CN115710253B - Aminobenzimidazole-containing derivatives, and preparation and application thereof - Google Patents

Aminobenzimidazole-containing derivatives, and preparation and application thereof Download PDF

Info

Publication number
CN115710253B
CN115710253B CN202110967824.6A CN202110967824A CN115710253B CN 115710253 B CN115710253 B CN 115710253B CN 202110967824 A CN202110967824 A CN 202110967824A CN 115710253 B CN115710253 B CN 115710253B
Authority
CN
China
Prior art keywords
compound
substituted
unsubstituted
alkyl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202110967824.6A
Other languages
Chinese (zh)
Other versions
CN115710253A (en
Inventor
张翱
耿美玉
沈安成
谢作权
宋子兰
王玺渊
张燕
丁春勇
丁健
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Jiaotong University
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Jiaotong University
Shanghai Institute of Materia Medica of CAS
Filing date
Publication date
Application filed by Shanghai Jiaotong University, Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Jiaotong University
Priority to CN202110967824.6A priority Critical patent/CN115710253B/en
Publication of CN115710253A publication Critical patent/CN115710253A/en
Application granted granted Critical
Publication of CN115710253B publication Critical patent/CN115710253B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention relates to aminobenzimidazole derivatives, and preparation and application thereof. Specifically, the compound has a structure shown in a formula I, wherein the definition of each group and substituent is described in the specification. The invention also discloses a preparation method of the compound and application of the compound in the aspect of treating autoimmune diseases.

Description

Aminobenzimidazole-containing derivatives, and preparation and application thereof
Technical Field
The invention relates to the field of biological medicine, in particular to an aminobenzimidazole derivative, and a preparation method and application thereof.
Background
Autoimmune diseases (autoimmune diseases, ADs) are highly (5% -8%) and diverse worldwide. There are over 80 autoimmune diseases identified at present, among which common ones include: systemic lupus erythematosus, type I diabetes, rheumatoid arthritis, inflammatory bowel disease, and the like. Most patients need to take medicine for a long time or even for a whole life, and the life quality of the patients is seriously influenced and the life safety of the patients is even threatened. Thus, autoimmune diseases become the third biggest killer to threaten human health following cardiovascular disease, cancer.
Currently, immunomodulating drugs (e.g., azathioprine, methotrexate, glucocorticoid, cyclosporin a, etc.) commonly used for the treatment of autoimmune diseases have a wide range of actions without disease specificity, and are associated with side effects such as infection and malignant tumor diseases. Drugs that block various pathways and components of the immune system, such as cytokines, cell adhesion molecules, co-stimulatory molecules, etc., are biological macromolecules that have significant side effects, including high cost of treatment. Thus, the search for autoimmune disease-specific small molecule drugs with new mechanisms is the most urgent need in this field.
Interferon gene stimulatory proteins (stimulator of interferon genes, STING) are important signaling molecules in the innate immune cGAS-STING pathway, activated when cGAS senses endogenous or exogenous double-stranded DNA (dsDNA), which catalyzes the activation of STING by produced cyclic guanylate (cGAMP), followed by recruitment of TBK1 protein, phosphorylating interferon regulatory factor 3 (IRF 3) and activating the innate immune system. When dsDNA activating STING signals is derived from necrosis or inappropriate apoptosis, secretion of inflammatory cytokines will be promoted to trigger inflammatory and autoimmune diseases. Research results show that negative regulation of STING signaling is expected to be an important strategy for treating autoimmune diseases.
While numerous studies have demonstrated that inhibition of the cGAS-STING pathway is an important strategy for the treatment of autoimmune diseases, studies targeting cGAS-STING pathway inhibitors have been in an early stage. In 2018 Simone m.haag et al reported on Nature that nitrofurans and indoles C-178 (formula II), H-151 (formula III) covalently bind to STING protein Cys91, blocking palmitoylation induced by STING activation, and thus blocking its assembly into multimeric complexes in the golgi apparatus, inhibiting downstream signaling. In addition, the inhibitor can reduce the production of inflammatory cytokines mediated by STING proteins in human and mouse cells and reduce the pathological characteristics of the autoinflammatory diseases of mice. In the same year Wang Chen et al reported on Cell Reports that small molecule AstinC (formula IV) was isolated from aster, a plant of the family asteraceae. Astin C can bind competitively to Cyclic Dinucleotide (CDNs) and inhibit STING (STING-r232 kd=53 nM). In a Trex1 gene-deficient mouse model, intravenous injection Astin C (1 mg/kg) can reduce the expression of cytokines and the abundance of autoantibodies in serum, and remarkably reduce the autoinflammatory response of the mouse. In addition, merck corporation 2019 reported in ACS med chem lett, a class of STING antagonists with tetrahydroisoquinoline core structures that can competitively bind to the binding site of cGAMP, but with a weaker cellular activity.
Based on the therapeutic potential of STING inhibitors for autoimmune diseases, the development of STING inhibitors has focused on each large pharmaceutical size. In 9 2018, north and IFM Due signed a dollar 8.4 billion collaboration agreement aimed at co-conducting a study of cGAS-STING inhibitors. However, the structural types of STING inhibitors reported so far are extremely limited, the activities are also mostly at the molecular level, the cellular activities are mostly weaker, and no inhibitors enter clinical studies.
Therefore, research on STING inhibitors with excellent cell and in vivo activities and high stability is urgent.
Disclosure of Invention
The invention aims to provide a device.
In a first aspect of the present invention there is provided a compound of formula I, or an isomer, prodrug, solvate, hydrate or a pharmaceutically acceptable salt thereof,
Wherein:
X is selected from CR 1 and N;
Y is selected from CR 5 and N;
n is selected from integers of 1-5, for example 1,2, 3, 4, 5;
R 1 is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C1-C8 haloalkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkanoyl, R a substituted or unsubstituted aminoacyl, R a substituted or unsubstituted C1-C8 alkylamido, R a substituted or unsubstituted C1-C8 alkenylamido, R a substituted or unsubstituted C1-C8 alkylamino, R a substituted or unsubstituted C1-C8 alkylthio, R a substituted or unsubstituted 3-8 membered heterocyclyl, R a substituted or unsubstituted 3-8 membered cycloalkyl, R a substituted or unsubstituted 5-10 membered aryl, R a substituted or unsubstituted 5-to 10 membered heteroaryl;
R 2、R4 is each independently selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C1-C8 haloalkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a is substituted or unsubstituted C2-C8 alkynyl, R a is substituted or unsubstituted C1-C8 alkoxy, R a is substituted or unsubstituted C1-C8 alkyl thioether group, R a is substituted or unsubstituted C1-C8 alkyl acyl, R a is substituted or unsubstituted aminoacyl, R a is substituted or unsubstituted C1-C8 alkylamide, R a is substituted or unsubstituted C1-C8 alkenylamide, R a is substituted or unsubstituted C1-C8 alkylamino, R a is substituted or unsubstituted 3-8 membered heterocyclic group, R a is substituted or unsubstituted 3-8 membered cycloalkyl, R a is substituted or unsubstituted 5-10 membered aryl, R a is substituted or unsubstituted 5-10 membered heteroaryl; Or R 2、R4 and the atom to which it is attached form a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted with R a;
R 3 is selected from hydrogen, R a substituted or unsubstituted C1-C8 alkyl;
R 5 is selected from hydrogen, halogen, R a substituted or unsubstituted C1-C8 alkyl;
r a is selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C1-C8 haloalkyl, substituted or unsubstituted C1-C8 alkoxy, substituted or unsubstituted C1-C8 alkoxyacyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted 3-8 membered cycloalkyl, R a substituted or unsubstituted 5-10 membered aryl, substituted or unsubstituted 5-10 membered heteroaryl, wherein the substitution is selected from hydrogen, halogen, hydroxy, cyano, C1-C8 alkyl, C1-C8 alkanoyl, 3-6 membered heterocyclyl, 3-6 membered cycloalkyl.
