CN117263952A - Condensed-cyclic compound, preparation method and application thereof - Google Patents

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

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CN117263952A
CN117263952A CN202311228762.2A CN202311228762A CN117263952A CN 117263952 A CN117263952 A CN 117263952A CN 202311228762 A CN202311228762 A CN 202311228762A CN 117263952 A CN117263952 A CN 117263952A
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membered
compound
alkyl
aryl
heterocyclyl
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李桂英
游泽金
何云
冉茂盛
孙晓阳
王利春
王晶翼
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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
    • C07D495/02—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 two hetero rings
    • C07D495/04—Ortho-condensed systems
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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Abstract

The invention discloses a fused ring compound, a preparation method and application thereof, wherein the fused ring compound has a structure shown in a formula I, and the compound can be used as an NLRP3 modulator (such as an agonist) and used for treating diseases (such as tumor diseases) related to NLRP3 inflammatory small body activity.

Description

Condensed-cyclic compound, preparation method and application thereof
The application is a divisional application of application number CN201980018863.2, application date 2019, 05 month and 05 day, and the invention name is condensed-ring compound, a preparation method and application.
Technical Field
The present invention relates to novel 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) for 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 effective anti-tumor immune response is caused; IL-18 can promote NK cell maturation, activate STAT1 downstream signal channels in immune cells, and enhance the killing function of the immune cells. Clinical studies have shown that down-regulation of NLRP3 is significantly inversely related to prognosis in liver cancer patients. Preclinical studies also show that NLRP3 deficient mice have higher colorectal tumor formation rates and worsen colorectal liver metastases. Therefore, NLRP3 plays an important role in tumor microenvironment, and can be used as a key target point of tumor immunotherapy and a tumor prognosis marker.
Despite the potential of NLRP3 agonists for tumor immunotherapy, only one compound is currently under clinical phase I studies, and compounds with NLRP3 agonistic activity are disclosed in 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 relates to a compound of formula I, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound:
wherein:
X 1 and X 2 Each independently selected from CH, CR 8 、NR 7 N, O or S, X 1 And X 2 At least one of them is NR 7 N, O or S, and X 1 、X 2 And (X) 1 And/or X 2 ) The linked carbon atoms together form a five membered heteroaromatic ring; r is R 7 Selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl group, the C 1-6 Alkyl and C 3-8 Cycloalkyl groups may be optionally substituted with one or more of the following groups: halogen, OH, CN, C 1-4 Alkoxy, C 1-4 A hydroxyalkyl group, a hydroxyl group,
X 3 c, N, O or S, and satisfies the following conditions:
(1) When X is 3 When O or S, R 2 And R is 6 Absence of;
(2) When X is 3 When N is present, R 2 And R is 6 Are not present at the same time;
R 1 selected from H, halogen, CN, NO 2 、C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, C (O) OR 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、S(O) 2 R 35 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 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, C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)OR 30 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、OR 37 、SR 37 ；
R 2 Selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-12 Aryl, -C 1-3 alkyl-C 6-12 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroarylA group, a 4-10 membered heterocyclic group, a C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-12 Aryl, -C 1-3 alkyl-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 、C(O)OR 30 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 31 R 32 ；
R 3 Selected from H, OH, halogen, CN, NO 2 、C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C (O) OR 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 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, 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, -C 6-12 aryl-C 1-4 Alkyl, 5-to 10-membered heteroaryl, 9-to 12-membered aryl-heterocyclo, C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、OR 37 、SR 37 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)OR 30 、C(＝NR 38 )NR 31 R 32 、NR 33 C(＝NR 38 )NR 31 R 32 、＝NNR 31 R 32 、P(R 39 ) 2 、P(OR 39 ) 2 、P(O)R 39 R 40 、P(O)OR 39 OR 30 ；
R 4 And R is 5 Each independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, or R 4 、R 5 And R is equal to 4 And R is 5 The attached nitrogen atoms together form a 4-7 membered heterocyclic ring; the C is 1-8 Alkyl, C 1-8 The alkoxy group may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 A hydroxyalkyl group;
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 group、C 1-4 A hydroxyalkyl group;
R 8 selected from halogen, C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, C 2-8 Heteroalkyl, 4-7 membered heterocyclyl, said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, C 2-8 Heteroalkyl, 4-7 membered heterocyclyl may be optionally substituted with one or more of the following substituents: OR (OR) 37 、NR 31 R 32 Halogen, CN;
v is- (V) 1 ) r –(V 2 ) s –(V 3 ) t -, wherein V 1 、V 2 And V 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 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, -O-, -S-, -N (R) 33 )-、-S(O)-、-S(O) 2 -、-C(O)-、-C(R 36a R 36b ) -; the C is 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Alkyloxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 An alkoxy group;
r, s, t are each independently selected from 0 and 1;
l is- (L) 1 ) n -(L 2 ) p –(L 3 ) q -, wherein L 1 、L 2 And L 3 Identical or different and are each independently selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Halogenated alkylene, C 1-8 Alkyloxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkylene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene and 5-to 10-membered heteroaryleneAryl, -O-, -S-, -N (R) 33 )-、-S(O)-、-S(O) 2 -、-C(O)-、-C(R 36a R 36b ) -; the C is 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Halogenated alkylene, C 1-8 Alkyloxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkylene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 An alkoxy group;
n, p, q are each independently selected from 0 or 1;
R 30 、R 37 、R 39 、R 40 each independently selected from hydrogen, C 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 Aryl, -C 1-8 Alkyl- (5-10 membered heteroaryl); the C is 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 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, C (O) O (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 ；
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 37 When present at the same time, each R 37 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;
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, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl; or R is 31 And R is 32 Forms together with the N atom to which each is attached a 3-8 membered heterocyclic group; or R is 33 And R is 34 Together with the C or N atom to which each is attached, form a 4-8 membered heterocyclyl; the C is 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NO 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl;
R 35 selected from C 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 Aryl, -C 1-8 Alkyl- (5-10 membered heteroaryl); the C is 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: OH, CN, NO 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, halogen, C 1-4 HaloalkanesOxy, C (O) O (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;
when a plurality of R 31 When present at the same time, each R 31 May be the same or different;
when a plurality of R 32 When present at the same time, each R 32 May be the same or different;
when a plurality of R 33 When present at the same time, each R 33 May be the same or different;
when a plurality of R 34 When present at the same time, each R 34 May be the same or different;
when a plurality of R 35 When present at the same time, each R 35 May be the same or different;
R 36a and R is 36b Identical or different, each independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-8 Hydroxyalkyl, C 1-8 A haloalkyl group; the C is 1-6 Alkyl, C 1-6 Alkoxy, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl may be optionally substituted with one or more of the following groups: OH, CN, NH 2 、NHCH 3 、N(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the Or R is 36a 、R 36b And R is equal to 36a 、R 36b The attached carbon atoms together form a 3-7 membered cycloalkyl or 4-7 membered heterocyclyl;
when more than one R 38 When present at the same time, each R 38 Identical or different and are each independently selected from H, OH, CN, NO 2 、S(O)R 35 、S(O) 2 R 35 . In some embodiments, R 1 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocycloThe method comprises the steps of carrying out a first treatment on the surface of the The C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl may be 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, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)OR 30 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、OR 37 、SR 37 . In some embodiments, R 1 Selected from C 6-12 Aryl (e.g., phenyl), 5-10 membered heteroaryl, 9-12 membered arylalkylheterocyclyl; the C is 6-12 Aryl (e.g., phenyl), 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl may be 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, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、-NR 33 C(O)R 34 、-NR 31 R 32 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)OR 30 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、OR 37 、SR 37 。
In some embodiments, R 1 Selected from halogen, 5-6 membered heteroaryl and C 6-12 Aryl, optionally, the 5-10 membered heteroaryl and C 6-12 Aryl groups optionally being substituted by one or more C' s 1-4 Alkyl substitution.
In some embodiments, R 1 Selected from fluorine, chlorine, bromine, iodine, 5-6 membered heteroaryl and phenyl, optionally said 5-6 membered heteroaryl and phenyl optionally substituted with one or more methyl, ethyl groups.
In some embodiments, R 1 Selected from the group consisting of fluorine, chlorine, bromine, iodine, 5-6 membered nitrogen containing heteroaryl, 5-6 membered sulfur containing heteroaryl, and phenyl, optionally said 5-6 membered nitrogen containing heteroaryl, 5-6 membered sulfur containing heteroaryl, and phenyl optionally substituted with one or more methyl, ethyl groups.
In some embodiments, the 5-6 membered nitrogen containing monocyclic heteroaryl contains 1, 2, or 3 nitrogen atoms, optionally, also contains 1 sulfur atom or oxygen atom.
In some embodiments, the 5-6 membered sulfur-containing monocyclic heteroaryl contains 1, 2, or 3 sulfur atoms.
In some embodiments, R 1 Selected from halogen (e.g., fluoro, chloro, bromo, iodo), phenyl, imidazolyl, pyridyl, thiazolyl, pyrazinyl, thienyl, pyrazolyl, pyridazinyl, pyrimidinyl; optionally, the phenyl, imidazolyl, pyridyl, thiazolyl, pyrazinyl, thienyl, pyrazolyl, pyridazinyl, pyrimidinyl are substituted with 1, 2, 3 or 4C 1-4 Alkyl (e.g., methyl, ethyl) substitution.
In some embodiments, R 1 Selected from bromine,
In some embodiments, R 2 Selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-12 Aryl, -CH 2 -C 6-12 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-12 Aryl, -CH 2 -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 、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 some embodiments, R 2 Selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl group, the C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl groups may be optionally substituted with one or more of the following substituents: halogen, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO 2 、OR 37 、SR 37 、C(O)R 30 、C(O)NR 31 R 32 、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 some embodiments, R 2 Selected from H, C 1-8 Alkyl, C 3-8 Cycloalkyl and-CH 2 -C 6-12 Aryl, said C 1-8 Alkyl, C 3-8 Cycloalkyl, -CH 2 -C 6-12 Aryl groups may be optionally substituted with one or more of the following substituents: halogen, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 HaloalkanesOxy, 4-7 membered heterocyclyl, CN, NO 2 、OR 37 、SR 37 、C(O)R 30 、C(O)NR 31 R 32 、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 some embodiments, R 2 Selected from H, C 1-8 Alkyl and C 3-8 Cycloalkyl group, the C 1-8 Alkyl, C 3-8 Cycloalkyl groups may be optionally substituted with one or more of the following substituents: halogen, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO 2 、OR 37 、SR 37 、C(O)R 30 、C(O)NR 31 R 32 、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 some embodiments, R 2 Selected from H, C 1-8 Alkyl and p-methoxybenzyl.
In some embodiments, R 2 Selected from H, C 1-8 Alkyl (e.g. C 1-4 Alkyl), preferably R 2 Selected from H, methyl and ethyl.
In some embodiments, R 2 Selected from H and methyl.
In some embodiments, R 3 Selected from C 1-8 Alkyl, 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 (e.g., 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl), 9-12 membered arylheterocyclo, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C (O) OR 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 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, 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, -C 6-12 aryl-C 1-4 Alkyl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (O) OR 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 、P(R 39 ) 2 、P(OR 39 ) 2 、P(O)R 39 R 40 、P(O)OR 39 OR 30 、＝NNR 31 R 32 。
In some embodiments, R 3 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl (e.g., 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl), 9-12 membered arylheterocyclo, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C (O) OR 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 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl optionally substituted with one or more of the following substituents: halogen, CN, NO 2 、C 1-4 Alkyl, C 3-8 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, -C (O) OR 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 、P(R 39 ) 2 、P(OR 39 ) 2 、P(O)R 39 R 40 、P(O)OR 39 OR 30 、＝NNR 31 R 32 。
In some embodiments, R 3 Selected from C 1-8 Alkyl, 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 (e.g., 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl), 9-12 membered arylheterocyclo, 9-12 membered arylheteroaryls, 9-12 membered arylcycloalkyl, OR 37 、SR 37 、C(O)R 30 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 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 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, -C 6-12 aryl-C 1-4 Alkyl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (O) OR 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 、P(R 39 ) 2 、P(OR 39 ) 2 、P(O)R 39 R 40 、P(O)OR 39 OR 30 、＝NNR 31 R 32 。
In some embodiments, R 3 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl (e.g., 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl), 9-12 membered arylheterocyclo, 9-12 membered arylheteroaryls, 9-12 membered arylcycloalkyl, OR 37 、SR 37 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl optionally substituted with one or more of the following substituents: halogen, CN, NO 2 、C 1-4 Alkyl, C 3-8 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, -C (O) OR 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 、P(R 39 ) 2 、P(OR 39 ) 2 、P(O)R 39 R 40 、P(O)OR 39 OR 30 、＝NNR 31 R 32 。
In some embodiments, R 3 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl (e.g., 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl), 9-12 membered arylheterocyclo, 9-12 membered arylheteroaryls, 9-12 membered arylcycloalkyl, OR 37 、SR 37 、C(O)R 30 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl optionally substituted with one or more of the following substituents: halogen, CN, NO 2 、C 1-4 Alkyl, C 3-8 Cycloalkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-4 Hydroxyalkyl, 4-7 membered heterocyclyl, C 6-10 Aryl, -C 6-10 aryl-C 1-4 Alkyl, 5-10 membered heteroaryl, 9-10 membered aryl-heterocyclo, C (O) OR 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 。
In some embodiments, R 3 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl (e.g., 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl), 9-12 membered arylheterocyclo, 9-12 membered arylheteroaryls, 9-12 membered arylcycloalkyl, OR 37 、SR 37 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl optionally substituted with one or more of 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, 4-7 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, 9-10 membered aryl-heterocyclo, C (O) OR 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 。
In some embodiments, R 3 Selected from C (O) R 30 、C 1-4 Alkyl, C 1-4 Alkoxy, benzyl, C 3-6 Cycloalkyl, C 6-12 Aryl (e.g., phenyl), OH, 4-10 membered heterocyclic group (e.g., 4-6 membered nitrogen-containing mono-heterocyclic group, 8-10 membered nitrogen-containing co-heterocyclic group, 6-10 membered nitrogen-containing spiro-heterocyclic group), 9-12 membered aromatic groupA heterocyclo group (e.g., benzo 5-6 membered nitrogen-containing monoheterocyclyl group), a 9-12 membered aryl-and-heteroaryl group (e.g., benzo 5-6 membered nitrogen-containing monoheteroaryl group), a 9-12 membered aryl-and-cycloalkyl group (e.g., benzo C) 5-6 Monocycloalkyl), 5-6 membered mono-heteroaryl (e.g., 5-6 membered nitrogen-containing mono-heteroaryl), 9-10 membered mono-heteroarylcycloalkyl (e.g., 4-6 membered nitrogen-containing mono-heteroaryl and C) 4-6 Monocycloalkyl), said C 1-4 Alkyl, C 6-12 Aryl (e.g., phenyl), 4-10 membered heterocyclyl (e.g., 4-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen-containing heterocyclo, 6-10 membered nitrogen-containing spiroheterocyclyl), 9-12 membered arylalkylheterocyclyl (e.g., benzo 5-6 membered nitrogen-containing monoheterocyclyl), 9-12 membered arylalkylheteroaryl (e.g., benzo 5-6 membered nitrogen-containing monoheteroaryl), 9-12 membered arylalkylcycloalkyl (e.g., benzo C) 5-6 Monocycloalkyl), 5-6 membered mono-heteroaryl (e.g., 5-6 membered nitrogen-containing mono-heteroaryl), 9-10 membered mono-heteroarylcycloalkyl (e.g., 4-6 membered nitrogen-containing mono-heteroaryl and C) 4-6 The monocyclic alkyl group may be optionally substituted with one or more of the following substituents: c (C) 1-4 Alkyl, OH, tolyl, S (O) 2 R 35 . In some embodiments, R 35 Is C 1-4 Alkyl (e.g., methyl).
In some embodiments, R 3 Selected from C 6-12 Aryl (e.g., phenyl), OH, 4-10 membered heterocyclyl (e.g., 5-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen-containing heterocyclyl, 6-10 membered nitrogen-containing spiroheterocyclyl), 9-12 membered aryl-heterocyclyl (e.g., benzo 5-6 membered nitrogen-containing monoheterocyclyl), 9-12 membered aryl-heteroaryl (e.g., benzo 5-6 membered nitrogen-containing monoheteroaryl), 9-12 membered aryl-cycloalkyl (e.g., benzo C) 5-6 Cycloalkyl), 5-6 membered mono-heteroaryl (e.g., 5-6 membered nitrogen containing mono-heteroaryl), 9-10 membered mono-heteroaryl cycloalkyl (e.g., 4-6 membered nitrogen containing mono-heteroaryl and C4-6 monocycloalkyl), said C 6-12 Aryl (e.g., phenyl), 4-10 membered heterocyclyl (e.g., 4-6 membered nitrogen-containing monoheterocyclyl, 8-10 membered nitrogen-containing heterocyclo, 6-10 membered nitrogen-containing spiroheterocyclyl), 9-12 membered arylalkylheterocyclyl (e.g., benzo 5-6 membered nitrogen-containing monoheterocyclyl), 9-12 membered arylalkylheteroaryl (e.g., benzo 5-6 membered nitrogen-containing monoheteroaryl), 9-12 membered arylalkylcycloalkyl (e.g., benzo C) 5-6 Cycloalkyl), 5-6 membered mono-heteroaryl (e.g., 5-6 membered nitrogen containing mono-heteroaryl),9-10 membered mono-heteroaryl and cycloalkyl (e.g., 4-6 membered nitrogen-containing mono-heteroaryl and C 4-6 The monocyclic alkyl group may be optionally substituted with one or more of the following substituents: c (C) 1-4 Alkyl, OH.
In some embodiments, the 4-6 membered nitrogen containing mono-heterocyclyl, 8-10 membered nitrogen containing heterocyclo, 6-10 membered nitrogen containing spiro-heterocyclyl, 5-6 membered nitrogen containing mono-heteroaryl each independently contain 1, 2 or 3 nitrogen atoms, optionally, each independently also contain 1 sulfur atom and/or 1 oxygen atom.
In some embodiments, the 5-6 membered nitrogen containing mono-heterocyclyl, 8-10 membered nitrogen containing heterocyclo, 6-10 membered nitrogen containing spiro-heterocyclyl, 5-6 membered nitrogen containing mono-heteroaryl each independently contain 1, 2 or 3 nitrogen atoms, optionally, each independently also contain 1 sulfur atom and/or 1 oxygen atom.
In some embodiments, R 3 Selected from phenyl, OH, and 4-10 membered heterocyclyl, said 4-10 membered heterocyclyl optionally being substituted with one or more of the following substituents: c1-4 alkyl, OH, S (O) 2 R 35 。
In some embodiments, R 3 Selected from phenyl, OH, and 4-10 membered heterocyclyl, said 4-10 membered heterocyclyl optionally being substituted with one or more of the following substituents: c (C) 1-4 Alkyl, OH.
In some embodiments, R 3 Selected from phenyl, OH, 4-6 membered nitrogen containing mono-heterocyclyl, 8-10 membered nitrogen containing co-heterocyclyl, or 6-10 membered nitrogen containing spiro-heterocyclyl, said 4-6 membered nitrogen containing mono-heterocyclyl, 8-10 membered nitrogen containing co-heterocyclyl, or 6-10 membered nitrogen containing spiro-heterocyclyl being optionally substituted with one or more of the following substituents: c (C) 1-4 Alkyl, OH or S (O) 2 R 35 。
In some embodiments, R 3 Selected from benzo C 5-6 Cycloalkyl, benzo 5-6 membered nitrogen containing mono-heterocyclyl, benzo 5-6 membered nitrogen containing mono-heteroaryl, 5-6 membered nitrogen containing mono-heteroaryl and C 5-6 Monocycloalkyl, said benzo C 5-6 Cycloalkyl, benzo 5-6 membered nitrogen containing mono-heterocyclyl, benzo 5-6 membered nitrogen containing mono-heteroaryl, 5-6 membered nitrogen containing mono-heteroaryl and C 5-6 Monocycloalkyl groups can optionally beSubstituted with one or more of the following substituents: c (C) 1-4 Alkyl or OH.
In some embodiments, R 3 Selected from the group consisting of
In certain embodiments, R 3 Having a cyclic structure, the carbon atoms on the cyclic structure optionally being oxo (oxo).
In some embodiments, R 3 Selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, benzyl substituted by methyl, 5-6 membered nitrogen containing mono-heteroaryl, C 3-8 Cycloalkyl groups.
In some embodiments, R 3 Selected from H, OH, methyl, ethyl, methoxy, t-butoxy, t-butoxycarbonyl, and optionally substituted with one or more (e.g., 2, 3 or 4) C' s 1-4 Alkyl, oxo (oxo), OH or S (O) 2 R 35 Substituted phenyl, benzyl, pyrrolidinyl, morpholinyl, piperazinyl, hexahydro-furo [3,4-c]Pyrrolyl, 5,6,7, 8-tetrahydro-quinolinyl, 1,2,3, 4-tetrahydro-naphthyl, 3, 4-dihydro-2H-benzo [1,4 ]]Oxazinyl, 1H-indazolyl, 1,2,3, 4-tetrahydro-isoquinolinyl, pyridinyl, indanyl, 2-oxa-6-aza-spiro [3.3 ]]Hexyl, azetidinyl, 1H-pyrrolyl, piperidinyl.
In some embodiments, R 3 Selected from H, methyl, ethyl, methoxy, t-butoxy, t-butoxycarbonyl, benzyl, cyclopropyl, phenyl, OH,
In some embodiments, R 3 Selected from phenyl, OH,
In some embodiments, R 4 Is hydrogen.
In some embodiments, R 5 Is hydrogen.
In some embodiments, R 4 And R is 5 Are all hydrogen.
In some embodiments, r, s, t are all 0.
In some 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 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Halogenated alkylene, C 1-8 Alkyloxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkylene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene-C (R) 36a R 36b )-、O、-N(R 33 ) -, -C (O) -; the C is 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Halogenated alkylene, C 1-8 Alkyloxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkylene C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, may be optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 An alkoxy group; n, p, q are each independently selected from 0 or 1.
In some 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 1-4 Alkyleneoxy group, O, NR 33 -CO-, 4-10 membered heterocyclyl (e.g. 6 membered nitrogen containing mono heterocyclyl) and aryl; n, p, q are each independently selected from 0 or 1.
In some embodiments, L is selected from the following groups: - (CH) 2 ) 3 -O-CH 2 -、-(CH 2 ) 3 -、-CH 2 -、-(CH 2 ) 2 C(CH 3 ) 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -O-, 4-10 membered heterocyclyl (e.g. 6 membered nitrogen containing mono heterocyclyl), -O- (CH) 2 ) 3 -O-、-(CH 2 ) 3 - (4-to 10-membered heterocyclic) -C (O) -or- (CH) 2 ) 3 -O-C 6-12 Aryl-.
In some embodiments, L is selected from the group consisting of-CH 2 -NR 33 -CO-、-CH 2 -NR 33 -. In some embodiments, R 33 Is hydrogen or C 1-4 Alkyl (e.g., methyl, ethyl).
In some embodiments, L is selected from the following groups: - (CH) 2 ) 3 -O-CH 2 -、-(CH 2 ) 3 -、-CH 2 -、-(CH 2 ) 2 C(CH 3 ) 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -O-、-O-(CH 2 ) 3 O-、-CH 2 -N(CH 2 CH 3 )-CO-、-CH 2 -N(CH 2 CH 3 )-CH 2 -、-CH 2 -NH-、-NH-(CH 2 ) 3 -、
In some embodiments, -L-R 3 Selected from the following groups: -C 1-4 alkylene-O-C 1-4 alkylene-C 6-12 Aryl, -C 1-4 alkylene-OH, -C 1-4 Alkylene- (6-10 membered nitrogen containing spiroheterocyclyl), -C 1-4 Alkylene- (4-6 membered nitrogen containing mono-heterocyclyl), -C 1-4 Alkylene- (4-6 membered nitrogen containing mono-heterocyclyl and 4-6 membered oxygen containing mono-heterocyclyl), -C 1-4 alkylene-C (CH) 3 ) 2 -OH、-C 1-4 Alkylene O- (5-6 membered nitrogen containing mono heteroaryl and C5-6 monocycloalkyl), -C 1-4 alkylene-O- (benzoC 5-6 monocycloalkyl), -C 1-4 alkylene-O- (benzo 5-6 membered nitrogen containing mono-heterocyclyl), -C 1-4 alkylene-O- (benzo 5-6 membered nitrogen containing mono heteroaryl), -C 1-4 alkylene-O-phenyl- (4-6 membered nitrogen containing mono-heterocyclyl), -C 1-4 alkylene-O-phenyl- (benzo 5-6 membered nitrogen containing mono-heterocyclyl), - (6 membered nitrogen containing mono-heterocyclyl) -C 6-12 Aryl, -C 1-4 Alkylene- (benzo 5-6 membered nitrogen containing mono-heterocyclyl), -C 1-4 alkylene-O- (5-6 membered nitrogen containing mono heteroaryl), -NH-C 1-4 alkylene-OH, -O-C 1-4 alkylene-O-benzyl, - (4-6 membered nitrogen containing mono-heterocyclyl) -C 1-4 Alkoxy, - (4-6 membered nitrogen containing mono-heterocyclyl) -OH, -C 1-3 Alkyl- (4-6 membered nitrogen containing mono-heterocyclyl) -OH, -C 1-4 alkylene-O- (4-6 membered nitrogen containing mono-heterocyclyl), -CH 2 -N(CH 2 CH 3 )-C(O)-O-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-CH 2 -C(O)-O-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-C 1-4 alkylene-C 6-12 Aryl, -CH 2 -N(CH 2 CH 3 ) -C (O) - (4-6 membered nitrogen containing mono-heterocyclyl), -CH 2 -N(CH 2 CH 3 ) -C (O) - (5-6 membered nitrogen containing mono heteroaryl), -CH 2 -NH-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)H、-CH 2 -N(CH 2 CH 3 )-C(O)-C 3-8 Cycloalkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-C 1-4 Alkyl, wherein, 4-6 membered nitrogen-containing mono-heterocyclic group, C 6-12 Aryl, 5-6 membered nitrogen containing mono heteroaryl, 5-6 membered nitrogen containing mono heterocyclyl may be optionally substituted with one or more of the following substituents: c (C) 1-3 Alkyl, oxo, -C (O) H, -S (O) 2 -C 1-3 An alkyl group.
In some embodiments, -L-R 3 Selected from the following groups: - (CH) 2 ) 3 -O-CH 2 -C 6-12 Aryl, - (CH) 2 ) 3 -OH、-CH 2 - (4-6 membered nitrogen-containing mono-heterocyclic group and 4-6 membered oxygen-containing mono-heterocyclic group),-CH 2 - (4-6 membered nitrogen-containing mono-heterocyclic group), - (CH) 2 ) 2 C(CH 3 ) 2 -OH、-(CH 2 ) 2 - (4-6 membered nitrogen-containing mono-heterocyclic group), - (CH) 2 ) 3 -O- (5-6 membered nitrogen containing mono-heteroaryl and C 5-6 Monocycloalkyl) - (CH) 2 ) 3 -O- (benzo C) 5-6 Monocycloalkyl) - (CH) 2 ) 3 -O- (benzo 5-6 membered nitrogen containing mono-heterocyclyl), - (CH) 2 ) 3 -O- (benzo 5-6 membered nitrogen containing mono heteroaryl), - (CH) 2 ) 3 -O-phenyl- (4-6 membered nitrogen containing mono-heterocyclyl), - (6 membered nitrogen containing mono-heterocyclyl) -phenyl, - (CH) 2 ) 3 - (benzo 5-6 membered nitrogen-containing mono-heterocyclic group), - (CH) 2 ) 3 -O- (5-6 membered nitrogen containing mono heteroaryl), - (CH) 2 ) 3 - (6-to 10-membered nitrogen containing spiroheterocyclyl), -NH- (CH) 2 ) 3 -OH、-(CH 2 ) 3 - (4-6 membered nitrogen-containing mono-heterocyclic group), -O- (CH) 2 ) 3 -O-benzyl, - (CH) 2 ) 3 - (4-6 membered nitrogen-containing mono-heterocyclic) -OH, - (CH) 2 ) 2 -OH, -6-membered nitrogen-containing mono-heterocyclyl-methoxy, -6-membered nitrogen-containing mono-heterocyclyl-OH, - (CH) 2 ) 3 -O- (4-6 membered nitrogen containing mono-heterocyclyl), -CH 2 -N(CH 2 CH 3 )-C(O)-O-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-CH 2 -C(O)-O-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-(CH 3 ) 2 -C 6-12 Aryl, -CH 2 -N(CH 2 CH 3 ) -C (O) - (4-6 membered nitrogen containing mono-heterocyclyl), -CH 2 -N(CH 2 CH 3 ) -C (O) - (5-6 membered nitrogen containing mono heteroaryl), -CH 2 -NH-CH 2 CH 3 、-CH 2 -N(CH 2 CH 3 )-C(O)H、-CH 2 -N(CH 2 CH 3 )-C(O)-C 3-8 Cycloalkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-CH 3 -C 6-12 Aryl, -CH 2 -N(CH 2 CH 3 )-CH 2 -C(O)-O-C 1-4 Alkyl, -CH 2 - (4-6 membered nitrogen-containing mono-heterocyclic group))、-(CH 2 ) 3 - (4-6 membered nitrogen-containing mono-heterocyclic group), wherein 4-6 membered nitrogen-containing mono-heterocyclic group, C 6-12 Aryl, 5-6 membered nitrogen containing mono heteroaryl, 5-6 membered nitrogen containing mono heterocyclyl may be optionally substituted with one or more of the following substituents: methyl, ethyl, oxo, -C (O) H, -S (O) 2 -CH 3 。
In some embodiments, -L-R 3 Selected from the following groups:
in some embodiments, X 1 Is CH or NR 7 The method comprises the steps of carrying out a first treatment on the surface of the Preferably X 1 CH.
