CN111253390B

CN111253390B - Ring-fused compound, preparation method and application thereof

Info

Publication number: CN111253390B
Application number: CN201811452539.5A
Authority: CN
Inventors: 李桂英; 何云; 游泽金; 王利春; 王晶翼
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2018-11-30
Filing date: 2018-11-30
Publication date: 2023-10-03
Anticipated expiration: 2038-11-30
Also published as: CN117088871A; CN111253390A

Abstract

The invention belongs to the field of medicines, and particularly relates to a compound shown in a formula I, wherein a stereoisomer, a tautomer or a mixture of the stereoisomer and the tautomer of the compound, pharmaceutically acceptable salts, eutectic crystals, polymorphs or solvates of the compound, or stable isotope derivatives, metabolites or prodrugs of the compound.

Description

Ring-fused compound, preparation method and application thereof

Technical Field

The invention belongs to the field of medicines, and in particular relates to a parallel-cyclic compound, wherein a stereoisomer, a tautomer or a mixture of the stereoisomers, the pharmaceutically acceptable salts, the eutectic, the polymorphs or the solvates of the compound, or a stable isotope derivative, a metabolite or a prodrug of the compound. The compounds of the invention are useful as NLRP3 modulators (e.g., agonists) for the treatment of diseases associated with NLRP3 inflammatory small body activity (e.g., neoplastic diseases).

Background

NLRP3 (NLR family pyrin domain containing 3) belongs to the NOD-like receptor family, and is an intracellular model recognition receptor most studied in recent years, mainly expressed in macrophages and neutrophils, and involved in the innate immunity of the organism, and resistant to pathogen infection and stress injury. NLRP3 inflammatory corpuscles play a very clear role in inflammatory and metabolic diseases, and excessive activation thereof can lead to immune diseases such as type 2 diabetes, rheumatoid arthritis and atherosclerosis. However, recent studies have shown that NLRP3 has anti-tumor effects in inhibiting tumor growth and metastasis.

After recognizing the pathogen-associated molecular pattern (PAMP) or the endogenous damage-associated molecular pattern (DAMP), the NOD domain of the NLRP3 protein oligomerizes and recruits proteins such as ASC and pro-caspase-1 to form functional NLRP3 inflammatory bodies. After the pro-caspase-1 is cleaved and activated to caspase-1, the caspase-1 cleaves the pro-IL-1β and pro-IL-18 in large amounts to convert them to active forms IL-1β and IL-18 and release them extracellular, amplifying the inflammatory response. The excited NLRP3 inflammatory corpuscles can obviously improve the level of immune factors IL-1 beta and IL-18 in the tumor microenvironment, and start natural immune killing and subsequent acquired immune response to exert the anti-tumor effect. Specifically, IL-1. Beta. Can induce CD8+ T cells to secrete interferon gamma (IFN-gamma), and also can induce CD4+ cells to secrete IL-17, so that effective anti-tumor immune response is caused; IL-18 can promote NK cell maturation, activate STAT1 downstream signal channels in immune cells, and enhance the killing function of the immune cells. Clinical studies have shown that down-regulation of NLRP3 is significantly inversely related to prognosis in liver cancer patients. Preclinical studies also show that NLRP3 deficient mice have higher colorectal tumor formation rates and worsen colorectal liver metastases. Therefore, NLRP3 plays an important role in tumor microenvironment, and can be used as a key target point of tumor immunotherapy and a tumor prognosis marker.

Despite the potential of NLRP3 agonists for tumor immunotherapy, only two companies currently report compounds with NLRP3 agonistic activity. VentiRx Pharmaceutical, VTX2337, which is a TLR8/NLRP3 inflammatory small body dual agonist, has entered phase II in clinical indications are ovarian and head and neck cancer (plos|one, 2016.02.29). Four patent applications (WO 2017184746, WO2017040670, WO2017184735, WO 2018152396) to Bristol-Myers Squibb company and IFM Therapeutis, INC (purchased by Bristol-Myers Squibb company) cover compounds of the same type of parent nucleus, which have a certain selectivity for TLR7 and TLR8, are currently still in preclinical research. Thus, there is a need to develop new, high-potency, low-toxicity NLRP3 agonists to meet clinical therapeutic needs.

Disclosure of Invention

The inventors of the present invention have, through creative efforts, obtained a new class of bicyclic compounds that can act as NLRP3 modulators (e.g., agonists), directly bind or modify NLRP3 at the protein level, and enhance the function of NLRP3 inflammatory bodies by activating, stabilizing, altering NLRP3 distribution or otherwise, thereby providing the following inventions:

in one aspect, the invention relates to a compound of formula I, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound:

Wherein:

X ¹ is CR (CR) ⁷ 、N，

X ² C, N, O or S, and satisfies the following conditions:

(1) When X is ² When C is R ⁶ Selected from H, C _1-6 Alkyl, C _3-8 Cycloalkyl group, the C _1-6 Alkyl and C _3-8 Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, OH, CN, NO ₂ 、C _1-4 Alkoxy, C _1-4 A hydroxyalkyl group;

(2) When X is ² In the case of N, O or S, R ⁶ Is absent and when X ² O, S R ² Absence of;

R ¹ selected from C _1-8 Alkyl, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo; the C is _1-8 Alkyl, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, optionally substituted with one or more of halogen, CN, NO ₂ 、C _1-4 Alkyl, C _3-8 Cycloalkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, C _1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, CO ₂ R ³⁰ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ 、S(O)NR ³¹ R ³² 、S(O) ₂ NR ³¹ R ³² 、S(O)R ³⁵ 、S(O) ₂ R ³⁵ 、OR ³⁷ 、SR ³⁷ ；

R ² Selected from H, C _1-8 Alkyl, C _2-8 Alkenyl, C _2-8 Alkynyl, C _6-12 Aryl, C _3-8 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, said C _1-8 Alkyl, C _2-8 Alkenyl, C _2-8 Alkynyl, C _6-12 Aryl, C _3-8 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl may optionally be substituted with one or more of the following substituents Multiple substitutions: halogen, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO ₂ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³¹ R ³² C(O)、C(O)OR ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³¹ R ³² ；

R ³ Selected from H, OH, halogen, CN, NO ₂ 、C _1-8 Alkyl, C _1-8 Haloalkyl, C _1-8 Alkoxy, C _1-8 Haloalkoxy, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryls, 9-12 membered aryl-cycloalkyl, CO ₂ R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、SO ₂ R ³⁵ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ 、C(＝NR ³⁸ )NR ³¹ R ³² 、NR ³³ C(＝NR ³⁸ )NR ³¹ R ³² 、P(R ³⁹ ) ₂ 、P(OR ³⁹ ) ₂ 、P(O)R ³⁹ R ⁴⁰ 、P(O)OR ³⁹ OR ³⁰ 、S(O)R ³⁵ 、S(O) ₂ R ³⁵ 、S(O)NR ³¹ R ³² 、S(O) ₂ NR ³¹ R ³² The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-8 Alkyl, C _1-8 Haloalkyl, C _1-8 Alkoxy, C _1-8 Haloalkoxy, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl optionally substituted with one or more of the following substituents: halogen, CN, NO ₂ 、C _1-4 Alkyl, C _3-8 NaphtheneRadical, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, C _1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, CO ₂ R ³⁰ 、C(O)R ³⁰ _、 C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、S(O)R ³⁵ 、S(O) ₂ R ³⁵ 、S(O)NR ³¹ R ³² 、S(O) ₂ NR ³¹ R ³² 、OR ³⁷ 、SR ³⁷ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ 、C(＝NR ³⁸ )NR ³¹ R ³² 、NR ³³ C(＝NR ³⁸ )NR ³¹ R ³² 、＝NNR ³¹ R ³² 、P(R ³⁹ ) ₂ 、P(OR ³⁹ ) ₂ 、P(O)R ³⁹ R ⁴⁰ 、P(O)OR ³⁹ OR ³⁰ ；

R ⁴ And R is ⁵ Each independently selected from H, C _1-15 Alkyl, C _1-8 Alkoxy, or R ⁴ 、R ⁵ And the nitrogen atom to which it is attached form a 4-7 membered heterocyclic ring; the C is _1-15 Alkyl, C _1-8 The alkoxy group may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

R ⁷ each independently selected from H, C _1-6 Alkyl, C _3-8 Cycloalkyl group, the C _1-6 Alkyl and C _3-8 Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, OH, CN, C _1-4 Alkoxy, C _1-4 A hydroxyalkyl group;

v is C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo; the C is _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-The 12 membered aryl-heterocyclo group may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

l is- (L) ¹ ) _n -(L ² ) _p –(L ³ ) _q -, wherein L ¹ 、L ² And L ³ Identical or different and are each independently selected from C _1-8 Alkylene, C _2-8 Alkenylene, C _2-8 Alkynylene, C _1-8 Halogenated alkylene, C _1-8 Alkyloxy, C _1-8 Haloalkoxy, C _1-8 Hydroxyalkylene, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, O, S, NR ³³ 、SO、SO ₂ 、CO、C(R ^36a R ^36b ) The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-8 Alkylene, C _2-8 Alkenylene, C _2-8 Alkynylene, C _1-8 Halogenated alkylene, C _1-8 Alkyloxy, C _1-8 Haloalkoxy, C _1-8 Hydroxyalkylene, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

n, p, q are each independently selected from 0 or 1;

R ³⁰ 、R ³⁷ 、R ³⁹ 、R ⁴⁰ each independently selected from: hydrogen, C _1-8 Alkyl, C _1-8 Hydroxyalkyl, C _1-8 Haloalkyl, C _1-8 Alkoxy, C _1-8 Haloalkoxy, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, C _1-8 alkyl-C _6-12 Aryl, C _1-8 Alkyl- (5-10 membered heteroaryl); the C is _1-8 Alkyl, C _1-8 Hydroxyalkyl, C _1-8 Haloalkyl, C _1-8 Alkoxy, C _1-8 Haloalkoxy, C _3-8 Cycloalkyl radicals4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, C _1-8 alkyl-C _6-12 Aryl, C _1-8 Alkyl- (5-10 membered heteroaryl) groups may be optionally substituted with one or more of the following substituents: OH, CN, NO ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Haloalkyl, halogen, C _1-4 Haloalkoxy, CO ₂ (C _1-6 Alkyl group, CONR ³¹ R ³² 、NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、S(O)R ³⁵ 、S(O) ₂ R ³⁵ 、S(O)NR ³¹ R ³² 、S(O) ₂ NR ³¹ R ³² ；

R ³¹ 、R ³² 、R ³³ 、R ³⁴ Each independently selected from: H. c (C) _1-8 Alkyl, C _1-8 Hydroxyalkyl, C _1-8 Alkoxy, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl; or R is ³¹ And R is ³² Forms together with the N atom to which each is attached a 3-8 membered heterocyclic group; or R is ³³ And R is ³⁴ Together with the C or N atom to which each is attached, form a 4-8 membered heterocyclyl; the C is _1-8 Alkyl, C _1-8 Hydroxyalkyl, C _1-8 Alkoxy, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NO ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Hydroxyalkyl, C _1-4 Haloalkyl, C _1-4 Haloalkoxy, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl;