In another preferred example, the haloalkyl is fluoroalkyl, chloroalkyl, bromoalkyl, preferably fluoroalkyl, further preferably trifluoromethyl.
In another preferred embodiment, the 3-6 membered cycloalkyl group comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, preferably cyclopentyl.
In another preferred embodiment, the 5-6 membered heterocyclic ring is a 5-6 membered heterocyclic ring containing 1-3 (e.g. 1, 2, 3) heteroatoms selected from N, O, S, preferably a 5-6 membered heterocyclic ring containing at least 2O, more preferably a 5-6 membered heterocyclic ring containing 2O, even more preferably a 6 membered heterocyclic ring containing 2O, such as a dioxolanyl group.
In another preferred embodiment, R 1 is selected from hydrogen, fluoro, chloro, bromo, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C6 alkenyl, R a substituted or unsubstituted C2-C6 alkynyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkylamino, R a substituted or unsubstituted C1-C8 alkylthio, wherein R a is as described above.
In another preferred embodiment, R 2、R4 is each independently selected from hydrogen, halogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C1-C8 haloalkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkyl thioether, R a substituted or unsubstituted 3-8 membered heterocyclyl, R a substituted or unsubstituted 3-8 membered cycloalkyl, R a substituted or unsubstituted 5-10 membered aryl, R a substituted or unsubstituted 5-10 membered heteroaryl, wherein R a is as described above.
In another preferred embodiment, R 2 is selected from C1-C8 alkyl, C1-C8 haloalkyl, 3-6 membered cycloalkyl and R 4 is hydrogen.
In another preferred embodiment, the atom to which R 2、R4 is attached forms a carbocyclic ring substituted or unsubstituted with R a or a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, S, wherein R a is as described above.
In another preferred embodiment, R 2、R4 and the atom to which it is attached form a 5-6 membered heterocyclic ring substituted or unsubstituted by R a containing at least 2O, wherein R a is as described above, said 5-6 membered heterocyclic ring preferably being
In another preferred embodiment, X is selected from CH, N; y is selected from CR 5 and N;
R 1 is selected from hydrogen, halogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C6 alkenyl, R a substituted or unsubstituted C2-C6 alkynyl;
R 2、R4 is each independently selected from hydrogen, R a substituted or unsubstituted C1-C6 alkyl, R a substituted or unsubstituted C1-C6 haloalkyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C6 alkylthio, R a substituted or unsubstituted 3-6 membered heterocyclyl, R a substituted or unsubstituted 3-6 membered cycloalkyl, or the atom to which R 2、R4 is attached forms a R a substituted or unsubstituted 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, O, S;
R 3 is hydrogen;
r 5 is selected from hydrogen, R a substituted or unsubstituted C1-C4 alkyl;
R a is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 alkyl, R a substituted or unsubstituted C1-C6 haloalkyl, substituted or unsubstituted 3-6 cycloalkyl, wherein the substitution is selected from hydrogen, halogen, hydroxy, cyano, C1-C8 alkyl, C1-C8 alkanoyl, 3-6 heterocyclyl, 3-6 cycloalkyl.
In another preferred embodiment, X is selected from CH, N; y is selected from CR 5 and N;
R 1 is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkanoyl, R a substituted or unsubstituted aminoacyl, R a substituted or unsubstituted C1-C8 alkylamido, R a substituted or unsubstituted C1-C8 alkenylamido, R a substituted or unsubstituted C1-C8 alkylamino, R a substituted or unsubstituted C1-C8 alkylsulfide, R a substituted or unsubstituted 3-6 membered heterocyclyl, R a substituted or unsubstituted 3-6 membered cycloalkyl, R a substituted or unsubstituted 5-6 membered heteroaryl;
R 2、R4 is selected from hydrogen, halogen, hydroxy, amino, cyano, nitro, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl, R a substituted or unsubstituted C1-C8 alkoxy, R a substituted or unsubstituted C1-C8 alkanoyl, R a substituted or unsubstituted aminoacyl, R a substituted or unsubstituted C1-C8 alkylamido, R a substituted or unsubstituted C1-C8 alkenylamido, R a substituted or unsubstituted C1-C8 alkylamino, R a substituted or unsubstituted C1-C8 alkylthio, R a substituted or unsubstituted 3-6 membered heterocyclyl, R a substituted or unsubstituted 3-6 membered cycloalkyl, R a substituted or unsubstituted 5-6 membered heteroaryl; r 2、R4 can be linked to form a 5-6 membered heterocycle, and the heterocycle can be substituted with R a;
R 3 is selected from hydrogen, R a substituted or unsubstituted C1-C8 alkyl
R 5 is selected from hydrogen, halogen, R a substituted or unsubstituted C1-C8 alkyl
R a is selected from hydrogen, halogen, hydroxy, cyano, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy acyl, substituted or unsubstituted C1-C8 alkylamino, substituted or unsubstituted 3-6 membered heterocyclyl, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 5-6 membered heteroaryl, said substitution being selected from hydrogen, halogen, hydroxy, cyano, C1-C8 alkyl, C1-C8 alkanoyl, 3-6 membered heterocyclyl, 3-6 membered cycloalkyl.
In another preferred embodiment, the compound is selected from the compounds listed in table 1.
TABLE 1
In a second aspect of the present invention, there is provided a process for the preparation of a compound of formula I, or an isomer, prodrug, solvate, hydrate or a pharmaceutically acceptable salt thereof, said process comprising:
a) Reacting a compound of formula 1 in the presence of a nitrating agent to obtain a compound of formula 2;
b) Carrying out reduction reaction on the compound of the formula 2 in the presence of a reducing agent to obtain a compound of the formula 3;
c) Reacting the compound of formula 3 with thiophosgene to obtain a compound of formula 4;
d) Reacting a compound of formula 4 with a compound of formula 5 in the presence of a condensing agent to obtain a compound of formula I;
Wherein X, Y, R 1、R2、R3、R4, n are as defined in the first aspect of the invention.
