CN117486861A

CN117486861A - Nitrogen-containing heterocyclic compound, preparation method and application thereof

Info

Publication number: CN117486861A
Application number: CN202310959210.2A
Authority: CN
Inventors: 许大强; 郑永勇; 党奎峰; 薛小超; 何旭芝; 王桂敏
Original assignee: Suozhi Biotechnology Zhejiang Co ltd
Current assignee: Suozhi Biotechnology Zhejiang Co ltd
Priority date: 2022-08-01
Filing date: 2023-08-01
Publication date: 2024-02-02
Also published as: WO2024027712A1

Abstract

The invention discloses a nitrogen-containing heterocyclic compound, a preparation method and application thereof. The invention provides a compound shown in a formula II. The compound has better inhibiting activity on TLR 7/8.

Description

Nitrogen-containing heterocyclic compound, preparation method and application thereof

Technical Field

The invention relates to a nitrogen-containing heterocyclic compound, a preparation method and application thereof.

Background

Autoimmune diseases are a series of chronic systemic inflammatory diseases characterized by a deregulation of the immune system, ultimately resulting in a reduced tolerance to self-antigens. Although the exact etiology and pathogenesis of these diseases is still unclear, abnormal processes of the innate and adaptive immune systems have been demonstrated to be involved in the occurrence of these diseases. Studies have shown that Toll-like receptors (TLRs) play an important role in a variety of autoimmune diseases, including sjogren's syndrome, systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, systemic sclerosis and psoriasis, among others (Liu y., et al, clin Rev Allergy immunol.,2014,47,136-147; thwaites R., et al, front immunol.,2014,5).

Toll-like receptors (Toll like receptors, TLR) 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 (PAMPs) (Kawai, t., et al, nature immunol.,2010,11,373-384). TLRs are expressed in various immune cells and can be classified into two types according to the site of expression: TLR expressed in cell membrane (TLR 1/2/4/5/6) and TLR expressed in endosomal membrane (TLR 3/7/8/9) recognize different components and molecules in PAMPs, respectively. 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, and 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.

Lupus erythematosus is a chronic and recurrent autoimmune connective tissue disease that, in addition to causing damage to the patient's skin, involves a variety of internal organs and connective tissue of the patient. Statistics from the U.S. lupus fund show that by now more than 150 tens of thousands of people in the united states have suffered from the disease, and at least 500 tens of thousands of patients worldwide.

Lupus erythematosus can be classified into Systemic Lupus Erythematosus (SLE), discoid lupus erythematosus, subacute cutaneous lupus erythematosus, deep lupus erythematosus, and the like. SLE is the most common, accounting for about 70% of all patients, and is the most serious type of lupus erythematosus, clinical manifestations include a series of symptoms such as pain, rash, fatigue, heat, joint swelling and the like, and lesions are easy to recur, various organs are easily damaged, and more than half of SLE patients can be damaged by permanent organs, so that SLE is also called as 'dead cancer'.

Aiming at systemic lupus erythematosus, the traditional treatment means mainly comprise immunosuppressants, glucocorticoids, antimalarial drugs and the like, but most of the systemic lupus erythematosus is difficult to cure and causes great harm to patients, and effective radical treatment means are still lacking at present.

Thus, there is an urgent need for new therapies that improve a greater proportion of patient populations and that can be used for long periods of time, safely. The phenomenon of significantly up-regulated expression of TLR7/9 and type I interferons was found in PBMC 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), and functional inhibition of TLR7/9 can alleviate pathological manifestations in lupus mice such as B6-Fasl pr and BXSB (Dwight h.kono, et al, PNAS,2009,106 (29): 12061-12066). In addition, TLR8 has been reported to be associated with rheumatoid arthritis (Enevold c., et al, J rheomol, 2010,37,905-910). Surprisingly, however, TLR9 knockout mice alone exhibit worsening of disease symptoms, leading to some problems with regard to the relationship of TLR9 signaling to autoimmune disease. Compounds that modulate TLR7 and/or TLR8 activity and methods of using these compounds may therefore provide substantial therapeutic benefit to a variety of autoimmune patients.

A series of TLR7/8 inhibitors are reported in WO2018005586A1, WO2018026620A1, WO2018047081A1, WO2018049089A1, WO2019028301A1, WO2020086503A1, WO2021067326A1, WO2022022489A1 publications. As a potential target for the treatment of autoimmune diseases, it is necessary to develop more TLR7/8 inhibitors.

Disclosure of Invention

The invention aims to solve the technical problem that the existing TLR7/8 inhibitor has a single structure, and therefore, the invention provides a nitrogen-containing heterocyclic compound, a preparation method and application thereof. The compound has better inhibiting activity on TLR 7/8.

The invention provides a compound shown in a formula II, pharmaceutically acceptable salt thereof, solvate thereof or solvate of pharmaceutically acceptable salt thereof:

wherein R is ¹ Is that

R ^a Independently C ₁ ～C ₆ Alkyl or C ₃ ～C ₆ Cycloalkyl;

x, Y, Z and W are independently-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-C(＝O)-、-NR ^a4 -, =n-, -O-, or-S-;

R ^a1 、R ^a2 、R ^a3 and R is ^a4 Independently hydrogen, C ₁ ～C ₃ Alkyl, halogen or C substituted by 1, 2 or 3 halogen ₁ ～C ₃ An alkyl group;

u is independently N or CH;

is a single bond or a double bond, two adjacent +.>Are not double bonds at the same time;

ring A is 3-10 membered heterocarbocycle or 3-10 membered carbocycle;

L ¹ is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

R ² is hydrogen, hydroxy, cyano, C ₁ ～C ₆ Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-6 membered heteroaryl, (R) ²⁷ )(R ^27a ) N-, is substituted by 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-to 10-membered cycloalkyl, substituted by 1, 2 or 3R ²³ Substituted C ₁ ～C ₆ Alkyl or by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl;

R ²¹ 、R ²² and R is ²³ Independently hydroxy, cyano, oxo, halogen or C ₁ ～C ₆ An alkyl group; r is R ²⁴ Is C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Independently hydrogen or C ₁ ～C ₆ An alkyl group; r is R ²⁵ Is C ₁ ～C ₆ An alkyl group; r is R ²⁶ Independently C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Independently hydrogen, C ₁ ～C ₆ Alkyl, C ₃ ～C ₆ Cycloalkyl, R ²⁷¹ - (c=o) -or C substituted by 1, 2 or 3 halogens ₁ ～C ₆ Alkyl, R ²⁷¹ Independently C ₁ ～C ₆ An alkyl group;

in the 3-10 membered heterocarbocycle, the number of heteroatoms is 1, 2 or 3, and the heteroatoms are one or more selected from N, O and S;

in the 3-10 membered heterocycloalkyl, the number of heteroatoms is independently 1, 2 or 3, and the heteroatoms are independently selected from one or more of N, O and S;

in the 5-6 membered heteroaryl, the number of heteroatoms is independently 1, 2, 3 or 4, and the heteroatoms are independently selected from one or more of N, O and S;

R ³ is C ₁ ～C ₆ Alkyl or C ₃ ～C ₆ Cycloalkyl;

R ^A hydrogen or halogen;

v is C-R ⁴ Or N, R ⁴ Is hydrogen, C ₁ ～C ₃ Alkyl, C ₃ ～C ₆ Cycloalkyl or halogen.

In one embodiment, the compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

Wherein R is ¹ Is that

R ^a Independently C ₁ ～C ₆ Alkyl or C ₃ ～C ₆ Cycloalkyl;

R ^a1 、R ^a2 、R ^a3 and R is ^a4 Independently hydrogen, C ₁ ～C ₃ Alkyl, halogenOr C substituted by 1, 2 or 3 halogens ₁ ～C ₃ An alkyl group;

u is independently N or CH;

ring A is 3-10 membered heterocarbocycle;

L ¹ is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

R ³ is C ₁ ～C ₆ Alkyl or C ₃ ～C ₆ Cycloalkyl;

R ^A hydrogen or halogen;

In one embodiment, in the compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, certain groups in the compound of formula II are defined as follows, and the remaining groups are defined as described in any of the other embodiments (hereinafter referred to as "in one embodiment"):

wherein R is ¹ Is that

R ^a Independently C ₁ ～C ₆ Alkyl or C ₃ ～C ₆ Cycloalkyl;

X、Y、z and W are independently-C (R) ^a1 )(R ^a2 )-、＝CR ^a3 -、-C(＝O)-、-NR ^a4 -, =n-, -O-, or-S-;

u is independently N or CH;

ring A is 3-10 membered heterocarbocycle;

L ¹ Is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

R ²¹ 、R ²² and R is ²³ Independently hydroxy, cyano, oxo, halogen or C ₁ ～C ₆ An alkyl group; r is R ²⁴ Is C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Independently hydrogen or C ₁ ～C ₆ An alkyl group; r is R ²⁵ Is C ₁ ～C ₆ An alkyl group; r is R ²⁶ Independently C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Independently hydrogen, C ₁ ～C ₆ Alkyl, C ₃ ～C ₆ Cycloalkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Independently C ₁ ～C ₆ An alkyl group;

R ³ Is C ₁ ～C ₆ Alkyl or C ₃ ～C ₆ Cycloalkyl;

R ⁴ is hydrogen, C ₁ ～C ₃ Alkyl, C ₃ ～C ₆ Cycloalkyl or halogen.

In one embodiment, R ^a In the above, the C ₁ ～C ₆ Alkyl groups can independently be C ₁ ～C ₃ An alkyl group; and may independently be methyl, ethyl, n-propyl or isopropyl, such as methyl.

In one embodiment, R ^a In the above, the C ₃ ～C ₆ Cycloalkyl groups can independently be C ₃ ～C ₄ Cycloalkyl; and can be independently cyclopropyl.

In one embodiment, R ^a1 、R ^a2 、R ^a3 Or R is ^a4 In the above, the C ₁ ～C ₃ Alkyl groups may independently be methyl groups.

In one embodiment, R ^a1 、R ^a2 、R ^a3 Or R is ^a4 In said C substituted by 1, 2 or 3 halogens ₁ ～C ₃ C in alkyl ₁ ～C ₃ Alkyl groups may independently be methyl groups.

In one embodiment, R ^a1 、R ^a2 、R ^a3 Or R is ^a4 In (2), the halogen may independently be fluorine.

In one embodiment, in ring A, the 3-to 10-membered heterocarbocycle may be a 6-to 8-membered heterocarbocycle.

In one embodiment, in ring a, the 3-to 10-membered heterocarbocycle may be monocyclic or bicyclic; the bicyclic ring may be a spiro ring or a bridged ring, such as a bridged ring.

In one embodiment, the number of heteroatoms in the 3-to 10-membered heterocarbocycle in ring A may be 1 or 2.

In one embodiment, in ring A, the heteroatom in the 3-to 10-membered heterocarbocycle may be N.

In one embodiment, the 3-to 10-membered heterocarbocycle in ring A is, for example

In one embodiment, in ring A, the 3-to 10-membered carbocycle is a 3-to 6-membered carbocycle, such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring, such asWherein the labeled carbon atom represents an S configuration, an R configuration, or a mixture thereof when chiral; the # labelled carbon atom means, in the case of a chiral carbon atom, the S configuration, the R configuration or mixtures thereof, e.g. +.>

In one embodiment, L ¹ Or L ² In the above, the C ₁ ～C ₆ Alkylene groups can independently be C ₁ ～C ₄ An alkylene group; and can independently be methylene, ethylene orThe q-terminal and R ² Is connected with each other.

In one embodiment, R ² In (1)The C is ₁ ～C ₆ Alkyl can be C ₁ ～C ₃ An alkyl group; and can be methyl, ethyl, n-propyl or isopropyl.

In one embodiment, R ² In said quilt 1, 2 or 3R ²³ Substituted C ₁ ～C ₆ C in alkyl ₁ ～C ₆ Alkyl can be C ₁ ～C ₃ An alkyl group; and can be methyl, ethyl, n-propyl or isopropyl.

In one embodiment, R ² Wherein the 3-to 10-membered cycloalkyl group may be a 3-to 6-membered cycloalkyl group; and may be a 3-to 4-membered cycloalkyl group, such as cyclopropyl or cyclobutyl, and cyclopropyl.

In one embodiment, R ² In said quilt 1, 2 or 3R ²² The 3-to 10-membered cycloalkyl group in the substituted 3-to 10-membered cycloalkyl group may be a 3-to 6-membered cycloalkyl group; and may be a 3-to 4-membered cycloalkyl group, such as cyclopropyl or cyclobutyl, and cyclopropyl.

In one embodiment, R ² Wherein the 3-to 10-membered heterocycloalkyl group may be a monocyclic or bicyclic ring; the bicyclic ring may be a spiro ring or a bridged ring, for example the 3-to 10-membered heterocycloalkyl is a monocyclic ring. In one embodiment, R ² In the 3-to 10-membered heterocycloalkyl group, the number of heteroatoms may be 1 or 2.

In one embodiment, R ² In the 3-to 10-membered heterocycloalkyl group, the heteroatom may be independently N or O.

In one embodiment, R ² Wherein the 3-to 10-membered heterocycloalkyl group may be a 3-to 6-membered heterocycloalkyl group; and can be 4-6 membered heterocyclic alkyl; and can also be

In one embodiment, R ² In said quilt 1, 2 or 3R ²¹ The 3-10 membered heterocycloalkyl group in the substituted 3-10 membered heterocycloalkyl group may be monocyclic or bicyclic; the bicyclic ring may be a spiro ring or a bridged ring, for example the 3-to 10-membered heterocycloalkyl is a monocyclic ring.

In one embodiment, R ² In 1, 2 or more of said quilts3R ²¹ The number of heteroatoms in the 3-to 10-membered heterocycloalkyl group in the substituted 3-to 10-membered heterocycloalkyl group may be 1 or 2.

In one embodiment, R ² In said quilt 1, 2 or 3R ²¹ In the 3-to 10-membered heterocycloalkyl group in the substituted 3-to 10-membered heterocycloalkyl group, the heteroatom may be independently N or S.

In one embodiment, R ² In said quilt 1, 2 or 3R ²¹ The 3-10 membered heterocycloalkyl group in the substituted 3-10 membered heterocycloalkyl group may be a 3-6 membered heterocycloalkyl group; and can be 4-6 membered heterocyclic alkyl; and can also be

In one embodiment, R ² In said 3-10 membered heterocycloalkyl and is substituted with 1, 2 or 3R ²¹ The 3-10 membered heterocycloalkyl groups in the substituted 3-10 membered heterocycloalkyl groups are each independently

In one embodiment, R ² In the above, the number of the hetero atoms of the 5-to 6-membered heteroaryl group may be 2.

In one embodiment, R ² In which the 5-to 6-membered heteroaryl group may be

In one embodiment, R ² In said quilt 1, 2 or 3R ²⁶ The number of heteroatoms in the 5-to 6-membered heteroaryl group in the substituted 5-to 6-membered heteroaryl group may be 3 or 4.

In one embodiment, R ² In said quilt 1, 2 or 3R ²⁶ In the 5-to 6-membered heteroaryl group in the substituted 5-to 6-membered heteroaryl group, the heteroatom may be N.

In one embodiment, R ² In the quilt 12 or 3R' s ²⁶ The 5-to 6-membered heteroaryl in the substituted 5-to 6-membered heteroaryl may be

In one embodiment, R ² In said 5-to 6-membered heteroaryl and is substituted with 1, 2 or 3R ²⁶ The 5-to 6-membered heteroaryl groups in the substituted 5-to 6-membered heteroaryl groups are each independently

In one embodiment, R ²¹ In the above, the C ₁ ～C ₆ Alkyl groups can independently be C ₁ ～C ₃ An alkyl group; and may independently be methyl, ethyl, n-propyl or isopropyl, such as methyl.

In one embodiment, R ²³ In (2), the halogen may independently be fluorine.

In one embodiment, R ²⁴ In the above, the C ₁ ～C ₆ Alkyl can be C ₁ ～C ₃ An alkyl group; and may be methyl, ethyl, n-propyl or isopropyl, for example methyl.

In one embodiment, R ²⁴¹ Or R is ^241a In the above, the C ₁ ～C ₆ Alkyl groups can independently be C ₁ ～C ₃ An alkyl group; but also independently methyl, ethyl, n-propyl or isopropyl.

In one embodiment, R ²⁵ In the above, the C ₁ ～C ₆ Alkyl can be C ₁ ～C ₃ An alkyl group; and may be methyl, ethyl, n-propyl or isopropyl, for example methyl.

In one embodiment, R ²⁶ In the above, the C ₁ ～C ₆ Alkyl groups can independently be C ₁ ～C ₃ An alkyl group; and may independently be methyl, ethyl, n-propyl or isopropyl, such as methyl.

In one embodiment, R ²⁷ Or R is ^27a In the above, the C ₁ ～C ₆ Alkyl groups can independently be C ₁ ～C ₃ An alkyl group; and may independently be methyl, ethyl, n-propyl or isopropyl, such as methyl.

In one embodiment, R ²⁷ Or R is ^27a In the above, the C ₃ ～C ₆ Cycloalkyl groups can independently be C ₃ ～C ₄ Cycloalkyl; and can be independently cyclopropyl.

In one embodiment, R ²⁷ Or R is ^27a In, the halogen may be F.

In one embodiment, R ²⁷ Or R is ^27a In said C substituted by 1, 2 or 3 halogens ₁ ～C ₆ C in alkyl ₁ ～C ₆ Alkyl groups can independently be C ₁ ～C ₃ An alkyl group; but also independently ethyl.

In one embodiment, R ²⁷¹ In the above, the C ₁ ～C ₆ Alkyl groups can independently be C ₁ ～C ₃ An alkyl group; and may independently be methyl, ethyl, n-propyl or isopropyl, such as methyl.

In one embodiment, R ³ In the above, the C ₁ ～C ₆ Alkyl can be C ₁ ～C ₃ An alkyl group; and may be methyl, ethyl, n-propyl or isopropyl, such as isopropyl.

In one embodiment, R ³ In the above, the C ₃ ～C ₆ Cycloalkyl can be C ₃ ～C ₄ Cycloalkyl; and can be cyclopropyl.

In one embodiment, R ^A The halogen can be fluorine, chlorine or bromine, and can also be fluorine.

In one embodiment, R ⁴ In the above, the C ₁ ～C ₃ The alkyl group may be methyl, ethyl, n-propyl or isopropyl.

In one embodiment, R ⁴ In the above, the C ₃ ～C ₆ Cycloalkyl can be C ₃ ～C ₄ Cycloalkyl; and can be cyclopropyl.

In one embodiment, R ⁴ In, the halogen may be fluorine.

In one embodiment, R ¹ Is that

Wherein R is ^a Independently C ₁ ～C ₆ Alkyl or C _3-6 Cycloalkyl;

u is independently N or CH;

is a single bond or a double bond, two adjacent +.>Not both double bonds.

In one embodiment, R ¹ Is thatFor example->

In one embodiment, ring A is a 3-to 10-membered heterocarbocycle.

In one embodiment, ring A is a 3-to 10-membered carbocyclic ring.

In one embodiment, L ¹ Is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -.

In one embodiment, L ² Is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -.

In one embodiment, R ² Is hydrogen, hydroxy, cyano, C ₁ ～C ₆ Alkyl, 3-10 membered cycloalkyl, 3-10 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-6 membered heteroaryl, (R) ²⁷ )(R ^27a ) N-, is substituted by 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-to 10-membered cycloalkyl, substituted by 1, 2 or 3R ²³ Substituted C ₁ ～C ₆ Alkyl or by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl;

wherein R is ²¹ 、R ²² And R is ²³ Independently hydroxy, cyano, oxo, halogen or C ₁ ～C ₆ An alkyl group; r is R ²⁴ Is C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Independently hydrogen or C ₁ ～C ₆ An alkyl group; r is R ²⁵ Is C ₁ ～C ₆ An alkyl group; r is R ²⁶ Independently C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Independently hydrogen, C ₁ ～C ₆ Alkyl, C ₃ ～C ₆ Cycloalkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Independently C ₁ ～C ₆ An alkyl group. In one embodiment, R ³ Is C ₁ ～C ₆ Alkyl or C _3-6 Cycloalkyl groups.

In one embodiment, R ⁴ Is hydrogen, C ₁ ～C ₃ Alkyl, C _3-6 Cycloalkyl or halogen.

In one embodiment, R ^A Is hydrogen or halogen.

In one embodiment, R ^A Is halogen.

In one embodiment, R ⁴ Is hydrogen or halogen.

In one embodiment, R ⁴ Is hydrogen.

In one embodiment, R ¹ Is that

R ^a Is C ₁ ～C ₆ An alkyl group;

x, Y and Z are independently-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-NR ^a4 -, -O-, -S-, or = N-;

R ^a1 、R ^a2 、R ^a3 and R is ^a4 Independently hydrogen or C ₁ ～C ₃ An alkyl group;

u is independently N or CH;

ring A is 3-10 membered heterocarbocycle or 3-10 membered carbocycle;

L ¹ is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

R ² is hydrogen, hydroxy, cyano, 3-10 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-6 membered heteroaryl, (R) ²⁷ )(R ^27a ) N-, is substituted by 1, 2 or 3R ²² Substituted 3-to 10-membered cycloalkyl, substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl or substituted with 1, 2 or 3R ²¹ Substituted 3-10 membered heterocycloalkyl;

R ²¹ and R is ²² Independently hydroxy, oxo, cyano, halogen or C ₁ ～C ₆ An alkyl group; r is R ²⁴ Is C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Independently hydrogen; r is R ²⁵ Is C ₁ ～C ₆ An alkyl group; r is R ²⁶ Independently C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Independently hydrogen, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₆ Alkyl, C substituted by 1, 2 or 3 halogens ₁ ～C ₆ Alkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Independently C ₁ ～C ₆ An alkyl group;

in the 3-10 membered heterocarbocycle, the number of heteroatoms is 1 or 2, and the heteroatoms are N;

in the 3-10 membered heterocycloalkyl, the number of the heteroatoms is independently 1 or 2, and the heteroatoms are independently selected from one or more of N, O and S;

in the 5-6 membered heteroaryl, the number of heteroatoms is 2 to 4, and the heteroatoms are independently selected from one or more of N, O and S;

v is C-R ⁴ Or N;

R ^A hydrogen or halogen;

R ³ is C ₁ ～C ₆ An alkyl group;

R ⁴ is hydrogen.

In one embodiment, R ¹ Is that

R ^a Is methyl;

x, Y and Z are independently-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-NR ^a4 -, -O-, -S-, =n-, or-C (=o) -;

u is independently N or CH;

ring A is 3-10 membered heterocarbocycle;

L ¹ is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

in the 5-6 membered heteroaryl, the number of heteroatoms is 2, and the heteroatoms are independently selected from one or more of N, O and S;

v is C-R ⁴ Or N;

R ^A hydrogen or halogen;

R ³ is C ₁ ～C ₆ An alkyl group;

R ⁴ is hydrogen.

In one embodiment, R ¹ Is that

R ^a Is C ₁ ～C ₆ An alkyl group;

x, Y and Z are independently-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-NR ^a4 -or-O-;

u is independently N or CH;

ring A is 3-10 membered heterocarbocycle;

L ¹ is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

R ²¹ and R is ²² Independently oxo, cyano, halogen or C ₁ ～C ₆ An alkyl group; r is R ²⁴ Is C ₁ ～C ₆ Alkyl groupOr (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Independently hydrogen; r is R ²⁵ Is C ₁ ～C ₆ An alkyl group; r is R ²⁶ Independently C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Independently hydrogen, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₆ Alkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Independently C ₁ ～C ₆ An alkyl group;

in the 3-10 membered heterocarbocycle, the number of heteroatoms is 1, and the heteroatoms are N;

R ³ is C ₁ ～C ₆ An alkyl group;

R ⁴ is hydrogen.

In one embodiment, R ¹ Is thatFor example, R ¹ Is->

As another example, R ¹ Is that

In one embodiment, R ^a Is C ₁ ～C ₆ Alkyl groups such as methyl.

In one embodiment, X, Y and Z are independently-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-NR ^a4 -, -O-, -S-, or = N-;

for example, X, Y and Z are independently-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-NR ^a4 -、-O-、-S-、=n-or-C (=o) -;

as another example, X, Y and Z are independently-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-NR ^a4 -or-O-.

In one embodiment, R ^a1 、R ^a2 、R ^a3 And R is ^a4 Independently hydrogen or C ₁ ～C ₃ An alkyl group.

In one embodiment, R ² Is hydrogen, hydroxy, cyano, 3-10 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-6 membered heteroaryl, (R) ²⁷ )(R ^27a ) N-, is substituted by 1, 2 or 3R ²² Substituted 3-to 10-membered cycloalkyl, substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl or substituted with 1, 2 or 3R ²¹ Substituted 3-10 membered heterocycloalkyl.

In one embodiment, R ²¹ And R is ²² Independently hydroxy, oxo, cyano, halogen or C ₁ ～C ₆ An alkyl group; r is R ²⁴ Is C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Independently hydrogen; r is R ²⁵ Is C ₁ ～C ₆ An alkyl group; r is R ²⁶ Independently C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Independently hydrogen, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₆ Alkyl, C substituted by 1, 2 or 3 halogens ₁ ～C ₆ Alkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Independently C ₁ ～C ₆ An alkyl group;

for example, R ²¹ And R is ²² Independently oxo, cyano, halogen or C ₁ ～C ₆ An alkyl group; r is R ²⁴ Is C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Independently hydrogen; r is R ²⁵ Is C ₁ ～C ₆ An alkyl group; r is R ²⁶ Independently C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Independently hydrogen, C ₃ ～C ₆ Cycloalkyl radicals、C ₁ ～C ₆ Alkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Independently C ₁ ～C ₆ An alkyl group.

In one embodiment, the number of heteroatoms in the 5-6 membered heteroaryl is 2, 3 or 4, and the heteroatoms are independently selected from one or more of N, O and S.

In one embodiment, V is C-R ⁴ As another example, N.

In one embodiment, R ^A For example hydrogen, and also for example halogen.

In one embodiment, R ³ Is C ₁ ～C ₆ An alkyl group.

In one embodiment, R ⁴ H.

In one embodiment, R ¹ In,wherein R is ^a Can be C ₁ ～C ₆ Alkyl or C _3-6 Cycloalkyl; x, Y and Z can independently be-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-C(＝O)-、-NR ^a4 -, =n-, -O-, or-S-; r is R ^a1 And R is ^a2 May independently be hydrogen or halogen; r is R ^a3 May be hydrogen or halogen; r is R ^a4 Can be hydrogen, C ₁ ～C ₃ Alkyl or trifluoromethyl.

In one embodiment, R ¹ In,wherein R is ^a Can be C ₁ ～C ₃ Alkyl or C _3-6 Cycloalkyl; x, Y and Z can independently be-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-C(＝O)-、-NR ^a4 -, =n-or-O-; r is R ^a1 And R is ^a2 May independently be hydrogen or fluorine; r is R ^a3 Can be hydrogen or fluorine; r is R ^a4 May be hydrogen, methyl or trifluoromethyl.

