CN112940004B - Heterocyclic compound and application thereof - Google Patents

Heterocyclic compound and application thereof Download PDF

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CN112940004B
CN112940004B CN201911264464.2A CN201911264464A CN112940004B CN 112940004 B CN112940004 B CN 112940004B CN 201911264464 A CN201911264464 A CN 201911264464A CN 112940004 B CN112940004 B CN 112940004B
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substituted
halogen
alkyl
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cycloalkyl
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CN112940004A (en
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周兵
耿美玉
高愚哲
谢作权
杨亚玺
王玺渊
张燕
丁健
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Shanghai Institute of Materia Medica of CAS
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The disclosure relates to a heterocyclic compound represented by general formula I, and pharmaceutically acceptable salts, stereoisomers, enantiomers, diastereomers, atropisomers, optical isomers, racemates, polymorphs, solvates or isotopically labeled compounds thereof, pharmaceutical compositions containing the heterocyclic compound and pharmaceutical uses thereof. The heterocyclic compounds disclosed by the invention are a class of immunomodulators, and particularly relate to immunomodulators of compounds for activating STING.

Description

Heterocyclic compound and application thereof
Technical Field
The disclosure relates to an immunomodulator, in particular to a heterocyclic compound and application thereof.
Background
The immune system of the human body can be generally divided into the "innate" and "adaptive" systems. The natural immune system plays an important role in resisting infection, inhibiting tumor growth and the pathogenesis of autoimmune diseases, mainly recognizes pathogenic microorganisms and cancer cell components through a pattern recognition receptor, starts a downstream signal path, finally kills the pathogenic microorganisms and the cancer cell components by inducing cytokine expression, adapts to the immune system and promotes the generation of antibodies and specific T lymphocytes.
STING (interferon gene stimulating factor, TMEM173, MITA, etc.) is a key node molecule in response to DNA invasion in cells, and under the stimulation of cytoplasmic DNA, it recognizes signals of cytoplasmic DNA receptors, playing a key role in inducing the process of interferon production. After recognition of foreign or endogenous "non-self" DNA by the host cell's DNA recognition receptor, a signal is transmitted to the node molecule STING, which then rapidly dimerizes and translocates from the endoplasmic reticulum to the nucleosome pericytes. Activation of STING results in upregulation of IRF3 and NK κ B pathways, leading to induction of interferon- β and other cytokines.
CDN was first found to be a second messenger responsible for controlling prokaryotic cellular responses. Direct bacterial CDN activation of STING has been verified by X-ray crystallography (Burdette DL et al, Nature Immunolog, 2013(14): 19-26). It has been found that the new CDN signaling molecule cGAMP activates STING, and its interaction with STING has also been validated by X-ray crystallography (Cai X et al, Molecular Cell,2014(54): 289-296).
Compounds that bind STING and act as agonists have been shown to induce type 1 interferon and other cytokines upon incubation with human PBMCs. Compounds that induce human interferon may be useful in the treatment of various disorders, for example in the treatment of allergic diseases and other inflammatory disorders, for example allergic rhinitis and asthma, in the treatment of infectious diseases, neurodegenerative diseases, pre-cancerous syndromes and cancer, and may also be useful as immunological compositions or vaccine adjuvants. Activation of STING may be a potential method for treating diseases associated with the type 1 IFN pathway, including inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, pre-cancerous syndromes, or as an immunological composition or vaccine adjuvant.
Disclosure of Invention
Technical purpose
It is an object of the present disclosure to provide a class of heterocyclic compounds, pharmaceutically acceptable salts, stereoisomers, enantiomers, diastereomers, atropisomers, racemates, polymorphs, solvates or isotopically labeled compounds thereof as immunomodulators.
It is another object of the present disclosure to provide a pharmaceutical composition.
It is a further object of the present disclosure to provide pharmaceutical uses of the compounds or pharmaceutical compositions.
