CN114057759B

CN114057759B - Fused tetracyclic derivative, preparation method thereof and application thereof in medicines

Info

Publication number: CN114057759B
Application number: CN202110903129.3A
Authority: CN
Inventors: 张晓敏; 费洪博; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-08-07
Filing date: 2021-08-06
Publication date: 2023-05-16
Anticipated expiration: 2041-08-06
Also published as: CN114057759A

Abstract

The present disclosure relates to fused tetracyclic derivatives, methods of preparation and pharmaceutical uses thereof. In particular, the disclosure relates to a fused tetracyclic derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a therapeutic agent, particularly application of the derivative as a TLR7/9 inhibitor and application of the derivative in preparing medicines for treating and/or preventing inflammatory and autoimmune diseases.

Description

Fused tetracyclic derivative, preparation method thereof and application thereof in medicines

Technical Field

The present disclosure belongs to the field of medicine, and relates to a fused tetracyclic derivative, a preparation method thereof and application thereof in medicine. In particular, the disclosure relates to fused tetracyclic derivatives of general formula (I), methods for their preparation, pharmaceutical compositions containing them and their use as TLR7/9 inhibitors in the treatment of inflammatory and autoimmune diseases.

Background

Toll Like Receptors (TLRs) are an evolutionarily conserved class of transmembrane innate immune receptors that are involved in the first line of defense in protecting human health and play an important role in the recognition of pathogen-associated molecular patterns (PAMP) (Kawai, T.et al., nature immunol.,11,2010,373-384). TLRs are expressed in various immune cells and can be classified into two types according to the expression sites: TLRs expressed in cell membranes (TLR 1/2/4/5/6) and TLRs expressed in endosomal membranes (TLR 3/7/8/9) recognize different components and molecules, respectively, in PAMP. Wherein TLR7/8/9 is mainly highly expressed in DC cells and B cells, TLR7/8 mainly recognizes ssRNA, and TLR9 mainly recognizes CpG-DNA. TLR7/8/9 binds its ligand and is activated, binds to the adaptor protein MyD88 in the cytoplasm, initiates NF- κb and IRF pathways, activates DC cells, produces type I interferon and other various inflammatory cytokines; in B cells, TLR7/8/9, in combination with nucleic acids, plays an important role in the production of antinuclear antibodies by B cells, and type I interferons secreted by DC cells also promote further proliferation and activation of such autoimmune B cells, thereby eliciting a series of inflammatory responses.

Systemic Lupus Erythematosus (SLE) belongs to an autoimmune connective tissue disease, and three major classes of clinical first-line drugs for SLE are: hormones, immunosuppressants and antimalarial drugs. In this century, only a new drug belimumab was approved by FDA, but it had moderate and delayed efficacy only in a small proportion of SLE patients (Navarra, s.v. et al Lancet 2011,377,721), and treatment was very limited. Thus, there is an urgent need for new therapies that improve a greater proportion of patient populations and that can be safely administered for long periods of timeIs used. The phenomenon of significantly up-regulated expression of TLR7/9 and type I interferon was found in PBMCs of patients with Systemic Lupus Erythematosus (SLE) (Beverly d.lc et al, mol immunol.,2014, 61:38-43). Mice overexpressing TLR7 have been reported to exacerbate autoimmune diseases and autoinflammation (Santiago-Raber ML, et al, J immunol.,2008, 181:1556-1562), whereas functional inhibition of TLR7/9 can alleviate B6-Fas ^lpr And pathological manifestations of lupus mice such as BXSB (Dlight H.Kono et al, PNAS,2009,106 (29): 12061-12066). Given the close relationship of TLR7/8/9 to antinuclear antibodies and type I interferons, small molecule inhibitors targeting TLR7/8/9 are likely to have potential for treating SLE.

Published TLR7/8/9 inhibitor patent applications include WO2019233941A1, WO2020020800A1, WO2018049089A1, WO2017106607A1, CN109923108A, WO2020048605A1 and the like.

Disclosure of Invention

The object of the present disclosure is to provide a compound represented by general formula (I), or a tautomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

z is selected from the group consisting of O atom, S atom and NH;

y is selected from chemical bond, CR ^2a R ^2b O atom, S atom and NR ^2c ；

Ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁰ selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, heteroalkyl, alkoxy, haloalkyl, deuteroalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, and

l is selected from the group consisting of a bond, an alkylene group, and a heteroalkylene group, wherein each of the alkylene and heteroalkylene groups is independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R is ¹ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

Each R is ² The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, deuteroalkyl, haloalkoxy, deuteroalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

R ^2a and R is ^2b The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, deuteroalkyl, haloalkoxy, deuteroalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

R ^2c selected from the group consisting of a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a deuterated alkyl group, and a hydroxyalkyl group;

each R is ³ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

each R is ⁴ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, and hydroxyalkyl;

each R is ⁵ The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, oxo, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, and aryl Groups and heteroaryl groups, wherein the alkyl, heteroalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each independently optionally substituted with a moiety selected from the group consisting of halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -C (O) OR ⁶ 、-C(O)NR ⁷ R ⁸ 、-NR ⁷ R ⁸ 、-S(O) ₂ R ⁹ One or more substituents of cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

R ⁶ selected from the group consisting of hydrogen atoms, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R ⁷ and R is ⁸ The same or different and are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

or R is ⁷ And R is ⁸ Together with the nitrogen atom to which they are attached, form a heterocyclic group, which is optionally substituted with one or more substituents selected from halogen, alkyl, oxo, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

R ⁹ selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

r is 1 or 2;

k is 0, 1, 2 or 3;

n is 0, 1, 2 or 3;

m is 0, 1 or 2;

p is 0, 1, 2 or 3;

q is 0, 1, 2, 3 or 4; and is also provided with

t is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is an O atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ Is a hydrogen atom or

Ring B, L, R ⁵ And t is as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein:

ring a, ring B, Y, L, R ¹ To R ⁵ R, k, n, m, p, q and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring a is a 3-to 8-membered heterocyclyl; preferably a 4 to 8 membered heterocyclyl; more preferably piperidinyl.

In some preferred embodiments of the present disclosure, the compound of formula (I) or formula (II), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring a is a 4 to 8 membered heterocyclic group containing at least one nitrogen atom;

ring B, Y, L, R ¹ To R ⁵ R, k, n, m, p, q and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Y is an O atom or a bond; preferably a chemical bond.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein r is 1.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

ring B, L, R ¹ To R ⁵ K, n, m, p, q and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the formula (I), formula (II), formula (III) or formulaIV) or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond or CH ₂ 。

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3 to 8 membered heterocyclyl or a 5 to 10 membered heteroaryl; preferably 3 to 6 membered heterocyclyl or 5 to 6 membered heteroaryl; more preferably piperidinyl or imidazolyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein k is 0, 1 or 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; preferably hydrogen, halogen and C _1-6 An alkyl group; more preferably C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, or 3.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; preferably C _1-6 Alkyl or hydrogen atoms; more preferably C _1-6 Alkyl or hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ The same or different, and are each independently a hydrogen atom or a halogen; preferably a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; preferably a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; preferably C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

ring a is a 4 to 8 membered heterocyclic group containing at least one nitrogen atom; y is an O atom or a bond; r is 1; k is 0, 1 or 2; l is a bond or CH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Ring B is a 3 to 8 membered heterocyclyl or a 5 to 10 membered heteroaryl; r is R ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; n is 0, 1, 2 or 3; r is R ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; m is 0, 1 or 2; r is R ³ The same or different, and are each independently a hydrogen atom or a halogen; p is 0, 1, 2 or 3; r is R ⁴ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; q is 0, 1, 2, 3 or 4; r is R ⁵ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; t is 0, 1, 2, 3 or 4.

In some preferred embodiments of the present disclosure, the compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

ring a is a 4 to 8 membered heterocyclic group containing at least one nitrogen atom; k is 0, 1 or 2; l is a bond or CH ₂ The method comprises the steps of carrying out a first treatment on the surface of the Ring B is a 3 to 6 membered heterocyclyl or a 5 to 6 membered heteroaryl; r is R ¹ Identical or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; n is 0, 1, 2 or 3; r is R ² Identical or different and are each independently C _1-6 Alkyl or hydrogen atoms; m is 0, 1 or 2; r is R ³ The same or different, and are each independently a hydrogen atom; r is R ⁴ The same or different, and are each independently a hydrogen atom; r is R ⁵ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and halogenated C _1-6 An alkyl group; t is 0, 1, 2, 3 or 4.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound of formula (IIIA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ To R ⁴ Y, r, k, n, m, p and q are as defined in formula (III).

Another aspect of the present disclosure relates to a compound of formula (IVA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ to R ⁴ K, n, m, p and q are as defined in formula (IV).

Another aspect of the present disclosure relates to a compound of formula (IIIA) or formula (IVA), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein said pharmaceutically acceptable salt is trifluoroacetate or hydrochloride salt.