In one embodiment, R ¹ In,wherein R is ^a Can be methyl, isopropyl or cyclopropyl; x, Y and Z can independently be-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-C(＝O)-、-NR ^a4 -, =n-or-O-; r is R ^a1 And R is ^a2 May independently be hydrogen or fluorine; r is R ^a3 Can be hydrogen or fluorine; r is R ^a4 May be hydrogen, methyl or trifluoromethyl.

In one embodiment, R ¹ In the above, theCan be->/>

In one embodiment, R ¹ In,wherein X, Y and Z can independently be-C (R ^a1 )(R ^a2 ) -, =n-, -O-, or-S-; r is R ^a1 And R is ^a2 And may independently be hydrogen.

In one embodiment, R ¹ In,wherein X, Y and Z can independently be-C (R ^a1 )(R ^a2 ) -, -O-or-S-; r is R ^a1 And R is ^a2 And may independently be hydrogen.

In one embodiment, R ¹ In,can be->

In one embodiment, R ¹ In,in which X, Y and Z can independently be =cr ^a3 -or-NR ^a4 -；R ^a3 And R is ^a4 Can be independently hydrogen, C ₁ ～C ₃ Alkyl, trifluoromethyl or halogen.

In one embodiment, R ¹ In,can be->

In one embodiment, R ¹ In,wherein X, Y and Z can independently be-C (R ^a1 )(R ^a2 ) -or = CR ^a3 -；R ^a1 、R ^a2 And R is ^a3 Can be independently hydrogen, C ₁ ～C ₃ Alkyl, trifluoromethyl or halogen. />

In one embodiment, R ¹ In,can be->

In one embodiment, R ¹ In,wherein X, Y and Z can independently be-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-C(＝O)-、-NR ^a4 -, =n-, -O-, or-S-; r is R ^a1 And R is ^a2 May independently be hydrogen or halogen; r is R ^a3 Can be hydrogen; r is R ^a4 Can be hydrogen, C ₁ ～C ₃ Alkyl or trifluoromethyl.

In one embodiment, R ¹ In,wherein X, Y and Z can independently be-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-C(＝O)-、-NR ^a4 -, =n-, -O-, or-S-; r is R ^a1 And R is ^a2 May independently be hydrogen or fluorine; r is R ^a3 Can be hydrogen; r is R ^a4 May be hydrogen, methyl or trifluoromethyl.

In one embodiment, R ¹ In,can be->

/>

In one embodiment, R ¹ In,wherein X, Y, Z and W can independently be-C (R ^a1 )(R ^a2 ) -, =n-, -O-, or-S-; r is R ^a1 And R is ^a2 Can independently be hydrogen; r is R ^a Can be C ₁ ～C ₃ An alkyl group.

In one embodiment, R ¹ In,wherein X, Y, Z and W can independently be-C (R ^a1 )(R ^a2 ) -, =n-, -O-, or-S-; r is R ^a1 And R is ^a2 Can independently be hydrogen; r is R ^a Can be methyl.

In one embodiment, R ¹ In,can be->

In one embodiment, R ¹ (may be)/>

In one embodiment, R ¹ (may be)

In one embodiment, R ¹ (may be)/>

In one embodiment, R ¹ In,can be->

In one embodiment, R ¹ Wherein R is ^a Can be C ₁ ～C ₃ Alkyl may be methyl, ethyl, n-propyl or isopropyl, or methyl.

In one embodiment, R ¹ In,can be->

In one embodiment, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -.

In one embodiment, L ¹ May be a single bond.

In one embodiment, L ¹ Is a single bond, methylene, ethylene, - (c=o) -orThe q-terminal and R ² Is connected with each other;

in one embodiment, L ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -.

In one embodiment, L ² May be a single bond.

In one embodiment, L ² Is a single bond, methylene, ethylene, - (c=o) -orThe q-terminal and R ² Is connected with each other;

in one embodiment, L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -.

In one embodiment, ring A may be a 6-to 8-membered heterocarbocycle.

In one embodiment, the number of heteroatoms in ring a may be 1 or 2, and the heteroatoms may be N.

In one embodiment, ring A may be a 6-8 membered heterocarbocycle, wherein the number of heteroatoms may independently be 1 or 2, and the heteroatoms may be N.

In one embodiment, ring A may beWherein the s terminal and L ¹ Is connected with each other.

In one embodiment, R ² Can be hydrogen, 3-10 membered heterocycloalkyl, substituted 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-to 10-membered cycloalkyl or by 1, 2 or 3R ²³ Substituted C ₁ ～C ₆ An alkyl group; r is R ²¹ Can be oxo, R ²² Can be cyano, R ²³ May be halogen.

In one embodiment, R ² Can be hydrogen, 3-6 membered heterocycloalkyl, substituted by 1, 2 or 3R ²¹ Substituted 3-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-to 4-membered cycloalkyl or by 1, 2 or 3R ²³ Substituted C ₁ ～C ₆ An alkyl group; r is R ²¹ Can be oxo, R ²² Can be cyano, R ²³ May be halogen.

In one embodiment, R ² Can be hydrogen, 4-6 membered heterocycloalkyl, substituted with 1, 2 or 3R ²¹ Substituted 4-6 membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 4-membered cycloalkyl or substituted by 1, 2 or 3R ²³ Substituted C ₁ ～C ₃ An alkyl group; r is R ²¹ Can be oxo, R ²² Can be cyano, R ²³ May be halogen.

In one embodiment, R ² Can be hydrogen,

In one embodiment, R ² Can be hydroxyl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-10 membered cycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-to 6-membered heteroaryl or substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl; r is R ²¹ Can be C ₁ ～C ₆ Alkyl or oxo; r is R ²² Can be cyano; r is R ²⁴ Can be C ₁ ～C ₆ Alkyl, (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₆ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₆ An alkyl group.

In one embodiment, R ² Can be hydroxyl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-6 membered cycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-to 6-membered heteroaryl or substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl; r is R ²¹ Can be C ₁ ～C ₃ Alkyl or oxo; r is R ²² Can be cyano; r is R ²⁴ Can be C ₁ ～C ₃ Alkyl, (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₃ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₃ An alkyl group.

In one embodiment, R ² Can be hydroxyl, substituted with 1, 2 or 3R ²¹ Substituted 5-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-membered cycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-membered heteroaryl or substituted with 1, 2 or 3R ²⁶ Substituted 5 membered heteroaryl; r is R ²¹ Can be C ₁ ～C ₃ Alkyl or oxo; r is R ²² Can be cyano; r is R ²⁴ Can be C ₁ ～C ₃ Alkyl, (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₃ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₃ An alkyl group.

In one embodiment, R ² Can be hydroxyl, substituted with 1, 2 or 3R ²¹ Substituted 5-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-membered cycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-membered heteroaryl or substituted with 1, 2 or 3R ²⁶ Substituted 5 membered heteroaryl; r is R ²¹ Can be methyl or oxo; r is R ²² Can be cyano; r is R ²⁴ Can be methyl, (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can independently be hydrogen or methyl; r is R ²⁵ Can be methyl; r is R ²⁶ Can be methyl.

In one embodiment, R ² Can be hydroxy,

In one embodiment, R ² Can be cyano, trifluoromethyl, 3-to 10-membered heterocycloalkyl, substituted by 1, 2 or 3R ²¹ Substituted 3-10 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl or (R) ²⁷ )(R ^27a )N-；R ²¹ Can be hydroxyl, oxo or halogen; r is R ²⁴ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Can be independently hydrogen, C ₁ ～C ₆ Alkyl, C ₃ ～C ₆ Cycloalkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Can be C ₁ ～C ₆ An alkyl group.

In one embodiment, R ² Can be cyano, trifluoromethyl, 3-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²¹ Substituted 3-6 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl or (R) ²⁷ )(R ^27a )N-；R ²¹ Can be hydroxyl, oxo or halogen; r is R ²⁴ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁷ And R is ^27a Can be independently hydrogen, C ₁ ～C ₃ Alkyl, C ₃ ～C ₆ Cycloalkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Can be C ₁ ～C ₃ An alkyl group.

In one embodiment, R ² Can be cyano, trifluoromethyl, 4-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²¹ Substituted 4-6 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, substituted by 1, 2 or 3R ²⁶ Substituted 5 membered heteroaryl or (R) ²⁷ )(R ^27a )N-；R ²¹ Can be hydroxyl, oxo or halogen; r is R ²⁴ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁷ And R is ^27a Can be independently hydrogen, C ₁ ～C ₃ Alkyl, C ₃ ～C ₆ Cycloalkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Can be C ₁ ～C ₃ An alkyl group.

In one embodiment, R ² Can be cyano, trifluoromethyl, 4-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²¹ Substituted 4-6 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, substituted by 1, 2 or 3R ²⁶ Substituted 5 membered heteroaryl or (R) ²⁷ )(R ^27a )N-；R ²¹ Can be hydroxy, oxygenSubstituted or halogen; r is R ²⁴ Can be methyl; r is R ²⁵ Can be methyl; r is R ²⁶ Can be methyl; r is R ²⁷ And R is ^27a Can be independently hydrogen, methyl, isopropyl, cyclopropyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Can be methyl.

In one embodiment, R ² Can be cyano, trifluoromethyl,

In one embodiment, R ² Can be hydrogen, hydroxy, cyano, trifluoromethyl,

in one embodiment, R ² Can be hydrogen, hydroxy, cyano, trifluoromethyl,/>

in one embodiment, R ² Is hydrogen, hydroxy, cyano,

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be a single bond; r is R ² Can be hydrogen, 3-10 membered heterocycloalkyl, substituted 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-to 10-membered cycloalkyl or by 1, 2 or 3R ²³ Substituted C ₁ ～C ₆ An alkyl group; r is R ²¹ Can be oxo, R ²² Can be cyano, R ²³ May be halogen.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be a single bond; r is R ² Can be hydrogen, 3-6 membered heterocycloalkyl, substituted by 1, 2 or 3R ²¹ Substituted 3-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-to 4-membered cycloalkyl or by 1, 2 or 3R ²³ Substituted C ₁ ～C ₆ An alkyl group; r is R ²¹ Can be oxo, R ²² Can be cyano, R ²³ May be halogen.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be a single bond; r is R ² Can be hydrogen, 4-6 membered heterocycloalkyl, substituted with 1, 2 or 3R ²¹ Substituted 4-6 membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 4-membered cycloalkyl or substituted by 1, 2 or 3R ²³ Substituted C ₁ ～C ₃ An alkyl group; r is R ²¹ Can be oxo, R ²² Can be cyano, R ²³ May be halogen.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be a single bond; r is R ² Can be hydrogen,

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (C =O)-；R ² Can be hydroxyl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-10 membered cycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-to 6-membered heteroaryl or substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl; r is R ²¹ Can be C ₁ ～C ₆ Alkyl or oxo; r is R ²² Can be cyano; r is R ²⁴ Can be C ₁ ～C ₆ Alkyl, (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₆ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₆ An alkyl group.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -; r is R ² Can be hydroxyl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-6 membered cycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-to 6-membered heteroaryl or substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl; r is R ²¹ Can be C ₁ ～C ₃ Alkyl or oxo; r is R ²² Can be cyano; r is R ²⁴ Can be C ₁ ～C ₃ Alkyl, (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₃ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₃ An alkyl group.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -; r is R ² Can be hydroxyl, substituted with 1, 2 or 3R ²¹ Substituted 5-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-membered cycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-membered heteroaryl or substituted by 1, 2 or 3R ²⁶ Substituted 5 membered heteroaryl; r is R ²¹ Can be C ₁ ～C ₃ Alkyl or oxo; r is R ²² Can be cyano; r is R ²⁴ Can be C ₁ ～C ₃ Alkyl, (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₃ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₃ An alkyl group.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -; r is R ² Can be hydroxyl, substituted with 1, 2 or 3R ²¹ Substituted 5-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-membered cycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-membered heteroaryl or substituted with 1, 2 or 3R ²⁶ Substituted 5 membered heteroaryl; r is R ²¹ Can be methyl or oxo; r is R ²² Can be cyano; r is R ²⁴ Can be methyl, (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can independently be hydrogen or methyl; r is R ²⁵ Can be methyl; r is R ²⁶ Can be methyl.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -; r is R ² Can be hydroxy,

In one embodiment, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -, wherein L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² Can be cyano, trifluoromethyl, 3-10 membered heterocycloalkyl, substituted 1, 2 or 3R ²¹ Substituted 3-10 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl or (R) ²⁷ )(R ^27a )N-；R ²¹ Can be hydroxyl, oxo or halogen; r is R ²⁴ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Can be independently hydrogen, C ₁ ～C ₆ Alkyl, C ₃ ～C ₆ Cycloalkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Can be C ₁ ～C ₆ An alkyl group.

In one embodiment, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -, wherein L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² Can be cyano, trifluoromethyl, 3-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²¹ Substituted 3-6 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl or (R) ²⁷ )(R ^27a )N-；R ²¹ Can be hydroxyl, oxo or halogen; r is R ²⁴ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁷ And R is ^27a Can be independently hydrogen, C ₁ ～C ₃ Alkyl, C ₃ ～C ₆ Cycloalkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Can be C ₁ ～C ₃ An alkyl group.

In one embodiment, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -, wherein L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² Can be cyano, trifluoromethyl, 4-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²¹ Substituted 4-6 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, substituted by 1, 2 or 3R ²⁶ Substituted 5 membered heteroaryl or (R) ²⁷ )(R ^27a )N-；R ²¹ Can be hydroxyl, oxo or halogen; r is R ²⁴ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁷ And R is ^27a Can be independently hydrogen, C ₁ ～C ₃ Alkyl, C ₃ ～C ₆ Cycloalkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Can be C ₁ ～C ₃ An alkyl group.

In one embodiment, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -, wherein L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² Can be cyano, trifluoromethyl, 4-to 6-membered heterocycloalkyl, substituted by 1, 2 or 3R ²¹ Substituted 4-6 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, substituted by 1, 2 or 3R ²⁶ Substituted 5 membered heteroaryl or (R) ²⁷ )(R ^27a )N-；R ²¹ Can be hydroxyl, oxo or halogen; r is R ²⁴ Can be methyl; r is R ²⁵ Can be methyl; r is R ²⁶ Can be methyl; r is R ²⁷ And R is ^27a Can be independently hydrogen, methyl, isopropyl, cyclopropyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Can be methyl.

In one embodiment, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -, wherein L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² Can be cyano, trifluoromethyl,

In one embodiment, L ¹ Is a single bond, methylene, ethylene or- (c=o) -orThe q-terminal is connected with L ² Is connected with each other.

In one embodiment, L ¹ Single bond, methylene, ethylene or- (c=o) -orThe q-terminal and R ² Is connected with each other.

In one aspect of the present invention,can be any one of the following structures

/>

In one aspect of the present invention,can be any one of the following structures>

In one aspect of the present invention,h, & gt> />

In one embodiment, R ² Can be hydrogen, hydroxy, 3-to 10-membered heterocycloalkyl, 5-to 6-membered heteroaryl, substituted with 1, 2 or 3R ²¹ Substituted 3-10 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -or (R) ²⁷ )(R ^27a )N-；R ²¹ Can be C ₁ ～C ₆ Alkyl, oxo or halogen; r is R ²⁴ Can be C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Can be independently hydrogen or C ₁ ～C ₆ An alkyl group.

In one embodiment, R ² Can be hydrogen or 3-10 membered heterocycloalkyl.

In one embodiment, R ² Can be hydrogen or 3-6 membered heterocycloalkyl.

In one embodiment, R ² Can be hydrogen or 4-6 membered heterocycloalkyl.

In one embodiment, R ² Can be hydrogen or

In one embodiment, R ² Can be hydroxyl, 5-6 membered heteroaryl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl or R ²⁴ -S(＝O) ₂ -；R ²¹ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁴ Can be C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₆ An alkyl group.

In one embodiment, R ² Can be hydroxyl, 5-6 membered heteroaryl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 6-membered heterocycloalkyl or R ²⁴ -S(＝O) ₂ -；R ²¹ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁴ Can be C ₁ ～C ₃ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₃ An alkyl group.

In one embodiment, R ² Can be hydroxyl, 5 membered heteroaryl, substituted with 1, 2 or 3R ²¹ Substituted 5-to 6-membered heterocycloalkyl or R ²⁴ -S(＝O) ₂ -；R ²¹ Can be methyl; r is R ²⁴ Can be methyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can independently be hydrogen or methyl.

In one embodiment, R ² Can be hydroxy,/>

In one embodiment, R ² Can be 3-10 membered heterocycloalkyl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl or (R) ²⁷ )(R ^27a )N-；R ²¹ May be oxo or halogen; r is R ²⁷ And R is ^27a Can be independently hydrogen or C ₁ ～C ₆ An alkyl group.

In one embodiment, R ² Can be 3 to 6A membered heterocycloalkyl group, substituted by 1, 2 or 3R ²¹ Substituted 3-to 6-membered heterocycloalkyl or (R) ²⁷ )(R ^27a )N-；R ²¹ May be oxo or halogen; r is R ²⁷ And R is ^27a Can be independently hydrogen or C ₁ ～C ₃ An alkyl group.

In one embodiment, R ² Can be 4-6 membered heterocycloalkyl, substituted with 1, 2 or 3R ²¹ Substituted 4-6 membered heterocycloalkyl or (R) ²⁷ )(R ^27a )N-；R ²¹ May be oxo or halogen; r is R ²⁷ And R is ^27a Can independently be hydrogen or methyl.

In one embodiment, R ² (may be)

In one embodiment, R ² Can be hydrogen, hydroxyl,

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be a single bond; r is R ² Can be hydrogen or 3-10 membered heterocycloalkyl.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be a single bond; r is R ² Can be hydrogen or 3-6 membered heterocycloalkyl.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be a single bond; r is R ² Can be hydrogen or 4-6 membered heterocycloalkyl.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be a single bond; r is R ² Can be hydrogen or

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -; r is R ² Can be hydroxyl, 5-6 membered heteroaryl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl or R ²⁴ -S(＝O) ₂ -；R ²¹ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁴ Can be C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₆ An alkyl group.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -; r is R ² Can be hydroxyl, 5-6 membered heteroaryl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 6-membered heterocycloalkyl or R ²⁴ -S(＝O) ₂ -；R ²¹ Can be C ₁ ～C ₃ An alkyl group; r is R ²⁴ Can be C ₁ ～C ₃ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₃ An alkyl group.

In one embodiment, L ¹ Can be a single bond; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -; r is R ² Can be hydroxyl, 5 membered heteroaryl, substituted with 1, 2 or 3R ²¹ Substituted 5-to 6-membered heterocycloalkyl or R ²⁴ -S(＝O) ₂ -；R ²¹ Can be methyl; r is R ²⁴ Can be methyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can independently be hydrogen or methyl.

In one embodiment, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene groupRadical or- (C=O) -, where L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² Can be 3-10 membered heterocycloalkyl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl or (R) ²⁷ )(R ^27a )N-；R ²¹ May be oxo or halogen; r is R ²⁷ And R is ^27a Can be independently hydrogen or C ₁ ～C ₆ An alkyl group.

In one embodiment, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -, wherein L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² Can be 3-6 membered heterocycloalkyl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 6-membered heterocycloalkyl or (R) ²⁷ )(R ^27a )N-；R ²¹ May be oxo or halogen; r is R ²⁷ And R is ^27a Can be independently hydrogen or C ₁ ～C ₃ An alkyl group.

In one embodiment, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -, wherein L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² Can be 4-6 membered heterocycloalkyl, substituted with 1, 2 or 3R ²¹ Substituted 4-6 membered heterocycloalkyl or (R) ²⁷ )(R ^27a )N-；R ²¹ May be oxo or halogen; r is R ²⁷ And R is ^27a Can independently be hydrogen or methyl.

In one embodiment, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -, wherein L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² (may be)

In one embodiment, R ³ Can be C ₁ ～C ₃ Alkyl or C _3-6 Cycloalkyl groups.

In one embodiment, R ³ Can be isopropyl or cyclopropyl.

In one embodiment, R ⁴ May be hydrogen or methyl.

In one embodiment, the compound of formula II may be any one of the following compounds:

/>

in one embodiment, the compound of formula IIOne stereoisomer of which peaks first out under the following conditions: a chromatographic column, ultimate XB-C18, a mobile phase, acetonitrile and water mixed solution containing 0.1v% formic acid; the elution gradient is: the volume percentage of acetonitrile in the flowing phase is 10% in 0-3min, the volume percentage of acetonitrile in the flowing phase is increased from 25% to 45% in 3-16min, and the volume percentage of acetonitrile in the flowing phase is 95% in 16-20 min; preferably, one stereoisomer has a retention time of 4.03min under the following conditions: chromatographic column Ultimate XB-C18, 21.2X250 mm,10 μm; mobile phase is acetonitrile and water mixed solution containing 0.1v% formic acid; mobile phase is acetonitrile and water mixed solution containing 0.1v% formic acid; the elution gradient is: the volume percentage of acetonitrile in the flowing phase is 10% in 0-3min, the volume percentage of acetonitrile in the flowing phase is increased from 25% to 45% in 3-16min, and the volume percentage of acetonitrile in the flowing phase is 95% in 16-20 min; flow rate: 20ml/min; column temperature: 30 ℃.

In one embodiment, the compound of formula IIMiddle in order toOne stereoisomer that peaks after the following conditions: a chromatographic column, ultimate XB-C18, a mobile phase, acetonitrile and water mixed solution containing 0.1v% formic acid; the elution gradient is: the volume percentage of acetonitrile in the flowing phase is 10% in 0-3min, the volume percentage of acetonitrile in the flowing phase is increased from 25% to 45% in 3-16min, and the volume percentage of acetonitrile in the flowing phase is 95% in 16-20 min; preferably, one stereoisomer has a retention time of 4.10min under the following conditions: chromatographic column Ultimate XB-C18, 21.2X250 mm,10 μm; mobile phase is acetonitrile and water mixed solution containing 0.1v% formic acid; mobile phase is acetonitrile and water mixed solution containing 0.1v% formic acid; the elution gradient is: the volume percentage of acetonitrile in the flowing phase is 10% in 0-3min, the volume percentage of acetonitrile in the flowing phase is increased from 25% to 45% in 3-16min, and the volume percentage of acetonitrile in the flowing phase is 95% in 16-20 min; flow rate: 20ml/min; column temperature: 30 ℃.

The invention also provides a pharmaceutical composition, which comprises a substance X and pharmaceutical excipients;

the substance X is a compound shown in the formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof.

The invention also provides application of the substance X in preparing TLR7 and/or TLR8 inhibitors;

In one embodiment, the TLR7 and/or TLR8 inhibitor may be selective over TLR 9.

In one embodiment, the TLR7 and/or TLR8 inhibitor is used in vitro.

The invention also provides application of the substance X in preparing medicines;

the substance X is a compound shown in the formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof;

the medicine is used for treating diseases related to TLR7 and/or TLR 8.

In one embodiment, the TLR7 and/or TLR8 related disease is an autoimmune disease, and is also sjogren's syndrome, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, systemic sclerosis, or psoriasis.

In one embodiment, the lupus erythematosus can be Systemic Lupus Erythematosus (SLE), discoid lupus erythematosus, or subacute cutaneous lupus erythematosus.

The invention also provides application of the substance X in preparing a medicament for treating autoimmune diseases;

in one embodiment, the autoimmune disease is sjogren's syndrome, lupus erythematosus, multiple sclerosis, rheumatoid arthritis, systemic sclerosis, or psoriasis.

Definition of the definition

The following terms used in the present invention are intended to have the following definitions unless otherwise indicated. A particular term should not be construed as being obscure without special definition, but rather should be construed in a generic sense.

The term "pharmaceutically acceptable" is intended to refer 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 human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, the base addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium calcium, ammonium, organic amine or magnesium salts or similar salts. When relatively basic functional groups are present in the compounds of the present invention, base addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities and can be converted to either base or acid addition salts.

Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.

Meaning that the group is attached to the rest of the compound at this site.

The "-" at the end of a group means that the group is attached to the remainder of the molecule through that site. For example, CH ₃ -C (=o) -means acetyl.

The number of atoms on a ring is generally defined as the number of ring elements, e.g., "3-7 membered ring" refers to a "ring" of 3-7 atoms arranged around a ring.

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

The term "alkyl" refers to a compound having a specified number of carbon atoms (e.g., C ₁ -C ₆ ) Straight or branched, saturated monovalent hydrocarbon radicals. Alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and the like.

The term "alkylene" is a divalent group that is attached to the remainder of the molecule by two single bonds, the remainder being defined as the term "alkyl".

The term "cycloalkyl" refers to a compound having the indicated number of carbon atoms (e.g., C ₃ -C ₁₀ ) A cyclic, saturated monovalent hydrocarbon group which is a monocyclic ring system or a bicyclic ring system, the bicyclic ring may be a spiro ring or a bridged ring, the spiro ring means that one carbon atom is shared between the monocyclic rings, and the bridged ring means that two or more carbon atoms are shared between the monocyclic rings. Cycloalkyl groups include, but are not limited to: etc.

The term "carbocycle" satisfies any of the following conditions, the remainder being defined as the term "cycloalkyl": 1. is connected with the rest of the molecule through more than two single bonds; 2. sharing two atoms and one bond with the rest of the molecule; the term "carbocycle" is a saturated ring.

The term "heterocycloalkyl" refers to a cyclic, saturated monovalent group of a specified number of ring atoms (e.g., 3-10 membered), of a specified number of heteroatoms (e.g., 1, 2, or 3), of a specified heteroatom species (one or more of N, O and S), which is a monocyclic ring system or a bicyclic ring system, which can be a spiro ring or a bridged ring, where spiro ring refers to sharing one carbon atom between monocyclic rings, and bridged ring refers to sharing more than two carbon atoms between monocyclic rings. The heterocycloalkyl group is attached to the remainder of the molecule via a carbon atom or heteroatom. Heterocycloalkyl groups include, but are not limited to:

Etc.

The term "heterocarbocycle" is attached to the remainder of the molecule by more than two single bonds, the remainder being defined as the term "heterocycloalkyl". The term "heterocarbocycle" is a saturated ring.

The term "5-6 membered heteroaryl" by itself or in combination with other terms, denotes a cyclic group with conjugated pi-electron system consisting of 5 to 6 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, respectively. The 5-6 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom, said 5-6 membered heteroaryl group including 5-and 6-membered heteroaryl groups and the like. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl and the like), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl and the like), furanyl (including 2-furanyl and 3-furanyl and the like), thienyl (including 2-thienyl and 3-thienyl and the like), pyridyl (including 2-pyridyl, 4-pyrimidyl and the like), pyrimidyl and the like.

The term "treatment" refers to the administration of one or more pharmaceutical substances, in particular a compound of formula (I) as described herein and or a pharmaceutically acceptable salt thereof, to an individual suffering from a disease or having symptoms of said disease, for curing, alleviating, modifying, treating, ameliorating, improving or affecting said disease or symptoms of said disease.

When referring to a chemical reaction, the terms "treating," "contacting," and "reacting" refer to adding or mixing two or more reagents under appropriate conditions to produce the indicated and/or desired product, it being understood that the reaction to produce the indicated and/or desired product may not necessarily result directly from the combination of the two reagents initially added, i.e., there may be one or more intermediates formed in the mixture that ultimately result in the formation of the indicated and/or desired product.

As used herein, a "patient" is defined as any warm-blooded animal, such as, but not limited to, mice, guinea pigs, dogs, horses, or humans, with the patient preferably being a human.

Technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that: the compound has better inhibiting activity on TLR 7/8.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

The reverse phase preparation purification conditions in the examples are as follows, unless otherwise specified: preparation of the column: ultimate XB-C18,21.2 x 250mm,10 μm; eluting: the mobile phase 0.1v% FA in H2O/ACN, elution gradient (ratio of ACN) 10v% (0-3 min), 25-45v% (3-16 min), 95v% (16-20 min), flow rate 20mL/min, column temperature 30℃and the reverse phase preparation purification procedure in examples 1-76 were referred to this condition.

Example 1

4- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one

Step A: 5-bromo-3-isopropyl-1H-indole (Compound 1.2)

Triethylsilane (8.72 g,76.53 mmol), trifluoroacetic acid (8.88 g,76.53 mmol) were dissolved in 80mL of toluene, and a solution of 5-bromo-1H-indole (5.0 g,25.51 mmol), acetone (3.70 g,63.78 mmol) in toluene (30 mL) was added at room temperature and stirred at 70℃for 2.5 hours. After the reaction is completed, naHCO is added into the reaction solution ₃ The solution was quenched, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (EA/PE (0-10%)) to give product 1.2 (5.0 g, yield: 83.3%). LCMS ESI (+) m/z:238.0 (M+1).

And (B) step (B): 4- (3-isopropyl-1H-indol-5-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (Compound 1.3)

1.2 (3.91 g,16.50 mmol) was dissolved in 60mL and 10mL of water and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (5.36 g,17.32 mmol), pd (dppf) Cl was added ₂ (0.61 g,0.82 mmol) and cesium carbonate (16.14 g,49.50 mmol), and the reaction solution was stirred at 80℃for 5 hours. After completion of the reaction, the reaction mixture was filtered, ethyl acetate was added to the filtrate, the extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (EA/PE (0-10%) to give product 1.3 (3.39 g, yield: 60%). LCMS ESI (+) m/z:341.2 (M+1).

Step C:4- (3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (Compound 1.4)

1.3 (3.39 g,83.35 mmol) was dissolved in 60mL of ethyl acetate, palladium on carbon (0.848 g) was added, and the reaction solution was stirred at room temperature for 5 hours. The reaction solution was filtered, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (EA/PE (0-10%)) to give product 1.4 (2.70 g, yield: 79%). LCMS ESI (+) m/z:343.2 (M+1).

Step D:4- (2-bromo-3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (Compound 1.5)

1.4 (2.70 g,7.89 mmol) was dissolved in 75mL of dichloroethane, and a solution of NBS (1.33 g,7.50 mmol) in dichloroethane (75 mL) was added dropwise under ice-water bath, and the reaction solution was stirred at 0-10℃for 0.5 hours. Adding Na into the reaction solution ₂ SO ₃ The solution was quenched, extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (EA/PE (0-10%)) to give product 1.5 (2.45 g, yield: 73%). LCMS ESI (+) m/z:421/423 (M+1).

Step E:4- (3-isopropyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (Compound 1.6)

1.5 (1.68 g,4.0 mmol) was dissolved in 33mL of 1, 4-dioxane, dibenzonitrile palladium dichloride (46 mg,0.12 mmol), S-Phos (197mg, 0.48 mmol), triethylamine (1.21 g,12.0 mmol) was added, and the reaction was stirred at 85℃for 3 hours. The reaction solution was dried by rotation, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (EA/PE (0-7%)) to give product 1.6 (0.534 g, yield: 29%). LCMS ESI (+) m/z:469.2 (M+1).

Step F:2- ((trifluoromethyl) sulfonyl) oxy) cyclopent-1-ene-1-carboxylic acid methyl ester (Compound 1.8)

Methyl 2-oxolane-1-carboxylate (10 g,70.35 mmol) and N, N-diisopropylethylamine (13.64 g,105.53 mmol) were dissolved in dichloromethane (100 mL). Trifluoromethanesulfonic anhydride (21.83 g,77.38 mmol) was dissolved in dichloromethane (50 mL) and the solution was slowly dropped into the reaction solution at-25 ℃. After the dripping, the reaction solution is stirred and reacted for 2 hours at the temperature of minus 25 ℃ to 0 ℃. The reaction solution was quenched with saturated sodium bicarbonate solution, extracted 2 times with dichloromethane, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by column chromatography (PE/EA (4%)) to give product 1.8 (16.0 g, yield: 83%). LCMS ESI (+) m/z:275 (M+1).

Step G:2- (trimethylsilyl) ethynyl) cyclopent-1-ene-1-carboxylic acid methyl ester (Compound 1.9)

Compound 1.8 (16.0 g,58.36 mmol), trimethylethynyl silicon (11.46 g,116.72 mmol), bis-triphenylphosphine palladium dichloride (4.10 g,5.84 mmol), cuprous iodide (1.11 g,5.84 mmol) and triethylamine (17.70 g,175.09 mmol) were dissolved in DMF (200 mL). The reaction system was replaced with argon 3 times. The reaction mixture was stirred at 60℃for 1 hour. The reaction solution was extracted twice with ethyl acetate and water. The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE/EA (4%)) to give product 1.9 (8.0 g, yield: 61.7%). LCMS ESI (+) m/z:223 (M+1).

Step H: 2-ethylcyclopent-1-ene-1-carboxylic acid (Compound 1.10)

Compound 1.9 (8 g,36.01 mmol) was dissolved in methanol (80 mL) and tetrahydrofuran (80 mL), and a lithium hydroxide solution (3.02 g,72.02mmol,72 mL) was added thereto, and the reaction mixture was stirred at 50℃for 2 hours. The reaction was concentrated under reduced pressure and purified by column chromatography (DCM/MeOH (10%)) to give product 1.10 (4.8 g, yield: 98%). LCMS ESI (+) m/z:137 (M+1).

Step I: 2-ethylcyclopent-1-ene-1-carboxamide (Compound 1.11)

Compound 1.10 (2.72 g,20.0 mmol) and N, N-diisopropylethylamine (7.75 g,60.0 mmol) were dissolved in N, N-dimethylformamide (50 mL). HATU (11.4 g,30.0 mmol) was added at room temperature, the reaction stirred at room temperature for 0.5 hours, ammonium chloride (3.21 g,60.0 mmol) was added to the reaction, and stirring was continued at room temperature overnight. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE/EA (40%)) to give product 1.11 (2.45 g, yield: 90%). LCMS ESI (+) m/z:136 (M+1).

Step J:2,5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one (Compound 1.12)

Compound 1.11 (2.45 g,18.13 mmol) was dissolved in dimethylamine in methanol (2M, 12 mL). The reaction mixture was stirred for 2 hours at 100℃with microwaves. The reaction mixture was concentrated under reduced pressure, and purified by column chromatography (PE/EA (4%)) to give product 1.12 (1.65 g, yield: 67.3%). LCMS ESI (+) m/z:136 (M+1).

Step K: 2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one (Compound 1.13)

Compound 1.12 (6755 mg,5.0 mmol) was dissolved in N, N-dimethylformamide (10 mL). Sodium hydride (240 mg,60%,6.0 mmol) was slowly added to the reaction solution at 0℃and the reaction was stirred for 30 minutes. Then methyl iodide was dropped into the reaction solution to continue the reaction with stirring at room temperature for 2 hours. The reaction solution was quenched with ammonium chloride solution, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM/MeOH (10%)) to give product 1.13 (650 mg, yield: 88%). LCMS ESI (+) m/z:150 (M+1).

Step L: 4-bromo-2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one (Compound 1.14)

Compound 1.13 (639 mg,4.28 mmol) was dissolved in acetonitrile (10 mL). NBS (800 mg,4.50 mmol) was added to the reaction solution at room temperature, and the reaction was stirred for 3 hours. The reaction was concentrated under reduced pressure and purified by column chromatography (DCM/MeOH (5%)) to give product 1.14 (980 mg, yield: 100%). LCMS ESI (+) m/z:228/230 (M+1).

Step M: tert-butyl 4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentane [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylate (Compound 1.15)

Compound 1.14 (120 mg,0.52 mmol), 4- (3-isopropyl-2- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (240 mg,0.51 mmol), potassium phosphate (326 mg,1.53 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride (37 mg,0.051 mmol) and water (2 mL) were dissolved in 1, 4-dioxan (10 mL). The reaction system was replaced with argon 3 times. The reaction mixture was stirred at 85℃for 2 hours. The reaction was concentrated under reduced pressure and purified by column chromatography (DCM/MeOH (5%)) to give product 1.15 (270 mg, crude yield: 108%). LCMS ESI (+) m/z:490 (M+1).

Step N:4- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one (Compound 1)

Compound 1.15 (270 mg,0.55 mmol) was dissolved in anhydrous methanol (3 mL) and dichloromethane (1 mL). A hydrogen chloride-dioxane solution (1 mL) was added dropwise to the reaction system at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and chromatographed (DCM/MeOH/NH) ₃ ·H ₂ O (10:1:0.1)) to give product 1 (156 mg, yield: 73%). LCMS ESI (+) m/z:390 (M+1). ¹ H NMR(400MHz,DMSO)δ10.77(s,1H),8.65(s,1H),7.56(s,1H),7.49(s,1H),7.25(d,J＝8.3Hz,1H),6.94(dd,J＝8.4,1.2Hz,1H),3.51(s,3H),3.37(s,2H),3.05–2.93(m,3H),2.88(ddd,J＝15.6,10.4,5.6Hz,1H),2.72(dd,J＝16.0,8.0Hz,4H),1.94(qd,J＝15.2,5.6Hz,6H),1.35(d,J＝7.2Hz,6H).

Example 2

2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentan [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

Compound 1 (40 mg,0.10 mmol) and DBU (61 mg,0.40 mmol) were dissolved in 1, 2-dichloroethane (3 mL), and then 2-bromoacetamide (17 mg,0.12 mmol) was added to the reaction system. The reaction mixture was stirred at room temperature for 18 hours. The reaction solution was extracted with methylene chloride 2 times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give product 2 (20 mg, yield: 44%) by reverse phase preparation and purification. LCMS ESI (+) m/z:447 (M+1), 224 (M/2+1). ¹ H NMR(400MHz,DMSO)δ10.68(s,1H),7.55(s,1H),7.49(s,1H),7.26(s,1H),7.21(d,J＝8.4Hz,1H),7.14(s,1H),6.97(dd,J＝8.4,1.2Hz,1H),3.50(s,3H),2.99(d,J＝7.2Hz,1H),2.95(d,J＝12.8Hz,2H),2.90(s,2H),2.75–2.68(m,5H),2.20(dd,J＝11.2,8.8Hz,2H),2.03–1.93(m,2H),1.81(dt,J＝25.2,10.0Hz,4H),1.35(d,J＝7.2Hz,6H).

Example 3

2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide

Compound 1 (15 mg,0.04 mmol) and 2-chloro-N-methylacetamide (13 mg,0.12 mmol) were dissolved in 5mL THF under nitrogen, DIEA (52 mg,0.4 mmol) was added and the reaction stirred at 70℃overnight. To the reaction solution was added 20mL of water, extracted with ethyl acetate (25 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 3 (8 mg, yield: 44%). LCMS ESI (+) m/z:461.2 (M+1). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.69(s,1H),7.72(q,J＝4.8Hz,1H),7.55(s,1H),7.49(s,1H),7.21(d,J＝8.3Hz,1H),6.97(d,J＝8.3Hz,1H),3.50(s,3H),3.01–2.96(m,1H),2.92(s,3H),2.89(s,1H),2.72(q,J＝7.7Hz,4H),2.65(d,J＝4.7Hz,3H),2.56–2.52(m,1H),2.18(td,J＝11.5,2.9Hz,2H),1.98(q,J＝7.5Hz,2H),1.80(dtd,J＝22.4,12.8,3.7Hz,4H),1.35(d,J＝7.0Hz,6H).

Example 4

2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) -N, N-dimethylacetamide

Compound 1 (40 mg,0.103 mmol) was dissolved in 2mL THF and 1mL DMF, 2-chloro-N, N-dimethylacetamide (19 mg,0.154 mmol), TEA (104 mg,1.03 mmol) was added and the reaction stirred at room temperature overnight. The reaction solution was dried by rotation, extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 4 (14.5 mg, yield: 30%). LCMS ESI (+) m/z:475.3 (M+1). ¹ H NMR(400MHz,DMSO)δ10.70(s,1H),7.55(s,1H),7.49(s,1H),7.22(d,J＝8.3Hz,1H),6.96(dd,J＝8.4,1.3Hz,1H),3.50(s,3H),3.45(s,2H),3.11(d,J＝9.3Hz,2H),3.03(d,J＝9.2Hz,3H),2.98(dd,J＝14.1,7.0Hz,1H),2.85(s,3H),2.72(dd,J＝16.0,8.0Hz,4H),2.61(dd,J＝16.8,9.4Hz,1H),2.41(s,2H),2.03–1.92(m,2H),1.82(s,4H),1.34(d,J＝7.0Hz,6H).

Example 5

4- (5- (1- (2- (1, 1-thioxo-morpholino) -2-oxoethyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one

Step A: ethyl 2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetate (compound 5.1)

Compound 1 (50 mg,0.118 mmol) was dissolved in 3mL of dichloromethane, DIEA (109 mg,0.846 mmol) and ethyl 2-bromoacetate (24 mg,0.141 mmol) were added, replaced three times with argon, and the reaction was stirred overnight at room temperature. To the reaction solution was added 5mL of water, extracted with methylene chloride (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 5.1 (65 mg, yield: 99.3%). LCMS ESI (+) m/z:476.3 (M+1).

And (B) step (B): 2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetic acid (Compound 5.2)

Compound 5.1 (65 mg,0.126 mmol) was dissolved in THF (1 mL) and MeOH (1 mL), naOH (100 mg) and 1.5mL of water were added, and the reaction was stirred at room temperature for 2 hours. Hydrochloric acid solution was added to the reaction solution to neutrality, and iPrOH was used: dcm=1:3 extraction three times, combined organic phases, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 5.2 (60 mg, yield: 106%). LCMS ESI (+) m/z:448.2 (M+1).

Step C:4- (5- (1- (2- (1, 1-thioxo-morpholino) -2-oxoethyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one (Compound 5)

Compound 5.2 (30 mg,0.067 mmol) was dissolved in 3mL of acetonitrile, HATU (38.4 mg,0.101 mmol), TEA (20.3 mg,0.201 mmol) and thiomorpholine 1, 1-dioxide (13.6 mg,0.101 mmol) were added and the reaction solution was stirred overnight at room temperature, quenched with water, extracted with dichloromethane (10 mLX 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by reverse phase to give compound 5 (5.2 mg, yield: 13.7%). LCMS ESI (+) m/z:565.2 (M+1). ¹ H NMR(400MHz,DMSO)δ10.68(s,1H),7.55(s,1H),7.47(s,1H),7.21(d,J＝8.3Hz,1H),6.96(d,J＝8.5Hz,1H),4.01(s,2H),3.87(s,2H),3.50(s,3H),3.29–3.27(m,2H),3.25(s,2H),3.13(s,2H),2.97(dd,J＝14.0,7.2Hz,3H),2.72(dd,J＝15.6,7.8Hz,4H),2.55(s,1H),2.13(t,J＝10.7Hz,2H),1.98(dd,J＝15.0,7.6Hz,2H),1.80(d,J＝10.6Hz,2H),1.70(t,J＝10.5Hz,2H),1.34(d,J＝7.0Hz,6H).

Example 6

4- (3-isopropyl-5- (1- (oxazol-2-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one

Compound 1 (40 mg,0.1 mmol) was dissolved in 5mL of DCM, triethylamine (40 mg,0.4 mmol), oxazole-2-carbaldehyde (39 mg,0.4 mmol), acetic acid (32 mg,0.2 mmol) and sodium borohydride acetate (85 mg,0.4 mmol) were added sequentially, and the reaction was stirred at room temperature for 2 hours. To the reaction solution was added 15mL of a saturated aqueous ammonium chloride solution, extracted with methylene chloride (10 mL X3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give product 6 (26 mg, yield: 56%). LCMS ESI (+) m/z:471.3 (M+1). ¹ H NMR(400MHz,CDCl3)δ8.07(s,1H),7.69(s,1H),7.60(s,1H),7.30(d,J＝8.4Hz,1H),7.14(d,J＝5.0Hz,2H),7.09(dd,J＝8.4,1.3Hz,1H),3.89(s,2H),3.57(s,3H),3.18(s,2H),3.01(dt,J＝14.1,7.0Hz,1H),2.88(t,J＝7.4Hz,2H),2.73(t,J＝7.5Hz,2H),2.64(t,J＝11.9Hz,1H),2.42(s,2H),2.06–2.01(m,2H),1.95(d,J＝11.7Hz,2H),1.71(s,2H),1.38(d,J＝7.1Hz,6H).

Example 7

4- (3-isopropyl-5- (1- (thiazol-2-ylmethyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one

Compound 1 (30 mg,0.077 mmol) was dissolved in 5mL of dichloromethane, triethylamine (31 mg,0.31 mmol), 2-aldehyde thiazole (35 mg,0.31 mmol), acetic acid (9.2 mg,0.15 mmol) and sodium triacetoxyborohydride (65.4 mg,0.31 mmol) were added, and the mixture was stirred at room temperature overnight. Spin-drying the solvent and purification by reverse phase preparation gave compound 7 (18 mg, yield: 48%). LCMS ESI (+) m/z:487.3 (M+1). ¹ H NMR(400MHz,DMSO)δ10.68(s,1H),7.72(d,J＝3.3Hz,1H),7.66(d,J＝3.3Hz,1H),7.56(s,1H),7.49(s,1H),7.21(d,J＝8.3Hz,1H),6.97(dd,J＝8.4,1.4Hz,1H),3.87(s,2H),3.50(s,3H),3.02(d,J＝13.1Hz,2H),3.00–2.94(m,1H),2.72(d,J＝7.5Hz,4H),2.63–2.54(m,1H),2.26(dd,J＝11.5,8.8Hz,2H),2.02–1.93(m,2H),1.84–1.69(m,4H),1.34(d,J＝7.0Hz,6H).

Example 8

4- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentan [ c ] pyridin-1-one

Compound 1 (40 mg,0.094 mmol) was dissolved in 3mL of dichloroethane, 1-bromo-2- (methylsulfonyl) ethane (21 mg,0.113 mmol), DBU (57 mg,0.37 mmol) was added and the reaction stirred at room temperature overnight. The reaction solution was extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 8 (38 mg, yield: 82%). LCMS ESI (+) m/z:496.2 (M+1).

LCMS ESI(+)m/z：496.2(M+1)。 ¹ H NMR(400MHz,DMSO)δ10.68(s,1H),7.55(s,1H),7.47(s,1H),7.20(d,J＝8.3Hz,1H),6.95(d,J＝8.4Hz,1H),3.50(s,3H),3.31(s,2H),3.07(s,3H),3.04–2.93(m,3H),2.78–2.68(m,6H),2.56(dd,J＝9.5,5.9Hz,1H),2.10(t,J＝10.6Hz,2H),2.01–1.93(m,2H),1.79(d,J＝11.3Hz,2H),1.68(dt,J＝12.0,9.0Hz,2H),1.34(d,J＝7.0Hz,6H).

Example 9

2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) ethanesulfonamide

Step A: 2-chloroethanesulfonamide (Compound 9.2)

2-Chloroethanesulfonyl chloride (100 mg,0.61 mmol) was dissolved in 5mL of THF, aqueous ammonia (0.5 mL) and triethylamine (186 mg,1.83 mmol) were added, and the reaction was stirred at room temperature overnight. The reaction solution was directly used for the next reaction. LCMS ESI (+) m/z:144 (M+1).

And (B) step (B): 2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) ethanesulfonamide (Compound 9)

9.2 (87 mg,0.61 mmol) was dissolved in 5mL THF and 4- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentadiene [ c ] was added]Pyridin-1-one (40 mg,0.103 mmol) and the reaction was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 9 (12 mg, yield: 24%). LCMS ESI (+) m/z:497 (M+1). ¹ H NMR(400MHz,DMSO)δ10.67(s,1H),7.55(s,1H),7.47(s,1H),7.20(d,J＝8.3Hz,1H),6.95(dd,J＝8.4,1.3Hz,1H),6.79(s,2H),3.50(s,3H),3.21–3.17(m,2H),3.02–2.93(m,3H),2.73(dt,J＝20.8,7.9Hz,6H),2.59–2.52(m,1H),2.11(dt,J＝16.8,8.5Hz,2H),2.03–1.92(m,2H),1.83–1.66(m,4H),1.34(d,J＝7.0Hz,6H).

Example 10

4- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one

Compound 1 (30 mg,0.077 mmol) was dissolved in 5mL of dichloromethane, triethylamine (31 mg,0.31 mmol), 3-oxetanone (22.2 mg,0.31 mmol), acetic acid (9.2 mg,0.15 mmol) and sodium triacetoxyborohydride (65.4 mg,0.31 mmol) were added, and the mixture was stirred at room temperature overnight. Spin-drying the solvent and purification by reverse phase preparation gave compound 10 (22 mg, yield: 64%). LCMS ESI (+) m/z:446.3 (M+1). ¹ H NMR(400MHz,DMSO)δ10.68(s,1H),7.55(s,1H),7.49(s,1H),7.21(d,J＝8.3Hz,1H),6.96(dd,J＝8.4,1.2Hz,1H),4.56(t,J＝6.5Hz,2H),4.46(t,J＝6.1Hz,2H),3.50(s,3H),3.42–3.39(m,1H),2.98(dt,J＝14.0,7.0Hz,1H),2.81(d,J＝10.9Hz,2H),2.72(q,J＝7.3Hz,4H),2.55(t,J＝4.1Hz,1H),1.98(dd,J＝14.9,7.5Hz,2H),1.88(dd,J＝11.3,9.2Hz,2H),1.74(dt,J＝12.0,7.7Hz,4H),1.34(d,J＝7.0Hz,6H).

Example 11

4- (5- (1- (dimethylglycine) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one

Dimethylglycine (10 mg,0.10 mmol) and triethylamine (50 mg,0.50 mmol) were dissolved in DMF (2 mL), HATU (38 mg,0.10 mmol) was added to the reaction system at room temperature and the reaction was stirred for 0.5 h. Compound 1 (40 mg,0.10 mmol) was then added and the reaction stirred at room temperature for 18 hours. The reaction solution was extracted with ethyl acetate 2 times, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to prepare and purify the product 11 (25 mg, yield: 53%) in reverse phase. LCMS ESI (+) m/z:475 (M+1), 238 (M/2+1). ¹ H NMR(400MHz,DMSO)δ10.69(s,1H),7.55(s,1H),7.47(s,1H),7.21(d,J＝8.4Hz,1H),6.94(dd,J＝8.4,1.2Hz,1H),4.53(d,J＝12.4Hz,1H),4.17(d,J＝12.4Hz,1H),3.50(s,3H),3.20–3.12(m,2H),3.08(d,J＝13.6Hz,1H),2.98(dt,J＝14.0,6.9Hz,1H),2.82(t,J＝12.0Hz,1H),2.75–2.69(m,3H),2.67–2.59(m,1H),2.22(s,6H),1.98(dq,J＝15.2,7.6Hz,3H),1.83(d,J＝12.4Hz,2H),1.72–1.60(m,1H),1.48(dd,J＝12.8,4.0Hz,1H),1.34(d,J＝7.2Hz,6H).

Example 12

4- (3-isopropyl-5- (1- (methylglycyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one

Step A: tert-butyl (2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentadi [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) (methyl) carbamate (compound 12.1)

Compound 1 (30 mg,0.077 mmol) was dissolved in 5mL of DMF, HATU (44 mg,0.115 mmol), DIPEA (30 mg, 0.231mmol) and N- (tert-butoxycarbonyl) -N-methylglycine (17.5 mg,0.092 mmol) were added and the reaction solution was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 12.1 (37 mg, yield: 86%), LCMS ESI (+) m/z:561.3 (M+1).

And (B) step (B): 4- (3-isopropyl-5- (1- (methylglycyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one (Compound 12)

Compound 12.1 (37 mg,0.066 mmol) was dissolved in 3mL of methanol, 3mL of 4M methanolic hydrochloric acid solution was added, and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase preparation to give product 12 (20 mg, yield: 66%). LCMS ESI (+) m/z:461.3 (M+1). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.77(s,1H),8.92(s,1H),7.56(s,1H),7.48(s,1H),7.23(d,J＝8.3Hz,1H),6.95(dd,J＝8.4,1.2Hz,1H),4.54(s,1H),4.15(dt,J＝15.8,5.5Hz,1H),4.05(dd,J＝16.2,6.6Hz,1H),3.77(d,J＝13.3Hz,1H),3.51(s,3H),3.18(t,J＝12.0Hz,1H),2.98(p,J＝7.0Hz,1H),2.94–2.84(m,1H),2.83–2.65(m,5H),2.58(t,J＝5.4Hz,3H),1.97(p,J＝7.6Hz,2H),1.88(d,J＝13.1Hz,2H),1.76–1.63(m,1H),1.58–1.43(m,1H),1.34(d,J＝7.0Hz,6H).

Example 13

4- (5- (1- (2-hydroxy-2-methylpropyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one

Compound 1 (15 mg,0.04 mmol) and 1-chloro-2-methylpropan-2-ol (217 mg,2.0 mmol) were dissolved in 5mL of DMF under nitrogen, DIEA (52 mg,0.4 mmol) was added and the reaction stirred at 120℃overnight. To the reaction solution was added 20mL of water, extracted with ethyl acetate (25 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 13 (2.5 mg, yield: 14%). LCMS ESI (+) m/z:462.3 (M+1). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.67(s,1H),7.55(s,1H),7.47(d,J＝1.5Hz,1H),7.20(d,J＝8.3Hz,1H),6.95(dd,J＝8.4,1.5Hz,1H),3.50(s,3H),3.10–2.94(m,4H),2.72(q,J＝7.8Hz,4H),2.30–2.20(m,4H),1.98(q,J＝7.5Hz,2H),1.73(td,J＝9.2,7.8,3.2Hz,4H),1.34(d,J＝7.0Hz,6H),1.11(s,6H).

Example 14

4- (3-isopropyl-5- (1- (2-morpholinoacetyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one

Compound 1 (70 mg) was dissolved in 10mL of NMP solution, and triethylamine (58 mg,0.58 mmol) and chloroacetyl chloride (33 mg,0.29 mmol) were added thereto, followed by stirring at room temperature for 1 hour. DBU (147 mg,0.78 mmol) and morpholine (50 mg,0.58 mmol) were added and stirred overnight at room temperature. Spin-drying the solvent and purification by reverse phase preparation gave compound 14 (40 mg, yield: 40%). LCMS ESI (+) m/z:517.3 (M+1). ¹ H NMR(400MHz,DMSO)δ10.70(s,1H),7.55(s,1H),7.47(s,1H),7.21(d,J＝8.3Hz,1H),6.94(dd,J＝8.4,1.2Hz,1H),4.52(d,J＝12.6Hz,1H),4.17(d,J＝13.0Hz,1H),3.59(t,J＝4.4Hz,4H),3.50(s,3H),3.28(s,1H),3.08(d,J＝13.3Hz,2H),2.98(dt,J＝14.1,7.0Hz,1H),2.84(dd,J＝16.0,8.0Hz,1H),2.72(d,J＝7.7Hz,4H),2.62(d,J＝10.8Hz,1H),2.43(d,J＝2.8Hz,4H),2.04–1.92(m,2H),1.83(t,J＝10.9Hz,2H),1.71(dd,J＝12.3,3.5Hz,1H),1.46(dd,J＝12.6,3.8Hz,1H),1.34(d,J＝7.0Hz,6H).