In some embodiments, X 2 Is S or NR 7 The method comprises the steps of carrying out a first treatment on the surface of the Preferably X 2 S.
In some embodiments, X 1 Is CH, X 2 S.
In some embodiments, X 1 And X 2 Each independently selected from CH, NR 7 N, O or S, X 1 And X 2 At least one of them is NR 7 N, O or S, and X 1 、X 2 And (X) 1 And/or X 2 ) The linked carbon atoms together form a five membered heteroaromatic ring;
R 2 selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-12 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-12 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl may 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 heterocycleRadical, CN, NO 2 、OR 37 、SR 37 、C(O)R 30 、C(O)NR 31 R 32 、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 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R 3 Selected from H, OH, halogen, CN, NO 2 、C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C (O) OR 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 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl optionally substituted with one or more of the following substituents: halogen, CN, NO 2 、C 1-4 Alkyl, C 3-8 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, C (O) OR 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 。
In some embodiments of the invention, the compound has the structure of formula II-1:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 1 、X 3 V and L are as defined above for formula I.
In some embodiments of the invention, the compound has the structure of formula II-2:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 1 、X 3 V and L are as defined above for formula I.
In some embodiments of the invention, the compound has the structure of formula II-3:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、X 1 、X 3 V and L are as defined above for formula I. In some embodiments of the invention, the compound has the structure of formula II-4:
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wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 1 、X 3 V and L are as defined above for formula I.
In some embodiments of the invention, the compound has the structure of formula II-5:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 1 、X 3 V and L are as defined above for formula I.
In some embodiments of the invention, the compound has the structure of formula III-1:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 1 、X 2 V and L are as defined above for formula I.
In some embodiments of the invention, the compound has the structure of formula III-2:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、X 1 、X 2 V and L are as defined above for formula I.
In some embodiments of the invention, the compound has the structure of formula III-3:
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wherein R is 1 、R 3 、R 4 、R 5 、X 1 、X 2 V and L are as defined above for formula I.
In some embodiments of the invention, the compound has the structure of formula IV:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 3 V and L are as defined above for formula II-1.
In some embodiments of the invention, the compound has the structure of formula V:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 L is as defined in formula II-1 above.
In a preferred embodiment, R 1 Selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from Br, C 1-6 Alkyl, C 1-8 Alkoxy group,C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from C 2-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably, R 1 Is a 5-6 membered heteroaryl; the alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, phenyl, aryl, heteroaryl may be optionally substituted with one or more of halogen, NO 2 、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, 4-7 membered heterocyclyl, C 6-10 Aryl, 5-6 membered heteroaryl, C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)OR 30 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、OR 37 、SR 37 。
In a preferred embodiment, R 1 Selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from Br, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from C 2-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably, R 1 Is 5-6 membered heteroaryl and C 6-10 An aryl group; preferably, R 1 Is a 5-6 membered heteroaryl; the alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, phenyl, aryl, heteroaryl may optionally be taken by one or more of the following substituentsF, cl, CN, OH, C generation 1-3 Alkyl, cyclopropyl, C 1-3 Alkoxy, 4-7 membered heterocyclyl.
In a preferred embodiment, R 1 Selected from bromine,/>
In a preferred embodiment, R 1 Is unsubstituted pyrazolyl.
In a preferred embodiment, R 2 Is methyl.
In a preferred embodiment, R 3 Is OH.
In a preferred embodiment, R 6 H.
In a preferred embodiment, L is- (CH) 2 ) 3 -。
In a preferred embodiment, R 1 Selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from Br, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from C 2-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably, R 1 Is 5-6 membered heteroaryl and C 6-10 An aryl group; preferably, R 1 Is a 5-6 membered heteroaryl; the alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, phenyl, aryl, heteroaryl may be optionally substituted with one or more of the following substituents F, cl, CN, OH, C 1-3 Alkyl, cyclopropyl, C 1-3 Alkoxy, 4-7 membered heterocyclyl;
R 2 is methyl, R 3 Is OH, R 6 Is H, -L-R 3 Is- (CH) 2 ) 3 -OH。
In some embodiments of the invention, the compound has the structure of formula V-1:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 As defined by formula V above.
In some embodiments of the invention, the compound has the structure of formula VI:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 L is as defined in formula III-2 above.
In a preferred embodiment, R 1 Selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from Br, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from C 2-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably, R 1 Is a 5-6 membered heteroaryl; the above alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, phenyl, aryl, heteroaryl groups may be optionally substituted with one or more of halogen, NO 2 、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, 4-7 membered heterocyclyl, C 6-10 Aryl, 5-6 membered heteroaryl, C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)OR 30 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、OR 37 、SR 37 。
In a preferred embodiment, R 1 Selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from Br, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from C 2-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably, R 1 Is a 5-6 membered heteroaryl; the above alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, phenyl, aryl, heteroaryl groups may be optionally substituted with one or more of the following substituents F, cl, CN, OH, C 1-3 Alkyl, cyclopropyl, C 1-3 Alkoxy, 4-7 membered heterocyclyl.
In a preferred embodiment, R 1 Selected from bromine,
In a preferred embodiment, R 1 Is unsubstituted pyrazolyl.
In a preferred embodiment, R 2 Selected from H, C 1-4 Alkyl and p-methoxybenzyl.
In a preferred embodiment, R 3 Selected from H, methyl, ethyl, methoxy, t-butoxy, benzyl, cyclopropyl, phenyl, OH,
In a preferred embodiment, R 1 Selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from Br, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from C 2-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably, R 1 Is a 5-6 membered heteroaryl; the above alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, phenyl, aryl, heteroaryl groups may be optionally substituted with one or more of the following substituents F, cl, CN, OH, C 1-3 Alkyl, cyclopropyl, C 1-3 Alkoxy, 4-7 membered heterocyclyl;
R 2 selected from H, C 1-4 Alkyl and p-methoxybenzyl; and is also provided with
-L-R 3 Selected from the following groups:
in some embodiments of the invention, the compound has the structure of formula VI-1:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 As defined in formula VI above.
In some embodiments of the invention, the compound has the structure of formula VII:
wherein R is 1 、R 3 、R 4 、R 5 L is as defined in formula III-3 above.
In a preferred embodiment, R 1 Selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from Br, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from C 2-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably, R 1 Is a 5-6 membered heteroaryl; the above alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, phenyl, aryl, heteroaryl groups may be optionally substituted with one or more of halogen, NO 2 、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, 4-7 membered heterocyclyl, C 6-10 Aryl, 5-6 membered heteroaryl, C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)OR 30 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、OR 37 、SR 37 。
In a preferred embodiment, R 1 Selected from halogen, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from Br, C 1-6 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl; preferably, R 1 Selected from C 2-6 Alkyl, C 3-8 Cycloalkyl, 4-7 membered heterocyclyl, phenyl and 5-6 membered heteroaryl; preferably, R 1 Selected from 5-6 membered heteroaryl, C 6-10 An aryl group; preferably, R 1 Is a 5-6 membered heteroaryl; the above alkyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, phenyl, aryl, heteroaryl groups may be optionally substituted with one or more of the following substituents F, cl, CN, OH, C 1-3 Alkyl, cyclopropyl, C 1-3 Alkoxy, 4-7 membered heterocyclyl.
In a preferred embodiment, R 1 Selected from bromine,
In a preferred embodiment, R 1 Is unsubstituted pyrazolyl.
In a preferred embodiment, -L-R 3 Is- (CH) 2 ) 3 -OH。
In a preferred embodiment, R 1 Selected from bromine,-L-R 3 Is- (CH) 2 ) 3 -OH。
In some embodiments of the invention, the compound has the structure of formula VII-1:
wherein R is 1 、R 3 、R 4 、R 5 As defined for formula VII above.
In an embodiment of the invention, the compounds of the invention are selected from, but are not limited to:
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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 neoplastic disease).
In some embodiments, the pharmaceutical composition is for preventing, alleviating and/or treating a cell proliferative disorder (e.g., cancer).
Optionally, the pharmaceutical composition of the invention further comprises one or more second therapeutic agents. In certain embodiments, the second therapeutic agent comprises other drugs for treating neoplastic diseases and the like.
In another aspect, the invention provides a pharmaceutical formulation comprising a compound as described above, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above.
In another aspect, the invention provides the use of a compound as described above, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, for the manufacture of a medicament for the prevention, alleviation and/or treatment of a disease associated with NLRP3 inflammatory platelet activity (e.g., a neoplastic disease).
In another aspect, the invention provides the use of a compound as described above, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, for preparing a formulation for modulating (e.g., increasing) the activity of an NLRP3 inflammatory body.
In some embodiments, the formulation is administered to a subject (e.g., mammal; e.g., bovine, equine, ovine, porcine, canine, feline, rodent, primate; e.g., human) in vivo to increase NLRP3 inflammatory body activity in cells in the subject; alternatively, the formulation is administered to cells in vitro (e.g., a cell line or a cell from a subject) to increase the activity of NLRP3 inflammatory bodies in the cells.
In another aspect, the invention provides a method of modulating (e.g., increasing) the activity of an NLRP3 inflammatory small body in a cell, comprising administering to the cell an effective amount of a compound as described above, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, or a pharmaceutical formulation as described above.
In another aspect, the invention provides a kit for modulating (e.g., increasing) the activity of an NLRP3 inflammatory oligomer, the kit comprising a compound, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition as described above, or a formulation as described above.
In another aspect, the invention provides a method of treating a disease associated with NLRP3 inflammatory small body activity (e.g., a neoplastic disease), comprising administering to a subject in need thereof a therapeutically, palliatively 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, glioma or sarcoma.
In some embodiments, the compounds of the invention are full agonists; in some embodiments, the compounds of the invention are partial agonists (partial agonists).
Definition of terms
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
The term "agonist" refers to a compound that binds to and activates a receptor to elicit a downstream biological effect (biological effect or response), including full agonists (full agonist) and partial agonists (partial agonist). Full agonists activate 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 1-8 Alkyl "," C 1-6 Alkyl "and" C 1-4 Alkyl "refers to straight or branched chain alkyl groups having 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, and hydroxyButyl, -CH (OH) CH 3 Etc.
The term "alkenyl" refers to 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 toEtc., the alkynylene group may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.
The term "alkoxy" means a group, preferably C, having an oxygen atom inserted at any reasonable position of an alkyl group (as defined above) 1 -C 6 Alkoxy or C 1 -C 3 An alkoxy group. C (C) 1 -C 6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, -CH 2 -OCH 3 Etc., the alkoxy groups may optionally beSubstituted 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, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, where 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. Wherein the point of attachment of the heteroalkyl group to the other group is on a carbon in the heteroalkyl backbone chain. 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 cyclic group including, but not limited to, monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl) and bicyclic alkyl, including spiro, fused (fused) or bridged ring systems (i.e., spiro alkyl, fused (fused) alkyl and bridged cycloalkyl groups, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, and the like). In the present invention, cycloalkyl groups may be optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally oxo (i.e. forms c=o).
The term "C 3-8 Cycloalkyl "means cycloalkyl having 3 to 8 ring-forming carbon atoms, which may be a monocyclic alkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), or a bicyclic alkyl group, such as C 3-8 Spirocycloalkyl, C 3-8 Bridged cycloalkyl, C 3-8 Condensed ring alkyl.
The term "aryl" refers to an all-carbon monocyclic or fused-polycyclic aromatic group having a conjugated pi-electron system. As used herein, the term "C 6-12 Aryl "means aryl having 6 to 12 carbon atoms, e.g. C 6 -C 10 Aryl is, for example, 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 "aryl-cycloalkyl" refers to a fused ring group formed by aryl and cycloalkyl groups (e.g., monocycloalkyl) sharing two adjacent atoms with each other, wherein the point of attachment to the other groups may be on the aryl or on the cycloalkyl. The term "9-12 membered arylcycloalkyl" refers to arylcycloalkyl groups containing a total of 9-12 ring atoms, such as phenylfused cyclopentyl, phenylfused cyclohexyl, for example,
the term "heterocyclyl" refers to a mono-or polycyclic (e.g., parallel, spiro, or bridged) group having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms, and one or more (e.g., 1, 2, 3, or 4) heteroatoms, including but not limited to oxygen, nitrogen, sulfur, optionally oxo (oxo) (e.g., to form c= O, S (=o) or S (=o) 2 )。
The term "3-14 membered heterocyclic group" means a heterocyclic group containing 3-14 ring atoms, including but not limited to 4-10 membered heterocyclic group, 4-7 membered heterocyclic group, 5-6 membered heterocyclic group, 4-7 membered nitrogen containing heterocyclic group, 4-7 membered oxygen containing heterocyclic group, 4-7 membered sulfur containing heterocyclic group, 5-6 membered nitrogen containing heterocyclic group, 5-6 membered oxygen containing heterocyclic group, 5-6 membered sulfur containing heterocyclic group, said "nitrogen containing heterocyclic group", "oxygen containing heterocyclic group", "sulfur containing heterocyclic group" optionally further containing one or more other hetero atoms selected from oxygen, nitrogen, sulfur. Examples of 3-14 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, and the like.
In the present invention, the heterocyclic group may form a fused ring structure with the heterocyclic group or the cycloalkyl group, and the point of attachment of the fused ring structure to the other group may be on any one of the heterocyclic group or the cycloalkyl group, and thus the heterocyclic group of the present invention also includes, but is not limited to, a heterocyclic-heterocyclic group, a heterocyclic-cycloalkyl group, a mono-heterocyclic-mono-heterocyclic group, a mono-heterocyclic-mono-cycloalkyl group, a 3-7-membered (mono) heterocyclic-3-7-membered (mono) heterocyclic group, a 3-7-membered (mono) heterocyclic-mono-cycloalkyl group, a 3-7-membered (mono) heterocyclic-C 4-6 (mono) cycloalkyl examples include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopentylazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl,
In the present invention, the heterocyclic group also includes bridged heterocyclic groups and spiro heterocyclic groups.
The term "bridged heterocyclic ring" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two saturated rings sharing two ring atoms that are not directly attached, including but not limited to 7-10 membered bridged heterocyclic rings, 8-10 membered bridged heterocyclic rings, 7-10 membered nitrogen-containing bridged heterocyclic rings, 7-10 membered oxygen-containing bridged heterocyclic rings, 7-10 membered sulfur-containing bridged heterocyclic rings, and the like, e.g. Etc. The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", "sulfur-containing bridged heterocycle" optionally also contains one or more further heteroatoms selected from oxygen, nitrogen, sulfur.
The term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two or more saturated rings sharing one ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, and the like, e.g. The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", "sulfur-containing spiroheterocycle" optionally also contains one or more further heteroatoms selected from oxygen, nitrogen, sulfur. The term "6-10 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 a total of 9-12 ring members, including but not limited to 9-10 membered arylalkylheterocyclylBenzoheterocyclyl, for example phenylo 5-8 membered heterocyclyl, for example phenylo 5-6 membered heterocyclyl, for example benzo5-6 membered mono-heterocyclyl, benzo5-6 membered nitrogen containing mono-heterocyclyl, benzo5-6 membered oxygen containing mono-heterocyclyl, benzo5-6 membered sulfur containing heterocyclyl, said "nitrogen containing heterocyclyl", "oxygen containing heterocyclyl", "sulfur containing heterocyclyl" optionally also containing one or more further 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 (e.g., 1, 2, 3, or 4) identical or different heteroatoms, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, e.g., 5, 6, 7, 8, 9, or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur. The carbon and heteroatoms on the heteroaryl group are optionally oxo (oxo) (e.g., to form c= O, S (=o) or S (=o) 2 )。
The term "5-10 membered heteroaryl" means heteroaryl containing 5 to 10 ring atoms, including 5-6 membered heteroaryl, 5-6 membered mono-heteroaryl, 5-10 membered nitrogen containing heteroaryl, 5-10 membered oxygen containing heteroaryl, 5-10 membered sulfur containing heteroaryl, 5-6 membered nitrogen containing heteroaryl, 5-6 membered oxygen containing heteroaryl, 5-6 membered sulfur containing heteroaryl, 5-6 membered nitrogen containing mono-heteroaryl, 5-6 membered oxygen containing mono-heteroaryl, 5-6 membered sulfur containing mono-heteroaryl. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl", "sulfur-containing heteroaryl", "nitrogen-containing mono-heteroaryl", "oxygen-containing mono-heteroaryl", "sulfur-containing mono-heteroaryl" optionally also contains one or more other heteroatoms selected from oxygen, nitrogen, sulfur. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and 5-10 membered bicyclic groups containing these groups.
In the present invention, heteroaryl (e.g., mono-heteroaryl) may share a fused ring structure formed by two adjacent atoms with aryl (e.g., monocyclic aryl, e.g., phenyl), heterocyclyl (e.g., mono-heterocyclyl), cycloalkyl (e.g., monocyclic alkyl), or another heteroaryl (e.g., another mono-heteroaryl), the points of attachment of which may be on any heteroaryl ring or on other rings, including, but not limited to, (mono) heteroarylo (mono) heteroaryl, (mono) heteroarylo (monocyclic) aryl, (mono) heteroarylo (mono) heterocyclyl, and (mono) heteroarylo (mono) cycloalkyl, e.g., 5-6 membered (mono) heteroarylo 5-6 membered (mono) heteroaryl, 5-6 membered (mono) heteroarylo phenyl, 5-6 membered (mono) heteroaryl and 5-6 membered (mono) heterocyclyl, or 5-6 membered (mono) heteroarylo C 4-6 (mono) cycloalkyl (e.g., 5-6 membered heteroaryl-cyclobutyl, 5-6 membered heteroaryl-cyclopentyl, 5-6 membered heteroaryl-cyclohexyl), examples of which include, but are not limited to, indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, Etc.
The term "aryl-heteroaryl" refers to a fused ring group formed by an aryl group (e.g., a monocyclic aryl group, such as phenyl) and a heteroaryl group (e.g., a mono-heteroaryl group, such as a 5-6 membered mono-heteroaryl group), the point of attachment to the other group being either on the aromatic ring or on the heteroaromatic ring. The "aryl-heteroaryl" includes, but is not limited to, monocyclic aryl-mono-heteroaryl. The term "9-12 membered arylalkylheteroaryl" refers to arylalkylheteroaryl groups containing a total of 9-12 ring members, such as benzo 5-6 membered nitrogen containing mono-heteroaryl.
The term "heteroarylcycloalkyl" refers to heteroaryl (e.g., mono-heteroaryl, e.g., 5-6 memberedMonoheteroaryl) and cycloalkyl groups (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 be optionally replaced with independently selected substituents, alone and/or together. 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 optionally replaced with an independently selected 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 invention, whichThe same as the compounds 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 invention 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 invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, 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 invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, 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 invention or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the invention" 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. 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.
For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.
The term "effective dose" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the condition being treated.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg, for example about 0.01 to about 10 mg/kg/day per kg body weight per day (single or divided administration). For a 70kg human, this amounts to about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.
The compounds of the present invention may be present in the pharmaceutical composition in an amount or amount of about 0.01mg to about 1000mg.
As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of, or preventing, a disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
The compounds of the invention may be present in the form of solvates (preferably hydrates) wherein the compounds of the invention comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds obtained by a method of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, and which, when administered into or onto the body, are converted to the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", vol.14, ACS Symposium Series (T. Higuchi and V. Stilla) and "Bioreversible Carriers in Drug Design," Pergamon Press,1987 (E. B. Roche eds., american Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g. "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".
The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, in Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, plenum Press,1973; and those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
The bonds in the structural formulae indicated herein by wavy lines "-" are intended to represent either cis or trans isomers, or a mixture of cis and trans isomers in any ratio.
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 of Compound V-1
R 2 Is hydrogen, R 4 、R 5 、R 6 R is as defined in formula V above 1 As defined in formula V above, but does not contain NO 2 ；
R 3 Selected from C 1-8 Alkyl, 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, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C (O) OR 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、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 、S(O)R 35 、S(O) 2 R 35 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 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, 5-10 membered heteroaryl, 9-12 membered arylRadical and heterocyclic radical, C (O) OR 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 ；
The first step: bromination of the compound V-1-1 yields the compound V-1-2.
In some embodiments, br can be used 2 Or brominating reaction with a brominating reagent such as NBS. In some embodiments, the reaction is carried out in a solvent, which may be DMF, CH 3 COOH、THF、CH 3 CN or DCM, etc. In some embodiments, the reaction temperature is from-20 ℃ to 180 ℃.
And a second step of: the compound V-1-2 is nitrified to generate the compound V-1-3.
In some embodiments, the nitration reaction may be performed using a nitrating agent such as concentrated nitric acid, fuming nitric acid, tetrabutylammonium nitrate, or the like. In some embodiments, the reaction is carried out in a solvent, and a solvent that may be used is acetic acid, propionic acid, butyric acid, or the like. In some embodiments, the reaction temperature is 100 ℃ to 150 ℃.
And a third step of: compound V-1-3 is chlorinated to compound V-1-4.
In some embodiments, POCl may be used 3 、PCl 3 Or PCl 5 And (3) carrying out chlorination reaction by using a chlorinating agent. In some embodiments, the reaction is carried out in a solvent, which may be DCM or DCE, etc. In some embodiments, the reaction is performed in the absence of a solvent. In some embodiments, the reaction temperature is rt to 110 ℃.
Fourth step: the compound V-1-4 is subjected to iodine substitution reaction to generate the compound V-1-5.
In some embodiments, iodine substitution reactions may be performed using iodine reagents such as KI or NaI. In some embodiments, the reaction is carried out in a solvent, which may be THF, CH 3 CN or 1, 4-dioxane, etc. In some embodiments, the reaction temperature is rt to 100 ℃.
Fifth step: compound V-1-5 is reduced to compound V-1-6.
In some embodiments, sodium dithionite, snCl may be used 2 And reducing agents such as Fe or Zn. In some embodiments, the reaction is carried out in a solvent, which may be MeOH, etOH, THF or 1, 4-dioxane, or the like. In some embodiments, the reaction temperature is from 0 ℃ to 110 ℃.
Sixth step: the compound V-1-6 is subjected to amino protection reaction under alkaline conditions to generate the compound V-1-7.
In some embodiments, a (Boc) may be used 2 And (3) reacting with an amino protecting reagent such as O. In some embodiments, one may use t BuOK、 t BuONa、 t BuOLi、NaH、NaOH、KOH、Cs 2 CO 3 、K 2 CO 3 Or Na (or) 2 CO 3 And (3) reacting with alkali. In some 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 some embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
Seventh step: compounds V-1-7 and R 3 Alkynes are subjected to coupling reactions (e.g. Sonogashira reactions) under the action of catalysts, copper sulfites and bases to form compounds V-1-8.
In some embodiments, the catalyst that can be used is Pd (PPh 3 ) 4 Or Pd (PPh) 3 )Cl 2 Etc. in some embodiments, the base that can be used is Et 2 NH, TEA, DIPEA, etc. In some embodiments, the reaction is carried out in a solvent, which may be 1, 4-dioxane, CH 3 CN or EA, etc. In some embodiments, the cuprous salt that can be used is CuI, cuBr, cuCl, or the like. In some embodiments, the reaction temperature is from-20℃to100℃。
Eighth step: the compound V-1-8 is closed to form a product V-1-9 under alkaline conditions.
In some embodiments, DBU, TEA, DIPEA, t BuOK、 t BuONa、 t BuOLi、NaOH、Cs 2 CO 3 、K 3 PO 4 Or Na (or) 2 CO 3 And (3) reacting with alkali. In some embodiments, the reaction is carried out in a solvent, which may be THF/H 2 O、MeOH/H 2 O、EtOH/H 2 O、DMF/H 2 O、DMSO/H 2 O、CH 3 CN/H 2 O or 1, 4-dioxane/H 2 O, etc. In some embodiments, the reaction temperature is rt to 120 ℃.
Ninth step: compounds V-1-9 are reacted with R under basic conditions 6 -Cl (or R) 6 -Br) to form the compound V-1-10.
In some embodiments, one may use t BuOK、 t BuONa、 t BuOLi、NaH、NaOH、KOH、Cs 2 CO 3 、K 2 CO 3 Or Na (or) 2 CO 3 And (3) reacting with alkali. In some embodiments, the reaction is carried out in a solvent, which may be THF, DCM, CH 3 CN, 1, 4-dioxane or DMF, etc. In some embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
Tenth step: the compound V-1-10 is oxidized to produce the compound V-1-11.
In some embodiments, m-CPBA, H can be used 2 O 2 Or CH (CH) 3 And an oxidizing agent such as COOOH. In some embodiments, the reaction is carried out in a solvent, which may be DCM, DCE, CHCl 3 Or DMF, etc. In some embodiments, the reaction temperature is from 0 ℃ to 100 ℃.
Eleventh step: compound V-1-11 reacts with NHR under the action of alkali and catalyst 4 R 5 The reaction is carried out to generate the compound V-1-12.
In some embodiments, a catalyst that may be used is TsCl or the like. In some embodiments, the base that can be used is TEA or DIPEA, or the like. In some embodimentsIn which the reaction is carried out in a solvent of DCM or CHCl 3 Or DCE, etc. In some embodiments, the reaction temperature is from 0 ℃ to 100 ℃.
Twelfth step: compounds V-1-12 and R 1 Y is subjected to a coupling reaction, a substitution reaction or V-1-12 is subjected to a reduction reaction to produce the compound V-1.
When Y is boric acid or a borate, R 1 When the halogen is other than H, CN or halogen, V-1-12 and R 1 And (3) carrying out Suzuki coupling reaction on the Y to generate a compound V-1. In some embodiments, pd (PPh 3 ) 4 Or Pd (dppf) Cl 2 And (3) carrying out reaction by using the catalyst. In some embodiments, cs may be used 2 CO 3 、K 3 PO 4 、Na 2 CO 3 、AcOK、NaHCO 3 Or K 2 CO 3 And (3) reacting with alkali. In some embodiments, the reaction is carried out in a solvent, which is 1, 4-dioxane/H 2 O、DMF/H 2 O、DMSO/H 2 O、CH 3 CN/H 2 O or toluene/H 2 O, etc. In some embodiments, the reaction temperature is from 60 ℃ to 160 ℃.
When Y is H, R 1 When the halogen is other than H, CN or halogen, V-1-12 and R 1 Y is coupled to the compound V-1 (e.g., ullmann reaction, heck reaction, buchwald-Hartwig reaction, or Sonogashira reaction). In some embodiments, cu may be used 2 O、CuI、CuBr、CuCl、PdCl 2 、Pd(OAc) 2 、Pd(PPh 3 ) 4 Or Pd (PPh) 3 ) 2 Cl 2 And (3) carrying out reaction by using the catalyst. In some embodiments, cs may be used 2 CO 3 、K 3 PO 4 、Na 2 CO 3 、AcOK、TEA、NaHCO 3 Or K 2 CO 3 And (3) reacting with alkali. In some embodiments, N '-dimethylethylenediamine, N' -dimethyl-1, 2-cyclohexanediamine, PPh may be used 3 Or XPhos, etc. In some embodiments, the reaction is carried out in a solvent, 1, 4-dioxane, EA, DMF, DMSO, CH 3 CN, toluene, etc. In some embodiments, the reaction temperature is from 60 ℃ to 160 ℃.
