1H-indazole, 145 mg (0.569 mmol, 1.2 eq) of pinacol 5-borate ester quinoline, 19 mg (0.024 mmol, 5% mmol) of PdCl2(dppf)CH2Cl2, and 4 ml of dioxane were added to a 50 ml single-necked flask. 106 mg (1.0 mmol, 2.0 eq) of sodium carbonate and 1 ml of water were added to a 10 ml centrifuge tube and dissolved at room temperature before being added to the reaction flask. The reaction mixture was reacted overnight at 80 °C under nitrogen protection. The reaction solution was loaded onto a column using a dry method, with a PE / EA ratio of 1:1, yielding 101 mg of a colorless solid, with a yield of 82.17%.

[0662] Example 116: Synthesis of TollB-7C-154:

[0663] Add 90 mg (456.77 μmol, 1.0 eq) of 6-bromo-1H-indazole, 139.84 mg (548.13 μmol, 1.2 eq) of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)quinoline, 96.82 mg (913.54 μmol, 2.0 eq) of anhydrous sodium carbonate, 18.65 mg (22.84 μmol, 5% eq) of PdCl2(dppf)CH2Cl2, 4 ml of 1,4-dioxane, and 1 ml of water to a 10 ml sealed tube. React overnight at 85 °C under nitrogen protection. Dry loading and column chromatography with DCM / MeOH = 60:1 yielded 66 mg of a white oily product, with a yield of 59%.

[0664] Example 117: Synthesis of TollB-7C-155:

[0665] Synthesis of 5-bromo-2-methyl-1-nitro-3-trifluorotoluene

[0666] 10 g (48.75 mmol) of 2-methyl-3-nitrotrifluorotoluene was added to a 200 ml single-necked flask, followed by 60 ml of concentrated sulfuric acid at room temperature. 8.36 g (29.25 mmol) of dibromohydantoin was added in portions with stirring at room temperature, and the reaction mixture was allowed to react at room temperature for 5 h. After the reaction was complete, the reaction mixture was poured into 200 ml of ice water; the mixture was extracted four times with EA (500 ml x 4), the organic phases were combined, and the mixture was washed once with saturated sodium carbonate solution; the mixture was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to obtain 13.57 g of a yellow oily liquid, with a yield of 90.78%. No further purification was required, and the liquid was used directly for the next reduction step.

[0667] Synthesis of 5-bromo-2-methyl-3-trifluoromethylaniline

[0668] 13 g (45.77 mmol) of 5-bromo-2-methyl-1-nitro-3-trifluorotoluene and 150 ml of anhydrous ethanol were added to a 500 ml single-necked flask. 34.71 g (183.08 mmol) of stannous chloride and 10 ml of concentrated hydrochloric acid were added to a 250 ml Erlenmeyer flask and dissolved by sonication. The solution was then added to the above reaction flask under ice bath conditions. After the addition was complete, the mixture was stirred at 60 °C for 3 h. The reaction solution was concentrated, and 12 N sodium hydroxide solution was added under ice bath conditions. The mixture was extracted five times with DCM (40 ml x 5). The organic phases were combined, washed once with 12 N sodium hydroxide solution, and once with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to obtain 5.71 g of a yellow oily substance, with a yield of 49.11%.

[0669] Synthesis of 6-bromo-4-trifluoromethyl-1H-indazole

[0670] 5.71 g (22.48 mmol) of 5-bromo-2-methyl-3-trifluoromethylaniline and 140 ml of toluene were added to a 250 ml single-necked flask. 4.66 g (45.63 mmol) of acetic anhydride was added with stirring at room temperature. After the addition was complete, the temperature was raised to 60 °C and the reaction was carried out for 3 h under TLC control (EA / PE = 1:5). The mixture was cooled to room temperature, and 6.24 g (53.27 mmol) of isoamyl nitrite, 0.73 g (7.42 mmol) of potassium acetate, and 7.96 g (77.99 mmol) of glacial acetic acid were added. After the addition was complete, the reaction was carried out at 80 °C. Night; the reaction solution was concentrated, 100 ml of saturated sodium carbonate solution was added, and the mixture was stirred at room temperature and extracted three times with EA (40 ml * 3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The EA / PE ratio was 1:100 and passed through a fast column to obtain a white solid. The white solid was placed in a 50 ml single-necked flask, 5 ml of methanol and 5 ml of water were added, and 0.90 g (22.48 mmol) of sodium hydroxide was added while stirring at room temperature. The mixture was refluxed for 6 h. The reaction solution was poured into ice water and stirred until it returned to room temperature. The solid was filtered, dried, and 4.1 g of white solid was obtained, with a yield of 68.83%.