R ³⁵ selected from: c (C) _1-8 Alkyl, C _1-8 Hydroxyalkyl, C _1-8 Haloalkyl, C _1-8 Alkoxy, C _1-8 Haloalkoxy, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, C _1-8 alkyl-C _6-12 Aryl, C _1-8 Alkyl- (5-10 membered heteroaryl); the C is _1-8 Alkyl, C _1-8 Hydroxyalkyl, C _1-8 Haloalkyl, C _1-8 Alkoxy, C _1-8 Haloalkoxy, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: OH, CN, NO ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _1-4 Haloalkyl, halogen, C _1-4 Haloalkoxy, CO ₂ (C _1-6 Alkyl group, CONR ³¹ R ³² 、NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、S(O)Me、S(O) ₂ Me、S(O)NR ³¹ R ³² 、S(O) ₂ NR ³¹ R ³² The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ³¹ 、R ³² 、R ³³ 、R ³⁴ As defined above;

R ^36a and R is ^36b Identical or different, each independently selected from H, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-8 Hydroxyalkyl, C _1-8 A haloalkyl group; the C is _1-6 Alkyl, C _1-6 Alkoxy, C _1-8 Hydroxyalkyl, C _1-8 Haloalkyl may be optionally substituted with one or more of the following groups: OH, CN, NH ₂ 、NHCH ₃ 、N(CH ₃ ) ₂ The method comprises the steps of carrying out a first treatment on the surface of the Or R is ^36a 、R ^36b And R is equal to ^36a 、R ^36b The attached carbon atoms together form a 3-7 membered cycloalkyl or heterocyclyl group;

R ³⁸ selected from: H. OH, CN, NO ₂ 、S(O)R ³⁵ 、S(O) ₂ R ³⁵ ；

When a plurality of R ³⁰ When present at the same time, each R ³⁰ May be the same or different;

when a plurality of R ³¹ When present at the same time, each R ³¹ May be the same or different;

when a plurality of R ³² When present at the same time, each R ³² May be the same or different;

when a plurality of R ³³ When present at the same time, each R ³³ May be the same or different;

when a plurality of R ³⁴ When present at the same time, each R ³⁴ May be the same or different;

when a plurality of R ³⁵ When present at the same time, each R ³⁵ May be the same or different;

when a plurality of R ³⁷ When present at the same time, each R ³⁷ May be the same or different;

when a plurality of R ³⁸ When present at the same time, each R ³⁸ May be the same or different;

when a plurality of R ³⁹ When present at the same time, each R ³⁹ May be the same or different;

when a plurality of R ⁴⁰ When present at the same time, each R ⁴⁰ May be the same or different.

In a preferred embodiment, R ¹ Selected from C _1-4 Alkyl, C _3-6 Cycloalkyl, 4-6 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo; the C is _1-4 Alkyl, C _3-6 Cycloalkyl, 4-6 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, optionally substituted with one or more of halogen, CN, NO ₂ 、C _1-4 Alkyl, C _3-8 Cycloalkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, C _1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, CO ₂ R ³⁰ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ 、S(O)NR ³¹ R ³² 、S(O) ₂ NR ³¹ R ³² 、S(O)R ³⁵ 、S(O) ₂ R ³⁵ 、OR ³⁷ 、SR ³⁷ ；

In a preferred embodiment, R ¹ Selected from C _1-4 Alkyl, C _3-6 Cycloalkyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo; the C is _1-4 Alkyl, C _3-6 Cycloalkyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, optionally substituted with one or more of halogen, CN, NO ₂ 、C _1-4 Alkyl, C _3-8 Cycloalkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, C _1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, CO ₂ R ³⁰ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ 、S(O)NR ³¹ R ³² 、S(O) ₂ NR ³¹ R ³² 、S(O)R ³⁵ 、S(O) ₂ R ³⁵ 、OR ³⁷ 、SR ³⁷ ；

Preferably, R ¹ Selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclohexyl, furophenyl, said phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclohexyl, furophenyl optionally substituted with one or more of halogen, CN, CH ₃ 、OCH ₃ 5-6 membered heterocyclyl, C (O) N (CH) ₃ ) ₂ ；

More preferably, R ¹ Selected from the group consisting of

In a preferred embodiment, V is selected from C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl; the C is _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-to 10-membered heteroaryl groups may optionally be substituted withIs a substitution of one or more of: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

preferably, V is selected from

In a preferred embodiment, X ¹ Selected from CH and N.

In a preferred embodiment, X ¹ CH.

In a preferred embodiment, X ² Is N, R ⁶ Is not present.

In a preferred embodiment, X ² Selected from O and S, R ⁶ Is absent and R ² Is not present.

In a preferred embodiment, R ² Selected from H, C _1-8 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _6-12 Aryl, C _3-8 Cycloalkyl, 5-8 membered heteroaryl, 4-6 membered heterocyclyl, said C _1-8 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _6-12 Aryl, C _3-8 Cycloalkyl, 5-8 membered heteroaryl, 4-6 membered heterocyclyl may be optionally substituted with one or more of the following substituents: halogen, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO ₂ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³¹ R ³² C(O)、C(O)OR ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³¹ R ³² ；

In a preferred embodiment, R ² Selected from H, C _1-8 Alkyl, C _6-12 Aryl, said C _1-8 Alkyl, C _6-12 Aryl groups may be optionally substituted with one or more of the following substituents: halogen, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO ₂ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³¹ R ³² C(O)、C(O)OR ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³¹ R ³² ；

In a preferred embodiment, R ² Selected from H, methyl, ethyl, propyl and butyl, preferably R ² Is methyl.

In a preferred embodiment, R ³ Selected from H, OH, halogen, CN, NO ₂ 、C _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, CO ₂ R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、SO ₂ R ³⁵ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, CN, NO ₂ 、C _1-4 Alkyl, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² ；

Preferably, R ³ Selected from OH, C _1-3 Alkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、OR ³⁷ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-3 Alkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: a methyl group;

more preferably, R ³ Selected from OH,

In a preferred embodiment, R ⁴ And R is ⁵ Each independently selected from H, C _1-3 Alkyl, C _3-6 Alkoxy, or R ⁴ 、R ⁵ And the nitrogen atom to which it is attached form a 4-7 membered heterocyclic ring; the C is _1-4 Alkyl, C _3-6 The alkoxy group may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group; preferably, R ⁴ And R is ⁵ All are H.

In a preferred embodiment, each L is independently selected from C _1-3 Alkylene, C _2-5 Alkenylene, C _2-5 Alkynylene, C _1-3 Alkyloxy, C _1-5 Hydroxyalkylene, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl; the C is _1-3 Alkylene, C _2-5 Alkenylene, C _2-5 Alkynylene, C _1-3 Alkyloxy, C _1-5 Hydroxyalkylene, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

preferably, each L is independently selected from methylene, ethylene and propylene; the methylene, ethylene and propylene groups may be optionally substituted with one or more of the following substituents: OH, C _1-6 An alkyl group; preferably, L is propylene.

In some embodiments of the invention, the compound has the structure of formula II:

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ V and L are as defined above for formula I.

In a preferred embodiment of the invention, the compounds have the structure of formula II above,

wherein R is ¹ Selected from C _1-4 Alkyl, C _3-6 Cycloalkyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo; the C is _1-4 Alkyl, C _3-6 Cycloalkyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, optionally substituted with one or more of halogen, CN, NO ₂ 、C _1-4 Alkyl, C _3-8 Cycloalkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, C _1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, CO ₂ R ³⁰ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ 、S(O)NR ³¹ R ³² 、S(O) ₂ NR ³¹ R ³² 、S(O)R ³⁵ 、S(O) ₂ R ³⁵ 、OR ³⁷ 、SR ³⁷ ；

More preferably, R ¹ Selected from the group consisting of

wherein R is ² Selected from H, C _1-8 Alkyl, C _6-12 Aryl, said C _1-8 Alkyl, C _6-12 Aryl groups may be optionally substituted with one or more of the following substituents: halogen, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO ₂ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³¹ R ³² C(O)、C(O)OR ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³¹ R ³² ；

Preferably, R ² Selected from H, methyl, ethyl, propyl and butyl, preferably R ² Is methyl.

wherein R is ³ Selected from OH, C _1-3 Alkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、OR ³⁷ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-3 Alkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: a methyl group;

more preferably, R ³ Selected from OH,

wherein V is selected from C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl; the C is _3-6 NaphtheneRadicals, 4-8 membered heterocyclic radicals, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

preferably, V is selected from

wherein each L is independently selected from the group consisting of methylene, ethylene, and propylene; the methylene, ethylene and propylene groups may be optionally substituted with one or more of the following substituents: OH, C _1-6 An alkyl group; preferably, L is propylene.

n, p, q are each independently selected from 0 or 1.

R ² Selected from H, C _1-8 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _6-12 Aryl, C _3-8 Cycloalkyl, 5-8 membered heteroaryl, 4-6 membered heterocyclyl, said C _1-8 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _6-12 Aryl, C _3-8 Cycloalkyl, 5-8 membered heteroaryl, 4-6 membered heterocyclyl may be optionally substituted with one or more of the following substituents: halogen, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO ₂ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³¹ R ³² C(O)、C(O)OR ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³¹ R ³² ；

R ³ Selected from H, OH, halogen, CN, NO ₂ 、C _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, CO ₂ R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、SO ₂ R ³⁵ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, CN, NO ₂ 、C _1-4 Alkyl, C _3-8 Cycloalkyl, 4-10 membered heterogeniesCyclic group, NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² ；

R ⁴ And R is ⁵ Each independently selected from H, C _1-3 Alkyl, C _3-6 Alkoxy, or R ⁴ 、R ⁵ And the nitrogen atom to which it is attached form a 4-7 membered heterocyclic ring; the C is _1-4 Alkyl, C _3-6 The alkoxy group may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

v is selected from C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl; the C is _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

l is each independently selected from C _1-3 Alkylene, C _2-5 Alkenylene, C _2-5 Alkynylene, C _1-3 Alkyloxy, C _1-5 Hydroxyalkylene, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl; the C is _1-3 Alkylene, C _2-5 Alkenylene, C _2-5 Alkynylene, C _1-3 Alkyloxy, C _1-5 Hydroxyalkylene, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group.

wherein R is ¹ Selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclohexyl, and furophenyl, said phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinylThe cyclohexyl and furophenyl groups can be optionally substituted with one or more of halogen, CN and CH ₃ 、OCH ₃ 5-6 membered heterocyclyl, C (O) N (CH) ₃ ) ₂ ；

R ² Selected from H, C _1-8 Alkyl, C _6-12 Aryl, said C _1-8 Alkyl, C _6-12 Aryl groups may be optionally substituted with one or more of the following substituents: halogen, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO ₂ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³¹ R ³² C(O)、C(O)OR ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³¹ R ³² ；

R ³ Selected from OH, C _1-3 Alkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、OR ³⁷ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-3 Alkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: a methyl group;

v is selected from

Each L is independently selected from the group consisting of methylene, ethylene, and propylene; the methylene, ethylene and methyleneThe propyl group may be optionally substituted with one or more of the following substituents: OH, C _1-6 An alkyl group.

wherein R is ¹ Selected from the group consisting of

R ² Selected from H, methyl, ethyl, propyl and butyl; preferably, R ² Is methyl;

R ³ selected from OH,

R ⁴ And R is ⁵ All are H;

v is selected from

Each L is independently selected from the group consisting of methylene, ethylene, and propylene; the methylene, ethylene and propylene groups may be optionally substituted with one or more of the following substituents: OH, C _1-6 An alkyl group; preferably, L is propylene.