Table B typical compounds of the present disclosure include, but are not limited to:

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another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

subjecting a compound of formula (IIIA) or a pharmaceutically acceptable salt thereof to reductive amination with a compound of formula (IIIB) or a compound of formula (IIIC) to give a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

Wherein:

l is a bond or CH ₂ ；

Ring a, ring B, R ¹ To R ⁵ Y, r, k, n, m, p, q and t are as defined in formula (III).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

subjecting a compound of formula (IVA) or a pharmaceutically acceptable salt thereof to reductive amination with a compound of formula (IIIB) or a compound of formula (IIIC) to give a compound of formula (IV) or a tautomer, racemate, enantiomer, diastereomer or a mixture thereof or a pharmaceutically acceptable salt thereof,

wherein:

l is a bond or CH ₂ ；

Ring B, R ¹ To R ⁵ K, n, m, p, q and t are as defined in formula (IV).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of formula (I), formula (II), formula (III), formula (IV) and table a of the present disclosure, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting TLR7 and/or TLR 9.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting TLR7 or TLR 9.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting TLR7 and TLR 9.

The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of inflammatory or autoimmune diseases. Wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.

The present disclosure further relates to a method of inhibiting TLR7 and/or TLR9 comprising administering to a patient in need thereof an effective inhibiting amount of a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of inhibiting TLR7 or TLR9 comprising administering to a patient in need thereof an effective inhibiting amount of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of inhibiting TLR7 and TLR9 comprising administering to a patient in need thereof an effective inhibiting amount of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a use in a medicament for the treatment and/or prophylaxis of inflammatory or autoimmune diseases comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.

The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in a medicament for inhibiting TLR7 or TLR 9.

The disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) and table a, or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in a medicament for inhibiting TLR7 and TLR 9.

The present disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) and table a or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in a medicament for the treatment and/or prevention of inflammatory or autoimmune diseases; wherein the inflammatory or autoimmune disease is preferably selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.

In view of their activity as selective inhibitors of TLR7 or TLR9, compounds of formula (I), formula (II), formula (III), formula (IV) and table a are useful for the treatment of TLR7 or TLR9 family receptor related diseases, respectively, but are not limited to inflammatory diseases such as crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease; autoimmune diseases such as graves' disease, rheumatoid arthritis, systemic lupus erythema, lupus nephritis, cutaneous lupus, psoriasis; autoinflammatory diseases including cyclic syndrome associated with Cryopyrin (CAPS), cyclic syndrome associated with TNF Receptors (TRAPS), familial Mediterranean Fever (FMF), adult stele disease, systemic onset juvenile idiopathic arthritis, gout, gouty arthritis; metabolic diseases including type 2 diabetes, atherosclerosis, myocardial infarction; destructive bone disorders such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-related bone disorders; proliferative disorders such as acute myelogenous leukemia, chronic myelogenous leukemia; angiogenic disorders, such as those including solid tumors, ocular neovascularization, and infantile hemangiomas; infectious diseases such as sepsis, septic shock, and shigellosis; neurodegenerative diseases such as Alzheimer's disease, parkinson's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury, neoplastic diseases and viral diseases such as metastatic melanoma, kaposi's sarcoma, multiple myeloma, and HIV infection and CMV retinitis, AIDS.

More specifically, specific conditions or diseases that may be treated with the compounds of the present disclosure include, but are not limited to, pancreatitis (acute or chronic), asthma, allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythema, scleroderma, chronic thyroiditis, graves 'disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, crohn's disease, psoriasis, graft versus host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, reiter's syndrome (Reiter's syndrome), gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory diseases, silicosis, pulmonary sarcoidosis, bone resorption diseases, allograft rejection, fever and myalgia caused by infection, cachexia secondary to infection, keloid formation, scar tissue formation, ulcerative colitis, pyresis (pyresis), influenza, osteoporosis, osteoarthritis, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; cerebral ischemia or neurodegenerative diseases caused by Alzheimer's disease, parkinson's disease, traumatic injury; angiogenic disorders including solid tumors, ocular neovascularization, and infantile hemangiomas; viral diseases including acute hepatitis infection (including hepatitis a, hepatitis b and hepatitis c), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; ischemia in stroke, myocardial ischemia, heart attack, organ hypoxia, vascular proliferation, heart and kidney reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthase-2, and pemphigus vulgaris. Preferred methods of treatment are those in which the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis and pemphigus vulgaris. Alternatively preferred is a method of treatment wherein the condition is ischemia reperfusion injury, which is cerebral ischemia reperfusion injury caused by stroke or myocardial ischemia reperfusion injury caused by myocardial infarction. In another preferred method of treatment, the condition is multiple myeloma.

The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, troches or syrups.

As a general guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of the active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

The compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroalkyl" refers to one or more-CH's in an alkyl group ₂ -substituted with a heteroatom selected from N, O, S and S (O); wherein said alkyl is as defined above; the heteroalkyl group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently optionally substituted with one or more substituents selected from the group consisting of D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkylene group containing from 1 to 12 (e.g., 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably containing from 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH) ₂ (-), 1-ethylene (-CH (CH) ₃ ) (-), 1, 2-ethylene (-CH) ₂ CH ₂ ) -, 1-propylene (-CH (CH) ₂ CH ₃ ) (-), 1, 2-propylene (-CH) ₂ CH(CH ₃ ) (-), 1, 3-propylene (-CH) ₂ CH ₂ CH ₂ (-), 1, 4-butylene (-CH) ₂ CH ₂ CH ₂ CH ₂ (-), etc. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

The term "heteroalkylene" refers to one or more-CH's in an alkylene group ₂ Is selected from N, O, S, S (O) and S (O) ₂ Is substituted by a heteroatom of (2); wherein the alkylene is as defined above; the heteroalkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently optionally substituted with one or more substituents selected from the group consisting of D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from the group consisting of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms (i.e., 3 to 12 membered cycloalkyl), preferably comprising 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl), more preferably comprising 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered, monocyclic, polycyclic group sharing one carbon atom (referred to as the spiro atom) between the monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered, mono-spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused ring alkyl" refers to 5 to 20 membered, all carbon polycyclic groups in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The condensed ring alkyl groups may be classified as a double ring, triple ring, tetra ring or polycyclic depending on the number of constituent rings, preferably a double ring or triple ring, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered, and the like. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly attached, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include

Etc.; preferably->

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl) wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from the group consisting of D atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms (i.e., a 3 to 20 membered heterocyclyl) in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), but excluding the ring portions of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably containing 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms (i.e., 3 to 12 membered heterocyclyl), 1 to 4 of which (e.g., 1,2,3, and 4) are heteroatoms; more preferably from 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) ring atoms (i.e., 3 to 8 membered heterocyclyl), wherein 1-3 is a heteroatom (e.g., 1,2, and 3); more preferably from 4 to 8 ring atoms (i.e., 4 to 8 membered heterocyclyl); more preferably 3 to 6 ring atoms (i.e., 3 to 6 membered heterocyclyl) of which 1-3 are heteroatoms; most preferably contain 5 or 6 ring atoms (i.e., a 5-membered heterocyclic group or a 6-membered heterocyclic group), 1 to 3 of which are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) therebetween, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, wherein one or more ring atoms are selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e. form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

the heterocyclyl ring includes heterocyclyl (including monocyclic, spiro, fused and bridged heterocyclic rings) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:

etc.

The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (fused polycyclic being a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9, or 10 membered), more preferably 5 or 6 membered, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, and the substituents are preferably independently optionally one or more substituents selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived from the removal of one hydrogen atom from the parent ring atom, or residues derived from the removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene".

In the chemical structure of the compounds of the present disclosure, the bond

Indicating the unspecified configuration, i.e.the bond +.>

Can be +.>

Or->

Or at the same time contain->

And->

Two configurations.

The term "amino protecting group" is intended to mean an amino group that is protected by an easily removable group in order to keep the amino group unchanged when the reaction is carried out at other positions of the molecule. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro. The amino protecting group is preferably t-butoxycarbonyl.

The term "hydroxy protecting group" is a suitable group known in the art for protecting hydroxy groups, see literature ("Protective Groups in Organic Synthesis", 5) ^Th Ed.T.W.Greene&P.g.m.wuts). As an example, preferably, the hydroxyl protecting group may be (C _1-10 Alkyl or aryl radicals ₃ Silyl groups, for example: triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and the like; may be C _1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 Alkoxy substituted C _1-6 Alkyl-or phenyl-substituted C _1-6 Alkyl, most preferably C _1-4 Alkoxy substituted C _1-4 Alkyl groups such as: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, and the like; may be (C) _1-10 Alkyl or aryl) acyl groups, for example: formyl, acetyl, benzoyl, p-nitrobenzoyl, and the like; may be (C) _1-6 Alkyl or C _6-10 Aryl) sulfonyl; may also be (C) _1-6 Alkoxy or C _6-10 Aryloxy) carbonyl.

The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, where heterocyclyl and alkyl are as defined above.

The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

The term "cycloalkyloxy" refers to a cycloalkyl-O-group, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S-, wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" refers to "=o".

The term "carbonyl" refers to c=o.

The term "carboxy" refers to-C (O) OH.

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

Compounds of the present disclosure include isotopic derivatives thereof. The term "isotopically-enriched derivative" refers to a compound that differs in structure only in the presence of one or more isotopically-enriched atoms. For example, with the structures of the present disclosure, replacement of hydrogen with "deuterium" or "tritium", or with ¹⁸ F-fluorine labeling [ ] ¹⁸ F isotope) instead of fluorine, or with ¹¹ C-， ¹³ C-, or ¹⁴ C-enriched carbon ¹¹ C-， ¹³ C-, or ¹⁴ C-carbon labeling; ¹¹ C-， ¹³ c-, or ¹⁴ C-isotopes) are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as diagnostic imaging tracers in vivo for diseases, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. Wherein each available hydrogen atom of the deuterated form of the compound attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds. Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, tridentate borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterated compounds generally retain activity comparable to non-deuterated compounds and may achieve better metabolic stability when deuterated at certain specific sites, thus achieving certain therapeutic advantages.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

"substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. The person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present disclosure which are safe and effective when used in a mammal, and which possess the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic and organic acids.