When Y is ZnCl 2 、ZnBr 2 Or ZnI 2 ，R 1 When the halogen is other than H, CN or halogen, V-1-12 and R 1 Y is subjected to the Negishi reaction to give the compound V-1. In some embodiments, pd (OAc) may be used 2 Or Pd (PPh) 3 ) 4 And (3) carrying out reaction by using the catalyst. In some embodiments, PPh may be used 3 The ligand reacts. In some embodiments, the reaction is carried out in a solvent, which may be DMF or NMP, or the like. In some embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
When Y is an organotin compound (e.g., sn (n-Bu) 3 )，R 1 When the halogen is other than H, CN or halogen, V-1-12 and R 1 Y is Stille reacted to give the compound V-1. In some embodiments, pdCl may be used 2 、Pd(OAc) 2 Or Pd (PPh) 3 ) 2 Cl 2 And (3) carrying out reaction by using the catalyst. In some embodiments, PPh may be used 3 The ligand reacts. In some embodiments, the reaction is carried out in a solvent, which may be 1, 4-dioxane, THF or CH 3 CN, etc. In some embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
When Y is Na or K, R 1 In the case of CN, V-1-12 and R 1 -Y is substituted to form compound V-1. In some embodiments, the reaction is carried out in a solvent, which may be 1, 4-dioxane, THF or CH 3 CN, etc. In some embodiments, the reaction temperature is from 0 ℃ to 110 ℃.
V-1-12 is reduced to produce the compound V-1 (R) 1 H).
In some embodiments, pd or Pd (OH) may be used 2 And reacting with a reducing agent. In some embodiments, the reaction is carried out in a solvent, which may be 1, 4-dioxane, THF, methanol, ethanol or toluene, and the like. In some embodiments, the reaction temperature is from 0 ℃ to 100 ℃.
Synthesis of Compound VI-1
R 1 、R 2 、R 3 、R 4 、R 5 As defined in formula VI above, but R 1 Does not contain NO 2 ，R 3 Does not contain halogen, OH, CN and NO 2 。
The first step: the compound VI-1-1 is subjected to nitration reaction to generate a compound VI-1-2.
In some embodiments, the reaction may be carried out using a nitrating agent such as concentrated nitric acid, fuming nitric acid, tetrabutylammonium nitrate, or the like. In some embodiments, the reaction is carried out in a solvent, and a solvent that may be used is acetic acid, propionic acid, butyric acid, or the like. In some embodiments, the reaction temperature is 100 ℃ to 150 ℃.
And a second step of: compounds VI-1-2 are chlorinated to compounds VI-1-3.
In some embodiments, POCl may be used 3 、PCl 3 Or PCl 5 And (3) reacting with a chlorinating agent. In some embodiments, the reaction is carried out in a solvent, which may be DCM or DCE, etc. In some embodiments, the reaction is performed in the absence of a solvent. In some embodiments, the reaction temperature is rt to 110 ℃.
And a third step of: compounds VI-1-3 and R 2 -NH 2 The compound VI-1-4 is produced by substitution reaction under the action of alkali.
In some embodiments, the base that can be used is TEA or DIPEA, or the like. In some embodiments, the reaction is carried out in a solvent, which may be NMP or DMF, or the like. In some embodiments, the reaction temperature is from 0 ℃ to 180 ℃.
Fourth step: compounds VI-1-4 are reduced to compounds VI-1-5.
In some embodiments, sodium dithionite, snCl may be used 2 And a reducing agent such as Fe, zn or Pd/C. In some embodiments, the reaction is carried out in a solvent, which may be MeOH, etOH, THF or 1, 4-dioxane, or the like. In some embodiments, the reaction temperature is rt to 110 ℃.
Fifth step: compounds VI-1-5 and R 3 The compound VI-1-6 is produced by condensation reaction of-COOH under alkaline condition, or VI-1-5 is directly reacted with R under the action of alkali 3 COCl reaction to form VI-1-6.
In some embodiments, the reaction may be performed using condensing agents such as HATU, DCC/NHS, EDCI/HOBt, or HBTU. In some embodiments, the base that can be used is TEA or DIPEA, or the like. In some 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 some embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
Sixth step: compound VI-1-6 is cyclized under basic conditions and then brominated to form compound VI-1-7.
In some embodiments, the ring closure reaction may be performed with a base such as TEA or DIPEA. In some embodiments, the ring closure reaction is carried out in a solvent, meOH, etOH, THF, CH being a solvent that can be used 3 CN or 1, 4-dioxane, etc. In some embodiments, the reaction temperature is from 60 ℃ to 100 ℃. In some embodiments, bromination reactions can be performed using brominating agents such as bromine, NBS, dibromohydantoin, and the like. In some embodiments, the bromination reaction is carried out in a solvent, which may be acetic acid, 1, 4-dioxane, DMF, EA, and the like. In some embodiments, the reaction temperature is from-20 ℃ to 100 ℃.
Seventh step: compounds VI-1-7 are oxidized to compounds VI-1-8.
In some embodiments, m-CPBA, H can be used 2 O 2 Or CH (CH) 3 And an oxidizing agent such as COOOH. In some embodiments, the reaction is carried out in a solvent, which may be DCM, DCE, CHCl 3 Or DMF, etc. In some embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
Eighth step: compounds VI-1-8 with NHR under the action of base and activator 4 R 5 The reaction is carried out to obtain the compound VI-1-9.
In some embodiments, activators that may be used are TsCl, ts 2 O, etc., and in some embodiments, the base that may be used is TEA or DIPEA, etc. In some embodiments, the reaction is carried out in a solvent,solvents which can be used are DCM, CHCl 3 Or DCE, etc. In some embodiments, the reaction temperature is from 0 ℃ to 80 ℃.
Ninth step: compounds VI-1-9 and R 1 Y may be subjected to a coupling reaction, a substitution reaction or VI-1-9 to give the compound VI-1. In some embodiments, the reaction conditions are the same as those of the twelfth step of V-1.
Synthesis of Compound VI
R 1 、R 2 、R 3 、R 4 、R 5 As defined in formula VI above, but R 1 Does not contain NO 2 ；
L is as defined for formula VI above, but n+p+q is not 0, and-LR 3 With carbon atoms being attached to-COOH or-COCl.
The first step: compounds VI-1-5 and R 3 L-COOH can be condensed under alkaline conditions to give the compound VI-2-1, or VI-1-5 can be reacted directly with R under the action of alkali 3 The reaction of L-COCl to VI-2-1, in some embodiments, the reaction conditions are as described in the fifth step of the synthesis of VI-1.
And a second step of: compound VI-2-1 is cyclized under alkaline conditions to form compound VI-2-2.
In some embodiments, the reaction may be performed using a base such as NaOH, KOH, TEA or DIPEA. In some embodiments, the reaction is carried out in a solvent, which may be MeOH, etOH, THF, CH 3 CN or 1, 4-dioxane, etc. In some embodiments, the reaction temperature is from 60 ℃ to 100 ℃.
And a third step of: the compound VI-2-2 is subjected to bromination reaction to generate a compound VI-2-3.
In some embodiments, the reaction may be performed using brominating agents such as bromine, NBS, and dibromohydantoin. In some embodiments, the reaction is carried out in a solvent, which may be acetic acid, 1, 4-dioxane, DMF, EA, and the like. In some embodiments, the reaction temperature is from-20 ℃ to 100 ℃.
Fourth step: compound VI-2-3 is oxidized to form compound VI-2-4, and in some embodiments, the reaction conditions are as described in the seventh step of VI-1.
Fifth step: compound VI-2-4 reacts with NHR under the action of alkali and activator 4 R 5 The reaction yields compound VI-2-5, and in some embodiments, the reaction conditions are as described in the eighth step of the synthesis of VI-1.
Sixth step: compounds VI-2-5 and R 1 Y is subjected to a coupling reaction, a substitution reaction or a reduction reaction of VI-2-5 to give the compound VI, in some embodiments, the reaction conditions are as described in the twelfth step of the synthesis of V-1.
Synthesis of Compound VI-2
R 1 、R 2 、R 4 、R 5 As defined in formula VI above, but R 1 Does not contain NO 2 ；
R 3a Is NR (NR) 31 R 32 、OR 37 Or SR (S.J) 37 ；
L is as defined for formula VI above, but n+p+q is not 0, and-LR 3a With carbon atoms attached to the imidazolyl group of VI-2;
R 31 、R 32 、R 37 as defined in the foregoing general formula I;
R 41 OPG and PG Bn, DMB, PMB, me, et, pr; w is selected from chlorine, bromine and iodine.
The first step: the compound VI-2-5a is deprotected under acidic conditions to form compound VI-2-6.
In some embodiments, BBr may be used 3 、AlCl 3 、FeCl 3 Or CF (CF) 3 COOH and other acids. In some embodiments, the reaction is carried out in a solvent, which may be THF, DCM, DCE, CH 3 CN or 1, 4-dioxane, etc. In some embodiments, the reaction temperature is from 20 ℃ to 160 ℃.
And a second step of: the compound VI-2-6 is subjected to halogenation reaction to generate the compound VI-2-7. In some embodiments, thionyl chloride, PCl may be used 3 、PCl 5 、PBr 3 Or HI and other halogenating agents. In some embodiments, the reaction is carried out in a solvent, which may be THF, DCM, DCE or 1, 4-dioxane, or the like. In some embodiments, the reaction temperature is from 20 ℃ to 120 ℃.
And a third step of: compounds VI-2-7 in the presence of a base and a phase transfer catalyst and HR 3a The reaction is carried out to generate the compound VI-2-8.
In some embodiments, the phase transfer catalyst that may be used is 18-crown-6-ether, benzyltriethylammonium chloride (TEBA), tetrabutylammonium iodide, tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium bisulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, or tetradecyltrimethylammonium chloride, and the like, and in some embodiments, the base that may be used is NaOH, KOH, TEA, DIPEA, or the like. In some embodiments, the reaction is carried out in a solvent, toluene, DCM, CHCl may be used as solvents 3 Or DCE, etc. In some embodiments, the reaction temperature is from 20 ℃ to 160 ℃.
Fourth step: compound VI-2 is prepared from compound VI-2-8 and R 1 Y is produced by coupling, substitution or by reduction of the compound VI-2-8. In some embodiments, the reaction conditions are as described in the twelfth step of the synthesis of V-1.
Synthesis of Compound VI-3
R 1 、R 2 、R 4 、R 5 As defined in formula VI above, but R 1 Does not contain NO 2 ；
L is as defined for formula VI above, but n+p+q is not 0, and both ends of L are each independently substituted with an imidazolyl group and R in VI-3-1 42 Are connected;
R 33 and R is 34 As defined in the foregoing general formula I;
R 42 is that
The first step: the compound VI-3-1 is subjected to Boc removal under acidic conditions to produce the compound VI-3-2.
In some embodiments, HCl, sulfuric acid, or CF may be used 3 COOH and other acids. In some embodiments, the reaction is carried out in a solvent, which may be methanol, ethanol, THF, DCM, DCE, CH 3 CN or 1, 4-dioxane, etc. In some embodiments, the reaction temperature is from 0 ℃ to 100 ℃.
And a second step of: compounds VI-3-2 and R 34 COOH can be subjected to condensation reaction under alkaline condition to form a compound VI-3, or VI-3-2 can be directly reacted with R under the action of alkali 34 COCl reaction to VI-3, in some embodiments, the reaction conditions are as described in the fifth step of the synthesis of VI-1.
Synthesis of Compound VI-4
R 1 、R 2 、R 3 、R 4 、R 5 As defined in formula VI above, but R 1 Does not contain NO 2 ；
L 1a is-NR 33b -, -O-or-S-;
L 2a selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Halogenated alkylene, C 1-8 Alkyloxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkylene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene-O-, -S-, -NR 33 -、-S(O)-、-S(O) 2 -、-C(O)-、-C(R 36a R 36b ) -; the C is 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Halogenated alkylene, C 1-8 Alkyloxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkylene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, 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;
p is 0 or 1; and when p is 0, R 3 By C atoms and L 1a Are connected; when p is 1, L 2a By C atoms and L 1a Are connected;
R 33b selected from H, C 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl; the C is 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NO 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl; the C is 6-12 Aryl groups 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 A haloalkyl group.
The first step: the compound VI-1-5 reacts with a ring-closing reagent to produce the compound VI-4-1.
In some embodiments, the ring-closing reagent that may be used is carbon disulfide, thiophotoGas, etc., in some embodiments, the reaction is carried out in the presence of a base, which may be TEA or DIPEA, etc. In some 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 some embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
And a second step of: compound VI-4-1 is combined with W-R under alkaline conditions 43 The reaction is carried out to generate the compound VI-4-2.
W-R 43 Is an alkylating agent, wherein W is chlorine, bromine, iodine, R 43 Selected from C 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl; the C is 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl may be optionally substituted with one or more of the following substituents: OH, CN, halogen, NO 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl.
In some embodiments, the reaction may be performed using a base such as NaOH, KOH, potassium carbonate, cesium carbonate, TEA, or DIPEA. In some embodiments, the reaction is carried out in a solvent, and the solvent that may be used is acetone, meOH, etOH, THF, CH 3 CN or 1, 4-dioxane, etc. In some embodiments, the reaction temperature is from 0 ℃ to 100 ℃.
And a third step of: compound VI-4-2 is oxidized to form compound VI-4-3.
In some embodiments, potassium permanganate, m-CPBA, H can be used 2 O 2 Or CH (CH) 3 And an oxidizing agent such as COOOH. In some embodiments, the reaction is carried out in a solvent selected from acetic acid, water, DCM, DCE, CHCl 3 Or DMF, etc. In some embodiments, the reaction temperature is from 0 ℃ to 160 ℃.
Fourth step: compound VI-4-3 in baseUnder the action of H-L 1a -(L 2a ) p -R 3 The reaction is carried out to generate the compound VI-4-4.
In some embodiments, the base that can be used is TEA or DIPEA, or the like. In some embodiments, the reaction is carried out in a solvent, which may be DMSO, NMP, CHCl 3 Or DMF, etc. In some embodiments, the reaction temperature is from 20 ℃ to 160 ℃.
Fifth step: the compound VI-4-4 is subjected to bromination reaction to generate a compound VI-4-5. In some embodiments, the reaction conditions are as described in the third step of VI-2 synthesis.
Sixth step: compound VI-4-5 is oxidized to form compound VI-4-6. In some embodiments, the reaction conditions are as described in the seventh step of VI-1.
Seventh step: compound VI-4-6 reacts with NHR under the action of alkali and activating agent 4 R 5 The reaction is carried out to generate the compound VI-4-7. In some embodiments, the reaction conditions are as described in the eighth step of VI-1 synthesis.
Eighth step: compound VI-4 is prepared from compound VI-4-7 and R 1 Y is produced by coupling, substitution or by reduction of the compound VI-4-7. In some embodiments, the reaction conditions are as described in the twelfth step of V-1 synthesis.
Synthesis of Compound VII-1
R 3 、R 4 、R 5 As defined for formula VII above; r is R 1 As defined in formula V above, but does not contain NO 2 ，R 3 Does not contain halogen, OH, CN and NO 2 。
The first step: the compound VII-1-1 is nitrified to generate the compound VII-1-2. In some embodiments, the reaction conditions are as described in the first step of VI-1 synthesis.
And a second step of: the compound VII-1-2 is reduced to produce the compound VII-1-3. In some embodiments, the reaction conditions are as described in the fourth step of VI-1 synthesis.
And a third step of: compounds VII-1-3 and R 3 The compound VII-1-4 is produced by condensation reaction of-COOH under alkaline condition, or VII-1-3 is directly reacted with R under the action of alkali 3 COCl reaction to form VII-1-4. In some embodiments, the reaction conditions are as described in the fifth step of VI-1 synthesis.
Fourth step: the compound VII-1-4 is cyclized to form the compound VII-1-5.
In some embodiments, POCl may be used 3 、PCl 5 、PCl 3 Reagents such as TEA or DIPEA. In some embodiments, the reaction is carried out in a solvent, which may be MeOH, etOH, THF, CH 3 CN, 1, 4-dioxane, DCM, DCE or CHCl 3 Etc. In some embodiments, the reaction temperature is rt to 100 ℃.
Fifth step: compound VII-1-5 is oxidized to produce compound VII-1-6.
In some embodiments, the oxidizing agent and solvent that may be used are as described in the seventh step of VI-1 synthesis. In some embodiments, the reaction temperature is from 0 ℃ to 100 ℃.
Sixth step: compound VII-1-6 and NHR under the action of alkali and activator 4 R 5 The reaction is carried out to obtain the compound VII-1-7. In some embodiments, the reaction conditions are as described in the eighth step of VI-1 synthesis.
Seventh step: compounds VII-1-7 and R 1 The compound VII-1 is produced by coupling reaction, substitution reaction or VII-1-7 reduction reaction. In some embodiments, the reaction conditions are the same as the twelfth step of the V-1 synthesis.
Advantageous effects
The compound has obvious agonist activity to NLRP3 and a signal path thereof, has no obvious toxic or side effect, and can be used for treating abnormal cell proliferation diseases (such as cancers).
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) and/or Mass Spectrometry (MS).
The reaction was monitored by silica gel Thin Layer Chromatography (TLC) or LC-MS.
Thin layer chromatography using silica gel GF 254 as stationary phase.
1 H NMR spectrum: bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD MHz).
LC/MS mass spectrometer: aglient 1260 Infinicity/Aglient 6120 Quadrapol.
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 C18 OBD (19 mm. Times.150 mm. Times.5.0 μm); column temperature: 25 ℃.
Elution conditions:
condition 1:10% -90% acetonitrile, 90% -10% ammonium formate aqueous solution (0.05%), 0-16min; flow rate: 24mL/min;
Condition 2:10% -46% acetonitrile, 90% -54% ammonium bicarbonate water solution (0.05%), 0-7.2min; flow rate: 24mL/min;
condition 3:10% -90% acetonitrile, 90% -10% formic acid water solution (0.05%), 0-16min; flow rate: 28mL/min;
condition 4:10% -90% acetonitrile, 90% -10% ammonium bicarbonate aqueous solution (0.05%), 0-16min; flow rate: 24mL/min;
condition 5:30% -90% acetonitrile, 70% -10% ammonium bicarbonate aqueous solution (0.05%), 0-16min; flow rate: 24mL/min;
condition 6:10% -90% acetonitrile, 90% -10% trifluoroacetic acid aqueous solution (0.05%), 0-16min; flow rate: 28mL/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: petroleum ether and ethyl acetate; the volume ratio of the solvent 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 this application are available from Acros Organics, aldrich Chemical Company or tertbe chemistry, among others.
Intermediate preparation: 7-bromo-2- (3-chloropropyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (1 k)
The first step: 6-nitrothieno [3,2-b ] pyridin-7-ol (1 b)
Compound 1a (200 g,1.33 mol) was added to 2L of propionic acid, heated to 100 ℃, and then 100mL of fuming nitric acid was slowly added dropwise to the above solution. After the dripping is finished, the temperature is raised to 130 ℃ and the stirring reaction is continued for 6 hours. Cooled to room temperature, 2L of petroleum ether was added to the reaction mixture, the mixture was filtered, the cake was rinsed with 1.5L of petroleum ether, and the cake was dried to give Compound 1b (210 g). MS (ESI, m/z): 197.1[ M+H ]] + .
And a second step of: 7-chloro-6-nitrothieno [3,2-b ] pyridine (1 c)
Compound 1b (210 g,1.06 mol), N-dimethylformamide (78 g,1.06 mol) and phosphorus oxychloride ((210 g,2.12 mol) were added to 1.5L of methylene chloride, the reaction was stirred at 40 ℃ for 2 hours, the reaction solution was concentrated to dryness under reduced pressure, a small amount of ethyl acetate was added to dissolve, the reaction was quenched with ice water, and the organic phase was concentrated after extraction with ethyl acetate to give compound 1c (200 g). MS (ESI, m/z):215.1[M+H] + .
and a third step of: n-methyl-6-nitrothieno [3,2-b ] pyridin-7-amine (1 d)
Compound 1c (70 g,325.6 mmol), methylamine hydrochloride (43.9 g,651.2 mmol) and N, N-diisopropylethylamine (84.2 g,651.2 mmol) were added sequentially to 350mL of N-methylpyrrolidone, and the reaction was stirred at 20℃for 16h. The reaction mixture was poured into 1.5L of ice-water, and the precipitated solid was collected by filtration and dried to give compound 1d (60 g). MS (ESI, m/z): 210.1[ M+H ] ] + .
Fourth step: n-methylthiophene [3,2-b ] pyridine-6, 7-diamine (1 e)
Compound 1d (45 g,0.21 mol), 10% Pd/C (4.5 g,10% m/m) was added to 700mL of methanol, and after three hydrogen substitutions, the reaction was stirred at 25℃for 16h. The reaction mixture was filtered to remove palladium on carbon, and the filtrate was concentrated to dryness under reduced pressure to give compound 1e (36 g). MS (ESI, m/z): 180.0[ M+H ]] + .
Fifth step: 4- (benzyloxy) -N- (7- (methylamino) thieno [3,2-b ] pyridin-6-yl) butanamide (1 f)
Compound 1e (36 g,0.2 mol), 4-benzyloxybutyric acid (40.7 g,0.21 mol), HATU (79.8 g,0.21 mmol), N-diisopropylethylamine (54.3 g,0.42 mol) was added to 75mL of N, N-dimethylformamide and the reaction stirred at 25℃for 2h. The reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phase was concentrated to give compound 1f (60 g). MS (ESI, m/z): 356.1[ M+H ]] + .
Sixth step: 2- (3- (benzyloxy) propyl) -7-bromo-1, 4-dimethyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (1 g)
Compound 1f (60 g,168.5 mmol) and sodium hydroxide (13.5 g,337 mmol) were added to 300mL of ethanol, and the mixture was heated to 80℃and reacted under stirring for 3h. The reaction mixture was adjusted to ph=7 with 6.0N hydrochloric acid, concentrated to dryness, redissolved in ethyl acetate, insoluble matter filtered off, and the filtrate was concentrated under reduced pressure to give 1g (50 g) of compound. MS (ESI, m/z): 338.2[ M+H ] ] + .
Seventh step: 2- (3- (benzyloxy) propyl) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (1H)
1g (50 g,0.15 mol) of the compound, N-bromosuccinimide (53.1 g,0.30 mol) was added to 400mL DMF/glacial acetic acidIn a mixed solvent of=1:1, the temperature is raised to 40 ℃ and the reaction is stirred for 4h. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with aqueous potassium carbonate to neutrality, and the organic phase was concentrated, and was slurried with a small amount of ethyl acetate and filtered to give compound 1h (40 g). MS (ESI, m/z): 416.0[ M+H ]] + .
Eighth step: 2- (3- (benzyloxy) propyl) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-5-oxy (1 i)
The compound 1h (40 g,96.2 mmol) and mCPBA (28.1 g,163.5 mmol) were added to 400mL of dichloromethane and the reaction stirred at room temperature for 4h. The reaction mixture was poured into 200mL of saturated aqueous sodium bicarbonate, and the organic phase was washed with water until no peroxide remained as detected by potassium iodide starch paper, and concentrated to dryness under reduced pressure to give compound 1i (32 g). MS (ESI, m/z): 432.2[ M+H ]] + .
Ninth step: 2- (3- (benzyloxy) propyl) -7-bromo-1-methyl-1H-imidazo [4,5-d thieno [3,2-b ] pyridin-4-amine (1)
Compound 1i (32 g,74.2 mmol) was added to 700mL of dichloromethane and 180mL of aqueous ammonia, and a solution of p-toluenesulfonyl chloride (21.1 g,111.3 mmol) in dichloromethane was added dropwise to the reaction mixture, followed by stirring at 25℃for 3 hours. The reaction mixture was poured into ice water, extracted with dichloromethane, washed with 3N hydrochloric acid to neutrality, and the organic phase was concentrated, followed by flash column chromatography (eluent system a) to give compound 1 (22 g). MS (ESI, m/z): 431.2[ M+H ] ] + .
Tenth step: 3- (4-amino-7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl-1-ol (1 j)
Compound 1 (22 g,51.0 mmol) and boron tribromide (19.1 g,76.5 mmol) were added to 220mL of dichloromethane and the reaction stirred at 25℃for 1h. The reaction mixture was quenched by adding 60mL of methanol, washed with saturated sodium bicarbonate, the organic phase was concentrated to dryness, slurried with a small amount of dichloromethane and filtered to give compound 1j (12 g). MS (ESI, m/z): 341.0[ M+H ]] + .
Eleventh step: 7-bromo-2- (3-chloropropyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (1 k)
Compound 1j (12 g,35.2 mmol) was taken up in thionyl chloride(25 mL,352 mmol) was added to 120mL of dichloromethane and the reaction was stirred at 40℃for 16h. The reaction mixture was concentrated, poured into 200mL of saturated sodium bicarbonate, filtered, the resulting solid was dissolved in a mixed solvent of DCM/meoh=1:1, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 1k (9 g). MS (ESI, m/z): 359.0[ M+H ]] + .
Intermediate preparation: 7-bromo-2- (3-chloropropyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (9 i)
The first step: n- (4-methoxybenzyl) -6-nitrothieno [3,2-b ] pyridin-7-amine (9 a)
Compound 1c (50 g,232.5 mmol), 4-methoxybenzylamine (38.2 g,279.0 mmol) and N, N-diisopropylethylamine (39.1 g,302.2 mmol) were added sequentially to 250mL of N-methylpyrrolidone and reacted for 16h with stirring at 20 ℃. The reaction mixture was poured into 1.5L of ice-water, and the precipitated solid was collected by filtration and dried to give compound 9a (62 g). MS (ESI, m/z): 315.1[ M+H ]] + .
And a second step of: 7- (4-methoxybenzyl) thieno [3,2-b ] pyridine-6, 7-diamine (9 b)
Compound 9a (20 g,63.5 mmol), ammonium chloride (13.5 g,254 mmol) and zinc powder (16.5 g,254 mmol) were added to 200mL of methanol and the reaction stirred at 25℃for 16h. To the reaction mixture was added 100mL of dichloromethane, filtered, and the resulting solid was refluxed with 200mL of tetrahydrofuran, filtered under heat, and the two filtrates were combined and concentrated to dryness under reduced pressure to give compound 9b (14 g). MS (ESI, m/z): 286.1[ M+H ]] + .
And a third step of: 4- (benzyloxy) -N- (7- ((4-methoxybenzyl) amine) thieno [3,2-b ] pyridin-6-yl) butanamide (9 c)
Compound 9b (14 g,48.9 mmol), 4-benzyloxybutyric acid (40.7 g,53.8 mmol), HATU (79.8 g,51.3 mmol) and N, N-diisopropylethylamine (54.3 g,102.7 mmol) were added to 70mL of N, N-dimethylformamide and the reaction stirred at 25℃for 2h. The reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phase was concentrated to give compound 9c (16 g). MS (ESI, m/z): 462.2[ M+H ] ] + .
Fourth step: 2- (3- (benzyloxy) propyl) -1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (9 d)
Compound 9c (15 g,32.5 mmol) and sodium hydroxide (13.5 g,81.3 mmol) were added to 150mL of ethanol, and the temperature was raised to 80℃and the reaction was stirred for 3h. The reaction mixture was adjusted to ph=7.0 with 6.0N hydrochloric acid, concentrated to dryness, redissolved in ethyl acetate, insoluble matter filtered off, and the filtrate concentrated under reduced pressure to give compound 9d (12 g). MS (ESI, m/z): 444.2[ M+H ]] + .
Fifth step: 2- (3- (benzyloxy) propyl) -7-bromo-1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (9 e)
Compound 9d (12 g,27.1 mmol) and N-bromosuccinimide (53.1 g,54.2 mmol) were added to a mixture of 120mL DMF/glacial acetic acid=1:1, and the mixture was heated to 40℃and stirred for 4h. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with aqueous potassium carbonate to neutrality, and the organic phase was concentrated, followed by beating with a small amount of ethyl acetate and filtration to give compound 9e (10 g). MS (ESI, m/z): 522.1[ M+H ]] + .