In some embodiments of the invention, the compound has the structure of formula II-A-1:

wherein R is ¹ 、R ² 、R ³ And L is as defined above for formula I; v' is selected from C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo.

In some embodiments of the invention, the compounds have the structure of formula II-A-1 above,

wherein R is ¹ Selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclohexyl, furophenyl, said phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclohexyl, furophenyl optionally substituted with one or more of halogen, CN, CH ₃ 、OCH ₃ 5-6 membered heterocyclyl, C (O) N (CH) ₃ ) ₂ ；

v' is selected from

Each L is independently selected from the group consisting of methylene, ethylene, and propylene; the methylene, ethylene and propylene groups may be optionally substituted with one or more of the following substituents: OH, C _1-6 An alkyl group.

wherein R is ¹ Selected from the group consisting of

R ³ selected from OH,

V is selected from

In some embodiments of the invention, the compound has the structure of formula II-A-2:

wherein R is ¹ 、R ² 、R ³ And L is as defined above for formula I;

v' is selected from C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo;

R ^4a and R is ^5a Each independently selected from H and not simultaneously H, C _1-3 Alkyl, C _1-8 Alkoxy, or R ^4a 、R ^5a Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring; the C is _1-3 Alkyl, C _1-8 The alkoxy, 4-7 membered heterocycle may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group.

In some embodiments of the invention, the compounds have the structure of formula II-A-2 above,

v' is selected from

wherein R is ¹ Selected from the group consisting of/>

R ³ selected from OH,

V is selected from

In some embodiments of the invention, the compound has the structure of formula III:

In a preferred embodiment of the invention, the compounds have the structure of formula III above,

Wherein R is ¹ Selected from C _1-4 Alkyl, C _3-6 Cycloalkyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo; the C is _1-4 Alkyl, C _3-6 Cycloalkyl, C _6-12 Aryl, 5-10 membered heteroarylThe radical, 9-12 membered aryl-heterocyclo radical may be optionally substituted by one or more of halogen, CN, NO ₂ 、C _1-4 Alkyl, C _3-8 Cycloalkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, C _1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, CO ₂ R ³⁰ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ 、S(O)NR ³¹ R ³² 、S(O) ₂ NR ³¹ R ³² 、S(O)R ³⁵ 、S(O) ₂ R ³⁵ 、OR ³⁷ 、SR ³⁷ ；

Preferably, R ¹ Selected from phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, cyclohexyl, furophenyl, optionally substituted with one or more of halogen, CN, CH ₃ 、OCH ₃ 5-6 membered heterocyclyl, C (O) N (CH) ₃ ) ₂ ；

More preferably, R ¹ Selected from the group consisting of/>

Preferably, R ² Selected from H, methyl, ethyl, propyl and butyl; preferably, R ² Is methyl.

preferably, R ³ Selected from OH,

wherein V is selected from C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl; the C is _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

preferably, V is selected from

wherein each L is independently selected from the group consisting of methylene, ethylene, and propylene; the methylene, ethylene and propylene groups may be optionally substituted with one or more of the following substituents: OH, C _1-6 An alkyl group.

n, p, q are each independently selected from 0 or 1.

R ² Selected from H, C _1-8 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _6-12 Aryl, C _3-8 Cycloalkyl, 5-8 membered heteroaryl, 4-6 membered heterocyclyl, said C _1-8 Alkyl, C _2-6 Alkenyl, C _2-6 Alkynyl, C _6-12 Aryl, C _3-8 Cycloalkyl, 5-8 membered heteroaryl, 4-6 membered heterocyclyl may optionally beSubstituted with one or more of the following substituents: halogen, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO ₂ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³¹ R ³² C(O)、C(O)OR ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³¹ R ³² ；

R ³ Selected from H, OH, halogen, CN, NO ₂ 、C _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, CO ₂ R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、SO ₂ R ³⁵ 、OR ³⁷ 、SR ³⁷ 、C(O)R ³⁰ 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ The method comprises the steps of carrying out a first treatment on the surface of the The C is _1-3 Alkyl, C _1-3 Alkoxy, C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, CN, NO ₂ 、C _1-4 Alkyl, C _3-8 Cycloalkyl, 4-10 membered heterocyclyl, NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² ；

v is selected from C _3-6 Cycloalkyl, 4-8 memberedHeterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl; the C is _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

v is selected from/>

wherein R is ¹ Selected from the group consisting of

R ² Selected from H, methyl, ethyl, propylAnd butyl; preferably, R ² Is methyl;

R ³ selected from OH,

R ⁴ And R is ⁵ All are H;

v is selected from

In some embodiments of the invention, the compound has the structure of formula IV:

wherein R is ¹ 、R ³ 、R ⁴ 、R ⁵ V and L are as defined above for formula I.

In a preferred embodiment of the invention, the compounds have the structure of formula IV above,

Wherein R is ¹ Selected from C _1-4 Alkyl, C _3-6 Cycloalkyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo; the C is _1-4 Alkyl, C _3-6 Cycloalkyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, optionally substituted with one or more of halogen, CN, NO ₂ 、C _1-4 Alkyl, C _3-8 Cycloalkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Haloalkoxy, C _1-4 Hydroxyalkyl, 4-10 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, CO ₂ R ³⁰ 、C(O)R ³⁰ 、C(O)NR ³¹ R ³² 、NR ³³ C(O)R ³⁴ 、NR ³¹ R ³² 、OC(O)R ³⁰ 、OC(O)NR ³¹ R ³² 、NR ³³ C(O)NR ³¹ R ³² 、NR ³³ C(O)OR ³⁰ 、S(O)NR ³¹ R ³² 、S(O) ₂ NR ³¹ R ³² ；S(O)R ³⁵ 、S(O) ₂ R ³⁵ 、OR ³⁷ 、SR ³⁷ ；

More preferably, R ¹ Selected from the group consisting of

Preferably, R ² Selected from H, methyl, ethyl, propyl anda butyl group; preferably, R ² Is methyl.

more preferably, R ³ Selected from OH,

preferably, V is selected from

n, p, q are each independently selected from 0 or 1.

R ⁴ And R is ⁵ Each independently selected from H, C _1-3 Alkyl, C _3-6 Alkoxy, or R ⁴ 、R ⁵ And R is equal to ⁴ And R is ⁵ The attached nitrogen atoms together form a 4-7 membered heterocyclic ring; the C is _1-4 Alkyl, C _3-6 The alkoxy group may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

v is selected from C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl; the C is _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 Alkoxy group；

v is selected from

wherein R is ¹ Selected from the group consisting of

R ³ selected from OH,

R ⁴ And R is ⁵ All are H;

v is selected from

In an embodiment of the invention, the compounds of the invention are selected from, but are not limited to:

in another aspect, the invention provides a pharmaceutical composition comprising a compound as described above, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound. Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers.

In some embodiments, the pharmaceutical composition is used to prevent and/or treat a disease associated with NLRP3 inflammatory body activity (e.g., a neoplastic disease).

Optionally, the pharmaceutical composition of the invention further comprises one or more second therapeutic agents. In certain embodiments, the second therapeutic agent comprises other drugs for treating neoplastic diseases and the like.

In another aspect, the invention provides a pharmaceutical formulation comprising a compound as described above, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above.

In another aspect, the invention provides the use of a compound as described above, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, for the manufacture of a medicament for the prevention and/or treatment of a disease associated with NLRP3 inflammatory body activity (e.g. a neoplastic disease).

In another aspect, the invention provides the use of a compound as described above, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, for preparing a formulation for modulating (e.g., increasing) the activity of an NLRP3 inflammatory body.

In some embodiments, the formulation is administered to a subject (e.g., mammal; e.g., bovine, equine, ovine, porcine, canine, feline, rodent, primate; e.g., human) in vivo to increase NLRP3 inflammatory body activity in cells in the subject; alternatively, the formulation is administered to cells in vitro (e.g., a cell line or a cell from a subject) to increase the activity of NLRP3 inflammatory bodies in the cells.

In another aspect, the invention provides a method of modulating (e.g., increasing) the activity of an NLRP3 inflammatory small body in a cell, comprising administering to the cell an effective amount of a compound as described above, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above.

In another aspect, the invention provides a kit for modulating (e.g., increasing) the activity of an NLRP3 inflammatory oligomer, the kit comprising a compound, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, or a formulation as described above.

In another aspect, the invention provides a method of treating a disease associated with NLRP3 inflammatory small body activity (e.g., a neoplastic disease), comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a compound of the invention, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, or a formulation as described above.

Optionally, the method further comprises administering to a subject in need thereof one or more second therapeutic agents. In some embodiments, the second therapeutic agent comprises an additional agent that treats a disease such as a tumor.

In the present invention, the neoplastic diseases include, but are not limited to: brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, female genital tract cancer, carcinoma in situ, lymphoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, or sarcoma.

In some embodiments, the compounds of the invention are full agonists; in some embodiments, the compounds of the invention are partial agonists (partial agonists).

Definition of terms

Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

The term "agonist" refers to a compound that binds to and activates a receptor to elicit a downstream biological effect (biological effect or response), including full agonists (full agonist) and partial agonists (partial agonist). Full agonists activate receptors and produce the greatest effect (maximal effect or E) _max ). Partial agonists can bind to and activate receptors, but produce only partial effects (partial effects) relative to full agonists. When a full agonist and a partial agonist coexist, the partial agonist may sometimes become a partial antagonist by competing with the full agonist for a binding site or other mechanism at the receptor. Potency of a partial agonist (potential, available from EC ₅₀ (concentration of compound at which 50% Emax is produced) is measured as possibly being higher or lower than the efficacy of a full agonist. The NLRP3 agonists of the invention include NLRP3 full agonists and NLRP3 partial agonists.

The term "NLRP3" is generally known as NLR family pyrin domain containing 3 and is an inflammatory body. In the present invention, when referring to "NLRP3", the meaning includes nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, short peptides, polypeptides, proteins, homologous or heterologous molecules, subtypes, precursors, mutants, variants, derivatives, various spliceosomes, alleles, different species, and activation fragments of NLRP3, and the like.