The term "therapeutically and/or prophylactically effective amount" with respect to a drug or pharmacologically active agent means a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

For a drug or pharmacologically active agent, the term "an inhibitory effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but achieves the intended effect. Determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and are effective for the intended use.

As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is shown that the parameter may vary by + -10%, and sometimes more preferably within + -5%. As will be appreciated by those skilled in the art, where parameters are not critical, numerals are generally given for illustration purposes only and are not limiting.

Methods of synthesizing compounds of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical scheme:

scheme one

A method of the present disclosure for the preparation of a compound of formula (III), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

In a first step, the compound of formula (IIID) or a salt thereof is deprotected under acidic conditions to remove the protecting group R ^w Obtaining a compound of formula (IIIA) or a pharmaceutically acceptable salt thereof;

secondly, carrying out reductive amination reaction on the compound shown in the general formula (IIIA) or pharmaceutically acceptable salt thereof and the compound shown in the general formula (IIIB) or the compound shown in the general formula (IIIC) under alkaline conditions in the presence of a reducing agent to obtain a compound shown in the general formula (III) or pharmaceutically acceptable salt thereof;

wherein:

R ^w is an amino protecting group; preferably t-butoxycarbonyl;

l is a bond or CH ₂ ；

Ring a, ring B, Y, R ¹ To R ⁵ R, k, n, m, p, q and t are as defined in formula (III).

Scheme II

A method of the present disclosure for the preparation of a compound of formula (IV), or a tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

in a first step, the compound of formula (IVD) or a salt thereof is deprotected under acidic conditions to give a protecting group R ^w Obtaining a compound of formula (IVA) or a pharmaceutically acceptable salt thereof;

secondly, carrying out reductive amination reaction on the compound shown in the general formula (IVA) or pharmaceutically acceptable salt thereof and the compound shown in the general formula (IIIB) or the compound shown in the general formula (IIIC) under alkaline conditions in the presence of a reducing agent to obtain a compound shown in the general formula (IV) or pharmaceutically acceptable salt thereof;

Wherein:

R ^w is an amino protecting group; preferably t-butoxycarbonyl;

l is a bond or CH ₂ ；

Ring B, R ¹ To R ⁵ K, n, m, p, q and t are as defined in formula (IV).

In the above-described synthetic schemes one and two, the reducing agent includes, but is not limited to, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium acetylborohydride, and the like, preferably sodium cyanoborohydride.

In the above synthesis schemes one and two, the reagent providing the basic condition includes organic bases including but not limited to triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide and inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; sodium acetate is preferred.

In the above synthesis schemes one and two, reagents providing acidic conditions include, but are not limited to, hydrogen chloride, 1, 4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, me ₃ SiCl and TMSOTf, preferably 1, 4-dioxane solutions of trifluoroacetic acid or hydrogen chloride.

The above synthesis schemes one and two are preferably carried out in solvents including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, and mixtures thereof.

Detailed Description

The present disclosure is further described below in conjunction with the examples, which are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 Units of (ppm) are given. NMR was performed using a Bruker AVANCE NEO 500.500M magnetonucleo-magnetic instrument with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290 DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS), waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q actual (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high pressure liquid chromatography.

Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.

High performance liquid chromatography was performed using Waters 2767, waters 2767-SQ detector 2, shimadzu LC-20AP and Gilson-281 preparative chromatographs.

Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.

An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: n-hexane/ethyl acetate system, B: the volume ratio of the methylene dichloride to the methanol is adjusted according to the polarity of the compound, and small amounts of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

9- (1 '-isobutyl- [1,4' -bipiperidin ] -4-yl) -2-methyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxaheptano [4,5-b ] indole 1

First step

2- (5-bromo-1H-indol-3-yl) ethanol 1b

2- (5-bromo-1H-indol-3-yl) acetic acid 1a (2.00 g,7.87mmol, leaching chemical) was dissolved in tetrahydrofuran (20 mL), cooled to 0deg.C, 1.0M lithium aluminum hydride in tetrahydrofuran (15.74 mL,15.74 mmol) was added dropwise, and heated under reflux with stirring for 1 hour. The reaction was quenched by dropwise addition of water (0.59 mL), 15% sodium hydroxide (0.59 mL), water (1.8 mL) in this order under ice-bath, filtered through celite, and concentrated under reduced pressure to give the title product 1b (1.80 g, yield: 95.2%).

MS m/z(ESI):240.1[M+1]。

Second step

5-bromo-3- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indole 1c

Compound 1b (1.80 g,7.50 mmol) was dissolved in N, N-dimethylformamide (20 mL), imidazole (1.02 g,14.98 mmol) was added, tert-butyldimethylchlorosilane (1.69 g,11.21 mmol) was added while stirring at room temperature for 16 hours. Water (30 mL) was added, extracted with ethyl acetate (30 mL. Times.2), concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1c (2.60 g, yield: 97.9%). MS m/z (ESI): 354.2[ M+1].

Third step

4- (3- (2- (((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester 1d

Compound 1c (2.60 g,7.34 mmol), tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (2.27 g,7.34mmol, shao Yuan chemical), bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (520 mg,0.734mmol, shao Yuan chemical), cesium carbonate (4.78 g,14.67 mmol) was dissolved in 1, 4-dioxan (40 mL) and water (4 mL), nitrogen was replaced three times, and reacted at 100℃for 2 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, filtered, concentrated under reduced pressure to give the title product 1d (3.00 g, yield: 89.5%).

MS m/z(ESI):457.2[M+1]。

Fourth step

4- (3- (2- ((tert-Butyldimethylsilanyloxy) ethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 1e

Compound 1d (3.00 g,6.57 mmol) was dissolved in ethyl acetate (30 mL) and methanol (30 mL), and wet palladium on carbon hydrogenation catalyst (140 mg) was added to replace hydrogen three times and reacted at room temperature for 16 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, filtered, concentrated under reduced pressure, to give the title product 1e (950 mg, yield: 31.5%).

MS m/z(ESI):459.3[M+1]。

Fifth step

4- (2-bromo-3- (2- ((tert-butyldimethylsilyl) oxy) ethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 1f

Compound 1e (950 mg,2.07 mmol) was dissolved in 1, 2-dichloroethane (20 mL), and a solution of N-bromosuccinimide (369 mg,2.07 mmol) in 1, 2-dichloroethane (20 mL) was added dropwise thereto under an ice bath, followed by reaction for 10 minutes under an ice bath. Quench with saturated aqueous sodium thiosulfate (50 mL), extract with methylene chloride (50 mL. Times.2), concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 1f (670 mg, yield: 60.2%).

MS m/z(ESI):537.1[M+1]。

Sixth step

5- (methoxymethoxy) -2-methylpyridine 1h

1g (5.00 g,45.82mmol, lechen chemical) of 6-methylpyridin-3-ol was dissolved in methylene chloride (50 mL), N-diisopropylethylamine (8.88 g,68.71 mmol) and bromomethyl methyl ether (7.44 g,59.54 mmol) were added dropwise in this order under ice bath, and the reaction was carried out at room temperature for 16 hours. Saturated aqueous sodium hydrogencarbonate (100 mL) was added to quench, and dichloromethane (50 mL. Times.2) was extracted and concentrated under reduced pressure to give the title product (3.30 g, yield: 47.0%) for 1 h.

MS m/z(ESI):154.1[M+1]。

Seventh step

4-bromo-5- (methoxymethoxy) -2-methylpyridine 1i

Compound 1h (3.30 g,21.54 mmol) was dissolved in tetrahydrofuran (50 mL), nitrogen was replaced three times, 1.3M t-butyllithium (17.4 mL,22.64 mmol) was added dropwise at-78℃and the reaction was stirred for 1 hour, and 1, 2-dibromotetrachloroethane (7.02 g,21.56 mmol) was added dropwise at-78℃and the reaction was stirred for 1 hour. Quench with saturated aqueous ammonium chloride (100 mL), extract with ethyl acetate (50 mL. Times.2), concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 1i (3.80 g, yield: 76.0%).

MS m/z(ESI):232.0[M+1]。

Eighth step

5- (methoxymethoxy) -2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine 1j

Compound 1i (3.80 g,16.37 mmol) and bis-pinacolato diboronate (4.57 g,18.00mmol, shao Yuan chemical) were dissolved in 1, 4-dioxane (100 mL) and potassium acetate (4.81 g,49.08 mmol) and 1,1' -bis (diphenylphosphine) ferrocene palladium dichloride (1.20 g,1.64 mmol) were added. The reaction was carried out at 85℃for 16 hours under nitrogen protection. Filtration over celite and concentration under reduced pressure gave the crude title product 1j (7.00 g) which was used in the next reaction without purification.