In another preferred embodiment, the nitrating agent is selected from the group consisting of: silver nitrate, sodium nitrate, copper nitrate, acetyl nitrate, concentrated nitric acid and concentrated sulfuric acid, or a combination thereof.
In another preferred embodiment, the reducing agent is selected from the group consisting of: hydrogen, sodium sulfide, sodium disulfide, lithium aluminum hydride, sodium borohydride, or a combination thereof.
In another preferred embodiment, when the reducing agent is hydrogen, a catalyst is also added, said catalyst being selected from the group consisting of: raney nickel, palladium on carbon, platinum on carbon, or combinations thereof.
In another preferred embodiment, step c) is carried out under alkaline conditions.
In another preferred embodiment, the condensing agent is selected from the group consisting of: n, N' -diisopropylcarbodiimide, HBTU, TBTU, HATU.
In another preferred embodiment, step d) comprises:
i) Mixing a compound of formula 4 with a compound of formula 5 in an organic solvent for reaction;
ii) adding a condensing reagent into the reaction liquid to perform condensation reaction, thus obtaining the compound of the formula I.
In another preferred embodiment, the method comprises:
Wherein X, Y, R 1、R2、R4, n are as defined in the first aspect of the invention.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising:
(i) One or more therapeutically effective amounts of a compound of the first aspect of the invention, or an isomer, prodrug, solvate, hydrate or a pharmaceutically acceptable salt thereof; and
(Ii) A pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition is an injection, a capsule, a tablet, a pill, a powder or a granule.
In another preferred embodiment, the pharmaceutical composition further comprises one or more second therapeutic agents, which are agents for the prevention and/or treatment of autoimmune diseases.
In a fourth aspect of the present invention there is provided the use of a compound according to the first aspect of the present invention, or an isomer, prodrug, solvate, hydrate or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to the third aspect of the present invention, for the preparation of a formulation for the prophylaxis and/or treatment of a disease associated with an interferon gene stimulatory protein.
In another preferred embodiment, the disorder associated with an interferon gene stimulatory protein is selected from the group consisting of: inflammatory diseases such as Singleton-Merten syndrome (SMS), aicarpi-Gouti re syndrome (AGS), systemic Lupus Erythematosus (SLE), familial chilblain lupus erythematosus (FCL), retinal vascular disease and leukodystrophy (RVCL), STING-related infant onset vascular disease (SAVI), psoriasis, scleroderma, cerebral apoplexy, myocardial infarction, cerebral trauma, atherosclerosis-related vascular disease, cardiovascular disease, diabetes and its complications, parkinson's disease, huntington's disease, familial amyotrophic lateral sclerosis, neurodegenerative disease, small intestine malabsorption syndrome, irritable bowel syndrome, sjogren's syndrome, multiple sclerosis, crohn's disease, non-alcoholic steatohepatitis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, autoimmune colitis, suppurative dermatitis, uveitis, mucositis and autoimmune diseases.
In a fifth aspect of the invention there is provided an inhibitor of an interferon gene stimulatory protein comprising one or more of the compounds of the first aspect of the invention, or an isomer, prodrug, solvate, hydrate or pharmaceutically acceptable salt thereof.
In a sixth aspect of the present invention, there is provided a method for preventing and/or treating a disease associated with an interferon gene stimulatory protein, comprising the steps of: administering to a patient in need thereof a therapeutically effective amount of one or more compounds of the first aspect of the invention, or an isomer, prodrug, solvate, hydrate or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the third aspect of the invention.
In another preferred embodiment, the method is diagnostic or non-diagnostic.
In another preferred embodiment, the method is therapeutic or non-therapeutic.
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
Through long-term and intensive research, the inventor develops a compound shown in a formula I with simple structure, convenient synthesis and stable metabolism for the first time, and the compound has an excellent inhibition effect on interferon gene stimulation proteins, so that the conduction of downstream signal channels is inhibited, and further, the effective treatment of inflammation and autoimmune diseases is realized. On this basis, the inventors completed the present invention.
Terminology
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, when used in reference to a specifically recited value, the term "about" means that the value can vary no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes 99 and 101 and all values therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).
As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …", or "consisting of …".
In the present invention, halogen is F, cl, br or I.
In the present invention, the term "C1-C6" means having 1,2, 3, 4,5 or 6 carbon atoms, "C1-C8" means having 1,2, 3, 4,5, 6, 7 or 8 carbon atoms, and so on. "5-14 membered" means having 5-14 ring atoms, and so on.
In the present invention, the term "alkyl" means a saturated linear or branched hydrocarbon moiety, for example the term "C1-C8 alkyl" refers to a straight or branched alkyl group having 1 to 8 carbon atoms, including without limitation methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like; ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl are preferred.
In the present invention, the term "haloalkyl" means an alkyl group substituted with a halogen atom, including fluoroalkyl, chloroalkyl, bromoalkyl, or iodoalkyl, including, without limitation, trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, monochloromethyl, dichloromethyl, trichloromethyl, and the like.
In the present invention, the term "alkoxy" denotes an-O- (C1-C8 alkyl) group. For example, the term "C1-C6 alkoxy" refers to straight or branched chain alkoxy groups having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy and the like.
In the present invention, the term "alkylthio" means an-S- (C1-C8 alkyl) group. For example, the term "C1-C6 alkyl sulfide group" refers to a straight or branched chain alkyl sulfide group having 1 to 6 carbon atoms, including without limitation methyl sulfide group (-S-CH 3), ethyl sulfide group (-S-CH 2CH3), propyl sulfide group, isopropyl sulfide group, butyl sulfide group, and the like.
In the present invention, the term "alkenyl" means a straight or branched hydrocarbon moiety containing at least one double bond, for example, the term "C2-C8 alkenyl" refers to a straight or branched alkenyl group containing one double bond having 2 to 8 carbon atoms, including without limitation ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
In the present invention, the term "alkynyl" refers to a straight or branched chain alkynyl group containing one triple bond, including, without limitation, ethynyl, propynyl, butynyl, isobutynyl, pentynyl, hexynyl, and the like.
In the present invention, the term "cycloalkyl" means a saturated cyclic hydrocarbon moiety, for example, the term "C3-C8 cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring, including, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. The terms "C3-C6 cycloalkyl", and "C5-C6 cycloalkyl" have similar meanings.
In the present invention, the term "heterocyclyl" means a cyclic group containing at least one (e.g. 1,2, 3) ring hetero atom (e.g. N, O or S), such as tetrahydrofuranyl, pyrrolyl, tetrahydropyridinyl or pyrrolidinyl, dioxolanyl, dioxane.
In the present invention, the term "aryl" means a hydrocarbyl moiety comprising one or more aromatic rings. For example, the term "C6-C10 aryl" refers to an aromatic cyclic group having 6 to 10 carbon atoms, such as phenyl, naphthyl, and the like, which does not contain heteroatoms in the ring.