The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

The term "halo" refers to substitution by a halogen atom, including F, cl, br or I.

The term "alkyl" is a straight or branched chain saturated aliphatic hydrocarbon group. The term "C _1-15 Alkyl "" C _1-8 Alkyl "," C _1-6 Alkyl "and" C _1-4 Alkyl "refers to straight or branched chain alkyl groups having 1 to 15 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl. The alkyl group may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.

The term "alkylene" refers to a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a straight or branched saturated hydrocarbon radical, which contains the indicated number of carbon atoms. For example an alkylene group of 1 to 8 carbon atoms, for example methylene (-CH) ₂ (-), ethylene (-CH) ₂ CH ₂ (-), isopropylidene (-CH (CH) ₃ )CH ₂ (-), etc.; the alkylene group may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.

The term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms, the term "C _1-8 Haloalkyl "," C _1-6 Haloalkyl groups "and" C _1-4 Haloalkyl "refers to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, respectively, such as-CF ₃ 、-C ₂ F ₅ 、-CHF ₂ 、-CH ₂ F、-CH ₂ CF ₃ 、-CH ₂ Cl or-CH ₂ CH ₂ CF ₃ Etc.

The term "hydroxyalkyl" refers to a group formed by substitution of the hydrogen atom of an alkyl group with one or more hydroxyl groups, e.g., C _1-4 Hydroxyalkyl or C _1-3 Hydroxyalkyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH (OH) CH ₃ Etc.

The term "alkenyl" is intended to mean containing oneMonovalent straight or branched hydrocarbon radicals of one or more carbon-carbon double bonds, e.g. -ch=ch ₂ 、-CH ₂ CH＝CH ₂ 、-C(CH ₃ )＝CH ₂ 、-CH ₂ -CH＝CH-CH ₃ Etc., the alkenyl group may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.

The term "alkenylene" refers to a divalent straight or branched chain aliphatic hydrocarbon radical containing one or more carbon-carbon double bonds, containing the indicated number of carbon atoms, e.g., 2 to 8 carbon atoms, e.g., -ch=ch-, -CH ₂ CH＝CH-、-C(CH ₃ ) =ch-etc., which may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.

The term "alkynyl" refers to monovalent straight or branched hydrocarbon groups having one or more carbon-carbon triple bonds, including but not limited to ethynyl, 2-propynyl, 2-butynyl, 1, 3-butynyl, and the like, which may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.

The term "alkynylene" refers to a divalent straight or branched chain hydrocarbon radical having one or more carbon-carbon triple bonds containing a specified number of carbon atoms, e.g., 2 to 8 carbon atoms, including but not limited toEtc., the alkynylene group may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.

The term "alkoxy" means a group, preferably C, having an oxygen atom inserted at any reasonable position of an alkyl group (as defined above) _1-8 Alkoxy, C ₁ -C ₆ Alkoxy, C ₁ -C ₄ Alkoxy or C ₁ -C ₃ An alkoxy group. C (C) ₁ -C ₆ Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, -CH ₂ -OCH ₃ Etc., the alkoxy groups may optionally be substituted with one or more (such as 1 to 3)The same or different substituents.

The term "alkyleneoxy" refers to a divalent alkoxy group, e.g., -OCH ₂ -、-OCH(CH ₃ )CH ₂ -、-OCH ₂ CH ₂ O-、-CH ₂ CH ₂ O-, etc., which may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.

The term "fused ring" or "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.

The term "spiro" refers to a ring system formed by two or more cyclic structures sharing one ring atom with each other.

The term "bridged ring" refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly attached to each other.

The term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon cyclic group including, but not limited to, monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl) and bicyclic alkyl, including spiro, fused (fused) or bridged ring systems (i.e., spiro alkyl, fused (fused) alkyl and bridged cycloalkyl groups, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, and the like). In the present invention, cycloalkyl groups may be optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally oxo (i.e. forms c=o).

The term "cycloalkylene" refers to a cycloalkyl group, as defined herein, having two monovalent radical centers resulting from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent cycloalkyl group. Typical cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, cyclohexenylene, and the like.

The term "C _3-8 Cycloalkyl "means cycloalkyl having 3 to 8 ring-forming carbon atoms, e.g. C _3-6 Cycloalkyl which may be a monocyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,Cyclooctyl) may also be bicycloalkyl, e.g. C _3-8 Spirocycloalkyl, C _3-8 Bridged cycloalkyl, C _3-8 Condensed ring alkyl, C _3-6 Spirocycloalkyl, C _3-6 Bridged cycloalkyl, C _3-6 Condensed ring alkyl.

The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic group having a conjugated pi-electron system. As used herein, the term "C _6-12 Aryl "means aryl containing 6 to 12 carbon atoms, preferably C ₆ -C ₁₀ Aryl, preferably phenyl or naphthyl. Aryl groups optionally substituted with one or more (such as 1 to 3) identical or different substituents (e.g. halogen, OH, CN, NO ₂ 、C ₁ -C ₆ Alkyl, etc.) substitution.

The term "arylene" refers to an aryl group as defined herein having two monovalent radical centers resulting from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent aryl group. Typical arylene groups include, but are not limited to, phenylene and naphthylene.

The term "aryl-cycloalkyl" refers to a fused ring group formed by aryl and cycloalkyl groups (e.g., monocycloalkyl) sharing two adjacent atoms with each other, wherein the point of attachment to the other groups may be on the aryl or on the cycloalkyl. The term "9-12 membered arylcycloalkyl" refers to arylcycloalkyl groups containing a total of 9-12 ring atoms, such as phenylfused cyclopentyl, phenylfused cyclohexyl, for example,

the term "heterocyclyl" refers to a mono-or polycyclic (e.g., parallel, spiro, or bridged) group having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms, and one or more (e.g., 1, 2, 3, or 4) heteroatoms, including but not limited to oxygen, nitrogen, sulfur, optionally oxo (oxo) (e.g., to form c= O, S (=o) or S (=o) ₂ )。

The term "heterocyclylene" refers to a heterocyclic group as defined herein having two monovalent radical centers derived from the same carbon atom or two different carbon atoms, one carbon atom and one heteroatom, or two heteroatoms of a parent heterocyclic group from which two hydrogen atoms have been removed.

The term "3-14 membered heterocyclyl" means heterocyclyl containing 3-14 ring atoms including, but not limited to, 4-10 membered heterocyclyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl, 4-7 membered nitrogen containing heterocyclyl, 4-7 membered oxygen containing heterocyclyl, 4-7 membered sulfur containing heterocyclyl, 5-6 membered nitrogen containing heterocyclyl, 5-6 membered oxygen containing heterocyclyl, 5-6 membered sulfur containing heterocyclyl, said "nitrogen containing heterocyclyl", "oxygen containing heterocyclyl", "sulfur containing heterocyclyl" optionally also containing one or more additional heteroatoms selected from oxygen, nitrogen, sulfur. Examples of 3-14 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,etc.

In the present invention, the heterocyclic group may form a fused ring structure with the heterocyclic group or the cycloalkyl group, and the point of attachment of the fused ring structure to the other group may be on any one of the heterocyclic group or the cycloalkyl group, and thus the heterocyclic group of the present invention also includes, but is not limited to, a heterocyclic-heterocyclic group, a heterocyclic-cycloalkyl group, a mono-heterocyclic-mono-heterocyclic group, a mono-heterocyclic-mono-cycloalkyl group, a 3-7-membered (mono) heterocyclic-3-7-membered (mono) heterocyclic group, a 3-7-membered (mono) heterocyclic-mono-cycloalkyl group, a 3-7-membered (mono) heterocyclic-C _4-6 (mono) cycloalkyl examples include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopentylazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl,

In the present invention, the heterocyclic group also includes bridged heterocyclic groups and spiro heterocyclic groups.

The term "bridged heterocyclic ring" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two saturated rings sharing two ring atoms that are not directly attached, including but not limited to 7-10 membered bridged heterocyclic rings, 8-10 membered bridged heterocyclic rings, 7-10 membered nitrogen-containing bridged heterocyclic rings, 7-10 membered oxygen-containing bridged heterocyclic rings, 7-10 membered sulfur-containing bridged heterocyclic rings, and the like, e.g. Etc. The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", "sulfur-containing bridged heterocycle" optionally also contains one or more further heteroatoms selected from oxygen, nitrogen, sulfur. />

The term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two or more saturated rings sharing one ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, and the like, e.g. The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", "sulfur-containing spiroheterocycle" optionally also contains one or more further heteroatoms selected from oxygen, nitrogen, sulfur. The term "6-to 10-membered nitrogen-containing spiroheterocyclyl" means a spiroheterocycle containing a total of 6 to 10 ring atoms and wherein at least one ring atom is a nitrogen atomA base.

The term "aryl-heterocyclyl" refers to a cyclic group formed by aryl and heterocyclyl sharing two adjacent carbon atoms with each other, the point of attachment to the other group being at either the aryl or the heterocyclyl. Wherein aryl and heterocyclyl are as defined above. For example, as used herein, the term "9-12 membered arylalkylheterocyclyl" means a radical containing an arylalkylheterocyclyl of 9-12 total ring atoms, including, but not limited to, 9-10 membered benzoheterocyclyl, such as phenyl and 5-8 membered heterocyclyl, such as phenyl and 5-6 membered heterocyclyl, such as benzo 5-6 membered mono-heterocyclyl, benzo 5-6 membered nitrogen-containing mono-heterocyclyl, benzo 5-6 membered oxygen-containing mono-heterocyclyl, benzo 5-6 membered sulfur-containing heterocyclyl, the "nitrogen-containing heterocyclyl", "oxygen-containing", "sulfur-containing heterocyclyl" optionally also containing one or more additional heteroatoms selected from oxygen, nitrogen, sulfur. The carbon and heteroatoms on the heterocyclyl are optionally oxo (oxo) (e.g. to form c= O, S (=o) or S (=o) ₂ )。

Examples include, but are not limited to: indazolyl group,

The term "heteroaryl" refers to a monocyclic or polycyclic aromatic group containing one or more heteroatoms either the same or different, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom) which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, for example 5, 6, 7, 8, 9 or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. The carbon and heteroatoms on the heteroaryl group are optionally oxo (oxo) (e.g., to form c= O, S (=o) or S (=o) ₂ )。

The term "heteroarylene" refers to a heteroaryl group as described above having two hydrogen atoms removed from the same carbon atom or two different carbon atoms of the parent heteroaryl group or two monovalent radical centers resulting from the removal of one hydrogen atom from a carbon atom and one hydrogen atom from a nitrogen atom.