[0671] Synthesis of TollB-7C-155

[0672] 200 mg (0.75 mmol) of 6-bromo-4-trifluoromethyl-1H-indazole, 231 mg (0.91 mmol) of quinoline 5-boronic acid pinacol ester, 31 mg (0.038 mmol) of PdCl2(dppf)CH2Cl2, and 20 ml of dioxane were added to a 50 ml single-necked flask. 160 mg (1.51 mmol) of sodium carbonate and 4 ml of water were added to a 10 ml centrifuge tube and dissolved at room temperature before being added to the reaction flask. The reaction mixture was reacted overnight at 80 °C under nitrogen protection. The reaction solution was loaded onto a column using a dry method, with a DCM / MeOH ratio of 200:1, yielding 180 mg of a colorless solid (76.14% yield).

[0673] The characterization parameters of each compound are shown in Table 1 below:

[0674]

[0675]

[0676]

[0677]

[0678]

[0679]

[0680] "-" indicates: Not detected

[0681] II. Pharmacological Activity Testing

[0682] Pharmacological Activity Example 1: Bioactivity Test of Small Molecule (Inhibitory Effect on TLR7)

[0683] HEK-Blue hTLR7 cells were cultured in DMEM medium supplemented with 10% fetal bovine serum, penicillin (50 U / mL), streptomycin (50 mg / mL), 100 mg / mL Normocin, and 5 mg / mL blasticidin. 50,000 HEK-Blue hTLR7 cells per well were placed in 96-well plates and cultured in fresh, serum-free DMEM medium. Cells were treated with 1 μg / mL R848 (a TLR7 activator) and the specified concentration of the corresponding compound, and incubated at 37°C and 5% CO2 for 24 hours. 50 μL of supernatant from each well was transferred to a new 96-well plate, and 50 μL of Quanti-Blue was added to each well. The plates were incubated at 37°C in the dark until a clear color change was observed (approximately 30 minutes). The absorbance was measured at 620 nm using a multi-plate reader. Finally, Prism software was used for plotting and data processing to determine the IC50. 50 (Half-inhibition concentration) numerical results. When normalizing the data, cells treated solely with R848 were considered 100% active, and untreated cells (i.e., without any modulators) were considered 0% active. The experimental results are shown in Table 2 below:

[0684] Table 2:

[0685]

[0686]

[0687] Pharmacological Activity Example 2: Specific Inhibitory Effect of Small Molecules on TLR7

[0688] HEK-Blue hTLR7 and HEK-Blue hTLR8 cells were cultured in DMEM medium supplemented with 10% fetal bovine serum, penicillin (50 U / mL), streptomycin (50 mg / mL), 100 mg / mL Normocin, and 5 mg / mL blasticidin. HEK-Blue hTLR7 cells (50,000 cells / well) or HEK-Blue hTLR8 cells (50,000 cells / well) were placed in 96-well plates and cultured in fresh, serum-free DMEM medium. Cells were treated with 1 μg / mL R848 (an activator of TLR7 and TLR8) and the corresponding compounds at specified concentrations, and incubated at 37°C and 5% CO2 for 24 hours. Transfer 50 μL of supernatant from each well to a new 96-well plate. Add 50 μL of Quanti-Blue to each well of the new 96-well plate and incubate at 37°C in the dark until a clear color change occurs (approximately 30 minutes). Measure the absorbance at 620 nm using a multi-microplate reader. Finally, use Prism software for plotting and data processing to determine the IC50. 50 (Half-inhibition concentration) numerical results. When normalizing the data, cells treated solely with R848 were considered 100% activity, and untreated cells (i.e., without any modulators) were considered 0% activity. Results are as follows... Figure 1 As shown.