Unless otherwise indicated, alkyl, haloalkyl, alkoxy, alkyl sulfide, cycloalkyl, heterocyclyl, and aryl described herein are substituted and unsubstituted groups. Possible substituents on alkyl, haloalkyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl and aryl groups include, but are not limited to: hydroxy, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfinyl, arylsulfinyl, C1-C10 alkylimino, C1-C10 alkylsulfonimino, arylsulfonyl imino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureyl, cyano, acyl, thio acyl, acyloxy, carboxyl and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl may also be fused to each other.
In the present invention, the substitution is mono-substitution or poly-substitution, and the poly-substitution is di-substitution, tri-substitution, tetra-substitution, or penta-substitution. The disubstitution means having two substituents and so on.
Salt type
As used herein, the term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention with acids or bases that are suitable for use as medicaments. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is the salts of the compounds of the present invention with acids. Suitable salts forming acids include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and the like; amino acids such as proline, phenylalanine, aspartic acid, and glutamic acid.
Another preferred class of salts are salts of the compounds of the invention with bases, such as alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., magnesium or calcium salts), ammonium salts (e.g., lower alkanolammonium salts and other pharmaceutically acceptable amine salts), such as methylamine, ethylamine, propylamine, dimethylamine, trimethylamine, diethylamine, triethylamine, tert-butylamine, ethylenediamine, hydroxyethylamine, dihydroxyethylamine, and triethylamine salts, and amine salts formed from morpholine, piperazine, lysine, respectively.
The term "solvate" refers to a complex of the compound of the invention coordinated to a solvent molecule to form a specific ratio. "hydrate" refers to a complex of the compound of the present invention coordinated to water.
The term "prodrug" includes a class of compounds which may themselves be biologically active or inactive, and which upon administration by an appropriate method undergo a metabolic or chemical reaction in the human body to convert to a compound of formula I, or a salt or solution of a compound of formula I. The prodrugs include, but are not limited to, carboxylic acid esters, carbonic acid esters, phosphoric acid esters, nitric acid esters, sulfuric acid esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds, phosphoramides, glucosides, ethers, acetals, and the like of the compound.
Pharmaceutical compositions and methods of administration
The invention also provides a pharmaceutical composition comprising:
(i) One or more therapeutically effective amounts of a compound of formula I, or an isomer, prodrug, solvate, hydrate or pharmaceutically acceptable salt thereof; and
(Ii) A pharmaceutically acceptable carrier.
Because the compound of the present invention has excellent antitumor activity, the compound of the present invention and various crystalline forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient are useful for the treatment, prevention and alleviation of diseases associated with tumors.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. The therapeutically effective amount is determined according to the age, condition, course of treatment, etc. of the subject. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-1000mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
The term "pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are sugars (e.g., glucose, sucrose, lactose, etc.), starches (e.g., corn starch, potato starch, etc.), celluloses and derivatives thereof (e.g., sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying agents (e.g., tween), wetting agents (e.g., sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The aminobenzimidazole derivatives represented by the above formula I and pharmaceutically acceptable salts thereof in the present invention may be administered alone or in combination with other pharmaceutically acceptable therapeutic agents.
The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The main advantages of the invention include:
(1) The compound has the characteristics of simple structure, easy synthesis and various administration modes;
(2) The compound has excellent inhibition effect on interferon gene stimulation protein, so that effective treatment of autoimmune diseases is realized;
(3) The compound may have a half maximal inhibitory concentration (IC 50) of less than 50nM against interferon gene stimulatory protein activation in a human cell.
The invention is further described below in conjunction with the specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
For the following examples, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise specified, the starting materials are generally available from commercial sources, such as ALDRICH CHEMICALS co. Commercially available solvents and reagents are generally used without further purification, anhydrous solvents are all processed by standard methods, and other reagents are commercially available in analytical purity. Unless otherwise indicated, all temperatures are expressed in degrees Celsius, room or ambient temperature refers to 20 to 25 degrees Celsius. The structure of the compounds was determined by nuclear magnetic resonance spectroscopy (NMR). The nuclear magnetic resonance hydrogen spectral shift (δ) is given in parts per million (ppm). The nuclear magnetic resonance hydrogen spectrum was measured by Mercury-400MHz nuclear magnetic resonance, with deuterated chloroform (CDCl 3) and deuterated methanol (CD 3 OD) as solvents, and Tetramethylsilane (TMS) as internal standard.
The chromatographic column generally uses 200-300 mesh silica gel as a carrier.
EXAMPLE 1 preparation of Compounds
The following preparation examples are illustrative of the preparation of a portion of the compounds of formula I of the present invention, each compound being represented by S1 through S23, respectively.
1. Synthesis of Compound S1
Step 1: compound 1a (1 eq) was dissolved in acetonitrile, and N-bromosuccinimide (1.1 eq) and silver nitrate (1.1 eq) were added, and the temperature was raised to 80 ℃ and reacted for about 3 hours. After the reaction was completed, insoluble matter was removed by filtration, the filtrate was diluted with dichloromethane, followed by washing with 4% aqueous sodium bicarbonate solution, and the organic phase was collected and purified by column to obtain compound 1b.
Step 2: compound 1b was dissolved in ethanol, 5% palladium on carbon (mass ratio: 20%) was added, and reacted at room temperature under a hydrogen atmosphere for about 6 hours, after the reaction was completed, palladium on carbon was removed by filtration, the filter cake was washed with an appropriate amount of ethanol, and the filtrate was collected and concentrated to an appropriate volume to obtain an ethanol solution of compound 1c, which was directly used in the next step.
Step 3: thiophosgene (1.5 eq) was dissolved in methylene chloride, calcium carbonate (3 eq) was suspended in water and the solution was added, stirred at room temperature for about 5 minutes, followed by the addition of an ethanol solution of compound 1c (1 eq) and the reaction continued for about 5 minutes. After the reaction is completed, water is added for dilution, dichloromethane is used for extraction, and an organic phase is collected and purified by a column to obtain the compound 1d.
Step 4: compound 1d (1 eq) was dissolved in dichloromethane, compound 1e (1.1 eq) was added, and the reaction was allowed to proceed overnight at room temperature, and after compound 1d was completely reacted, N' -diisopropylcarbodiimide (3 eq) was added to the reaction solution, and the reaction was continued for about 8 hours. After the reaction is completed, the reaction solution is poured into water, extracted by methylene dichloride, and the organic phase is collected and purified by a column to obtain the compound S1.1H NMR(400MHz,CD3OD)δ7.49(s,1H),7.44(s,1H),7.37(dd,J＝8.9,4.3Hz,1H),7.30–7.25(m,2H),7.13(dd,J＝9.5,2.3Hz,1H),6.93(td,J＝9.3,2.4Hz,1H).
