CN111825694B - Condensed-cyclic compound, preparation method and application thereof - Google Patents

Condensed-cyclic compound, preparation method and application thereof Download PDF

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CN111825694B
CN111825694B CN201910313420.8A CN201910313420A CN111825694B CN 111825694 B CN111825694 B CN 111825694B CN 201910313420 A CN201910313420 A CN 201910313420A CN 111825694 B CN111825694 B CN 111825694B
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compound
alkyl
membered
pharmaceutically acceptable
acceptable salt
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CN111825694A (en
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何云
蔡家强
李桂英
游泽金
田强
宋宏梅
薛彤彤
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present invention relates to compounds of formula X, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of said compounds, or stable isotopic derivatives, metabolites or prodrugs of said compounds. As NLRP3 modulators (e.g., agonists or partial agonists), these compounds are useful in the treatment of abnormal cell proliferation diseases (e.g., cancer).

Description

Condensed-cyclic compound, preparation method and application thereof
Technical Field
The present invention relates to a novel class of fused ring compounds, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, co-crystals, polymorphs or solvates of said compounds, or stable isotopic derivatives, metabolites or prodrugs of said compounds. The compounds of the invention are useful as NLRP3 modulators (e.g., agonists or partial agonists) in the treatment of abnormal cell proliferation diseases (e.g., cancer).
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 an effective anti-tumor immune effect 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 for NLRP3 agonists for tumor immunotherapy, only one compound is currently in clinical phase I studies, four published compound patent applications (WO 2017184746, WO2017184735, WO2018152396, WO 2019014402). 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 fused ring 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 the NLRP3 distribution or otherwise, thereby providing the following invention:
in one aspect, the invention provides a compound having the structure shown in formula X, 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:
wherein:
X 2 c, N, O or S, and satisfies the following conditions:
(1) When X is 2 When O or S, R 2 And R is 6 Absence of;
(2) When X is 2 When N is present, R 2 And R is 6 Are not present at the same time;
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;
R 2 selected from H, C 1-8 Alkyl, C 2-8 Heteroalkyl, C 1-4 Hydroxyalkyl, 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 Heteroalkyl, C 1-4 Hydroxyalkyl, 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 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 33 C(O)R 34 、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, halogen, CN, NO 2 、C 1-8 Alkyl, C 1-8 Alkoxy, C 2-8 Heteroalkyl, 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, 9-12 membered heteroaryl-cycloalkyl, CO 2 R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、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 Alkoxy, C 2-8 Heteroalkyl, 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 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 group5-to 10-membered heteroaryl, 9-to 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 Selected from C 1-15 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl; the C is 1-15 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl groups 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 Alkyloxy, C 1-8 Hydroxyalkylene, C 2-8 Alkylene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, 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 Alkyloxy, C 1-8 Hydroxyalkylene, C 2-8 Alkylene, C 3-8 Cycloalkyl, 4-10 membered heterocycleRadical, C 6-12 Arylene, 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, NR 31 R 32 ；
n, p, q are each independently selected from 0, 1 or 2; when n is 2, two L 1 May be the same or different; when p is 2, two L 2 May be the same or different; when q is 2, two L 3 May be the same or different;
selected from (I)>Wherein R is 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 5 Each independently selected from H, halogen, C 1-6 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, said C 1-6 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, may be optionally substituted with one or more of the following groups: halogen, OH, CN, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl group, NR 31 R 32 ；
m is 0, 1 or 2;
and (II)Wherein R is 1 The definition is as shown in formula (I); x is X 1 Is CR (CR) 7 Or N, R 7 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, 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;
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 2-8 Heteroalkyl, 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 2-8 Heteroalkyl, 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 The alkyl- (5-10 membered heteroaryl) group may optionally be taken by one or more of the following substituentsAnd (3) substitution: 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 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl; or R is 31 And R is 32 And together with the N atom to which it is attached form a heterocyclic group containing 3 to 8 members; 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 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 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 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Heteroalkyl, 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 2-8 Heteroalkyl, 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 And R is 36b Are linked together to form a 3-7 membered cycloalkyl or 4-7 membered heterocyclyl group together with the carbon atom to which they are attached;
R 38 selected from H, OH, CN, NO 2 、S(O)R 35 And 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 the two components are in the same time,each R is 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 certain embodiments, R 1 Selected from C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl; the C is 3-6 Cycloalkyl, 4-7 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of halogen, CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 A hydroxyalkyl group;
in certain embodiments, R 2 Selected from H, C 1-8 Alkyl, C 2-8 Heteroalkyl, C 1-4 Hydroxyalkyl group, C 1-8 Alkyl, C 2-8 Heteroalkyl, C 1-4 Hydroxyalkyl 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, OR 37 、SR 37 、C(O)R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、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 certain embodiments, R 3 Selected from H, halogen, CN, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl9-12 membered arylcycloalkyl, 9-12 membered heteroarylcycloalkyl, -CO 2 R 30 、-C(O)R 30 、-C(O)NR 31 R 32 、-NR 33 C(O)R 34 、-NR 31 R 32 、NR 33 C(O)NR 31 R 32 、-S(O) 2 R 35 、-OR 37 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Heteroalkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroarylo, 9-12 membered aryl-heterocyclo-cycloalkyl or 9-12 membered heteroaryl-cycloalkyl optionally substituted with one or more of the following substituents: halogen, CN, 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 、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 ；
In certain embodiments, R 4 Selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl; the C is 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl groups may be optionally substituted with one or more of the following substituents: halogen, OH, CN, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 An alkoxy group;
in certain embodiments, R 7 Selected from H, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 2-6 Heteroalkyl, 4-7 membered heterocyclyl, said C 1-4 Alkyl group,C 3-6 Cycloalkyl, C 2-6 The heteroalkyl or 4-7 membered heterocyclyl may be optionally substituted with one or more of the following groups: halogen, OH, CN, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl groups.
In certain embodiments, R 5 Selected from halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4-7 membered heterocyclyl, said C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or 4-7 membered heterocyclyl may be optionally substituted with one or more of the following groups: halogen, OH, CN, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl group, NR 31 R 32 The method comprises the steps of carrying out a first treatment on the surface of the When a plurality of R 5 When present at the same time, each R 5 May be the same or different;
in certain embodiments, 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 1-4 Alkyloxy, C 1-4 Hydroxyalkylene, C 2-6 Alkylene, C 3-6 Cycloalkylene, 4-7 membered heterocyclylene, phenylene, 5-6 membered heteroarylene, 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 1-4 Alkyloxy, C 1-4 Hydroxyalkylene, C 2-6 Alkylene, C 3-6 Cycloalkylene, 4-7 membered heterocyclylene, 5-6 membered heteroarylene may be optionally substituted with one or more of the following substituents: halogen, OH, CN, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, NR 31 R 32 ；
Wherein R is 30 、R 31 、R 32 、R 33 、R 34 、R 35 、R 37 、R 36a 、R 36b As defined above.
In certain embodiments, X 1 Is CR (CR) 7 ，R 7 Selected from H, halogen, C 1-4 Alkyl, C 2-6 Heteroalkyl, optionally, the C 1-4 Alkyl or C 2-6 Heteroalkyl groups are substituted with one or more halogens.
In certain embodiments, X 2 Is N or C, preferably N, and R 2 Selected from H, C 1-8 Alkyl, C 2-8 Heteroalkyl, C 1-4 Hydroxyalkyl group, C 1-8 Alkyl, C 2-8 Heteroalkyl, or C 1-4 Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: halogen, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, 4-7 membered heterocyclyl, OR 37 、NR 31 R 32 。
In certain embodiments, R 2 Selected from H, C 1-4 Alkyl, C 2-6 Heteroalkyl, C 1-4 Hydroxyalkyl group, C 1-4 Alkyl, C 2-6 Heteroalkyl or C 1-4 Hydroxyalkyl groups may be optionally substituted with one or more of the following substituents: halogen, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, 4-7 membered heterocyclyl, OR 37 、NR 31 R 32 。
In certain embodiments, R 1 Selected from C 6-12 Aryl and 5-10 membered heteroaryl, said C 6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of halogen, CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 A hydroxyalkyl group;
in certain embodiments, R 1 Selected from phenyl and 5-6 membered heteroaryl, which phenyl or 5-6 membered heteroaryl may be optionally substituted with one or more of halogen, -CN, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl, -C 1-4 Alkoxy, -C 1-4 Haloalkoxy, -C 1-4 Hydroxyalkyl groups.
In certain embodiments, R 3 Selected from H, CN, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroarylRadical, -CO 2 R 30 、-C(O)R 30 、-S(O) 2 R 35 、-OR 37 、-NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)R 34 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-6 Alkyl, C 3-6 Cycloalkyl, 4-8 membered nitrogen containing heterocyclyl, 4-8 membered oxygen containing heterocyclyl, phenyl, 5-6 membered heteroaryl may be optionally substituted by one or more of the following substituents: c (C) 1-4 Alkyl, halogen, CN, C 3-8 Cycloalkyl, C 1-3 Alkoxy, OH, -S (O) 2 R 35 、-C(O)R 30 、-NR 31 R 32 、NR 33 C(O)NR 31 R 32 Or NR (NR) 33 C(O)R 34 。
In certain embodiments, R 4 Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl group, the C 1-4 Alkyl or C 3-6 Cycloalkyl groups may be optionally substituted with one or more halogens.