Example 15

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4- (3-isopropyl-5- (1- (4-methylpiperazine-1-carbonyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentan [ c ] pyridin-1-one

Step A: 4-Nitrophenyl 4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentan [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid ester (Compound 15.1)

Compound 1 (50 mg,0.12 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), DIPEA (31 mg,0.24 mmol) and 4-nitrophenoxy chloride (36 mg,0.18 mmol) were added at 0deg.C and reacted at room temperature for 2 hours. After the reaction was completed, the reaction was quenched by dropwise addition of saturated sodium bicarbonate solution, then extracted with DCM (20 ml×3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the product 15.1 (60 mg, yield: 90%). LCMS ESI (+) m/z:555 (M+1).

And (B) step (B): 4- (3-isopropyl-5- (1- (4-methylpiperazine-1-carbonyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentan [ c ] pyridin-1-one (compound 15)

Compound 15.1 (35 mg,0.06 mmol) and 1-methylpiperazine (30 mg,0.30 mmol) were added to DMF (4 mL) and reacted under microwaves at 150℃for 1.5 hours. After completion of the reaction, 10mL of water was added to the reaction solution, followed by extraction with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give product 15 (19 mg, yield: 41%). LCMS ESI (+) m/z:516 (M+1). ¹ H NMR(400MHz,d ₆ -DMSO)δ10.69(s,1H),8.14(s,1H),7.55(s,1H),7.47(s,1H),7.21(d,J＝8.3Hz,1H),6.95(dd,J＝8.4,1.1Hz,1H),3.71(d,J＝12.9Hz,2H),3.50(s,3H),3.17(s,4H),2.98(dt,J＝14.1,7.0Hz,1H),2.85(t,J＝11.9Hz,2H),2.72(dd,J＝15.9,7.6Hz,5H),2.35(s,4H),2.21(s,3H),2.06–1.90(m,2H),1.79(d,J＝11.0Hz,2H),1.71–1.54(m,2H),1.34(d,J＝7.0Hz,6H).

Example 16

2- (4- (3-isopropyl-2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

Step A: 5-bromo-1, 4-dimethyl-3-nitropyridin-2 (1H) -one (Compound 16.2)

5-bromo-4-methyl-3-nitropyridin-2 (1H) -one (500 mg,1.28 mmol) was dissolved in 7mL DMF, sodium hydride (103 mg,2.58 mmol) was added, the reaction stirred at room temperature for 0.5H, methyl iodide (366 mg,2.58 mmol) was added and the reaction stirred at room temperature for 2H. To the reaction solution was added 15mL of water, extracted with ethyl acetate (10 mL X3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 16.2 (333 mg, yield: 63%). LCMS ESI (+) m/z:247/249 (M+1).

And (B) step (B): (E) -5-bromo-4- (2- (dimethylamino) vinyl) -1-methyl-3-nitropyridin-2 (1H) -one (Compound 16.3)

Compound 16.2 (333 mg,1.35 mmol) was dissolved in 10mL of DMF, DMF-DMA (0.6 mL) was added and the reaction was stirred at 80℃for 4 hours. The reaction solution was concentrated under reduced pressure to give 16.3 (406 mg, yield: 100%). LCMS ESI (+) m/z:302/304 (M+1).

Step C: 4-bromo-6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one (Compound 16.4)

Compound 16.3 (406 mg,1.35 mmol) was dissolved in 10mL of acetic acid, iron powder (378 mg,6.75 mmol) was added, and the reaction was stirred overnight at 110 ℃. The reaction solution was filtered, concentrated under reduced pressure, added with water (10 mL), adjusted ph=7 with sodium hydrogencarbonate solution, extracted with ethyl acetate (3×35 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give product 16.4 (118 mg, yield: 39%). LCMS ESI (+) m/z:227/229 (M+1).

Step D:4- (3-isopropyl-2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (Compound 16.5)

Compound 16.4 (50 mg,0.22 mmol) and tert-butyl 4- (3-isopropyl-2- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H-indol-5-yl) piperidine-1-carboxylate (155 mg,0.33 mmol) were dissolved in 5mL dioxane and 1mL water, and potassium phosphate (140 mg,0.66 mmol) and PdCl were added ₂ (dppf) (32 mg,0.04 mmol), the reaction was stirred at 85℃for 2 hours. The reaction mixture was poured into water (10 mL), extracted with dichloromethane (3X 35 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentratedFiltration, concentration under reduced pressure and purification by column chromatography gave 16.5 (105 mg, yield: 98%). LCMS ESI (+) m/z:489.3 (M+1).

Step E:4- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one (Compound 16.6)

Compound 16.5 (105 mg,0.22 mmol) was dissolved in 3mL of methanol, HCl/MeOH (1 mL) was added dropwise, and the reaction was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to give 16.6 (85 mg, yield: 100%). LCMS ESI (+) m/z:389.2 (M+1).

Step F:2- (4- (3-isopropyl-2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide (Compound 16)

Compound 16.6 (47 mg,0.12 mmol) was dissolved in 3mL of dichloroethane, DBU (0.1 mL) and 2-bromoacetamide (19 mg,0.14 mmol) were added dropwise, and the reaction was stirred at room temperature for 4.5 hours. The reaction solution was added to water (10 mL), extracted with methylene chloride (3X 25 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give product 16 (5.7 mg, yield: 10%). LCMS ESI (+) m/z:446.2 (M+1). ¹ H NMR(400MHz,DMSO)δ12.12(s,1H),10.78(s,1H),8.20(s,1H),7.52(s,1H),7.33(t,J＝2.6Hz,1H),7.24(d,J＝8.3Hz,2H),7.21(s,1H),7.13(s,1H),6.97(d,J＝8.3Hz,1H),6.19(s,1H),3.59(s,3H),3.13(dt,J＝13.1,6.6Hz,2H),2.94(d,J＝11.0Hz,2H),2.89(s,2H),2.19(t,J＝10.0Hz,2H),1.83(dd,J＝22.6,12.8Hz,4H),1.37(d,J＝7.0Hz,6H).

Example 17

2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolyl [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide

Step A: pyridine-3, 4-dicarboxylic acid dimethyl ester (Compound 17.2)

Pyridine-3, 4-dicarboxylic acid (2.00 g,11.97 mmol) was added to 20mL thionyl chloride and the reaction was allowed to react overnight at 80 ℃. Concentrated under reduced pressure, added to 10mL of methanol at 0deg.C, and the reaction mixture was warmed to room temperature and stirred for 0.5 hours. The solid was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 17.2 (2.00 g, yield: 85%) of the product, LCMS ESI (+) m/z:196.1 (M+1).

And (B) step (B): 3, 4-bis (methoxycarbonyl) pyridine 1-oxide (Compound 17.3)

Compound 17.2 (500 mg,2.56 mmol) was dissolved in 7mL of acetonitrile, urea (308 mg,5.13 mmol) and 30% hydrogen peroxide (0.5 mL,5.13 mmol) were added at 0deg.C, trifluoroacetic anhydride (1.08 g,5.13 mmol) was slowly added, and the reaction was stirred at room temperature overnight. Water was added to dilute, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 17.3 (500 mg, yield: 93%). LCMS ESI (+) m/z:212.0 (M+1).

Step C: 2-chloropyridine-3, 4-dicarboxylic acid dimethyl ester (Compound 17.4)

Compound 17.3 (500 mg,2.37 mmol) was added to 6mL phosphorus oxychloride and reacted overnight at 110℃under nitrogen. The reaction solution was concentrated under reduced pressure, and the residue was added dropwise to water, adjusted to pH 8 with sodium hydrogencarbonate solution, extracted with ethyl acetate (15 mLx 2), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give product 17.4 (200 mg, yield: 37%). LCMS ESI (+) m/z:230.0 (M+1).

Step D: (2-chloropyridine-3, 4-diyl) dimethanol (Compound 17.5)

Compound 17.4 (155 mg,0.68 mmol) was dissolved in 5mL of ethanol and stirred at room temperature, sodium borohydride (154 mg,4.06 mmol) was added in portions, and the reaction was stirred at room temperature for 1 hour. After the completion of the reaction, pH was adjusted to 5 with formic acid, concentrated under reduced pressure, and purified by column chromatography to give 17.5 (100 mg, yield: 85%). LCMS ESI (+) m/z:174.0 (M+1).

Step E: 4-chloro-1, 3-dihydrofuran [3,4-c ] pyridine (Compound 17.6)

Compound 17.5 (100 mg,0.58 mmol) was added to 5mL of anhydrous dichloromethane, followed by manganese dioxide (100 mg,1.16 mmol), triethylsilane (1 mL) and trifluoroacetic acid (2 mL) in that order, and the reaction was stirred at room temperature overnight. The reaction solution was purified by column chromatography through a suction filter funnel covered with celite, washing with methylene chloride, concentrating under reduced pressure to give the product 17.6 (75 mg, yield: 83%). LCMS ESI (+) m/z:156.0 (M+1).

Step F: n- (2, 4-Dimethoxybenzyl) -1, 3-dihydrofuro [3,4-c ] pyridin-4-amine (Compound 17.7)

Compound 17.6 (75 mg,0.48 mmol) and 2, 4-dimethoxybenzylamine (162 mg,0.97 mmol) were dissolved in 5mL of anhydrous toluene, followed by sequential addition of Pd ₂ (dba) ₃ (44 mg,0.05 mmol), BINAP (60 mg,0.10 mmol) and t-Buona (184 mg,1.92 mmol). The reaction was carried out overnight at 100℃under nitrogen. After the completion of the reaction, the mixture was concentrated under reduced pressure, and purified by column chromatography to give 17.7 (70 mg, yield: 51%). LCMS ESI (+) m/z:287.1 (M+1).

Step G:1, 3-Dihydrofurano [3,4-c ] pyridin-4-amine (Compound 17.8)

Compound 17.7 (35 mg,0.12 mmol) was added to 2mL of trifluoroacetic acid, and the reaction was stirred at room temperature for 1 hour. After the completion of the reaction, the solid was concentrated under reduced pressure, washed with ethyl acetate, twice with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 17.8 (15 mg, yield: 90%) of the product, LCMS ESI (+) m/z:137.1 (M+1).

Step H: 7-bromo-1, 3-dihydrofuran [3,4-c ] pyridin-4-amine (Compound 17.9)

Compound 17.8 (15 mg,0.11 mmol) was dissolved in 3mL of acetonitrile, NBS (21 mg,0.12 mmol) was added thereto, and the mixture was reacted at room temperature for 2 hours. After the completion of the reaction, the mixture was concentrated under reduced pressure, and purified by column chromatography to give 17.9 (10 mg, yield: 42%). LCMS ESI (+) m/z:215.0 217.0 (M+1).

Step I: 6-bromo-7, 9-dihydrofuro [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridine (Compound 17.10)

Compound 17.9 (10 mg,0.05 mmol) was dissolved in 3mL of DMF and DMF-DMA (18 mg,0.15 mmol) was added and the reaction stirred at 85℃for 2.5 hours. Then concentrated under reduced pressure, the solid was dissolved in 3mL of methanol, pyridine (5 mg,0.06 mmol) and hydroxylamine-0-sulfonic acid (7 mg,0.06 mmol) were added, and the reaction was stirred at room temperature overnight. After the completion of the reaction, the mixture was concentrated under reduced pressure, a potassium phosphate solution and ethyl acetate were added to extract, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 17.10 (7 mg, yield: 59%) of a product, LCMS ESI (+) m/z:240.0 (M+1).

Step J: tert-butyl 4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolyl [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (Compound 17.11)

Compound 17.10 (7 mg,0.029 mmol) and tert-butyl 4- (3-isopropyl-2- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) -1H-indol-5-yl) piperidine-1-carboxylate (14 mg,0.029 mmol) were added to a mixture of 3mL 1, 4-dioxane and 0.6mL water followed by potassium phosphate (18 mg,0.087 mmol) and Pd (dppf) Cl ₂ (4 mg, 0.006mmol) and under nitrogen, 85℃for 2 hours. The reaction was quenched with water, extracted with ethyl acetate (5 mLX) and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give product 17.11 (6 mg, yield: 41%), LCMS ESI (+) m/z:502.3 (M+1). ¹ H NMR(400MHz,MeOD)δ8.73(s,1H),8.47(s,1H),7.59(s,1H),7.31(d,J＝8.4Hz,1H),7.05(d,J＝8.3Hz,1H),5.45(s,2H),5.18(s,2H),4.21(d,J＝13.0Hz,2H),3.11(dt,J＝14.0,7.0Hz,1H),2.89(d,J＝19.0Hz,2H),2.77(t,J＝12.1Hz,1H),1.85(d,J＝12.3Hz,2H),1.66(td,J＝12.6,3.8Hz,2H),1.49(s,9H),1.44(d,J＝7.0Hz,6H).

Step K:6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolyl [1,5-a ] pyridine (Compound 17.12)

Compound 17.11 (6 mg,0.012 mmol) was added to 1mL of methanol, 1mL of 4M hydrogen chloride in methanol was added to the ice bath, and the reaction mixture was reacted at room temperature for 2 hours. Concentration under reduced pressure gave crude 17.12 (4 mg), LCMS ESI (+) m/z:402.1 (M+1).

Step L:2- (4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazolyl [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide (Compound 17)

Compound 17.12 (4 mg,0.01 mmol) was dissolved in 3mL of DCE, 2-bromoacetamide (2 mg,0.01 mmol) and DBU (6 mg,0.04 mmol) were added and the reaction stirred at room temperature for 3 hours. After the completion of the reaction, water and ethyl acetate were added to extract, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give product 17 (2.3 mg, yield: 50%), LCMS ESI (+) m/z:459.2 (M+1).

¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.49(s,1H),7.64(s,1H),7.32(d,J＝8.4Hz,1H),7.10(dd,J＝8.5,1.5Hz,1H),5.47(t,J＝3.0Hz,2H),5.21–5.16(m,2H),4.59(s,2H),3.38(s,1H),3.26(s,1H),3.12(dt,J＝17.6,7.0Hz,1H),2.81–2.71(m,1H),2.64(t,J＝9.8Hz,2H),2.08-1.96(m,4H),1.45(d,J＝7.0Hz,6H).

Example 18

4- (5- (1- (2- (3, 3-difluoropyrrolidin-1-yl) acetyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one

Compound 1 (50 mg) was dissolved in 10mL of NMP solution, and triethylamine (40 mg,0.38 mmol) and chloroacetyl chloride (22 mg,0.19 mmol) were added thereto, followed by stirring at room temperature for 1 hour. DBU (98 mg,0.64 mmol) and 3, 3-difluoropyrrolidine (55 mg,0.38 mmol) were added and stirred overnight at room temperature. Spin-drying the solvent and purification by reverse phase preparation gave compound 18 (14 mg, yield: 20%). LCMS ESI (+) m/z:537.3 (M+1). ¹ H NMR(400MHz,DMSO)δ10.70(s,1H),7.55(s,1H),7.47(s,1H),7.21(d,J＝8.3Hz,1H),6.94(dd,J＝8.4,1.3Hz,1H),4.52(d,J＝13.0Hz,1H),4.03(d,J＝13.1Hz,1H),3.50(s,3H),3.14–2.93(m,4H),2.87–2.78(m,3H),2.78–2.58(m,6H),2.28(ddd,J＝22.6,9.4,4.7Hz,3H),1.98(dd,J＝14.8,7.4Hz,2H),1.82(d,J＝11.3Hz,2H),1.66(dd,J＝21.3,12.1Hz,1H),1.54–1.43(m,1H),1.33(d,J＝7.0Hz,6H).

Example 19

4- (3-isopropyl-5- (1- (2- (methylsulfonyl) acetyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentan [ c ] pyridin-1-one

The specific reaction equation is shown below:

2- (methylsulfonyl) acetic acid (17 mg,0.12 mmol) was dissolved in 5mL of DMF, DIPEA (39 mg,0.3 mmol) and HATU (57 mg,0.15 mmol) were added sequentially and the reaction stirred at room temperature for 0.5 h, then Compound 1 (40 mg,0.1 mmol) was added and stirred at room temperature overnight. To the reaction solution was added 15mL of water, extracted with methylene chloride (10 mL X3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified in the opposite direction to give product 19 (17.9 mg, yield: 35%). LCMS ESI (+) m/z:510 (M+1). ¹ H NMR(400MHz,DMSO)δ10.70(s,1H),7.55(s,1H),7.47(s,1H),7.22(d,J＝8.3Hz,1H),6.94(d,J＝8.4Hz,1H),4.56(d,J＝14.5Hz,1H),4.49(t,J＝9.6Hz,2H),4.12(d,J＝13.1Hz,1H),3.50(s,3H),3.22–3.10(m,5H),3.01–2.96(m,1H),2.86(t,J＝12.0Hz,1H),2.72(t,J＝8.0Hz,4H),2.00–1.95(m,2H),1.84(s,2H),1.77–1.68(m,1H),1.54–1.47(m,1H),1.34(d,J＝7.0Hz,6H).

Example 20

4- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) -4-oxobutyronitrile

The specific reaction equation is shown below:

3-Cyanopropionic acid (12 mg,0.12 mmol) was dissolved in 5mL of DMF, DIPEA (39 mg,0.3 mmol) and HATU (57 mg,0.15 mmol) were added sequentially, the reaction stirred at room temperature for 0.5 h, compound 1 (40 mg,0.1 mmol) was added and stirring at room temperature was continued overnight. To the reaction solution was added 15mL of water, extracted with methylene chloride (10 mL X3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified in the opposite direction to give 20 (24 mg, yield: 51%). LCMS ESI (+) m/z:471 (M+1). ¹ H NMR(400MHz,DMSO)δ10.70(s,1H),7.55(s,1H),7.48(s,1H),7.21(d,J＝8.3Hz,1H),6.95(dd,J＝8.4,1.3Hz,1H),4.56(d,J＝13.3Hz,1H),3.94(d,J＝13.5Hz,1H),3.50(s,3H),3.12(t,J＝12.0Hz,1H),3.01–2.94(m,1H),2.88–2.78(m,2H),2.78–2.73(m,2H),2.70(s,2H),2.67(dd,J＝3.6,1.9Hz,2H),2.64(d,J＝6.6Hz,2H),2.02–1.93(m,2H),1.83(d,J＝12.3Hz,2H),1.67(dt,J＝12.4,8.9Hz,1H),1.50(dt,J＝12.3,8.7Hz,1H),1.33(d,J＝7.0Hz,6H).

Example 21

N- (2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-4-yl) -1H-indol) -5-yl) piperidin-1-yl) -2-oxoethyl) methanesulfonamide

The specific reaction equation is shown below:

compound 1 (40 mg,0.1 mmol) was dissolved in 4 mM LDMF, and (methylsulfonyl) glycine (18.4 mg,0.12 mmol), EDCI (28.8 mg,0.15 mmol), DMAP (18.3 mg,0.15 mmol) and DIPEA (25.8 mg,0.2 mmol) were added and the reaction stirred at room temperature for 2 hours. To the reaction mixture was added 5mL of water, extracted with ethyl acetate (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give compound 21 (7.6 mg, yield: 14.5%). LCMS ESI (+) m/z:525.2 (M+1).

¹ H NMR(400MHz,DMSO)δ10.70(s,1H),7.55(s,1H),7.48(s,1H),7.21(d,J＝8.3Hz,1H),7.02(s,1H),6.97–6.92(m,1H),4.53(d,J＝13.0Hz,1H),4.11–3.80(m,3H),3.50(s,3H),3.13(t,J＝12.5Hz,1H),3.02–2.94(m,4H),2.84(t,J＝12.0Hz,1H),2.76–2.65(m,5H),2.03–1.92(m,2H),1.84(d,J＝12.2Hz,2H),1.68(d,J＝13.1Hz,1H),1.52(d,J＝8.8Hz,1H),1.34(d,J＝7.0Hz,6H).

Example 22

4- (5- (1- (2- (3, 3-difluoropyrrolidin-1-yl) -2-oxoethyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-1-one

The specific reaction equation is shown below:

step A: ethyl 2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetate (compound 22.1)

Compound 1 (100 mg,0.26 mmol) and ethyl 2-bromoacetate (43.4 mg,0.26 mmol) were dissolved in 10mL of DCE, DBU (79 mg,0.52 mmol) was added, and the reaction was stirred at room temperature for 1 hour. To the reaction solution was added 20mL of a saturated ammonium chloride solution, which was extracted with ethyl acetate (25 mLX), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give a product 22.1 (120 mg, yield: 98.4%). LCMS ESI (+) m/z:476.3 (M+1).

And (B) step (B): 2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetic acid (Compound 22.2)

Compound 22.1 (120 mg,0.25 mmol) was dissolved in 10mL of ethanol, 2mL of 10% aqueous NaOH solution was added, and the reaction mixture was stirred at room temperature for 1 hour. To the reaction solution was added 20mL of a diluted hydrochloric acid solution, extracted with ethyl acetate (25 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give product 22.2 (102 mg, yield: 91.3%). Lcmsei (+) m/z:448.3 (M+1).

Step C:4- (5- (1- (2- (3, 3-difluoropyrrolidin-1-yl) -2-oxoethyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-1-one (compound 22)

Compound 22.2 (102 mg,0.23 mmol) and 3, 3-difluoropyrrolidine (24.6 mg,0.23 mmol) were dissolved in 10mL DMF and HATU (129.2 mg,0.34 mmol) and DIEA (59.3 mg,0.46 mmol) were added and the reaction stirred at room temperature for 1 h. To the reaction solution was added 20mL of a saturated ammonium chloride solution, which was extracted with ethyl acetate (25 mLX), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 22 (28 mg, yield: 22.9%). LCMS ESI (+) m/z:537.3 (M+1). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.68(s,1H),7.55(s,1H),7.47(d,J＝1.5Hz,1H),7.21(d,J＝8.3Hz,1H),6.96(dd,J＝8.4,1.6Hz,1H),4.08(t,J＝13.1Hz,1H),3.84(t,J＝7.4Hz,1H),3.72(t,J＝13.4Hz,1H),3.53(t,J＝7.5Hz,1H),3.50(s,3H),3.16(d,J＝19.2Hz,2H),3.02–2.91(m,3H),2.72(q,J＝7.8Hz,4H),2.41(ddd,J＝28.4,14.1,6.9Hz,3H),2.24–2.13(m,2H),1.97(p,J＝7.6Hz,2H),1.82–1.63(m,4H),1.34(d,J＝7.0Hz,6H).

Example 23

4- (3-isopropyl-5- (1- (2- (2-methyl-2H-tetrazol-5-yl) acetyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-1-one

The specific reaction equation is shown below:

step A:2- (2-methyl-2H-tetrazol-5-yl) acetic acid ethyl ester (Compound 23.2)

Compound 23.1 (1.0 g,6.41 mmol) was dissolved in 40mL of acetonitrile, then methyl iodide (2.27 g,16.02 mmol) and potassium carbonate (2.21 mg,16.02 mmol) were added, stirred overnight at 80℃and the reaction was complete as detected by LCMS, extracted with ethyl acetate (100 mLX 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give product 23.2 (190 mg, yield: 17%). LCMS ESI (+) m/z:171.0 (M+1).

And (B) step (B): 2- (2-methyl-2H-tetrazol-5-yl) acetic acid (Compound 23.3)

Compound 23.2 (180 mg,1.05 mmol) was dissolved in 3mL of methanol and 1mL of water, then sodium hydroxide (127 mg,3.17 mmol) was added and reacted at room temperature for 2 hours. Direct spin-dry, add DCM: meoh=10:1 solvent 20mL to dissolve, filter, concentrate under reduced pressure, oil pump dry to give crude 23.3 (300 mg). LCMS ESI (+) m/z:143.1 (M+1).

Step C:4- (3-isopropyl-5- (1- (2- (2-methyl-2H-tetrazol-5-yl) acetyl) piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-1-one (compound 23)

Compound 23.3 (30 mg,0.206 mmol) and 4- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c]Pyridin-1-one (40 mg,0.103 mmol) was dissolved in 4mL of DMF, then DMAP (25 mg,0.206 mmol), DIPEA (66 mg,0.515 mmol) and EDCI (39 mg,0.206 mmol) were added and the reaction stirred overnight at room temperature. LCMS monitoring reaction 50%. Purification by reverse phase preparation gave product 23 (14.2 mg, yield: 13%). LCMS ESI (+) m/z:514.3 (M+1). ¹ H NMR(400MHz,DMSO)δ10.70(s,1H),7.56(s,1H),7.49(s,1H),7.22(d,J＝8.3Hz,1H),6.96(d,J＝8.4Hz,1H),4.53(d,J＝12.6Hz,1H),4.34(s,3H),4.12(d,J＝16.5Hz,3H),3.50(s,3H),3.20(s,1H),2.98(d,J＝7.0Hz,1H),2.85(t,J＝12.1Hz,1H),2.75–2.66(m,5H),1.98(dd,J＝14.9,7.5Hz,2H),1.84(d,J＝12.6Hz,2H),1.69(dd,J＝12.4,3.5Hz,1H),1.52(dd,J＝12.7,4.0Hz,1H),1.35(d,J＝7.0Hz,6H).

Example 24

N-cyclopropyl-2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

The specific reaction equation is shown below:

compound 22.2 (50 mg,0.112 mmol) was dissolved in 3mL of DMF, HATU (63.9 mg,0.168 mmol) and TEA (34 mg,0.336 mmol) were added, the reaction stirred at room temperature for 30 min, cyclopropylamine (9.6 mg,0.168 mmol) was added under ice-bath conditions and the reaction stirred at room temperature for 1 h. To the reaction solution was added 5mL of water, extracted with methylene chloride (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give compound 24 (7.4 mg, yield: 13.6%). LCMS ESI (+) m/z:487.2 (M+1). ¹ H NMR(400MHz,DMSO)δ10.68(s,1H),7.74(d,J＝3.6Hz,1H),7.55(s,1H),7.48(s,1H),7.20(d,J＝8.3Hz,1H),6.97(d,J＝8.4Hz,1H),3.50(s,3H),3.03–2.95(m,1H),2.90(d,J＝12.5Hz,4H),2.72(dd,J＝15.4,7.7Hz,4H),2.68–2.61(m,2H),2.17(t,J＝9.7Hz,2H),2.03–1.92(m,2H),1.86–1.69(m,4H),1.34(d,J＝7.0Hz,6H),0.70–0.56(m,2H),0.54–0.41(m,2H).