Technical scheme
In one aspect, the present disclosure provides a heterocyclic compound represented by the general formula (I), a pharmaceutically acceptable salt, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, an optical isomer, a racemate, a polymorph, a solvate, or an isotopically labeled compound thereof:
Figure BDA0002312459850000021
wherein, X2、X3、X4Are respectively and independently selected from C or N;
ring A is selected from the group consisting of 0 to 3RAAn optionally substituted 5-membered aromatic heterocycle;
B. the C rings are each independently selected from 0 to 4R1Optionally substituted benzene ring, substituted with 0-4R1An optionally substituted 5-to 6-membered heteroaromatic ring;
RAindependently selected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -C (O) NRaRb、S(O)2NRaRb、-NRjC(O)Rk；
R1Independently selected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk； -C(O)NRaRbOr S (O)2NRaRb；
R2、R3、R4Are independently selected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、 C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk、-C(O)NRaRb、S(O)2NRaRbOr none;
R5、R5’each independently selected from hydrogen and C1～C6An alkyl group;
Ra、Rb、Rd、Reeach independently selected from hydrogen and C1～C6Alkyl, or C3～C6A cycloalkyl group;
Rxselected from hydrogen, halogen, by 0-4RhOptionally substituted C1～C6Alkyl, -O (CH)2)mRc、 -NRfRg、-C(O)Rf、-CO2Rf、-C(O)NRfRg、-NRfC(O)Rg；
RcIndependently selected from hydrogen, by 0-4RhOptionally substituted C1～C6Alkyl, with 0-4RiAn optionally substituted 6-to 10-membered aromatic ring, substituted with 0 to 4RiOptionally substituted 5-to 10-membered aromatic heterocycle substituted with 0 to 4RiOptionally substituted 3-to 10-membered cycloalkyl, substituted with 0 to 4RiAn optionally substituted 3-to 8-membered non-aromatic heterocyclic group, or 5-to 10-membered cycloalkenyl group;
Rf、Rgare independently selected respectivelyFrom 0 to 4R of hydrogenhOptionally substituted C1～C6Alkyl, with 0 to 4RiAn optionally substituted 6-to 10-membered aromatic ring, substituted with 0 to 4RiOptionally substituted 5-to 10-membered aromatic heterocycle substituted with 0 to 4RiOptionally substituted 3-to 10-membered cycloalkyl, substituted with 0 to 4RiAn optionally substituted 3-to 8-membered non-aromatic heterocyclic group, or 5-to 10-membered cycloalkenyl group;
Rhindependently selected from halogen, -ORj、-NRjRk、-C(O)Rj、-CO2Rj、-C(O)NRjRk、 -NRjC(O)Rk0 to 4RiAn optionally substituted 6-to 10-membered aromatic ring substituted with 0 to 4RiOptionally substituted 5-to 10-membered aromatic heterocycle substituted with 0 to 4RiOptionally substituted 3-to 10-membered cycloalkyl, substituted with 0 to 4RiAn optionally substituted 3-to 8-membered non-aromatic heterocyclic group, or 5-to 10-membered cycloalkenyl group;
Riindependently selected from halogen, hydroxy, amino, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen-substituted C1～C6Alkyl, hydroxy substituted C1～C6Alkyl, amino substituted C1～C6Alkyl, cyano;
or two RiAnd the ring atoms to which they are attached, form a 3-to 8-membered saturated or unsaturated ring.
m is 0 to 6;
Rjindependently selected from hydrogen, C1～C6Alkyl or C3～C6A cycloalkyl group;
Rkindependently selected from hydrogen, hydroxy, amino, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen-substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, or halogen substituted C3～C6A cycloalkyl group;
l is selected from 0 to 4RnOptionally substituted C4～C6Alkylene of (a) with 0 to 4RnOptionally substituted C4～C6Alkenylene group of (A) is substituted by 0 to 4RnOptionally substituted C4～C6Alkynylene of (a); wherein, optionally substituted C4～C6Alkylene of (a), optionally substituted C4～C6Alkenylene of (a), optionally substituted C4～C6Of alkynylene of (a) — CH2-、-CHRn-or-C (R)n)2May be substituted by-O-, -S-, -NRm-substitution;
Rmselected from hydrogen, C1～C6Alkyl radical, C3～C6A cycloalkyl group;
Rnselected from halogen, hydroxy, amino, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen-substituted C1～C6An alkyl group.
In another aspect, the present disclosure provides a pharmaceutical composition comprising the above heterocyclic compound, a pharmaceutically acceptable salt, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph, a solvate, or an isotopically labeled compound thereof, and a pharmaceutically acceptable excipient.
In another aspect, the present disclosure provides a pharmaceutical use of the heterocyclic compound, a pharmaceutically acceptable salt, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph, a solvate, or an isotopically labeled compound thereof, or the pharmaceutical composition.