In certain embodiments, R 5 Selected from halogen, C 1-4 Alkyl, m is 0 or 1.
In certain embodiments, 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 1-4 Alkylene, C 2-6 Heteroalkylene, 4-7 membered heterocyclylene, O, S, NR 33 、C 1-4 Alkyleneoxy, CO; the C is 1-4 Alkylene, C 2-6 Heteroalkylene, 4-7 membered heterocyclylene or C 1-4 The alkyleneoxy group may be optionally substituted with one or more of the following substituents: halogen, OH, NR 31 R 32 。
n, p, q are each independently 0, 1 or 2.
In certain embodiments, R 30 Selected from H and C 1-4 An alkyl group; preferably, R 30 Selected from the group consisting of H, methyl, ethyl, propyl and t-butyl.
In certain embodiments, R 37 Selected from H, C 1-8 Alkyl (e.g. C 1-4 Alkyl), 4-10 membered heterocyclyl (e.g., 4-7 membered heterocyclyl); the C is 1-8 The alkyl or 4-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CONR 31 R 32 、NR 31 R 32 、NR 33 C(O)R 34 The method comprises the steps of carrying out a first treatment on the surface of the In certain embodiments, R 37 Selected from H, methyl, ethyl, propyl and tert-butyl; wherein R is 31 、R 32 、R 33 、R 34 As defined above.
In certain embodiments, R 31 、R 32 、R 33 、R 34 Each independently selected from H, C 1-8 Alkyl (e.g. C 1-4 Alkyl group, C 1-8 Hydroxyalkyl (e.g. C 1-4 Hydroxyalkyl group, C 1-8 Alkoxy (e.g. C 1-4 Alkoxy), 4-10 membered heterocyclyl (e.g., 4-7 membered heterocyclyl); the C is 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy or 4-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, 4-10 membered heterocyclyl (e.g., 4-7 membered mono-heterocyclyl containing 1-2 heteroatoms selected from nitrogen, oxygen, sulfur); in certain embodiments, R 33 Selected from H and C 1-4 An alkyl group; preferably, R 33 Selected from the group consisting of H, methyl, ethyl, propyl and t-butyl.
In certain embodiments, R 31 、R 32 And together with the N atom to which they are attached form a 3-8 membered heterocyclic group (e.g., 4-7 membered heterocyclic group), or R 33 、R 34 And the C or N atoms to which both are attached, respectively, form a 4-8 membered heterocyclyl (e.g., a 4-7 membered heterocyclyl), which 3-8 membered heterocyclyl or 4-8 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, 4-10 membered heterocyclyl (e.g., 4-7 membered heterocyclyl).
In certain embodiments, R 35 Selected from C 1-8 Alkyl (examples)Such as C 1-4 Alkyl), said C 1-8 Alkyl (e.g. C 1-4 Alkyl) may be optionally substituted with one or more of the following substituents: OH, NR 31 R 32 The method comprises the steps of carrying out a first treatment on the surface of the In certain embodiments, R 35 Selected from the group consisting of H, methyl, ethyl, propyl and t-butyl.
In certain embodiments, R 36a And R is 36b Each independently selected from H, C 1-6 Alkyl (e.g. C 1-4 Alkyl), said C 1-6 The alkyl group may be optionally substituted with one or more of the following groups: OH, NH 2 、NHCH 3 、N(CH 3 ) 2 . In certain embodiments, R 36a 、R 36b And together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl or 4-7 membered heterocyclyl, said C 3-6 Cycloalkyl or 4-7 membered heterocyclyl may be optionally substituted with one or more of the following groups: OH, NH 2 、NHCH 3 、N(CH 3 ) 2 。
In certain embodiments, R 38 Selected from H, CN and S (O) 2 R 35 。
In certain embodiments, X 1 CH.
In certain embodiments, X 2 Is N, R 6 Absent, R 2 Is H or C 1-4 An alkyl group.
In certain embodiments, R 1 Selected from phenyl, pyrrolyl, oxazolyl, imidazolyl, pyrazolyl, pyridyl and pyrimidinyl. In certain embodiments, R 1 Is pyrazolyl, for example 1H-pyrazol-3-yl, 1H-pyrazol-1-yl.
In certain embodiments, R 2 Selected from H, methyl, ethyl, propyl, butyl, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl, 2-methoxyethyl, 2-methoxypropyl.
In certain embodiments, R 3 Selected from H, C 1-4 Alkyl, cyclopropyl, 4-7 membered heterocyclyl (e.g., piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl), phenyl, 5-6 membered heteroaryl (e.g., pyridinyl, pyrazolyl), OR 37 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-4 Alkyl, cyclopropyl, 4-7 membered nitrogen containing heterocyclyl, phenyl, 5-6 membered heteroaryl may optionally be substituted with one or more (e.g. 1, 2, 3 or 4) methyl groups F, cl, CN, C 1-3 Alkoxy, OH, S (O) 2 R 35 Or C (O) R 30 And (3) substitution.
In certain embodiments, 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 methylene, ethylene, propylene, O, NR 33 、C 1-4 Alkyleneoxy, CO.
In certain embodiments, R 4 Selected from methyl, isopropyl, cyclopropyl, trifluoromethyl.
In certain embodiments, R 7 Selected from H, F, cl, methyl, cyclopropyl.
In certain embodiments, R 5 Selected from F, cl, C 1-4 An alkyl group.
In certain embodiments, m is 0 or 1; preferably, m is 0.
In certain embodiments, n, p, q are each independently 0, 1, or 2.
In certain embodiments, -L-R 3 Selected from: methyl group,
In some embodiments, the compounds of the invention have a structure represented by formula III or formula IV:
R 1 、R 3 、R 4 、R 5 、X 1 l, m are as defined above for formula X; x is X 2 When O or S, R 2 Absence of; x is X 2 When N is present, R 2 As defined above for formula X.
In some embodiments, the compounds of the invention have a structure represented by formula V or formula VI:
R 1 、R 2 、R 3 、R 4 、R 5 、X 1 L, m are as defined above for formula X.
In some embodiments, the compounds of the present invention have Sup>A structure represented by formulSup>A V-A or formulSup>A VI-A:
R 1 、R 2 、R 3 、R 4 l is as defined above for formula X.
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, ameliorate and/or treat a disease associated with NLRP3 inflammatory body activity (e.g., a cell proliferation disorder, such as 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 an additional agent for treating a disease such as a tumor.
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 isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, for the manufacture of a medicament for the prevention, alleviation and/or treatment of a disease associated with NLRP3 inflammatory small body activity (e.g., a cell proliferative disorder, such as 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) NLRP3 inflammatory small body activity, the kit comprising 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.
In another aspect, the invention provides a method of preventing, alleviating and/or 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: lung cancer, pancreatic cancer, breast cancer, head and neck cancer, liver cancer, melanoma, and glioma.
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 the receptor 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 "alkeneThe radical "means a monovalent straight or branched hydrocarbon radical containing 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 to Etc., 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, iso-propoxyButoxy, t-butoxy, pentoxy, hexoxy, -CH 2 -OCH 3 Etc., the alkoxy groups may be optionally substituted with one or more (such as 1 to 3) identical 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 "heteroalkyl" refers to an optionally substituted alkyl group containing two or more carbon atoms having one or more backbone chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. The numerical ranges given refer to the number of carbons in the chain, e.g. C 2-8 Heteroalkyl groups contain 2-8 carbon atoms. For example, -CH 2 OCH 2 CH 3 、-CH 2 NHCH 2 CH 3 or-CH 2 N(Me)CH 2 CH 3 Referred to as C 3 A heteroalkyl group. The term "heteroalkylene" denotes the corresponding divalent group, e.g., -CH 2 OCH 2 CH 2 -。
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 ring radical, e.g., "C 3-8 Cycloalkyl "means cycloalkyl having 3 to 8 ring-forming carbon atoms, e.g. C 3-6 Cycloalkyl, which may be a monocycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), or bicycloalkyl, such as 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. 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 "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 an aryl group containing 6 to 12 carbon atoms, such as 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 compound 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 (e.g., fused, spiro, or bridged) including, but not limited to, oxygen, nitrogen, sulfur atoms, the carbon atoms and heteroatoms on the heterocyclyl optionally being oxo (oxo) (e.g., forming c= O, S (=o) or S (=o) 2 ). For example, a 3-14 membered heterocyclic group "means a heterocyclic group containing 3-14 ring atoms, including but not limited to 4-10 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 4-7 membered nitrogen containing heterocyclic groups, 4-7 membered oxygen containing heterocyclic groups, 4-7 membered sulfur containing heterocyclic groups, 5-6 membered nitrogen containing heterocyclic groups, 5-6 membered oxygen containing heterocyclic groups, 5-6 membered sulfur containing heterocyclic groups, said" nitrogen containing heterocyclic groups "," oxygen containing heterocyclic groups "," sulfur containing heterocyclic groups "optionally also contain one or more other 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
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.