The term "5-10 membered heteroaryl" means heteroaryl containing 5 to 10 ring atoms, including 5-6 membered heteroaryl, 5-6 membered mono-heteroaryl, 5-10 membered nitrogen containing heteroaryl, 5-10 membered oxygen containing heteroaryl, 5-10 membered sulfur containing heteroaryl, 5-6 membered nitrogen containing heteroaryl, 5-6 membered oxygen containing heteroaryl, 5-6 membered sulfur containing heteroaryl, 5-6 membered nitrogen containing mono-heteroaryl, 5-6 membered oxygen containing mono-heteroaryl, 5-6 membered sulfur containing mono-heteroaryl. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl", "sulfur-containing heteroaryl", "nitrogen-containing mono-heteroaryl", "oxygen-containing mono-heteroaryl", "sulfur-containing mono-heteroaryl" optionally also contains one or more other heteroatoms selected from oxygen, nitrogen, sulfur. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and 5-10 membered bicyclic groups containing these groups.

In the present invention, heteroaryl (e.g., mono-heteroaryl) may share a fused ring structure formed by two adjacent atoms with aryl (e.g., monocyclic aryl, e.g., phenyl), heterocyclyl (e.g., mono-heterocyclyl), cycloalkyl (e.g., monocyclic alkyl), or another heteroaryl (e.g., another mono-heteroaryl), the points of attachment of which may be on any heteroaryl ring or on other rings, including, but not limited to, (mono) heteroarylo (mono) heteroaryl, (mono) heteroarylo (monocyclic) aryl, (mono) heteroarylo (mono) heterocyclyl, and (mono) heteroarylo (mono) cycloalkyl, e.g., 5-6 membered (mono) heteroarylo 5-6 membered (mono) heteroaryl, 5-6 membered (mono) heteroarylo phenyl, 5-6 membered (mono) heteroaryl and 5-6 membered (mono) heterocyclyl, or 5-6 membered (mono) heteroarylo C _4-6 (mono) cycloalkyl (e.g., 5-6 membered heteroaryl-cyclobutyl, 5-6 membered heteroaryl-cyclopentyl, 5-6 membered heteroaryl-cyclohexyl), examples of which include, but are not limited to, indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, Etc.

The term "aryl-heteroaryl" refers to a fused ring group formed by an aryl group (e.g., a monocyclic aryl group, such as phenyl) and a heteroaryl group (e.g., a mono-heteroaryl group, such as a 5-6 membered mono-heteroaryl group), the point of attachment to the other group being either on the aromatic ring or on the heteroaromatic ring. The "aryl-heteroaryl" includes, but is not limited to, monocyclic aryl-mono-heteroaryl. The term "9-12 membered arylalkylheteroaryl" refers to arylalkylheteroaryl groups containing a total of 9-12 ring members, such as benzo 5-6 membered nitrogen containing mono-heteroaryl.

The term "heteroarylcycloalkyl" refers to heteroaryl (e.g., mono-heteroaryl, e.g., 5-6 membered mono-heteroaryl) and cycloalkyl (e.g., C _4-6 Cycloalkyl) and the point of attachment to other groups may be on the heteroaryl ring or on the cycloalkyl. The "heteroarylcycloalkyl" includes, but is not limited to, mono-heteroaryl monocycloalkyl. The term "9-10 membered heteroarylcycloalkyl" refers to heteroarylcycloalkyl containing a total of 9-10 ring atoms, e.g., 4-6 membered nitrogen containing monoheteroaryl and C _4-6 A monocyclic alkyl group.

The term "substitution" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

If a substituent is described as "optionally substituted with … …," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may each be replaced with an independently selected optional substituent. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced with an independently selected optional substituent.

If substituents are described as "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

As used herein, the term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, under reasonable conditions.

As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.

The invention also includes all pharmaceutically acceptable isotopic compounds of the present invention, which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g ² H、 ³ H) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of carbon (e.g ¹¹ C、 ¹³ C, C is a metal alloy ¹⁴ C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g ³⁶ Cl); isotopes of fluorine (e.g ¹⁸ F) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of iodine (e.g ¹²³ I, I ¹²⁵ I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g ¹³ N is N ¹⁵ N); isotopes of oxygen (e.g ¹⁵ O、 ¹⁷ O and O ¹⁸ O); isotopes of phosphorus (e.g ³² P) is as follows; isotopes of sulfur (e.g ³⁵ S). The term "stable isotope derivative" refers to a stable compound in which one or more atoms in the compound of the present invention are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature.

The term "stereoisomer" refers to an isomer of a compound formed as a result of the compound containing at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, they can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). The compounds of the invention may exist as a mixture of two or more different structural forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, nitroso-oximes may exist in solution in equilibrium in the following tautomeric forms:

It is to be understood that the scope of the present application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) or mixtures thereof.

Unless otherwise indicated, the compounds of the present application are intended to exist as stereoisomers (which include cis and trans isomers), optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, or mixtures thereof. The compounds of the present application may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which may be single polymorphs or mixtures of any ratio of more than one polymorphs. It will also be appreciated that certain compounds of the application may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present application, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs thereof, which, upon administration to a patient in need thereof, are capable of providing the compounds of the application or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the application" it is also intended to encompass the various derivative forms of the compounds described above.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Such as hexafluorophosphate, meglumine salt, and the like. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: properties, selection, and Use" (Wiley-VCH, 2002).

By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, in particular for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents, as desired. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The pharmaceutical compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection, intravenously, intra-arterially, subcutaneously, intraperitoneally, intramuscularly or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic formulation or by inhalation.

For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.

Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups.

The term "effective dose" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the condition being treated.

The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.

The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg, for example about 0.01 to about 10 mg/kg/day per kg body weight per day (single or divided administration). For a 70kg human, this amounts to about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.

The compounds of the present invention may be present in the pharmaceutical composition in an amount or in an amount of about 0.01mg to about 1000mg, suitably 0.1-500mg, preferably 0.5-300mg.

As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing, a disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.

Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds obtained by a method of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.

The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, and which, when administered into or onto the body, are converted to the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", vol.14, ACS Symposium Series (T. Higuchi and V. Stilla) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987 (E. B. Roche eds., american Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g. "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".

The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, in Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, plenum Press,1973; and those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.

The bonds in the structural formulae indicated herein by wavy lines "-" are intended to mean that the structure represents either the cis or trans isomer, or a mixture of cis and trans isomers in any proportion, or the R-or S-configuration isomer.

As used hereinThe bond in the structural formula is a single bond or a double bond.

As used hereinIndicating that the double bond is not located at a certain position, but still ensures that the ring in which it is located has aromaticity.

As used hereinIndicating the presence or absence of a bond in the structural formula.

As used herein, "room temperature" refers to 15-30deg.C.

Preparation method

Synthesis method of compounds II-A-1 and II-A-2

Wherein R is ¹ 、R ² 、R ³ L is as defined above for formula I;

v' is selected from C _6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo.

The first step: compound II-1 and R under alkaline conditions ² X is subjected to substitution reaction to generate a compound II-2.

Wherein X is selected from chlorine, bromine and iodine;

the solvent is selected from DMF, DMSO, THF, CH ₃ CN, DCM, etc., and the base used is selected from triethylamine, N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide, sodium hydroxide, etc., and the reaction temperature is-20 ℃ to 180 ℃.

And a second step of: compound II-2 and R under alkaline conditions ^4a R ^5a NH is subjected to substitution reaction to generate a compound II-3.

The solvent is selected from DMF, DMSO, THF, CH ₃ CN, DCM, etc., and the base used is selected from triethylamine, N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide, sodium hydroxide, etc., and the reaction temperature is 20-150 ℃.

And a third step of: the compound II-3 is reduced by a reducing agent to the compound II-4.

The reducing agent is selected from Zn powder/ammonium formate, zn powder/ammonium chloride, sodium hydrosulfite or Fe powder/ammonium formate, the solvent is selected from methanol, ethanol or THF, and the reaction temperature is 20-110 ℃.

Fourth step: the compound II-4 is subjected to condensation reaction in the presence of a condensation reagent to generate the compound II-5.

The condensation reagent is selected from HATU, HBTU, TBTU and EDCI, the base is selected from triethylamine, N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide and sodium hydroxide, the solvent is selected from THF, DMF or 1, 4-dioxane, and the reaction temperature is 20-100 ℃.

Fifth step: compound II-5 is cyclized under basic conditions to form compound II-6.

The base is selected from triethylamine, N-diisopropylethylamine, potassium carbonate, potassium tert-butoxide, sodium hydroxide and the like, the solvent is selected from MeOH, etOH, THF, 1, 4-dioxane and the like, and the reaction temperature is 20-150 ℃.

Sixth step: compounds II-6 with V '-boric acid or esters thereof or V' -organotin compounds (e.g. R ¹ Sn(n-Bu) ₃ ) Through coupling reaction (such as Suzuki reaction, stille reaction) to obtain the compound II-7.

The catalyst used is selected from Pd (PPh) ₃ ) ₄ And Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ Etc., the base used is selected from Cs ₂ CO ₃ 、K ₃ PO ₄ 、Na ₂ CO ₃ 、AcOK、NaHCO ₃ And K ₂ CO ₃ Etc., the solvent used is selected from 1, 4-dioxane/H ₂ O、DMF/H ₂ O、DMSO/H ₂ O、CH ₃ CN/H ₂ O and toluene/H ₂ O, etc., said reaction temperature being 60 ℃ to 180 ℃.

Route a:

wherein R is ^4a Is H, R ^5a For example, tert-octyl, tert-butoxycarbonyl.

A-first step: the compound II-7 is reacted with an excess of bromine to form the compound II-8.

The solvent is selected from 1, 4-dioxane, DMF, EA and the like, and the reaction temperature is between-20 ℃ and 100 ℃;

a-second step: compounds II-8 and R ¹ -boric acid or R ¹ -boric acid esters or R ¹ Organotin compounds (e.g. R ¹ Sn(n-Bu) ₃ ) Through coupling reaction (such as Suzuki reaction and Stille reaction), the compound II-A-1 is produced.

The catalyst used is selected from Pd (PPh) ₃ ) ₄ And Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ Etc., all ofWith a base selected from Cs ₂ CO ₃ 、K ₃ PO ₄ 、Na ₂ CO ₃ 、AcOK、NaHCO ₃ And K ₂ CO ₃ Etc., the solvent used is selected from 1, 4-dioxane/H ₂ O、DMF/H ₂ O、DMSO/H ₂ O、CH ₃ CN/H ₂ O and toluene/H ₂ O, etc., said reaction temperature being 60 ℃ to 180 ℃.

Route B:

wherein R is ^4a Is H, R ^5a For protecting groups, such as tert-octyl, tert-butoxycarbonyl, benzyl, 3-methoxybenzyl, 2, 4-dimethoxybenzyl.

B-first step: the compound II-7 is subjected to bromination reaction to generate a compound II-9.

The brominating agent is selected from bromine (calculated amount), NBS, dibromohydantoin and the like, the solvent is selected from 1, 4-dioxane, DMF, EA and the like, and the reaction temperature is between-20 ℃ and 100 ℃.