Advantageous effects
The compounds or compositions of the present disclosure can be effectively used to activate interferon gene stimulating factors and as immunomodulators in diseases associated with immunomodulation.
Detailed Description
To make the features and effects of the present invention comprehensible to those having ordinary knowledge in the art, general description and definitions are made with respect to terms and phrases mentioned in the specification and claims. 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.
In this document, the terms "comprising," "including," "having," "containing," or any other similar term, are intended to be open-ended franslational phrase (open-ended franslational phrase) and are intended to cover non-exclusive inclusions. For example, a composition or article comprising a plurality of elements is not limited to only those elements recited herein, but may include other elements not expressly listed but generally inherent to such composition or article. In addition, unless expressly stated to the contrary, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or". For example, the condition "a or B" is satisfied in any of the following cases: a is true (or present) and B is false (or not present), a is false (or not present) and B is true (or present), both a and B are true (or present). Furthermore, in this document, the terms "comprising," including, "" having, "" containing, "and" containing "are to be construed as specifically disclosed and to cover both closed and semi-closed conjunctions, such as" consisting of … "and" consisting essentially of ….
All features or conditions defined in numerical ranges or percentage ranges herein are for brevity and convenience only. Accordingly, the description of a range of values or percentages should be considered to cover and specifically disclose all possible subranges and individual values within the range, particularly integer values. For example, a description of a range of "1 to 8" should be considered to have specifically disclosed all subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so on, particularly subranges bounded by all integer values, and should be considered to have specifically disclosed individual values such as 1, 2, 3, 4, 5,6, 7, 8, and so on, within the range. Unless otherwise indicated, the foregoing explanatory methods apply to all matters contained in the entire disclosure, whether broad or not.
If an amount or other value or parameter is expressed as a range, preferred range, or a list of upper and lower limits, it is to be understood that all ranges subsumed therein for any pair of that range's upper or preferred value and that range's lower or preferred value, whether or not such ranges are separately disclosed, are specifically disclosed herein. Further, when a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the precision of the number of significant digits of the value, provided that the object of the invention is achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.
In this document, where Markush group (Markush group) or Option language is used to describe features or examples of the invention, those skilled in the art will recognize that a sub-group of all elements or any individual element within a Markush group or list of options may also be used to describe the invention. For example, if X is described as being "selected from the group consisting of1、X2And X3The group "also indicates that X has been fully described as X1Is claimed with X1And/or X2Claim (5). Furthermore, where Markush group or Option terminology is used to describe a feature or example of the invention, those skilled in the art will recognize that any combination of sub-groups of all elements or individual elements within a Markush group or list of options can also be used to describe the invention. Accordingly, for example, if X is described as being "selected from" X1、X2And X3Group consisting of "and Y is described as" selected from the group consisting of1、Y2And Y3The group "formed indicates that X has been fully described as X1Or X2Or X3And Y is Y1Or Y2Or Y3Claim (5).
The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application and uses thereof. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or the summary of the invention or the following detailed description or examples.