Example 25

N- (2- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta-di [ c ] pyridin-4-yl) -1H-indol) -5-yl) piperidin-1-yl) -2-oxoethyl) acetamide

The specific reaction equation is shown below:

compound 1 (30 mg,0.077 mmol) was dissolved in 4mL of DMF, acetylglycine (18 mg,0.154 mmol), EDCI (29.5 mg,0.154 mmol), DMAP (18.8 mg,0.154 mmol) and DIPEA (50 mg,0.385 mmol) were added and the reaction stirred at room temperature overnight. To the reaction solution was added 5mL of water, extracted with methylene chloride (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 25 (15.4 mg, yield: 41.0%). LCMS ESI (+) m/z:489.3 (M+1). ¹ H NMR(400MHz,DMSO)δ10.70(s,1H),7.96(t,J＝5.2Hz,1H),7.52(d,J＝8.4Hz,2H),7.21(d,J＝8.4Hz,1H),6.95(d,J＝9.5Hz,1H),4.53(d,J＝13.5Hz,1H),4.08–3.82(m,3H),3.50(s,3H),3.12(t,J＝12.3Hz,1H),3.04–2.93(m,1H),2.83(t,J＝12.1Hz,1H),2.75–2.67(m,5H),2.03–1.93(m,2H),1.92–1.78(m,5H),1.73–1.59(m,1H),1.58–1.43(m,1H),1.34(d,J＝7.0Hz,6H).

Example 26

2- (4-bromophenyl) ethan-1-ol-2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide

The specific reaction equation is shown below:

compound 17.12 (25 mg,0.0623 mmol) was dissolved in 3mL of tetrahydrofuran, 2-chloro-N-methylacetamide (20.1 mg,0.187 mmol), DIEA (80.6 mg, 0.627 mmol), K was added ₂ CO ₃ (17.2 mg,0.124 mmol) and KI (20.6 mg,0.124 mmol), the reaction was stirred at 60℃overnight. To the reaction mixture was added 5mL of water, extracted with ethyl acetate (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give compound 26 (4.1 mg, yield: 13.9%). LCMS ESI (+) m/z:473.3 (M+1). ¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.49(s,1H),7.64(s,1H),7.32(d,J＝8.4Hz,1H),7.11(s,1H),5.46(s,2H),5.19(d,J＝3.1Hz,2H),3.36(s,2H),3.24(d,J＝11.3Hz,2H),3.12(dt,J＝14.1,7.0Hz,1H),2.81(s,3H),2.75(t,J＝11.4Hz,1H),2.64(t,J＝10.6Hz,2H),2.11–1.93(m,4H),1.45(d,J＝7.0Hz,6H).

Example 27

4- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazol [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -4-oxobutanenitrile

The specific reaction equation is shown below:

3-Cyanopropionic acid (7 mg,0.07 mmol) was dissolved in 5mL of DMF, DIPEA (23 mg,0.18 mmol) and HATU (34 mg,0.09 mmol) were added sequentially, the reaction stirred at room temperature for 0.5 h, compound 17.12 (25 mg,0.06 mmol) was added and stirred at room temperature overnight. 15mL of water was added to the reaction mixture, extracted with methylene chloride (10 mL X3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified in the reverse direction to give product 27 (13.2 m) g, yield: 45%). LCMS ESI (+) m/z:483.2 (M+1). ¹ H NMR(400MHz,DMSO)δ11.01(s,1H),8.92(s,1H),8.61(s,1H),7.56(s,1H),7.29(d,J＝8.4Hz,1H),7.03(dd,J＝8.4,1.1Hz,1H),5.42(s,2H),5.12(t,J＝3.0Hz,2H),4.57(d,J＝12.9Hz,1H),3.95(d,J＝13.0Hz,1H),3.16–3.01(m,2H),2.89–2.67(m,4H),2.65(d,J＝6.6Hz,2H),1.84(d,J＝12.1Hz,2H),1.75–1.65(m,1H),1.57–1.48(m,1H),1.38(d,J＝7.0Hz,6H).

Example 28

N- (2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) methanesulfonamide

The specific reaction equation is shown below:

compound 17.12 (25 mg,0.0623 mmol) was dissolved in 3mL of DMF, and (methylsulfonyl) glycine (19 mg,0.125 mmol), EDCI (24 mg,0.125 mmol), DMAP (15.3 mg,0.125 mmol) and DIPEA (24.2 mg,0.188 mmol) were added and the reaction stirred at room temperature for 2 hours. To the reaction mixture was added 5mL of water, extracted with ethyl acetate (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give compound 28 (7.1 mg, yield: 21.3%). LCMS ESI (+) m/z:537.2 (M+1).

¹ H NMR(400MHz,DMSO)δ11.01(s,1H),8.92(s,1H),8.61(s,1H),7.57(s,1H),7.30(d,J＝8.4Hz,1H),7.03(t,J＝6.9Hz,2H),5.42(s,2H),5.13(s,2H),4.55(d,J＝12.0Hz,1H),4.05–3.88(m,3H),3.30(s,1H),3.14(t,J＝12.3Hz,1H),3.06(dd,J＝14.1,7.1Hz,1H),2.97(s,3H),2.87(t,J＝11.8Hz,1H),1.85(d,J＝11.6Hz,2H),1.77–1.66(m,1H),1.54(dd,J＝22.0,12.7Hz,1H),1.38(d,J＝7.0Hz,6H).

Example 29

4- (5- (1- (cyclopropylglycinyl) piperidin-4-yl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-1-one

The specific reaction equation is shown below:

compound 1 (50 mg,0.12 mmol) was dissolved in 5mL of NMP, triethylamine (38.96 mg,0.38 mmol) and chloroacetyl chloride (21.74 mg,0.19 mmol) were added, the reaction was allowed to react at 0℃for 0.5 hours, then allowed to react at room temperature for 4 hours, the starting material disappeared, DBU (97.63 mg,0.64 mmol) and cyclopropylamine (10.99 mg,0.19 mmol) were then added, and the reaction was allowed to react at room temperature overnight. To the reaction solution was added 5mL of ammonium chloride, extracted with ethyl acetate (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give compound 29 (2.1 mg, yield: 4.0%). LCMS ESI (+) m/z:487.3 ¹ HNMR(400MHz,CDCl ₃ )δ7.83(s,1H),7.57(s,1H),7.31(d,J＝8.5Hz,1H),7.17(s,1H),7.03(s,1H),4.80(d,J＝13.4Hz,1H),3.88(d,J＝13.5Hz,1H),3.80–3.64(m,2H),3.60(s,3H),3.20(t,J＝12.3Hz,1H),3.04(p,J＝6.9Hz,1H),2.91(t,J＝7.4Hz,3H),2.81–2.67(m,3H),2.40(s,1H),2.12–1.95(m,7H),1.40(d,J＝7.1Hz,6H),0.70(s,2H),0.58(d,J＝6.3Hz,2H).

Example 30

1- (4- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) methyl) cyclopropane-1-carbonitrile

The specific reaction equation is shown below:

compound 1 (10 mg,0.025 mmol) was dissolved in 5mL of acetonitrile, 1- (bromomethyl) cyclopropane-1-carbonitrile (4.1 mg,0.025 mmol), DIPEA (6.63 mg,0.051 mmol) was added, the reaction was reacted overnight at 80℃to which was added 5mL of ammonium chloride, extracted with ethyl acetate (10 mLX 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give compound 30 (3 mg, yield: 25%). LCMS ESI (+) m/z:469.3. ¹ H NMR(400MHz,DMSO)δ10.68(s,1H),7.56(s,1H),7.48(s,1H),7.21(d,J＝8.3Hz,1H),6.97(dd,J＝8.4,1.6Hz,1H),3.50(s,3H),3.12(d,J＝11.3Hz,2H),3.04–2.93(m,1H),2.72(q,J＝7.8Hz,4H),2.52(s,1H),2.45(s,2H),2.12(td,J＝11.4,2.9Hz,2H),1.96(q,J＝7.8Hz,2H),1.86–1.66(m,4H),1.34(d,J＝7.0Hz,6H),1.30–1.21(m,2H),0.99–0.88(m,2H).

example 31

2- (3, 3-difluoropyrrolidin-1-yl) -1- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazol [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethanone

The specific reaction equation is shown below:

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compound 17.12 (20 mg,0.05 mmol) was added to 3mL of N-methylpyrrolidone, triethylamine (25 mg,0.25 mmol) was added, chloroacetyl chloride (8 mg,0.08 mmol) was added to an ice bath, and the reaction solution was reacted at room temperature for 1.5 hours. DBU (38 mg,0.25 mmol) and 3, 3-difluoropyrrolidine hydrochloride (11 mg,0.08 mmol) were added and the reaction stirred at room temperature overnight. After the completion of the reaction, water and ethyl acetate were added to extract, and the organic phase was washed with saturated brine and dried Drying over sodium sulfate, filtration, concentration under reduced pressure, and purification by reverse phase preparation gave product 31 (11.7 mg, yield: 43%), LCMS ESI (+) m/z:549.3 (M+1). ¹ H NMR(400MHz,DMSO)δ11.01(s,1H),8.91(s,1H),8.61(s,1H),7.55(s,1H),7.30(d,J＝8.4Hz,1H),7.03(d,J＝8.5Hz,1H),5.42(s,2H),5.13(s,2H),4.53(d,J＝12.0Hz,1H),4.04(d,J＝13.0Hz,1H),3.51(d,J＝14.2Hz,1H),3.30(d,J＝6.7Hz,1H),3.14–2.95(m,4H),2.83(dt,J＝6.7,4.8Hz,2H),2.66(dd,J＝19.4,10.6Hz,2H),2.24(ddd,J＝28.0,13.8,6.3Hz,2H),1.84(d,J＝11.6Hz,2H),1.68(dt,J＝12.0,9.0Hz,1H),1.50(dt,J＝12.3,8.6Hz,1H),1.38(d,J＝7.0Hz,6H).

Example 32

6- (3-isopropyl-5- (1- (2- (methylsulfonyl) ethyl) piperidin-4-yl) -1H-indol-2-yl) -7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridine

The specific reaction equation is shown below:

compound 17.12 (30 mg,0.07 mmol) was dissolved in 2mL of dichloroethane, 1-bromo-2- (methylsulfonyl) ethane (16 mg,0.08 mmol), DBU (42 mg,0.28 mmol) was added and the reaction stirred at room temperature overnight. The reaction solution was extracted with methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 32 (16.1 mg, yield: 46%), LCMS ESI (+) m/z:508.2 (M+1). ¹ H NMR(400MHz,DMSO)δ10.99(s,1H),8.92(s,1H),8.61(s,1H),7.55(s,1H),7.29(d,J＝8.4Hz,1H),7.04(d,J＝8.5Hz,1H),5.42(s,2H),5.13(s,2H),3.10–2.99(m,6H),2.76(s,2H),2.59(s,1H),2.52(s,2H),2.12(s,2H),1.86–1.64(m,4H),1.38(d,J＝7.0Hz,

Example 33

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6- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -7, 9-dihydrofuran [3,4-c ] [1,2,4] triazol [1,5-a ] pyridine

The specific reaction equation is shown below:

compound 17.12 (25 mg,0.06 mmol) was added to 3mL of dichloromethane, 3-oxetanone (18 mg,0.25 mmol), acetic acid (7 mg,0.13 mmol) and sodium triacetoxyborohydride (53 mg,0.25 mmol) were added, and the reaction was stirred at room temperature overnight. After the completion of the reaction, the reaction was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give product 33 (10.4 mg, yield: 37%), LCMS ESI (+) m/z:458.2 (M+1). ¹ HNMR(400MHz,DMSO)δ11.00(s,1H),8.91(s,1H),8.61(s,1H),7.57(s,1H),7.29(d,J＝8.4Hz,1H),7.05(dd,J＝8.4,1.3Hz,1H),5.42(d,J＝2.9Hz,2H),5.13(t,J＝3.1Hz,2H),4.56(t,J＝6.5Hz,2H),4.47(t,J＝6.1Hz,2H),3.05(dt,J＝14.0,7.0Hz,1H),2.82(d,J＝11.0Hz,2H),2.59(ddd,J＝11.4,9.8,4.1Hz,1H),2.53(d,J＝1.9Hz,1H),1.88(dt,J＝10.9,5.6Hz,2H),1.84–1.68(m,4H),1.39(d,J＝7.0Hz,6H).

Example 34

2- (cyclopropylamino) -1- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazol [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethanone

The specific reaction equation is shown below:

compound 17.12 (35 mg,0.09 mmol) was added to 4mL of N-methylpyrrolidone, triethylamine (44 mg,0.44 mmol) was added, chloroacetyl chloride (15 mg,0.13 mmol) was added to an ice bath, and the reaction solution was reacted at room temperature for 1.5 hours. DBU (66 mg,0.44 mmol) and cyclopropylamine (7 mg,0.13 mmol) were then added and the reaction stirred at room temperature overnight. After the completion of the reaction, water and ethyl acetate were added to extract, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give product 34 (8.3 mg, yield: 19%), LCMS ESI (+) m/z:499.3 (M+1). ¹ H NMR(400MHz,DMSO)δ11.02(s,1H),8.92(s,1H),8.62(s,1H),7.57(s,1H),7.30(d,J＝8.4Hz,1H),7.04(dd,J＝8.4,1.3Hz,1H),5.43(s,2H),5.13(t,J＝3.1Hz,2H),4.58(d,J＝12.4Hz,1H),3.95(d,J＝13.2Hz,1H),3.47(d,J＝15.1Hz,2H),3.06(dd,J＝18.4,11.3Hz,2H),2.87(tt,J＝11.6,3.1Hz,1H),2.67(dd,J＝7.9,6.2Hz,1H),2.53(d,J＝1.9Hz,1H),2.18(ddd,J＝10.0,6.7,3.6Hz,1H),1.85(d,J＝11.5Hz,2H),1.67(ddd,J＝16.5,13.3,4.3Hz,1H),1.53(ddd,J＝25.1,12.6,4.0Hz,1H),1.39(d,J＝7.0Hz,6H),0.42–0.32(m,2H),0.31–0.23(m,2H).

Example 35

2- (4- (2- (1, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide

The specific reaction equation is shown below:

step A: 4-bromo-1, 6-dimethyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one (Compound 35.2)

NaH (27 mg,0.664 mmol) was placed in a 100mL three-necked flask, replaced with argon three times, and 4-bromo-6-methyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] was added dropwise under ice-bath conditions ]Dissolution of pyridin-7-one (100 mg, 0.447 mmol) in DMF (5 mL)The reaction mixture was stirred at room temperature for 30 minutes, and then CH was added ₃ I (94.2 mg,0.664 mmol), the reaction was stirred at room temperature for 1 hour. To the reaction solution was added 5mL of an aqueous ammonium chloride solution, which was extracted with ethyl acetate (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 35.2 (87 mg, yield: 81.8%), LCMS ESI (+) m/z:241.0 (M+1).

And (B) step (B): tert-butyl 4- (2- (1, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (Compound 35.3)

Compound 35.2 (67 mg,0.28 mmol) was dissolved in 5mL of 1, 4-dioxane solution and 1mL of water, 4- (2- (((12-azamethylene) phosphino) iodoborane) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (196.6 mg,0.42 mmol), K was added ₃ PO ₄ (178.3mg，0.84mmol)，Pd(dppf)Cl ₂ (41 mg,0.056 mmol) and the reaction was replaced with argon three times and stirred at 85℃for 2 hours. To the reaction solution was added 5mL of water, extracted with ethyl acetate (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 35.3 (141 mg, yield: 100%), LCMS ESI (+) m/z:503.3 (M+1).

Step C:4- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -1, 6-dimethyl-1, 6-dihydro-7H-pyrrolo [2,3-c ] pyridin-7-one (Compound 35.4)

To compound 35.3 (141 mg,0.28 mmol) was added dropwise a methanol solution of hydrochloric acid (5 mL), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was neutralized with aqueous NaOH, extracted with iPrOH: dcm=1:3 (10 mLX 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 35.4 (113 mg, yield: 100%), LCMS ESI (+) m/z:403.2 (M+1).

Step D:2- (4- (2- (1, 6-dimethyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide (Compound 35)

Compound 35.4 (11)3mg,0.28 mmol) was dissolved in 5mL DCE, 2-bromoacetamide (47 mg,0.336 mmol) and DBU (170 mg,1.12 mmol) were added and the reaction stirred at room temperature for 3 hours. To the reaction solution was added 5mL of water, extracted with ethyl acetate (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give compound 35 (22.5 mg, yield: 17.5%), LCMS ESI (+) m/z:460.3 (M+1). ¹ H NMR(400MHz)δ10.76(s,1H),7.52(s,1H),7.32(d,J＝2.8Hz,1H),7.26(s,1H),7.24(d,J＝8.3Hz,1H),7.19(s,1H),7.14(s,1H),6.97(dd,J＝8.4,1.4Hz,1H),6.10(d,J＝2.8Hz,1H),4.11(s,3H),3.54(s,3H),3.14–3.05(m,1H),3.03–2.84(m,4H),2.52(s,1H),2.20(s,2H),1.91–1.72(m,4H),1.36(d,J＝7.0Hz,6H).

Example 36

1- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazol [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-morpholinoethanone

The specific reaction equation is shown below:

compound 17.12 (20 mg,0.05 mmol) was added to 3mL of N-methylpyrrolidone, triethylamine (25 mg,0.25 mmol) was added, chloroacetyl chloride (8 mg,0.08 mmol) was added to an ice bath, and the reaction solution was reacted at room temperature for 1.5 hours. DBU (38 mg,0.25 mmol) and morpholine (7 mg,0.08 mmol) were added and the reaction stirred at room temperature overnight. After the completion of the reaction, water and ethyl acetate were added to extract, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give product 36 (11.5 mg, yield: 44%), LCMS ESI (+) m/z:529.3 (M+1). ¹ H NMR(400MHz,DMSO)δ11.02(s,1H),8.92(s,1H),8.61(s,1H),7.55(s,1H),7.30(d,J＝8.4Hz,1H),7.02(dd,J＝8.4,1.3Hz,1H),5.42(t,J＝2.8Hz,2H),5.13(t,J＝3.1Hz,2H),4.53(d,J＝12.5Hz,1H),4.18(d,J＝13.1Hz,1H),3.60(t,J＝4.5Hz,4H),3.31(d,J＝13.5Hz,2H),3.11–3.03(m,2H),2.87(t,J＝12.0Hz,1H),2.69–2.61(m,1H),2.44(d,J＝3.3Hz,4H),1.85(t,J＝10.9Hz,2H),1.74(td,J＝12.2,3.4Hz,1H),1.48(ddd,J＝25.3,12.6,3.7Hz,1H),1.38(d,J＝7.0Hz,6H).

Example 37

1- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one

The specific reaction equation is shown below:

step A: tert-butyl (2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl) -1H-indol-5-yl) piperidin-1-yl) -2-oxoethyl) (methyl) carbamate (Compound 37.1)

Compound 17.12 (30 mg,0.075 mmol) was dissolved in 5mL of DMF, HATU (42 mg,0.112 mmol), DIPEA (29 mg,0.224 mmol) and N- (tert-butoxycarbonyl) -N-methylglycine (18.4 mg,0.097 mmol) were added and the reaction solution was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 37.1 (36 mg, yield: 85%), LCMS ESI (+) m/z:573.3 (M+1).

And (B) step (B): 1- (4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (methylamino) ethan-1-one (Compound 37)

Compound 37.1 (36 mg,0.063 mmol) was dissolved in 3mL of methanol, 3mL of 4M methanolic hydrochloride was added, and the reaction was stirred at room temperature for 2 hours. Concentrating the reaction solution under reduced pressure, and preparing pure residue by reversed phaseThe product 37 (3.4 mg, yield: 12%) was obtained by LCMS ESI (+) m/z:473.3 (M+1). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.04(s,1H),8.92(s,1H),8.61(s,1H),7.56(s,1H),7.30(d,J＝8.4Hz,1H),7.03(d,J＝9.6Hz,1H),5.42(s,2H),5.13(s,2H),4.56(d,J＝12.5Hz,1H),3.90(d,J＝13.4Hz,1H),3.62–3.49(m,2H),3.15–2.99(m,2H),2.87(t,J＝13.7Hz,1H),2.75–2.66(m,1H),2.52(d,J＝1.9Hz,1H),2.38(s,3H),1.85(d,J＝11.8Hz,2H),1.75–1.62(m,1H),1.53(d,J＝7.8Hz,1H),1.38(d,J＝7.0Hz,6H).

Example 38

(4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) (4-methylpiperazin-1-yl) methanone

The specific reaction equation is shown below:

Step A: 4-Nitrophenyl 4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylate (Compound 38.1)

Compound 17.12 (40 mg,0.09 mmol) was dissolved in anhydrous DCM (4 mL), DIPEA (24 mg,0.18 mmol) and 4-nitrophenoxy acid chloride (28 mg,0.14 mmol) were added at 0deg.C and reacted at room temperature for 2 hours. After completion of the reaction, the reaction was quenched by dropwise addition of saturated sodium bicarbonate solution, then extracted with DCM (20 mLX 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give product 38.1 (43 mg, yield: 84%), LCMS ESI (+) m/z:567.2 (M+1).

And (B) step (B): (4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) (4-methylpiperazin-1-yl) methanone (Compound 38)

38.1 (43 mg,0.076 mmol) and 1-methylpiperazine (38 mg,0.379 mmol) were added to DMF (4 mL) and reacted under microwaves at 150℃for 1.5 hours. After completion of the reaction, 10mL of water was added to the reaction mixture, followed by extraction with EA (20 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified in reverse phase to give product 38 (14 mg, yield: 35%) by LCMS ESI (+) m/z:528.3 (M+1). ¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.49(s,1H),7.60(s,1H),7.31(d,J＝8.4Hz,1H),7.08(dd,J＝8.5,1.5Hz,1H),5.46(t,J＝3.0Hz,2H),5.21–5.14(m,2H),3.88(d,J＝13.1Hz,2H),3.44–3.34(m,4H),3.16–3.06(m,1H),3.01(dd,J＝12.6,10.7Hz,2H),2.83(ddd,J＝12.0,8.4,3.5Hz,1H),2.68(s,4H),2.47(s,3H),1.91(d,J＝10.8Hz,2H),1.77(qd,J＝12.7,3.9Hz,2H),1.45(d,J＝7.1Hz,6H).

Example 39

2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazol [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethane-1-sulfonamide

The specific reaction equation is shown below:

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step A: 2-chloroethanesulfonamide (Compound 39.2)

2-Chloroethanesulfonyl chloride (100 mg,0.61 mmol) was dissolved in 5mL of THF, and aqueous ammonia (0.5 mL) was added and the reaction solution was stirred at room temperature overnight. The reaction solution was used directly in the next reaction, LCMS ESI (+) m/z:144.0 (M+1).

And (B) step (B): 2- (4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazol [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethane-1-sulfonamide (Compound 39)

Compound 39.2 (87 mg,0.61 mmol) and triethylamine (186 mg,1.83 mmol) were dissolved in 5mL THF and the compound was added17.12 (25 mg,0.06 mmol), and the reaction was stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 39 (3.5 mg, yield: 12%), LCMS ESI (+) m/z:509.2 (M+1). ¹ H NMR(400MHz,DMSO)δ10.99(s,1H),8.91(s,1H),8.61(s,1H),7.56(s,1H),7.29(d,J＝8.4Hz,1H),7.04(d,J＝7.6Hz,1H),6.80(s,2H),5.42(s,2H),5.13(s,2H),3.22–3.17(m,2H),3.05(dd,J＝14.0,7.2Hz,1H),2.99(d,J＝11.2Hz,2H),2.81–2.73(m,2H),2.59(t,J＝8.0Hz,1H),2.13(t,J＝11.2Hz,2H),2.04–1.95(m,2H),1.79(d,J＝12.0Hz,2H),1.38(d,J＝7.2Hz,6H).

Example 40

1- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazol [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2-methylpropan-2-ol

Compound 17.12 (40 mg,0.1 mmol) and 1-chloro-2-methylpropan-2-ol (1.1 g,10.0 mmol) were dissolved in 3mL of DMF under nitrogen, DIEA (52 mg,0.4 mmol) was added, and the reaction stirred at 120℃for 2 hours. To the reaction solution was added 20mL of water, extracted with ethyl acetate (25 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 40 (5.5 mg, yield: 12%), LCMS ESI (+) m/z:474.3 (M+1). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.99(s,1H),8.92(s,1H),8.61(s,1H),7.55(d,J＝1.5Hz,1H),7.29(d,J＝8.3Hz，1H)，7.04(dd J＝8.5，1.5Hz，1H)，5.42(t J＝3.3Hz，2H)，5.13(t J＝3.4Hz，2H)，3.14–2.99(m,4H),2.30(d,J＝6.2Hz,4H),1.80–1.69(m,4H),1.38(d,J＝7.0Hz,6H),1.12(s,6H).

Example 41

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N-cyclopropyl-2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl) -1H-indol-5-yl) piperidin-1-yl) acetamide

The specific reaction equation is shown below:

step A: ethyl 2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetate (Compound 41.1)

Compound 17.12 (50 mg,0.125 mmol) was dissolved in 3mL DCM and ethyl 2-bromoacetate (31.3 mg,0.87 mmol) and DIPEA (97 mg,0.75 mmol) were added and the reaction stirred at room temperature for 2 hours. To the reaction solution was added 5mL of water, extracted with ethyl acetate (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give compound 41.1 (49 mg, yield: 80.4%), LCMS ESI (+) m/z:488.3 (M+1).

And (B) step (B): 2- (4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetic acid (Compound 41.2)

Compound 41.1 (49 mg,0.10 mmol) was dissolved in 1mL of methanol and 1mL of tetrahydrofuran, a solution of sodium hydroxide (10 mg,0.25 mmol) in water (1.5 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was adjusted to pH to neutrality with aqueous hydrochloric acid, extracted with iPrOH: DCM=1:3 (10 mLX 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give Compound 41.2 (50 mg, yield: 100%), LCMS ESI (+) m/z:460.2 (M+1).

Step C: n-cyclopropyl-2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl) -1H-indol-5-yl) piperidin-1-yl) acetamide (Compound 41)

Compound 41.2 (50 mg,0.11 mmol) was dissolved in 3mL of DMF, HATU (62.7 mg,0.165 mmol) and triethylamine (33.4 mg,0.33 mmol) were added and the reaction stirred at room temperature for 30 minutes, then cyclopropylamine (9.4 mg,0.165 mmol) was added dropwise and the reaction stirred at room temperature for 1 hour. The reaction solution was adjusted to pH to neutrality with an aqueous ammonium chloride solution, extracted with ethyl acetate (10 mLX), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase to give Compound 41 (10.1 mg, yield: 18.4%), LCMS ESI (+) m/z:499.3 (M+1). ¹ HNMR(400MHz,DMSO)δ10.99(s,1H),8.92(s,1H),8.61(s,1H),7.74(d,J＝3.9Hz,1H),7.56(s,1H),7.29(d,J＝8.4Hz,1H),7.05(d,J＝8.5Hz,1H),5.42(s,2H),5.13(s,2H),3.08–3.01(m,1H),2.90(d,J＝9.8Hz,4H),2.68–2.66(m,1H),2.52(d,J＝1.2Hz,1H),2.17(dd,J＝11.0,8.0Hz,2H),1.83–1.72(m,4H),1.39(d,J＝7.0Hz,6H),0.62(td,J＝7.0,4.8Hz,2H),0.54–0.45(m,2H).