Sixth step: 2- (3- (benzyloxy) propyl) -7-bromo-1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine-5-oxide (9 f)
Compound 9e (10 g,19.2 mmol) and mCPBA (5.64 g,32.6 mmol) were added to 200mL of dichloromethane and the reaction stirred at room temperature for 4h. The reaction mixture was poured into 200mL of saturated aqueous sodium bicarbonate, and the organic phase was washed with water until no peroxide remained as detected by potassium iodide starch paper, and concentrated under reduced pressure to give compound 9f (10 g). MS (ESI, m/z): 538.1[ M+H ] ] + .
Seventh step: 2- (3- (benzyloxy) propyl) -7-bromo-1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (9 g)
Compound 9f (10 g,18.6 mmol) was added to 200mL of dichloromethane and 50mL of aqueous ammonia, and a solution of p-toluenesulfonyl chloride (5.3 g,27.9 mmol) in dichloromethane was added dropwise to the reaction mixture, followed by stirring at 25℃for 3 hours. The reaction mixture was poured into ice water, extracted with dichloromethane and washed neutral with 3N hydrochloric acid, the organic phase was concentrated, and subjected to flash column chromatography (elutionThe preparation A) gave 9g (5 g) of compound. MS (ESI, m/z): 537.2[ M+H ]] + .
Eighth step: 3- (4-amine-7-bromo-1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl-1-ol (9H)
9g (5 g,9.3 mmol) of the compound and boron tribromide (3.5 g,14.0 mmol) were added to 50mL of methylene chloride, and the mixture was stirred at 25℃for 1 hour. The reaction mixture was quenched by adding 20mL of methanol, washed with saturated sodium bicarbonate, and the organic phase was concentrated to dryness and slurried with a small amount of dichloromethane and filtered to give compound 9h (3.4 g). MS (ESI, m/z): 447.1[ M+H ]] + .
Ninth step: 7-bromo-2- (3-chloropropyl) -1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (9 i)
Compound 9h (3.4 g,7.6 mmol) and thionyl chloride (5.5 mL,76 mmol) were added to 40mL of dichloromethane and the reaction was stirred at 40℃for 16h. The reaction mixture was concentrated to dryness, poured into 100mL of saturated sodium bicarbonate, filtered, and the resulting solid was redissolved in a mixed solvent of DCM/meoh=1:1, dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness to give compound 9i (2.5 g). MS (ESI, m/z): 465.0[ M+H ]] + .
Example 1:2- (3- (benzyloxy) propyl) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (1)
The first step: 6-nitrothieno [3,2-b ] pyridin-7-ol (1 b)
Compound 1a (thieno [3,2-b ] pyridin-7-ol) (6.0 g,39.685 mmol) was dissolved in 200mL of propionic acid, heated to 110℃and concentrated nitric acid (5.5 g,59.360 mmol) was added dropwise to the reaction mixture, after 10 minutes, and the mixture was heated to 130℃for 1.5 hours. The reaction mixture was cooled to room temperature, filtered under reduced pressure, and the filter cake was washed with 50mL of methanol and 50mL of water in this order, and dried under vacuum to give compound 1b (4.6 g). The crude product was used directly in the next reaction.
1 H NMR(DMSO-d 6 ,400MHz)δ13.42(s,1H),9.12(s,1H),8.17(d,J＝5.2,1H),7.36(d,J＝5.2,1H).
And a second step of: 7-chloro-6-nitrothieno [3,2-b ] pyridine (1 c)
Compound 1b (6-nitrothieno [3, 2-b)]Pyridin-7-ol) (2.1 g,10.700 mmol) was added to 60mL of 1, 2-dichloroethane, phosphorus oxychloride (10.5 g,68.480 mmol) was added dropwise, the temperature was raised to 85℃under nitrogen protection for reaction, and after the reaction was completed, the solvent and phosphorus oxychloride were concentrated and removed. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, extracted with dichloromethane, the organic phases combined, and dried over anhydrous Na 2 SO 4 Drying, filtration and concentration under reduced pressure gave compound 1c (2.1 g). The crude product was used directly in the next reaction.
1 H NMR(CDCl 3 ,400MHz)δ9.21(s,1H),8.05(d,J＝5.6,1H),7.63(d,J＝5.6,1H).
And a third step of: n-methyl-6-nitrothieno [3,2-b ] pyridin-7-amine (1 d)
Compound 1c (7-chloro-6-nitrothieno [3, 2-b)]Pyridine) (1.5 g,6.990 mmol) was dissolved in 60mL NMP and MeNH was added dropwise at room temperature 2 After adding DIPEA (2.0 g,15.480 mmol) and stirring at room temperature for 4h, 120mL of water was added dropwise to the reaction mixture, stirring at room temperature was continued for 1h, and suction filtration under reduced pressure was performed to give compound 1d (1.3 g). The crude product was used directly in the next reaction.
1 H NMR(CDCl 3 ,400MHz)δ9.20(s,1H),7.82(d,J＝5.2,1H),7.45(d,J＝5.2,1H),3.54(d,J＝5.2,3H).
Fourth step: n (N) 7 -methylthiophene [3,2-b ]]Pyridine-6, 7-diamine (1 e)
Compound 1d (N-methyl-6-nitrothieno [3,2-b ] pyridin-7-amine) (1.5 g,7.170 mmol) was added to 50mL of methanol, air was replaced with nitrogen, 10% Pd/C (1.08 g, 8.89mmol) was added, nitrogen was replaced with a balloon containing hydrogen, and the reaction was carried out overnight at 25 ℃. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to give compound 1e (1.2 g).
1 H NMR(DMSO-d 6 ,400MHz)δ7.87(s,1H),7.55(d,J＝5.2,1H),7.17(d,J＝5.2,1H),5.45(q,J＝5.2,1H),4.56(s,2H),3.23(d,J＝5.6,3H).
Fifth step: 4- (benzyloxy) -N- (7- (methylamino) thieno [3,2-b ] pyridin-6-yl) butanamide (1 f)
Compound 1e (N) 7 -methylthiophene [3,2-b ]]Pyridine-6, 7-diamine) (3.9 g,26.260 mmol), 4-phenoxybutyric acid (5.1 g,21.760 mmol) was dissolved in 60mL DMF, HATU (11.0 g,28.930 mmol), DIPEA (6.0 g,46.430 mmol) was added at room temperature and reacted under nitrogen for 5h at 25 ℃. EA 200mL was added, washed sequentially with saturated sodium chloride solution and water, extracted, and the organic phase was taken up in anhydrous Na 2 SO 4 Drying and concentration of the solvent under reduced pressure gave compound 1f (6.9 g). The crude product was used directly in the next reaction. MS (ESI, m/z): 356.2[ M+H ]] + .
Sixth step: 2- (3- (benzyloxy) propyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (1 g)
Compound 1f (4- (benzyloxy) -N- (7- (methylamino) thieno [3, 2-b)]Pyridin-6-yl) butyramide (2.5 g,7.030 mmol) was dissolved in 50mL MeOH and DIPEA (3.7 g,28.630 mmol) was added at room temperature and the reaction was heated at reflux for 16h. Concentrating under reduced pressure, dissolving the residue with EA, washing with 0.1N hydrochloric acid, extracting, and mixing the organic phases with anhydrous Na 2 SO 4 After drying and concentrating the solvent under reduced pressure, purification by silica gel column chromatography (DCM: meoh=20:1) afforded compound 1g (1.9 g). MS (ESI, m/z): 338.2[ M+H ]] + .
Seventh step: 2- (3- (benzyloxy) propyl) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (1H)
1g of (2- (3- (benzyloxy) propyl) -1-methyl-1H-imidazo [4, 5-d)]Thieno [3,2-b]Pyridine) (3.4 g,10.080 mmol) was dissolved in a mixed solvent of 30mL DMF and 30mL glacial acetic acid, and a solution of NBS (3.6 g,21.150 mmol) in 30mL DMF was added dropwise at room temperature, and after the addition was completed, the temperature was raised to 60℃for 4h. Extracting with water and EA, and collecting the organic layer with anhydrous Na 2 SO 4 After drying, concentrating the solvent under reduced pressure, purification by silica gel column chromatography (DCM: meoh=20:1) afforded compound 1h (3.1 g). MS (ESI, m/z): 416.1[ M+H ] ] + .
1 H NMR(DMSO-d 6 ,400MHz)δ8.87(s,1H),7.85(s,1H),7.32-7.22(m,5H),4.47(s,2H),3.91(s,3H),3.58(t,J＝6.0,2H),3.01(t,J＝7.2,2H),2.14-2.07(m,2H).
Eighth step: 2- (3- (benzyloxy) propyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine 5-oxide (1 i)
Compound 1H (2- (3- (benzyloxy) propyl) -7-bromo-1-methyl-1H-imidazo [4, 5-d)]Thieno [3,2-b]Pyridine) (1.3 g,3.850 mmol) was dissolved in 50mL chloroform, and m-CBPA (1.4 g,6.250 mmol) was added at room temperature and reacted at 25℃for 6h. Adding saturated Na 2 SO 3 The solution was stirred at room temperature for 0.5h, extracted and the organic layers combined with anhydrous Na 2 SO 4 Drying, concentrating the solvent under reduced pressure, and purifying by recrystallization (PE: ea=3:1) gave compound 1i (1.0 g). MS (ESI, m/z): 432.1[ M+H ]] + .
Ninth step: 2- (3- (benzyloxy) propyl) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (1)
Compound 1i (2- (3- (benzyloxy) propyl) -1-methyl-1H-imidazo [4, 5-d)]Thieno [3,2-b]Pyridine 5-oxide) (1.4 g,3.239 mmol) was dissolved in 30mL dichloromethane and NH was added 4 A solution of TsCl (1.29 g, 6.79mmol) in 10mL of methylene chloride was added dropwise over an ice bath with the addition of OH 25mL, and the temperature was raised to 25℃after completion of the addition to react for 2h. EA extraction, combining organic layers with anhydrous Na 2 SO 4 After drying, concentrating the solvent under reduced pressure, purification by silica gel column chromatography (DCM: meoh=20:1) afforded compound 1 (1.1 g).
MS(ESI,m/z):431.0[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ7.40(s,1H),7.31-7.27(m,5H),6.26(s,2H),4.48(s,2H),3.83(s,3H),3.54(t,J＝7.2,2H),2.95(t,J＝7.2,2H),2.07-2.03(m,2H).
Example 2:2- (3- (benzyloxy) propyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (2)
Compound 1 (100.0 mg,0.231 mmol), compound 2a (3- (4, 5-tetramethyl)-1,3, 2-Dioxyborolan-2-yl) -1H-pyrazole) (89.460 mg,0.463 mmol), na 2 CO 3 (61.440 mg,0.579 mmol) and Pd (dppf) Cl 2 ·CH 2 Cl 2 (18.930 mg,0.023 mmol) was placed in a 25mL single-port flask, DMF (2 mL), water (0.5 mL) and EtOH (0.2 mL) were added and the reaction was heated to 105℃overnight under nitrogen. Cooled to room temperature, EA and water were added, extraction was performed, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by Prep-HPLC to give compound 2 (7 mg).
MS(ESI,m/z):419.2[M+H]+。
1 H NMR(DMSO-d 6 ,400MHz)δ12.97(s,1H),7.83(s,1H),7.53(s,1H),7.33-7.25(m,5H),6.77(s,1H),6.12(s,2H),4.49(s,2H),3.90(s,3H),3.57(t,J＝6.4,2H),2.96(t,J＝7.6,2H),2.10-2.03(m,2H).
Prep-HPLC separation conditions:
instrument model: agilent 1260
Chromatographic column: waters XBridge Prep C 18 OBD(19mm×150mm×5.0μm)
Chromatographic column temperature: 25 DEG C
Flow rate: 20.0mL/min
Detection wavelength: 214nm, 254nm, 280nm
Mobile phase a:100% acetonitrile; mobile phase B:100% water, 0.05% amine formate
Elution gradient: 0min:30% A,70% B;20.0min:60% A,40% B.
Example 3:3- (4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propan-1-ol (3)
Compound 2 (70.0 mg,0.167 mmol) was placed in a 25mL single-port bottle, TFA (3 mL) was added, and the mixture was heated to 76℃and reacted under reflux overnight. Cooled to room temperature, meOH was added, insoluble material was removed by filtration, the organic phase was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give compound 3 (1 mg).
MS(ESI,m/z):329.1[M+H]+。
1 H NMR(DMSO-d 6 ,400MHz)δ12.98(s,1H),7.84(s,1H),7.54(s,1H),6.78(s,1H),6.14(s,2H),4.63(t,J＝5.2,1H),3.93(s,3H),3.53(t,J＝5.6,2H),2.93(t,J＝7.6,2H),1.97-1.90(m,2H).
Prep-HPLC: the conditions were the same as in example 2 except for the following two.
Elution gradient: 0min:10% A,90% B;6.5min:26% A,74% B.
Example 4:2- (3- (benzyloxy) propyl) -1-methyl-7-phenyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (4)
Under nitrogen, compound 1 (100.000 mg, 0.231mmol), compound 4a (phenylboronic acid) (56.530 mg,0.463 mmol), na were reacted under nitrogen 2 CO 3 (61.440 mg,0.579 mmol) and Pd (dppf) Cl 2 ·CH 2 Cl 2 (9.470 mg,0.012 mmol) was placed in a 25mL single-port bottle, toluene (2 mL), water (0.5 mL) and EtOH (1 mL) were added, and the mixture was heated to 90℃under nitrogen to react for 2h. Cooled to room temperature, EA and water were added, extraction was performed, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by Prep-HPLC to give compound 4 (1 mg).
MS(ESI,m/z):429.2[M+H]+。
1 H NMR(DMSO-d 6 ,400MHz)δ7.81(d,J＝7.7Hz,2H),7.71(s,1H),7.48(t,J＝7.5Hz,2H),7.42–7.24(m,6H),6.21(s,2H),4.50(s,2H),3.93(s,3H),3.58(t,J＝6.4,2H),2.98(t,J＝7.6,2H),2.12-2.07(m,2H).
Prep-HPLC: the conditions were the same as in example 2 except for the following two.
Elution gradient: 0min:40% A,60% B;20min:90% A,10% B.
Example 5:3- (4-amino-1-methyl-7-phenyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propan-1-ol (5)
Compound 4 (80.0 mg,0.186 mmol) was placed in a 25mL single-port bottle, TFA (3 mL) was added, and the reaction was heated to 76℃and refluxed overnight. Cooled to room temperature, meOH was added, insoluble material was removed by filtration, the organic phase was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give compound 5 (2 mg).
MS(ESI,m/z):339.1[M+H]+。
1 H NMR(DMSO-d 6 ,400MHz)δ7.79(d,J＝7.5Hz,2H),7.70(s,1H),7.47(t,J＝7.6Hz,2H),7.36(t,J＝7.3Hz,1H)，6.19(s,2H),4.62(t,J＝5.2,1H),3.94(s,3H),3.52(t,J＝5.6,2H),2.93(t,J＝7.6,2H),1.96-1.89(m,2H).
Prep-HPLC: the conditions were the same as in example 2 except for the following two.
Elution gradient: 0min:20% A,80% B;8.4min:45% A,55% B.
Example 6:2- (3- (benzyloxy) propyl) -1-methyl-7- (1H-pyrazol-1-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (6)
1 (200.0 mg, 0.460 mmol), compound 6a (1H-pyrazole) (63.270 mg,0.929 mmol), CH under nitrogen 3 NHCH 2 CH 2 NHCH 3 (16.390mg,0.186mmol)，Cs 2 CO 3 (302.630 mg,0.929 mmol) and CuI (17.700 mg,0.092 mmol) were placed in a 25mL dry three-necked flask, dried DMF (2 mL) was added and the mixture was heated to 110℃under nitrogen and reacted overnight. Cooled to room temperature, EA and water were added, extraction was performed, the organic phase was concentrated under reduced pressure, and the residue was separated and purified by Prep-HPLC to give compound 6 (1 mg).
MS(ESI,m/z):419.2[M+H]+。
1 H NMR(DMSO-d 6 ,400MHz)δ8.62(s,1H),7.75(s,1H),7.54(s,1H),7.33-7.27(m,5H),6.61(s,1H),6.20(s,2H),4.49(s,2H),3.88(s,3H),3.56(t,J＝5.6,2H),2.96(t,J＝7.6,2H),2.08-2.04(m,2H).
Prep-HPLC: the conditions were the same as in example 2 except for the following two.
Elution gradient: 0min:30% A,70% B;8.0min:54% A,46% B.
Example 7:3- (4-amino-1-methyl-7- (1H-pyrazol-1-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propan-1-ol (7)
Compound 6 (130.0 mg,0.310 mmol) was placed in a 25mL single-port flask, TFA (3 mL) was added, and the mixture was heated to 76℃and reacted under reflux overnight. Cooled to room temperature, meOH was added, insoluble material was removed by filtration, the organic phase was concentrated under reduced pressure, and the residue was purified by Prep-HPLC to give compound 7 (1 mg).
MS(ESI,m/z):329.1[M+H]+。
1 H NMR(DMSO-d 6 ,400MHz)δ8.62(d,J＝2.4,1H),7.76(d,J＝1.6,1H),7.54(s,1H),6.62(t,J＝2.4,1H),6.20(s,2H),4.64(t,J＝5.2,1H),3.90(s,3H),3.53(t,J＝6.0,2H),2.93(t,J＝7.6,2H),1.96-1.89(m,2H).
Prep-HPLC: the conditions were the same as in example 2 except for the following two.
Elution gradient: 0min:10% A,90% B;8.4min:31% A,69% B.
Example 8:2- (3- (benzyloxy) propyl) -1-methyl-7- (6-methylpyridin-2-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (66)
Compound 1 (50.00 mg,0.116 mmol), 66a (6-methylpyridin-2-yl) boronic acid (31.75 mg,0.231 mmol), K were reacted under nitrogen 2 CO 3 (40.00 mg,0.289 mmol) and Pd (dppf) Cl 2 ·CH 2 Cl 2 (9.47 mg,0.01 mmol) was placed in a 25mL single-necked flask, DMF (2 mL) and water (0.5 mL) were added, and the mixture was heated to 125℃under nitrogen and reacted overnight. Cooling to room temperature, adding EAAnd water, extract, concentrate the organic phase under reduced pressure, and isolate and purify the residue by Prep-HPLC to give compound 66 (2 mg).
MS(ESI,m/z):444.1[M+H] + 。
1 H NMR(DMSO-d 6 ,400MHz)δ7.95-7.90(m,2H),7.76(t,J＝7.6,1H),7.34-7.18(m,6H),6.23(s,2H),4.51(s,2H),3.96(s,3H),3.58(t,J＝6.4,2H),2.99(t,J＝7.6,2H),2.55(s,3H),2.06-2.12(m,2H).
Prep-HPLC: the conditions were the same as in example 2 except for the following two.
Elution gradient: 0min:30% A,70% B;12.0min:90% A,10% B.
Example 9:3- (4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propan-1-ol (9)
The first step: 2- (3- (benzyloxy) propyl) -1- (4-methoxybenzyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (9 j)
9g (50 mg, 93.03. Mu. Mol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (36 mg, 186.06. Mu. Mol), pd (dppf) Cl 2 (8 mg, 9.76. Mu. Mol), sodium carbonate (25 mg, 232.57. Mu. Mol) were added to a mixed solvent of 3mL of DMF and 0.3mL of water, N 2 The reaction was stirred under heating to 110℃under protection for 3h, and the reaction solvent was concentrated to dryness under reduced pressure to give compound 9j (40 mg). MS (ESI, m/z): 525.2[ M+H ]] + .
And a second step of: 3- (4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propan-1-ol (9)
Compound 9j (150 mg, 285.91. Mu. Mol) was added to 5mL of trifluoroacetic acid, reacted at 80℃for 20 hours with stirring, insoluble matters were removed by suction filtration, the filtrate was concentrated, and isolated and purified by Prep-HPLC (elution condition 1), and lyophilized to give formate salt 9s (12 mg) of compound 9.
MS(ESI,m/z):315.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ13.22-12.10(br,2H),8.19(s,1H),7.79(s,1H),7.48(s,1H),6.72(s,1H),6.06(s,2H),4.63(s,1H),3.49(t,J＝6.4Hz,2H),2.89(t,J＝7.6Hz,2H),2.02–1.90(m,2H).
Example 10:3- (4-amino-7- (1H-pyrazol-1-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propan-1-ol (10)
The first step: 2- (3- (benzyloxy) propyl) -1- (4-methoxybenzyl) -7- (1H-pyrazol-1-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (10 a)
9g (200 mg, 372.80. Mu. Mol), 1H-pyrazole (51 mg, 745.60. Mu. Mol), cuI (28 mg, 149.12. Mu. Mol), cesium carbonate (243 mg, 745.60. Mu. Mol), N' -dimethylethylenediamine (29 mg, 298.24. Mu. Mol) were added to 2mL of DMF 2 Heating to 120 ℃ under protection, and stirring to react for 20h. Washing with water, EA extraction, and concentration of the reaction solvent to dryness under reduced pressure gave compound 10a (150 mg). MS (ESI, m/z): 525.2[ M+H ] ] + .
And a second step of: 3- (4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) -1-propanol (10)
Compound 10a (150 mg, 285.91. Mu. Mol) was added to 3mL of trifluoroacetic acid and the reaction stirred at 80℃for 26h. Insoluble matter was removed by suction filtration, the filtrate was concentrated, purified by Prep-HPLC (eluting condition 1), and lyophilized to give compound 10 (11 mg).
MS(ESI,m/z):315.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.80(s,1H),8.57(s,1H),7.74(s,1H),7.47(s,1H),6.58(s,1H),6.12(s,2H),4.63(s,1H),3.49(t,J＝5.2Hz,2H),2.89(d,J＝7.2Hz,2H),2.01–1.90(m,2H).
Example 11: 1-methyl-2- ((4-methylpiperazin-1-yl) methyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (37)
The first step: 2- (benzyloxy) -N- (7- (methylamino) thieno [3,2-b ] pyridin-6-yl) acetamide (11 a)
Compound 1e (3.0 g,16.7 mmol), benzyloxyacetic acid (4.17 g,25.1 mmol), HATU (7.63 g,20 mmol), N-diisopropylethylamine (4.33 g,33.4 mmol) was added to 30mL of N, N-dimethylformamide and the reaction stirred at 25℃for 4h. The reaction mixture was poured into ice water, extracted with ethyl acetate, and the organic phase was concentrated, followed by flash column chromatography (eluent system a) to give compound 11a (4.8 g). MS (ESI, m/z): 328.1[ M+H ]] + .
And a second step of: 2- ((benzyloxy) methyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (11 b)
Compound 11a (2.0 g,6.11 mmol), sodium hydroxide (0.73 g,18.33 mmol) and 20mL of ethanol were added, and the temperature was raised to 90℃and the reaction was stirred for 2h. The reaction mixture was adjusted to ph=7.0 with 6.0N hydrochloric acid, concentrated to dryness and flash column chromatographed (eluent system a) to give compound 11b (1.2 g). MS (ESI, m/z): 310.2[ M+H ] ] + .
And a third step of: 2- ((benzyloxy) methyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine-5-oxide (11 c)
Compound 11b (1.2 g,3.88 mmol) and mCPBA (1.0 g,5.82 mmol) were added to 20mL of dichloromethane and the reaction stirred at room temperature for 16h. The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate, the organic phase was washed twice with water, and when no peroxide remained as detected by potassium iodide starch paper, the organic phase was concentrated to dryness under reduced pressure, and then subjected to flash column chromatography (eluent system a) to give compound 11c (1.0 g). MS (ESI, m/z): 326.1[ M+H ]] + .
Fourth step: 2- ((benzyloxy) methyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (11 d)
Compound 11c (1.0 g,3.07 mmol), p-toluenesulfonyl chloride (0.48 g,6.76 mmol), 20mL of methylene chloride and 5mL of ammonia were added and reacted at 25℃with stirring for 16h. The reaction mixture was poured into ice water, the organic phase was concentrated after extraction with dichloromethane, and flash column chromatography (eluent system a) was performed to give compound 11d (0.86 g). MS (ESI, m/z): 325.1[ M+H ]] + .
Fifth step: 2- ((benzyloxy) methyl) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (11 e)
Compound 11d (0.8 g,2.47 mmol), N-bromosuccinimide (0.88 g,4.93 mmol) and 10mL of a chloroform/glacial acetic acid=1:1 were added to the mixture, and the mixture was stirred at 25℃for 2 hours. The reaction mixture was poured into ice water, extracted with dichloromethane, and the organic phase was concentrated and subjected to flash column chromatography (eluent system a) to give compound 11e (0.75 g). MS (ESI, m/z): 403.0[ M+H ] ] + .
Sixth step: (4-amine-7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methanol (11 f)
Compound 11e (0.75 g,1.86 mmol) was added to 10mL trifluoroacetic acid and the reaction stirred at 80℃for 16h. The reaction mixture was concentrated to dryness, redissolved in methanol, adjusted to ph=9.0 with 6N sodium hydroxide solution, extracted with ethyl acetate and the organic phase concentrated to give crude compound 11f (0.60 g). MS (ESI, m/z): 313.0[ M+H ]] + .
Seventh step: 7-bromo-2- (chloromethyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (11 g)
Compound 11f (0.6 g,1.92 mmol) was added to a mixture of 4mL thionyl chloride and 2mL dichloromethane and the reaction stirred at 25℃for 16h. The reaction mixture was concentrated to dryness, redissolved in dichloromethane, quenched with methanol to residual thionyl chloride, concentrated to dryness with solvent, and flash column chromatography (eluent system a) to give 11g (0.48 g) of compound. MS (ESI, m/z): 333.0[ M+H ]] + .
Eighth step: 7-bromo-1-methyl-2- ((4-methylpiperazin-1-yl) methyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (11H)
11g (120 mg,0.36 mmol) of compound, N-methylpiperazine (217 mg,2.17 mmol), tetrabutylammonium iodide (26.7 mg,0.072 mmol) and TEA (219 mg,2.17 mmol) were added to 5mL of toluene, N 2 Heating to 100 ℃ under protection to react for 16h. The spin-dried reaction solvent was subjected to flash column chromatography (eluent system A) to give compound 11h (110 mg). MS (ESI, m/z): 395.0[ M+H ]] + .
Ninth step: 1-methyl-2- ((4-methylpiperazin-1-yl) methyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (37)
Compound 11H (110 mg,0.28 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (108 mg,0.56 mmol), pd (dppf) Cl 2 (90 mg,0.11 mmol), sodium carbonate (88 mg,0.83 mmol) and N are added to a mixed solvent of 2.0mL DMF and 0.5mL water 2 Heating to 110 ℃ under protection, and stirring to react for 16h. The reaction solvent was concentrated to dryness under reduced pressure, and purified by Prep-HPLC (eluting condition 2) to give compound 37 (6 mg).
MS(ESI,m/z):383.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.99(s,1H),7.83(s,1H),7.53(s,1H),6.78(s,1H),6.24(s,2H),4.00(s,3H),3.82–3.71(m,2H),2.45–2.31(m,8H),2.14(s,3H).
Example 12:
3- ((4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) amino) propan-1-ol (67)
The first step: 1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine-2 (3H) -thione (12 a)
Compound 1e (1.00 g,5.58 mmol) and carbon disulphide (2.54 g,33.36 mmol) are added to 30mL absolute ethanol and heated to 85℃for 2.5h. The reaction mixture was concentrated to give compound 12a (1.23 g). MS (ESI, m/z): 222.0[ M+H ] ] + .
And a second step of: 1-methyl-2-methylsulfanyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (12 b)
Compound 12a (1.23 g,5.56 mmol), methyl iodide (0.95 g,6.67 mmol), K 2 CO 3 (2.30 g,16.67 mmol) was added to 50mL of acetone and reacted at room temperature for 16h. The reaction mixture was concentrated and diluted with water, extracted with EA three times (100 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated to give Compound 12b (1.1 g). MS (ESI, m/z): 236.0[ M+H ]] + .
And a third step of: 1-methyl-2-methanesulfonyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (12 c)
Compound 12b (1.10 g,4.67 mmol) and potassium permanganate (1.33 g,8.41 mmol) were added to a mixed solvent of 50mL of water and 5mL of glacial acetic acid, and reacted at room temperature for 3h. The system was cooled to 5 ℃ in an ice bath, saturated aqueous sodium bisulphite solution was added dropwise to the system until the purple color faded, suction filtration was carried out, and the filter cake was dried to obtain compound 12c (1.1 g). MS (ESI, m/z): 268.0[ M+H ]] + .