According to one embodiment of the present disclosure, there is provided a heterocyclic compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, an optical isomer, a racemate, a polymorph, a solvate, or an isotopically labeled compound thereof:
Figure BDA0002312459850000061
wherein, X2、X3、X4Are respectively and independently selected from C or N;
ring A is selected from the group consisting of 0 to 3RAAn optionally substituted 5-membered aromatic heterocycle;
B. the C rings are respectively and independently selected from 0 to 4R1Optionally substituted benzene ring, substituted with 0-4R1An optionally substituted 5-to 6-membered aromatic heterocycle;
RAindependently selected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -C (O) NRaRb、S(O)2NRaRb、-NRjC(O)Rk；
R1Independently selected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk； -C(O)NRaRbOr S (O)2NRaRb；
R2、R3、R4Are independently selected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、 C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk、-C(O)NRaRb、S(O)2NRaRbOr none;
R5、R5’each independently selected from hydrogen and C1～C6An alkyl group;
Ra、Rb、Rd、Reeach independently selected from hydrogen and C1～C6Alkyl, or C3～C6A cycloalkyl group;
Rxselected from hydrogen, halogen, by 0-4RhOptionally substituted C1～C6Alkyl, -O (CH)2)mRc、 -NRfRg、-C(O)Rf、-CO2Rf、-C(O)NRfRg、-NRfC(O)Rg；
RcIndependently selected from hydrogen, by 0-4RhOptionally substituted C1～C6Alkyl, with 0 to 4RiAn optionally substituted 6-to 10-membered aromatic ring, substituted with 0 to 4RiOptionally substituted 5-to 10-membered aromatic heterocycle substituted with 0 to 4RiOptionally substituted 3-to 10-membered cycloalkyl, substituted with 0 to 4RiAn optionally substituted 3-to 8-membered non-aromatic heterocyclic group, or 5-to 10-membered cycloalkenyl group;
Rf、Rgeach independently selected from hydrogen and 0-4RhOptionally substituted C1～C6Alkyl, with 0 to 4RiAn optionally substituted 6-to 10-membered aromatic ring, substituted with 0 to 4RiOptionally substituted 5-to 10-membered aromatic heterocycle substituted with 0 to 4RiOptionally substituted 3-to 10-membered cycloalkyl, substituted with 0 to 4RiAn optionally substituted 3-to 8-membered non-aromatic heterocyclic group, or 5-to 10-membered cycloalkenyl group;
Rhindependently selected from halogen, -ORj、-NRjRk、-C(O)Rj、-CO2Rj、-C(O)NRjRk、 -NRjC(O)Rk0 to 4RiAn optionally substituted 6-to 10-membered aromatic ring substituted with 04RiOptionally substituted 5-to 10-membered aromatic heterocycle, substituted with 0 to 4RiOptionally substituted 3-to 10-membered cycloalkyl, substituted with 0 to 4RiAn optionally substituted 3-to 8-membered non-aromatic heterocyclic group, or 5-to 10-membered cycloalkenyl group;
Riindependently selected from halogen, hydroxy, amino, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen-substituted C1～C6Alkyl, hydroxy substituted C1～C6Alkyl, amino substituted C1～C6Alkyl, cyano;
or two RiAnd the ring atoms to which they are attached, form a 3-to 8-membered saturated or unsaturated ring.
m is 0 to 6;
Rjindependently selected from hydrogen, C1～C6Alkyl or C3～C6A cycloalkyl group;
Rkindependently selected from hydrogen, hydroxy, amino, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen-substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, or halogen substituted C3～C6A cycloalkyl group;
l is selected from 0 to 4RnOptionally substituted C4～C6Alkylene of (a) with 0 to 4RnOptionally substituted C4～C6Alkenylene group of (A) is substituted by 0-4RnOptionally substituted C4～C6Alkynylene of (a); wherein, optionally substituted C4～C6Alkylene of (a), optionally substituted C4～C6Alkenylene of (a), optionally substituted C4～C6Of alkynylene of (a) — CH2-、-CHRn-or-C (R)n)2May be substituted by-O-, -S-, -NRm-substitution;
Rmselected from hydrogen, C1～C6Alkyl radical, C3～C6A cycloalkyl group;
Rnselected from halogen, hydroxy, amino, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen-substituted C1～C6An alkyl group.