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 groups, examples of which include, but are not limited to, pyrrolidinyl groupsAnd cyclopropyl, cyclopentyl and aziridinyl, pyrrolidinyl and cyclobutyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and 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 spiro heterocycle", "oxygen-containingThe spiro heterocycle "," sulfur-containing spiro heterocycle "optionally also contains one or more other heteroatoms selected from oxygen, nitrogen, sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.
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, 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 groups may optionally be oxo (oxo) (e.g., to form c= O, S (=o) or S (=o) 2 ). For example, "5-10 membered heteroaryl" means a heteroaryl group containing 5 to 10 ring atomsAnd radicals 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.
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.
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 hydrochloride, 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, intraarterially, subcutaneously, intraperitoneally, intramuscularly, intratumorally 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 person this corresponds 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; furthermore, larger doses may be employed where tolerated, or 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 or alleviating, inhibiting the progression of, or preventing the 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 present invention are metabolites of the compounds of the present invention, i.e., substances formed by the in vivo oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic hydrolysis, etc. of the compounds of the present invention upon administration. The invention also includes compounds obtained by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite 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.
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 compound V-A
R 1 、R 2 、R 3 、R 4 L is as defined above for formula V, but n+p+q in L is other than 0 and is at R 3 -L-COOH and R 3 in-L-COCl, -L-R 3 With carbon atoms bound to-COOH or-COCl, whereby-L-R in V-A 3 With carbon atoms attached to the imidazole ring.
The first step: the compound V-A-1 is subjected to nitration reaction to generate Sup>A compound V-A-2.
In certain embodiments, the nitration reaction may be performed using a nitrating agent such as concentrated nitric acid or fuming nitric acid. In certain embodiments, the reaction is carried out in a solvent, and solvents that may be used are acetic acid, propionic acid, butyric acid, or the like. In certain embodiments, the reaction temperature is from 60 ℃ to 150 ℃.
And a second step of: the compound V-A-2 is chlorinated to produce the compound V-A-3.
In certain embodiments, POCl may be used 3 、PCl 3 Or PCl 5 And (3) carrying out chlorination reaction by using a chlorinating agent. In certain embodiments, the reaction is carried out in a solvent, which may be DCM or DCE, etc. In certain embodiments, the reaction is performed under solvent-free conditions. In certain embodiments, the reaction temperature is rt to 110 ℃.
And a third step of: compounds V-A-3 and R 2 NH 2 And carrying out substitution reaction under the action of alkali to generate the compound V-A-4.
In certain embodiments, the base that can be used is TEA or DIPEA, or the like. In certain embodiments, the reaction is carried out in a solvent, which may be NMP or DMF, or the like. In certain embodiments, the reaction temperature is from 0 ℃ to 153 ℃.
Fourth step: compound V-A-4 is reduced to compound V-A-5.
In certain embodiments, sodium dithionite, snCl may be used 2 Reducing agent such as Fe, zn or Pd/C. At the position ofIn certain embodiments, the reaction is carried out in a solvent, which may be MeOH, etOH, THF or 1, 4-dioxane, and the like. In certain embodiments, the reaction temperature is rt to 110 ℃.
Fifth step: the compound V-A-5 reacts with R under the action of condensing agent and alkali 3 The L-COOH is subjected to condensation reaction to generate Sup>A compound V-A-6 or the compound V-A-5 is directly reacted with R under the action of alkali 3 The reaction of L-COCl to give the compound V-A-6.
In certain embodiments, condensing agents that may be used are HATU, DCC/NHS, EDCI/HOBt, or HBTU, among others. In certain embodiments, the base that can be used is TEA or DIPEA, or the like. In certain embodiments, the reaction is carried out in a solvent, which may be THF, DCM, DCE, CH 3 CN, 1, 4-dioxane or DMF, etc. In certain embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
Sixth step: the compound V-A-6 is closed to form the compound V-A-7 under alkaline conditions.
In certain embodiments, the reaction may be carried out using a base such as TEA or DIPEA. In certain embodiments, the reaction is carried out in a solvent, which may be MeOH, etOH, THF, CH 3 CN or 1, 4-dioxane, etc. In certain embodiments, the reaction temperature is from 60 ℃ to 100 ℃.
Seventh step: compound V-A-7 is oxidized to compound V-A-8.
In certain embodiments, m-CPBA, H can be used 2 O 2 Or CH (CH) 3 And oxidizing reaction is carried out by using an oxidant such as COOOH. In certain embodiments, the reaction is carried out in a solvent, which may be DCM, DCE, CHCl 3 Or DMF, etc. In certain embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
Eighth step: compounds V-A-8 and R 4 MgX reacts to generate Sup>A compound V-A-9,
wherein X is selected from chlorine, bromine and iodine.
In certain embodiments, the reaction is carried out in a solvent, which may be used is selected from THF, 1, 4-dioxane, toluene, and the like. In certain embodiments, the reaction temperature is from-20 ℃ to 100 ℃.
Ninth step: compounds V-A-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 ) The compound V-A is produced through coupling reaction (such as Suzuki reaction and Stille reaction).
In certain embodiments, pd (PPh 3 ) 4 Or Pd (dppf) Cl 2 ·CH 2 Cl 2 And (3) carrying out reaction by using the catalyst. In certain embodiments, a member selected from Cs may be used 2 CO 3 、K 3 PO 4 、Na 2 CO 3 、AcOK、NaHCO 3 And K 2 CO 3 And the like. In certain embodiments, the reaction is carried out in a solvent, which may be 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. In certain embodiments, the reaction temperature is from 60 ℃ to 180 ℃.
Synthesis method of compound VI-A
R 1 、R 2 、R 3 、R 4 L is as defined in formula VI above, but n+p+q in L is other than 0 and is at R 3 -L-COOH and R 3 in-L-COCl, -L-R 3 With carbon atoms bound to-COOH or-COCl, whereby-L-R in V-A 3 With carbon atoms attached to the imidazole ring.
The first step: the compound VI-A-1 undergoes nitration to produce the compound VI-A-2.
In certain embodiments, the nitration reaction may be performed using a nitrating agent selected from concentrated nitric acid, fuming nitric acid, and the like. In certain embodiments, the reaction is carried out in a solvent, and solvents that may be used are acetic acid, propionic acid, butyric acid, or the like. In certain embodiments, the reaction temperature is from 60 ℃ to 150 ℃.
And a second step of: the compound VI-A-2 is chlorinated to form the compound VI-A-3.
In certain embodiments, POCl may be used 3 、PCl 3 Or PCl 5 And (3) carrying out chlorination reaction by using a chlorinating agent. In certain embodiments, the reaction is carried out in a solvent, which may be DCM or DCE, etc. In certain embodiments, the reaction is performed under solvent-free conditions. In certain embodiments, the reaction temperature is rt to 110 ℃.
And a third step of: compounds VI-A-3 and R 2 NH 2 And carrying out substitution reaction under the action of alkali to generate a compound VI-A-4.
In certain embodiments, the base that may be used is selected from TEA, DIPEA, and the like. In certain embodiments, the reaction is carried out in a solvent, which may be selected from NMP, DMF, and the like. In certain embodiments, the reaction temperature is from 0 ℃ to 153 ℃.
Fourth step: compound VI-A-4 is reduced to compound VI-A-5.
In certain embodiments, sodium dithionite, snCl may be used 2 Reducing agent such as Fe, zn or Pd/C. In certain embodiments, the reaction is carried out in a solvent, which may be MeOH, etOH, THF or 1, 4-dioxane, or the like. In certain embodiments, the reaction temperature is rt to 110 ℃.
Fifth step: the compound VI-A-5 reacts with R under the action of condensing agent and alkali 3 The L-COOH is subjected to condensation reaction to generate a compound VI-A-6 or the compound VI-A-5 is directly reacted with R under the action of alkali 3 The reaction of L-COCl gives the compound VI-A-6.
In certain embodiments, condensing agents that may be used are HATU, DCC/NHS, EDCI/HOBt, or HBTU, among others. In certain embodiments, the base that can be used is TEA or DIPEA, or the like. In certain embodiments, the reaction is carried out in a solvent, which may be THF, DCM, DCE, CH 3 CN, 1, 4-dioxane or DMF, etc. In certain embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
Sixth step: the compound VI-A-6 is cyclized under alkaline conditions to form the compound VI-A-7.
In certain embodiments, the reaction may be carried out using a base such as TEA or DIPEA. In certain embodiments, the reaction is carried out in a solvent, which may be MeOH, etOH, THF, CH 3 CN or 1, 4-dioxane, etc. In certain embodiments, the reaction temperature is from 60 ℃ to 100 ℃.
Seventh step: compound VI-A-7 is oxidized to compound VI-A-8.
In certain embodiments, m-CPBA, H can be used 2 O 2 Or CH (CH) 3 And an oxidizing agent such as COOOH. In certain embodiments, the reaction is carried out in a solvent, which may be DCM, DCE, CHCl 3 Or DMF, etc. In certain embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
Eighth step: compounds VI-A-8 and R 4 MgX reacts to generate a compound VI-A-9,
wherein X is selected from chlorine, bromine and iodine.
In certain embodiments, the reaction is carried out in a solvent, which may be used is selected from THF, 1, 4-dioxane, toluene, and the like. In certain embodiments, the reaction temperature is from-20 ℃ to 100 ℃.