Fourth step: 3- ((1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) amino) propan-1-ol (12 d)
Compound 12c (0.80 g,2.99 mmol) and 3-amino-1-propanol (2.95 g,39.22 mmol) were added to 10mL of DMF and heated to 120℃for reaction for 3h. Dilution with water, EA extraction three times (100 mL. Times.3), combining and drying over anhydrous sodium sulfate, and thin layer chromatography (eluent system A) gave compound 12d (450 mg). MS (ESI, m/z): 263.1[ M+H ] ] + .
Fifth step: n- (3- (benzyloxy) propyl) -N- (4-methoxybenzyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-amine (12 e)
Compound 12d (200 mg,0.76 mmol) was added to 15mL of DMF, the system was cooled to 0deg.C under ice-salt bath, 60% NaH (29.80 mg,0.78 mmol) and p-methoxybenzyl chloride (119.40 mg,0.76 mmol) were successively added to the system, the reaction was allowed to proceed to room temperature for 1h, and 60% NaH (29.80 mg,0.78 mmol) and benzyl bromide (130.40 mg,0.76 mmol) were successively added to the system, and the reaction was continued at room temperature for 1h. Dilution with water, EA extraction three times (100 mL. Times.3), combining and drying over anhydrous sodium sulfate, and thin layer chromatography (eluent system B) gave compound 12e (210 mg). MS (ESI, m/z): 473.2[ M+H ]] + .
Sixth step: n- (3- (benzyloxy) propyl) -7-bromo-N- (4-methoxybenzyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-amine (12 f)
Compound 12e (210 mg,0.44 mmol) was added to a mixture of 3mL DMF and 0.5mL glacial acetic acid, NBS (158 mg,0.89 mmol) was added to the system and heated to 65℃for 0.5h. The reaction mixture was diluted with water, extracted three times with EA (50 ml×3), and dried over anhydrous sodium sulfate after combining. Column chromatography (eluent system B) gave compound 12f (100 mg). MS [ (MS) ESI,m/z):551.1[M+H] + .
Seventh step: 2- ((3-benzyloxy) propyl) (4-methoxybenzyl) amino) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine-5-oxide (12 g)
Compound 12f (100 mg,0.18 mmol) was added to 10mL DCM and the addition of mCPBA (38 mg,0.22 mmol) to the system continued and reacted at room temperature for 3h. The reaction mixture was washed twice with saturated sodium hydrogencarbonate (50 mL. Times.2), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give 12g (103 mg) of a compound. MS (ESI, m/z): 567.1[ M+H ]] + .
Eighth step: n (N) 2 - (3- (benzyloxy) propyl) -7-bromo-N2- (4-methoxybenzyl) -1-methyl-1H-imidazo [4,5-d]Thieno [3,2-b]Pyridine-2, 4-diamine (12 h)
12g (103 mg,0.18 mmol) of the compound was added to 15mL of DCM, and 2mL of ammonia water and p-toluenesulfonyl chloride (100 mg,1.42 mmol) were successively added to the system and reacted at room temperature for 3 hours. The reaction mixture was diluted with DCM, washed three times with water (50 mL. Times.3) and the organic layer was dried over anhydrous sodium sulfate. Column chromatography (eluent system B) gave compound 12h (15 mg). MS (ESI, m/z): 566.1[ M+H ]] + .
Ninth step: n (N) 2 - (3- (benzyloxy) propyl) -N 2 - (4-methoxybenzyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d]Thieno [3,2-b]Pyridine-2, 4-diamine (12 i)
The compound 12H (55 mg, 97.09. Mu. Mol), 1H-pyrazole-3-boronic acid pinacol ester (35 mg, 194.17. Mu. Mol) and [1,1' -bis (diphenylphosphine) ferrocene ]Palladium dichloride dichloromethane Complex (8 mg, 9.71. Mu. Mol), K 2 CO 3 (34 mg, 242.72. Mu. Mol) was added to a mixed solvent of 2mL of DMF and 0.5mL of water, N 2 Heating to 120 ℃ under protection for reaction for 2h. The system was filtered through celite, the filtrate was diluted with water, extracted three times with EA (50 mL. Times.3), combined, dried over anhydrous sodium sulfate, and concentrated to give compound 12i (54 mg). MS (ESI, m/z): 554.2[ M+H ]]+.
Tenth step: 3- ((4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) amino) propan-1-ol (67)
Compound 12i (54 mg,97.09 μmol) was added to 10mL of trifluoroacetic acid, heated to 75 ℃ for 16h, the system concentrated and diluted with methanol, saturated potassium carbonate adjusted to ph=9, stirred at room temperature for 0.5h, suction filtered, the filtrate was purified by Prep-HPLC (eluting condition 3) and lyophilized to give formate 67s (7 mg) of compound 67.
MS(ESI,m/z):344.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ13.57(s,1H),13.21(s,1H),7.98–7.76(m,3H),7.63(s,1H),7.20(s,1H),6.86(s,1H),4.54(s,1H),3.78(s,3H),3.55–3.46(m,4H),1.85–1.77(m,2H).
Example 13:
1-methyl-2- (3-morpholinopropyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (68)
The first step: 7-bromo-1-methyl-2- (3-morpholinopropyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (13 a)
Compound 1k (30 mg,0.08 mmol), morpholine (22 mg,0.25 mmol), TEA (26 mg,0.25 mmol), tetrabutylammonium iodide (3 mg, 8.42. Mu. Mol) were added to 3mL of toluene, and the mixture was heated to 100℃for 16h after nitrogen substitution. The reaction mixture was concentrated to give compound 13a (35 mg). MS (ESI, m/z): 410.1[ M+H ] ] + .
And a second step of: 1-methyl-2- (3-morpholinopropyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (68)
Compound 13a (35 mg,0.09 mmol), 1H-pyrazole-3-boronic acid pinacol ester (33 mg,0.17 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane Complex (7 mg, 8.50. Mu. Mol), K 2 CO 3 (30 mg,0.21 mmol) was added to a mixed solvent of 3mL DMF and 0.8mL water, N 2 Heating to 120 ℃ under protection for reaction for 3h. The system was filtered through celite, and the filtrate was purified by Prep-HPLC (elution condition 4) and lyophilized to give compound 68 (2 mg).
MS(ESI,m/z):398.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.98(s,1H),7.83(s,1H),7.53(s,1H),6.77(s,1H),6.11(s,2H),3.93(s,3H),3.54–3.51(m,2H),2.91(t,J＝7.5Hz,2H),2.43–2.30(m,7H),2.03–1.90(m,3H).
Example 14:
2- (3- (benzyloxy) propoxy) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (69)
The first step: 2- (3- (benzyloxy) propoxy) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (14 a)
Compound 12c (500 mg,1.87 mmol) and 3-benzyloxy-1-propanol (3.11 g,18.70 mmol) were added to 50mL acetonitrile, and the system was further charged with 60% NaH (7197 mg,18.70 mmol) and heated to 50℃for 16h. The system was concentrated and diluted with water, extracted with EA three times (100 mL. Times.3), dried over anhydrous sodium sulfate, and purified by column chromatography (eluent system B) to give compound 14a (590 mg). MS (ESI, m/z): 354.1[ M+H ] ] + .
And a second step of: n- (3- (benzyloxy) propyl) -7-bromo-N- (4-methoxybenzyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-amine (14 b)
Compound 14a (4815 mg,1.37 mmol) was added to a mixture of 10mL DMF and 2.5mL glacial acetic acid, and NBS (488 mg,2.74 mmol) was added to the system and heated to 65℃for 2h. The reaction mixture was diluted with water, extracted three times with EA (50 ml×3), and dried over anhydrous sodium sulfate after combining. Column chromatography (eluent system B) gave compound 14B (466 mg). MS (ESI, m/z): 432.0[ M+H ]] + .
And a third step of: 2- (3- (benzyloxy) propoxy) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine 5-oxide (14 c)
Compound 14b (463 mg,0.18 mmol) was added to 30mL DCM and the addition of mCPBA (223 mg,1.29 mmol) to the system continued and reacted at room temperature for 3h. The reaction mixture was washed twice with saturated sodium hydrogencarbonate (50 mL. Times.2), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 14c (483 mg). MS (ESI, m/z): 448.0[ M+H ]] + .
Fourth step: 2- (3- (benzyloxy) propoxy) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (14 d)
Compound 14c (4478 mg,1.08 mmol) was added to 30mL of DCM and the reaction was continued with the sequential addition of 5mL of ammonia and p-toluenesulfonyl chloride (190 mg,2.70 mmol) at room temperature for 3h. The reaction mixture was diluted with DCM, washed three times with water (50 mL. Times.3) and the organic layer was dried over anhydrous sodium sulfate. Column chromatography (eluent system A) gave compound 14d (100 mg). MS (ESI, m/z): 447.0[ M+H ] ] + .
Fifth step: 2- (3- (benzyloxy) propoxy) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (69)
Compound 14d (75 mg, 166.66. Mu. Mol), 1H-pyrazole-3-boronic acid pinacol ester (65 mg, 333.31. Mu. Mol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane Complex (14 mg, 16.67. Mu. Mol), K 2 CO 3 (58 mg, 416.64. Mu. Mol) was added to a mixed solvent of 3mL of DMF and 0.8mL of water, N 2 Heating to 120 ℃ under protection to react for 1h. The system was filtered through celite, and the filtrate was purified by Prep-HPLC (elution condition 5) and lyophilized to give compound 69 (20 mg).
MS(ESI,m/z):435.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.96(s,1H),7.82(s,1H),7.51(s,1H),7.36–7.20(m,5H),6.77(s,1H),5.90(s,2H),4.59(t,J＝6.3Hz,2H),4.50(s,2H),3.69–3.60(m,5H),2.15–2.06(m,2H).
Example 15:1- (3- (4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) pyrrolidin-3-ol (70)
The first step: 1- (3- (4-amino-7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) pyrrolidin-3-ol (15 a)
Compound 1k (30 mg, 83.41. Mu. Mol), 35b (20 mg, 225.22. Mu. Mol), tetrabutylsodium iodide (3 mg, 8.34. Mu. Mol) andTEA (25 mg, 250.23. Mu. Mol) was added to 5mL of toluene and the reaction was stirred at 100℃for 22h. Insoluble matter was removed by suction filtration, and the filtrate was concentrated to give crude 15a (30 mg). MS (ESI, m/z): 410.0[ M+H ]] + .
And a second step of: 1- (3- (4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) pyrrolidin-3-ol (70)
Compound 15a (40 mg, 97.48. Mu. Mol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (38 mg, 194.96. Mu. Mol), pd (dppf) Cl 2 (8 mg, 9.76. Mu. Mol), sodium carbonate (26 mg, 243.71. Mu. Mol) were added to a mixed solvent of 3mL of DMF and 0.3mL of 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 lyophilized by Prep-HPLC purification (eluting condition 4) to give compound 70 (5 mg).
MS(ESI,m/z):398.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ13.01(s,1H),7.82(s,1H),7.55(s,1H),6.77(d,J＝1.6Hz,1H),6.15(s,2H),4.73(d,J＝4.4Hz,1H),4.20–4.16(m,1H),3.93(s,3H),2.92(t,J＝7.4Hz,2H),2.70(dd,J＝9.5,6.2Hz,1H),2.61–2.38(m,8H),2.32(dd,J＝9.6,3.7Hz,1H),2.02–1.88(m,3H),1.54(ddd,J＝13.0,8.2,5.5Hz,1H).
Example 16: 1-methyl-7- (1H-pyrazol-3-yl) -2- (3- (pyrrolidin-1-yl) propyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (71)
The first step: 7-bromo-1-methyl-2- (3- (pyrrolidin-1-yl) propyl) -1H imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (16 a)
Compound 1k (151 mg,0.42 mmol), tetrahydropyrrole (60 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 reaction solvent was subjected to flash column chromatography (eluent system A) to give compound 16a (126 mg). MS (ESI, m/z): 394.1[ M+H ]] + .
And a second step of: 1-methyl-7- (1H-pyrazol-3-yl) -2- (3- (pyrrolidin-1-yl) propyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (71)
Compound 16a (126 mg,0.33 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxacyclopent-2-yl) -1H pyrazole (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 to react for 6h. The reaction solvent was concentrated to dryness under reduced pressure by filtration through celite, and the resultant was purified by Prep-HPLC (elution condition 4) to give compound 71 (15 mg).
MS(ESI,m/z):382.2[M+H] + .
1 HNMR(DMSO-d 6 ,400MHz)δ12.98(s,1H),7.81-7.82(m,1H),7.53(s,1H),6.76-6.77(m,1H),6.12(s,2H),3.92(s,3H),2.89-2.91(m,2H),2.48-2.50(m,2H),2.42-2.44(m,4H),1.92-1.93(m,2H),1.66-1.68(m,4H).
Example 17:2- (3- (azetidin-1-yl) propyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (72)
The first step: 2- (3- (azetidin-1-yl) propyl) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (17 a)
Compound 1k (151 mg,0.42 mmol), azetidine (48 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 reaction solvent was subjected to flash column chromatography (eluent system A) to give compound 17a (126 mg). MS (ESI, m/z): 380.0[ M+H ]] + .
And a second step of: 2- (3- (azetidin-1-yl) propyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (72)
Compound 17a (125 mg,0.33 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxacyclopent-2-yl) -1H pyrazole (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 to react for 6h. The reaction solvent was concentrated to dryness under reduced pressure by filtration through celite, and the resultant was purified by Prep-HPLC (eluting condition 4) to give compound 72 (15 mg).
MS(ESI,m/z):368.2[M+H] + .
1 HNMR(CD3OD-d 4 ,400MHz)δ7.72(d,J＝2.4Hz,1H),7.51(s,1H),6.71(d,J＝2.4Hz,1H),3.95(s,3H),3.31-3.34(m,4H),2.90-2.92(m,2H),2.62-2.64(m,2H),2.12-2.13(m,2H),1.89-1.92(m,2H).
Example 18:
1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine hydrochloride (73 s)
The first step: 7-bromo-1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -1H imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (18 a)
Compound 1k (100 mg,0.27 mmol), N-methylpiperazine (162 mg,1.62 mmol), tetrabutylammonium iodide (20.54 mg,0.05 mmol), TEA (168.80 mg,1.62 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 18a (80 mg). MS (ESI, m/z): 423.1[ M+H ]] + .
And a second step of: 1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (73)
Compound 18a (50 mg,0.12 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (45.83 mg,0.24 mmol), pd (dppf) Cl 2 (9 mg,0.01 mmol), sodium carbonate (31.30 mg,0.29 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 the reaction solvent to dryness under reduced pressure, and separating and purifying by Prep-HPLC (eluting condition 4)And compound 73.
MS(ESI,m/z):411.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.97(s,1H),7.83(s,1H),7.53(s,1H),6.77(s,1H),6.12(s,2H),3.92(s,3H),2.88(t,J＝7.2Hz,7.6Hz,2H),2.42–2.26(m,10H),2.10(s,3H),1.95–1.88(m,2H).
And a third step of: 1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine hydrochloride (73 s)
To the resulting preparation of compound 73 was added 0.5mL of 1N hydrochloric acid, and the mixture was lyophilized to obtain compound 73s (10 mg).
MS(ESI,m/z):411.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ14.44(s,1H),12.22(s,2H),8.63(s,2H),7.90(s,1H),7.75(s,1H),6.92(d,J＝8.6Hz,1H),4.00(s,3H),3.85–3.34(m,10H),3.12–3.08(m,2H),2.83(s,3H),2.33–2.29(m,2H).
Example 19:
2- (3- (2, 2-Dimethylmorpholine) propyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (74)
The first step: 7-bromo-2- (3- (2, 2-dimethylmorpholinopropyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (19 a)
Compound 1k (30 mg,0.08 mmol), 2-dimethylmorpholine (29 mg,0.25 mmol), TEA (26 mg,0.25 mmol), tetrabutylammonium iodide (3 mg, 8.42. Mu. Mol) were added to 4mL of toluene, and the mixture was heated to 100℃for 16h after nitrogen substitution. The reaction mixture was concentrated to give compound 19a (37 mg). MS (ESI, m/z): 438.1[ M+H ]] + .
And a second step of: 2- (3- (2, 2-Dimethylmorpholine) propyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (74)
Compound 19a (37 mg,0.09 mmol), 1H-pyrazole-3-boronic acid pinacol ester (33 mg,0.17 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane Complex (7 mg, 8.50. Mu. Mol), na 2 CO 3 (27 mg,0.26 mmol) was added to a mixed solvent of 3mL DMF and 0.8mL water, N 2 Heating to 110 ℃ under protection for reaction for 4 hours. The system was filtered through celite, and the filtrate was purified by Prep-HPLC (elution condition 4) and lyophilized to give compound 74 (8 mg).
MS(ESI,m/z):426.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.98(s,1H),7.82(s,1H),7.53(s,1H),6.77(s,1H),6.12(s,2H),3.93(s,3H),3.57(t,J＝4.8Hz,2H),2.91(t,J＝7.5Hz,2H),2.34(t,J＝6.8Hz,2H),2.31–2.25(m,2H),2.16(s,2H),1.98–1.88(m,2H),1.14(s,6H).
Example 20:
1-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -7- (1H-pyrazol-1-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (75)
Compound 18a (36 mg,0.09 mmol), 1H-pyrazole (19 mg,0.28 mmol), cuI (35 mg,0.18 mmol), cesium carbonate (86 mg,0.26 mmol) were added to 5mL DMSO, N 2 Heating to 120 ℃ under protection, and stirring to react for 10h. The resulting filtrate was diluted with water, extracted with EA, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure to give a crude product, which was purified by Prep-HPLC (elution condition 4) to give compound 75 (5 mg).
MS(ESI,m/z):411.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ8.62(s,1H),7.75(s,1H),7.54(s,1H),6.61(s,1H),6.21(s,2H),3.90(s,3H),2.89(t,J＝4.8Hz,2H),2.41(t,J＝7.5Hz,7H),2.34(t,J＝6.8Hz,2H),2.31–2.25(m,2H),2.18(s,3H),1.95–1.91(m,3H).
Example 21:
2- (4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) ethanol (76)
The first step: 3- (benzyloxy) -N- (7- ((4-methoxybenzyl) amino) thieno [3,2-b ] pyridin-6-yl) propanamide (21 a)
Compound 9b (5.00 g,17.52 mmol), 4-benzyloxypropionic acid (4.08 g,21.03 mmol), HATU (9.99 g,26.28 mmol) were added to 100mL DMF and the reaction was continued with the addition of DIPEA (6.79 g,53.56 mmol) at room temperature for 16h. The reaction mixture was diluted with water, extracted with EA three times (100 mL. Times.3), combined, dried over anhydrous sodium sulfate, and concentrated to give Compound 21a (8.09 g). MS (ESI, m/z): 448.2[ M+H ]] + .
And a second step of: 2- (2- (benzyloxy) ethyl) -1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (21 b)
Compound 21a (8.09 g,17.53 mmol) and NaOH (3.2 g,0.08 mol) were added to 120mL of absolute ethanol and heated to 80℃for reaction for 4h. The system was concentrated and diluted with DCM and column chromatography (eluent system A) gave compound 21b (5.00 g). MS (ESI, m/z): 430.2[ M+H ]] + .
And a third step of: 2- (2- (benzyloxy) ethyl) -7-bromo-1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (21 c)
Compound 21b (4.17 g,9.40 mmol) was added to 140mL DMF and NBS (1.76 g,9.87 mmol) was added to the system and heated to 65℃for 22h. The reaction mixture was diluted with water, extracted three times with EA (100 ml×3), and dried over anhydrous sodium sulfate after combining. Column chromatography (eluent system B) gave compound 21c (2.36 g). MS (ESI, m/z): 508.1[ M+H ] ] + .
Fourth step: 2- (2- (benzyloxy) ethyl) -7-bromo-1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine-5-oxide (21 d)
Compound 21c (2.31 g,4.42 mmol) was added to 85mL DCM and m-CPBA (1.53 g,8.84 mmol) was added to the system and reacted at room temperature for 4h. The reaction mixture was washed twice with saturated sodium hydrogencarbonate (100 mL. Times.2), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 21d (2.38 g). MS (ESI, m/z): 524.1[ M+H ]] + .
Fifth step: 2- (2- (benzyloxy) ethyl) -7-bromo-1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (21 e)
Compound 21d (2.38 g,16.88 mmol) was added to 100mL of DCM and the reaction was continued with the sequential addition of 46mL of ammonia and p-toluenesulfonyl chloride (1.02 g,14.41 mmol) at room temperature for 3h. The reaction mixture was diluted with DCM, washed three times with water (200 mL. Times.3) and the organic layer was dried over anhydrous sodium sulfate. Column chromatography (eluent system A) gave compound 21e (1.00 g). MS (ESI, m/z): 523.1[ M+H ]] + .
Sixth step: 2- (2- (benzyloxy) ethyl) -1- (4-methoxybenzyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (21 f)
Compound 21e (500 mg,0.95 mmol), 1H-pyrazole-3-boronic acid pinacol ester (350 mg,1.9 mmol) and [1,1' -bis (diphenylphosphine) ferrocene ]Palladium dichloride dichloromethane Complex (80 mg, 97.1. Mu. Mol), na 2 CO 3 (254.4 mg,2.4 mmol) was added to a mixed solvent of 20mL DMF and 5mL water, N 2 Heating to 110 ℃ under protection for reaction for 2h. The system was filtered through celite, the filtrate was diluted with water, extracted three times with EA (50 mL. Times.3), combined, dried over anhydrous sodium sulfate, and concentrated to give compound 21f (300 mg). MS (ESI, m/z): 511.2[ M+H ]] + .
Seventh step: 2- (4-amino-7-bromo-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) ethanol (76)
Compound 21f (50 mg,98 μmol) was added to 20mL of trifluoroacetic acid, heated to 75 ℃ for 16h, the system was concentrated and diluted with EA, saturated sodium bicarbonate solution adjusted to ph=8, stirred at room temperature for 0.5h, then the layers were separated, the organic layer was dried over anhydrous sodium sulfate, the system was filtered through celite, and the filtrate was isolated and purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 76 (10 mg).
MS(ESI,m/z):301.0[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ13.06(s,2H),7.90(s,1H),7.60(s,1H),6.84(s,1H),6.23(s,2H),5.08(s,1H),3.96(t,J＝6.5Hz,2H),3.11(t,J＝6.5Hz,2H).
Example 22:
2- (4-Methoxypiperidin-1-yl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (77)
The first step: 2- (4-methoxypiperidin-1-yl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (22 a)
Compound 12c (1.00 g,3.74 mmol) and 4-methoxypiperidine (2.79 g,24.22 mmol) were added to 25mL of DMSO and reacted for 14h at 120 ℃. The system was filtered, the filtrate was diluted with water, extracted with EA three times (100 mL. Times.3), combined, dried over anhydrous sodium sulfate, and subjected to thin layer chromatography (eluent system A) to give compound 22a (350 mg). MS (ESI, m/z): 303.1[ M+H ] ] + .
And a second step of: 7-bromo-2- (4-methoxypiperidin-1-yl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (22 b)
Compound 22a (250 mg,0.83 mmol) was added to a mixture of 15mL DMF and 3.8mL glacial acetic acid, NBS (309 mg,1.74 mmol) was added to the system and heated to 65℃for 2h. The reaction mixture was diluted with water, extracted three times with EA (50 ml×3), and dried over anhydrous sodium sulfate after combining. Column chromatography (eluent system a) gave compound 22b (80 mg). MS (ESI, m/z): 381.0[ M+H ]] + .
And a third step of: 7-bromo-2- (4-methoxypiperidin-1-yl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine-5-oxide (22 c)
Compound 22b (80 mg,0.21 mmol) was added to 20mL DCM and the addition of mCPBA (72 mg,0.42 mmol) to the system was continued and reacted at room temperature for 2h. The reaction mixture was washed twice with saturated sodium hydrogencarbonate (50 mL. Times.2), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 22c (83 mg). MS (ESI, m/z): 397.0[ M+H ]] + .
Fourth step: 7-bromo-2- (4-methoxypiperidin-1-yl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (22 d)
Compound 22c (83 mg,0.21 mmol) was added to 15mL of DCM and the system was successively added with 3mL of aqueous ammonia and p-toluenesulfonyl chloride (37 mg,0.52 mmol) and reacted at room temperature for 4.5h. For the reaction mixture The mixture was diluted with DCM, washed three times with water (50 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate. Thin layer chromatography (eluent system a) afforded compound 22d (40 mg). MS (ESI, m/z): 396.0[ M+H ]] + .
Fifth step: 2- (4-Methoxypiperidin-1-yl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (77)
Compound 22d (40 mg, 100.93. Mu. Mol), 1H-pyrazole-3-boronic acid pinacol ester (39 mg, 201.86. Mu. Mol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane Complex (8 mg, 10.09. Mu. Mol), na 2 CO 3 (32 mg, 302.80. Mu. Mol) was added to a mixed solvent of 2mL of DMF and 0.5mL of water, N 2 Heating to 110 ℃ under protection to react for 2.5h. The system was filtered through celite, and the filtrate was purified by Prep-HPLC (elution condition 6) and lyophilized to give the trifluoroacetate salt 77s of compound 77 (20 mg).
MS(ESI,m/z):384.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ13.62(s,1H),13.22(s,1H),8.07(s,2H),7.91(s,1H),7.66(s,1H),6.88(s,1H),3.86(s,3H),3.51–3.44(m,3H),3.31(s,3H),3.14–3.06(m,2H),2.01(s,2H),1.73–1.63(m,2H).
Example 23:
1- (4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) piperidin-4-ol (79)
The first step: 1- (1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) piperidin-4-ol (23 a)
Compound 12c (3.00 g,11.22 mmol) and 4-hydroxypiperidine (15.00 g,148.30 mmol) are added to 100mL DMF and heated to 130℃for 20h. 100mL of water was added to the system, stirred at room temperature for 0.5h, suction filtered, and the filter cake was dried to give compound 23a (2.2 g). MS (ESI, m/z): 289.1[ M+H ] ] + .
And a second step of: 1- (7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) piperidin-4-ol (23 b)
Compound 23a (333 mg,1.15 mmol) was added to a mixture of 12mL DMF and 3mL glacial acetic acid, NBS (400 mg,2.25 mmol) was added continuously to the system, and the mixture was heated to 65℃for 1h. The reaction mixture was diluted with water, extracted three times with EA (50 ml×3), and dried over anhydrous sodium sulfate after combining. Compound 23b (210 mg) was obtained by thin layer chromatography (eluent system A). MS (ESI, m/z): 367.0[ M+H ]] + .
And a third step of: 2- (4-benzyloxy) piperidin-1-yl) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine (23 c)
Compound 23b (200 mg,0.54 mmol) was added to 25mL of DMF, 60% NaH (63 mg,1.63 mmol) was added continuously to the system, the reaction was continued at room temperature for 0.5h, benzyl bromide (186 mg,1.09 mmol) and tetrabutylammonium iodide (101 mg,0.27 mmol) were added sequentially to the system, and the mixture was heated to 30℃for 8h. The system was diluted with water, extracted with EA three times (100 mL. Times.3), combined, dried over anhydrous sodium sulfate, and subjected to thin layer chromatography (eluent system B) to give compound 23c (90 mg). MS (ESI, m/z): 457.1[ M+H ]] + .
Fourth step: 2- (4-benzyloxy) piperidin-1-yl) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine-5-oxide (23 d)
Compound 23c (90 mg,0.20 mmol) was added to 20mL DCM and the addition of mCPBA (68 mg,0.39 mmol) to the system continued and reacted at room temperature for 4h. The reaction mixture was washed twice with saturated sodium hydrogencarbonate (50 mL. Times.2), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 23d (93 mg). MS (ESI, m/z): 473.1[ M+H ]] + .
Fifth step: 2- (4-benzyloxy) piperidin-1-yl) -7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (23 e)
Compound 23d (93 mg,0.20 mmol) was added to 15mL of DCM, and 3mL of aqueous ammonia and p-toluenesulfonyl chloride (69 mg,0.98 mmol) were added sequentially to the system and reacted at room temperature for 3h. The reaction mixture was diluted with DCM, washed three times with water (50 mL. Times.3) and the organic layer was dried over anhydrous sodium sulfate. Thin layer chromatography (eluent system a) afforded compound 23e (25 mg). MS (ESI, m/z): 472.1[ M+H ]] + .