B-second step: compounds II-9 and R ¹ -boric acid or R ¹ -boric acid esters or R ¹ Organotin compounds (e.g. R ¹ Sn(n-Bu) ₃ ) Through coupling reaction (such as Suzuki reaction and Stille reaction), the compound II-10 is produced. The reaction conditions are as described in the A-second step.

B-third step: deprotection of compound II-10 under acidic conditions ^5a To produce the compound II-A-1.

The acid is selected from trifluoroacetic acid, trifluoromethanesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, nitric acid, aluminum trichloride, boron tribromide, boron trichloride and the like, the reaction is carried out in a solvent, the solvent is selected from 1, 4-dioxane, DCM, methanol, EA and the like, or the reaction does not need a solvent and is directly dissolved by acid; the reaction temperature is-20 ℃ to 100 ℃.

Route C:

wherein R is ^4a And R is ^5a Each independently selected from H and not simultaneously H, C _1-3 Alkyl, C _1-8 Alkoxy, or R ^4a 、R ^5a Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring; the C is _1-3 Alkyl, C _1-8 Alkoxy, 4-7 membered heterocycle, optionallyOptionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

c-first step: the compound II-7 is subjected to bromination reaction to generate a compound II-11.

The brominating agent is selected from bromine, NBS, dibromohydantoin and the like, the solvent is selected from 1, 4-dioxane, DMF, EA and the like, and the reaction temperature is between-20 ℃ and 100 ℃.

C-second step: compounds II-11 and R ¹ -boric acid or R ¹ -boric acid esters or R ¹ Organotin compounds (e.g. R ¹ Sn(n-Bu) ₃ ) Through coupling reaction (such as Suzuki reaction, stille reaction) to obtain the compound II-A-2. The reaction conditions are as described in the A-second step.

In some embodiments, when R ³ In the case of groups which can be removed under acidic conditions, such as O-benzyl, O-3-methoxybenzyl, O-2, 4-dimethoxybenzyl, OMe, compounds II-A-1' can also be obtained from II-A-1 by acid treatment. The reaction conditions are as described in the B-third step.

Wherein R is ¹ 、R ² L is as defined above for formula I;

Advantageous effects

The compound has obvious agonistic activity to NLRP3 and a signal path thereof, has no obvious toxic or side effect, and can be used for treating diseases (such as tumors) related to NLRP3 inflammatory body activity.

Detailed Description

Examples

The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.

Abbreviations in the present invention have the following meanings:

the structure of the compound is characterized by nuclear magnetic resonance spectrum ¹ H NMR) or Mass Spectrometry (MS).

The reaction was monitored by silica gel Thin Layer Chromatography (TLC) or LC-MS.

LC/MS mass spectrometer: aglient 1260 Informance/Aglient 6120 Quaadrupole

Prep-HPLC using Agilent 1260 preparative liquid chromatography, detection wavelength: 214nm, 254nm; flow rate: 20.0-25.0mL/min; chromatographic column: waters SunFire Prep C18OBD (19 mm. Times.150 mm. Times.5.0 μm); column temperature: 25 ℃.

Elution conditions:

condition 1:10% -90% of mobile phase A and 90% -10% of mobile phase B;

condition 2:30% -90% of mobile phase A and 70% -10% of mobile phase B;

mobile phase a:100% acetonitrile; mobile phase B:0.05% ammonium bicarbonate aqueous solution.

The microwave reaction was performed using a biotageinitiator+microwave reactor.

Column chromatography generally uses 200-300 mesh silica gel (Qingdao ocean) as the stationary phase. Eluent system a: dichloromethane and methanol; eluent system B: the volume ratio of petroleum ether to ethyl acetate is adjusted according to the polarity of the compound.

In the following examples, the reaction temperature was room temperature (15℃to 30 ℃) unless otherwise specified.

The reagents used in the present application are available from Acros Organics, aldrich Chemical Company or tertbe chemistry, among others.

Example 1:3- (4-amino-1-methyl-6- (5-phenylthiophen-2-yl) -1H-imidazo [4,5-c ] pyridin-2-yl) propan-1-ol (1)

The first step: 2, 6-dichloro-N-methyl-3-nitropyridin-4-amine (1 b)

Compound 1a (5.0 g,24.15 mmol), K ₂ CO ₃ (6.66 g,48.30 mmol) was added to 40mL acetonitrile, heated to 80℃and stirred for reaction for 12h. After the completion of the reaction, the mixture was filtered through celite, and the filtrate was dried by spin-drying to give Compound 1B (4.80 g) by flash column chromatography (eluent system B). MS (ESI, m/z): 222.0[ M+H ]] ⁺ .

And a second step of: 6-chloro-N-methyl-3-nitro-N- (2, 4-trimethylpentan-2-yl) pyridine-2, 4-diamine (1 c)

Compound 1b (4.80 g,21.71 mmol), tert-octylamine (5.61 g,43.42 mmol) and triethylamine (6.58 mg,65.13 mmol) were added to 40mL of dichloromethane and heated to 40℃and the reaction stirred for 12h. After the reaction, the solvent was dried by flash column chromatography (eluent system B) to give compound 1c (5.10 g). MS (ESI, m/z): 315.1[ M+H ]] ⁺ .

And a third step of: 6-chloro-N-methyl-N- (2, 4-trimethylpentan-2-yl) pyridine-2, 3, 4-triamine (1 d)

Compound 1c (5.0 g,15.87 mmol), zinc powder (5.17 g,79.35 mmol), HCOONH4 (3.0 g,47.16 mmol) were added to 30mL MeOH and the reaction stirred at room temperature for 3h. After the completion of the reaction, the mixture was filtered through celite, and the filtrate was dried by spin-drying to obtain Compound 1d (3.60 g) by flash column chromatography (eluent system B). MS (ESI, m/z): 270.2[ M+H ]] ⁺ .

Fourth step: 4- (benzyloxy) -N- (6-chloro-4- (methylamino) -2- ((2, 4-trimethylpentan-2-yl) amino) pyridin-3-yl) butanamide (1 e)

Compound 1d (3.60 g, 128.04. Mu. Mol), benzyloxybutyric acid (5.61 g,43.42 mmol), HATU (6.58 mg,65.13 mmol), DIPEA (5.17 g,79.35 mmol) were added to 15mL DMF, N ₂ The reaction was stirred at room temperature under protection for 12h. After the reaction, the reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phase was concentrated, followed by flash column chromatography (eluent system B) to give Compound 1e (5.58)g)。MS(ESI,m/z):461.3[M+H] ⁺ .

Fifth step: 2- (3- (benzyloxy) propyl) -6-chloro-1-methyl-N- (2, 4-trimethylpentan-2-yl) -1H-imidazo [4,5-c ] pyridin-4-amine (1 f)

Compound 1e (5.50 g,11.96 mmol), naOH (1.44 g,35.88 mmol) were added to 40mL ethanol, N ₂ Heating to 90 ℃ under protection, and stirring to react for 12h. After the completion of the reaction, the mixture was filtered through celite, and the filtrate was dried by spin-drying to obtain Compound 1f (4.20 g) by flash column chromatography (eluent system B). MS (ESI, m/z): 443.2[ M+H ] ] ⁺ .

Sixth step: 2- (3- (benzyloxy) propyl) -1-methyl-6- (thiophen-2-yl) -N- (2, 4-4-trimethylpent-2-yl) -1H imidazo [4,5-c ] pyridin-4-amine (1 g)

Compound 1f (160 mg, 361.15. Mu. Mol), 2-thiopheneboronic acid (92.42 mg, 722.31. Mu. Mol), pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (29.51 mg, 36.11. Mu. Mol) potassium carbonate (149.74 mg, 1080. Mu. Mol) was added to 10mL DMF and 1mL water, N ₂ Heating to 120 ℃ under protection for reaction for 5h. After the completion of the reaction, the mixture was filtered through celite, and the filtrate was dried by spin-drying to obtain 1g (145 mg) of the compound by flash column chromatography (eluent system B). MS (ESI, m/z): 491.2[ M+H ]] ⁺ .

Seventh step: 2- (3- (benzyloxy) propyl) -6- (5-bromothiophen-2-yl) -1-methyl-1H-imidazo [4,5-C ] pyridin-4-amine (1H)

1g (130 mg, 264.93. Mu. Mol) of the compound was dissolved in 7mL of chloroform, bromine (67.82 mg,423.88umol,21.74 mL) diluted with chloroform was added at 25℃and stirring was continued for 20 minutes, after LC-MS monitoring that the reaction of the starting materials was complete, bromine was quenched with water until the solution became colorless from red, then concentrated directly to dryness, then the solid was soaked with EA, filtered, and the filtrate was concentrated to dryness to give the product 1h, which was directly used for the next reaction. MS (ESI, m/z): 457.0[ M+H ]] ⁺ .

Eighth step: 2- (3- (benzyloxy) propyl) -1-methyl-6- (5-phenylthiophen-2-yl) -1H imidazo [4,5-c ] pyridin-4-amine (1 i)

Compound 1h (90 mg, 127.90. Mu. Mol), phenylboronic acid (38.87 mg, 255.80. Mu. Mol), pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (12 mg, 14.04. Mu. Mol), potassium carbonate (53.03 mg, 383.70. Mu. Mol) and 5mL of 1, 4-di-sodium carbonate were addedOxygen hexacyclic ring and 0.5mL water, N ₂ Heating to 90 ℃ under protection for reaction for 5h. After the completion of the reaction, the mixture was filtered through celite, and purified by flash column chromatography (elution system A) to give Compound 1i (35 mg). MS (ESI, m/z): 454.1[ M+H ]] ⁺ .

Ninth step: 3- (4-amino-1-methyl-6- (5-phenylthiophen-2-yl) -1H-imidazo [4,5-c ] pyridin-2-yl) propan-1-ol (1)

Compound 1i (35 mg, 72.3. Mu. Mol) was dissolved in 4mL trifluoroacetic acid, N ₂ Heating to 80 ℃ under protection, and stirring to react for 12h. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure and redissolved in 2mL of methanol using 1M NaOH/H ₂ The O solution was adjusted to ph=9.0 and Prep-HPLC (elution condition 1) was used to isolate the title compound 1 (3 mg).

MS(ESI,m/z):364.4[M+H] ⁺ .