Ninth step: the compound VI-A-9 is subjected to bromination reaction to generate a compound VI-A-10.
In certain embodiments, the reaction may be carried out using a brominating agent selected from the group consisting of bromine, NBS, dibromohydantoin, and the like. In certain embodiments, the reaction is carried out in a solvent, which may be selected from acetic acid, 1, 4-dioxane, DMF, EA, and the like. In certain embodiments, the reaction temperature is from-20 ℃ to 100 ℃.
Tenth step: compounds VI-A-10 and R 1 -boric acid or R 1 -boric acid esters or R 1 Organotin compounds (e.g. R 1 Sn(n-Bu) 3 ) The compound VI-A is produced through coupling reaction (such as Suzuki reaction and Stille reaction).
In certain embodiments, a catalyst selected from Pd (PPh 3 ) 4 And Pd%dppf)Cl 2 ·CH 2 Cl 2 Etc. to carry out the reaction. In certain embodiments, a member selected from Cs may be used 2 CO 3 、K 3 PO 4 、Na 2 CO 3 、AcOK、NaHCO 3 And K 2 CO 3 And the like. In certain embodiments, the reaction is carried out in a solvent, which may be 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. In certain embodiments, the reaction temperature is from 60 ℃ to 180 ℃.
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.
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.
1 H NMR spectrum: bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD MHz). Thin layer chromatography using silica gel GF 254 as stationary phase.
LC/MS mass spectrometer: aglient 1260 Informance/Aglient 6120 Quaadrupole
The compound can be separated and purified by chromatography silica gel plates, silica gel column chromatography, preparative high performance liquid chromatography (Prep-HPLC) and Flash column chromatography.
Prep-HPLC using Agilent 1260 preparative liquid chromatography, detection wavelength: 214nm, 254nm; chromatographic column: waters SunFire Prep C18OBD (19 mm. Times.150 mm. Times.5.0 μm); column temperature: 25 ℃.
Elution conditions:
condition 1:10% -90% acetonitrile and 90% -10% ammonium bicarbonate aqueous solution (0.05%); 0-16min; flow rate: 25mL/min;
condition 2:30% -90% acetonitrile and 70% -10% ammonium bicarbonate aqueous solution (0.05%); 0-16min; flow rate: 25mL/min;
condition 3:10% -90% acetonitrile and 90% -10% ammonium bicarbonate aqueous solution (0.05%); 0-16min; flow rate: 20mL/min;
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.
Flash column chromatography using a Biotage flash column chromatograph.
The microwave reaction was performed using a biotageinitiator+microwave reactor.
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 1:2- (3- (benzyloxy) propyl) -1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (1)
3- (1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propanol (2)
The first step: synthesis of the Compound (4-benzyloxy) - (7- (methylamino) thieno [3,2-b ] pyridin-6-yl) butanamide (1 b)
DIPEA (1.44 g,11.16 mmol), HATU (1.06 g,2.79 mmol) were added sequentially to 4-benzyloxybutyric acid (541.80 mg,2.79 mmol), compound 1a (500 mg,2.79 mmol) in DMF (4 mL), and then the reaction was stirred at room temperature for 5hr. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried and concentrated to give compound 1b (850 mg).
MS(ESI,m/z):356.1[M+H] +
And a second step of: synthesis of the Compound 2- (3- (benzyloxy) propyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (1 c)
Sodium hydroxide (184.55 mg,4.61 mmol) was added to ethanol (4 mL) of compound 1b (820 mg,2.31 mmol). Then heating to 90 ℃ for reaction for 2hr. Concentrating under reduced pressure, adding water and ethyl acetate, and extracting. The organic layer was dried and concentrated, and purified by column chromatography (eluent system a) to give compound 1c (500 mg).
MS(ESI，m/z):338.1[M+H] +
And a third step of: synthesis of the Compound 2- (3- (benzyloxy) propyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine-2, 5-oxide (1 d)
M-chloroperoxybenzoic acid (382.29 mg,2.22 mmol) was added in portions to compound 1c (500 mg,1.48 mmol) in DCM (5 mL) and the reaction stirred at room temperature for 4hr. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane, and the organic layer was dried and concentrated, followed by purification by column chromatography (eluent system a) to give compound 1d (400 mg). MS (ESI, m/z): 354.1[ M+H ] ] +
Fourth step: synthesis of Compound (2- (3- (benzyloxy) propyl) -1, 4-dimethyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (1 e)
Compound 1d (500 mg,1.41 mmol) was added to anhydrous THF (4 mL) and then methyl magnesium bromide (2.5M, 5.66 mL) was slowly added to the reaction system. The reaction was kept at room temperature for 1hr. The reaction mixture was quenched with water, extracted with ethyl acetate, and the organic layer was dried and concentrated, followed by separation and purification by column chromatography (eluent system B) to give Compound 1e (400 mg). MS (ESI, m/z): 352.1[ M+H ]] + 。
Fifth step: synthesis of (2-3 (benzyloxy) propyl) -7-bromo-1, 4-dimethyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (1 f)
NBS (405.12 mg,2.28 mmol) was added in portions to acetic acid (1 mL) chloroform (1 mL) of compound 1e (400 mg,1.14 mmol). After stirring at room temperature for 2hr, dichloromethane and water are added for extraction. The organic layer was concentrated by drying, and purified by column chromatography (eluent system B) to give compound 1f (300 mg). MS (ESI, m/z): 430.1[ M+H ]] +
1 H NMR(400MHz,MeOD)δ7.49(s,1H),7.16–7.07(m,5H),4.40(s,2H),3.85(s,3H),3.64(t,J＝5.8Hz,2H),3.08(t,J＝7.4Hz,2H),2.79(s,3H),2.22–2.11(m,2H).
Sixth step: synthesis of the Compound 2- (3- (benzyloxy) propyl) -1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (1)
Pd (dppf) Cl 2 (101.91 mg, 139.42. Mu. Mol), cesium carbonate (181.24 mg, 557.67. Mu. Mol) was added to the water/dioxane of compound 1k (64.93 mg, 334.60. Mu. Mol), compound 1f (120 mg, 278.84. Mu. Mol). N (N) 2 Heating to 100deg.C under protection for 16hr. After concentration, the compound 1 (50 mg) was obtained by separation and purification by column chromatography (eluent system a). MS (ESI, m/z): 418.1[ M+H ]] +
1 H NMR(400MHz,DMSO-d6)δ13.07(s,1H),7.86(d,J＝9.3Hz,2H),7.35–7.22(m,5H),6.87(s,1H),4.50(s,2H),3.97(d,J＝8.1Hz,3H),3.59(t,J＝6.2Hz,2H),3.01(t,J＝7.5Hz,2H),2.74(s,3H),2.16–2.05(m,2H).
Seventh step: synthesis of the Compound 3- (1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propanol (2)
Boron tribromide (47.90 mg, 191.60. Mu. Mol) was slowly added to compound 1 (40 mg, 95.80. Mu. Mol) in DCM (5 mL) at room temperature. After stirring the reaction at room temperature for five minutes, ethyl acetate and water were added to dilute the reaction mixture, the pH was adjusted to 8, and extraction was performed with ethyl acetate. The organic layer was dried and concentrated, and then purified by Prep-HPLC (eluting condition 1) to give compound 2 (3 mg).
MS(ESI，m/z):328.1[M+H] +
1 H NMR(400MHz,DMSO-d6)δ13.09(s,1H),7.84(s,2H),6.85(d,J＝1.8Hz,1H),4.66(s,1H),3.97(s,3H),3.55(d,J＝4.3Hz,2H),2.97(t,J＝7.6Hz,2H),2.74(s,3H),1.97(dd,J＝14.3,6.7Hz,2H).
Example 2:1, 4-dimethyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (3)
1, 4-dimethyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine hydrochloride (3 a)
The first step: 3- (7-bromo-1, 4-dimethyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl-1-ol (2 a)
Compound 1f (320 mg,0.74 mmol) was added to 3mL trifluoroacetic acid and the reaction heated to 80℃with stirring for 16h. The reaction was concentrated, redissolved in 3mL MeOH, ph=9.0 adjusted with 2N sodium hydroxide solution and the reaction stirred for an additional 30min. Flash column chromatography (eluent system a) afforded compound 2a (180 mg). MS (ESI, m/z): 340.0[ M+H ] ] + .
And a second step of: 7-bromo-2- (3-chloropropane) -1, 4-dimethyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (2 b)
Compound 2a (180 mg,0.53 mmol) and DMF (4 mg,0.05 mmol) were added to 4mL thionyl chloride/tetrahydrofuran (1:1) and the reaction stirred at room temperature for 12h. Flash column chromatography (eluent system A) after spin-drying the reaction solvent afforded compound 2b (150 mg). MS (ESI, m/z): 358.0[ M+H ]] + .
And a third step of: 7-bromo-1, 4-dimethyl-2- (3- (4-methylpiperazin-1-yl) propyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (2 c)
Compound 2b (150 mg,0.42 mmol), N-methylpiperazine (9 mg,0.84 mmol), tetrabutylammonium iodide (29 mg,0.08 mmol), DIPEA (109 mg,0.84 mmol) were added to 5mL toluene, N 2 Heating to 100 ℃ under protection to react for 12h. The spin-dried reaction solvent was subjected to flash column chromatography (eluent system A) to give compound 2c (140 mg). MS (ESI, m/z): 422.1[ M+H ]] + .