Example 42

(S) -1- (4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazolyl [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (3-fluoropyrrolidin-1-yl) ethanone

The specific reaction equation is shown below:

compound 17.12 (14 mg,0.03 mmol) was added to 2mL of N-methylpyrrolidone, triethylamine (18 mg,0.17 mmol) was added, chloroacetyl chloride (6 mg,0.05 mmol) was added to the ice bath, the reaction solution was reacted at room temperature for 1.5 hours, DBU (27 mg,0.17 mmol) and 3- (S) -fluoropyrrolidine hydrochloride (7 mg,0.05 mmol) were further added, and the reaction solution was stirred at room temperature overnight. After the completion of the reaction, water and ethyl acetate were added to the mixture to extract the mixture, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and washed with brineFiltration, concentration under reduced pressure, purification by reverse phase preparation gave compound 42 (4.8 mg, yield: 26%), LCMS ESI (+) m/z:531.2 (M+1). ¹ H NMR(400MHz,DMSO)δ11.02(s,1H),8.91(s,1H),8.61(s,1H),7.55(s,1H),7.30(d,J＝8.4Hz,1H),7.03(d,J＝8.5Hz,1H),5.42(s,2H),5.13(t,J＝3.1Hz,2H),4.54(d,J＝12.0Hz,1H),4.09(t,J＝11.5Hz,1H),3.12(dd,J＝18.8,6.6Hz,2H),3.03(dd,J＝14.1,6.9Hz,2H),2.96(dd,J＝7.9,6.1Hz,2H),2.91–2.81(m,2H),2.70–2.67(m,1H),2.53(d,J＝1.9Hz,2H),2.25–2.09(m,1H),1.97(ddd,J＝28.8,15.1,7.5Hz,1H),1.84(d,J＝12.3Hz,2H),1.78–1.63(m,1H),1.54–1.45(m,1H),1.38(d,J＝7.0Hz,6H).

Example 43

6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridine

Reference example 1, 4- (2- (7, 9-dihydrofuran [3, 4-c)][1,2,4]Triazole [1,5-a ]]Pyridine-6-yl) -3-isopropyl-1H-indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester and 4M hydrochloric acid. LCMS ESI (+) m/z:402.2. ¹ H NMR(400MHz,MeOD)δ8.92(s,1H),8.87(s,1H),7.67(s,1H),7.38(d,J＝8.3Hz,1H),7.14(d,J＝8.3Hz,1H),5.51(s,2H),5.25(s,2H),3.54(d,J＝11.3Hz,2H),3.20(t,J＝12.1Hz,2H),3.14(s,1H),3.02(t,J＝10.9Hz,1H),2.14(d,J＝13.6Hz,2H),2.04(dd,J＝23.3,11.7Hz,2H),1.47(d,J＝6.2Hz,6H).

Example 44

2- (4- (2- (8, 9-dihydro-7H-cyclopenta [ c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetamide

With reference to example 1, 2- (4- (3-isopropyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide and 6-bromo-8, 9-dihydro-7H-cyclopentane [ c ]][1,2,4]Triazolo [1,5-a ]]Pyridine is used as a raw material. LCMS ESI (+) m/z:457.2. ¹ H NMR(400MHz,DMSO)δ10.78(s,1H),7.58–7.48(m,2H),7.32–7.21(m,2H),7.16(d,J＝3.2Hz,1H),7.00(dd,J＝8.4,1.5Hz,1H),3.17(s,2H),2.98–2.93(m,5H),2.81(t,J＝7.6Hz,2H),2.67(dt,J＝3.6,1.8Hz,1H),2.33(dt,J＝3.6,1.8Hz,1H),2.23(dd,J＝12.3,9.2Hz,2H),2.03(q,J＝7.7Hz,2H),1.88–1.74(m,4H),1.34(d,J＝7.0Hz,6H).

example 45

2- (4- (3-isopropyl-2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrazolo [3,4-c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

Reference example 1, 4-bromo-6-methyl-1-tosyl-1, 6-dihydro-7H-pyrazolo [3,4-c]Pyridin-7-one and 2- (4- (3-isopropyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide are prepared as raw materials. LCMS ESI (+) m/z:447.2. ¹ H NMR(400MHz,DMSO)δ13.6(s,1H),11.6(s,1H),8.38(d,J＝4.2Hz,1H),7.62(s,1H),7.54(s,1H),7.30(d,J＝8.3Hz,2H),7.19(s,2H),3.67(s，3H)，3.29(s,2H),3.14–2.88(m,5H),2.29(m,1H),1.86–1.76(m,4H),1.35(d,J＝7.0Hz,6H).

example 46

2- (4- (3-isopropyl-2- (7-methoxy-2, 3-dihydrobenzofuran-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

Prepared according to example 2 starting from 3-isopropyl-2- (7-methoxy-2, 3-dihydrobenzofuran-4-yl) -5- (piperidin-4-yl) -1H-indole hydrochloride and 2-bromoacetamide. LCMS ESI (+) m/z:448.3. ¹ H NMR(400MHz,DMSO)δ10.67(s,1H),7.50(s,1H),7.25(s,1H),7.21(d,J＝8.3Hz,1H),7.13(s,1H),6.95(t,J＝8.3Hz,2H),6.78(d,J＝8.3Hz,1H),4.55(t,J＝8.7Hz,2H),3.81(s,3H),3.16(t,J＝8.7Hz,2H),3.07(dd,J＝14.0,7.0Hz,1H),2.94(d,J＝10.8Hz,2H),2.89(s,2H),2.19(t,J＝11.2Hz,3H),1.82(dd,J＝23.9,12.5Hz,4H),1.35(d,J＝7.0Hz,6H).

Example 47

2- (4- (4-fluoro-3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentan [ c ] pyridin-4-yl) -1H-pyrrolo [2,3-c ] pyridin-5-yl) piperazin-1-yl) acetamide

Reference example 2, 4- (4-fluoro-3-isopropyl-5- (piperazin-1-yl) -1H-pyrrolo [2, 3-c)]Pyridin-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentane [ c]The pyridine-1-ketone and 2-bromoacetamide are used as raw materials to prepare the preparation. LCMS ESI (+) m/z:467.2. ¹ H NMR(400MHz,DMSO)δ11.34(d,J＝2.2Hz,1H),8.21(d,J＝1.6Hz,1H),7.68(s,1H),7.18(dd,J＝28.4,3.2Hz,2H),3.51(s,3H),3.22(t,J＝4.7Hz,4H),2.99(dq,J＝10.2,3.5Hz,1H),2.94(s,2H),2.72(dt,J＝13.8,7.6Hz,4H),2.63(t,J＝4.8Hz,4H),1.99(p,J＝7.6Hz,2H),1.26(dd,J＝7.0,1.2Hz,6H).

example 48

1- ((4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) methyl) cyclopropane-1-carbonitrile

Reference example 30 as 6- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -7, 9-dihydrofuran [3,4-c][1,2,4]Triazolo [1,5-a ]]Pyridine hydrochloride and 1- (bromomethyl) cyclopropane-1-carbonitrile. LCMS ESI (+) m/z:481.2. ¹ H NMR(400MHz,DMSO)δ11.08(s,1H),8.93(s,1H),8.62(s,1H),7.59(s,1H),7.33(d,J＝6.2Hz,1H),7.06(d,J＝8.4Hz,1H),5.43(s,2H),5.13(t,J＝3.0Hz,2H),3.48(s,2H),3.17(s,2H),3.05(dd,J＝14.0,7.0Hz,1H),2.90(s,1H),2.58(s,2H),2.15(s,2H),2.03–1.96(m,1H),1.82(s,1H),1.51(s,2H),1.39(d,J＝7.0Hz,6H),1.32(d,J＝15.0Hz,2H).

example 49

2- (4- (3-isopropyl-2- (6-methyl-7-oxo-2, 3,6, 7-tetrahydrofuran [2,3-c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

Reference example 2, 4- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -6-methyl-2, 3-dihydrofuran [2,3-c]The pyridine-7 (6H) -ketone and 2-bromoacetamide are used as raw materials to prepare the preparation. LCMS ESI (+) m/z:449.2. ¹ H NMR(400MHz,DMSO)δ10.73(s,1H),7.50(s,1H),7.31(s,1H),7.26(s,1H),7.22(d,J＝8.3Hz,1H),7.14(s,1H),6.98(d,J＝8.4Hz,1H),4.55(t,J＝9.3Hz,2H),3.54(s,3H),3.07(dt,J＝9.1,8.2Hz,4H),2.94(d,J＝11.0Hz,2H),2.90(s,2H),2.19(td,J＝10.9,2.2Hz,2H),1.81(ddd,J＝25.1,17.3,7.0Hz,4H),1.37(d,J＝7.0Hz,6H).

Example 50

2- (4- (3-isopropyl-2- (5-methyl-4-oxo-1, 3,4, 5-tetrahydrofuran [3,4-c ] pyridin-7-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

Reference example 1, 7-bromo-5-methyl-3, 5-dihydrofuran [3,4-c]Pyridin-4 (1H) -one and 2- (4- (3-isopropyl-2- (4, 5-tetramethyl-1, 3-dioxolan-2-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide are prepared as raw materials. LCMS ESI (+) m/z:449.3. ¹ H NMR(400MHz,DMSO)δ10.72(s,1H),7.72(s,1H),7.50(s,1H),7.26–7.19(m,2H),7.13(s,1H),7.00–6.95(m,1H),4.93(d,J＝3.5Hz,4H),3.56(s,3H),3.03(dd,J＝14.0,7.0Hz,1H),2.95–2.87(m,4H),2.56(s,1H),2.17(s,2H),1.78(d,J＝14.7Hz,4H),1.36(d,J＝7.0Hz,6H).

example 51

2- (4- (3-isopropyl-2- (2-isopropyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-) 4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

Reference example 1, 2- (4- (3-isopropyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide and 4-bromo-2-isopropyl-2, 5,6, 7-tetrahydro-1H-cyclopenta [ c ]]The pyridine-1-ketone is used as a raw material to prepare the medicine. LCMS ESI (+) m/z:475.3. ¹ H NMR(400MHz,DMSO)δ10.71(s,1H),7.49(s,1H),7.43(s,1H),7.25(s,1H),7.21(d,J＝8.3Hz,1H),7.13(s,1H),6.97(d,J＝8.3Hz,1H),5.15(dt,J＝13.6,6.8Hz,1H),3.01–2.91(m,4H),2.89(s,2H),2.74(t,J＝7.5Hz,4H),2.19(t,J＝10.0Hz,2H),2.01–1.95(m,2H),1.79(dd,J＝24.5,10.1Hz,4H),1.35(d,J＝7.0Hz,6H),1.31(d,J＝6.8Hz,6H).

example 52

2- (4- (3-isopropyl-2- (2-methyl-1-oxo-1, 2,5,6,7, 8-hexahydroisoquinolin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

Prepared with reference to example 1 starting from 4-bromo-2-methyl-5, 6,7, 8-tetrahydroisoquinolin-1 (2H) -one and 2- (4- (3-isopropyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide. LCMS ESI (+) m/z:461.3. ¹ H NMR(400MHz,DMSO)δ10.66(s,1H),7.48(s,2H),7.24(s,1H),7.19(d,J＝8.3Hz,1H),7.13(s,1H),6.96(d,J＝7.8Hz,1H),3.46(s,3H),2.95–2.87(m,5H),2.45–2.36(m,4H),2.16(d,J＝10.8Hz,2H),2.08(s,1H),1.86–1.74(m,4H),1.60(s,4H),1.31(d,J＝5.4Hz,6H).

Example 53

2- (4- (6-fluoro-3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentan [ c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

Reference example 2, 4- (6-fluoro-3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentane [ c ]]The pyridine-1-ketone and 2-bromoacetamide are used as raw materials to prepare the preparation. LCMS ESI (+) m/z:465.2. ¹ H NMR(400MHz,DMSO)δ10.80(s,1H),7.57(s,1H),7.51(d,J＝7.3Hz,1H),7.27(s,1H),7.14(d,J＝3.2Hz,1H),7.00(d,J＝11.3Hz,1H),3.50(s,3H),3.01–2.93(m,3H),2.91(s,2H),2.80(ddt,J＝11.9,8.2,3.7Hz,1H),2.71(q,J＝8.1Hz,4H),2.21(td,J＝11.5,2.5Hz,2H),1.97(p,J＝7.6Hz,2H),1.87(qd,J＝12.3,3.6Hz,2H),1.75(dd,J＝13.1,3.6Hz,2H),1.34(d,J＝7.0Hz,6H).

example 54

2- (5- (3-isopropyl-2- (2-methyl-1-oxo-2, 5,6, 7-tetrahydro-1H-cyclopentan [ c ] pyridin-4-yl) -1H-indol-5-yl) hexahydrocyclopentan [ c ] pyrrol-2 (1H) -yl) acetamide

Reference example 2, 2-bromoacetamide and 4- (3-isopropyl-5- (octahydrocyclopentane [ c)]Pyrrol-5-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentane [ c]The pyridine-1-ketone is used as a raw material to prepare the medicine. LCMS ESI (+) m/z:473.3. ¹ HNMR(400MHz,DMSO)δ10.66(s,1H),7.56(s,1H),7.48(s,1H),7.20(d,J＝8.4Hz,1H),7.18–7.09(m,2H),7.03(d,J＝8.2Hz,1H),3.50(s,3H),3.03–2.92(m,4H),2.77–2.66(m,6H),2.61(q,J＝7.0Hz,2H),2.32(dd,J＝9.0,5.8Hz,2H),2.22(dt,J＝12.4,6.3Hz,2H),2.03–1.89(m,2H),1.52(td,J＝11.9,7.9Hz,2H),1.33(d,J＝7.0Hz,6H).

example 55

1- (3, 3-difluoropyrrolidin-1-yl) -2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1, 2), 4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one

Referring to example 5, 2- (4-)2- (7, 9-dihydrofuran [3, 4-c)][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetic acid and 3, 3-difluoropyrrolidine. LCMS ESI (+) m/z:549.3. ¹ H NMR(400MHz,MeOD)δ8.76(s,1H),8.50(s,1H),7.64(s,1H),7.33(d,J＝8.4Hz,1H),7.11(dd,J＝8.4,1.3Hz,1H),5.48(t,J＝3.0Hz,2H),5.22–5.18(m,2H),4.59(s,2H),4.03(t,J＝12.6Hz,1H),3.85(dd,J＝14.7,7.4Hz,2H),3.72(t,J＝7.6Hz,1H),3.58(s,1H),3.50(s,1H),3.13(dd,J＝8.7,5.4Hz,1H),2.75(dd,J＝10.0,5.3Hz,1H),2.61–2.33(m,4H),1.99(s,4H),1.46(d,J＝7.0Hz,6H).

Example 56

(S) -2- (4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (3-fluoropyrrolidin-1-yl) ethan-1-one

Reference example 5, 2- (4- (2- (7, 9-dihydrofuran [3, 4-c))][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl acetic acid and (S) -3-fluoropyrrolidine. LCMS ESI (+) m/z:531.3. ¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.49(s,1H),7.63(s,1H),7.31(d,J＝8.4Hz,1H),7.09(d,J＝8.4Hz,1H),5.46(d,J＝2.9Hz,2H),5.32(dd,J＝52.8,25.7Hz,1H),5.19(t,J＝3.2Hz,2H),3.99–3.66(m,3H),3.57–3.33(m,3H),3.24(t,J＝11.6Hz,2H),3.11(dd,J＝14.1,7.0Hz,1H),2.77–2.63(m,1H),2.49(d,J＝11.4Hz,2H),2.38–2.07(m,2H),1.97(d,J＝23.2Hz,4H),1.45(d,J＝7.0Hz,6H).

example 57

1- (3, 3-difluoroazetidin-1-yl) -2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1, 2), 4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) ethan-1-one

Reference example 5, at 2- (4- (2- (7, 9-dihydrofuran [3, 4-c))][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetic acid and 3, 3-difluoroazetidine. LCMS ESI (+) m/z:535.3. ¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.49(s,1H),7.61(s,1H),7.31(d,J＝8.4Hz,1H),7.09(dd,J＝8.4,1.3Hz,1H),5.46(t,J＝3.0Hz,2H),5.19(t,J＝3.3Hz,2H),4.72(t,J＝12.0Hz,2H),4.58(s,1H),4.37(t,J＝12.1Hz,2H),3.27(s,1H),3.12(dd,J＝9.0,4.8Hz,3H),2.66(dd,J＝13.0,7.8Hz,1H),2.44–2.29(m,2H),2.01–1.86(m,4H),1.45(d,J＝7.0Hz,6H).

example 58

2- (4-bromophenyl) ethan-1-ol (S) -1- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1, 5-) a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -2- (3-hydroxypyrrolidin-1-yl) ethan-1-one

Reference example 14, 2-chloro-1- (4- (2- (7, 9-dihydrofuran [3, 4-c))][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl-ethane-1-one and R-pyrrolidin-3-ol as starting materials. LCMS ESI (+) m/z:529.3. ¹ H NMR(400MHz,DMSO)δ11.01(s,1H),8.92(s,1H),8.61(s,1H),7.55(s,1H),7.29(d,J＝8.4Hz,1H),7.02(d,J＝8.4Hz,1H),5.42(s,2H),5.13(d,J＝3.0Hz,2H),4.53(d,J＝12.6Hz,1H),4.23–4.11(m,2H),3.43(s,1H),3.28(d,J＝9.2Hz,2H),3.06(dt,J＝14.1,9.9Hz,3H),2.83(dt,J＝13.2,10.5Hz,2H),2.63(d,J＝10.4Hz,1H),2.42–2.38(m,1H),1.98(dd,J＝12.9,7.2Hz,1H),1.83(d,J＝12.4Hz,2H),1.80–1.41(m,4H),1.38(d,J＝7.0Hz,6H).

Example 59

2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (3-fluoroazetidin-1-yl) ethan-1-one

Reference example 5, 2- (4- (2- (7, 9-dihydrofuran [3, 4-c))][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetic acid and 3-fluoroazetidine. LCMS ESI (+) m/z:517.3. ¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.49(s,1H),7.62(s,1H),7.31(d,J＝8.4Hz,1H),7.09(dd,J＝8.4,1.4Hz,1H),5.46(d,J＝3.3Hz,2H),5.37–5.23(m,1H),5.20–5.16(m,2H),4.70–4.54(m,3H),4.41–4.28(m,2H),4.12–4.03(m,1H),3.19(d,J＝11.6Hz,2H),3.11(dd,J＝14.1,7.1Hz,1H),2.74–2.65(m,1H),2.46(s,2H),1.96(t,J＝10.3Hz,4H),1.45(d,J＝7.0Hz,6H).

example 60

(S) -2- (4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (3-hydroxypyrrolidin-1-yl) ethan-1-one

Reference example 5, 2- (4- (2- (7, 9-dihydrofuran [3, 4-c))][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl acetic acid and (S) -pyrrolidin-3-ol. LCMS ESI (+) m/z:529.3. ¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.49(s,1H),7.65(s,1H),7.33(d,J＝8.4Hz,1H),7.11(d,J＝8.3Hz,1H),5.47(s,2H),5.20–5.17(m,2H),4.64–4.43(m,3H),3.73(d,J＝4.2Hz,1H),3.65(dd,J＝9.0,4.3Hz,2H),3.60–3.50(m,2H),3.47(d,J＝8.9Hz,2H),3.13(dd,J＝14.0,7.0Hz,1H),2.84(d,J＝5.3Hz,3H),2.06(dd,J＝29.2,9.1Hz,5H),1.45(d,J＝7.0Hz,6H).

example 61

(R) -2- (4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (3-hydroxypyrrolidin-1-yl) ethan-1-one

Reference example 5, 2- (4- (2- (7, 9-dihydrofuran [3, 4-c))][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl acetic acid and (R) -pyrrolidin-3-ol. LCMS ESI (+) m/z:529.3. ¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.50(d,J＝10.3Hz,1H),7.63(s,1H),7.32(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),5.46(s,2H),5.20–5.17(m,2H),4.95(s,1H),4.58(s,1H),4.46(d,J＝24.8Hz,1H),3.68(dd,J＝8.6,4.6Hz,2H),3.59(d,J＝8.5Hz,1H),3.52(s,2H),3.33(s,1H),3.11(dd,J＝13.9,6.7Hz,1H),2.68(dd,J＝55.1,7.3Hz,3H),2.04(ddd,J＝26.3,11.3,6.6Hz,6H),1.45(d,J＝7.0Hz,6H).

Example 62

(R) -2- (4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (3-fluoropyrrolidin-1-yl) ethan-1-one

Reference example 5, 2- (4- (2- (7, 9-dihydrofuran [3, 4-c))][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl acetic acid and (R) -3-fluoropyrrolidine. LCMS ESI (+) m/z:531.3. ¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.49(s,1H),7.66(s,1H),7.35(d,J＝8.4Hz,1H),7.12(d,J＝8.5Hz,1H),5.47(t,J＝3.0Hz,2H),5.40–5.24(m,1H),5.20–5.15(m,2H),4.04–3.89(m,2H),3.89–3.68(m,3H),3.59(tdd,J＝16.6,11.2,5.6Hz,4H),3.14(dd,J＝14.1,7.0Hz,1H),3.04(s,2H),2.95–2.88(m,1H),2.37–2.26(m,1H),2.13(d,J＝19.1Hz,4H),1.46(d,J＝7.0Hz,6H).

example 63

2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -1- (pyrrolidin-1-yl) ethan-1-one

Reference realityExample 5 as 2- (4- (2- (7, 9-dihydrofuran [3, 4-c))][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl acetic acid and pyrrolidine. LCMS ESI (+) m/z:513.3. ¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.49(s,1H),7.64(s,1H),7.33(d,J＝8.4Hz,1H),7.10(d,J＝8.5Hz,1H),5.46(s,2H),5.18(t,J＝3.0Hz,2H),3.65(s,2H),3.54(t,J＝6.8Hz,2H),3.48(t,J＝6.9Hz,2H),3.41–3.36(m,2H),3.12(dt,J＝14.0,7.0Hz,1H),2.85–2.64(m,3H),2.13–1.98(m,6H),1.92(dd,J＝13.5,6.7Hz,2H),1.45(d,J＝7.0Hz,6H).

example 64

2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N-isopropylacetamide

Reference example 5, 2- (4- (2- (7, 9-dihydrofuran [3, 4-c))][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl acetic acid and isopropylamine as raw materials. LCMS ESI (+) m/z:501.3. ¹ H NMR(400MHz,MeOD)δ8.65(s,1H),8.39(s,1H),7.53(s,1H),7.21(s,1H),7.00(d,J＝8.4Hz,1H),5.37(s,2H),5.09(s,2H),4.00–3.90(m,1H),3.10(s,2H),3.01(dd,J＝13.8,6.9Hz,3H),2.59(s,1H),2.39(s,2H),1.85(s,4H),1.35(d,J＝7.0Hz,6H),1.10(d,J＝6.4Hz,6H).

Example 65

2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) -N- (2, 2-trifluoroethyl) acetamide

Reference example 5, 2- (4- (2- (7, 9-dihydrofuran [3, 4-c))][1,2,4]Triazolo [1,5-a ]]Pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetic acid and 2, 2-trifluoroethan-1-amine. LCMS ESI (+) m/z:541.3. ¹ H NMR(400MHz,MeOD)δ8.75(s,1H),8.49(s,1H),7.63(s,1H),7.31(d,J＝8.4Hz,1H),7.10(dd,J＝8.4,1.4Hz,1H),5.46(t,J＝3.0Hz,2H),5.23–5.15(m,2H),4.02–3.98(m,1H),3.95(d,J＝9.3Hz,1H),3.22(s,2H),3.14–3.05(m,3H),2.71–2.61(m,1H),2.42(t,J＝10.4Hz,2H),1.96(dt,J＝27.5,8.2Hz,4H),1.45(d,J＝7.0Hz,6H).

example 66

2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-fluoro-3-isopropyl-1H-pyrrolo [2,3-c ] pyridin-5-yl) piperidin-1-yl) acetamide

Reference example 2, 6- (4-fluoro-3-isopropyl-5- (piperidin-4-yl) -1H-pyrrolo [2,3-c]Pyridin-2-yl) -7, 9-dihydrofuran [3,4-c][1,2,4]Triazolo [1,5-a ]]Pyridine and 2-bromoacetamide are used as raw materials. LCMS ESI (+) m/z:478.2. ¹ H NMR(400MHz,MeOD)δ8.96(s,1H),8.39(s,1H),8.17(s,1H),5.41(s,2H),4.63(s,2H),3.29(s,2H),2.89(m,1H),2.78(m,1H),2.51-2.31(m,4H),1.74-1.49(m,4H),1.41(d,J＝7.0Hz,6H).

example 67

2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl) acetic acid

Reference example 2, tert-butyl 2- (4- (2- (8, 9-dihydro-7H-cyclopenta [ c ])][1,2,4]Triazolo [1,5-a ]]Pyridine-6-yl) -3-isopropyl-1H-indol-5-yl) piperidin-1-yl acetate and dioxane solution of hydrochloric acid. LCMS ESI (+) m/z:460.2. ¹ H NMR(400MHz,MeOD)δ8.76(s,1H),8.49(s,1H),7.67(s,1H),7.35(d,J＝8.4Hz,1H),7.11(d,J＝8.4Hz,

1H),5.47(t,J＝3.0Hz,2H),5.18(t,J＝3.2Hz,2H),3.74(d,J＝11.3Hz,2H),3.66(s,2H),3.13(dt,J＝14.0,7.0Hz,3H),2.97(s,1H),2.16(d,J＝14.9Hz,4H),1.46(d,J＝7.0Hz,6H).