According to another embodiment of the disclosure, the heterocyclic compound of formula I is a compound of formula II:
Figure BDA0002312459850000071
ring A is selected from the group consisting of 0 to 2RAAn optionally substituted 5-membered aromatic heterocycle;
b ring selected from
Figure BDA0002312459850000081
C ring selected from
Figure BDA0002312459850000082
RB1、RB2、RB3、RC1、RC2、RC3Each independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6A cycloalkyl group;
R2、R3、R4are independently selected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、 C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk、-C(O)NRaRbOr S (O)2NRaRb；
Ra、Rb、Rd、Re、Rj、Rk、RA、R5、R5’、RxL in the presence ofWhen used, are as defined above for formula I;
according to another embodiment of the present disclosure, the heterocyclic compound of formula I is a heterocyclic compound of formula III:
Figure BDA0002312459850000083
a ring is selected from the group consisting of 0 to 2RAAn optionally substituted thiophene ring;
RB1、RB2、RB3、RC1、RC2、RC3each independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6A cycloalkyl group;
R2、R3、R4are each independently selected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、 C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk、-C(O)NRaRbOr S (O)2NRaRb；
Ra、Rb、Rd、Re、Rj、Rk、RA、R5、R5’、RxL, when present, is as defined above for formula I;
according to another embodiment of the present disclosure, the heterocyclic compound of formula I is a heterocyclic compound of formula IV:
Figure BDA0002312459850000091
RB1、RB2、RB3、RC1、RC2、RC3each independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6A cycloalkyl group;
R5、R5’、Rxl, when present, is as defined above for formula I;
according to another embodiment of the present disclosure the heterocyclic compound of formula I is a heterocyclic compound of formula V:
Figure BDA0002312459850000092
RB1、RB2、RB3、RC1、RC2、RC3each independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6A cycloalkyl group;
R5、R5’、Rxwhen present, are as defined above for formula I;
according to another embodiment of the present disclosure, the heterocyclic compound of formula I is a heterocyclic compound of formula VI:
Figure BDA0002312459850000093
Rxis selected from-O (CH)2)mRc；
RcAnd m, when present, are as defined above for formula I;
according to another embodiment of the present disclosure, the heterocyclic compound of formula I is a heterocyclic compound of formula VII:
Figure BDA0002312459850000101
ring A is selected from the group consisting of 0 to 2RAAn optionally substituted thiophene ring;
R2、R3、R4are independently selected from hydrogen, -ORd、-NRdReHalogen, -CN, C (O) ORd、 C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk、-C(O)NRaRbOr S (O)2NRaRb；
Ra、Rb、Rd、Re、Rj、RkEach independently selected from hydrogen and C1～C6An alkyl group;
ring B, ring C, ring RA、R5、R5’、RxL, when present, is as defined above for formula I;
according to another embodiment of the present disclosure, the heterocyclic compound of formula I is selected from the following compounds:
Figure BDA0002312459850000102
Figure BDA0002312459850000111
Figure BDA0002312459850000121
。
according to another embodiment of the disclosure, the isotopically labeled compound is, for example, a deuterium substituted compound. Isotopically labeled compounds can be used for applications such as metabolic detection.
According to another embodiment of the present disclosure, there is provided a pharmaceutical composition comprising the above heterocyclic compound, a pharmaceutically acceptable salt, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph, a solvate or an isotopically labeled compound thereof, and a pharmaceutically acceptable excipient.
According to another embodiment of the present disclosure, there is provided a use of the aforementioned compound, a pharmaceutically acceptable salt, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph, a solvate, or an isotopically labeled compound thereof, or a pharmaceutical composition of the aforementioned for the preparation of a medicament for activating STING class.
According to another embodiment of the present disclosure, there is provided a use of the aforementioned compound, a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate or isotopically labeled compound thereof or the aforementioned pharmaceutical composition for the manufacture of a medicament for the treatment of a disease associated with STING activity.
According to another embodiment of the present disclosure, the disease associated with STING activity is one or more of a disease associated with inflammatory, autoimmune, infectious, cancer, pre-cancerous syndrome.
According to another embodiment of the present disclosure, there is provided a use of the aforementioned compound, a pharmaceutically acceptable salt, stereoisomer, enantiomer, diastereomer, atropisomer, racemate, polymorph, solvate or isotopically labeled compound or the aforementioned pharmaceutical composition thereof in the manufacture of a medicament for the treatment of an inflammatory, autoimmune, infectious, cancer or precancerous syndrome.
According to another embodiment of the present disclosure, there is provided a use of the aforementioned compound, a pharmaceutically acceptable salt, a stereoisomer, an enantiomer, a diastereomer, an atropisomer, a racemate, a polymorph, a solvate, or an isotopically labeled compound thereof, or the aforementioned pharmaceutical composition for the preparation of an immunoadjuvant.
For exemplary purposes, the following examples may be used only for explaining technical aspects of the present disclosure, and are not intended to limit the present disclosure to these examples.
The raw materials and equipment used in the embodiments of the present disclosure are known products and obtained by purchasing commercially available products.
In the examples, the reaction temperature is room temperature, unless otherwise specified.
In the examples, M is mole per liter, unless otherwise specified.