MS m/z(ESI):280.1[M+1]。

Ninth step

4- (3- (2- (tert-Butyldimethylsilanyloxy) ethyl) -2- (5- (methoxymethoxy) -2-methylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 1k

The compound 4- (2-bromo-3- (2- ((tert-butyldimethylsilyloxy) ethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 1f (1.04 g,1.93 mmol) and compound 1j (3.24 g,11.61 mmol) were dissolved in 55mL of a mixed solution of 1, 4-dioxane and water (V: V=10:1), and potassium phosphate (3.29 g,15.50 mmol) and 1,1' -bis (diphenylphosphine) ferrocene palladium dichloride (141 mg,0.19 mmol) were added. Under the protection of nitrogen, the reaction is carried out for 5 hours at 80 ℃. The residue obtained was purified by silica gel column chromatography on celite filtration, concentration under reduced pressure, and the resulting residue was purified with eluent system A to give the title product 1k (900 mg, yield: 76.3%).

MS m/z(ESI):610.1[M+1]。

Tenth step

4- (3- (2-hydroxyethyl) -2- (5- (methoxymethoxy) -2-methylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 1l

Compound 1k (300 mg,0.49 mmol) was dissolved in tetrahydrofuran (10 mL) and 1.0M tetrabutylammonium fluoride (1.47 mL,1.47 mmol) was added. The reaction was stirred at room temperature for 16 hours. Water (30 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.2), concentration was performed under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 1l (240 mg, yield: 98%).

MS m/z(ESI):496.2[M+1]。

Eleventh step

4- (3- (2-hydroxyethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -6-methylpyridin-3-ol hydrochloride 1m

Compound 1l (240 mg,0.48 mmol) was dissolved in dichloromethane (6 mL) and 4M hydrogen chloride/1, 4-dioxane solution (7.1 mL,28.4 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to give the crude title product 1m (205 mg, yield: 99%), which was directly subjected to the next reaction without purification. MS m/z (ESI) 352.1[ M+1].

Twelfth step

5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2- (5-hydroxy-2-methylpyridin-4-yl) -3- (2-hydroxyethyl) -1H-indole-1-carboxylic acid tert-butyl ester 1n

The crude compound 1m (205 mg,0.48 mmol) was dissolved in dichloromethane (10 mL), N-diisopropylethylamine (512 mg,3.96 mmol) and di-tert-butyl dicarbonate (432 mg,1.98 mmol) were added dropwise in sequence under ice-bath, and reacted at room temperature for 16 hours. Quench by addition of saturated aqueous sodium bicarbonate (50 mL), extract with dichloromethane (30 mL. Times.2) and concentrate to dryness to give the title product 1n (100 mg, yield: 37.8%).

MS m/z(ESI):552.2[M+1]。

Thirteenth step

9- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2-methyl-6H-pyrido [3',4':2,3] oxyheptano [4,5-b ] indole-12 (7H) -carboxylic acid tert-butyl ester 1o

Compound 1n (90 mg,0.16 mmol) was dissolved in 20mL of a mixed solution of tetrahydrofuran and toluene (V: V=1:1), nitrogen was replaced three times, tri-n-butylphosphine (165 mg,0.82 mmol) was added dropwise at room temperature, and then a toluene solution (10 mL) of azodicarbonyl dipiperidine (206 mg,0.82mmol, leaching chemical) was added dropwise, and the mixture was heated at 60℃and stirred for 1 hour. The residue obtained was concentrated and purified by silica gel column chromatography with eluent system B to give the title product 1o (70 mg, yield: 80.4%).

MS m/z(ESI):534.3[M+1]。

Fourteenth step

2-methyl-9- (piperidin-4-yl) -7, 12-dihydro-6H-pyrido [3',4':2,3] oxaheptyl [4,5-b ] indole trifluoroacetate salt 1p

Compound 1o (70 mg,0.13 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (2 mL) was added. The reaction was stirred at room temperature for 2 hours. Concentration to dryness gave the title product 1p (70 mg, yield: 95.0%) which was used in the next reaction without purification.

MS m/z(ESI):334.1[M+1]。

Fifteenth step

Crude compound 1p (70 mg,0.21 mmol) and 1-isobutylpiperidin-4-one (65 mg,0.42 mmol) were dissolved in 11mL of dichloromethane and methanolTo the mixture (V: v=10:1) was added sodium acetate (69 mg,0.84 mmol), and the mixture was stirred at room temperature for 16 hours. Sodium cyanoborohydride (25 mg,0.42 mmol) was added and the reaction was carried out at room temperature for 48 hours. Quenched with saturated aqueous sodium thiosulfate (50 mL), extracted with dichloromethane (50 mL. Times.2), concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (column Boston Phlex Prep C, 5um 30 x 150mm; mobile phase: water (10 mmol/L NH) ₄ HCO ₃ ): acetonitrile = 45% -65% acetonitrile; gradient elution for 15min, flow rate: 30 mL/min) to give the title product 1 (10 mg, yield: 10.1%).

MS m/z(ESI):473.4[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.65(s,1H),8.29(s,1H),7.40(s,1H),7.32-7.26(m,2H),7.17-7.16(m,1H),4.41-4.39(m,2H),3.33-3.31(m,2H),3.09-3.07(m,2H),2.95-2.93(m,2H),2.61-2.54(m,4H),2.36-2.31(m,3H),2.11-2.00(m,5H),1.90-1.55(m,8H),0.90-0.88(m,6H)。

Example 2

9- (1- ((1H-imidazol-4-yl) methyl) piperidin-4-yl) -2-methyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxaheptano [4,5-b ] indole 2

Compound 1p (660 mg,1.62 mmol) and 4-imidazole formaldehyde (312 mg,3.25 mmol) were dissolved in dichloromethane (10 mL) and methanol (1 mL), sodium acetate (53 mg,6.50 mmol) was added, and stirred at room temperature for 16 hours. Sodium cyanoborohydride (194 mg,3.24 mmol) was added, and the reaction was completed at room temperature for 48 hours. Quenched with saturated aqueous sodium thiosulfate (50 mL), extracted with dichloromethane (50 mL. Times.2), concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (column Boston Phlex Prep C5 um 30 x 150mm; mobile phase: water (10 mmol/L NH) ₄ HCO ₃ ): acetonitrile = 20% -40% acetonitrile; gradient elution for 15min, flow rate: 30 mL/min) to give the title product 2 (18 mg, yield: 2.7%).

MS m/z(ESI):414.2[M+1]。

¹ HNMR(500MHz,CDCl ₃ )δ8.05(s,1H),7.65-7.40(m,2H),7.35-7.20(m,2H),7.15-6.78(m,2H),4.35-4.28(m,2H),3.52(s,2H),3.29-3.22(m,2H),2.98-2.96(m,2H),2.57-2.54(m,1H),2.42(s,3H),2.20-2.08(m,2H),1.94-1.73(m,4H)。

Example 3

9- (1 '-isobutyl- [1,4' -bipiperidin ] -4-yl) -2, 4-dimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxyheptano [4,5-b ] indole 3

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First step

3- (methoxymethoxy) -2, 6-dimethylpyridine 3b

2, 6-Dimethylpyridin-3-ol 3a (2.73 g,22.17mmol, leaching chemical) was dissolved in dichloromethane (40 mL), N-diisopropylethylamine (4.30 g,33.27 mmol) and bromomethyl methyl ether (3.60 g,28.81 mmol) were added dropwise in succession under ice bath and reacted at room temperature for 16 hours. Quench with saturated aqueous sodium bicarbonate (100 mL), extract with dichloromethane (50 mL. Times.2), concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 3b (2.65 g, yield: 71.5%).

MS m/z(ESI):168.1[M+1]。

Second step

4-bromo-3- (methoxymethoxy) -2, 6-dimethylpyridine 3c

Compound 3b (2.65 g,15.85 mmol) was dissolved in tetrahydrofuran (20 mL), nitrogen was replaced three times, 1.3M t-butyllithium (12.8 mL,12.8 mmol) was added dropwise at-78deg.C, the reaction was stirred for 1 hour at-78deg.C, and 1, 2-dibromotetrachloroethane (5.16 g,15.85 mmol) was added dropwise at-78deg.C, the reaction was stirred for 1 hour at-78deg.C. Quench with saturated aqueous ammonium chloride (100 mL), extract with ethyl acetate (50 mL. Times.2), concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 3c (2.30 g, yield: 59.0%).

MS m/z(ESI):246.0[M+1]。

Third step

3- (methoxymethoxy) -2, 6-dimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine 3d

Compound 3c (2.30 g,9.35 mmol) and bispinacol diboronate (2.61 g,10.28 mmol) were dissolved in 1, 4-dioxane (100 mL) and potassium acetate (2.91 g,29.69 mmol) and 1,1' -bis (diphenylphosphine) ferrocene palladium (II) dichloride (683 mg,0.93 mmol) were added. The reaction was carried out at 85℃for 16 hours under nitrogen protection. Filtration over celite and concentration under reduced pressure gave the title product 3d (5.30 g) which was used directly in the next reaction.

Fourth step

4- (3- (2- ((tert-Butyldimethylsilanyloxy) ethyl) -2- (3- (methoxymethoxy) -2, 6-dimethylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 3e

The crude compound 1f (2.50 g,4.65 mmol) and compound 3d (5.45 g,18.59 mmol) were dissolved in 55mL of an aqueous solution of 1, 4-dioxane (V: V=10:1), and potassium phosphate (5.92 g,27.89 mmol) and 1,1' -bis (diphenylphosphine) ferrocene palladium (II) dichloride (340 mg,0.47 mmol) were added. Under the protection of nitrogen, the reaction is carried out for 5 hours at 80 ℃. The residue obtained was purified by silica gel column chromatography on celite, filtration and concentration under reduced pressure to give the title product 3e (1.00 g, yield: 34.5%).