¹ H NMR(DMSO-d6,400MHz)δ8.24(s,1H),7.68(d,J＝7.3Hz,2H),7.62(d,J＝3.8Hz,1H),7.50(d,J＝3.8Hz,1H),7.43(t,J＝7.7Hz,2H),7.38(s,1H),7.30(t,J＝7.4Hz,1H),6.13(s,2H),3.72(s,3H),3.51(s,2H),2.91–2.85(m,2H),1.95–1.87(m,2H)。

Example 2: 3- (4-amino-6- (5- (3-fluorophenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-2-yl) propan-1-ol (2)

The first step: 2- (3- (benzyloxy) propyl) -6- (5- (3-fluorophenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-4-amine (2 a)

Compound 1h (32.12 mg, 70.22. Mu. Mol), 3-fluorobenzeneboronic acid (19.65 mg, 140.45. Mu. Mol), pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (6 mg, 7.02. Mu. Mol), potassium carbonate (19.41 mg, 140.45. Mu. Mol) were added to 5mL of 1, 4-dioxane and 0.5mL of water, N ₂ Heating to 90 ℃ under protection for reaction for 5h. After the completion of the reaction, the mixture was filtered through celite, and purified by flash column chromatography (elution system A) to give Compound 2a (20 mg). MS (ESI, m/z): 473.2[ M+H ]] ⁺ .

And a second step of: 3- (4-amino-6- (5- (3-fluorophenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-C ] pyridin-2-yl) propan-1-ol (2)

Compound 2a (20 mg, 12.33. Mu. Mol) was dissolved in 4mL trifluoroacetic acid, N ₂ Heating to 80 ℃ under protection, and stirring to react for 12h. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure and redissolved in 2mL of methanol using 1M NaOH/H ₂ The O solution was adjusted to ph=9.0 and Prep-HPLC (elution condition 2) was used to isolate the title compound 2 (2 mg).

MS(ESI,m/z):383.1[M+H] ⁺ .

¹ H NMR(CD3OD,400MHz)δ7.45-7.49(m,1H),7.17-7.21(m,3H),7.11-7.14(m,1H),6.74-6.76(m,1H),6.47-6.48(m,1H),3.67(t,J＝6.0Hz,2H),3.16(s,3H),2.91-2.95(m,2H),1.99-2.06(m,2H).

Example 3:3- (4-amino-6- (5- (4-methoxyphenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-2-yl) propan-1-ol (3)

The first step: 2- (3- (benzyloxy) propyl) -6- (5- (4-methoxyphenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-4-amine (3 a)

Compound 1h (90 mg, 127.90. Mu. Mol), 4-methoxyphenylboronic acid (38.87 mg, 255.80. Mu. Mol), pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (12 mg, 14.04. Mu. Mol), potassium carbonate (53.03 mg, 383.70. Mu. Mol) were added to 5mL of 1, 4-dioxane and 0.5mL of water, N ₂ Heating to 90 ℃ under protection for reaction for 5h. After the completion of the reaction, the mixture was filtered through celite and purified by flash column chromatography (elution system A) to give Compound 3a (35 mg). MS (ESI, m/z): 485.2[ M+H ]] ⁺ .

And a second step of: 3- (4-amino-6- (5- (4-methoxyphenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-2-yl) propan-1-ol (3)

Compound 3a (35 mg, 72.3. Mu. Mol) was dissolved in 4mL trifluoroacetic acid, N ₂ Heating to 80 ℃ under protection, and stirring to react for 12h. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure and redissolved in 2mL of methanol with 1M NaOH/H ₂ The O solution was adjusted to ph=9.0 and Prep-HPLC (elution condition 1) was used to isolate the title compound 3 (3 mg).

MS(ESI,m/z):395.1[M+H] ⁺ .

¹ H NMR(DMSO-d6,400MHz)δ7.27-7.29(m,3H),7.06-7.08(m,2H),6.74-6.76(m,1H),6.18-6.19(m,1H),6.07(s,2H),4.58(t,J＝5.2Hz,1H),3.84(s,3H),3.47-3.51(m,2H),3.03(s,3H),2.77(t,J＝8.0Hz,2H),1.83-1.90(m,2H).

Example 4:4- (5- (4-amino-2- (3-hydroxypropyl) -1-methyl-1H-imidazo [4,5-c ] pyridin-6-yl ] thiophen-2-yl) -N, N-dimethylbenzamide (4)

The first step: 4- (5- (4-amino-2- (3- (benzyloxy) propyl) -1-methyl-1H-imidazo [4,5-c ] pyridin-6-yl) thiophen-2-yl-N, N-dimethylbenzamide (4 a)

Compound 1h (90 mg, 127.90. Mu. Mol), (4- (dimethylcarbamoyl) phenyl) boronic acid (49.37 mg, 255.80. Mu. Mol), pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (12 mg, 14.04. Mu. Mol), potassium carbonate (53.03 mg, 383.70. Mu. Mol) were added to 5mL of 1, 4-dioxane and 0.5mL of water, N ₂ Heating to 90 ℃ under protection for reaction for 5h. After the completion of the reaction, the mixture was filtered through celite, and purified by flash column chromatography (elution system a) to give compound 4a (40 mg). MS (ESI, m/z): 526.2[ M+H ]] ⁺ .

And a second step of: 4- (5- (4-amino-2- (3-hydroxypropyl) -1-methyl-1H-imidazo [4,5-c ] pyridin-6-yl ] thiophen-2-yl) -N, N-dimethylbenzamide (4)

Compound 4a (40 mg, 76.2. Mu. Mol) was dissolved in 4mL trifluoroacetic acid, N ₂ Heating to 80 ℃ under protection, and stirring to react for 12h. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure and redissolved in 2mL of methanol using 1M NaOH/H ₂ The O solution was adjusted to ph=9.0 and Prep-HPLC (elution condition 1) was used to isolate the title compound 4 (2 mg).

MS(ESI,m/z):436.1[M+H] ⁺ .

¹ H NMR(DMSO-d6,400MHz)δ7.23-7.73(m,7H),6.16-6.24(m,2H),4.63(m,1H),3.73-3.75(m,2H),3.51-3.53(m,2H),2.82-3.06(m,9H),1.90-1.92(m,2H).

Example 5:3- (4-amino-6- (5- (4-fluorophenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-2-yl) propan-1-ol (5)

The first step: 2- (3- (benzyloxy) propyl) -6- (5- (4-fluorophenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-4-amine (5 a)

Compound 1h (75 mg, 106.58. Mu. Mol), 4-fluorophenyl boronic acid (29.83 mg, 213.17. Mu. Mol), pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (12 mg, 14.04. Mu. Mol), potassium carbonate (44.19 mg, 319.75. Mu. Mol) were added to 5mL of 1, 4-dioxane and 0.5mL of water, N ₂ Heating to 90 ℃ under protection for reaction for 5h. After the completion of the reaction, the mixture was filtered through celite and purified by flash column chromatography (elution system A) to give Compound 5a (30 mg). MS (ESI, m/z): 473.2[ M+H ] ] ⁺ .

And a second step of: 3- (4-amino-6- (5- (4-fluorophenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-C ] pyridin-2-yl) propan-1-ol (5)

Compound 5a (30 mg, 63.6. Mu. Mol) was dissolved in 4mL trifluoroacetic acid, N ₂ Heating to 80 ℃ under protection, and stirring to react for 12h. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure and redissolved in 2mL of methanol using 1M NaOH/H ₂ Ph=9.0 adjusted with O solution, and Prep-HPLC (elution condition 2) was performed to isolate the title compound 5 (3 mg)

MS(ESI,m/z):383.1[M+H] ⁺ .

¹ H NMR(DMSO-d6,400MHz)δ7.40-7.42(m,2H),7.30-7.37(m,3H),6.75-6.77(m,1H),6.15(s,1H),6.14(s,2H),4.58(t,J＝5.2Hz,1H),3.47-3.52(m,2H),3.02(s,3H),2.77(t,J＝8.0Hz,2H),1.83-1.90(m,2H).

Example 6: 3- (4-amino-6- (5- (2-fluorophenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-2-yl) propan-1-ol (6)

The first step: 2- (3- (benzyloxy) propyl) -6- (5- (2-fluorophenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-4-amine (6 a)

Compound 1h (75 mg, 106.58. Mu. Mol), 2-fluorophenyl boronic acid (29.83 mg, 213.17. Mu. Mol), pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (12 mg, 14.04. Mu. Mol), potassium carbonate (44.19 mg, 319.75. Mu. Mol) were added to 5mL of 1, 4-dioxane and 0.5mL of water, N ₂ Heating to 90 ℃ under protection for reaction for 5h. After the completion of the reaction, the mixture was filtered through celite and purified by flash column chromatography (elution system A) to give Compound 6a (30 mg). MS (ESI, m/z): 473.2[ M+H ]] ⁺ .

And a second step of: 3- (4-amino-6- (5- (2-fluorophenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-2-yl) propan-1-ol (6)

Compound 6a (30 mg, 63.6. Mu. Mol) was dissolved in 4mL trifluoroacetic acid, N ₂ Heating to 80 ℃ under protection, and stirring to react for 12h. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure and redissolved in 2mL of methanol using 1M NaOH/H ₂ Ph=9.0 adjusted with O solution, and Prep-HPLC (elution condition 2) was performed to isolate the title compound 6 (2 mg)

MS(ESI,m/z):383.1[M+H] ⁺ .

¹ H NMR(DMSO-d6,400MHz)δ7.80-7.84(m,1H),7.56-7.57(m,1H),7.41-7.42(m,1H),7.33(s,1H),7.26-7.33(m,3H),6.16(s,2H),4.61(t,J＝5.2Hz,1H),3.73(s,3H),3.48-3.52(m,2H),2.88(t,J＝8.0Hz,2H),1.87-1.94(m,2H).

Example 7:3- (4-amino-6- (5- (2-fluoro-4-methoxyphenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-2-yl) propan-1-ol (7)

The first step: 2- (3- (benzyloxy) propyl) -6- (5- (2-fluoro-4-methoxyphenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-4-amine (7 a)

Compound 1h (32.12 mg, 70.22. Mu. Mol), 2-fluoro-4-methoxyphenylboronic acid (23.88 mg, 140.45. Mu. Mol), pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (6 mg, 7.02. Mu. Mol), potassium carbonate (19.41 mg, 140.45. Mu. Mol) were added to 5mL of 1, 4-dioxane and 0.5mL of water, N ₂ Heating to 90 ℃ under protection for reaction for 5h. After completion of the reaction, the mixture was filtered through celite, and purified by flash column chromatography (elution system a) to give compound 7a (30 mg). MS (ESI, m/z): 503.1[ M+H ]] ⁺ .

And a second step of: 3- (4-amino-6- (5- (2-fluoro-4-methoxyphenyl) thiophen-2-yl) -1-methyl-1H-imidazo [4,5-c ] pyridin-2-yl) propan-1-ol (7)

Compound 7a (30 mg, 59.76. Mu. Mol) was dissolved in 4mL trifluoroacetic acid, N ₂ Heating to 80 ℃ under protection, and stirring to react for 12h. After the reaction, the reaction mixture was concentrated to dryness under reduced pressure and redissolved in 2mL of methanol using 1M NaOH/H ₂ The O solution was adjusted to ph=9.0 and Prep-HPLC (elution condition 1) was used to isolate the title compound 7 (3 mg).

MS(ESI,m/z):413.1[M+H] ⁺ .