Fourth step: 1, 4-dimethyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (3)
Compound 2c (140 mg,0.33 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (128 mg,0.66 mmol), pd (dppf) Cl 2 (57 mg,0.07 mmol), sodium carbonate (70 mg,0.66 mmol) were added to a mixed solvent of 5mL DMF and 1mL water, N 2 Heating to 110 ℃ under protection, and stirring to react for 3h. Concentrating under reduced pressure, and separating and purifying by Prep-HPLC (eluting condition 2) to obtain compound 3.MS (ESI, m/z): 410.2[ M+H ]] +
Fifth step: 1, 4-dimethyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine hydrochloride (3 a)
To the collected solution of compound 3 obtained in the fourth step, 0.5mL of 6N hydrochloric acid was added and the mixture was lyophilized to obtain compound 3a (24 mg).
MS(ESI,m/z):410.2[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ13.07(s,1H),11.93–11.82(m,2H),7.93–7.82(m,2H),6.86(s,1H),3.99(s,3H),2.94(t,J＝7.4Hz,2H),2.74(s,3H),2.51–2.24(m,10H),2.07(s,3H),2.05–1.92(m,2H).
Example 3:2- (3- (azetidin-1-yl) propyl) -1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (5)
The first step: 2- (3- (azetidin-1-yl) propyl) -7-bromo-1, 4-dimethyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (3 a)
Compound 2b (50 mg,0.14 mmol), silacyclobutane (48 mg,0.84 mmol), tetrabutylammonium iodide (10 mg,0.03 mmol), TEA (85 mg,0.84 mmol) were added to 3mL toluene, N 2 Heating to 100 ℃ under protection to react for 16h. Spin-drying the reaction solvent gave compound 3a (53 mg), the crude product was used directly in the next step. MS (ESI, m/z)):379.1[M+H] + .
And a second step of: 2- (3- (azetidin-1-yl) propyl) -1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (5)
Compound 3a (53 mg,0.13 mmol), 1H-pyrazole-3-boronic acid pinacol ester (61 mg,0.31 mmol), pd (dppf) Cl 2 (10 mg,0.01 mmol), sodium carbonate (40 mg,0.38 mmol) were added to a mixed solvent of 4mL DMF and 1mL water, N 2 Heating to 100 ℃ under protection, and stirring and reacting for 4h. The reaction solvent was concentrated to dryness under reduced pressure, purified by Prep-HPLC (elution condition 3), and lyophilized to give Compound 5 (16 mg)
MS(ESI,m/z):367.2[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ13.09(s,1H),7.85(d,J＝3.4Hz,2H),6.85(d,J＝2.3Hz,1H),4.00–3.96(m,3H),3.04(m,4H),2.92(t,J＝7.6Hz,2H),2.74(s,3H),2.44(t,J＝6.8Hz,2H),1.98–1.90(m,2H),1.84–1.72(m,2H).
Example 4:3- (4-isopropyl-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propan-1-ol (6)
The first step: 2- (3- (benzyloxy) propyl) -4-isopropyl-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (4 a)
Compound 1d (400 mg,1.13 mmol) and isopropyl magnesium bromide (830 mg,5.65 mmol) were added to 8mL of anhydrous tetrahydrofuran and reacted at 25℃with stirring for 8h. The reaction solution was poured into ice water, extracted with methylene chloride, and the organic phase was concentrated, followed by flash column chromatography (eluent system a) to give compound 4a (310 mg). MS (ESI, m/z): 380.2[ M+H ]] + .
And a second step of: 2- (3- (benzyloxy) propyl) -7-bromo-4-isopropyl-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (4 b)
To a mixed solvent of compound 4a (310 mg,0.82 mmol), N-bromosuccinimide (292 mg,1.64 mmol) and 6mL chloroform/glacial acetic acid (1:1) was added and the reaction was stirred at room temperature for 2h. The reaction solution is reacted Poured into ice water, extracted with dichloromethane and the organic phase concentrated, followed by flash column chromatography (eluent system a) to give compound 4b (290 mg). MS (ESI, m/z): 458.1[ M+H ]] + .
And a third step of: 3- (7-bromo-4-isopropyl-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl-1-ol (4 c)
Compound 4b (290 mg,0.63 mmol) was added to 3mL trifluoroacetic acid and the reaction was heated to 80℃with stirring for 16h. The reaction solution was concentrated to dryness, redissolved in 3mL MeOH, ph=9.0 adjusted with 2N sodium hydroxide solution and the reaction was stirred for an additional 30min. Flash column chromatography (eluent system A) gave compound 4c (150 mg). MS (ESI, m/z): 368.1[ M+H ]] + .
Fourth step: 3- (4-isopropyl-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propan-1-ol (6)
Compound 4c (31 mg,0.085 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (33 mg,0.17 mmol), pd (dppf) Cl 2 (8 mg,0.01 mmol), sodium carbonate (18 mg,0.17 mmol) were added to a mixed solvent of 2.5mL DMF and 0.5mL water, N 2 Heating to 110 ℃ under protection, and stirring to react for 3h. The reaction solvent was concentrated to dryness under reduced pressure, and isolated and purified by Prep-HPLC (elution condition 1) to give Compound 6 (5 mg)
MS(ESI,m/z):356.1[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ13.05(s,1H),7.94(s,1H),7.86(s,1H),6.88(s,1H),4.65(t,J＝5.2Hz,1H),3.99(s,3H),3.88–3.74(m,1H),3.65–3.52(m,2H),2.98(t,J＝7.6Hz,2H),2.03–1.88(m,2H),1.37(d,J＝6.9Hz,6H).
Example 5:4- (3- (1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) -2, 2-dimethylmorpholine (7)
The first step: 4- (3- (7-bromo-1, 4-dimethyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) -2, 2-dimethylmorpholine (5 b)
Compound 2b (40 mg, 111.52. Mu. Mol), compound 5a (12.84 mg, 111.52. Mu. Mol), TEA (11.28 mg, 111.52. Mu. Mol) and tetrabutylammonium iodide (41.19 mg, 111.52. Mu. Mol) were added to toluene (2 mL) at room temperature, and the mixture was heated to 99℃for 16 hours. Ethyl acetate was added for filtration, and the mother liquor was concentrated to dryness and purified by preparative plate separation (eluting system a) to give compound 5b (35 mg). MS (ESI, m/z): 439.1[ M+H ]] +
And a second step of: 4- (3- (1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) -2, 2-dimethylmorpholine (7)
Pd (dppf) Cl at room temperature 2 (2.92 mg, 4.00. Mu. Mol), potassium carbonate (22.09 mg, 160.04. Mu. Mol) were added to a mixed solvent of compound 5b (15.53 mg, 80.02. Mu. Mol), 5c (35 mg, 80.02. Mu. Mol) and dioxane (2 mL)/water (0.5 mL). N (N) 2 Heating to 90 ℃ under protection for reaction for 3hr. Adding ethyl acetate for dilution, filtering and concentrating to obtain a crude product. Separation and purification by Prep-HPLC (elution condition 1) gave Compound 7 (5 mg)
MS(ESI,m/z):425.2[M+H] +
1 H NMR(DMSO-d6，400MHz)δ13.07(s,1H),7.86(d,J＝7.9Hz,2H),6.86(s,1H),3.99(s,3H),3.58–3.52(m,2H),2.97(t,J＝7.5Hz,2H),2.74(s,3H),2.36(t,J＝6.8Hz,2H),2.29(s,2H),2.16(s,2H),2.00–1.93(m,2H),1.14(s,6H).
Example 6:3- (1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-c ] quinolin-2-yl) propan-1-ol (8)
The first step: 2- (3-benzyloxy) propyl-7-bromo-1-methyl-1H-imidazo [4,5-c ] quinoline 5-oxide (6 b)
Compound 6a (607 mg,1.48 mmol) and mCPBA (385 mg,2.23 mmol) were added to 10mL of dichloromethane, the reaction was stirred at room temperature for 4h, quenched with ice water, extracted with dichloromethane and the organic phase concentrated, followed by flash column chromatography (eluent system A) to give compound 6b (494 mg). MS (ESI, m/z): 428.1[ M+H ]] + .
And a second step of: (2-3 (benzyloxy) propyl) -7-bromo-1, 4-dimethyl-1H-imidazo [4,5-c ] quinoline (6 c)
Compound 6b (494 mg,1.16 mmol) was added to 8mL of anhydrous tetrahydrofuran, then methyl magnesium bromide (691 mg,5.81 mmol) was added, the reaction was stirred at 25℃for 1h, quenched with ice water, extracted with dichloromethane and the organic phase concentrated, followed by flash column chromatography (eluent system A) to give compound 6c (140 mg). MS (ESI, m/z): 426.1[ M+H ]] + .