MS m/z(ESI):624.2[M+1]。

Fifth step

4- (3- (2-hydroxyethyl) -2- (3- (methoxymethoxy) -2, 6-dimethylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 3f

To a solution of compound 3e (1.00 g,1.60 mmol) in tetrahydrofuran (10 mL) was added 1.0M tetrabutylammonium fluoride (4.80 mL,4.80 mmol). The reaction was stirred at room temperature for 16 hours. Water (30 mL) was added, extraction was performed with ethyl acetate (30 mL. Times.2), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 3f (460 mg, yield: 56.3%).

MS m/z(ESI):510.3[M+1]。

Sixth step

4- (3- (2-hydroxyethyl) -5- (piperidin-4-yl) -1H-indol-2-yl) -2, 6-dimethylpyridine-3-carbo-l hydrochloride 3g

To a solution of compound 3f (460 mg,0.90 mmol) in dichloromethane (8 mL) was added 4M hydrogen chloride/1, 4 dioxane solution (11.28 mL). The reaction was stirred at room temperature for 1 hour. Concentrated to dryness to give 3g (460 mg, yield: 116.3%) of the title product.

MS m/z(ESI):366.1[M+1]。

Seventh step

5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2- (3-hydroxy-2, 6-dimethylpyridin-4-yl) -3- (2-hydroxyethyl) -1H-indole-1-carboxylic acid tert-butyl ester 3H

3g (460 mg,1.26 mmol) of the compound was dissolved in methylene chloride (20 mL), N-diisopropylethylamine (1.30 mg,10.06 mmol) and di-tert-butyl dicarbonate (1.10 g,5.04 mmol) were successively added dropwise under an ice bath, and the mixture was reacted at room temperature for 16 hours. Quench with saturated aqueous sodium bicarbonate (50 mL), extract with dichloromethane (30 mL. Times.2), concentrate to dryness and purify the resulting residue by silica gel column chromatography on eluent system B to give the title product for 3h (620 mg, yield: 87.1%).

MS m/z(ESI):566.2[M+1]。

Eighth step

4- (2- (3-hydroxy-2, 6-dimethylpyridin-4-yl) -3- (2-hydroxyethyl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 3i

Compound 3h (620 mg,1.10 mmol) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL) and water (10 mL), lithium hydroxide monohydrate (460 mg,10.95 mmol) was added, and the mixture was heated at 60℃for 16 hours with stirring. Concentrated, water (20 mL) and methylene chloride (20 mL) were added, the reaction solution ph=9 was adjusted with 1M hydrochloric acid, the solution was separated, the organic phase was washed with water and saturated sodium chloride successively, the organic phase was concentrated to dryness, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 3i (290 mg, yield: 56.8%).

MS m/z(ESI):466.2[M+1]。

Ninth step

4- (2, 4-dimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxyheptano [4,5-b ] indol-9-yl) piperidine-1-carboxylic acid tert-butyl ester 3j

Compound 3i (290 mg,0.62 mmol) was dissolved in tetrahydrofuran (10 mL) and toluene (10 mL), replaced with nitrogen three times, and tri-n-butylphosphine (630 mg,3.11 mmol) was added dropwise at room temperature followed by azodicarbonyl dipiperidine (319 mg,3.21mmol, lechen chemical) in toluene (10 mL) and heated at 60℃for 1 hour with stirring. The residue obtained was concentrated and purified by silica gel column chromatography with eluent system B to give the title product 3j (1.90 g), the crude product was used in the next reaction without purification.

MS m/z(ESI):448.2[M+1]。

Tenth step

2, 4-dimethyl-9- (piperidin-4-yl) -7, 12-dihydro-6H-pyrido [3',4':2,3] oxaheptano [4,5-b ] indole hydrochloride 3k

To a solution of compound 3j (1.90 g,4.38 mmol) in dichloromethane (20 mL) was added 4M hydrogen chloride/1, 4-dioxane solution (54.8 mL). The reaction was stirred at room temperature for 2 hours. Concentrated to dryness to give the title product 3k (1.80 g, yield: 97.8%).

MS m/z(ESI):348.1[M+1]。

Eleventh step

Compound 3k (900 mg,2.59 mmol) and 1-isobutylpiperidin-4-one (804 mg,5.18 mmol) were dissolved in a mixture solvent of 11mL of dichloromethane and methanol (V: V=10:1), and sodium acetate (850 mg,10.37 mmol) was added thereto and stirred at room temperature for 16 hours. Sodium cyanoborohydride (310 mg,5.18 mmol) was added, and the reaction was completed at room temperature for 48 hours. Quenched with saturated aqueous sodium thiosulfate (50 mL), extracted with dichloromethane (50 mL. Times.2), concentrated under reduced pressure, and purified by HPLC (column: xbridge C18 OBD,5um,30 mm. Times.150 mm; mobile phase: water (10 mmol/L NH) ₄ HCO ₃ ): acetonitrile = 70% -95% acetonitrile; gradient elution for 15min, flow rate: 30 mL/min) to give the title product 3 (10 mg, yield: 0.8%).

MS m/z(ESI):487.3[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.38(s,1H),7.41(s,1H),7.32-7.30(m,1H),7.18-7.14(m,2H),4.43-4.40(m,2H),3.34-3.31(m,2H),3.10-3.06(m,2H),2.96-2.93(m,2H),2.62-2.56(m,1H),2.54(s,3H),2.52(s,3H),2.36-2.30(m,3H),2.06-2.05(m,2H),1.93-1.75(m,9H),1.67-1.62(m,2H),0.89-0.86(m,6H)。

Example 4

9- (1- ((1H-imidazol-4-yl) methyl) piperidin-4-yl) -2, 4-dimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxaheptano [4,5-b ] indole 4

Compound 3k (900 mg,2.59 mmol) and 4-imidazole formaldehyde (498 mg,5.18 mmol) were dissolved in dichloromethane (20 mL) and methanol (1 mL), sodium acetate (850 mg,10.37 mmol) was added, and stirred at room temperature for 16 hours. Sodium cyanoborohydride (310 mg,5.18 mmol) was added and the reaction was completed at room temperature for 48h. Quenched with saturated aqueous sodium thiosulfate (50 mL), extracted with dichloromethane (50 mL. Times.2), the combined organic phases concentrated under reduced pressure and purified by high performance liquid chromatography (column: sharpsil T-C18,5um,30 mm. Times.150 mm; mobile phase: water (10 mmol/L NH) ₄ HCO ₃ ): acetonitrile = 10% -30% acetonitrile; gradient elution for 15min, flow rate: 30 mL/min) to give the title product 4 (20 mg, yield: 1.8%).

MS m/z(ESI):428.3[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ7.59(s,1H),7.32-7.26(m,3H),7.11-7.05(m,2H),4.38-4.36(m,2H),3.83(s,2H),3.31-3.24(m,4H),2.75-2.59(m,3H),2.48(s,3H),2.47(s,3H),2.03-1.93(m,4H)。

Example 5

9- (1 '-isobutyl- [1,4' -bipiperidin ] -4-yl) -2,4, 7-trimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxaheptano [4,5-b ] indole 5

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First step

2- (5-bromo-1H-indol-3-yl) acetic acid methyl ester 5b

Methanol (90 mL) was added to the reaction flask under ice bath, thionyl chloride (5.24 g,44.04 mmol) was added dropwise, a methanol solution (30 mL) of 5-bromoindole-3-acetic acid (10.00 g,39.36mmol, medicine was added dropwise under ice bath, the temperature was naturally raised to room temperature, and the reaction was stirred for 16 hours. The reaction mixture was concentrated to 1/3 of the original volume, water (150 mL), ethyl acetate (100 mL. Times.2) was added thereto, the organic phases were combined and concentrated under reduced pressure to give the crude title product 5b (10.50 g, yield: 99.5%) which was directly subjected to the next reaction without purification.

MS m/z(ESI):268.0[M+1]。

Second step

5-bromo-3- (2-methoxy-2-oxoethyl) -1H-indole-1-carboxylic acid tert-butyl ester 5c

The crude compound 5b (10.50 g,39.16 mmol) was dissolved in dichloromethane (200 mL), and 4-dimethylaminopyridine (4.82 g,39.13 mmol) and di-tert-butyl dicarbonate (17.09 g,78.31 mmol) were reacted at room temperature for 5 minutes. 10% aqueous citric acid (1400 mL) was added, extracted with dichloromethane (200 mL. Times.2), the combined organic phases concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5c (14.40 g, yield: 99.9%).

MS m/z(ESI):311.9[M-55]。

Third step

5-bromo-3- (1-methoxy-1-oxopropan-2-yl) -1H-indole-1-carboxylic acid tert-butyl ester 5d

Compound 5c (14.00 g,38.02 mmol) was dissolved in tetrahydrofuran (150 mL), nitrogen was replaced three times, 1.0M lithium bis (trimethylsilyl) amide (43.7 mL,43.7 mmol) was added dropwise at-78℃and the reaction was stirred at that temperature for 5 hours, methyl iodide (26.98 g,190.08 mmol) was added dropwise at-78℃and the temperature was raised to-10℃and the reaction was stirred for 0.5 hour. Quench by addition of saturated aqueous ammonium chloride (150 mL), extract with ethyl acetate (100 mL. Times.2), concentrate under reduced pressure and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 5d (13.30 g, yield: 91.5%).