¹ H NMR(DMSO-d6,400MHz)δ7.71-7.75(m,1H),7.52-7.53(m,1H),7.48-7.49(m,1H),7.34(s,1H),7.05-7.08(m,1H),6.84-6.87(m,1H),6.11(s,2H),4.61(t,J＝5.2Hz,1H),3.94(s,3H),3.72(s,3H),3.47-3.50(m,2H),2.88(t,J＝8.0Hz,2H),1.87-1.94(m,2H).

Drug effect screening method and data

Experimental example 1 agonism of the compounds of the invention on IL-1 beta expression in THP-1 cells after PMA induced differentiation.

The present experiment uses HTRF (homogeneous time resolved fluorescence) assay to test the effect of the compounds of the present invention on IL-1β levels of the NLRP3 downstream cytokines to assess the agonism of the compounds on the hllrp 3 inflammatory body or hllrp 3 inflammatory body pathway at the cellular level.

The reagent used is as follows: RPMI 1640 (Hyclone); heat-inactivated FBS (fetal bovine serum) (Gibco); PMA (tetradecanoyl phorbol acetate) (Biyun Tian)

And (3) cells: THP-1 (Nanjing Ke Bai)

The kit comprises: IL-1. Beta. Assay kit (CISBIO)

The experimental steps are as follows:

1) THP-1 cells in logarithmic growth phase were grown at 5X 10 ⁵ Density of individual/well inoculated in T75 flask, placed at 37℃in 5% CO ₂ After 24h of culture in a cell culture incubator, THP-1 suspension cells were induced to become adherent macrophages with 1. Mu.M PMA. The medium was RPMI 1640 containing 10% heat-inactivated FBS and 0.05mM beta-mercaptoethanol.

2) After cell induction for 24h, adherent cells were trypsinized, centrifuged at 1000rpm for 5min, the supernatant removed, and the cell density resuspended to 2X 10 using RPMI 1640 medium containing 2% heat-inactivated FBS ⁶ mu.L/well of cell resuspension was plated in 96-well plates at 1X 10 cells per well ⁵ And each.

3) Preparing a proper amount of DMSO solution of a compound to be tested with 10mM, preparing a 2 Xtest concentration with RPMI 1640 culture medium containing 2% heat-inactivated FBS, adding 50 μl/well diluent into cells of a 96-well plate, mixing thoroughly, placing the 96-well plate at 37deg.C, 5% CO ₂ Is cultured for 6 hours, and the supernatant is collected, and the IL-1 beta level is measured according to the instruction of the IL-1 beta detection kit.

4)EC ₅₀ The fit was performed by GraphPad software log (agonist) vs. response-Variable slope four-parameter method.

The agonism of the compounds of the invention on IL-1β in THP-1 cells after PMA induced differentiation is shown in Table 1.

Experimental example 2 THP1 cells deficient in NLRP3 after PMA-induced differentiation by the inventive Compound (THP 1- _def IL-1 beta agonism in NLRP3 cells)

The present experiment uses HTRF (homogeneous time resolved fluorescence) assay to test the effect of the compounds of the present invention on IL-1β levels in THP1-defNLRP3 cells to assess the specificity of the compounds for hllrp 3 inflammatory corpuscles or hllrp 3 inflammatory corpuscle pathway agonism.

And (3) cells: THP1- _def NLRP3(InvivoGen)

The kit comprises: IL-1. Beta. Assay kit (CISBIO)

The experimental steps are as follows:

1) THP1- _def NLRP3 cells at 5X 10 ⁵ Density of individual/well inoculated in T75 flask, placed at 37℃in 5% CO ₂ After 24h of culture in an incubator of (C), THP1 was induced with 1. Mu.M PMA) _def NLRP3 suspension cells become adherent macrophages. The medium was RPMI 1640 containing 10% heat-inactivated FBS and 0.05mM beta-mercaptoethanol.

2) After cell induction for 24h, adherent cells were trypsinized, centrifuged at 1000rpm for 5min, and the supernatant was removed and the cell density was resuspended to 2X 10 using RPMI 1640 medium containing 2% heat-inactivated FBS ⁶ mu.L/well of cell resuspension was plated in 96-well plates at 1X 10 cells per well ⁵ And each.

THP1- _def The agonism of IL-1β expression in NLRP3 cells is shown in Table 1.

Experimental example 3: agonism of hTLR7 by the inventive Compounds

This experiment tests activation of TLR7 signaling pathway by compounds of the invention by detecting luciferase in HEK-hTLR 7-NF-kB-reporter cells to assess the specificity of compounds for agonism of NLRP3 pathway.

Reagent: DMEM (High glucose); FBS (fetal bovine serum) (Gibco); bright-Glo ^TM Luciferase detection kit (Promega)

And (3) cells: HEK-hTLR7-NF-kB-Luciferase Gene cells (humanized TLR7 NF-kB-Luciferase reporter Gene cells) (Nanjac Bai)

1) The HEK-hTLR7-NF-kB-Luciferase cells in logarithmic growth phase were pancreatin digested and resuspended to 2X 10 with medium ⁶ The concentration of each mL was added to 50. Mu.L/well of cell resuspension in 96-well plates, the number of cells per well being 1X 10 ⁶ And each. Preparing a proper amount of DMSO solution of 10mM compound to be tested into 2 Xtest concentration with culture medium, adding 50 μl/well into 96-well plate cells, placing 96-well plate at 37deg.C, 5% CO ₂ Is cultured in an incubator for 16 hours. The medium was DMEM (High glucose) containing 10% fbs.

2) After the cell incubation has ended, 100. Mu.l/well Bright-Glo is added ^TM Luciferase detection reagent, incubated at room temperature for 5min, and the microplate reader reads the relative Luciferase activity units (Relative Luciferase Unit, RLU).

3) Stimulation of hTLR7 by tested Compounds EC ₅₀ The fit was performed by GraphPad software log (agonist) vs. response-Variable slope four-parameter method.

The agonism of hTLR7 by the compounds of the invention is shown in table 1.

Experimental example 4: agonism of hTLR8 by the inventive Compounds

This experiment tests the activation of TLR8 signaling pathway by compounds of the invention by detecting the secretion of alkaline phosphatase in HEK-Blue cell lines to assess the specificity of the compounds for agonism of the NLRP3 pathway.

Reagent: DMEM (High glucose); FBS (fetal bovine serum) (Gibco); QUANTI-Blue/InvivoGen/rep-qb2;

and (3) cells: HEK-Blue ^TM hTLR8 cells (humanized TLR8 cells) (InvivoGen)

The experimental steps are as follows:

1) HEK-Blue in logarithmic growth phase ^TM hTLR8 cells were pancreatin digested and resuspended to 2X 10 with medium ⁶ The concentration of individual/mL was added to 50. Mu.L/well of cell suspension in 96-well plates; preparing a proper amount of DMSO solution of 10mM compound to be tested into 2 Xtest concentration with culture medium, adding 50 μl/well into 96-well plate cells, placing 96-well plate at 37deg.C, 5% CO ₂ Is cultivated in an incubatorAnd (5) culturing for 16 hours. The medium was DMEM (High glucose) containing 10% fbs.

2) After the cell incubation, 10. Mu.L of the cell culture supernatant was transferred to a 96-well plate, 90. Mu.L/well of QUANTI-Blue detection solution was added, and incubated at 37℃for 3 hours, with an ELISA reader OD ₆₂₀ And (5) reading.

3) Stimulation of hTLR8 by tested Compounds EC ₅₀ The fit was performed by GraphPad software log (agonist) vs. response-Variable slope four-parameter method.

The agonism of hTLR8 by the compounds of the application is shown in table 1.

TABLE 1

The results show that the compounds (e.g. compound 1, compound 3, compound 4, compound 5) of the application have a significant agonistic effect on IL-1β expression in THP-1 cells after PMA-induced differentiation, but on THP1- _def IL-1β expression in NLRP3 cells had no agonism at the highest compound test concentration (27 μM); all compounds had no apparent activation of hTLR7 and hTLR 8. In conclusion, the compounds of the present application (e.g., compound 1, compound 3, compound 4, compound 5) have significant agonistic activity on hNLRP3 and its signaling pathway.

Various modifications of the application, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this disclosure (including all patents, patent applications, journal articles, books, and any other publications) is hereby incorporated by reference in its entirety.

Claims

1. A compound of formula I:

wherein:

X ¹ is CR (CR) ⁷ ，

X ² Is N, R ⁶ There is no time for the existence of the non-woven fabric,

R ¹ selected from C _6-12 An aryl group; the C is _6-12 Aryl groups may be optionally substituted with one or more of halogen, CN, C _1-4 Alkyl, C _1-4 Haloalkyl, C _1-4 Alkoxy, C _1-4 Hydroxyalkyl or C (O) NR ³¹ R ³² ；

R ² Selected from H and C _1-8 An alkyl group;

R ³ OH;

R ⁴ and R is ⁵ Each independently selected from H;

R ⁷ independently selected from H, C _1-6 Alkyl, said C _1-6 The alkyl group may be optionally substituted with one or more of the following groups: halogen, OH, CN, C _1-4 Alkoxy, C _1-4 A hydroxyalkyl group;

v is selected from

L is- (L) ¹ ) _n -(L ² ) _p –(L ³ ) _q -, wherein L ¹ 、L ² And L ³ Identical or different and are each independently selected from C _1-8 An alkylene group; the C is _1-8 The alkylene group may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO ₂ 、C _1-6 Alkyl, C _1-4 Haloalkyl, C _1-4 Hydroxyalkyl, C _1-4 An alkoxy group;

n, p, q are each independently selected from 0 or 1;

R ³¹ 、R ³² each independently selected from: h and C _1-8 An alkyl group; the C is _1-8 The alkyl group may be optionally substituted with one or more of the following substituents: OH, CN or halogen.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is phenyl, optionally substituted with one or more of halogen, CN, CH ₃ 、OCH ₃ 、C(O)N(CH ₃ ) ₂ 。

3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein:

R ¹ selected from the group consisting of

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure of formula II:

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ V and L are as defined in any one of claims 1 to 3.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

6. a pharmaceutical composition comprising a compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 6, further comprising one or more pharmaceutically acceptable carriers.

8. The pharmaceutical composition of any one of claims 6-7, further comprising one or more second therapeutic agents.

9. The pharmaceutical composition of claim 8, wherein the second therapeutic agent comprises an additional agent for treating a neoplastic disease.

10. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 6 to 9.

11. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to any one of claims 6 to 9 or a pharmaceutical formulation according to claim 10 for the manufacture of a medicament for the prevention and/or treatment of a disease associated with NLRP3 inflammatory body activity.

12. The use according to claim 11, wherein the disease is a neoplastic disease.

13. The use of claim 11, the medicament for modulating the activity of an NLRP3 inflammatory body.

14. The use of claim 11, the medicament for increasing the activity of NLRP3 inflammatory bodies.