Sixth step: 2- (4-benzyloxy) piperidin-1-yl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (23 f)
Compound 23e (25 mg, 52.92. Mu. Mol), 1H-pyrazole-3-boronic acid pinacol ester (21 mg, 105.84. Mu. Mol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane Complex (4 mg, 5.29. Mu. Mol), na 2 CO 3 (17 mg, 158.76. Mu. Mol) was added to a mixed solvent of 2mL of DMF and 0.5mL of water, N 2 Heating to 110 ℃ under protection for reaction for 3h. The system was diluted with water, extracted with EA three times (50 mL. Times.3), combined, dried over anhydrous sodium sulfate, and concentrated to give compound 23f (24 mg). MS (ESI, m/z): 460.2[ M+H ]] + .
Seventh step: 1- (4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) piperidin-4-ol (79)
Compound 23f (24 mg,52.92 μmol) was added to 10mL of trifluoroacetic acid, heated to 75 ℃ for 16h, the system concentrated and diluted with methanol, saturated potassium carbonate adjusted to ph=9, stirred at room temperature for 0.5h, filtered and purified by Prep-HPLC (eluting condition 3), and lyophilized to give formate 79s (1 mg) of compound 79.
MS(ESI,m/z):370.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.95(s,1H),8.25(s,1H),7.81(s,1H),7.51(s,1H),6.76(s,1H),5.92(s,2H),4.78(d,J＝3.8Hz,1H),3.78(s,3H),3.74–3.67(m,1H),3.46–3.41(m,2H),3.03–2.95(m,2H),1.95–1.85(m,2H),1.67–1.55(m,2H).
Example 24: 1-methyl-7- (1H-pyrazol-1-yl) -2- (3- (pyrrolidin-1-yl) propyl) -1H imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (80)
Compound 16a (36 mg,0.09 mmol), 1H-pyrazole (19 mg,0.28 mmol), cuI (35 mg,0.18 mmol), cesium carbonate (86 mg,0.26 mmol) were added to 5mL DMSO, N 2 Heating to 120 ℃ under protection, and stirring to react for 10h. Filtering with diatomite, diluting the filtrate with water, extracting with EA, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude productPurification by Prep-HPLC (elution condition 4) afforded compound 80 (5 mg).
MS(ESI,m/z):382.2[M+H] + .
1 HNMR(CD 3 OD-d 4 ,400MHz)δ8.25-8.26(m,1H),7.70(s,1H),7.28(s,1H),6.55(s,1H),3.88(s,3H),2.92-2.94(m,2H),2.74-2.77(m,6H),2.09-2.13(m,2H),1.84-1.86(m,4H).
Example 25:2- (3- (azetidin-1-yl) propyl) -1-methyl-7- (1H-pyrazol-1-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (81)
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The first step: 2- (3- (azetidin-1-yl) propyl) -1-methyl-7- (1H-pyrazol-1-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (81)
Compound 17a (35 mg,0.09 mmol), 1H-pyrazole (19 mg,0.28 mmol), cuI (35 mg,0.18 mmol), cesium carbonate (86 mg,0.26 mmol) were added to 5mL DMSO, N 2 Heating to 120 ℃ under protection, and stirring to react for 10h. The filtrate was diluted with water, extracted with EA, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give a crude product, which was purified by Prep-HPLC (eluting condition 4) to give compound 81 (5 mg).
MS(ESI,m/z):368.1[M+H] + .
1 HNMR(CD 3 OD-d 4 ,400MHz)δ8.29(s,1H),7.71(s,1H),7.31(s,1H),6.56(s,1H),3.92(s,3H),3.30-3.32(m,4H),2.91-2.94(m,2H),2.61-2.63(m,2H),2.12-2.15(m,2H),1.88-1.92(m,2H).
Example 26:
2- (3- (azetidin-3-yloxy) propyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (82)
The first step: sodium 1-tert-Butoxycarbonyl azetidinate (26 b)
Compound 26a (1.00 g,5.77 mmol) was added to 16mL of anhydrous THF, the system was cooled to 5℃under ice bath, 60% NaH (53 mg,1.39 mmol) was added to the system, and the reaction was allowed to proceed for 2h at room temperature. The reaction mixture was concentrated to give compound 26b (1.13 g).
And a second step of: tert-butyl 3- (3- (4-amino-7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propoxy) azetidine-1-carboxylate (61 d)
Compound 26b (1.13 g,5.77 mmol), 1k (104 mg,0.29 mmol) and tetrabutylammonium iodide (53 mg,0.14 mmol) were added to 20mL of toluene, and the mixture was heated to 100℃for 16h after nitrogen substitution. The reaction mixture was concentrated and diluted with water, extracted with EA three times (50 ml×3), and dried over anhydrous sodium sulfate after combination to give compound 26c (40 mg). MS (ESI, m/z): 496.1[ M+H ]] + .
And a third step of: 2- (3- (azetidin-3-yloxy) propyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (82)
Compound 26c (40 mg, 80.59. Mu. Mol) was added to 5mL of TFA and reacted at room temperature for 16h. The system was concentrated and diluted with methanol, saturated potassium carbonate adjusted to ph=10, and after filtration, purified by Prep-HPLC (elution condition 1) and lyophilized to give formate 82s (6 mg) of compound 82.
MS(ESI,m/z):384.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ13.05(s,1H),8.31(s,1H),7.81(s,1H),7.54(s,1H),6.76(d,J＝2.1Hz,1H),6.14(s,2H),4.37–4.30(m,1H),3.98–3.89(m,6H),3.73–3.67(m,2H),3.47(t,J＝6.2Hz,2H),2.95(t,J＝7.5Hz,2H),2.07–1.96(m,2H).
Example 27:
2- (3-morpholinopropyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (83)
The first step: 3- (4-amino-7-bromo-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propan-1-ol (27 a)
9g (500 mg,0.93 mmol) of the compound was added to 20mL of trifluoroacetic acid, heated to 75℃for 24 hours, the system was concentrated and diluted with EA, saturated sodium hydrogencarbonate solution was used to adjust the pH of the system to 8, and after stirring at room temperature for 0.5 hours, the layers were separated, and the organic layer was dried over anhydrous sodium sulfate. Column chromatography (eluent system A) gave compound 27a (280 mg). MS (ESI, m/z): 327.0[ M+H ] ] + .
And a second step of: 7-bromo-2- (3-chloropropyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (27 b)
Compound 27a (130 mg,0.40 mmol) was added to 9mL of thionyl chloride and reacted at room temperature for 24h, and the system was concentrated to give compound 27b (137 mg). MS (ESI, m/z): 344.9[ M+H ]] + .
And a third step of: 7-bromo-2- (3-morpholinopropyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (27 c)
Compound 27b (200 mg,0.58 mmol), morpholine (151 mg,1.74 mmol), TEA (234 mg,2.31 mmol), tetrabutylammonium iodide (21 mg, 57.86. Mu. Mol) were added to 15mL toluene, and the mixture was heated to 100℃for 4 hours after nitrogen substitution. The reaction mixture was concentrated and diluted with water, extracted with EA three times (50 ml×3), and dried over anhydrous sodium sulfate after combination to give compound 27c (55 mg). MS (ESI, m/z): 396.0[ M+H ]] + .
Fourth step: 2- (3-morpholinopropyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (83)
Compound 27c (55 mg,0.14 mmol), 1H-pyrazole-3-boronic acid pinacol ester (54 mg,0.28 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane Complex (11 mg, 13.88. Mu. Mol), na 2 CO 3 (44 mg,0.42 mmol) was added to a mixed solvent of 6mL DMF and 1.5mL water, N 2 Heating to 100 ℃ under protection for reaction for 4 hours. The system was filtered through celite, and the filtrate was purified by Prep-HPLC (elution condition 4) and lyophilized to give compound 83 (8 mg).
MS(ESI,m/z):384.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.91(s,1H),12.78(s,1H),7.82(s,1H),7.48(s,1H),6.74(s,1H),6.04(s,2H),3.59–3.53(m,4H),2.94–2.82(m,2H),2.41–2.31(m,6H),2.01–1.89(m,2H).
Example 28:
tert-butyl ((4-amino-1- (4-methoxybenzyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) (ethyl) carbamate (84)
2- ((ethylamino) methyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (88)
The first step: tert-butylethyl (2- ((7- ((4-methoxybenzyl) amino) thieno [3,2-b ] pyridin-6-yl) amino) -2-oxoethyl) carbamate (28 a)
Compound 9b (28 g,98.24 mmol), BOC-N-ethylglycine (23.93 g,117.89 mmol), HATU (63.85 g,196.48 mmol) were added to 500mL DMF and the reaction was continued with the addition of DIPEA (25.54 g,196.48 mmol) to the system for 16h at room temperature. The reaction mixture was diluted with water, extracted with EA three times (300 mL. Times.3), combined, dried over anhydrous sodium sulfate, and concentrated to give compound 28a (30 g). MS (ESI, m/z): 471.2[ M+H ]] + .
And a second step of: tert-butylethyl ((1- (4-methoxybenzyl) -1H imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) carbamate (28 b)
Compound 28a (30 g,63.83 mmol) and NaOH (12.76 g,0.32 mol) were added to 600mL of absolute ethanol and heated to 80℃for 4h. The system was concentrated and diluted with DCM and column chromatographed (eluent system a) to give compound 28b (25 g). MS (ESI, m/z): 453.1[ M+H ] ] + .
And a third step of: 2- ((Boc) (ethyl) amino) methyl) -1- (4-methoxybenzyl) -1H imidazo [4,5-d ] thieno [3,2-b ] pyridine 5-oxide (28 c)
Compound 28b (25 g,55.3 mmol) was added to 500mL of chloroform, and m-CPBA (19.08 g,110.6 mmol) was added to the system and reacted at room temperature for 4h. The reaction mixture was washed twice with saturated sodium hydrogencarbonate (300 mL. Times.2), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 28c (23 g). MS (ESI, m/z): 469.1[ M+H ]] + .
Fourth step: tert-butyl ((4-amino-1- (4-methoxybenzyl) -1H imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) (ethyl) carbamate (28 d)
Compound 28c (23 g,49.14 mmol) was added to 500mL of DCM, and 200mL of ammonia and p-toluenesulfonyl chloride (18.74 g,98.28 mmol) were added sequentially to the system and reacted at room temperature for 3h. The reaction mixture was diluted with DCM, washed three times with water (400 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate. Column chromatography (eluent system A) gave compound 28d (18 g). MS (ESI, m/z): 468.1[ M+H ] +.
Fifth step: tert-butyl ((4-amino-7-bromo-1- (4-methoxybenzyl) -1H imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) (ethyl) carbamate (28 e)
Compound 28d (18 g,38.54 mmol) was added to 360mL of DMF and NBS (13.72 g,77.08 mmol) was added to the system and heated to 65℃for 5h. The reaction mixture was diluted with water, extracted with EA three times (200 mL. Times.3), dried over anhydrous sodium sulfate, and subjected to column chromatography (eluent system A) to give compound 28e (10 g). MS (ESI, m/z): 546.1[ M+H ] +.
Sixth step: tert-butyl ((4-amino-1- (4-methoxybenzyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) (ethyl) carbamate (84)
Compound 28e (10 g,18.35 mmol), 1H-pyrazole-3-boronic acid pinacol ester (5.34 g,27.53 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane Complex (1.6 g,1.8 mmol), na 2 CO 3 (3.89 g,36.7 mmol) was added to a mixed solvent of 200mL DMF and 50mL water, N 2 Heating to 120 ℃ under protection for reaction for 2h. The system was filtered through celite, the filtrate was diluted with water, extracted with EA three times (100 mL. Times.3), combined, dried over anhydrous sodium sulfate, and purified by column chromatography (eluent system A) to give crude compound 84 (5 g). 50mg was isolated and purified by Prep-HPLC (elution condition 4) and lyophilized to give compound 84 (10 mg).
MS(ESI,m/z):534.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.92(s,1H),7.79(t,J＝1.7Hz,1H),7.48(s,1H),6.94–6.86(m,4H),6.72(t,J＝2.1Hz,1H),6.23(s,2H),5.58(s,2H),4.72(s,2H),3.68(s,3H),3.13(s,2H),1.25(s,9H),1.02(t,J＝6.9Hz,3H).
Seventh step: 2- ((ethylamino) methyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (88)
Compound 84 (100 mg,196 μmol) was added to 5mL of trifluoroacetic acid, heated to 75 ℃ for reaction 16h, concentrated and diluted with EA, saturated sodium bicarbonate solution adjusted system ph=8, stirred at room temperature for 0.5h, then separated, dried over anhydrous sodium sulfate, filtered through celite, and the filtrate was isolated and purified by Prep-HPLC (eluting condition 4), and lyophilized to give compound 88 (10 mg).
MS(ESI,m/z):314.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.92(s,2H),7.79(d,J＝2.3Hz,1H),7.49(s,1H),6.72(d,J＝2.3Hz,1H),6.21(s,2H),3.98(s,2H),2.67–2.62(m,2H),1.09(t,J＝7.1Hz,3H).
Example 29:
n- ((4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethyl-2- (m-tolyl) acetamide (85)
Compound 88 (70 mg,0.17 mmol), m-methylphenylacetic acid (37 mg,0.25 mmol), HATU (127.40 mg,0.34 mmol) were added to 3mL DMF and the reaction was continued with the addition of DIPEA (144 mg,1.12 mmol) to the system at room temperature for 2h. Purification by Prep-HPLC (elution condition 5) and lyophilization afforded compound 85 (4 mg).
MS(ESI,m/z):446.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.92(s,1H),8.19(s,1H),7.81(s,1H),7.50(d,J＝8.6Hz,1H),7.18(dd,J＝14.9,7.3Hz,1H),7.12–6.97(m,3H),6.73(s,1H),6.22(s,2H),4.88–4.69(m,2H),3.82–3.75(m,2H),3.56–3.48(m,2H),2.28–2.21(m,3H),1.12–1.00(m,3H).
Example 30:
n- ((4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylmorpholine-4-carboxamide (86)
Compound 88 (70 mg,0.17 mmol) and DIPEA (115 mg,0.89 mmol) were added to 2mL of DMF, and 4-morpholinocarbonyl chloride (50 mg,0.34 mmol) was added to the system and reacted at room temperature for 2h. Purification by Prep-HPLC (elution condition 3) and lyophilization afforded compound 86 (10 mg).
MS(ESI,m/z):427.2[M+H] + .
1 H NMR(DMSO-d6,400MHz)δ12.93(s,1H),7.81(s,1H),7.49(s,1H),6.74(s,1H),6.45–6.10(m,2H),4.55(s,2H),3.75–3.55(m,5H),3.22–3.08(m,5H),1.11(s,3H).
Example 31:
n- ((4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethyl-1-methyl-1H-pyrrole-2-carboxamide (87)
Compound 88 (70 mg,0.17 mmol), N-methyl-2-pyrrole carboxylic acid (31 mg,0.25 mmol), HATU (127.40 mg,0.34 mmol) were added to 3mL DMF and the reaction was continued with the addition of DIPEA (144 mg,1.12 mmol) to the system at room temperature for 2h. Purification by Prep-HPLC (elution condition 4) and lyophilization afforded compound 87 (3 mg).
MS(ESI,m/z):421.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.94(s,1H),8.18(s,1H),7.80(s,1H),7.50(s,1H),6.93(s,1H),6.74(s,1H),6.45(s,1H),6.22(s,2H),6.08–5.98(m,1H),4.94–4.85(m,2H),3.72(s,3H),3.60(s,2H),1.19(t,J＝6.9Hz,3H).
Example 32:
n- ((4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylacetamide (89)
Compound 88 (100 mg,0.32 mmol), acetic anhydride (65.15 mg,0.64 mmol), triethylamine (161.15 mg,1.6 mmol) were added to 3mL DCM and reacted at room temperature for 2h. Purification by Prep-HPLC (elution condition 3) and lyophilization afforded compound 89 (5 mg).
MS(ESI,m/z):356.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.92(s,2H),7.80(s,1H),7.50(d,J＝8.6Hz,1H),6.75(m,1H),6.28(s,2H),4.80–4.73(m,2H),3.48–3.35(m,2H),2.16–2.14(m,3H),1.16–0.99(m,3H).
Example 33:
n- ((4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylcyclopropane carboxamide (90)
Compound 88 (100 mg,0.32 mmol), cyclopropanecarboxylic acid (32.97 mg,0.38 mmol), HATU (242.52 mg,0.64 mmol) were added to 2mL DMF and the reaction was continued with the addition of DIPEA (206.20 mg,1.6 mmol) to the system at room temperature for 2h. Purification by Prep-HPLC (elution condition 3) and lyophilization afforded formate salt 90s of compound 90 (5 mg).
MS(ESI,m/z):382.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.93(s,2H),8.28(s,1H),7.80(s,1H),7.49(m,1H),6.73(s,1H),6.27(s,2H),5.00–4.74(m,2H),3.68–3.43(m,2H),2.03–1.97(m,1H),1.21–1.03(m,3H),0.84–0.70(m,4H).
Example 34:
1- ((4-amino-1-ethyl-7- (thiophen-2-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) pyrrolidin-2-one (91)
The first step: synthesis of the Compound N-ethyl-6-nitrothieno [3,2-b ] pyridin-7-amine (91 a)
TEA (2.07 g,20.50 mmol) in turn, aqueous ethylamine (68%, 5 mL) was added to a solution of Compound 1c (1.1 g,5.13 mmol) in NMP (5 mL) at room temperature. The reaction was carried out at room temperature for 1h. The reaction mixture was poured into water (20 mL) and a solid was precipitated. Filtering to obtain compound 91a (900 mg). MS (ESI, m/z): 224.1[ M+H ] ] +
And a second step of: synthesis of Compound N7 ethyl thieno [3,2-b ] pyridine-6, 7-diamine (91 b)
Palladium on carbon (447.93. Mu. Mol) was added to a solution of compound 91a (1 g,4.48 mmol) in methanol (10 mL) at room temperature. The reaction was then stirred under a hydrogen atmosphere for 5h. Palladium on carbon was removed by filtration, and the mother liquor was directly concentrated to dryness to give compound 91b (720 mg). MS (ESI, m/z): 194.1[ M+H ]] +
And a third step of: synthesis of Compound 2- (2-oxopyrrolidin-1-yl) ethyl acetate (91 d)
Cesium carbonate (22.91 g,70.50 mmol) was added to a solution of ethyl bromoacetate (3.92 g,23.50 mmol), 91c (2 g,23.50 mmol) in DMF (5 mL) at room temperature, and then the reaction was stirred at room temperature for 16h. Then ethyl acetate is added and the mixture is washed with clear water. Extraction and concentration gave compound 91d (3 g). MS (ESI, mz): 172.2[ M+1 ]] + 。
Fourth step: synthesis of Compound 2- (2-oxopyrrolidin-1-yl) acetic acid (91 e)
Sodium hydroxide (1.40 g,35.05 mmol) was added to a solution of compound 91d (3 g,17.52 mmol) in water (2 mL) and ethanol (5 mL) at room temperature. Then reacted at room temperature for 4 hours. After ph=3 was adjusted with dilute hydrochloric acid, the compound 91e (700 mg) was obtained by column chromatography purification (eluting system a).
1 H NMR(400MHz,DMSO-d 6 )δ3.49(s,2H),3.39(t,J＝7.0Hz,2H),2.17(t,J＝8.1Hz,2H),1.93 -1.83(m,2H).
Fifth step: synthesis of the Compound N- (7-ethylamino) thieno [3,2-b ] pyridin-6-yl) -2- (2-oxopyrrolidin-1-yl) acetamide (91 f)
HATU (983.09 mg,2.59 mmol), DIPEA (668.71 mg,5.17 mmol) were added sequentially to a solution of compound 91e (370.31 mg,2.59 mmol), compound 91b (500 mg,2.59 mmol) in DMF (3 mL) at room temperature. The reaction was then maintained at room temperature for 16h. Then, after washing with water, the ethyl acetate layer was dried and concentrated, followed by separation and purification by column chromatography (eluting system a) to give compound 91f (500 mg). MS (ESI, mz): 318.2[ M+1 ]] +
Sixth step: synthesis of Compound 1- ((1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) pyrrolidin-2-one (91 g)
Sodium hydroxide (125.63 mg,3.14 mmol) was added to a solution of compound 91f (500 mg,1.57 mmol) in ethanol (4 mL) at room temperature. Then the temperature is raised to 90 ℃ for reaction for 4 hours. The reaction was quenched by addition of dilute hydrochloric acid to adjust ph=7, and purified by column chromatography (eluting system a) to give 91g (300 mg) of the compound. MS (ESI, m/z): 301.1[ M+H ]] + 。
Seventh step: synthesis of Compound 1- ((7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) pyrrolidin-2-one (91H)
NBS (177.76 mg, 998.74. Mu. Mol) was added to a mixed solution of 91g (300 mg, 998.74. Mu. Mol) of compound in chloroform (2 mL) and acetic acid (2 mL) at room temperature, followed by stirring at room temperature for 16h. The reaction was quenched with water and extracted with DCM. After concentration, the compound was purified by preparative plate separation (eluting system a) to give compound 91h (150 mg). MS (ESI, m/z): 379.0[ M+H ] ] + 。
Eighth step: the compound 7-bromo-1-methyl-2- ((2-oxopyrrolidin-1-yl) methyl) -1H imidazo [4,5-d ] thieno [3,2-b ] pyridine 5-oxide (91 i)
Metroproperoxide benzoic acid (102.04 mg, 593.24. Mu. Mol) was added to a solution of compound 91h (150 mg, 395.49. Mu. Mol) in DCM (4 mL) at room temperature, and then left to react at room temperature for 4h. The reaction was quenched by addition of saturated sodium bicarbonate solution and then extracted with DCM. The organic layer was dried and concentrated to give compound 91i (120 mg). MS (ESI, m/z): 397.0[ M+H ]] + 。
Ninth step: compound 1- ((4-amino-7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) pyrrolidin-2-one (91 j)
Ammonia (5 mL) and p-toluenesulfonyl chloride (57.88 mg, 303.59. Mu. Mol) were added sequentially to a solution of compound 91i (120 mg, 303.59. Mu. Mol) in DCM (5 mL) at room temperature, and the reaction was stirred at room temperature for 2h. The dry solvent was then concentrated directly and purified by preparative plate (eluting system a) to give compound 91j (30 mg). MS (ESI, m/z): 395.0[ M+H ]] + 。
Tenth step: synthesis of Compound 1- ((4-amino-1-ethyl-7- (thiophen-2-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) pyrrolidin-2-one (91)
Pd (dppf) Cl was added sequentially at room temperature 2 (2.78 mg, 3.80. Mu. Mol), potassium carbonate (21.00 mg, 152.17. Mu. Mol), 2-thiopheneboronic acid (9.74 mg, 76.09. Mu. Mol), compound 91j (30 mg, 76.09. Mu. Mol) in water (0.5 mL), dioxane (2 mL) were added. Then the temperature is raised to 90 ℃ for reaction for 5 hours under the protection of nitrogen. Ethyl acetate 5mL was added and the reaction mixture was diluted. Then washed with water, and the ethyl acetate layer was concentrated by drying, and purified by Prep-HPLC (eluting condition 5) to give compound 91 (15 mg). MS (ESI, m/z): 398.1[ M+H ] ] + 。
1 H NMR(400MHz，DMSO-d 6 )δ7.60(dd，J＝5.1，1.0Hz，1H)，7.48(dd，J＝3.6，1.0Hz，1H)，7.46(s，1H)，7.15(dd，J＝5.1，3.6Hz，1H)，6.40(s，2H)，4.71(s，2H)，4.32(q，J＝7.1Hz，2H)，3.36(m，2H)，2.33(t，J＝8.1Hz，2H)，1.95(dd，J＝15.0，7.5Hz，2H)，1.37(t，J＝7.2Hz，3H).
Example 35:
n- ((4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethyl-1-methylpiperidine-4-carboxamide (92)
Compound 88 (100 mg,0.32 mmol), 1-methylpiperidine-4-carboxylic acid (54.34 mg,0.38 mmol), HATU (242.52 mg,0.64 mmol) were added to 2mL DMF and the reaction was continued with the addition of DIPEA (206.20 mg,1.6 mmol) to the system for 2h at room temperature. Purification by Prep-HPLC (elution condition 4) and lyophilization afforded compound 92 (2 mg).
MS(ESI,m/z):439.1[M+H] + .
1 HNMR(DMSO-d 6 ,400MHz)δ12.93(s,2H),7.81(s,1H),7.50(s,1H),6.74(s,1H),6.12(s,2H),4.83–4.71(m,2H),3.51(s,2H),2.80–2.67(m,2H),2.15–2.11(m,3H),1.92–1.84(m,2H),1.68–1.58(m,4H),1.24–0.99(m,3H).
Example 36:
n- ((4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylcyclopropane carboxamide (93)
The first step: tert-butylethyl (2- ((7-methylamino) thieno [3,2-b ] pyridin-6-yl) amino) -2-oxoethyl) carbamate (93 a)
Compound 1e (5.65 g,31.52 mmol), boc-N-ethylglycine (7.69 g,37.83 mmol), HATU (23.11 g,60.78 mmol) were added to 30mL DMF and the reaction was continued with the addition of DIPEA (20.37 g,0.16 mol) at room temperature for 16h. The reaction mixture was diluted with water, extracted three times with EA, dried over anhydrous sodium sulfate, and concentrated to give compound 93a (11.49 g). MS (ESI, m/z): 365.2[ M+H ]] + .
And a second step of: tert-butylethyl ((1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) carbamate (93 b)
Compound 93a (11.49 g,31.52 mmol) and sodium hydroxide (6.31 g,0.16 mol) were added to 100mL of absolute ethanol and heated to 90℃for 4h. Concentrated, diluted with water, extracted with EA three times (100 ml×3), and dried over anhydrous sodium sulfate. Column chromatography (eluent system B) gave compound 93B (9.66 g). MS (ESI, m/z): 347.2[ M+H ]] + .
And a third step of: tert-butyl (7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) (ethyl) carbamate (93 c)
Compound 93b (9.56 g,27.59 mmol) was added to 20To the system was added NBS (9.56 g,53.71 mol) in a mixed solvent of 0mL of DMF and 50mL of glacial acetic acid, and the mixture was heated to 65℃to react for 1 hour. The reaction mixture was diluted with water, extracted three times with EA, and dried over anhydrous sodium sulfate after combining. Column chromatography (eluent system B) gave compound 93c (7.23 g). MS (ESI, m/z): 425.1[ M+H ]] + .
Fourth step: 7-bromo-2- ((tert-butoxycarbonyl) (ethyl) amino) methyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridine-5-oxide (93 d)
Compound 93c (7.18 g,16.88 mmol) was added to 280mL DCM and the addition of mCPBA (5.83 g,33.76 mol) to the system continued and reacted at room temperature for 16h. The reaction mixture was washed three times with saturated sodium hydrogencarbonate (100 mL. Times.3), and the organic layer was dried over anhydrous sodium sulfate and concentrated to give compound 93d (7.45 g). MS (ESI, m/z): 441.1[ M+H ] ] + .
Fifth step: tert-butyl ((4-amino-7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) (ethyl) carbamate (93 e)
Compound 93d (7.45 g,16.88 mmol) was added to 180mL of DCM and the reaction was continued with 60mL of ammonia and p-toluenesulfonyl chloride (3.30 g,46.79 mmol) in sequence at room temperature for 5h. The reaction mixture was diluted with DCM, washed three times with water (200 mL. Times.3) and the organic layer was dried over anhydrous sodium sulfate. Column chromatography (eluent system A) gave compound 93e (4.18 g). MS (ESI, m/z): 440.1[ M+H ]] + .
Sixth step: tert-butyl ((4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) (ethyl) carbamate (93 f)
Compound 93e (4.08 g,8.34 mmol), 1H-pyrazole-3-boronic acid pinacol ester (4.08 g,21.03 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane Complex (1.02 g,1.2 mmol), na 2 CO 3 (2.65 g,25.02 mmol) in a mixed solvent of 80mL DMF and 20mL water, N 2 Heating to 100 ℃ under protection for reaction for 4 hours. The system was filtered through celite, the filtrate was diluted with water, extracted three times with EA, and dried over anhydrous sodium sulfate after combination. Column chromatography (eluent system A) gave compound 93f (4.1 g). MS (ESI, m/z): 428.2[ M+H ] ] + .