MS m/z(ESI):325.9[M-55]。

Fourth step

2- (5-bromo-1H-indol-3-yl) propionic acid methyl ester 5e

Compound 5d (13.30 g,34.79 mmol) was dissolved in dichloromethane (40 mL) and trifluoroacetic acid (20 mL) was added. The reaction was stirred at room temperature for 1 hour. Concentrated to dryness, quenched with saturated aqueous sodium bicarbonate (250 mL), extracted with ethyl acetate (200 mL. Times.2), concentrated under reduced pressure, and the resulting residue purified by silica gel column chromatography with eluent system A to give the title product 5e (9.80 g, yield: 99.8%).

MS m/z(ESI):282.0[M+1]

Fifth step

2- (5-bromo-1H-indol-3-yl) propan-1-ol 5f

Compound 5e (10.10 g,35.80 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to 0deg.C, and a 1.0M solution of lithium aluminum hydride in tetrahydrofuran (71.63 mL,71.63 mmol) was added dropwise and the reaction stirred at room temperature for 16 hours. The reaction was quenched by dropwise addition of water (2.8 mL), 15% sodium hydroxide (2.8 mL), water (8.4 mL) in this order under ice-bath, filtered through celite, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5f (8.90 g, yield: 97.8%).

MS m/z(ESI):253.9[M+1]。

Sixth step

5-bromo-3- (1-methoxy-1-oxopropan-2-yl) -1H-indole-1-carboxylic acid tert-butyl ester 5g

Compound 5f (8.90 g,35.02 mmol) was dissolved in N, N-dimethylformamide (60 mL), imidazole (4.77 g,70.07 mmol) was added, tert-butyldimethylchlorosilane (4.33 g,52.58 mmol) was added while stirring at room temperature for 16 hours. Water (100 mL) was added, extracted with ethyl acetate (100 mL. Times.2), concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 5g (12.70 g, yield: 98.4%).

MS m/z(ESI):366.0[M-1]。

Seventh step

4- (3- (1- ((tert-Butyldimethylsilanyloxy) propan-2-yl) -1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester for 5H

5g (12.70 g,34.48 mmol) of tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (10.66 g,34.48mmol, shao Yuan chemical), bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine ] palladium (II) (2.44 g,3.45mmol, after obtaining a medicine), cesium carbonate (22.47 g,68.96 mmol) were dissolved in 1, 4-dioxan (100 mL) and water (5 mL), nitrogen was replaced three times, and reacted at 100℃for 2 hours. The residue obtained was purified by silica gel column chromatography with eluent system A, filtered, concentrated under reduced pressure, to give the title product for 5h (16.00 g, yield: 98.6%).

MS m/z(ESI):471.1[M+1]。

Eighth step

4- (3- (1- ((tert-Butyldimethylsilanyloxy) propan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 5i

The compound (5 h) (4.70 g,9.98 mmol) was dissolved in ethyl acetate (50 mL) and methanol (50 mL), and a wet palladium on carbon hydrogenation catalyst (106 mg) was added to replace hydrogen three times and reacted at room temperature for 16 hours. The residue obtained was purified by filtration, concentration under reduced pressure and column chromatography on silica gel using an eluent system A to give the title product 5i (4.40 g, yield: 93.2%).

MS m/z(ESI):473.2[M+1]。

Ninth step

4- (2-bromo-3- (1- ((tert-butyldimethylsilyl) oxy) propan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 5j

Compound 5i (4.40 g,9.31 mmol) was dissolved in 1, 2-dichloroethane (100 mL), and a solution of N-bromosuccinimide (1.66 g,9.33 mmol) in 1, 2-dichloroethane (40 mL) was added dropwise thereto under ice-bath, followed by reaction for 10 minutes under ice-bath. Quench with saturated aqueous sodium thiosulfate (100 mL), extract with methylene chloride (100 mL. Times.2), concentrate under reduced pressure, and purify the resulting residue by silica gel column chromatography on eluent system A to give the title product 5j (3.00 g, yield: 58.4%).

MS m/z(ESI):551.1[M+1]。

Tenth step

4- (3- (1- ((tert-Butyldimethylsilanyloxy) propan-2-yl) -2- (3- (methoxymethoxy) -2, 6-dimethylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 5k

Compound 5j (3.00 g,5.44 mmol) and crude compound 3d (10.80 g,36.84 mmol) were dissolved in 200mL of a mixed solution of 1, 4-dioxane and water (V: V=10:1), and potassium phosphate (9.24 g,43.53 mmol) and 1,1' -bis (diphenylphosphine) ferrocene palladium (II) dichloride (390 mg,0.54 mmol) were added. Under the protection of nitrogen, the reaction is carried out for 5 hours at 80 ℃. The residue obtained was purified by silica gel column chromatography on celite, filtration and concentration under reduced pressure to give the title product 5k (2.60 g, yield: 74.9%).

MS m/z(ESI):638.2[M+1]。

Eleventh step

4- (3- (1-hydroxy-propan-2-yl) -2- (3- (methoxymethoxy) -2, 6-dimethylpyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 5l

To a solution of compound 5k (2.60 g,4.08 mmol) in tetrahydrofuran (30 mL) was added 1.0M tetrabutylammonium fluoride (8.17 mL,8.17 mmol). The reaction was stirred at room temperature for 16 hours. Water (60 mL) was added, extraction was performed with ethyl acetate (60 mL. Times.2), the organic phase was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5l (1.10 g, yield: 51.5%).

MS m/z(ESI):524.2[M+1]。

Twelfth step

4- (3- (1-hydroxy-prop-2-yl) -5- (piperidin-4-yl) -1H-indol-2-yl) -2, 6-dimethylpyridine-3-carbo-l hydrochloride 5m

To a solution of compound 5l (1.10 g,2.10 mmol) in dichloromethane (20 mL) was added 4M hydrogen chloride/1, 4 dioxane solution (21 mL). The reaction was stirred at room temperature for 1 hour. Concentrated to dryness to give the title product 5m (950 mg, yield: 99.9%).

MS m/z(ESI):380.1[M+1]。

Thirteenth step

5- (1- (tert-Butoxycarbonyl) piperidin-4-yl) -2- (3-hydroxy-2, 6-dimethylpyridin-4-yl) -3- (1-hydroxypropyl-2-yl) -1H-indole-1-carboxylic acid tert-butyl ester 5n

Compound 5m (950 mg,2.50 mmol) was dissolved in dichloromethane (50 mL), N-diisopropylethylamine (2.59 g,20.03 mmol) and di-tert-butyl dicarbonate (2.19 g,10.01 mmol) were added dropwise in this order under ice-bath, and the reaction was carried out at room temperature for 16 hours. Saturated aqueous sodium bicarbonate (100 mL) was added, quenched, extracted with dichloromethane (60 mL. Times.2), and concentrated to dryness to give the title product 5n (3.70 g), which was used in the next reaction without purification.

MS m/z(ESI):580.2[M+1]。

Fourteenth step

4- (2- (3-hydroxy-2, 6-dimethylpyridin-4-yl) -3- (1-hydroxypropan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester 5o

The crude compound 5n (3.70 g,6.38 mmol) was dissolved in tetrahydrofuran (50 mL), methanol (50 mL) and water (50 mL), lithium hydroxide monohydrate (2.68 mg,63.82 mmol) was added, and the mixture was heated at 60℃for 16 hours with stirring. Concentrated, water (50 mL) and methylene chloride (50 mL) were added, the reaction solution ph=9 was adjusted with 1M hydrochloric acid, the solution was separated, the organic phase was washed with water and saturated sodium chloride, the organic phase was concentrated to dryness, and the obtained residue was purified by silica gel column chromatography with eluent system B to give the title product 5o (890 mg, yield: 29.1%).

MS m/z(ESI):480.2[M+1]。

Fifteenth step

4- (2, 4, 7-trimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxaheptano [4,5-b ] indol-9-yl) piperidine-1-carboxylic acid tert-butyl ester 5p

Compound 5o (780 mg,1.86 mmol) was dissolved in tetrahydrofuran (30 mL) and toluene (30 mL), replaced with nitrogen three times, and tri-n-butylphosphine (1.88 g,9.28 mmol) was added dropwise at room temperature followed by azodicarbonyl dipiperidine (2.41 g,9.28 mmol) in toluene (30 mL) and heated at 60℃for 1 hour. The residue obtained was concentrated and purified by silica gel column chromatography with eluent system A to give the title product 5p (420 mg, yield: 49.0%). MS m/z (ESI) 462.1[ M+1].

Sixteenth step

2,4, 7-trimethyl-9- (piperidin-4-yl) -7, 12-dihydro-6H-pyrido [3',4':2,3] oxaheptyl [4,5-b ] indole trifluoroacetate 5q

To a solution of compound 5p (200 mg,0.45 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The reaction was stirred at room temperature for 2 hours. Concentrated to dryness to give the title product 5q (256 mg, yield: 99.5%). MS m/z (ESI) 362.1[ M+1].