[0689] The preferred embodiments of the present invention have been described above, but are not intended to limit the invention. Those skilled in the art can make modifications and variations to the embodiments disclosed herein without departing from the scope and spirit of the invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, R1 is selected from H, D, halogen, C1-C15 alkyl, halogenated C1-C15 alkyl, nitro, cyano, -C(O)OR a -OC(O)R a -C(O)NR a R a '、-NR a 'C(O)R a -S(O)2R a -OR a -SR a ; R2, R3, R4, and R5 may be the same or different, and each may be independently selected from: H, D, halogen, hydroxyl, carboxyl, nitro, cyano, C1-C15 alkyl, halo-C1-C15 alkyl, C1-C15 alkoxy, halo-C1-C15 alkoxy, hydroxyl-substituted C1-C15 alkyl, and C1-C6 alkoxy-substituted C1-C15 alkyl. Ar is selected from one of the following structures: X1 is selected from: N or CR 11 ; X2 is selected from: N or CR 12 ; X3 is selected from: N or CR 13 ; X4 is selected from: N or CR 14 ; X5 is selected from: N or CR 15 ; R 11 R 12 R 13 R 14 R 15 The same or different, each independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -L1-R s -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c Or R 11 R 12 R 13 R 14 R 15 Any two adjacent connections in the loop form a substituted or unsubstituted ring; R 16 R 17 R 18 R 19 The same or different, each independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -L1-Rs, -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c ; n1 is selected from: 1, 2, 3 or 4; n2 is selected from: 1, 2, or 3; n3 is selected from: 1, 2, 3, 4, 5, or 6; R is selected from: H, D, substituted or unsubstituted C1-C15 alkyl groups, -C(O)R b -C(O)OR b -S(O)2R b R c -S(O)2NR b R c -L1-R s ; R 20 Selected from: H, D, substituted or unsubstituted C1-C6 alkyl groups, -C(O)R b -C(O)NR b R c ; R a R a 'Identical or different, independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl; R b R c Same or different, independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl, -L1-R s ; L1 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups; L2 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups; R s Selected from substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted 5-15 heterocyclic alkyl, and substituted or unsubstituted 5-20 heteroaryl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R a R a 'Same or different, independently selected from: H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, 2,2,2-trifluoroethyl.

3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The Choose one of the following structures:

4. The compound of formula (I) according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, characterized in that, R 11 R 12 R 13 R 14 R 15 Whether identical or different, each is independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, C1-C15 alkyl, halo-C1-C15 alkyl, hydroxy-substituted C1-C15 alkyl, C1-C4 alkoxy-substituted C1-C15 alkyl, -L1-R s -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c Or R 11 R 12 R 13 R 14 R 15 Any two adjacent connections in R form a substituted or unsubstituted ring; b R c The same or different, independently selected from: H, D, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C4 alkoxy-substituted C1-C6 alkyl, -L1-R s .

5. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, L1 is selected from single bonds, -(CR n R m ) m -, R n R m The same or different, each independently selected from: H, D, C1-C4 alkyl; m selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; L2 selected from single bond, -(CR p R q ) p -, R p R q The same or different, each independently selected from: H, D, C1-C4 alkyl; p selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

6. The compound of formula (I) according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, characterized in that, R 11 R 12 R 13 R 14 R 15 The same or different, each independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, mercapto, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, C1-C4 alkoxy-substituted C1-C6 alkyl, -OC1-C6 alkyl, -SC1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)Ph, -C(O)OC1-C6 alkyl, -C(O)OPh, -NHC(O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -NHC(O)OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH2.