And a third step of: 2- (3- (methoxy) propyl) -1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-c ] quinoline (6 d)
Compound 6c (140 mg,0.33 mmol), (1H-pyrazol-3-yl) boronate (128 mg,0.66 mmol), pd (dppf) Cl 2 (57 mg,0.07 mmol), sodium carbonate (56 mg,0.66 mmol) were added to a mixed solvent of 5mL DMF and 1mL water, N 2 Heating to 110 ℃ under protection, and stirring and reacting for 6h. Filtering with diatomite, concentrating the filtrate under reduced pressure to dry, and subjecting to flash column chromatography (eluent system A) to obtain compound 6d (45 mg) & MS (ESI, m/z): 412.2[ M+H ]] + .
Fourth step: 3- (1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-c ] quinolin-2-yl) propan-1-ol (8)
Compound 6d (45 mg,0.33 mmol) was added to 5mL of trifluoroacetic acid, stirred at 65℃for 10hr, concentrated under reduced pressure, redissolved with methanol, adjusted to pH 8-9 with saturated sodium bicarbonate, filtered, concentrated, and isolated by Prep-HPLC (elution condition 2) to give compound 8 (15 mg).
MS(ESI,m/z):322.2[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ13.09(s,1H),8.50-8.59(m,2H),8.07-8.14(m,1H),7.86-7.87(m,1H),6.95(s,1H),4.66-4.67(m,1H),4.24(s,3H),3.59-3.60(m,2H),3.11-3.13(m,2H),2.91(s,3H),1.95-1.98(m,2H).
Example 7:1, 4-dimethyl-7- (1H-pyrazol-3-yl) -2- (3- (pyrrolidin-1-yl) propyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (9)
The first step: 7-bromo-1, 4-dimethyl-2- (3- (pyrrolidin-1-yl) propyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (7 a)
Compound 2b (30 mg,0.08 mmol), tetrahydropyrrole (34 mg,0.48 mmol), tetrabutylammonium iodide (15 mg,0.04 mmol), TEA (48 mg,0.48 mmol) were added to 5mL toluene, N 2 Heating to 100 ℃ under protection to react for 12h. The spin-dried solvent was subjected to flash column chromatography (eluent system A) to give compound 7a (20 mg). MS (ESI, m/z): 393.1[ M+H ] ] + .
And a second step of: 1, 4-dimethyl-7- (1H-pyrazol-3-yl) -2- (3- (pyrrolidin-1-yl) propyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (9)
Compound 7a (20 mg,0.05 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (20 mg,0.10 mmol), pd (dppf) Cl 2 (8 mg,0.01 mmol), sodium carbonate (70 mg,0.66 mmol) and N are added to a mixed solvent of 2.5mL DMF and 0.5mL water 2 Heating to 110 ℃ under protection, and stirring to react for 3h. Concentrating under reduced pressure, and separating and purifying by Prep-HPLC (eluting condition 2) to obtain compound 9 (6 mg)
MS(ESI,m/z):381.2[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ13.08(s,1H),7.93–7.82(m,2H),6.86(s,1H),3.99(s,3H),2.99(t,J＝7.4Hz,2H),2.80–2.64(m,9H),2.13–1.96(m,2H),1.74(s,4H).
Example 8: 4-isopropyl-1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (10)
The first step: 7-bromo-2- (3-chloropropane) -4-isopropyl-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (8 a)
Compound 4c (150 mg,0.41 mmol) and DMF (3 mg,0.04 mmol) were added to a 4mL thionyl chloride/tetrahydrofuran (1:1) mixture and the reaction stirred at room temperature for 12h. Flash column chromatography (eluent system A) after spin-drying of the solvent afforded compound 8a (125 mg).
MS(ESI,m/z):386.0[M+H] + .
And a second step of: 7-bromo-4-isopropyl-1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (8 b)
Compound 8a (125 mg,0.32 mmol), N-methylpiperazine (20 mg,1.92 mmol), tetrabutylammonium iodide (22 mg,0.06 mmol), TEA (194 mg,1.92 mmol) were added to 5mL toluene, N 2 Heating to 100 ℃ under protection to react for 12h. The spin-dried solvent was subjected to flash column chromatography (eluent system A) to give compound 8b (130 mg). MS (ESI, m/z): 450.1[ M+H ]] + .
And a third step of: 4-isopropyl-1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (10)
Compound 8b (75 mg,0.17 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (66 mg,0.34 mmol), pd (dppf) Cl 2 (16 mg,0.02 mmol), sodium carbonate (36 mg,0.34 mmol) were added to a mixed solvent of 5mL DMF and 1mL water, N 2 Heating to 110 ℃ under protection, and stirring to react for 3h. Concentrating under reduced pressure, and separating and purifying by Prep-HPLC (eluting condition 2) to obtain compound 10 (20 mg)
MS(ESI,m/z):438.2[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ13.05(s,1H),7.93(s,1H),7.86(s,1H),6.88(s,1H),3.98(m,3H),3.86–3.74(m,1H),2.94(t,J＝7.3Hz,2H),2.45–1.86(m,15H),1.36(d,J＝6.9Hz,6H).
Example 9:4- (3- (1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) morpholine (11)
The first step: 4- (3- (7-bromo-1, 4-dimethyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) morpholine (9 a)
Compound 2b (150 mg,0.42 mmol), morpholine (7 mg,0.84 mmol), tetrabutylammonium iodide (29 mg,0.08 m) mol), DIPEA (109 mg,0.84 mmol) was added to 5mL toluene, N 2 Heating to 100 ℃ under protection to react for 12h. Flash column chromatography of the spin-dried solvent (eluent system A) afforded compound 9a (140 mg). MS (ESI, m/z): 409.1[ M+H ]] + .
And a second step of: 4- (3- (1, 4-dimethyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) morpholine (11)
Compound 9a (140 mg,0.34 mmol), (1H-pyrazol-3-yl) boronic acid (77 mg,0.68 mmol), pd (dppf) Cl 2 (57 mg,0.07 mmol), sodium carbonate (58 mg,0.66 mmol) were added to a mixed solvent of 5mL DMF and 1mL water, N 2 Heating to 110 ℃ under protection, and stirring to react for 3h. Concentrating under reduced pressure, separating and purifying by Prep-HPLC (eluting condition 1), and lyophilizing to obtain compound 11 (10 mg)
MS(ESI,m/z):397.1[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ13.09(s,1H),7.88–7.84(m,2H),6.86(s,1H),3.98(s,3H),3.53(m,4H),2.95(t,J＝7.4Hz,2H),2.75(s,3H),2.49–2.31(m,6H),1.99(t,J＝7.2Hz,2H).
Example 10:4- (3- (4-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) morpholine (12)
The first step: 2- (3- (methoxy) propyl) -1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine-5-oxide (10 b)
Compound 10a (657 mg,1.48 mmol) and mCPBA (385 mg,2.23 mmol) were added to 10mL of dichloromethane and the reaction stirred at room temperature for 4h. The reaction solution was poured into ice water, and after extraction with methylene chloride, the organic phase was concentrated, followed by flash column chromatography (eluent system a) to give compound 20b (534 mg). MS (ESI, m/z): 460.2[ M+H ] ] + .
And a second step of: 2- (3- (methoxy) propyl) -1- (4-methoxybenzyl) -4-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (20 c)
Compound 10b (534 mg,1.16 mmol) was added to 8mL dry tetradTo the tetrahydrofuran was then added methyl magnesium bromide (691 mg,5.81 mmol) and the reaction was stirred at 25℃for 8h. The reaction solution was poured into ice water, and after extraction with methylene chloride, the organic phase was concentrated, followed by flash column chromatography (eluent system a) to give compound 10c (388 mg). MS (ESI, m/z): 458.2[ M+H ]] + .
And a third step of: 3- (7-bromo-1- (4-methoxybenzyl) -4-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propan-1-ol (10 d)
Compound 10c (3838 mg,0.85 mmol), N-bromosuccinimide (300 mg,1.70 mmol) was added to 6mL dichloromethane/glacial acetic acid (2:1) and reacted for 2h with stirring at 25 ℃. The reaction solution was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate overnight, filtered, and the organic phase was concentrated, followed by flash column chromatography (eluent system a) to give compound 10d (320 mg). MS (ESI, m/z): 448.0[ M+H ]] + .
Fourth step: 7-bromo-2- (3-chloropropyl) -1- (4-methoxybenzyl) -4-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (10 e)
Compound 10d (237 mg,0.53 mmol) and DMF (4 mg,0.05 mmol) were added to a 4mL thionyl chloride/tetrahydrofuran (1:1) mixture and the reaction stirred at room temperature for 12h. Flash column chromatography (eluent system A) after spin-drying of the solvent afforded compound 10e (195 mg). MS (ESI, m/z): 466.0[ M+H ] ] + .
Fifth step: 4- (3- (7-bromo-1- (4-methoxybenzyl) -4-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) morpholine (10 f)
Compound 10e (195 mg,0.42 mmol), morpholine (73 mg,0.84 mmol), tetrabutylammonium iodide (29 mg,0.08 mmol), DIPEA (109 mg,0.84 mmol) were added to 5mL DMF, N 2 Heating to 100 ℃ under protection to react for 12h. The spin-dried solvent was subjected to flash column chromatography (eluent system A) to give compound 10f (170 mg).
MS(ESI,m/z):517.1[M+H] + .