Seventeenth step

Compound 5q (128 mg,0.35 mmol) and 1-isobutylpiperidin-4-one (110 mg,0.71 mmol) were dissolved in a mixture solvent of 11mL of dichloromethane and methanol (V: V=10:1), sodium acetate (116 mg,1.41 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Sodium cyanoborohydride (42 mg,0.70 mmol) was added, and the reaction was completed at room temperature for 16 hours. Quenched with saturated aqueous sodium thiosulfate (50 mL), extracted with dichloromethane (50 mL. Times.2), concentrated under reduced pressure, and purified by high performance liquid chromatography (column Boston Phlex Prep C, 5um 30 x 150mm; mobile phase: water (10 mmol/L NH) ₄ HCO ₃ ): acetonitrile = 52% -72% acetonitrile; gradient elution for 15min, flow rate: 30 mL/min) to give the title product 5 (8 mg, yield: 4.5%).

MS m/z(ESI):501.3[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.55(s,1H),7.48(s,1H),7.32-7.28(m,1H),7.17-7.13(m,2H),4.50-4.47(m,1H),4.06-4.02(m,1H),3.55-3.48(m,1H),3.15-3.07(m,2H),2.99-2.92(m,2H),2.64-2.31(m,11H),2.09-2.04(m,2H),1.96-1.72(m,8H),1.70-1.60(m,2H),1.53-1.51(m,3H),0.90-0.85(m,6H)。

Example 6

9- (1- ((1H-imidazol-4-yl) methyl) piperidin-4-yl) -2,4, 7-trimethyl-7, 12-dihydro-6H-pyrido [3',4':2,3] oxaheptano [4,5-b ] indol 6

Compound 5q (128 mg,0.35 mmol) and 4-imidazole formaldehyde (68 mg,0.71 mmol) were dissolved in dichloromethane (20 mL) and methanol (1 mL), sodium acetate (850 mg,10.37 mmol) was added, and stirred at room temperature for 16 hours. Sodium cyanoborohydride (310 mg,5.18 mmol) and the reaction was completed at room temperature for 16 hours. Quenched with saturated aqueous sodium thiosulfate (50 mL), extracted with dichloromethane (50 mL. Times.2), the combined organic phases concentrated under reduced pressure and purified by HPLC (column Boston Phlex Prep C: 5um 30 x 150mm; mobile phase: water (10 mmol/L NH) ₄ HCO ₃ ): acetonitrile = 25% -45% acetonitrile; gradient elution for 15min, flow rate: 30 mL/min) to give the title product 6 (20 mg, yield: 12.8%).

MS m/z(ESI):442.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ7.58(s,1H),7.41(s,1H),7.32-7.31(m,1H),7.24(s,1H),7.10-7.08(m,1H),6.92(s,1H),4.48-4.45(m,1H),4.01-3.99(m,1H),3.62(s,2H),3.53-3.48(m,1H),3.09-3.07(m,2H),2.75-2.59(m,3H),2.50(s,3H),2.47(s,3H),2.25-2.20(m,2H),1.95-1.79(m,4H),1.50-1.48(m,3H)。

Biological evaluation

The present disclosure is explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1 inhibition of the activation pathway of human TLR7 by the compounds of the present disclosure

Experimental material and instrument

1.HEK-Blue ^TM hTLR7 cells (Invivogen)

2. Raximote (R848/Resiquimod, invivogen)

3. Alkaline phosphatase Detection Medium (Quanti-Blue Detection, invivogen)

4. Blasticidin (Blastidin, invivogen)

5. Bleomycin (Zeocin, invivogen)

6. Neomycin (Normocin, invivogen)

DMEM HIGH sugar Medium (DMEM/HIGH Glucose, GE Healthcare)

8. Fetal bovine serum (Gibco)

9. Phosphate buffer (Shanghai Yuan Pe biotechnology Co., ltd.)

10. Sterile pure water (Shanghai Hengrui homemade)

11.15mL centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well flat bottom cell culture plate (Corning)

14. Constant temperature cell incubator (Thermo scientific)

15. Incubator (Shanghai Yiheng scientific instrument limited company)

PHERAstar FS enzyme label instrument (BMG Labtech)

Step II, experiment

HEK-Blue purchased from Invivogen ^TM hTLR7 cells co-transfected with a human Toll-like receptor 7 (TLR 7) gene and a secreted alkaline phosphatase reporter gene (SEAP) under the control of an IFN- β minimal promoter (minimum promoter) containing 5 NF-kB and AP-1 binding sites into HEK293 cells, upon activation of TLR7 with an agonist, SEAP secretion is induced by downstream NF-kB and AP-1, and upon addition of an antagonistic compound, the pathway is inhibited, SEAP secretion is reduced, and OD620 is measured by the SEAP substrate, thereby assessing the activity of the compound on the TLR7 pathway.

20mM test compound in 100% DMSO was serially diluted to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. Mu.M with 100% DMSO and blank wells 100% DMSO and 20-fold diluted in DMEM/high-sugar medium (complete medium, supra) containing 10% inactivated FBS; diluting R848 to 10 μm with sterile water; 10. Mu.M 848 diluted with 20. Mu.L/well sterile water was added to 96 well cell culture plates, and the above compound diluted in complete medium and 100% DMSO were added to wells containing R848 at 20. Mu.L per well; negative control wells were added with 20 μl of sterile water and 20 μl of 100% dmso diluted in complete medium.

HEK-Blue ^TM hTLR7 cells were cultured in DMEM/high-sugar medium containing 10% inactivated FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin and 100. Mu.g/mL Zeocin. Taking cells which grow well to 70% -80%, discarding the growth medium, adding 5-10mL of PBS preheated at 37 ℃ for washing the cells once, adding 2-5mL of PBS preheated for culturing at 37 ℃ for 1-2 minutes, blowing off the cells by a liquid transfer device, transferring the cells to a 15mL centrifuge tube, counting the cells, and regulating the cell density to 4.8 x 10 by using DMEM high-sugar culture medium containing 10% inactivated FBS ⁵ /mL. Add 160 μL of the cell suspension after density adjustment is added into the 96-well cell culture plate, the final cell number per well is 76500/well, the final concentration of R848 is 1 μM, and the final concentrations of the tested compounds are 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM respectively; the cells were incubated in a 37℃5% CO2 incubator for 20 hours, then 20. Mu.L of the supernatant was taken, 180. Mu.L of the prepared alkaline phosphatase detection medium was added, and after incubation in a 37℃incubator for 120 minutes in the absence of light, the absorbance of OD620 was read by an ELISA reader. The inhibition was calculated using the following formula: inhibition ratio = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100%, an inhibition curve was drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition ratio, and the concentration of the compound when the inhibition ratio reached 50%, i.e., IC, was calculated ₅₀ The values are shown in Table 1.

Table 1 IC of compounds of the present disclosure as measured by the TLR7 pathway in humans ₅₀ Values.

Conclusion: the compounds of the present disclosure have inhibitory effects on the TLR7 pathway.

Test example 2 inhibition of the human TLR8 pathway by the presently disclosed compounds

Experimental material and instrument

1.HEK-Blue ^TM hTLR8 cells (Invivogen)

2. Raximote (R848/Resiquimod, invivogen)

3. Alkaline phosphatase Detection Medium (Quanti-Blue Detection, invivogen)

4. Blasticidin (Blastidin, invivogen)

5. Bleomycin (Zeocin, invivogen)

6. Neomycin (Normocin, invivogen)

DMEM HIGH sugar Medium (DMEM/HIGH Glucose, GE Healthcare)

8. Fetal bovine serum (Gibco)

9. Phosphate buffer (Shanghai Yuan Pe biotechnology Co., ltd.)

10. Sterile pure water (Shanghai Hengrui homemade)

11.15mL centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well flat bottom cell culture plate (Corning)

14. Constant temperature cell incubator (Thermo scientific)

15. Incubator (Shanghai Yiheng scientific instrument limited company)

PHERAstar FS enzyme label instrument (BMG Labtech)

Step II, experiment

HEK-Blue purchased from Invivogen ^TM hTLR8 cells obtained by co-transfecting a human Toll-like receptor 8 (TLR 8) gene and a secreted alkaline phosphatase reporter gene (SEAP) under the control of an IFN- β minimal promoter comprising 5 NF-kB and AP-1 binding sites into HEK293 cells, whereby upon activation of TLR8 with an agonist, SEAP secretion is induced by downstream NF-kB and AP-1, upon addition of an antagonistic compound, the pathway is inhibited and SEAP secretion is reduced, and the activity of the compound on the TLR8 pathway is assessed by measuring OD620 via a SEAP substrate

20mM test compound in 100% DMSO was serially diluted to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. Mu.M with 100% DMSO and blank wells 100% DMSO and 20-fold diluted in DMEM/high-sugar medium (complete medium, supra) containing 10% inactivated FBS; diluting R848 to 60 μm with sterile water; mu.L/well of 60. Mu. M R848 diluted with sterile water was added to 96-well cell culture plates, and the above compound diluted in complete medium and 100% DMSO were added to wells containing R848 at 20. Mu.L/well; negative control wells were added with 20 μl of sterile water and 20 μl of 100% dmso diluted in complete medium.