Example 68

2- (4- (3-isopropyl-2- (6-methyl-7-oxo-6, 7-dihydrothieno [2,3-c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) acetamide

Reference example 2, 4- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -6-methyldienyl [2,3-c]The pyridine-7 (6H) -ketone and 2-bromoacetamide are used as raw materials to prepare the preparation. LCMS ESI (+) m/z:463.2. ¹ H NMR(400MHz,DMSO)δ10.92(s,1H),8.05(d,J＝5.2Hz,1H),7.62(s,1H),7.54(s,1H),7.25(d,J＝8.3Hz,2H),7.14(s,1H),7.08(d,J＝5.2Hz,1H),7.01(dd,J＝8.4,1.3Hz,1H),3.63(s,3H),3.04–2.88(m,6H),2.19(t,J＝10.0Hz,2H),1.86–1.76(m,4H),1.35(d,J＝7.0Hz,6H).

example 69

2- (4- (2- (7, 9-dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -4-fluoro-3-isopropyl-1H-pyrrolo [2,3-c ] pyridin-5-yl) piperazin-1-yl) acetamide

Reference example 2, 6- (4-fluoro-3-isopropyl-5- (piperazin-1-yl) -1H-pyrrolo [2, 3-c)]Pyridin-2-yl) -7, 9-dihydrofuran [3,4-c][1,2,4]Triazolo [1,5-a ]]Pyridine and 2-bromoacetamide are used as raw materials. LCMS ESI (+) m/z:479.2. ¹ H NMR(400MHz,MeOD)δ8.96(s,1H),8.36(s,1H),8.16(s,1H),5.42(s,2H),4.65(s,2H),3.32(t,11.3Hz,4H),3.29(s,2H),2.78(m,1H),2.56(t,J＝11.2Hz,4H),1.40(d,J＝7.2Hz,6H).

example 70

2- (4- (3-isopropyl-2- (6-methyl-7-oxo-6, 7-dihydro-1H-pyrrolo [2,3-c ] pyridin-4-yl) -1H-indol-5-yl) piperidin-1-yl) -N-methylacetamide

Reference example 3,4- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -6-methyl-1H-pyrrolo [2,3-c]The pyridine-7 (6H) -ketone and 2-chloro-N-methylacetamide are used as raw materials. LCMS ESI (+) m/z:460.2. ¹ H NMR(400MHz,DMSO)δ12.13(s,1H),10.79(s,1H),7.73(q,J＝4.6Hz,1H),7.52(d,J＝1.5Hz,1H),7.33(t,J＝2.7Hz,1H),7.28–7.19(m,2H),6.97(dd,J＝8.4,1.6Hz,1H),6.19(t,J＝2.4Hz,1H),3.59(s,3H),3.16–3.10(m,1H),2.91(d,J＝12.6Hz,4H),2.65(d,J＝4.7Hz,3H),2.55(dq,J＝10.6,3.3Hz,1H),2.18(td,J＝11.3,2.8Hz,2H),1.91–1.72(m,4H),1.37(d,J＝7.0Hz,6H).

example 71

4- (3-isopropyl-5- (1- (oxetan-3-yl) piperidin-4-yl) -1H-indol-2-yl) -6-methyl-1H-pyrrolo [2,3-c ] pyridin-7 (6H) -one

Reference example 6, 4- (3-isopropyl-5- (piperidin-4-yl) -1H-indol-2-yl) -6-methyl-1H-pyrrolo [2,3-c]The pyridine-7 (6H) -ketone and oxetan-3-ketone are used as raw materials to prepare the medicine. LCMS ESI (+) m/z:445.2. ¹ H NMR(400MHz,DMSO)δ12.13(s,1H),10.78(s,1H),7.52(d,J＝1.5Hz,1H),7.33(t,J＝2.7Hz,1H),7.27–7.19(m,2H),6.97(dd,J＝8.4,1.6Hz,1H),6.19(t,J＝2.3Hz,1H),4.56(t,J＝6.4Hz,2H),4.46(t,J＝6.1Hz,2H),3.59(s,3H),3.41(s,1H),3.16–3.10(m,1H),2.82(dt,J＝11.6,3.0Hz,2H),2.57(tt,J＝11.2,4.1Hz,1H),1.88(td,J＝11.2,2.6Hz,2H),1.76(dtd,J＝28.0,12.5,3.6Hz,4H),1.37(d,J＝7.0Hz,6H).

example 72

6- (5- (4- (3, 3-difluoroazetidin-1-yl) cyclohexyl) -3-isopropyl-1H-indol-2-yl) -7, 9-dihydrofuro [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridine

Step A: 3-isopropyl-5- (1, 4-dioxaspiro [4.5] dec-8-yl) -2- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -1H-indole (Compound 72.2)

The compound 2-bromo-3-isopropyl-5- (1, 4-dioxaspiro [4.5] dec-8-yl) -1H-indole (225 mg,0.6 mmol), 4, 5-tetramethyl-1, 3, 2-dioxaborane (768 mg,6 mmol), bis (benzonitrile) palladium (II) chloride (23 g,0.06 mmol), 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl (30 mg,0.072 mmol) and triethylamine (182 mg,1.8 mmol) were dissolved in 1,4 dioxane (10 ml). The reaction system was replaced with argon 3 times. The reaction mixture was stirred at 85℃for 3 hours. The reaction was concentrated under reduced pressure and purified by column chromatography (MeOH/DCM (2%)) to give product 72.2 (213 mg, yield: 83%). LCMS ESI (+) m/z:426 (M+1).

And (B) step (B): 6- (3-isopropyl-5- (1, 4-dioxoaspirin [4.5] dec-8-yl) -1H-indol-2-yl) -7, 9-dihydrofuro [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridine (Compound 72.3)

Compound 72.2 (128 mg,0.3 mmol), 6-bromo-7, 9-dihydro [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridine (72 mg,0.3 mmol), 1' -bis-diphenylphosphino ferrocene palladium dichloride (22 mg,0.03 mmol), potassium phosphate (190 mg,0.9 mmol) was dissolved in 1, 4-dioxane (5 ml) and water (1 ml). The reaction system was replaced with argon 3 times. The reaction mixture was stirred at 80℃for 16 hours. The reaction was filtered, the filtrate was concentrated under reduced pressure, and purified by column chromatography (MeOH/DCM (2%)) to give product 72.3 (34 mg, yield: 25%). LCMS ESI (+) m/z:459 (M+1).

Step C:4- (2- (7, 9-Dihydrofuran [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridin-6-yl) -3-isopropyl-1H-indol-5-yl) cyclohexan-1-one (Compound 72.4)

Compound 72.3 (34 mg,0.074 mmol) was dissolved in dichloromethane (4 ml). Trifluoroacetic acid (1 ml) was added dropwise to the reaction system at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a product 72.4 (30 mg, yield: 98%). LCMS ESI (+) m/z:415 (M+1).

Step D:6- (5- (4- (3, 3-Difluoroazetidin-1-yl) cyclohexyl) -3-isopropyl-1H-indol-2-yl) -7, 9-dihydrofuro [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridine (Compound 72)

Compound 72.4 (30 mg,0.072 mmol), 3-difluoroazetidine hydrochloride (93 mg,0.72 mmol), acetic acid (5 drops) were dissolved in DMF (3 ml) and tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 1 hour. Then, sodium cyanoborohydride (23 mg,0.36 mmol) was slowly added to the reaction solution at 0℃and the reaction was continued with stirring at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 72 (7.32 mg, yield: 21%).

LCMS ESI(+)m/z：492(M+1)。

¹ H NMR(400MHz,DMSO)δ10.98(s,1H),8.91(s,1H),8.61(s,1H),7.54(s,1H),7.27(d,J＝8.4Hz,1H),7.01(dd,J＝8.4,1.2Hz,1H),5.42(s,2H),5.13(t,J＝3.2Hz,2H),3.57(t,J＝10.8Hz,4H),3.04(dt,J＝14.0,7.2Hz,1H),2.57(d,J＝12.4Hz,1H),2.22(s,1H),1.86(d,J＝11.2Hz,4H),1.52(dd,J＝23.2,12.4Hz,2H),1.38(d,J＝7.2Hz,6H),1.15(dd,J＝22.8,11.4Hz,2H).

Example 73

4- (5- (4- (3, 3-difluoroazetidin-1-yl) cyclohexyl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentan [ c ] pyridin-1-one

Step A:4- (3-isopropyl-5- (1, 4-dioxaspiro [4.5] dec-8-yl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-1-one (Compound 73.1)

Compound 72.1 (250 mg,0.66 mmol), 2-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2,5,6, 7-tetrahydro-1H-cyclopenta [ c ] pyridin-1-one (284 mg,1.32 mmol), potassium carbonate (274 mg,1.98 mmol), tris (dibenzylideneacetone) dipalladium (60 mg,0.065 mmol) and 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (63 mg,0.13 mmol) were dissolved in 1, 4-dioxane (12 ml) and water (2 ml). The reaction system was replaced with argon 3 times. The reaction mixture was stirred at 80℃for 4 hours. The reaction mixture was concentrated under reduced pressure, and purified by column chromatography (PE/EA (50%)) to give 73.1 (156 mg, yield: 53%). LCMS ESI (+) m/z:447 (M+1).

And (B) step (B): 4- (3-isopropyl-5- (4-oxocyclohexyl) -1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentane [ c ] pyridin-1-one (Compound 73.2)

Compound 73.1 (156 mg,0.35 mmol) was dissolved in dichloromethane (6 ml). Trifluoroacetic acid (2 ml) was added dropwise to the reaction system at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a product 73.2 (120 mg, yield: 85%). Lcmsei (+) m/z:403 (M+1).

Step C:4- (5- (4- (3, 3-Difluoroazetidin-1-yl) cyclohexyl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-1-one (Compound 73)

Compound 73.2 (40 mg,0.1 mmol), 3-difluoroazetidine hydrochloride (129 mg,1.0 mmol), acetic acid (5 drops) were dissolved in DMF (3 ml) and tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (31 mg,0.5 mmol) was then slowly added to the reaction solution at 0℃and the reaction was continued with stirring at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 73 (5.70 mg, yield: 12%). LCMS ESI (+) m/z:480 (M+1).

¹ H NMR(400MHz,DMSO)δ10.66(s,1H),7.55(s,1H),7.46(s,1H),7.19(d,J＝8.4Hz,1H),6.93(dd,J＝8.4,1.6Hz,1H),3.56(t,J＝12.4Hz,4H),3.50(s,3H),3.02–2.93(m,1H),2.71(dd,J＝16.0,8.0Hz,4H),2.54(s,1H),2.20(t,J＝11.2Hz,1H),2.01–1.93(m,2H),1.84(d,J＝10.8Hz,4H),1.50(dd,J＝23.2,12.4Hz,2H),1.33(d,J＝7.2Hz,6H),1.14(dd,J＝22.0,11.2Hz,2H).

Example 74

(S) -4- (5- (4- (3-fluoropyrrolidin-1-yl) cyclohexyl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-1-one

Step A: (S) -4- (5- (4- (3-fluoropyrrolidin-1-yl) cyclohexyl) -3-isopropyl-1H-indol-2-yl) -2-methyl-2, 5,6, 7-tetrahydro-1H-cyclopentyl [ c ] pyridin-1-one (compound 74)

Compound 73.2 (40 mg,0.1 mmol), (3S) -3-fluoropyrrolidine hydrochloride (129 mg,1.0 mmol), acetic acid (5 drops) were dissolved in DMF (3 ml) and tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (31 mg,0.5 mmol) was then slowly added to the reaction solution at 0℃and the reaction was continued with stirring at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation to give product 74 (9.71 mg, yield: 20%). LCMS ESI (+) m/z:476 (M+1).

¹ H NMR(400MHz,DMSO)δ10.66(d,J＝5.6Hz,1H),8.14(s,1H),7.55(s,1H),7.46(d,J＝5.6Hz,1H),7.20(dd,J＝8.4,4.4Hz,1H),6.94(d,J＝8.4Hz,1H),5.25(d,J＝56.4Hz,1H),3.50(s,3H),2.98(dt,J＝14.4,7.2Hz,2H),2.85(s,1H),2.72(dd,J＝16.0,8.0Hz,4H),2.62(s,1H),2.56(d,J＝16.4Hz,1H),2.44–2.36(m,1H),2.25–1.82(m,9H),1.65–1.49(m,3H),1.40(s,1H),1.33(dd,J＝7.2,1.2Hz,6H).

Example 75, example 76

Wherein the labeled carbon atom is in the S configuration, the R configuration, or a mixture thereof; the # labelled carbon atom being in S configuration, R configuration or mixtures thereof

(S) -6- (5- (4- (3-fluoropyrrolidin-1-yl) cyclohexyl) -3-isopropyl-1H-indol-2-yl) -7, 9-dihydrofuro [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridine

Step A: (S) -6- (5- (4- (3-fluoropyrrolidin-1-yl) cyclohexyl) -3-isopropyl-1H-indol-2-yl) -7, 9-dihydrofuro [3,4-c ] [1,2,4] triazolo [1,5-a ] pyridine

Compound 72.4 (20 mg,0.048 mmol), (3S) -3-fluoropyrrolidine hydrochloride (62 mg,0.48 mmol), acetic acid (5 drops) were dissolved in DMF (3 ml) and tetrahydrofuran (3 ml). The reaction mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (15 mg,0.24 mmol) was then slowly added to the reaction solution at 0℃and the reaction was continued with stirring at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by reverse phase preparation (preparation column: ultimate XB-C18, 21.2X 250mm,10 μm; eluent: mobile phase: 0.1% FA in H2O/ACN, elution gradient (ratio of ACN) 10% (0-3 min), 25-45% (3-16 min), 95% (16-20 min)) to give product 75 (retention time: 4.03min,4.2mg, yield: 18%) and product 76 (retention time: 4.10min,3.3mg, yield: 14%). LCMS ESI (+) m/z:488 (M+1).

Wherein compound 75 isIs a stereoisomer of (a).

Compound 76 isThe other stereoisomer of (a).

75: ¹ H NMR(400MHz,DMSO)δ10.98(s,1H),8.92(s,1H),8.62(s,1H),8.15(s,1H),7.55(s,1H),7.28(d J＝8.4Hz，1H)，7.03(d J＝7.6Hz，1H)，5.43(s，2H)，5.35–5.16(m 1H)，5.13(s，2H)，3.06(dd J

＝14.0,7.2Hz,2H),2.94(d,J＝7.2Hz,2H),2.83(dd,J＝11.6,4.8Hz,1H),2.75(dd,J＝10.4,3.2Hz,1H),2.61–2.58(m,1H),2.31–2.23(m,1H),2.22–2.11(m,1H),2.07(d,J＝12.4Hz,2H),2.03–1.83(m,4H),1.57(dd,J＝24.4,12.0Hz,2H),1.39(d,J＝7.2Hz,6H).

76: ¹ H NMR(400MHz,DMSO)δ10.97(s,1H),8.91(s,1H),8.61(s,1H),8.14(s,1H),7.54(s,1H),7.30(d,J＝8.4Hz,1H),7.05(d,J＝8.4Hz,1H),5.42(s,2H),5.29(d,J＝54.8Hz,1H),5.13(s,2H),3.05(dt,J＝14.0,7.2Hz,2H),2.94(d,J＝16.8Hz,2H),2.71(s,1H),2.18(d,J＝20.8Hz,2H),2.08–1.85(m,6H),1.63(t,J＝15.2Hz,4H),1.38(d,J＝7.2Hz,6H).

Effect example one, evaluation of cellular level efficacy of the compounds of the present application

1. Antagonism of the compounds of the present application on the activation pathway of human TLR7

1.1 Experimental materials and instruments

1.1.1 materials and reagents

1) HEK-Blue hTLR7 cells (InvivoGen)

2) HEK alkaline phosphatase detection Medium (HEK-Blue) ^TM Detection,InvivoGen)

3) DMEM high sugar culture medium (DMEM, gibco)

4) Blasticidin (Blastidin, invivoGen)

5) Bleomycin (Zeocin) ^TM ,InvivoGen)

6) Neomycin (Normocin) ^TM ,InvivoGen)

7) Penicillin-Streptomycin solution (PS, penicillin-Streptomycin, gibco)

8) Fetal bovine serum (FBS, gibco)

9) Phosphate buffer (PBS, gibco)

10 Leidesimotide (R848, MCE)

11)DMSO(Sigma)

1.1.2 consumables and instruments

1) 384-well flat bottom cell culture plate (Corning)

2) Vibration plate instrument (QILINBEIER)

3) 15ml centrifuge tube (Corning)

4) Centrifuge (Eppendorf)

5) CO2 constant temperature cell culture box (Thermo Scientific)

6) Microscope (OLYMPUS)

7) Automatic cell counter (CountessII, gibco)

8) Enzyme label instrument (Multiplate reader, perkinelmer)

9) Sound wave liquid processor (ECHO LABCYTE)

1.2 Experimental procedure

The purpose of this experiment was to detect compounds in HEK-Blue by HEK alkaline phosphatase detection medium ^TM Antagonistic activity in hTLR7 cells.

HEK-Blue hTLR7 cells were cultured in complete medium (DMEM high-sugar medium containing 10% inactivated fetal bovine serum, 100ug/mL neomycin, 100ug/mL bleomycin, 10ug/mL blasticidin, 0.5% penicillin-streptomycin solution). Taking cells with good growth and cell density of 80-90%, removing the supernatant of the growth medium, washing the cells once by using preheated PBS, adding the preheated PBS, and culturing and digesting the cells at 37 ℃. Complete medium was added to terminate digestion, the cell suspension was transferred to a 15mL centrifuge tube, and the supernatant was removed by centrifugation. Adding detection medium, dispersing cells, and counting to obtain a concentration of 3.3X10 ⁵ /mL cell suspension. The cell suspension was added to 384 well cell culture plates at 30 uL/well with 10000 cells per well.

Agonist R848 was made up to 40mM using 100% dmso; test compounds were prepared as stock solutions using 100% dmso at a concentration of 10mM. Stock solutions of test compounds were prepared with 100% dmso at test concentrations and 3-fold graded dilutions to 600, 200, 66.67, 22.22, 7.41, 2.47, 0.82, 0.27, 0.09, 0.03uM on 96-well dispensing plates; negative control wells were 100% dmso; 40mM stock of R848 was diluted to 480uM with 100% DMSO. The dispensing plate is vibrated and mixed uniformly on a vibration plate instrument (320 rpm) for standby.

The dispensing plates were centrifuged and test solutions were added to 384 well cell culture plates containing cell suspensions using ECHO: adding the test compound to the wells containing the cell suspension at a final concentration of 50 nL/wellSub 1000, 333.3, 111.1, 37, 12.3, 4.1, 1.3, 0.45, 0.15, 0.05nM, and agonist R848, 50 nL/well was added as compound group; 100% DMSO was added to wells containing cell suspension, 50 nL/well, and agonist R848, 50 nL/well as a positive control; 100% DMSO was added to wells containing cell suspension, 100 nL/well, as a negative control. The final concentration of agonist R848 in each well was 0.8um and the final concentration of dmso in each well was 0.33%. The cell plates were then incubated at 37℃in a 5% CO2 incubator for 16 hours. The cell plates were then removed and centrifuged at 1000rpm for 1 min, and the optical density value OD at 620nm was read per well using an microplate reader ₆₂₀ 。

Antagonistic activity of the test compounds was calculated using the following formula: inhibition (%) =100- (OD) ₆₂₀ Compound-OD ₆₂₀ Positive control mean)/(OD ₆₂₀ Negative control mean-OD ₆₂₀ Positive control mean) ×100, the dosing curve of the test compound was plotted using Graphpad Prism software, and the compound concentration at which the inhibition rate reached 50%, i.e. the antagonistic activity IC50 value, was calculated as shown in table 1.

2. Antagonism of the compounds of the present application on the activation pathway of human TLR8

2.1 Experimental materials and instruments

2.1.1 materials and reagents

1) HEK-Blue hTLR8 cells (InvivoGen)

3) DMEM high sugar culture medium (DMEM, gibco)

4) Blasticidin (Blastidin, invivoGen)

5) Bleomycin (Zeocin) ^TM ,InvivoGen)

6) Neomycin (Normocin) ^TM ,InvivoGen)

7) Penicillin-Streptomycin solution (PS, penicillin-Streptomycin, gibco)

8) Fetal bovine serum (FBS, gibco)

9) Phosphate buffer (PBS, gibco)

10 Leidesimotide (R848, MCE)

11)DMSO(Sigma)

2.1.2 consumables and instruments

1) 384-well flat bottom cell culture plate (Corning)

2) Vibration plate instrument (QILINBEIER)

3) 15 ml centrifuge tube (Corning)

4) Centrifuge (Eppendorf)

5) CO2 constant temperature cell culture box (Thermo Scientific)

6) Microscope (OLYMPUS)

7) Automatic cell counter (CountessII, gibco)

8) Enzyme label instrument (Multiplate reader, perkinelmer)

9) Sound wave liquid processor (ECHO LABCYTE)

2.2 Experimental procedure

The purpose of this experiment was to detect compounds in HEK-Blue by HEK alkaline phosphatase detection medium ^TM Antagonistic activity in hTLR8 cells.

HEK-Blue hTLR8 cells were cultured in complete medium (DMEM high-sugar medium containing 10% inactivated fetal bovine serum, 100ug/mL neomycin, 100ug/mL bleomycin, 30ug/mL blasticidin, 0.5% penicillin-streptomycin solution). Taking cells with good growth and cell density of 80-90%, removing the supernatant of the growth medium, washing the cells once by using preheated PBS, adding the preheated PBS, and culturing and digesting the cells at 37 ℃. Complete medium was added to terminate digestion, the cell suspension was transferred to a 15mL centrifuge tube, and the supernatant was removed by centrifugation. Adding detection medium, dispersing cells, and counting to obtain a concentration of 3.3X10 ⁵ /mL cell suspension. The cell suspension was added to 384 well cell culture plates at 30 uL/well with 10000 cells per well.

Agonist R848 was made up to 40mM using 100% dmso; test compounds were prepared as stock solutions using 100% dmso at a concentration of 10mM. Stock solutions of test compounds were prepared with 100% dmso at test concentrations and 3-fold graded dilutions to 600, 200, 66.67, 22.22, 7.41, 2.47, 0.82, 0.27, 0.09, 0.03uM on 96-well dispensing plates; negative control wells were 100% dmso; 40mM stock of R848 was diluted to 1.8mM with 100% DMSO. The dispensing plate is vibrated and mixed uniformly on a vibration plate instrument (320 rpm) for standby.

The dispensing plates were centrifuged and test solutions were added to 384 well cell culture plates containing cell suspensions using ECHO: adding a test compound to a well containing a cell suspension at a final concentration of 1000, 333.3, 111.1, 37, 12.3, 4.1, 1.3, 0.45, 0.15, 0.05nM, and adding an agonist R848, 50 nL/well as a compound group; 100% DMSO was added to wells containing cell suspension, 50 nL/well, and agonist R848, 50 nL/well as a positive control; 100% DMSO was added to wells containing cell suspension, 100 nL/well, as a negative control. The final concentration of agonist R848 in each well was 3um and the final concentration of dmso in each well was 0.33%. The cell plates were then incubated at 37℃in a 5% CO2 incubator for 16 hours. The cell plates were then removed and centrifuged at 1000rpm for 1 min, and the optical density value OD at 620nm was read per well using an microplate reader ₆₂₀ 。

3. Antagonism of the compounds of the present application on the activation pathway of human TLR9

3.1 Experimental materials and instruments

3.1.1 materials and reagents

1) HEK-Blue hTLR9 cells (InvivoGen)

3) DMEM high sugar culture medium (DMEM, gibco)

4) Blasticidin (Blastidin, invivoGen)

5) Bleomycin (Zeocin) ^TM ,InvivoGen)

6) Neomycin (Normocin) ^TM ,InvivoGen)

7) Penicillin-Streptomycin solution (PS, penicillin-Streptomycin, gibco)

8) Fetal bovine serum (FBS, gibco)

9) Phosphate buffer (PBS, gibco)

10)CpG ODN2006(InvivoGen)

11)DMSO(Sigma)

3.1.2 consumables and instruments

1) 384-well flat bottom cell culture plate (Corning)

2) Vibration plate instrument (QILINBEIER)

3) 15ml centrifuge tube (Corning)

4) Centrifuge (Eppendorf)

5) CO2 constant temperature cell culture box (Thermo Scientific)

6) Microscope (OLYMPUS)

7) Automatic cell counter (CountessII, gibco)

8) Enzyme label instrument (Multiplate reader, perkinelmer)

9) Sound wave liquid processor (ECHO LABCYTE)

3.2 Experimental procedure

The purpose of this experiment was to detect compounds in HEK-Blue by HEK alkaline phosphatase detection medium ^TM Antagonistic activity in hTLR9 cells.

HEK-Blue hTLR9 cells were cultured in complete medium (DMEM high-sugar medium containing 10% inactivated fetal bovine serum, 100ug/mL neomycin, 100ug/mL bleomycin, 10ug/mL blasticidin, 0.5% penicillin-streptomycin solution). Taking cells with good growth and cell density of 80-90%, removing the supernatant of the growth medium, washing the cells once by using preheated PBS, adding the preheated PBS, and culturing and digesting the cells at 37 ℃. Complete medium was added to terminate digestion, the cell suspension was transferred to a 15mL centrifuge tube, and the supernatant was removed by centrifugation. Adding detection medium, dispersing cells, and counting to give a concentration of 5×10 ⁵ /mL cell suspension. The cell suspension was added to 384 well cell culture plates at 30 uL/well with 15000 cells per well.

Using sterile water carried by the kit to prepare an agonist ODN2006 into a storage solution with the concentration of 300uM; test compounds were prepared as stock solutions using 100% dmso at a concentration of 30mM. Stock solutions of test compounds were prepared in 96-well dispensing plates with 100% dmso at test concentrations and 3-fold graded dilutions to 30000, 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, 1.52uM; the negative control wells were 100% dmso. The dispensing plate is vibrated and mixed uniformly (except for ODN 2006) on a vibration plate instrument (320 rpm) for standby.

The dispensing plates were centrifuged and test solutions were added to 384 well cell culture plates containing cell suspensions using ECHO: adding a test compound to wells containing cell suspension at a final concentration of 50 nL/well of 50000, 16666.67, 5555.56, 1851.85, 617.28, 205.76, 68.59, 22.86, 7.62, 2.54nM in that order, and adding an agonist ODN2006 stock solution at 100 nL/well as a compound group; adding 100% dmso to wells containing cell suspension, 50 nL/well, and adding agonist ODN2006, 100 nL/well as a positive control; cell suspension wells served as negative control. The final concentration of agonist ODN2006 in each well was 1um and the final concentration of dmso in each well was 0.167%. The cell plates were then incubated at 37℃in a 5% CO2 incubator for 16 hours. The cell plates were then removed and centrifuged at 1000rpm for 1 min, and the optical density value OD at 620nm was read per well using an microplate reader ₆₂₀ 。

Antagonistic activity of the test compounds was calculated using the following formula: inhibition (%) =100- (OD) ₆₂₀ Compound-OD ₆₂₀ Positive control mean)/(OD ₆₂₀ Negative control mean-OD ₆₂₀ Positive control mean) ×100, the measured action curve of the test compound was plotted using Graphpad Prism software, and the compound concentration at which the inhibition rate reached 50%, i.e., antagonistic activity IC, was calculated ₅₀ The values are shown in Table 1.

Wherein, in addition to measuring the compounds of the examples, IC's of the control Enpator and Afimetacan were also measured ₅₀ Values.

TABLE 1 Activity of the inventive Compounds in HEK-Blue hTLR7/8/9 cells

/>

Conclusion: the compound has obvious antagonism to HEK-Blue-hTLR7/8 cells, and has no obvious antagonism to HEK-Blue hTLR9 cells.

Effect example two Compounds of the present application test for IL-6 inhibition in animals

Experimental materials: preparation of compound solution: gardiquimod was added to the Saline vortex, sonicated to homogeneity, and formulated as a Gardiquimod clear solution at a final concentration of 0.2 mg/ml. Test compounds were vortexed with 5% DMSO, 3.7% HCl, PEG400, saline, sonicated to homogeneity and formulated as a clear solution of test material at a final concentration of 0.03mg/ml (final concentration of 5% DMSO+1% (3.7% HCL) +40% PEG400+54% Saline).

Experimental animals: BALB/c female mice, beijing Veitz laboratory animal technologies Co., ltd, 8 weeks old.