Sixth step: 4- (3- (1- (4-methoxybenzyl) -4-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) morpholine (10 g)
Compound 10f (170 mg,0.33 mmol), (1H-pyrazol-3-yl) boronate (128 mg,0.66 mmol), pd (dppf) Cl 2 (57 mg,0.07 mmol), sodium carbonate (56 mg,0.66 mmol) were added to a mixed solvent of 5mL DMF and 1mL water, N 2 Heating to 110 ℃ under protection, and stirring and reacting for 6h. Filtering with diatomite, concentrating the filtrate under reduced pressure, and subjecting to flash column chromatography (eluent system A) to obtain 10g (55 mg) of compound (MS (ESI, m/z): 503.2[ M+H)] + .
Seventh step: 4- (3- (4-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) morpholine (12)
10g (55 mg,0.11 mmol) of the compound was added to 5mL of trifluoroacetic acid, stirred at 65℃for 10hr, concentrated under reduced pressure, redissolved in methanol, adjusted to pH 8-9 with saturated sodium bicarbonate, filtered, and the filtrate concentrated and purified by Prep-HPLC (elution condition 1) to give compound 12 (13 mg).
MS(ESI,m/z):383.2[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ13.03(s,2H),7.78-7.83(m,2H),6.81(s,1H),3.53-3.55(m,4H),2.90-2.92(m,2H),2.73(s,3H),2.34-2.35(m,6H),1.95-2.02(m,2H).
Example 11: 4-cyclopropyl-1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (13)
The first step: 2- (3- (benzyloxy) propyl) -4-cyclopropyl-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (11 a)
Compound 1d (200 mg,0.56 mmol) and isopropyl magnesium bromide (410 mg,2.83 mmol) were added to 5mL of anhydrous tetrahydrofuran, and the reaction was stirred at 25℃for 16h. The reaction solution was poured into ice water, extracted with methylene chloride, and the organic phase was concentrated, followed by flash column chromatography (eluent system a) to give compound 11a (150 mg). MS (ESI, m/z): 378.2[ M+H ]] + .
And a second step of: 2- (3- (benzyloxy) propyl) -7-bromo-4-cyclopropyl-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (11 b)
Compound 11a (150 mg,0.40 mmol), N-bromosuccinimide (106 mg,0.60 mmol) were added to 10mL chloroform/glacial acetic acid (1:1) and the reaction stirred at room temperature for 16h.
The reaction solution was poured into ice water, extracted with dichloromethane, and the organic phase was concentrated, followed by flash column chromatography (eluent system a) to give compound 11b (140 mg). MS (ESI, m/z): 456.1[ M+H ]] + .
And a third step of: 3- (7-bromo-4-cyclopropyl-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl-1-ol (11 c)
Compound 11b (100 mg,0.22 mmol) was added to 5mL trifluoroacetic acid and the reaction was heated to 80℃with stirring for 16h. The reaction was concentrated, redissolved in 3mL MeOH, ph=9.0 adjusted with 2N sodium hydroxide solution, and stirred for 30min. Flash column chromatography (eluent system a) gave compound 11c (70 mg). MS (ESI, m/z): 366.0[ M+H ]] + .
Fourth step: 7-bromo-2- (3-chloropropane) -4-cyclopropyl-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (11 d)
Compound 11c (70 mg,0.19 mmol) and 5mL of thionyl chloride were added to 5mL of dichloromethane, and the reaction was stirred at room temperature for 3h. Flash column chromatography (eluent system A) after spin-drying of the solvent afforded compound 11d (55 mg). MS (ESI, m/z): 386.0[ M+H ]] + .
Fifth step: 7-bromo-4-cyclopropyl-1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (11 e)
Compound 11d (50 mg,0.13 mmol), N-methylpiperazine (65 mg,0.65 mmol), 18-crown-6 (14 mg,0.06 mmol), TEA (66 mg,0.65 mmol) were added to 5mL toluene, N 2 Heating to 100 ℃ under protection to react for 16h. The spin-dried solvent was subjected to flash column chromatography (eluent system A) to give compound 11e (30 mg). MS (ESI, m/z): 448.1[ M+H ]] + .
Sixth step: 4-cyclopropyl-1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (13)
Compound 11e (30 mg,0.067 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (26 mg,0.13 mmol), pd (dppf) Cl 2 (11 mg,0.013 mmol), sodium carbonate (21 mg,0.20 mmol) were added to a mixed solvent of 4mL DMF and 1mL water, N 2 Heating to 110 ℃ under protection, and stirring to react for 3h. The solvent was concentrated under reduced pressure, and isolated and purified by Prep-HPLC (eluting condition 1) to give compound 13 (12 mg).
MS(ESI,m/z):436.2[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ13.04(s,1H),7.84(s,2H),6.86(s,1H),3.98(s,3H),2.98–2.90(m,2H),2.86–2.77(m,1H),2.49–2.11(m,10H),2.08(s,3H),2.02–1.93(m,2H),1.22–1.11(m,2H),1.09–0.99(m,2H).
Example 12: 1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1H-imidazo [4,5-c ] quinoline (22)
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The first step: 2- (3- (benzyloxy) propyl) -7-bromo-1-methyl-4- (trifluoromethyl) -1H-imidazo [4,5-c ] quinoline 5-oxygen (12 a)
Compound 6b (1.9 g,4.46 mmol), trifluoromethyl trimethylsilane (1.9 g,13.37 mmol), cesium fluoride (177 mg,2.67 mmol) and three were added to 50mL of anhydrous tetrahydrofuran at 0deg.C and reacted under stirring at 0deg.C for 12h. The reaction solution was poured into ice water, extracted with dichloromethane, and the organic phase was concentrated, followed by flash column chromatography (eluent system a) to give compound 12a (1.1 g). MS (ESI, m/z): 494.1[ M+H ]] + .
And a second step of: 2- (3- (benzyloxy) propyl) -7-bromo-1-methyl-4- (trifluoromethyl) -1H-imidazo [4,5-c ] quinoline (12 b)
Compound 12a (500 mg,1.01 mmol), zinc powder (106 mg,0.60 mmol), ammonium chloride (106 mg,0.60 mmol), 5mL tetrahydrofuran, 5mL water were added to the reaction flask, and the reaction was carried out at room temperature for 3 hours. The reaction solution was poured into ice water, extracted with dichloromethane, and the organic phase was concentrated, followed by flash column chromatography (eluent system a) to give compound 12b (300 mg). MS (ESI, m/z): 478.1[ M+H ] ] + .
And a third step of: 3- (7-bromo-1-methyl-4- (trifluoromethyl) -1H-imidazo [4,5-c ] quinolin-2-yl) propyl-1-ol (12 c)
Compound 12b (300 mg,0.63 mmol) was added to 5mL trifluoroacetic acid and heatedThe reaction was stirred at 80℃for 16h. The reaction was concentrated, redissolved in 3mL MeOH, ph=9.0 adjusted with 2N sodium hydroxide solution, and stirred for 30min. Flash column chromatography (eluent system a) gave compound 12c (215 mg). MS (ESI, m/z): 388.0[ M+H ]] + .
Fourth step: 7-bromo-2- (3-chloropropane) -1-methyl-4- (trifluoromethyl) -1H-imidazo [4,5-c ] quinoline (12 d)
Compound 12c (215 mg,0.55 mmol), N-dimethylformamide (20 mg,0.277 mmol), 3mL of thionyl chloride, 3mL of dichloromethane were added to the reaction flask, and the reaction was carried out at room temperature for 3 hours. Spin-drying the solvent and flash column chromatography (eluent system A) gave compound 12d (180 mg). MS (ESI, m/z): 408.0[ M+H ]] + .
Fifth step: 7-bromo-1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -4- (trifluoromethyl) -1H-imidazo [4,5-c ] quinoline (12 e)
Compound 12d (70 mg,0.17 mmol), N-methylpiperazine (100 mg,0.86 mmol), tetrabutylammonium iodide (13 mg,0.04 mmol), TEA (87 mg,0.86 mmol) were added to 5mL toluene, N 2 Heating to 100 ℃ under protection to react for 16h. Spin-drying the solvent and flash column chromatography (eluent system A) gave compound 12e (60 mg). MS (ESI, m/z): 470.1[ M+H ] ] + .
Sixth step: 1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -4- (trifluoromethyl) -1H-imidazo [4,5-c ] quinoline (22)
Compound 12e (60 mg,0.13 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (50 mg,0.26 mmol), pd (dppf) Cl 2 (31 mg,0.038 mmol), sodium carbonate (41 mg,0.38 mmol) were added to a mixed solvent of 4mL DMF and 1mL water, N 2 Heating to 110 ℃ under protection, and stirring to react for 3h. After the completion of the reaction, the reaction solvent was concentrated to dryness under reduced pressure, and was separated and purified by Prep-HPLC (elution condition 1) to give compound 22 (18 mg)
MS(ESI,m/z):458.2[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ13.58(s,0.25H),13.07(s,0.75H),8.77–8.58(m,2H),8.40–8.31(m,0.75H),8.28–8.18(m,0.25H),7.88(s,0.75H),7.62(s,0.25H),7.09–7.01(m,1H),4.27(s,3H),3.11–3.01(m,2H),2.45–1.88(m,15H).
Biological evaluation
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.