HEK-Blue ^TM hTLR8 cells were cultured in DMEM/high-sugar medium containing 10% inactivated FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin and 100. Mu.g/mL bleomycin. Taking good growth, and growing to 70-80%Removing the cells, discarding the growth medium, adding 5-10mL of PBS preheated at 37 ℃ for washing the cells once, adding 2-5mL of PBS preheated at 37 ℃ for culturing for 1-2 minutes, blowing off the cells by a liquid-transferer, transferring the cells to a 15mL centrifuge tube, counting the cells, and regulating the cell density to 4.8 x 10 by using DMEM high-sugar medium containing 10% of inactivated FBS ⁵ /mL. Adding 160 mu L of cell suspension with density regulated into the 96-well cell culture plate, wherein the final cell number per well is 76500/well, the final concentration of R848 is 6 mu M, and the final concentrations of the tested compounds are 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM respectively; the cells were placed at 37℃in 5% CO ₂ Culturing in an incubator for 20 hours, then taking 20 mu L of supernatant, adding 180 mu L of prepared alkaline phosphatase detection medium, incubating for 120 minutes at 37 ℃ in a dark place, and reading an OD620 absorbance value by an enzyme-labeled instrument. The inhibition was calculated using the following formula: inhibition ratio = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100%, an inhibition curve was drawn by Graphpad Prism software according to each concentration of the compound and the corresponding inhibition ratio, and the concentration of the compound when the inhibition ratio reached 50%, i.e., IC, was calculated ₅₀ The values are shown in Table 2.

Table 2 IC of compounds of the present disclosure as measured by the TLR8 pathway in humans ₅₀ Values.

Examples numbering	IC ₅₀ (nM)
		1	>10000
2	>10000
		3	>10000
6	>10000

Conclusion: the compounds of the present disclosure have weak inhibition of TLR8 pathway and selectivity for TLR7 and TLR9 pathways.

Test example 3 inhibition of the human TLR9 activation pathway by compounds of the present disclosure

Experimental material and instrument

1.HEK-Blue ^TM hTLR9 cells (Invivogen)

2.CpG ODN2006(Invivogen)

3. Alkaline phosphatase Detection Medium (Quanti-Blue Detection, invivogen)

4. Blasticidin (Blastidin, invivogen)

5. Bleomycin (Zeocin, invivogen)

6. Neomycin (Normocin, invivogen)

DMEM HIGH sugar Medium (DMEM/HIGH Glucose, GE Healthcare)

8. Fetal bovine serum (Gibco)

9. Phosphate buffer (Shanghai Yuan Pe biotechnology Co., ltd.)

10. Sterile pure water (Shanghai Hengrui homemade)

11.15mL centrifuge tube (Corning)

12.96 hole dispensing plate (Corning)

13.96 well flat bottom cell culture plate (Corning)

14. Constant temperature cell incubator (Thermo scientific)

15. Incubator (Shanghai Yiheng scientific instrument limited company)

PHERAstar FS enzyme label instrument (BMG Labtech)

Step II, experiment

HEK-Blue purchased from Invivogen ^TM hTLR9 cells co-transfected with human Toll-like receptor 9 (TLR 9) gene and a secreted alkaline phosphatase reporter gene (SEAP) in HEK293 cellsUnder the control of an IFN- β minimal promoter containing 5 NF-kB and AP-1 binding sites, upon activation of TLR9 with an agonist, SEAP secretion is induced by downstream NF-kB and AP-1, and upon addition of an antagonistic compound, the pathway is inhibited and SEAP secretion is decreased, and OD620 is measured by the SEAP substrate, thereby evaluating the activity of the compound on the TLR9 pathway.

20mM test compound in 100% DMSO was serially diluted to 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.0256. Mu.M with 100% DMSO and blank wells 100% DMSO and 20-fold diluted in DMEM/high-sugar medium (complete medium, supra) containing 10% inactivated FBS; diluting ODN2006 to 10 μm with sterile water; adding 20. Mu.L/well of 10. Mu.M ODN2006 diluted with sterile water to a 96-well cell culture plate, and adding the above compound diluted in complete medium and 100% DMSO to wells containing ODN2006 at 20. Mu.L/well; negative control wells were added with 20 μl of sterile water and 20 μl of 100% dmso diluted in complete medium.

HEK-Blue ^TM hTLR9 cells were cultured in DMEM/high-sugar medium (complete medium, supra) containing 10% FBS, 100. Mu.g/mL neomycin, 10. Mu.g/mL blasticidin and 100. Mu.g/mL bleomycin. Taking cells which grow well and reach 70-80% of full cells, discarding the growth medium, adding 5-10mL of PBS preheated at 37 ℃ for washing the cells once, adding 2-5mL of PBS preheated at 37 ℃ for culturing for 1-2 minutes, blowing off the cells by a liquid transfer device, transferring the cells to a 15mL centrifuge tube, counting the cells, and regulating the cell density to 4.8 x 10 by using DMEM high-sugar medium containing 10% inactivated FBS ⁵ /mL. Adding 160 mu L of cell suspension with density regulated into the 96-well cell culture plate, wherein the final cell number per well is 76500/well, the final ODN2006 concentration is 1 mu M, and the final test compound concentrations are 10000, 2000, 400, 80, 16, 3.2, 0.64 and 0.128nM respectively; the cells were placed at 37℃in 5% CO ₂ The culture was carried out in an incubator for 20 hours, then 20. Mu.L of the supernatant was taken, 180. Mu.L of the prepared alkaline phosphatase detection medium was added, and after incubation in an incubator at 37℃for 15 minutes in the absence of light, the absorbance of OD620 was read by an microplate reader. The inhibition was calculated using the following formula: inhibition = {1- (OD test compound-OD negative control well)/(OD blank well-OD negative control well) } ×100% by Graphpad Prism software according to the concentration and phase of the compound The inhibition curves were plotted against the inhibition rate and the concentration of compound at which the inhibition rate reached 50%, i.e. IC, was calculated ₅₀ The values are shown in Table 3.

Table 3 IC of compounds of the present disclosure as measured by the TLR9 pathway in humans ₅₀ Values.

Examples numbering	IC ₅₀ (nM)
		1	34
2	110
		3	18
4	86
		5	26
6	60

Conclusion: the compounds of the present disclosure have inhibitory effects on the TLR9 pathway.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

z is an O atom;

y is a chemical bond;

ring a is a 3 to 8 membered heterocyclyl;

R ⁰ is that

L is a bond or C _1-6 An alkylene group;

ring B is a 3 to 8 membered heterocyclyl or a 5 to 10 membered heteroaryl;

each R is ¹ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group;

each R is ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group;

each R is ³ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 A hydroxyalkyl group;

each R is ⁴ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, nitro, hydroxy and C _1-6 A hydroxyalkyl group;

each R is ⁵ Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl and C _1-6 A haloalkyl group;

r is 1;

k is 1;

n is 0, 1, 2 or 3;

m is 0, 1 or 2;

p is 0, 1, 2 or 3;

q is 0, 1, 2, 3 or 4; and is also provided with

t is 0, 1, 2, 3 or 4.

2. A compound of formula (I) according to claim 1, wherein ring a is piperidinyl, or a pharmaceutically acceptable salt thereof.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound of formula (III):

wherein:

ring B, Y, L, R ¹ To R ⁵ R, k, n, m, p, q and t are as defined in claim 1.

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound represented by the general formula (IV):

wherein:

ring B, L, R ¹ To R ⁵ K, n, m, p, q and t are as defined in claim 1.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein L is a bond or CH ₂ 。

6. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is a 3 to 6 membered heterocyclyl or a 5 to 6 membered heteroaryl.

7. A compound of formula (I) according to claim 1, wherein ring B is piperidinyl or imidazolyl, or a pharmaceutically acceptable salt thereof.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ Is C _1-6 An alkyl group.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ² Identical or different and are each independently a hydrogen atom or C _1-6 An alkyl group.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ The same or different, and are each independently a hydrogen atom or a halogen.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ Is a hydrogen atom.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl and halogenated C _1-6 An alkyl group.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ Is a hydrogen atom.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁵ Is a hydrogen atom or C _1-6 An alkyl group.

15. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from any one of the following:

16. a compound of formula (IIIA) or a pharmaceutically acceptable salt thereof:

wherein:

R ¹ to R ⁴ Y, r, k, n, m, p and q are as defined in claim 3.

17. The compound of formula (IIIA) or a pharmaceutically acceptable salt thereof according to claim 16 wherein said pharmaceutically acceptable salt is trifluoroacetate or hydrochloride salt.

18. The compound of formula (IIIA) according to claim 16 or 17 or a pharmaceutically acceptable salt thereof selected from any one of the following:

19. a process for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 3, which comprises:

subjecting a compound of formula (IIIA) or a pharmaceutically acceptable salt thereof to reductive amination with a compound of formula (IIIB) or a compound of formula (IIIC) to give a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein:

l is a bond or CH ₂ ；

Ring a, ring B, Y, R ¹ To R ⁵ R, k, n, m, p, q and t are as defined in claim 3.

20. A pharmaceutical composition comprising a compound of general formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

21. Use of a compound of general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 20 in the manufacture of a medicament for inhibiting TLR7 or TLR 9.

22. Use of a compound of general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 20 in the manufacture of a medicament for inhibiting TLR7 and TLR 9.

23. Use of a compound of general formula (I) according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 20 in the manufacture of a medicament for the treatment and/or prophylaxis of inflammatory or autoimmune diseases.

24. The use according to claim 23, wherein the inflammatory or autoimmune disease is selected from Systemic Lupus Erythematosus (SLE), rheumatoid arthritis, multiple Sclerosis (MS) and sjogren's syndrome.