Seventh step: 2- ((ethylamino) methyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine hydrochloride (93 g)
Compound 93f (3.56 g,8.33 mmol) was added to 30mL 4N dioxane hydrochloride and reacted at room temperature for 16h. The reaction mixture was concentrated to give 93g (3.46 g) of a compound. MS (ESI, m/z): 328.2[ M+H ]] + .
Eighth step: n- ((4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylcyclopropane carboxamide (93)
93g (70 mg,0.20 mmol) of compound, cyclopropanecarboxylic acid (18 mg,0.21 mmol) and HATU (109.72 mg,0.29 mmol) were added to 3mL of DMF and the reaction was continued with the addition of DIPEA (124 mg,0.96 mmol) to the system at room temperature for 2h. Purification by Prep-HPLC (elution condition 4) and lyophilization afforded compound 93 (16 mg).
MS(ESI,m/z):396.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.98(s,1H),7.83(s,1H),7.54(s,1H),6.78(s,1H),6.35–6.13(m,2H),5.14–4.78(m,2H),4.00–3.86(m,3H),3.65–3.37(m,2H),2.10–1.92(m,1H),1.17–0.96(m,3H),0.86–0.67(m,4H).
Example 37:
n- ((4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylacetamide (94)
93g (70 mg,0.20 mmol) of compound, acetic acid (13 mg,0.21 mmol) and HATU (109.72 mg,0.29 mmol) were added to 3mL of DMF and the reaction was continued with the addition of DIPEA (124 mg,0.96 mmol) to the system at room temperature for 2h. Purification by Prep-HPLC (elution condition 4) and lyophilization afforded compound 94 (9 mg).
MS(ESI,m/z):370.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.99(s,1H),7.83(s,1H),7.54(d,J＝3.5Hz,1H),6.79(t,J＝2.0Hz,1H),6.38–6.13(m,2H),4.92–4.78(m,2H),4.02–3.87(m,3H),3.42–3.35(m,2H),2.11(s,3H),1.11–0.95(m,3H).
Example 38:
2- (3- (2, 6-Dimethylmorpholine) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (95)
The first step: 7-bromo-2- (3- (2, 6-dimethylmorpholinopropyl) -1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (95 a)
Compound 9i (80 mg,0.17 mmol), 2, 6-dimethylmorpholine (99 mg,0.86 mmol), TEA (70 mg,0.69 mmol), tetrabutylammonium iodide (6 mg,0.02 mmol) were added to 8mL toluene, and the mixture was heated to 100℃for 16h after nitrogen substitution. The reaction mixture was concentrated and diluted with water, extracted with EA three times (20 mL. Times.3), dried over anhydrous sodium sulfate, and subjected to thin layer chromatography (eluent system A) to give compound 95a (48 mg).
MS(ESI,m/z):544.1[M+H] + .
And a second step of: 2- (3- (2, 6-Dimethylmorpholine) propyl) -1- (4-methoxybenzyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (95 b)
Compound 95a (48 mg,0.09 mmol), 1H-pyrazole-3-boronic acid pinacol ester (34 mg,0.18 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane Complex (7.2 mg, 8.82. Mu. Mol), na 2 CO 3 (28 mg,0.26 mmol) was added to a mixed solvent of 4mL DMF and 1mL water, N 2 Heating to 100 ℃ under protection for reaction for 4 hours. The system was concentrated directly to give compound 95b (47 mg). MS (ESI, m/z): 532.2[ M+H ] ] + .
And a third step of: 2- (3- (2, 6-Dimethylmorpholine) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (95)
Compound 95b (80 mg,0.09 mmol) was added to 5mL of trifluoroacetic acid, heated to 75 ℃ for 16h, the system concentrated and diluted with methanol, saturated potassium carbonate adjusted to ph=8, filtered and purified by Prep-HPLC (eluting condition 3) to give formate salt 95s of compound 95 (4 mg) by lyophilization.
MS(ESI,m/z):412.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.93(s,1H),8.21(s,2H),7.79(s,1H),7.49(s,1H),6.73(s,1H),6.09(s,2H),3.53–3.49(m,2H),2.87(t,J＝7.6Hz,2H),2.75(d,J＝10.2Hz,2H),2.35(t,J＝7.0Hz,2H),2.02–1.89(m,2H),1.57(t,J＝10.7Hz,2H),1.03(d,J＝6.3Hz,6H).
Example 39:
n- ((4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylcarboxamide (96)
Compound 88 (80 mg,0.26 mmol), ethyl formate (95 mg,1.28 mmol), TEA (78 mg,0.77 mmol) were added to 5mL of absolute ethanol, heated to 52℃for 4h, ethyl formate (95 mg,1.28 mmol) was further added, reacted at 52℃for 6h, the system was concentrated, purified by Prep-HPLC (elution condition 5), and lyophilized to give compound 96 (7 mg).
MS(ESI,m/z):342.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ13.40–12.70(m,2H),8.27(d,J＝16.9Hz,1H),7.82(s,1H),7.50(s,1H),6.75(s,1H),6.35–6.05(m,2H),4.71(s,2H),3.46–3.38(m,1H),3.30–3.22(m,1H),1.17–0.92(m,3H).
Example 40:
n- ((4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylpropionamide (97)
93g (70 mg,0.20 mmol) of the compound, propionic acid (16 mg,0.21 mmol) and HATU (109.72 mg,0.29 mmol) were added to 3mL of DMF and the reaction was continued with the addition of DIPEA (124 mg,0.96 mmol) to the system at room temperature for 2h. Purification by Prep-HPLC (elution condition 3) and lyophilization afforded formate 97s (7 mg) of compound 97.
MS(ESI,m/z):384.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.98(s,1H),8.15(s,1H),7.83(s,1H),7.54(s,1H),6.78(s,1H),6.30–6.10(m,2H),4.91–4.78(m,2H),3.99–3.87(m,3H),3.42–3.37(m,2H),2.45–2.38(m,2H),1.09–0.96(m,6H).
Example 41:
n- (4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethyl-2- (3-methylphenyl) acetamide (98)
93g (30 mg, 82.45. Mu. Mol), m-methylphenylacetic acid (12 mg, 82.45. Mu. Mol), HBTU (32 mg, 123.99. Mu. Mol) were added to 2mL of DMF and the system was continuously charged with DIPEA (32 mg, 247.34. Mu. Mol) and reacted at room temperature for 1 hour. Purification by Prep-HPLC (elution condition 4) and lyophilization afforded compound 98 (13 mg).
MS(ESI,m/z):460.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ13.00(s,1H),7.84(s,1H),7.55(d,J＝5.5Hz,1H),7.23–6.97(m,4H),6.79(s,1H),6.34–6.11(m,2H),4.98–4.78(m,2H),3.95–3.86(m,3H),3.75(s,2H),3.49–3.41(m,2H),2.30–2.20(m,3H),1.08–0.98(m,3H).
Example 42:
n- (4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethyl-1-methyl-1H-pyrrole-2-carboxamide (99)
93g (30 mg, 82.45. Mu. Mol), N-methyl-2-pyrrole carboxylic acid (10 mg, 82.45. Mu. Mol), HBTU (32 mg, 123.99. Mu. Mol) were added to 2mL of DMF and the reaction was continued with the addition of DIPEA (32 mg, 247.34. Mu. Mol) to the system at room temperature for 4 hours. Purification by Prep-HPLC (elution condition 4) and lyophilization afforded compound 99 (6 mg).
MS(ESI,m/z):435.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.99(s,1H),7.83(s,1H),7.55(s,1H),6.92(t,J＝2.0Hz,1H),6.79(s,1H),6.44(dd,J＝3.8,1.6Hz,1H),6.20(s,2H),6.02(dd,J＝3.7,2.6Hz,1H),5.01(s,2H),3.92(s,3H),3.70(s,3H),3.60–3.50(m,2H),1.13(t,J＝7.1Hz,3H).
Example 43:
n- ((4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylpropionamide (100)
Compound 88 (100 mg,0.32 mmol), propionic anhydride (83.20 mg,0.64 mmol), triethylamine (161.15 mg,1.6 mmol) were added to 3mL DCM and reacted at room temperature for 2h. The system was directly concentrated to dryness, purified by Prep-HPLC (elution condition 4), and lyophilized to give compound 100 (7 mg).
MS(ESI,m/z):370.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.94(s,2H),7.81(s,1H),7.51(s,1H),6.74(s,1H),6.23(s,2H),4.80–4.73(m,2H),3.50–3.38(m,2H),2.53–2.42(m,2H),1.15–0.97(m,6H).
Example 44:
n- ((4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylcarboxamide (101)
93g (70 mg,0.19 mmol) of compound, formic acid (18 mg,0.38 mmol) and HATU (109.72 mg,0.29 mmol) were added to 3mL of DMF and the reaction was continued with the addition of DIPEA (124 mg,0.96 mmol) to the system at room temperature for 2h. Purification by Prep-HPLC (elution condition 4) and lyophilization afforded compound 101 (20 mg).
MS(ESI,m/z):356.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.94(s,1H),8.27-8.14(m,1H),7.77(s,1H),7.49(s,1H),6.72(s,1H),6.24(s,2H),4.81–4.70(m,2H),3.90–3.83(m,3H),3.27–3.19(m,2H),1.02(t,J＝7.1Hz,2H),0.88(t,J＝7.1Hz,1H).
Example 45:
2- ((4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-)) methyl) (ethyl) amino) acetic acid tert-butyl ester (102)
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93g (100 mg,0.27 mmol) of the compound, t-butyl bromoacetate (80 mg,0.42 mmol) and potassium carbonate (114 mg,0.83 mmol) were added to 5mL of DMF, reacted at 25℃for 4 hours, water was added, extracted three times with EA, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by Prep-HPLC (elution condition 5) and lyophilization afforded compound 102 (70 mg).
MS(ESI,m/z):442.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ13.01(s,1H),7.84(s,1H),7.54(s,1H),6.79(s,1H),6.38(s,2H),4.05(s,3H),4.02(s,2H),3.30(s,2H),2.65(d,J＝7.2Hz,2H),1.36(s,9H),0.99(t,J＝7.1Hz,3H).
Example 46:
n- ((4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethyl-1-methylpiperidine-4-carboxamide (103)
93g (70 mg,0.19 mmol) of the compound, 1-methylpiperidine-4-carboxylic acid (55 mg,0.38 mmol) and HATU (109.72 mg,0.29 mmol) were added to 3mL of DMF and the reaction was continued with the addition of DIPEA (124 mg,0.96 mmol) to the system at room temperature for 2h. Purification by Prep-HPLC (elution condition 3) and lyophilization afforded formate salt 103s of compound 103 (7 mg).
MS(ESI,m/z):453.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ13.01(s,1H),8.21(s,1H),7.82(s,1H),7.55(m,1H),6.79-6.72(m,1H),6.26-6.14(m,2H),4.93-4.85(m,2H),3.97–3.85(m,3H),3.44–3.35(m,2H),3.0-2.97(m,2H),2.77–2.58(m,1H),2.33(s,3H),2.31-2.25(m,2H),1.77–1.67(m,4H),1.10-0.98(m,3H)
Example 47:
n- (4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) methyl) -N-ethylmorpholine-4-carboxamide (104)
93g (50 mg,0.14 mmol) of the compound, DIPEA (53 mg,0.41 mmol) and 3mL of DMF were added, the temperature of the system was lowered to 0℃and 4-morpholinocarbonyl chloride (21 mg,0.14 mmol) was further added to the system and reacted at 0℃for 7 hours. Purification by Prep-HPLC (elution condition 4) and lyophilization afforded compound 104 (37 mg).
MS(ESI,m/z):441.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.98(s,1H),7.88–7.78(m,1H),7.54(s,1H),6.78(t,J＝2.0Hz,1H),6.20(s,2H),4.63(s,2H),3.90(s,3H),3.63–3.55(m,4H),3.23–3.16(m,6H),1.06(t,J＝7.0Hz,3H).
Example 48:
2- (3- (4- (methylsulfonyl) piperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (105)
The first step: 7-bromo-1- (4-methoxybenzyl) -2- (3- (4- (methylsulfonyl) piperazin-1-yl) propyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (105 a)
Compound 9i (100 mg,0.21 mmol), 1-methylsulfonylpiperazine (51.66 mg,0.32 mmol), tetrabutylammonium iodide (14.76 mg,0.04 mmol), TEA (42.42 mg,0.42 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 105a (80 mg).
MS(ESI,m/z):594.1[M+H] + .
And a second step of: 1- (4-methoxybenzyl) -2- (3- (4- (methylsulfonyl) piperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (105 b)
Compound 105a (80 mg,0.13 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (50.7 mg,0.26 mmol), pd (dppf) Cl 2 (9 mg,0.01 mmol), sodium carbonate (31.30 mg,0.29 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. The reaction solvent was concentrated to dryness under reduced pressure and subjected to flash column chromatography (eluent system a) to give compound 105b (70 mg).
And a third step of: 2- (3- (4- (methylsulfonyl) piperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (105)
Compound 105b (70 mg,0.12 mmol) and TFA were added to a single-port flask and heated to 75 ℃ for reaction 12h. The reaction solvent was dried by spin-drying, isolated and purified by Prep-HPLC (elution condition 3), and lyophilized to give formate 105s (7 mg) of compound 105.
MS(ESI,m/z):461.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.94(s,2H),8.19(s,1H),7.80(d,J＝2.4Hz,1H),7.49(s,1H),6.73(d,J＝2.0Hz,1H),6.16(s,2H),3.04–3.03(m,4H),2.90–2.86(t,J＝7.6Hz,9.2Hz,2H),2.79(s,3H),2.47–2.41(m,6H),1.99–1.92(m,2H).
Example 49:
2- ((2, 6-Dimethylmorpholine) methyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (106)
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The first step: 7-bromo-2- ((2, 6-dimethylmorpholinomethyl) -1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (106 a)
11g (80 mg,0.24 mmol) of the compound, 2, -6-dimethylmorpholine (167 mg,1.45 mmol), 18-crown-6 (13 mg,0.048 mmol) and TEA (146 mg,1.45 mmol) were added to 5mL of toluene, N 2 Heating to 100 ℃ under protection to react for 16h. The spin-dried reaction solvent was subjected to flash column chromatography (eluent system a) to give compound 106a (75 mg). MS (ESI, m/z): 410.1[ M+H ]] + .
And a second step of: 2- ((2, 6-Dimethylmorpholine) methyl) -1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (106)
Compound 106a (75 mg,0.18 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (70 mg,0.36 mmol), pd (dppf) Cl 2 (45 mg,0.054 mmol), sodium carbonate (58 mg,0.54 mmol) and N in a mixed solvent of 2.0mL DMF and 0.5mL water 2 Heating to 110 ℃ under protection, and stirring to react for 16h. The reaction solvent was concentrated to dryness under reduced pressure, and isolated and purified by Prep-HPLC (eluting condition 5) to give compound 106 (15 mg).
MS(ESI,m/z):398.1[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ12.99(s,1H),7.83(s,1H),7.54(s,1H),6.78(s,1H),6.26(s,2H),4.09–3.97(m,3H),3.95–3.89(m,0.5H),3.80–3.72(m,1.5H),3.70–3.65(m,0.5H),3.61–3.52(m,1.5H),2.75–2.70(m,1.5H),2.49–2.44(m,0.5H),2.16–2.10(m,0.5H),1.77(t,J＝10.7Hz,1.5H),1.12(d,J＝6.4Hz,1.5H),1.03(d,J＝6.4Hz,4.5H).
Example 50:
1- (4- (3- (4-amino-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) piperazin-1-yl) ethanone (107)
The first step: 1- (4- (3- (4-amino-7-bromo-1- (4-methoxybenzyl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) piperazin-1-yl) ethanone (107 a)
Compound 9i (100 mg,0.21 mmol), 1-acetylpiperazine (40.96 mg,0.32 mmol), tetrabutylammonium iodide (14.76 mg,0.04 mmol), TEA (42.42 mg,0.42 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 107a (75 mg).
MS(ESI,m/z):558.1[M+H] + .
And a second step of: 1- (4- (3- (4-amino-1- (4-methoxybenzyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) piperazin-1-yl) ethanone (107 b)
Compound 107a (75 mg,0.13 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (50.7 mg,0.26 mmol), pd (dppf) Cl 2 (9 mg,0.01 mmol), sodium carbonate (31.30 mg,0.29 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. The reaction solvent was concentrated to dryness under reduced pressure and subjected to flash column chromatography (eluent system a) to give compound 107b (60 mg).
And a third step of: 2- (3- (4- (methylsulfonyl) piperazin-1-yl) propyl) -7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-4-amine (107)
Compound 107b (60 mg,0.11 mmol) and TFA were added to a single-port flask and reacted for 12h at 75 ℃. The reaction solvent was dried by spin-drying, isolated and purified by Prep-HPLC (elution condition 3), and lyophilized to give formate salt 107s (5 mg) of compound 107.
MS(ESI,m/z):425.2[M+H] + .
1 H NMR(DMSO-d 6 ,400MHz)δ8.28(s,2H),7.80(d,J＝2.0Hz,1H),7.49(s,1H),6.73(d,J＝2.4Hz,1H),6.20(s,2H),3.43–3.38(m,4H),2.88(t,J＝7.6Hz,7.6Hz,2H),2.41–2.31(m,6H),2.00–1.93(m,5H).
Example 51:
1- (4- (3- (4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) piperazin-1-yl) ethanone (108)
The first step: 1- (4- (3- (4-amino-7-bromo-1-methyl-1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) piperazin-1-yl) ethanone (108 b)
A solution of compound 1k (50 mg, 139.02. Mu. Mol), compound 108a (26.73 mg, 208.52. Mu. Mol), TEA (56.27 mg, 556.06. Mu. Mol) and tetrabutylammonium iodide (51.35 mg, 139.02. Mu. Mol) in toluene (4 mL) was heated to 99℃at room temperature and reacted for 16 hours. The reaction mixture was concentrated to dryness, and purified by preparative plate (eluting system a) to give compound 108b (50 mg). MS (ESI, m/z): 439.1[ M+H ]] + 。
And a second step of: 1- (4- (3- (4-amino-1-methyl-7- (1H-pyrazol-3-yl) -1H-imidazo [4,5-d ] thieno [3,2-b ] pyridin-2-yl) propyl) piperazin-1-yl) ethanone (108)
Pd (dppf) Cl at room temperature 2 (4.86 mg, 6.65. Mu. Mol), potassium phosphate (112.72 mg, 531.70. Mu. Mol) was added to a dioxane (2 mL)/water (0.5 mL) mixed solvent of compound 108c (33.53 mg, 172.80. Mu. Mol), 108b (60 mg, 132.92. Mu. Mol). After 2 minutes of nitrogen blowing, the system was placed in a microwave, and reacted for 5 hours at a temperature of 90 ℃. Adding ethyl acetate for dilution, filtering and concentrating to obtain a crude product. Finally, purification by Prep-HPLC (eluting condition 4) afforded compound 108 (5 mg).
MS(ESI,m/z):439.1[M+H] +
1 H NMR(400MHz,MeOD)δ7.73(d,J＝2.3Hz,1H),7.52(s,1H),6.72(d,J＝2.4Hz,1H),3.98(s,3H),3.56-3.51(m,2H),3.51-3.46(m,2H),2.97(t,J＝7.5Hz,2H),2.57-2.43(m,6H),2.07(s,3H),1.98(s,2H).
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.
The reagent used is as follows: RPMI 1640 (Hyclone); heat-inactivated FBS (fetal bovine serum) (Gibco); PMA (tetradecanoyl phorbol acetate) (Biyun Tian)
And (3) cells: THP-1 (Nanjing Ke Bai)
The kit comprises: IL-1. Beta. Assay kit (CISBIO)
The experimental steps are as follows:
1) THP-1 cells in logarithmic growth phase were grown at 5X 10 5 Density of individual/well inoculated in T75 flask, placed at 37℃in 5% CO 2 After 24h incubation in the 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 24 hours of cell induction culture, 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 cells were plated in 96-well plates at a cell number of 1X 10 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 Culturing in an incubator for 6 hours, collecting supernatant, and measuring the IL-1 beta level according to the instruction of the IL-1 beta detection kit.
4)EC 50 The results are shown in Table 1, fitted by the GraphPad software log (agonist) vs. response-Variable slope four-parameter method.
Experimental example 2 THP-1 cells deleted of NLRP3 after PMA induced differentiation by the inventive Compound (THP-1) def Agonism of IL-1 beta expression in NLRP3 cells)
This experiment uses HTRF detection to test the compounds of the invention for THP-1 def The effect of IL-1 beta levels in NLRP3 cells to assess the specificity of the compounds for agonism on NLRP3 inflammatory bodies or hllrp 3 inflammatory body pathways.
The reagent used is as follows: as described in Experimental example 1
And (3) cells: THP-1 def NLRP3(InvivoGen)
The kit comprises: IL-1. Beta. Assay kit (CISBIO)
The experimental steps are as follows:
1) THP-1 to be in logarithmic growth phase def NLRP3 cells at 5X 10 5 Density of individual/well inoculated in T75 flask, placed at 37℃in 5% CO 2 Culturing in incubator for 24 hr, inducing THP-1 with 1 μM 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 24 hours, 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 Culturing in an incubator for 6 hours, collecting supernatant, and measuring the IL-1 beta level according to the instruction of the IL-1 beta detection kit.
4)EC 50 The results are shown in Table 1, fitted by the GraphPad software log (agonist) vs. response-Variable slope four-parameter method.
Experimental example 3: the compound of the invention is used for treating hTLR 7 Is an agonistic effect of (a)
The experiment is carried out by detecting HEK-hTLR 7 Testing of compounds of the invention for TLR by luciferase in NF- κB-reporter cells 7 Activation of the signaling pathway to assess the specificity of the compound for agonism of the NLRP3 pathway.
Reagent: DMEM (High glucose); FBS (fetal bovine serum) (Gibco); bright-Glo TM Luciferase detection kit (Promega)
And (3) cells: human HEK-TLR 7 NF- κB-fluorescenceLuciferase reporter gene cell (Nanjing Kebai)
1) Human HEK-hTLR in logarithmic growth phase 7 -NF- κb-luciferase reporter cell pancreatin digestion, resuspended to 2×10 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 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)EC 50 The results are shown in Table 1, fitted by the GraphPad software log (agonist) vs. response-Variable slope four-parameter method.
Experimental example 4: the compound of the invention is used for treating hTLR 8 Is an agonistic effect of (a)
This experiment tests the compounds of the invention for TLR by detecting the secretion of alkaline phosphatase in HEK-Blue cell lines 8 Activation of the signaling pathway to assess the specificity of the compound 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 hTLR 8 Cells (humanized TLR 8 cells) (InvivoGen)
The experimental steps are as follows:
1) HEK-Blue in logarithmic growth phase TM hTLR 8 Cells were digested with pancreatin 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 containing 10% FBS.
2) After the cell incubation, 10. Mu.L of the cell culture supernatant was transferred to a 96-well plate, 90. Mu.L/well of QUANTI-Blue detection solution was added, and incubated at 37℃for 3 hours, with an ELISA reader OD 620 And (5) reading.
3)EC 50 The results are shown in Table 1, fitted by the GraphPad software log (agonist) vs. response-Variable slope four-parameter method.
TABLE 1
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The results show that the compounds of the invention represented by compounds 2, 3, 5, 6, 7, 9s, 10, 37, 67s-81, 83-106 have remarkable agonism on IL-1β expression in THP-1 cells after PMA induced differentiation, but have remarkable agonism on THP-1 def IL-1β expression in NLRP3 cells had no agonism at the highest compound test concentration (27 μM); compound 5 vs hTLR 7 With weak activation, other compounds showed a response to hTLR at 100. Mu.M 7 No obvious activation; all of the above compounds at 100. Mu.M vs. hTLR 8 No apparent activation. In conclusion, the compounds of the invention (e.g., compounds 2, 3, 5, 6, 7, 9s, 10, 37, 67s-81, 83-106) have significant specific agonistic activity towards hllrp 3 and/or its signaling pathway.
Experimental example 5: hERG assay
By predictors TM hERG Fluorescence Polarization Assay Kit (manufacturer: thermoFisher), inhibition of hERG potassium ion channel by test compounds was demonstrated according to the kit, at concentrations of 1 and 10. Mu.M, and test results are shown in Table 2.
TABLE 2
Compounds of formula (I) IC 50 (μM)
9s >10
10 >10
37 >10
76 >10
88 >10
92 >10
95s >10
The inhibition of hERG by compound 73s was tested using a manual patch clamp method.
Cell lines: overexpression of hERG potassium ion channel HEK-293 (human embryonic kidney cell)
Negative control: extracellular fluid containing 0.1% dmso; positive control: quinidine (Quinidine)
Test compound concentration: 1. Mu.M and 10. Mu.M
Reaction temperature: 22-24 DEG C
And (3) data acquisition: PATCHMASTER V2X60 software.
The experimental steps are as follows:
dissolving a compound to be tested in DMSO to prepare a 10mM mother solution, and diluting the mother solution to 1mM (secondary mother solution) with DMSO; the secondary mother solution was diluted to 30mL of extracellular fluid at 30 μl for electrophysiological detection.
Cells were transferred to a cell bath embedded in an inverted microscope platform, extracellular fluid (2.7 ml/min) was perfused, and after stabilization for 5 min, membrane voltage was clamped at-80 mV, cells were given a voltage stimulus of 2s, +20mV, hERG potassium channels were activated, repolarized to-50 mV for 5s, and an outward tail current was generated at a stimulation frequency of 15 seconds/time.
Extracellular fluid (2 ml/min) was perfused and recorded continuously, and after current stabilization, extracellular fluid containing the test compound was perfused and recorded continuously until the inhibition of hERG current by the compound reached a steady state.
IC of Compound 73s 50 >The inhibition rate of positive control quinidine in this experiment was 90.7% for hERG potassium ion channel at 30 μm at 10 μm, indicating that the assay system was normal.
The results showed that the compounds of the present invention represented by compounds 9s, 10, 37, 73s, 76, 88, 92, 95s had no significant inhibitory effect on hERG and were less likely to cause 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. The experiment uses P450-Glo TM CYP1A2 Screening System、CYP2D6Cyan Screening Kit and +.>The inhibitory activity of the compounds on CYP1A2, CYP2D6 and CYP3A4 was measured separately according to the kit instructions. The test results are shown in Table 3A.
TABLE 3A
The results showed that the compounds of the present invention represented by compounds 9s, 10, 67s, 68, 70, 74, 75, 78, 80, 81, 83, 86, 88 had no significant inhibitory effect on the CYP1A2, CYP2D6 and CYP3A4 enzymes.
In addition, the inhibition of CYP1A2, CYP2D6, CYP3A4 by compound 73s was measured by the LC-MS method. The specific tests are as follows:
reagent and reference substance:
the experimental steps are as follows:
after pre-incubation of a mixture of probe substrate (50. Mu.l), PBS (49. Mu.l), test compound or positive inhibitor (1. Mu.l) and HLM (50. Mu.l, incubation at 0.1 mg/ml) for 5min at 37℃NADPH (50. Mu.l) was added and incubated for a further 30min. Then 800. Mu.l of glacial acetonitrile containing an internal standard was added to each reaction incubation to terminate the reaction, vortexing and centrifuging, and the supernatant was taken for LC-MS/MS analysis.
LC-MS/MS: mass spectrometry used Sciex API 5500. Liquid chromatography employed the Waters ACQUITY UPLC I-CLASS system. The chromatographic column is Hypersil GOLD C 18 (2.1 mm. Times.50 mm,1.9 μm). Mobile phase: phase A is water+0.1% formic acid, and phase B is acetonitrile; the flow rate was 0.4ml/min and the column temperature was 40 ℃. The ion source is ESI source positive ion mode, and the scanning mode is multi-reaction monitoring (MRM).
The concentration of the primary metabolite produced by each probe substrate at different concentrations of the compound was determined using vehicle (DMSO) as a negative control to determine the half inhibitory concentration (IC 50 ). The test results are shown in Table 3B.
TABLE 3B
The results show that compound 73s has no significant inhibitory effect on CYP1A2, CYP2D6 and CYP3 A4.