Reagent: 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 in 10mM, preparing a 2 Xtest concentration with RPMI 1640 culture medium containing 2% heat-inactivated FBS, adding 50 μl/well diluent into 96-well plate cells, mixing thoroughly, placing the 96-well plate at 37deg.C and 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 results are shown in Table I.
Experimental example 2 the present inventionTHP1 cells deleted for NLRP3 after PMA induced differentiation by Ming Compound (THP 1- def Agonism of IL-1 beta expression in NLRP3 cells)
The test adopts HTRF (homogeneous time-resolved fluorescence) detection method to test the THP 1-doped-type compound of the invention def The effect of IL-1β levels in NLRP3 cells to assess the specificity of the compound for hllrp 3 inflammatory bodies or hllrp 3 inflammatory body pathway agonism.
The reagent used is as follows: as described in Experimental example 1
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.
3) Preparing a proper amount of DMSO solution of 10mM compound to be tested into 2 Xtest concentration with RPMI 1640 culture medium containing 2% heat-inactivated FBS, adding 50 μl/well diluent into 96-well plate cells, mixing thoroughly, placing the plate at 37deg.C and 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 results are shown in Table I.
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-hTLR7-NF- κb-reporter cells to assess the specificity of the 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- κB-Luciferase Gene cell (humanized TLR7NF- κB-Luciferase reporter cell) (Nanjac Bai)
1) HEK-hTLR7-NF- κB-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 and 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 results are shown in Table I.
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) Will be in logarithmic growth phaseHEK-Blue 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 and 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, 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. The results are shown in Table 1.
TABLE 1 agonistic Activity and specificity of the inventive Compounds for hNLRP3
The results show that the compounds of the invention (e.g. compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 22) have a pronounced agonistic effect on IL-1β expression in THP-1 cells after PMA-induced differentiation, but not on THP1- def IL-1. Beta. Expression in NLRP3 cells had no agonism at the highest compound test concentration (27. Mu.M) and no apparent activation of hTLR7 and hTLR8 at the highest compound test concentration (100. Mu.M). In conclusion, the compounds of the invention (e.g., compounds 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 22) have significant agonistic activity on hNLRP3 and its signaling pathways.
Experimental example 5: hERG assay
By predictors TM hERG Fluorescence Polarization Assay Kit (manufacturer: thermoFisher), the inhibition of hERG potassium ion channel by the test compound (at a concentration of 10. Mu.M) was demonstrated by the kit, and the test results are shown in Table 2.
TABLE 2 inhibition assay results of hERG by Compounds
Numbering of compounds IC 50 (μM)
1 >10
2 >10
6 >10
7 >10
11 >10
The results show that the compounds represented by compounds 1, 2, 6, 7 and 11 of the present application have no significant inhibitory effect on hERG, resulting in a low probability of prolongation of cardiac QT interval.
Experimental example 6: CYP enzyme inhibition assay
CYP450 is the most important enzyme system in drug metabolism, and enzymes involved in metabolism interact with drugs, the most predominant of which are CYP1A2, CYP2D6 and CYP3A4.
In assays for testing inhibition of CYP450 enzymes by fluorescence, P450-Glo is used TM CYP1A2Screening System、CYP2D6Cyan Screening Kit and +.>CYP3A4Red Screening Kit inhibition of CYP1A2, CYP2D6 and CYP3A4 by the compounds is determined respectively according to the kit instructionsActivity. The test results are shown in Table 3.
TABLE 3 test results of inhibition of CYP enzyme by Compounds
The results show that the compounds represented by compounds 2, 3, 6, 9, 10, 11 and 12 have no obvious inhibition effect on CYP1A2, CYP2D6 and CYP3A4 enzymes.
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 (19)

1. A compound having the structure shown in formula X or a pharmaceutically acceptable salt thereof:
wherein:
X 2 is N, R 2 And R is 6 Are not present at the same time;
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;
R 2 selected from H and C 1-8 An alkyl group;
R 3 selected from H, C 1-8 Alkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, NR 33 C(O)R 34 And OH; the 4-10 membered heterocyclyl may be optionally substituted with one or more of the following substituents: c (C) 1-4 An alkyl group;
R 4 selected from C 1-15 Alkyl and C 3-8 Cycloalkyl; the C is 1-15 Alkyl, C 3-8 Cycloalkyl groups 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 and O;
n, p, q are each independently selected from 0, 1 or 2; when n is 2, two L 1 May be the same or different; when p is 2, two L 2 May be the same or different; when q is 2, two L 3 May be the same or different;
selected from->Wherein R is 1 Selected from 5-10 membered heteroaryl;
X 1 is CR (CR) 7 ，R 7 Selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, said C 1-6 Alkyl, C 1-6 Alkoxy, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, 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;
R 33 、R 34 each independently selected from H, C 1-8 An alkyl group;
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.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having one or more of the following characteristics:
(1)R 1 selected from 5-6 membered heteroaryl;
(2)R 2 selected from H and C 1-4 An alkyl group;
(3)R 3 selected from H, C 1-6 Alkyl, 4-8 membered heterocyclyl, C 6-12 Aryl, -NR 33 C(O)R 34 and-OH;
(4)R 4 selected from C 1-4 Alkyl and C 3-6 Cycloalkyl; the C is 1-4 Alkyl or C 3-6 Cycloalkyl groups may be optionally substituted with one or more of the following substituents: halogen, OH, CN, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 An alkoxy group;
(5)R 7 selected from H, halogen, C 1-4 Alkyl, C 3-6 Cycloalkyl, C 2-6 Heteroalkyl, 4-7 membered heterocyclyl, said C 1-4 Alkyl, C 3-6 Cycloalkyl, C 2-6 The heteroalkyl or 4-7 membered heterocyclyl 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;
(6) 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 1-4 Alkylene and O.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein,
X 1 is CR (CR) 7 ，R 7 Selected from H, halogen, C 1-4 Alkyl, C 2-6 Heteroalkyl group, C 1-4 Alkyl or C 2-6 Heteroalkyl groups are optionally substituted with one or more halogens.
4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein,
X 2 is N, and R 2 Selected from H and C 1-4 An alkyl group.
5. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein,
R 33 、R 34 each independently selected from H and C 1-4 An alkyl group.
6. The compound according to any one of claims 1-2 and 4-5, or a pharmaceutically acceptable salt thereof, wherein,
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 1-4 Alkylene and O.
7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein L is- (L) 1 ) n -(L 2 ) p –(L 3 ) q -, wherein L 1 、L 2 And L 3 The same or different and are each independently selected from methylene, ethylene, propylene and O.
8. The compound according to any one of claims 1, 4-5 and 7, or a pharmaceutically acceptable salt thereof, wherein,
R 3 Selected from H, C 1-6 Alkyl, 4-8 membered nitrogen-containing heterocyclyl, 4-8 membered oxygen-containing heterocyclyl, phenyl, -OH and NR 33 C(O)R 34 The method comprises the steps of carrying out a first treatment on the surface of the The 4-8 membered nitrogen containing heterocyclyl, 4-8 membered oxygen containing heterocyclyl may be optionally substituted with one or more of the following substituents: c (C) 1-4 An alkyl group.
9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from H, C 1-4 Alkyl, piperazinyl, morpholinyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, phenyl, OH.
10. The compound according to any one of claim 1 to 2, 4 to 5, 7 and 9, or a pharmaceutically acceptable salt thereof, wherein,
-L-R 3 selected from: methyl group,
11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a structure represented by formula IV:
R 1 、R 2 、R 3 、R 4 、X 1 l is as defined in any one of claims 1 to 10.
12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, having the structure of formula VI:
R 1 、R 2 、R 3 、R 4 、X 1 l is as defined in any one of claims 1 to 10.
13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula VI-a:
R 1 、R 2 、R 3 、R 4 l is as defined in any one of claims 1 to 10.
14. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:
15. a pharmaceutical composition comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, further comprising one or more pharmaceutically acceptable carriers.
16. A pharmaceutical formulation comprising a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15.
17. Use of a compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the prevention, alleviation and/or treatment of a disease associated with NLRP3 inflammatory body activity.
18. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the prevention, alleviation and/or treatment of a cell proliferative disorder.
19. Use of a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the prevention, alleviation and/or treatment of a neoplastic disease.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002016370A1 (en) * 2000-08-22 2002-02-28 Hokuriku Seiyaku Co., Ltd. 1h-imidazopyridine derivatives
WO2017184735A1 (en) * 2016-04-19 2017-10-26 Ifm Therapeutics, Inc Nlrp3 modulators
WO2017184746A1 (en) * 2016-04-19 2017-10-26 Ifm Therapeutics, Inc Nlrp3 modulators

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WO2012143143A1 (en) * 2011-04-21 2012-10-26 Origenis Gmbh Heterocyclic compounds as kinase inhibitors

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2002016370A1 (en) * 2000-08-22 2002-02-28 Hokuriku Seiyaku Co., Ltd. 1h-imidazopyridine derivatives
WO2017184735A1 (en) * 2016-04-19 2017-10-26 Ifm Therapeutics, Inc Nlrp3 modulators
WO2017184746A1 (en) * 2016-04-19 2017-10-26 Ifm Therapeutics, Inc Nlrp3 modulators

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