2. Synthesis of Compound S2
The synthesis method refers to the compound S1, the compound 2a is used for replacing the compound 1e, and other experimental steps are the same, so that the compound is obtained S2.1H NMR(400MHz,MeOD)δ7.47(s,1H),7.36(dd,J＝8.9,4.3Hz,1H),7.13(dd,J＝9.5,2.5Hz,1H),7.09(d,J＝8.1Hz,1H),7.04(s,1H),6.92(td,J＝9.1,2.5Hz,1H),6.84(d,J＝8.2Hz,1H),2.66(q,J＝7.6Hz,2H),1.23(t,J＝7.6Hz,3H).
3. Synthesis of Compound S3
The synthesis method refers to the compound S1, the compound 3a is used for replacing the compound 1e, and other experimental steps are the same, so that the compound is obtained S3.1H NMR(400MHz,CD3OD)δ7.49(s,2H),7.37(dd,J＝8.9,4.2Hz,1H),7.31–7.24(m,2H),7.13(dd,J＝9.5,2.2Hz,1H),6.93(td,J＝9.3,2.3Hz,1H).
4. Synthesis of Compound S4
Synthetic methods referring to compound S1, compound 4a (see j.med.chem.2014,57,7933.) was substituted for compound 1e, and the other experimental procedures were identical to give the compound S4.1H NMR(400MHz,CD3OD)δ7.48(s,1H),7.40–7.37(m,1H),7.10(br,2H),7.03–7.00(m,1H),6.96–6.91(m,1H).
5. Synthesis of Compound S5
Step 1: the synthesis method refers to the compound S1, the compound 5a is used for replacing the compound 1e, and other experimental steps are the same, so that the compound 5b is obtained.
Step 2: compound 5b (1 eq) was dissolved in a mixed solvent of N, N '-dimethylformamide/water (volume ratio of 2:1) under nitrogen protection, followed by addition of compound 5c (1.5 eq), [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.1 eq) and potassium phosphate (3 eq), and reaction was carried out at 45 ℃ for about 6 hours. After the reaction was completed, the reaction solution was poured into water, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound 5d.
Step 3: dissolving compound 5d in ethanol, adding 5% palladium/carbon (mass ratio is 20%), reacting at room temperature under hydrogen atmosphere for about 6 hr, filtering to remove palladium/carbon after the reaction is completed, washing filter cake with appropriate amount of ethanol, collecting filtrate, and purifying with column to obtain the final product S5.1H NMR(400MHz,CD3OD)δ7.46(s,1H),7.35(dd,J＝8.8,4.3Hz,1H),7.13(dd,J＝9.5,2.4Hz,1H),7.10–7.08(m,2H),6.94–6.87(m,2H),3.06–2.97(m,1H),2.08–2.01(m,2H),1.84–1.78(m,2H),1.71–1.58(m,4H).
6. Synthesis of Compound S6
The synthesis method refers to the compound S5, the compound 6a is used for replacing the compound 5c, and other experimental steps are the same, so that the compound is obtained S6.1H NMR(400MHz,MeOD)δ7.50(s,1H),7.39(dd,J＝8.7,4.1Hz,1H),7.22–7.04(m,3H),6.99–6.92(m,2H),2.71–2.56(m,2H),2.14–1.57(m,7H).
7. Synthesis of Compound S7
The synthesis method refers to the compound S1, the compound 7a is used for replacing the compound 1a, and other experimental steps are the same, so that the compound S7 is obtained. 1 H NMR (400 MHz, meOD) delta 7.50 (s, 1H), 7.46 (s, 1H), 7.33-7.26 (m, 4H).
8. Synthesis of Compound S8
The synthesis method refers to the compound S1, the compound 8a is used for replacing the compound 1c, and other experimental steps are the same, so that the compound S8 is obtained. 1 H NMR (400 mhz, meod) delta 7.93 (d, j=8.2 hz, 1H), 7.68 (s, 1H), 7.52-7.36 (m, 4H), 7.13 (t, j=7.4 hz, 1H).
9. Synthesis of Compound S9
Synthetic method referring to compound S1, substituting compound 9a for compound 1a, and other experimental steps are the same to obtain compound S9.1H NMR(400MHz,CD3OD)δ7.62(s,1H),7.52–7.47(m,3H),7.39(d,J＝8.7Hz,1H),7.34(d,J＝8.2Hz,1H),7.29-7.26(m,1H).
10. Synthesis of Compound S10
The synthesis method refers to the compound S8, the compound 4a is used for replacing the compound 1e, and other experimental steps are the same, so that the compound is obtained S9.1H NMR(400MHz,CD3OD)δ7.61(d,J＝1.7Hz,1H),7.45(s,1H),7.33(d,J＝8.6Hz,1H),7.26–7.23(m,1H),7.01(s,2H).
11. Synthesis of Compound S11
Step 1: under the protection of nitrogen, the compound 11a (1 eq) and the compound 11b (2 eq), potassium carbonate (2 eq) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.1 eq) are mixed in a mixed solvent of 1, 4-dioxane/water (volume ratio of 10:1), and heated to 100 ℃ for reaction overnight. After the reaction was completed, the reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, and the organic phase was collected and purified by column to obtain compound 11c.
Step 2: the compound 11c was dissolved in ethanol, 5% palladium on carbon (mass ratio: 20%) was added, and reacted at room temperature under a hydrogen atmosphere for about 6 hours, after the reaction was completed, palladium on carbon was removed by filtration, washed with an appropriate amount of ethanol, and the filtrate was collected and dried to obtain the compound 11d, which was directly used in the next step.
Step 3: compound 11d was dissolved in methanol, and a 4N solution of 1, 4-dioxane of hydrogen chloride was added thereto, and the mixture was reacted at room temperature for about 3 hours. After the reaction is completed, the mixture is directly dried by spinning and is carried with two sides by methanol, and the compound 11e is obtained by pumping and is directly used in the next step.
Step 4: compound 11e (1 eq) was suspended in acetonitrile, triethylamine (2 eq) was added and stirred at room temperature until the solution became clear, then compound 1d (1 eq) was added, and the reaction was carried out at room temperature overnight, and after the reaction was completed to give an intermediate, N' -diisopropylcarbodiimide (3 eq) was added to the reaction solution and the reaction was continued for about 8 hours. After the reaction is completed, the reaction solution is poured into water, extracted by ethyl acetate, and the organic phase is collected and purified by a column to obtain the compound S11.1H NMR(400MHz,CD3OD)δ7.45(s,1H),7.33(dd,J＝8.7,4.3Hz,1H),7.14(dd,J＝9.5,2.5Hz,1H),7.11–7.07(m,2H),6.95–6.88(m,2H),1.91–1.83(m,1H),1.55–1.48(m,2H),1.29–1.23(m,2H).
12. Synthesis of Compound S12
Synthetic method referring to compound S11, substituting compound 12a for compound 11b, other experimental procedures were the same to obtain the compound S12.1H NMR(400MHz,CD3OD)δ7.43(s,1H),7.35(dd,J＝8.6,4.4Hz,1H),7.16(dd,J＝9.5,2.5Hz,1H),7.14–7.10(m,2H),6.98–6.85(m,2H),3.16–3.07(m,1H),2.28–2.21(m,2H),2.08–1.87(m,4H).