7. The compound of formula (I) according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, characterized in that, R 11 R 12 R 13 R 14 R 15 One, two, three or more are selected from: -R s C1-C6 alkylene-R s -OR s -OC1-C6 alkylene-R s -C1-C6 alkylene-OR s -C1-C6 alkylene OC1-C6 alkylene-R s -SR s -SC1-C6 alkylene-R s -C1-C6 alkylene-SR s -C1-C6 alkylene SC1-C6 alkylene-R s -NH-R s -N(C1-C6 alkyl)-R s -NH-C1-C6 alkylene-R s -N(C1-C6 alkyl)-C1-C6 alkylene-R s -C1-C6 alkylene-NH-R s -C1-C6 alkylene-N(C1-C6 alkyl)-R s -C1-C6 alkylene-NH-C1-C6 alkylene-R s -C1-C6 alkylene-N(C1-C6 alkyl)-C1-C6 alkylene-R s -S(O)2-C1-C6 alkylene-R s The remainder are independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, mercapto, amino, C1-C6 alkyl, halo-C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, -OC1-C6 alkyl, -SC1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)Ph, -C(O)OC1-C6 alkyl, -C(O)OPh, -NHC(O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -NHC(O)OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH2; Preferred, R 11 R 12 R 13 R 14 R 15 At most one of them is selected from: -R s C1-C6 alkylene-R s -OR s -OC1-C6 alkylene-R s -C1-C6 alkylene-OR s -C1-C6 alkylene OC1-C6 alkylene-R s -SR s -SC1-C6 alkylene-R s -C1-C6 alkylene-SR s -C1-C6 alkylene SC1-C6 alkylene-R s -NH-R s -N(C1-C6 alkyl)-R s -NH-C1-C6 alkylene-R s -N(C1-C6 alkyl)-C1-C6 alkylene-R s -C1-C6 alkylene-NH-R s -C1-C6 alkylene-N(C1-C6 alkyl)-R s -C1-C6 alkylene-NH-C1-C6 alkylene-R s -C1-C6 alkylene-N(C1-C6 alkyl)-C1-C6 alkylene-R s -S(O)2-C1-C6 alkylene-R s The remainder are independently selected from: H, D, fluorine, chlorine, bromine, iodine, cyano, nitro, hydroxyl, mercapto, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, -OC1-C6 alkyl, -SC1-C6 alkyl, -C(O)C1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)Ph, -C(O)OC1-C6 alkyl, -C(O)OPh, -NHC(O)C1-C6 alkyl, -C(O)NHC1-C6 alkyl, -NHC(O)OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH2.

8. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R s Selected from substituted or unsubstituted: phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, aziridine, pyrrolidine, pyrazolidine, imidazolyl, tetrahydrooxazolyl, tetrahydrothiazolyl, tetrahydroisooxazolyl, tetrahydroisothiazolyl, morpholinyl, thiomorpholinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxolinyl, quinazolinyl, triazolyl, pyrazolyl, pyrrolyl, imidazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, adamantyl, quininecycloyl; Preferred, R s Selected from one of the following structures, substituted or unsubstituted: R 21 R 22 Whether identical or different, each is independently selected from: H, D, C1-C6 alkyl, -C(O)R d -C(O)NR d R e -S(O)2R d -S(O)2NR d R e ; R d R e The same or different, independently selected from: H, D, substituted or unsubstituted C1-C6 alkyl.

9. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 16 R 17 R 18 R 19 Selected from: H, D, halogen, hydroxyl, C1-C4 alkyl, halo-C1-C4 alkyl, C1-4 alkoxy; R selected from H, D, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, -C1-C6 alkylene-R s R s ;R 20 Selected from: H, D, C1-C4 alkyl groups.

10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R 11 R 12 R 13 R 14 R 15 Any two adjacent carbon atoms in the ring form substituted or unsubstituted rings together with the carbon atoms they are attached to: imidazolidine-2-one ring, pyrazole ring, pyrrole ring, imidazolium ring, thiophene ring, furan ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring; Preferably, the Choose one of the following structures: Among them, R 21 R 22 Whether identical or different, each is independently selected from: H, D, C1-C6 alkyl, -C(O)R d -C(O)NR d R e -S(O)2R d -S(O)2NR d R e ; R 23 Whether identical or different, each is independently selected from: H, D, C1-C6 alkyl, -C(O)R d -C(O)NR d R e -S(O)2R d -S(O)2NR d R e -L1-R s ; R d R e The same or different, independently selected from: H, D, substituted or unsubstituted C1-C6 alkyl; R 31 The same or different, each independently selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -L1-R s -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c .

11. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Ar is selected from one of the following structures:

12. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from:

13. A compound of formula (II) or a pharmaceutically acceptable salt thereof: in, R 17 Selected from: H, D, halogen, cyano, nitro, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C2-C15 alkynyl, -L1-Rs, -L2OR b -L2SR b -L2C(O)R b -L2C(O)OR b -L2OC(O)R b -L2C(O)NR b R c -L2OC(O)NR b R c -L2NR b C(O)R c -L2NR b C(O)OR c -L2NR b R c -L2S(O)2R b R c -L2S(O)2NR b R c -L2NR b S(O)2R c ; n2 is selected from: 1, 2, or 3; R b R c Same or different, independently selected from: H, D, substituted or unsubstituted C1-C15 alkyl, -L1-R s ; L1 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups; L2 is selected from single-bonded, substituted or unsubstituted C1-C15 alkylene groups; R s Selected from substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted 5-15 heterocyclic alkyl, and substituted or unsubstituted 5-20 heteroaryl; Ar1 is selected from: substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C6-C25 aryl, substituted or unsubstituted 5-15 heterocyclic alkyl, substituted or unsubstituted 5-20 heteroaryl; Preferably, Ar1 is selected from substituted or unsubstituted: phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, azacyclobutane, tetrahydropyrroleyl, tetrahydropyrazolyl, tetrahydroimidazolyl, morpholinyl, pyridinyl, pyrimidinyl, quinolinyl, quinoxalolinyl, quinazolinyl, triazolyl, pyrazolyl, pyrroleyl, furanyl, thiophenyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl.

14. The compound of formula (II) according to claim 13, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is selected from:

15. A pharmaceutical composition comprising at least one of a compound of formula (I) according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, and / or a compound of formula (II) according to any one of claims 13-14 or a pharmaceutically acceptable salt thereof.

16. Use of the compound of formula (I) according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, the compound of formula (II) according to any one of claims 13-14 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating TLR7-dependent immune responses; preferably, the immune response is related to an autoimmune disease or an inflammatory disease.

17. Use of the compound of formula (I) according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, the compound of formula (II) according to any one of claims 13-14 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating autoimmune diseases.

18. The use according to claim 16 or 17, characterized in that, The autoimmune diseases mentioned are selected from: arthritis caused by autoimmunity, autoimmune pancreatitis, mixed connective tissue disease, systemic lupus erythematosus, antiphospholipid syndrome, irritable bowel syndrome, type I diabetes, Sjögren's syndrome, scleroderma, multiple sclerosis, autoimmune hepatitis, Still's disease, Crohn's disease, ulcerative colitis, polymyositis, glomerulonephritis, sclerosing cholangitis, autoimmune skin diseases, uveitis, pernicious anemia, hypoparathyroidism, polyangiitis overlap syndrome, Kawasaki disease, sarcoidosis, hypopituitarism, and cold syndrome; Alternatively, the autoimmune disease may be associated with RNA-containing immune complexes.

19. A method for preparing a compound of formula (I) according to any one of claims 1-12, wherein the compound is selected from: Method 1: Compound (A) reacts with compound (B) to produce compound (I); or Method 2: Compound (C) reacts with compound (D) to produce compound (I); in, Xa is selected from halogens, preferably chlorine, bromine, or iodine; M is selected from: -B(OH)2, The definitions of R1-R5 and Ar are as described in any one of claims 1-12.

20. A method for preparing a compound of formula (II) as described in any one of claims 13-14, wherein the compound is selected from: Method 3: Compound (E) reacts with compound (F) to produce compound (II); or Method 4: Compound (G) reacts with compound (H) to produce compound (II); in, Xa is selected from halogens, preferably chlorine, bromine, or iodine; M is selected from: -B(OH)2, Ar1, R 17 L1, R s The definition of n2 is as described in any one of claims 13-14.

Images