Experimental example 7: CYP3A4 enzyme induction test
The 10mM test compound was diluted 3-fold in DMSO at seven concentration points as a 100X stock solution. Rifampicin was used as positive control and 1% DMSO was used as negative control.
Centrifugally collecting Hep G2C 3A liver cancer cells of the CYP3A 4-luciferase reporter gene system stably expressing in logarithmic growth phase, and re-suspending to 4X 10 5 Individual cells/ml. The 384-well white cell plates were subjected to 5% CO at 37℃according to 25. Mu.l/Kong Jiazhi 384 2 Culturing in an incubator for 24 hours.
Transferring 300nl from the 100 Xmother liquor to a cell plate, and placing in 5% CO at 37deg.C 2 Culturing in an incubator for 72 hours. Add 30. Mu.l/well Brigh-Glo TM (Promega) incubation for 2 min at room temperature, the relative chemiluminescent fluorescence values (RLU) were read by the microplate reader. EC50 values of compound 73s on CYP3A4 enzyme induction were calculated using Prism 5 software, and the relative induction activity of compound 73s (10 μm)% = ((compound signal value-negative control signal value)/(positive control signal value-negative control signal value)) ×100%. The test results are shown in Table 4.
TABLE 4 Induction of CYP3A4 enzymes by Compound 73s
The results showed that the induction activity of compound 73s on CYP3A4 luciferase at 10. Mu.M was 3% of that of positive control rifampicin, and that compound 73s on CYP3A4 enzyme EC 50 >10. Mu.M. In conclusion, compound 73s of the present invention had no significant induction of CYP3A4 enzyme.
Experimental example 8: in vivo efficacy of single-sided inoculation of CT26 mouse colon cancer subcutaneous transplantation tumor
CT26 mouse colon cancer cells were cultured in vitro in monolayer, and cells were collected and counted by centrifugation while the cells were in the logarithmic growth phase.
0.1ml of the mixture containing 3X 10 5 PBS resuspension of individual CT26 cells was inoculated subcutaneously at the scapula on one side of the mice. Until the tumor grows to a volume of about 100mm 3 At this time, mice were randomly divided into 4 groups of 8 according to tumor volume.
Compound 73s was given by intratumoral injection at three doses of 5 μg,50 μg,500 μg, twice weekly for two consecutive weeks. Tumor volumes and animal body weights were measured twice weekly.
The inhibition of the growth of the transplanted tumor of the mice by the compound is evaluated by calculating the tumor inhibition rate TGI (%) according to the tumor volume, and the calculation formula is as follows: TGI (%) =100% - (T) Vt -T V0 )/(C Vt -C V0 ) X 100%; when tumor regressions occur, TGI (%) =100% - (T Vt -T V0 )/T V0 ×100％。T V0 Mean tumor volume for the test compound group at the time of group administration; t (T) Vt Average tumor volume for the test compound group at day t; c (C) V0 Mean tumor volume for vehicle group at time of group dosing; c (C) Vt Mean tumor volume of vehicle group at day t. If the tumor is reduced from the initial volume, i.e. V t <V 0 Defined as tumor Partial Regression (PR); if the tumor completely disappeared, it is defined as complete tumor regression (CR). Statistical analysis of differences between the two groups P-values were calculated using t-test. The test results are shown in Table 5.
TABLE 5 in vivo efficacy of Compound 73s against CT26 mouse colon cancer subcutaneous engraftment
The results show that the compound 73s has obvious dose-dependent tumor inhibition effect on CT26 subcutaneous transplantation tumor model compared with the vehicle group, and the subcutaneous tumor of the 7/8 mice completely regresses in the 500 mu g dose group.
Experimental example 9: in vivo efficacy on double-sided inoculation of CT26 mouse colon cancer subcutaneous transplantation tumor
(1) CT26 mouse colon cancer cells were cultured in vitro in monolayer, and cells were collected and counted by centrifugation while the cells were in the logarithmic growth phase.
(2) 0.1ml of the mixture containing 3X 10 5 CT2The PBS resuspension of 6 cells was inoculated subcutaneously at bilateral scapula of mice. When the bilateral shoulder blade tumor of the mouse grows to be about 100mm in volume 3 At this time, mice were randomly divided into 4 groups of 8 based on tumor volumes on both sides.
(3) Compound 73s was administered by intratumoral injection twice a week for two consecutive weeks at a dose of 50 μg,500 μg, respectively, to the tumor on the right side of the mice. Bilateral tumor volumes and animal body weights were measured.
(4) The inhibition of the growth of the transplanted tumor of the mice by the compound 73s is evaluated by calculating the tumor inhibition rate TGI (%) according to the tumor volume, and the calculation formula is as follows: TGI (%) =100% - (T) Vt -T V0 )/(C Vt -C V0 ) X 100%; when tumor regressions occur, TGI (%) =100% - (T Vt -T V0 )/T V0 ×100％。T V0 Average tumor volume for the test compound group at the time of group administration; t (T) Vt Average tumor volume for the test compound group at day t; c (C) V0 Mean tumor volume for vehicle group at time of group dosing; c (C) Vt Mean tumor volume of vehicle group at day t. If the tumor is reduced from the initial volume, i.e. V t <V 0 Defined as tumor Partial Regression (PR); if the tumor completely disappeared, it is defined as complete tumor regression (CR). Statistical analysis of differences between the two groups P-values were calculated using t-test. The results are shown in tables 6A and 6B.
Inhibition of subcutaneous colon tumor in CT26 mice on the administration side by Compound 73s of Table 6A
Inhibition of subcutaneous colon tumor in non-dosing side CT26 mice by Compound 73s of Table 6B
The results in tables 6A and 6B show that intratumoral injection of compound 73s of the invention has significant dose-dependent tumor inhibiting effect on the administration side compared with vehicle group in a double-sided inoculation CT26 subcutaneous transplantation tumor model, and that 6/8 mice subcutaneous tumor completely regress on the administration side of 500 μg dose group, and 1/8 mice subcutaneous tumor partially regress; and the compound 73s of the invention has obvious tumor inhibiting effect on non-administration side tumors. In conclusion, the intratumoral injection of the compound 73s has obvious tumor inhibiting effect on bilateral CT26 tumors.
Various modifications of the invention, 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 application (including all patents, patent applications, journal articles, books, and any other publications) is incorporated herein by reference in its entirety.

Claims (17)

1. A compound of formula I, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound:
wherein:
X 1 and X 2 Each independently selected from CH, CR 8 、NR 7 N, O or S, X 1 And X 2 At least one of them is NR 7 N, O or S, and X 1 、X 2 And (X) 1 And/or X 2 ) The linked carbon atoms together form a five membered heteroaromatic ring; r is R 7 Selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl group, the C 1-6 Alkyl and C 3-8 Cycloalkyl groups are optionally substituted with one or more of the following groups: halogen, OH, CN, C 1-4 Alkoxy, C 1-4 A hydroxyalkyl group, a hydroxyl group,
X 3 c, N, O or S, and satisfies the following conditions:
(1) When X is 3 When O or S, R 2 And R is 6 Absence of;
(2) When X is 3 When N is present, R 2 And R is 6 Are not present at the same time;
R 1 selected from H, halogen, CN, NO 2 、C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, C (O) OR 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、S(O) 2 R 35 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo 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, C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)OR 30 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、OR 37 、SR 37 ；
R 2 Selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-12 Aryl, -C 1-3 alkyl-C 6-12 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, said C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 6-12 Aryl, -C 1-3 alkyl-C 6-12 Aryl, C 3-8 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl 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 、C(O)OR 30 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 31 R 32 ；
R 3 Selected from H, OH, halogen, CN, NO 2 、C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 2-8 Heteroalkyl, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C (O) OR 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 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, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl optionallySubstituted 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, -C 6-12 aryl-C 1-4 Alkyl, 5-to 10-membered heteroaryl, 9-to 12-membered aryl-heterocyclo, C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、OR 37 、SR 37 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)OR 30 、C(＝NR 38 )NR 31 R 32 、NR 33 C(＝NR 38 )NR 31 R 32 、＝NNR 31 R 32 、P(R 39 ) 2 、P(OR 39 ) 2 、P(O)R 39 R 40 、P(O)OR 39 OR 30 ；
R 4 And R is 5 Each independently selected from H, C 1-8 Alkyl, C 1-8 Alkoxy, or R 4 、R 5 And R is equal to 4 And R is 5 The attached nitrogen atoms together form a 4-7 membered heterocyclic ring; the C is 1-8 Alkyl, C 1-8 The alkoxy group is 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 A hydroxyalkyl group;
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 8 selected from halogen, C 1-8 Alkyl, C 1-8 Alkoxy group,C 3-8 Cycloalkyl, C 2-8 Heteroalkyl, 4-7 membered heterocyclyl, said C 1-8 Alkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, C 2-8 The heteroalkyl, 4-7 membered heterocyclyl may be optionally substituted with one OR more of OR 37 、NR 31 R 32 Halogen, CN;
v is- (V) 1 ) r –(V 2 ) s –(V 3 ) t -, wherein V 1 、V 2 And V 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 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 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 An alkoxy group;
r, s, t are each independently selected from 0 and 1;
l is- (L) 1 ) n -(L 2 ) p –(L 3 ) q -, wherein L 1 、L 2 And L 3 Identical or different and are each independently selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Halogenated alkylene, C 1-8 Alkyloxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkylene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, -O-, -S-, -N (R) 33 )- 、-S(O)-、-S(O) 2 -、-C(O)-、-C(R 36a R 36b ) -; the C is 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Halogenated alkylene, C 1-8 Alkyloxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkylene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 An alkoxy group;
n, p, q are each independently selected from 0 or 1;
R 30 、R 37 、R 39 、R 40 each independently selected from: hydrogen, C 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, -C 1-8 alkyl-C 6-12 Aryl, -C 1-8 Alkyl- (5-10 membered heteroaryl); the C is 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene 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, C (O) O (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 ；
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 37 When present at the same time, each R 37 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;
R 31 、R 32 、R 33 、R 34 each independently selected from: H. c (C) 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl; or R is 31 And R is 32 Forms together with the N atom to which each is attached a 3-8 membered heterocyclic group; or R is 33 And R is 34 Together with the C or N atom to which each is attached, form a 4-8 membered heterocyclyl; the C is 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Alkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl optionally substituted with one or more of the following substituents: OH, CN, halogen, NO 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl;
R 35 selected from: c (C) 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, -C 1-8 alkyl-C 6-12 Aryl, -C 1-8 Alkyl- (5-10 membered heteroaryl); the C is 1-8 Alkyl, C 1-8 Hydroxyalkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl 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, C (O) O (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;
when a plurality of R 31 When present at the same time, each R 31 May be the same or different;
when a plurality of R 32 When present at the same time, each R 32 May be the same or different;
when a plurality of R 33 When present at the same time, each R 33 May be the same or different;
when a plurality of R 34 When present at the same time, each R 34 May be the same or different;
when a plurality of R 35 When present at the same time, each R 35 May be the same or different;
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 is optionally substituted with one or more of the following groups: OH, CN, NH 2 、NHCH 3 、N(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the Or R is 36a 、R 36b And R is equal to 36a 、R 36b The attached carbon atoms together form a 3-7 membered cycloalkyl or 4-7 membered heterocyclyl;
when more than one R 38 When present at the same time, each R 38 Identical or different, and are each independently selected from: H. OH, CN, NO 2 、S(O)R 35 、S(O) 2 R 35 。
2. The compound of claim 1, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, wherein,
R 1 selected from C 1-8 Alkyl, C 1-8 Haloalkyl、C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo; the C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl and heterocyclyl 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, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、NR 33 C(O)R 34 、NR 31 R 32 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 33 C(O)OR 30 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、OR 37 、SR 37 ；
Preferably, R 1 Selected from C 6-12 Aryl (e.g., phenyl), 5-10 membered heteroaryl (e.g., 5-6 membered heteroaryl), 9-12 membered aryl-heterocyclo; the C is 6-12 Aryl (e.g., phenyl), 5-10 membered heteroaryl (e.g., 5-6 membered heteroaryl), 9-12 membered aryl and heterocyclyl are 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, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (O) OR 30 、C(O)R 30 、C(O)NR 31 R 32 、-NR 33 C(O)R 34 、-NR 31 R 32 、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 、S(O)NR 31 R 32 、S(O) 2 NR 31 R 32 、S(O)R 35 、S(O) 2 R 35 、OR 37 、SR 37 ；
Preferably, R 1 Selected from halogen, 5-6 membered heteroaryl and C 6-12 Aryl, optionally, the 5-6 membered heteroaryl and C 6-12 Aryl radicals being substituted by one or more C' s 1-4 Alkyl substitution;
preferably, R 1 Selected from fluorine, chlorine, bromine, iodine, 5-6 membered heteroaryl and phenyl, optionally said 5-6 membered heteroaryl and phenyl optionally substituted with one or more methyl, ethyl;
preferably, R 1 Selected from the group consisting of fluorine, chlorine, bromine, iodine, 5-6 membered nitrogen containing heteroaryl, 5-6 membered sulfur containing heteroaryl, and phenyl, optionally said 5-6 membered nitrogen containing heteroaryl, 5-6 membered sulfur containing heteroaryl, and phenyl optionally substituted with one or more methyl, ethyl;
preferably, the 5-6 membered nitrogen containing monocyclic heteroaryl group contains 1, 2 or 3 nitrogen atoms, optionally also contains 1 sulfur or oxygen atom;
preferably, the 5-6 membered sulfur-containing monocyclic heteroaryl group contains 1, 2, or 3 sulfur atoms;
preferably, R 1 Selected from halogen (e.g., fluoro, chloro, bromo, iodo), phenyl, imidazolyl, pyridyl, thiazolyl, pyrazinyl, thienyl, pyrazolyl, pyridazinyl, pyrimidinyl; optionally, the phenyl, imidazolyl, pyridyl, thiazolyl, pyrazinyl, thienyl, pyrazolyl, pyridazinyl, pyrimidinyl are substituted with 1, 2, 3 or 4C 1-4 Alkyl (e.g., methyl, ethyl) substitution;
preferably, R 1 Selected from bromine,
3. The compound of claim 1 or 2, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, wherein,
R 2 selected from H, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl group, the C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-8 Cycloalkyl groups may be optionally substituted with one or more of the following substituents: halogen, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO 2 、OR 37 、SR 37 、C(O)R 30 、C(O)NR 31 R 32 、C(O)OR 30 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 31 R 32 ；
Preferably, R 2 Selected from H, C 1-8 Alkyl, C 3-8 Cycloalkyl and-CH 2 -C 6-12 Aryl, said C 1-8 Alkyl, C 3-8 Cycloalkyl, -CH 2 -C 6-12 Aryl groups may be optionally substituted with one or more of the following substituents: halogen, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, 4-7 membered heterocyclyl, CN, NO 2 、OR 37 、SR 37 、C(O)R 30 、C(O)NR 31 R 32 、C(O)OR 30 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 31 R 32 ；
Preferably, R 2 Selected from H, C 1-8 Alkyl and C 3-8 Cycloalkyl group, the C 1-8 Alkyl, C 3-8 Cycloalkyl groups may optionally be substituted withOne or more substitutions of (a): 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 、C(O)OR 30 、OC(O)R 30 、OC(O)NR 31 R 32 、NR 33 C(O)NR 31 R 32 、NR 31 R 32 ；
Preferably, R 2 Selected from H, C 1-8 Alkyl and p-methoxybenzyl;
preferably, R 2 Selected from H, C 1-8 Alkyl (e.g. C 1-4 Alkyl), preferably R 2 Selected from H, methyl and ethyl;
preferably, R 2 Selected from H and methyl.
4. A compound according to any one of claims 1 to 3, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, wherein,
R 3 selected from C 1-8 Alkyl, 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 (e.g., 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl), 9-12 membered arylheterocyclo, 9-12 membered arylheteroaryl, 9-12 membered arylcycloalkyl, C (O) OR 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 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, 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, -C 6-12 aryl-C 1-4 Alkyl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, -C (O) OR 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)2R 35 、S(O)NR 31 R 32 、S(O)2NR 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 、P(R 39 ) 2 、P(OR 39 ) 2 、P(O)R 39 R 40 、P(O)OR 39 OR 30 、＝NNR 31 R 32 ；
Preferably, R 3 Selected from C 1-8 Alkyl, 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 (e.g., 5-6 membered heteroaryl)A group, 9-10 membered heteroaryl-cycloalkyl), 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl, OR 37 、SR 37 、C(O)R 30 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 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 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, -C (O) OR 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 、P(R 39 ) 2 、P(OR 39 ) 2 、P(O)R 39 R 40 、P(O)OR 39 OR 30 、＝NNR 31 R 32 ；
Preferably, R 3 Selected from C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl (e.g., 5-6 membered heteroaryl, 9-10 membered heteroarylcycloalkyl), 9-12 membered arylheterocyclo, 9-12 membered arylheteroaryls, 9-12 membered arylcycloalkyl, OR 37 、SR 37 、C(O)R 30 The method comprises the steps of carrying out a first treatment on the surface of the The C is 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 3-8 Cycloalkyl, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, 9-12 membered aryl-heterocyclo, 9-12 membered aryl-heteroaryl, 9-12 membered aryl-cycloalkyl optionally substituted with one or more of 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, 4-7 membered heterocyclyl, C 6-10 Aryl, -C 6-10 aryl-C 1-4 Alkyl, 5-10 membered heteroaryl, 9-10 membered aryl-heterocyclo, C (O) OR 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 ；
Preferably, R 3 Selected from H, methyl, ethyl, methoxy, t-butoxy, benzyl, cyclopropyl, phenyl, OH,
5. The compound of any one of claims 1-4, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, said compound having one or more of the following characteristics:
(1)R 4 Is hydrogen;
(2)R 5 is hydrogen;
(3) r, s and t are all 0.
6. The compound of any one of claims 1-5, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, wherein,
l is- (L) 1 ) n -(L 2 ) p –(L 3 ) q -, wherein L 1 、L 2 And L 3 Identical or different and are each independently selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Halogenated alkylene, C 1-8 Alkyloxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkylene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene, -C (R 36a R 36b )-、O、-N(R 33 ) -, -C (O) -; the C is 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkynylene, C 1-8 Halogenated alkylene, C 1-8 Alkyloxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkylene, C 3-8 Cycloalkylene, 4-10 membered heterocyclylene, C 6-12 Arylene, 5-10 membered heteroarylene optionally substituted with one or more of the following substituents: halogen, OH, CN, NO 2 、C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 An alkoxy group; n, p, q are each independently selected from 0 or 1;
preferably, 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 1-4 Alkyleneoxy group, O, NR 33 -CO-, 4-10 membered heterocyclyl (e.g. 6 membered nitrogen containing mono heterocyclyl) and aryl; n, p, q are each independently selected from 0 or 1;
preferably, L is selected from the following groups: - (CH) 2 ) 3 -O-CH 2 -、-(CH 2 ) 3 -、-CH 2 -、-(CH 2 ) 2 C(CH 3 ) 2 、-(CH 2 ) 2 -、-(CH 2 ) 3 -O-, 4-10 membered heterocyclyl (e.g. 6 membered nitrogen containing mono heterocyclyl), -O- (CH) 2 ) 3 -O-、-(CH 2 ) 3 - (4-to 10-membered heterocyclic) -C (O) -or- (CH) 2 ) 3 -O-C 6-12 An aryl group;
preferably, L is selected from the group consisting of-CH 2 -NR 33 -CO-、-CH 2 -NR 33 -；R 33 Is hydrogen or C 1-4 Alkyl (e.g., methyl, ethyl);
preferably, L is selected from the following groups: - (CH) 2 ) 3 -O-CH 2 -、-(CH 2 ) 3 -、-CH 2 -、-(CH 2 ) 2 C(CH 3 ) 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -O-、-O-(CH 2 ) 3 O-、-CH 2 -N(CH 2 CH 3 )-CO-、-CH 2 -N(CH 2 CH 3 )-CH 2 -、-CH 2 -NH-、-NH-(CH 2 ) 3 -、
7. The compound of any one of claims 1-6, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, wherein,
-L-R 3 selected from the following groups: -C 1-4 alkylene-O-C 1-4 alkylene-C 6-12 Aryl, -C 1-4 alkylene-OH, -C 1-4 Alkylene- (6-10 membered nitrogen containing spiroheterocyclyl), -C 1-4 Alkylene- (4-6 membered nitrogen containing mono-heterocyclyl), -C 1-4 Alkylene- (4-6 membered nitrogen containing mono-heterocyclyl and 4-6 membered oxygen containing mono-heterocyclyl), -C 1-4 alkylene-C (CH) 3 ) 2 -OH、-C 1-4 Alkylene O- (5-6 membered nitrogen containing mono heteroaryl and C5-6 monocycloalkyl), -C1-4 alkylene
-O- (benzoC 5-6 monocycloalkyl), -C1-4 alkylene-O- (benzo5-6 membered nitrogen containing mono-heterocyclyl), -C1-4 alkylene-O- (benzo5-6 membered nitrogen containing mono-heteroaryl), -C1-4 alkylene-O-phenyl- (4-6 membered nitrogen containing mono-heterocyclyl), -C 1-4 alkylene-O-phenyl- (benzo 5-6 membered nitrogen containing mono-heterocyclyl), - (6 membered nitrogen containing mono-heterocyclyl) -C 6-12 Aryl, -C 1-4 Alkylene- (benzo 5-6 membered nitrogen containing mono-heterocyclyl), -C 1-4 alkylene-O- (5-6 membered nitrogen containing mono heteroaryl), -NH-C 1-4 alkylene-OH, -O-C 1-4 alkylene-O-benzyl, - (4-6 membered nitrogen containing mono-heterocyclyl) -C 1-4 Alkoxy, - (4-6 membered nitrogen containing mono-heterocyclyl) -OH, -C 1-3 Alkyl- (4-6 membered nitrogen containing mono-heterocyclyl) -OH, -C 1-4 alkylene-O- (4-6 membered nitrogen containing mono-heterocyclyl), -CH 2 -N(CH 2 CH 3 )-C(O)-O-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-CH 2 -C(O)-O-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-C 1-4 alkylene-C 6-12 Aryl, -CH 2 -N(CH 2 CH 3 ) -C (O) - (4-6 membered nitrogen containing mono-heterocyclyl), -CH 2 -N(CH 2 CH 3 ) -C (O) - (5-6 membered nitrogen containing mono heteroaryl), -CH 2 -NH-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)H、-CH 2 -N(CH 2 CH 3 )-C(O)-C 3-8 Cycloalkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-C 1-4 Alkyl, wherein, 4-6 membered nitrogen-containing mono-heterocyclic group, C 6-12 Aryl, 5-6 membered nitrogen containing mono heteroaryl, 5-6 membered nitrogen containing mono heterocyclyl may be optionally substituted with one or more of the following substituents: c (C) 1-3 Alkyl, oxo, -C (O) H, -S (O) 2 -C 1-3 An alkyl group;
preferably, -L-R 3 Selected from the following groups: - (CH) 2 ) 3 -O-CH 2 -C 6-12 Aryl, - (CH) 2 ) 3 -OH、-CH 2 - (4-6 membered nitrogen-containing mono-heterocyclic group and 4-6 membered oxygen-containing mono-heterocyclic group), -CH 2 - (4-6 membered nitrogen-containing mono-heterocyclic group), - (CH) 2 ) 2 C(CH 3 ) 2 -OH、-(CH 2 ) 2 - (4-6 membered nitrogen-containing mono-heterocyclic group), - (CH) 2 ) 3 -O- (5-6 membered nitrogen containing mono-heteroaryl and C5-6 monocycloalkyl), -CH 2) 3-O- (benzoC 5-6 monocycloalkyl), -CH 2) 3-O- (benzo5-6 membered nitrogen containing mono-heterocyclyl), -CH 2) 3-O- (benzo5-6 membered nitrogen containing mono-heteroaryl), -CH 2) 3-O-phenyl- (4-6 membered nitrogen containing mono-heterocyclyl), -6 membered nitrogen containing mono-heterocyclyl-phenyl, -CH 2 ) 3 - (benzo 5-6 membered nitrogen-containing mono-heterocyclic group), - (CH) 2 ) 3 -O- (5-6 membered nitrogen containing mono heteroaryl), - (CH) 2 ) 3 - (6-to 10-membered nitrogen containing spiroheterocyclyl), -NH- (CH) 2 ) 3 -OH、-(CH 2 ) 3 - (4-6 membered nitrogen-containing mono-heterocyclic group), -O- (CH) 2 ) 3 -O-benzyl, - (CH) 2 ) 3 - (4-6 membered nitrogen-containing mono-heterocyclic) -OH, - (CH) 2 ) 2 -OH, -6-membered nitrogen-containing mono-heterocyclyl-methoxy, -6-membered nitrogen-containing mono-heterocyclyl-OH, - (CH) 2 ) 3 -O- (4-6 membered nitrogen containing mono-heterocyclyl), -CH 2 -N(CH 2 CH 3 )-C(O)-O-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-CH 2 -C(O)-O-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-(CH 3 ) 2 -C 6-12 Aryl, -CH 2 -N(CH 2 CH 3 ) -C (O) - (4-6 membered nitrogen containing mono-heterocyclyl), -CH 2 -N(CH 2 CH 3 ) -C (O) - (5-6 membered nitrogen containing mono heteroaryl), -CH 2 -NH-CH 2 CH 3 、-CH 2 -N(CH 2 CH 3 )-C(O)H、-CH 2 -N(CH 2 CH 3 )-C(O)-C 3-8 Cycloalkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-C 1-4 Alkyl, -CH 2 -N(CH 2 CH 3 )-C(O)-CH 3 -C 6-12 Aryl, -CH 2 -N(CH 2 CH 3 )-CH 2 -C(O)-O-C 1-4 Alkyl, -CH 2 - (4-6 membered nitrogen-containing mono-heterocyclic group), - (CH) 2 ) 3 - (4-6 membered nitrogen-containing mono-heterocyclic group), wherein 4-6 membered nitrogen-containing mono-heterocyclic group, C 6-12 Aryl, 5-6 membered nitrogen containing mono heteroaryl, 5-6 membered nitrogen containing mono heterocyclyl may be optionally substituted with one or more of the following substituents: methyl, ethyl, oxo, -C (O) H, -S (O) 2 -CH 3 ；
Preferably, -L-R 3 Selected from the following groups:
8. the compound of any one of claims 1-7, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, said compound having one or more of the following characteristics:
(1)X 1 Is CH or NR 7 ；
(2)X 2 Is S or NR 7 ；
(3)X 1 Is CH, X 2 S.
9. The compound of any one of claims 1-8, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, said compound having the structure of formula II-1:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 1 、X 3 V and L are as defined above for formula I.
10. The compound of any one of claims 1-9, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, said compound having the structure of formula IV:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、X 3 V and L are as defined above for formula II-1.
11. The compound of claim 10, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, said compound having the structure of formula VI:
Wherein R is 1 、R 2 、R 3 、R 4 、R 5 L is as defined in formula II-1 above.
12. The compound of claim 11, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, said compound having the structure of formula VI-1:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 As defined in formula VI above.
13. The compound of any one of claims 1-12, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, said compound being selected from the group consisting of:
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14. a pharmaceutical composition comprising a compound according to any one of claims 1-13, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound;
optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers;
Preferably, the pharmaceutical composition is for preventing, alleviating and/or treating a disease associated with NLRP3 inflammatory body activity (e.g., a neoplastic disease);
preferably, the pharmaceutical composition is for preventing, alleviating and/or treating a cell proliferative disorder (e.g. cancer);
optionally, the pharmaceutical composition further comprises one or more second therapeutic agents;
preferably, the second therapeutic agent is an additional drug comprising a therapeutic agent for treating a neoplastic disease;
preferably, the neoplastic disease is selected from: lung cancer, pancreatic cancer, breast cancer, head and neck cancer, liver cancer, melanoma, glioma or sarcoma.
15. A pharmaceutical formulation comprising a compound according to any one of claims 1-13, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutical composition according to claim 14.
16. Use of a compound according to any one of claims 1-13, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph, or solvate of said compound, or a stable isotopic derivative, metabolite, or prodrug of said compound, or a pharmaceutical composition according to claim 14, 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 neoplastic disease).
17. A kit for modulating (e.g., increasing) the activity of an NLRP3 inflammatory body, the kit comprising a compound of any one of claims 1-13, 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 of claim 14, or a pharmaceutical formulation of claim 15.
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