13. Synthesis of Compound S13
Synthetic method referring to Compound S11, compound 13a (see ACS Med. Chem. Lett.2012,3, 726-730) was used instead of Compound 11b, and the other experimental procedures were the same to give Compound S13.1H NMR(400MHz,CD3OD)δ7.50(s,1H),7.33(dd,J＝8.8,4.3Hz,1H),7.17(dd,J＝9.5,2.4Hz,1H),7.13–7.11(m,2H),6.98–6.89(m,2H),2.97–2.89(m,1H),1.92–1.81(m,2H),1.69–1.56(m,4H),1.01(s,6H).
14. Synthesis of Compound S14
Synthetic method referring to compound S1, compound 14a is used to replace compound 1b, and other experimental steps are the same to obtain compound S14.1H NMR(400MHz,CD3OD)δ8.24(dd,J＝4.7,1.3Hz,1H),7.97(dd,J＝7.9,1.5Hz,1H),7.62(s,1H),7.48(s,1H),7.35–7.30(m,2H),7.13(dd,J＝7.9,4.8Hz,1H).
15. Synthesis of Compound S15
Synthetic method referring to Compound S11, substituting Compound 14c for Compound 1d and Compound 15a (Synthesis of reference Compound 11 e) for Compound 11e, other experimental procedures were the same to give Compound S14.1H NMR(400MHz,CD3OD)δ8.24(dd,J＝4.8,1.3Hz,1H),7.95(d,J＝7.7Hz,1H),7.59(s,1H),7.15–7.10(m,3H),6.98–6.95(m,1H),3.05–2.97(m,1H),2.07–2.00(m,1H),1.84–1.76(m,2H),1.73–1.65(m,2H),1.62–1.53(m,2H).
16. Synthesis of Compound S16
Synthetic method referring to compound S1, compound 16a is used to replace compound 1a, and other experimental steps are the same to obtain compound S14.1H NMR(400MHz,CD3OD)δ8.16(t,J＝2.2Hz,1H),7.69(dd,J＝8.9,2.9Hz,1H),7.66(s,1H),7.32–7.30(m,2H),7.06(dd,J＝8.2,1.3Hz,1H).
17. Synthesis of Compound S17
Synthetic method referring to compound S15, compound 16d is substituted for compound 14c, and other experimental steps are the same to obtain compound S17.1H NMR(400MHz,CD3OD)δ8.15(t,J＝2.1Hz,1H),7.67(dd,J＝8.8,2.7Hz,1H),7.63(s,1H),7.12–7.10(m,2H),6.90(dd,J＝8.2,1.3Hz,1H),3.06–2.98(m,1H),2.08–2.01(m,2H),1.84–1.78(m,2H),1.72–1.58(m,4H).
18. Synthesis of Compound S18
Step 1: synthetic method referring to compound S1, compound 18a was substituted for compound 1a, and other experimental steps were identical to obtain compound 18e.
Step 2: compound 18e (1 eq) was dissolved in N, N-dimethylformamide under nitrogen protection, and diphenylphosphine palladium dichloride (0.02 eq), cuprous iodide (0.03 eq), triethylamine (2 eq) and compound 18f (3 eq) were added and reacted at room temperature for about two hours. After the reaction was completed, the reaction solution was poured into water, extracted 3 times with ethyl acetate, and the organic phase was collected and purified by column to obtain 18g of a compound.
Step 3: the compound (18 g) was dissolved in methanol, and potassium carbonate (1 eq) was added thereto and reacted at room temperature for about 5 hours. After the reaction is completed, the reaction solution is poured into water, extracted for 3 times by ethyl acetate, and the organic phase is collected and purified by a column to obtain the compound S18.1H NMR(400MHz,CD3OD)δ7.65(s,1H),7.55–7.48(m,3H),7.36(d,J＝8.7Hz,1H),7.32(d,J＝8.2Hz,1H),7.29-7.26(m,1H)3.94(s,1H).
19. Synthesis of Compound S19
Synthetic method referring to compound 18g, compound 19a was substituted for compound 18f, and other experimental procedures were the same to give the compound S19.1H NMR(400MHz,CD3OD)δ7.64(s,1H),7.50–7.45(m,3H),7.37(d,J＝8.7Hz,1H),7.31(d,J＝8.2Hz,1H),7.28-7.25(m,1H),1.46–1.42(m,1H),0.87–0.83(m,2H),0.72–0.68(m,2H).
20. Synthesis of Compound S20
Step 1: compound 18e (1 eq) was dissolved in ultra-dry acetonitrile under nitrogen protection, and compound 20a (1.5 eq), tris (o-methylphenyl) phosphorus (0.2 eq), palladium acetate (0.1 eq) and triethylamine (3 eq) were added in this order and reacted at 90 ℃ for about 6 hours. After the reaction is completed, cooling to room temperature, pouring the reaction solution into water, extracting for 3 times by using ethyl acetate, collecting an organic phase, and purifying by a column to obtain a compound S20.1H NMR(400MHz,CD3OD)δ7.64(s,1H),7.51–7.46(m,3H),7.39(d,J＝8.6Hz,1H),7.30(d,J＝8.2Hz,1H),7.29-7.26(m,1H),6.77(d,J＝16.1Hz,1H),6.15–6.06(m,1H),3.58(d,J＝5.8Hz,2H).
21. Synthesis of Compound S21
Synthetic method referring to compound S20, compound 21a is substituted for compound 20a, other experimental steps are the same, and the compound is obtained S21.1H NMR(400MHz,CD3OD)δ7.69(s,1H),7.59–7.52(m,3H),7.39(d,J＝8.7Hz,1H),7.33(d,J＝8.4Hz,1H),7.30-7.27(m,1H),7.15(d,J＝8.2Hz,1H),6.27(d,J＝16.4Hz,1H).
22. Synthesis of Compound S22
Synthetic methods referring to compound S1, compound 22a (see CN 104024222.) was substituted for compound 1e, and the other experimental procedures were the same to give the compound S22.1H NMR(400MHz,CD3OD)δ7.53(s,1H),7.48(s,1H),7.41(dd,J＝8.9,4.3Hz,1H),7.36(d,J＝8.5Hz,1H),7.29(d,J＝8.4Hz,1H),7.17(dd,J＝9.4,2.4Hz,1H),6.97(td,J＝9.1,2.5Hz,1H).
23. Synthesis of Compound S23
Synthetic methods referring to compound S1, compound 23a (see Russ.Chem.Bull., int.Ed.,69, 2370-2377.) was substituted for compound 1b, and the other experimental procedures were the same to give the compound S23.1H NMR(400MHz,CD3OD)δ7.41(s,1H),7.27(dd,J＝8.7,4.4Hz,1H),7.25–7.21(m,2H),7.13(dd,J＝9.5,2.3Hz,1H),7.08–7.03(m,1H),2.36(s,3H).