The experimental method comprises the following steps: animals were randomly assigned to a blank, control, and experimental group, 6 animals per group. After grouping the animals, the corresponding compound of the invention (0.3 mg/kg) and the control Afimeta (0.3 mg/kg) were administered; 0.5h after administration, gardiquimod 2mg/kg was intraperitoneally injected. The experimental endpoint was reached 1.5h after Gardiquimod administration. At the end of the experiment, the mice were anesthetized, hearts were bled into anticoagulation tubes, and plasma was collected for IL-6 cytokine detection. IL-6 inhibition was calculated by plasma IL-6 concentrations in control and experimental groups. The calculation formula is as follows: inhibition ratio= (Avg (Vehicle) -Avg (Group))/(Avg (Vehicle) -Avg (NC)) × 100%. Wherein: avg (Vehicle): control group plasma IL-6; avg (Group): plasma IL-6 of the experimental group; avg (NC): blank plasma IL-6.

TABLE 2 in vivo IL-6 inhibition experiments in animals of partial inventive Compounds

/>

Conclusion: the compound has obvious inhibiting effect on IL-6.

Effect example III, effect of the compounds of the present application on hERG channel currents

The rapidly activating potassium channel encoded by the human ether-a-go-go-related gene (hERG) is an important ion channel involved in the formation of phase 3 repolarization of myocardial action potential. Blocking hERG channels by drugs can lead to prolongation of cardiac repolarization, and electrocardiogram manifests as prolongation of QT interval, called long QT interval syndrome. Drug-induced delayed repolarization of the ventricles may in some cases trigger fatal arrhythmia-torsades de pointes.

The experiment uses whole cell patch clamp technology to study the inhibition of hERG potassium channel by compounds and evaluate the risk of inducing ventricular repolarization toxicity.

Cell culture

HEK293 cell line stably expressing hERG potassium channel was used and hERG potassium channel cells were purchased from Creacell Inc. (cat# A-0320).

HEK293 cell line with stable expression of hERG potassium channel was cultured in DMEM medium containing 10% fetal bovine serum and 0.8mg/mL G418 at 37℃and carbon dioxide concentration of 5%.

Cell passage: the old medium was removed and washed once with PBS, then 2mL of TrypLE was added ^TM Express solution, incubated at 37℃for about 1 min. When the cells were detached from the bottom of the dish, about 5ml of complete medium, pre-warmed at 37℃was added. The cell suspension was gently swirled with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000rpm for 5min to collect the cells. Expanding or maintaining culture, inoculating cells into 10cm cell culture dishes, each cell culture dish inoculating 6×10 cells ⁵ cells (final volume: 10 mL).

The cell density must not exceed 80% while maintaining the electrophysiological activity of the cells.

Patch clamp detection, trypLE for cells prior to assay ^TM Express separation, adding culture medium to stop digestion, centrifuging, re-suspending cell count, and adjusting cell density to 2-3×10 ⁶ cells/mL were then gently mixed with a room temperature equilibration shaker for 15-20min and assayed on the machine.

Patch clamp detection

Electrophysiological detection was performed using a fully automated patch clamp QPatch 48X (sonoion) device. The prepared cells were placed on a centrifuge of a Qpatch table, and the cells were washed using a multiple centrifugation/suspension method, and the cell culture medium was replaced with extracellular fluid. One MTP-96 plate was removed and then placed in the MTP source position. The QPlate chip is removed and then the QPlate is placed in the QPlate source location. The robot arm scans the MTP-96 plate and QPlate chip bar code and grabs it to the measurement station. The intracellular and extracellular fluids are aspirated from the fluid reservoir and added to the intracellular fluid reservoir, cell and test sample reservoir, respectively, of the QPlate chip. At the measurement station, all measurement sites on the QPlate are subjected to initial quality control. The quality control process includes sucking cell suspension from the cell container of the centrifuge, positioning the cells onto the chip hole via the pressure controller, and creating high resistance seal to form whole cell record mode. Once a stable control current baseline is obtained, the test substance is aspirated from the test substance MTP-96 plate and applied to the cells in a concentration gradient.

The voltage stimulation protocol for whole cell patch clamp recording whole cell hERG potassium current is as follows: the cell membrane voltage was clamped at-80 mV after the whole cell seal was formed. The clamp voltage is divided from-80 mV to-50 mV for 0.5s (used as leakage current detection), then is stepped to 30mV for 2.5s, and then is quickly restored to-50 mV for 4s, so that the tail current of the hERG channel can be excited. Data were collected repeatedly every 10s and the effect of drug on hERG tail current was observed. The leakage current was measured with a stimulus of-50 mV for 0.5 s. Test data is collected by Qpatch and stored in a connected service station.

Data analysis

First, the current after each drug concentration is acted and the blank current are markedNormalizationThen calculating the inhibition rate corresponding to each drug concentration>Average and standard errors were calculated for each concentration and the semi-inhibitory concentration for each compound was calculated using the following equation:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ x) HillSlope) non-linear fit to the dose-dependent effect using the above equation, where C represents the concentration of the test agent, IC ₅₀ H represents the Hill coefficient for the half-inhibitory concentration. Curve fitting and IC ₅₀ Is done using Graphpad software. The results of some of the compound tests are shown in table 3:

TABLE 3 half Inhibitory Concentration (IC) of example compounds on hERG current ₅₀ )

Examples	IC ₅₀ (μM)	Examples	IC ₅₀ (μM)
				Afimetoran	21.3	2	28.9
16	>30	17	25.8
				26	>30	32	>30
33	>30	35	>30
				39	>30	43	>30
53	>30	54	>30
				56	>30	66	>30
68	>30	70	>30

The results show that: the compounds of the invention have weak inhibition on hERG channels.

Claims

1. A compound according to formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof:

wherein R is ¹ Is that

R ^a Independently C ₁ ～C ₆ Alkyl or C ₃ ～C ₆ Cycloalkyl;

u is independently N or CH;

ring A is 3-10 membered heterocarbocycle or 3-10 membered carbocycle;

L ¹ is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

R ³ is C ₁ ～C ₆ Alkyl or C ₃ ～C ₆ Cycloalkyl;

R ^A hydrogen or halogen;

2. The compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein in the compound of formula II, ring a is a 3-10 membered heterocarbocycle.

3. The compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula II is a compound of formula I;

Wherein R is ¹ Is that

R ^a Independently C ₁ ～C ₆ Alkyl or C ₃ ～C ₆ Cycloalkyl;

u is independently N or CH;

ring A is 3-10 membered heterocarbocycle;

L ¹ is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

R ³ is C ₁ ～C ₆ Alkyl or C ₃ ～C ₆ Cycloalkyl;

R ⁴ is hydrogen, C ₁ ～C ₃ Alkyl, C ₃ ～C ₆ Cycloalkyl or halogen.

4. A compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein the compound of formula II meets one or more of the following conditions:

a) In the ring A, the 3-10 membered heterocarbocycle is a 6-8 membered heterocarbocycle;

b) In the ring A, the 3-10 membered heterocarbocycle is a single ring or a double ring, and the double ring is a spiro ring or a bridged ring;

c) In the ring A, the number of hetero atoms in the 3-10 membered hetero-carbocycle is 1 or 2;

d) In the ring A, in the 3-10 membered heterocarbocycle, the heteroatom is N;

e)L ¹ in the above, the C ₁ ～C ₆ Alkylene is C ₁ ～C ₄ An alkylene group;

f)L ² in the above, the C ₁ ～C ₆ Alkylene is C ₁ ～C ₄ An alkylene group;

g)L ¹ and L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -;

h)R ² in the above, the C ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group;

i)R ² in said quilt 1, 2 or 3R ²³ Substituted C ₁ ～C ₆ C in alkyl ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group;

j)R ² wherein the 3-10 membered cycloalkyl is 3-6 membered cycloalkyl;

k)R ² in said quilt 1, 2 or 3R ²² The 3-10 membered cycloalkyl in the substituted 3-10 membered cycloalkyl is 3-6 membered cycloalkyl;

l)R ² wherein the 3-10 membered heterocycloalkyl is a monocyclic or bicyclic ring, and the bicyclic ring is a spiro or bridged ring;

m)R ² in the 3-10 membered heterocycloalkyl, the number of heteroatoms is 1 or 2;

n)R ² in the 3-10 membered heterocycloalkyl, the heteroatom is N and/or O;

o)R ² wherein the 3-10 membered heterocycloalkyl is a 3-6 membered heterocycloalkyl;

p)R ² in said quilt 1, 2 or 3R ²¹ The 3-10 membered heterocycloalkyl in the substituted 3-10 membered heterocycloalkyl is a single ring or a double ring, and the double ring is a spiro ring or a bridged ring;

q)R ² in said quilt 1, 2 or 3R ²¹ The number of hetero atoms in the 3-10 membered heterocycloalkyl group in the substituted 3-10 membered heterocycloalkyl group is 1 or 2;

r)R ² in said quilt 1, 2 or 3R ²¹ In the 3-10 membered heterocycloalkyl group in the substituted 3-10 membered heterocycloalkyl group, a heteroatom is N and/or S;

s)R ² in said quilt 1, 2 or 3R ²¹ The 3-10 membered heterocycloalkyl group in the substituted 3-10 membered heterocycloalkyl group is a 3-6 membered heterocycloalkyl group;

t)R ² wherein the number of hetero atoms in the 5-6 membered heteroaryl group is 2;

u)R ² in said quilt 1, 2 or 3R ²⁶ In the 5-6 membered heteroaryl group in the substituted 5-6 membered heteroaryl group, the number of heteroatoms is 3 or 4;

v)R ² in said quilt 1, 2 or 3R ²⁶ Substituted 5-6 membered heterogeniesIn the 5-6 membered heteroaryl group in the aryl group, the heteroatom is N;

w)R ³ in the above, the C ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group;

x)R ³ in the above, the C ₃ ～C ₆ Cycloalkyl radicals are C ₃ ～C ₄ Cycloalkyl;

y)R ⁴ in the above, the C ₁ ～C ₃ Alkyl is methyl, ethyl, n-propyl or isopropyl;

z)R ⁴ in the above, the C ₃ ～C ₆ Cycloalkyl radicals are C ₃ ～C ₄ Cycloalkyl;

aa)R ⁴ wherein the halogen is fluorine.

5. The compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 4, wherein the compound of formula II satisfies one or more of the following conditions:

a)L ¹ in the above, the C ₁ ～C ₆ Alkylene is methylene, ethylene orThe q-terminal is connected with L ² Is connected with each other;

b)L ² in the above, the C ₁ ～C ₆ Alkylene is methylene, ethylene orThe q-terminal and R ² Is connected with each other;

c)R ² in the above, the C ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl;

d)R ² In said quilt 1, 2 or 3R ²³ Substituted C ₁ ～C ₆ C in alkyl ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl;

e)R ² wherein the 3-10 membered cycloalkyl is 3-4 membered cycloalkyl;

f)R ² in said quilt 1, 2 or 3R ²² The 3-to 10-membered cycloalkyl group in the substituted 3-to 10-membered cycloalkyl group is a 3-to 4-membered cycloalkyl group such as cyclopropyl or cyclobutyl;

g)R ² wherein the 3-10 membered heterocycloalkyl is a 4-6 membered heterocycloalkyl;

h)R ² in said quilt 1, 2 or 3R ²¹ The 3-10 membered heterocycloalkyl group in the substituted 3-10 membered heterocycloalkyl group is a 4-6 membered heterocycloalkyl group;

i)R ² wherein the 5-to 6-membered heteroaryl is

j)R ² In said quilt 1, 2 or 3R ²⁶ The 5-6 membered heteroaryl group in the substituted 5-6 membered heteroaryl group is

k)R ³ In the above, the C ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl;

l)R ³ in the above, the C ₃ ～C ₆ Cycloalkyl is cyclopropyl;

m)R ⁴ in the above, the C ₃ ～C ₆ Cycloalkyl is cyclopropyl.

6. The compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 5, wherein the compound of formula II satisfies one or more of the following conditions:

a)R ² wherein the 3-10 membered cycloalkyl is a ring Propyl or cyclobutyl;

b)R ² wherein the 3-10 membered heterocycloalkyl is

c)R ² In said quilt 1, 2 or 3R ²¹ The 3-10 membered heterocycloalkyl group in the substituted 3-10 membered heterocycloalkyl group is

7. A compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein the compound of formula II meets one or more of the following conditions:

a)R ^a in the above, the C ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group;

b)R ^a in the above, the C ₃ ～C ₆ Cycloalkyl radicals are C ₃ ～C ₄ Cycloalkyl;

c)R ^a1 、R ^a2 、R ^a3 or R is ^a4 In the above, the C ₁ ～C ₃ Alkyl is methyl;

d)R ^a1 、R ^a2 、R ^a3 or R is ^a4 In said C substituted by 1, 2 or 3 halogens ₁ ～C ₃ C in alkyl ₁ ～C ₃ Alkyl is methyl;

e)R ^a1 、R ^a2 、R ^a3 or R is ^a4 Wherein the halogen is fluorine;

f)R ²¹ in the above, the C ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group;

g)R ²³ wherein the halogen is fluorine;

h)R ²⁴ in the above, the C ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group;

i)R ²⁴¹ or R is ^241a In the above, the C ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group;

j)R ²⁵ in the above, the C ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group;

k)R ²⁶ in the above, the C ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group;

l)R ²⁷ or R is ^27a In the above, the C ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group;

m)R ²⁷ or R is ^27a In the above, the C ₃ ～C ₆ Cycloalkyl radicals are C ₃ ～C ₄ Cycloalkyl;

n)R ²⁷¹ in the above, the C ₁ ～C ₆ Alkyl is C ₁ ～C ₃ An alkyl group.

8. The compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 7, wherein the compound of formula II satisfies one or more of the following conditions:

a)R ^a In the above, the C ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl;

b)R ^a in the above, the C ₃ ～C ₆ Cycloalkyl is cyclopropyl;

c)R ²¹ in the above, the C ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl;

d)R ²⁴ in the above, the C ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl;

e)R ²⁴¹ or R is ^241a In the above, theC ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl;

f)R ²⁵ in the above, the C ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl;

g)R ²⁶ in the above, the C ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl;

h)R ²⁷ or R is ^27a In the above, the C ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl;

i)R ²⁷ or R is ^27a In the above, the C ₃ ～C ₆ Cycloalkyl is cyclopropyl;

j)R ²⁷¹ in the above, the C ₁ ～C ₆ Alkyl is methyl, ethyl, n-propyl or isopropyl.

9. A compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein the compound of formula II meets one or more of the following conditions:

a)R ^a in the above, the C ₁ ～C ₆ Alkyl is methyl;

b) In the ring A, the 3-10 membered heterocarbocycle is a single ring or a double ring; the double ring is a bridge ring;

preferably, in ring A, the 3-to 10-membered heterocarbocycle is

c) In ring A, the 3-to 10-membered carbocycle is a 3-to 6-membered carbocycle, such as a cyclopropane ring, a cyclobutane ring, a cyclopentane ring or a cyclohexane ring, for example

d)R ² In which the 3-to 10-membered cycloalkyl group is substituted with 1, 2 or 3R groups ²² Substituted 3-10 membered cycloalkanesThe 3-10 membered cycloalkyl groups in the radicals are each independently cyclopropyl;

e)R ² wherein the 3-10 membered heterocycloalkyl is a single ring;

f)R ² in said quilt 1, 2 or 3R ²¹ 3-10 membered heterocycloalkyl in substituted 3-10 membered heterocycloalkyl is monocyclic;

preferably, R ² In said 3-10 membered heterocycloalkyl and is substituted with 1, 2 or 3R ²¹ The 3-10 membered heterocycloalkyl groups in the substituted 3-10 membered heterocycloalkyl groups are each independently

g)R ² In said 5-to 6-membered heteroaryl and is substituted with 1, 2 or 3R ²⁶ The 5-to 6-membered heteroaryl groups in the substituted 5-to 6-membered heteroaryl groups are each independently

h)R ²¹ 、R ²⁴ 、R ²⁵ 、R ²⁶ 、R ²⁷ 、R ^27a 、R ²⁷¹ And R is ³ In the above, the C ₁ ～C ₆ Alkyl groups are each independently methyl;

i)R ²⁷ or R is ^27a Wherein, the halogen is F;

j)R ²⁷ or R is ^27a In said C substituted by 1, 2 or 3 halogens ₁ ～C ₆ C in alkyl ₁ ～C ₆ Alkyl groups can independently be C ₁ ～C ₃ An alkyl group; but also independently ethyl;

k)R ^A wherein said halogen is fluorine, chlorine or bromine, for example fluorine;

l)R ³ in the above, the C ₁ ～C ₆ The alkyl group is isopropyl.

10. A compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein the compound of formula II meets one or more of the following conditions:

a)R ¹ Is that

For example, R1 isAs another example, R ¹ Is->

b)R ^a Is C ₁ ～C ₆ Alkyl groups such as methyl;

c) X, Y and Z are independently-C (Ra 1) (Ra 2) -, - =CRa3-, -NRa4-, -O-, -S-, or = N-;

for example, X, Y and Z are independently-C (Ra 1) (Ra 2) -, =cra3-, -NRa4-, -O-, -S-, =n-, or-C (=o) -;

as another example, X, Y and Z are independently-C (Ra 1) (Ra 2) -, =cra3-, -NRa4-, or-O-;

d)R ^a1 、R ^a2 、R ^a3 and R is ^a4 Independently hydrogen or C ₁ ～C ₃ An alkyl group;

e)R ² is hydrogen, hydroxy, cyano, 3-10 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, 5-6 membered heteroaryl, (R) ²⁷ )(R ^27a ) N-, is substituted by 1, 2 or 3R ²² Substituted 3-to 10-membered cycloalkyl, substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl or substituted with 1, 2 or 3R ²¹ Substituted 3-10 membered heterocycloalkyl;

f)R ²¹ and R is ²² Independently hydroxy, oxo, cyano, halogen or C ₁ ～C ₆ An alkyl group; r is R ²⁴ Is C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，

R ²⁴¹ And R is ^241a Independently hydrogen; r is R ²⁵ Is C ₁ ～C ₆ An alkyl group; r is R ²⁶ Independently C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Independently hydrogen, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₆ Alkyl, C substituted by 1, 2 or 3 halogens ₁ ～C ₆ Alkyl or R ²⁷¹ -(C＝O)-，

R ²⁷¹ Independently C ₁ ～C ₆ An alkyl group;

for example, R ²¹ And R is ²² Independently oxo, cyano, halogen or C ₁ ～C ₆ An alkyl group; r is R ²⁴ Is C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，

R ²⁴¹ And R is ^241a Independently hydrogen; r is R ²⁵ Is C ₁ ～C ₆ An alkyl group; r is R ²⁶ Independently C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Independently hydrogen, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₆ Alkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Independently C ₁ ～C ₆ An alkyl group;

g) In the 5-6 membered heteroaryl, the number of heteroatoms is 2, 3 or 4, and the heteroatoms are independently selected from one or more of N, O and S;

h)R ³ is C ₁ ～C ₆ An alkyl group;

i)R ⁴ h.

11. A compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein the compound of formula II meets one or more of the following conditions:

a)R ¹ in,wherein R is ^a Is C ₁ ～C ₆ Alkyl or C _3-6 Cycloalkyl; x, Y and Z can independently be-C (R ^a1 )(R ^a2 )-、

＝CR ^a3 -、-C(＝O)-、-NR ^a4 -, =n-, -O-, or-S-; r is R ^a1 And R is ^a2 May independently be hydrogen or halogen; r is R ^a3 May be hydrogen or halogen; r is R ^a4 Can be hydrogen, C ₁ ～C ₃ Alkyl or trifluoromethyl;

b)R ¹ in,wherein X, Y and Z are independently-C (R ^a1 )(R ^a2 ) -, =n-, -O-, or-S-; r is R ^a1 And R is ^a2 Can independently be hydrogen;

c)R ¹ in,in X, Y and Z are independently =cr ^a3 -or-NR ^a4 -；R ^a3 And R is ^a4 Can be independently hydrogen, C ₁ ～C ₃ Alkyl, trifluoromethyl or halogen;

d)R ¹ in,wherein X, Y and Z are independently-C (R ^a1 )(R ^a2 ) -or = CR ^a3 -；R ^a1 、R ^a2 And R is ^a3 Can be independently hydrogen, C ₁ ～C ₃ Alkyl, trifluoromethyl or halogen;

e)R ¹ in,in X, Y and Z are independently =cr ^a3 -or-NR ^a4 -；R ^a3 And R is ^a4 Can be independently hydrogen, C ₁ ～C ₃ Alkyl, trifluoromethyl or halogen;

f)R ¹ in,wherein X, Y and Z are independently-C (R ^a1 )(R ^a2 )-、＝CR ^a3 -、-C(＝O)-、-NR ^a4 -、＝N-、

-O-or-S-; r is R ^a1 And R is ^a2 May independently be hydrogen or halogen; r is R ^a3 Can be hydrogen; r is R ^a4 Can be hydrogen, C ₁ ～C ₃ Alkyl or trifluoromethyl;

g)R ¹ in,wherein X, Y, Z and W are independently-C (R ^a1 )(R ^a2 ) -, =n-, -O-, or-S-; r is R ^a1 And R is ^a2 Can independently be hydrogen; r is R ^a Can be C ₁ ～C ₃ An alkyl group;

h)L ¹ is a single bond; l (L) ² Can be a single bond; r is R ² Can be hydrogen, 3-10 membered heterocycloalkyl, substituted 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-to 10-membered cycloalkyl or by 1, 2 or 3R ²³ Substituted C ₁ ～C ₆ An alkyl group; r is R ²¹ Can be oxo, R ²² Can be cyano, R ²³ Can be halogen;

alternatively, L ¹ Is a single bond; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -; r is R ² Can be hydroxyl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl, substituted by 1, 2 or 3R ²² Substituted 3-10 membered cycloalkyl, R ²⁴ -S(＝O) ₂ -、

R ²⁵ -S(＝O) ₂ - (NH) -, 5-to 6-membered heteroaryl or substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl; r is R ²¹ Can be C ₁ ～C ₆ Alkyl or oxo; r is R ²² Can be cyano; r is R ²⁴ Can be C ₁ ～C ₆ Alkyl, (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogen or C ₁ ～C ₆ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₆ An alkyl group;

alternatively, L ¹ Is C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -, wherein L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² Can be cyano, trifluoromethyl, 3-to 10-membered heterocycloalkyl, substituted by 1, 2 or 3R ²¹ Substituted 3-10 membered heterocycloalkyl, R ²⁴ -S(＝O) ₂ -、R ²⁵ -S(＝O) ₂ - (NH) -, substituted by 1, 2 or 3R ²⁶ Substituted 5-to 6-membered heteroaryl or (R) ²⁷ )(R ^27a )N-；R ²¹ Can be hydroxyl, oxo or halogen; r is R ²⁴ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁵ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁶ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Can be independently hydrogen,

C ₁ ～C ₆ Alkyl, C ₃ ～C ₆ Cycloalkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Can be C ₁ ～C ₆ An alkyl group;

alternatively, L ¹ Is a single bond; l (L) ² Can be a single bond; r is R ² Can be hydrogen or 3-10 membered heterocycloalkyl;

alternatively, L ¹ Is a single bond; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -; r is R ² Can be hydroxyl, 5-6 membered heteroaryl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl or R ²⁴ -S(＝O) ₂ -；R ²¹ Can be C ₁ ～C ₆ An alkyl group; r is R ²⁴ Can be C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Can be independently hydrogenOr C ₁ ～C ₆ An alkyl group;

alternatively, L ¹ Can be C ₁ ～C ₆ Alkylene or- (c=o) -; l (L) ² Can be C ₁ ～C ₆ Alkylene or- (c=o) -, wherein L ¹ And L ² Not simultaneously C ₁ ～C ₆ Alkylene group, and L ¹ And L ² Not both- (c=o) -; r is R ² Can be 3-10 membered heterocycloalkyl, substituted with 1, 2 or 3R ²¹ Substituted 3-to 10-membered heterocycloalkyl or (R) ²⁷ )(R ^27a )N-；R ²¹ May be oxo or halogen; r is R ²⁷ And R is ^27a Can be independently hydrogen or C ₁ ～C ₆ An alkyl group.

12. A compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein the compound of formula II meets one or more of the following conditions:

a)R ¹ is that

Preferably, R1 is

b) Ring A isWherein the s terminal and L ¹ Is connected with each other; preferably, ring A is +.>Wherein the s terminal and L ¹ Is connected with each other;

c)L ¹ is a single bond, methylene, ethylene or- (c=o) -orThe q-terminal is connected with L ² Is connected with each other; />

d)L ² Is a single bond, methylene, ethylene or- (c=o) -orThe q-terminal and R ² Is connected with each other;

e)R ² is hydrogen, hydroxy, cyano, trifluoromethyl,

Preferably, R ² Is hydrogen, hydroxy, cyano, < >>

Further preferably, ->Is H,

/>

f)R ³ Is isopropyl or cyclopropyl;

g)R ⁴ is hydrogen or methyl.

13. A compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3, wherein the compound of formula II is according to any one of the following schemes:

scheme one: the compound shown in the formula II is a compound shown in the formula I, wherein

R ¹ Is that

R ^a Is C ₁ ～C ₆ An alkyl group;

u is independently N or CH;

ring A is 3-10 membered heterocarbocycle;

L ¹ is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

R ²¹ and R is ²² Independently oxo, cyano, halogen or C ₁ ～C ₆ An alkyl group; r is R ²⁴ Is C ₁ ～C ₆ Alkyl or (R) ²⁴¹ )(R ^241a )N-，R ²⁴¹ And R is ^241a Independently hydrogen; r is R ²⁵ Is C ₁ ～C ₆ An alkyl group; r is R ²⁶ Independently C ₁ ～C ₆ An alkyl group; r is R ²⁷ And R is ^27a Independently hydrogen, C ₃ ～C ₆ Cycloalkyl, C ₁ ～C ₆ Alkyl or R ²⁷¹ -(C＝O)-，R ²⁷¹ Independently C ₁ ～C ₆ An alkyl group;

R ³ Is C ₁ ～C ₆ An alkyl group;

R ⁴ is hydrogen;

scheme II:

R ¹ is that

R ^a Is C ₁ ～C ₆ An alkyl group;

u is independently N or CH;

ring A is 3-10 membered heterocarbocycle or 3-10 membered carbocycle;

L ¹ is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

v is C-R ⁴ Or N;

R ^A hydrogen or halogen;

R ³ is C ₁ ～C ₆ An alkyl group;

R ⁴ is hydrogen;

scheme III: r is R ¹ Is that

R ^a Is methyl;

u is independently N or CH;

ring A is 3-10 membered heterocarbocycle;

L ¹ is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

L ² is a single bond, C ₁ ～C ₆ Alkylene or- (c=o) -;

v is C-R ⁴ Or N;

R ^A hydrogen or halogen;

R ³ is C ₁ ～C ₆ An alkyl group;

R ⁴ is hydrogen.

14. A compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 3 wherein the compound of formula II is of any one of the following structures:

/>

15. a pharmaceutical composition comprising substance X and a pharmaceutical excipient;

the substance X is a compound of formula II, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14.

16. Use of substance X in the preparation of TLR7 and/or TLR8 inhibitors;

17. The application of a substance X in the preparation of medicines;

the substance X is a compound shown in the formula II, a pharmaceutically acceptable salt, a solvate or a solvate of the pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14;

the medicine is used for treating diseases related to TLR7 and/or TLR 8.

18. Use of substance X in the manufacture of a medicament for the treatment of autoimmune diseases;