EXAMPLE 2 inhibitory Activity of Compounds on STING in human THP1-Dual and murine Raw-Lucia reporter cells
1. Half maximal inhibitory concentration (IC 50) test of Compounds on STING activation in human cells
1.1 Detection principle: a Dual-report system of an Interferon Stimulating Gene (ISG) and a nuclear transcription inflammatory factor (NF-kB) is constructed in a human monocyte strain THP1-Dual cell, the expression of downstream luciferase and alkaline phosphatase can be respectively regulated and controlled under the action of an activator or inhibitor, and then the signal intensity of a corresponding channel is reflected by adding a corresponding luciferase or alkaline phosphatase detection reagent. In this study, since STING modulators are mainly modulating the ISG pathway, we used an ISG pathway reporter system to observe the inhibition of compounds on the ISG pathway stimulated by STING positive agonist MSA-2 to infer the inhibitory activity of compounds on STING pathway.
1.2 Experimental method:
1) Compounds were formulated in 10mM stock solution in DMSO.
2) In 96-well plates, 20ul of compound diluted with physiological saline was added to each well, and the initial test concentration (1. Mu.M) and concentration gradient (3-fold dilution) of the compound were set to 10. Mu.M for the STING agonist MSA-2, based on the primary screening activity of the compound.
3) THP1-Dual cell count, cell concentration adjusted to 5X 10 5/ml, and incubation was performed by adding 180. Mu.l of cells per well. The experiments were set up in different groups, including: cell blank (vehicle), stimulus (MSA-2), dosing group with different concentration gradients (MSA-2+ compound), vehicle DMSO content 0.2%, three wells each. Mu.l of each cell was added with a different set of reagents, so that the final volume of each test well was 200. Mu.l.
4) After incubation for 24h in a 37℃cell incubator, 20ul of culture broth was taken per well into a new 96-well plate with light-transmitting bottom, followed by addition of luciferase detection reagent QUANTI-Luc luciferase detection reagent and immediate determination of Lum fluorescence value using spectra-MAX190 (Molecular Devices).
5) Calculate IC 50. Inhibition ratio was calculated first = [ control (Lum) -dosing (Lum) ]/control (Lum) ×100, and then IC 50 values were calculated by four-parameter fitting method of GRAPHPAD PRISM 8.4.3 software.
2. Half maximal inhibitory concentration (IC 50) test of compounds for STING activation in murine cells
2.1 Detection principle: murine Raw-Lucia cells, in which an ISG reporter system is constructed, regulate the expression of downstream luciferase under the action of an activator or inhibitor, are used as subjects. And then the signal intensity of the channel is reflected by adding a corresponding luciferase detection reagent. In this study, we observed the inhibition of the STING positive agonist MSA-2 stimulated ISG pathway by the compound to infer the inhibitory activity of the compound on STING pathway.
2.2 Experimental method:
1) Compounds were formulated in 10mM stock solution in DMSO.
2) In 96-well plates, 20ul of compound diluted with physiological saline was added to each well, and the initial test concentration (1. Mu.M) and concentration gradient (3-fold dilution) of the compound were set to 50. Mu.M for STING agonist MSA-2, based on the primary screening activity of the compound.
3) Raw-Lucia cell counts, cell concentrations adjusted to 5X 10 5/ml, and incubation was performed with 180. Mu.l of cells added per well. The experiments were set up in different groups, including: cell blank group, stimulation group (cell+MSA-2+ solvent), dosing group with different concentration gradients (cell+MSA-2+ compound), and solvent DMSO content of 0.6%, and three wells were respectively arranged. Mu.l of each cell was added with a different set of reagents, and thus the final volume of each test well was 200. Mu.l.
4) After incubation for 24h in a 37℃cell incubator, 20ul of culture broth was taken per well into a new 96-well plate with light-transmitting bottom, followed by addition of luciferase detection reagent QUANTI-Luc luciferase detection reagent and immediate determination of Lum fluorescence value using spectra-MAX190 (Molecular Devices).
5) Calculate IC 50. Inhibition ratio was calculated first = [ control (Lum) -dosing (Lum) ]/control (Lum) ×100, and then IC 50 values were calculated by four-parameter fitting method of GRAPHPAD PRISM 8.4.3 software.
The half maximal inhibitory concentration (IC 50) of the compounds on STING activation in human THP1-Dual and murine Raw-Lucia reporter cells is shown in Table 2.
Table 2A: <50nM; b:50-500nM; c:500-1000nM; d: 1000nM
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (14)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,
Wherein:
X is selected from CH and N;
Y is selected from CR 5;
n is an integer from 1 to 3;
R 1 is selected from hydrogen, halogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C1-C8 haloalkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl;
R 2 is selected from the group consisting of C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkylthio, C1-C8 haloalkylthio, R a substituted or unsubstituted 3-8 membered heterocyclyl, R a substituted or unsubstituted 3-8 membered cycloalkyl;
R 4 is hydrogen, or R 2、R4 forms with the atom to which it is attached a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted with R a;
R 3 is hydrogen;
r 5 is selected from hydrogen, C1-C8 alkyl;
R a is selected from hydrogen, halogen, cyano, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, 3-8 membered heterocyclyl, 3-8 membered cycloalkyl;
Wherein the compound does not include
2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen, fluoro, chloro, bromo, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C6 alkenyl, R a substituted or unsubstituted C2-C6 alkynyl, wherein R a is as defined in claim 1.
3. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkyl sulfide, C1-C8 haloalkylsulfanyl, R a substituted or unsubstituted 3-8 membered cycloalkyl;
R 4 is hydrogen or the atom to which R 2、R4 is attached forms a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted with R a, wherein R a is as defined in claim 1.
4. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl sulfide, C1-C6 haloalkylsulfanyl, R a substituted or unsubstituted 3-6 membered cycloalkyl;
R 4 is hydrogen, or the atom to which R 2、R4 is attached forms a 5-6 membered heterocyclic ring substituted or unsubstituted by R a containing at least 2O, wherein R a is selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl.
5. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C1-C8 alkyl, C1-C8 haloalkyl, 3-6 membered cycloalkyl and R 4 is hydrogen.
6. A compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2、R4 forms a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, S, substituted or unsubstituted with R a, with the atom to which R 2、R4 is attached, wherein R a is as defined in claim 1.
7. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from CH, N; y is selected from CR 5;
r 1 is selected from hydrogen, halogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C8 alkenyl, R a substituted or unsubstituted C2-C8 alkynyl;
R 2 is selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C8 alkyl sulfide, C1-C8 haloalkylsulfanyl, R a substituted or unsubstituted 3-6 membered cycloalkyl;
R 4 is hydrogen, or R 2、R4 may be linked to a 5-6 membered heterocyclic ring containing 1-3 heteroatoms selected from N, O, S, and the heterocyclic ring may be substituted with R a;
R 3 is hydrogen;
r 5 is selected from hydrogen, C1-C8 alkyl;
R a is selected from hydrogen, halogen, cyano, C1-C8 alkyl, C1-C8 alkoxy, 3-6 membered heterocyclyl, and 3-6 membered cycloalkyl.
8. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from CH, N; y is selected from CR 5;
R 1 is selected from hydrogen, halogen, R a substituted or unsubstituted C1-C8 alkyl, R a substituted or unsubstituted C2-C6 alkenyl, R a substituted or unsubstituted C2-C6 alkynyl;
r 2 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C1-C6 alkyl sulfide, C1-C6 haloalkylsulfanyl, 3-6 cycloalkyl, C1-C6 alkyl substituted 3-6 cycloalkyl, halogenated 3-6 cycloalkyl,
R 4 is hydrogen, or R 2、R4 forms with the atom to which it is attached a halogen substituted or unsubstituted 5-6 membered heterocycle containing 1-3 heteroatoms selected from N, O, S;
R 3 is hydrogen;
R 5 is selected from hydrogen, C1-C4 alkyl;
R a is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, 3-6 membered cycloalkyl.
9. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
10. A process for the preparation of a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, which comprises:
a) Reacting a compound of formula 1 in the presence of a nitrating agent to obtain a compound of formula 2;
b) Carrying out reduction reaction on the compound of the formula 2 in the presence of a reducing agent to obtain a compound of the formula 3;
c) Reacting the compound of formula 3 with thiophosgene to obtain a compound of formula 4;
d) Reacting a compound of formula 4 with a compound of formula 5 in the presence of a condensing agent to obtain a compound of formula I;
Wherein X, Y, R 1、R2、R3、R4, n are as defined in claim 1.
11. A pharmaceutical composition comprising:
(i) One or more therapeutically effective amounts of a compound of claim 1, or a pharmaceutically acceptable salt thereof; and
(Ii) A pharmaceutically acceptable carrier.
12. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 11 for the preparation of a formulation for the prevention and/or treatment of a disease associated with an interferon gene stimulating protein, wherein the disease associated with an interferon gene stimulating protein is selected from the group consisting of: singleton-Merten syndrome (SMS), aicarpi-Gouti res syndrome (AGS), systemic Lupus Erythematosus (SLE), familial chilblain lupus erythematosus (FCL), retinal vascular disease and leukodystrophy (RVCL), STING-related infant onset vascular disease (SAVI), psoriasis, scleroderma, cerebral apoplexy, myocardial infarction, cerebral trauma, atherosclerosis-related vascular disease, cardiovascular disease, diabetes and its complications, familial amyotrophic lateral sclerosis, neurodegenerative disease, small intestine malabsorption syndrome, irritable bowel syndrome, sjogren's syndrome, multiple sclerosis, crohn's disease, nonalcoholic steatohepatitis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, suppurative sweat gland, uveitis, mucositis and autoimmune disease.
13. The use according to claim 12, wherein the disorder associated with the interferon gene stimulatory protein is selected from the group consisting of: parkinson's disease, huntington's disease, autoimmune colitis.
14. An inhibitor of an interferon gene stimulatory protein, wherein said inhibitor comprises one or more compounds of claim 1 or a pharmaceutically acceptable salt thereof.
CN202110967824.6A 2021-08-23 Aminobenzimidazole-containing derivatives, and preparation and application thereof Active CN115710253B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110967824.6A CN115710253B (en) 2021-08-23 Aminobenzimidazole-containing derivatives, and preparation and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110967824.6A CN115710253B (en) 2021-08-23 Aminobenzimidazole-containing derivatives, and preparation and application thereof

Publications (2)

Publication Number Publication Date
CN115710253A CN115710253A (en) 2023-02-24
CN115710253B true CN115710253B (en) 2024-07-02

Family

ID=

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101616910A (en) * 2006-09-07 2009-12-30 比奥根艾迪克Ma公司 Indazole derivatives as interleukin 1 receptor associated kinase conditioning agent
CN115768761A (en) * 2020-03-25 2023-03-07 卡尔那生物科学株式会社 Novel benzimidazole derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101616910A (en) * 2006-09-07 2009-12-30 比奥根艾迪克Ma公司 Indazole derivatives as interleukin 1 receptor associated kinase conditioning agent
CN115768761A (en) * 2020-03-25 2023-03-07 卡尔那生物科学株式会社 Novel benzimidazole derivatives

Similar Documents

Publication Publication Date Title
CN113544128B (en) KRAS-G12C inhibitors
CN113767103B (en) Novel spirocyclic K-Ras G12C inhibitors
CA3165238A1 (en) Kras mutant protein inhibitors
CN115335379A (en) Spiro-containing quinazoline compounds
KR102499780B1 (en) Heterocyclic compound serving as fgfr4 inhibitor
CN112694475A (en) Cycloalkyl and heterocycloalkyl inhibitors, and preparation method and application thereof
CN111393404B (en) Benzothiophene compounds, and pharmaceutical composition and application thereof
CN112778301A (en) Tetrahydropyridopyrimidine inhibitor and preparation method and application thereof
CN115043842A (en) Amino-substituted bicyclic inhibitor and preparation method and application thereof
CN115109078A (en) Pyrimidopyridine inhibitor and preparation method and application thereof
CN112824410A (en) Aza-heptacyclic inhibitor and preparation method and application thereof
EP4032890A1 (en) Heterocyclic amide compound, pharmaceutically acceptable salt thereof, and preparation method therefor and use thereof
CN114835703A (en) Substituted pyrimidopyridone inhibitor and preparation method and application thereof
CN108947952B (en) 2-substituted amino-5-trifluoromethyl-8-nitrobenz (thio) pyran-4-ketone compound and preparation method and application thereof
KR20230118891A (en) Novel Camptothecin Derivatives, Compositions Containing Them and Uses Thereof
CN115710253B (en) Aminobenzimidazole-containing derivatives, and preparation and application thereof
JP7329052B2 (en) Fluorine-containing substituted benzothiophene compounds and pharmaceutical compositions and applications thereof
CN115215844A (en) Substituted pyrimido-ring inhibitor and preparation method and application thereof
CN115710253A (en) Amino-containing benzimidazole derivatives, and preparation and application thereof
CN115215869A (en) Substituted tricyclic inhibitor and preparation method and application thereof
CN113880804A (en) Novel benzimidazole compounds
CN114380805A (en) Substituted benzo or pyrido pyrimidine amine inhibitor and preparation method and application thereof
CN115710255A (en) Benzo-heterocycle-substituted urea derivative and preparation and application thereof
CN115960117B (en) Sulfur-containing fused ring derivative inhibitor, preparation method and application thereof
CN114907323B (en) Quinoxalinone compounds, preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
SE01 Entry into force of request for substantive examination
GR01 Patent grant