PE refers to petroleum ether; EA means ethyl acetate; DCM refers to dichloromethane; MeOH refers to methanol; DMF means N, N-dimethylformamide; DMSO refers to dimethyl sulfoxide; DMAP refers to 4-dimethylaminopyridine; DIPEA refers to diisopropylethylamine; boc means t-butyloxycarbonyl; TFA means trifluoroacetic acid; EDCI refers to 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
Example 1: synthesis of S-4
Figure BDA0002312459850000141
Step 1: methyl 4-chloro-3-methoxy-5-nitrobenzoate (2.0g, 8.2mmol) was added to a single-necked flask containing aqueous ammonia (20mL) and stirred at 50 ℃ for 3 h. After cooling, filtration and washing of the solid with ice water, S-1(1.4g, 6.1mmol) was obtained after drying. MS (ESI) M/z 231[ M + H ]]+。
Step 2: the intermediate compound S-1(1.4g, 6.1mmol) was dispersed in dry DCM (10mL) while cooling on ice, and a solution of boron tribromide in dichloromethane (1M, 20mL) was slowly added dropwise thereto. After the dropwise addition, the ice bath was removed, and the reaction was carried out overnight at room temperature under nitrogen protection. The reaction solution was poured into ice water, stirred for 30min, filtered, and the filter cake was washed with water and dried to give S-2(1.2g,5.6 mmol). MS (ESI) M/z 217[ M + H ]]+。
And step 3: to a solution of S-2(1.2g,5.6mmol) in DMF (10mL) was added potassium carbonate (1.28g,9.2mmol) and 4- (3-chloropropyl) morpholine (1.13g,6.9mmol) and reacted at 70 ℃ for 16 h. After the reaction, the filtrate was poured into water and extracted with ethyl acetate, the organic phase was concentrated,purification on silica gel (DCM/MeOH ═ 8:1, v/v) afforded S-3(1.6g, 4.7 mmol). MS (ESI) M/z 344[ M + H ]]+。
And 4, step 4: to a solution of S-3(0.9g, 2.6mmol) in ethanol (10mL) were added N-t-butoxycarbonyl-1, 4-butanediamine (0.9g, 4.8mmol) and DIPEA (0.9g, 6.9mmol), and reacted at 130 ℃ for 16 h. The reaction mixture was concentrated and purified by silica gel column (EA/PE 1:1) to obtain S-4(1.1g, 2.2 mmol). MS (ESI) M/z 496[ M + H ]]+。
Example 2: synthesis of T-1
Figure BDA0002312459850000142
Step 1: 1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (CAS:50920-65-5) (2.00g, 12.9mmol) was dispersed in dry DCM (40mL) and oxalyl chloride (1.9g, 15.6mmol) and catalytic amount of DMF were added dropwise thereto under ice bath. After 1 hour of reaction at room temperature, the solvent and excess oxalyl chloride were removed by rotary evaporation under reduced pressure to give T-1-1(2.23 g).
Step 2: t-1-1(2.23g, 12.9mmol) was dissolved in dry acetone (10mL) at 0 ℃ and added dropwise to a solution of potassium thiocyanate (2.5g, 25.7mmol) in acetone (50mL) and stirred at room temperature for 3h, the reaction system was filtered to remove inorganic salts, and the crude filtrate after concentration was purified by silica gel column (eluent: ethyl acetate/petroleum ether (v/v) ═ 1/15) to give T-1(2.0g, 10.2mmol), a tan liquid. The liquid can be prepared into 0.5M 1, 4-dioxane solution, and stored in a refrigerator for refrigeration.
Example 3: synthesis of M-1
Figure BDA0002312459850000151
Step 1: 5-chlorothiophene-2-carboxylic acid methyl ester (1.2g) was added to concentrated aqueous ammonia (5mL), stirred at room temperature for 24h, EA extracted, the organic phase concentrated, and purified with silica gel column to give M-1-1(0.9 g).
Step 2: to concentrated sulfuric acid (5mL) was added M-1-1(0.9g) under ice-bath conditions, followed by addition of potassium nitrate (0.7g, 6.9mmol), the ice-bath was removed, the reaction mixture was reacted at room temperature for 1 hour, and then the reaction mixture was poured into ice water, extracted with EA, and purified with silica gel column (PE/EA ═ 2:1) to give M-1(0.7 g).
Example 4: synthesis of M-2
Figure BDA0002312459850000152
Step 1: 4-bromothiophene-2-carboxylic acid methyl ester (0.6g, 2.7mmol) was added to concentrated aqueous ammonia (5mL) and reacted at room temperature for 24h, followed by EA extraction, concentration of the organic phase and purification on silica gel column to give M-2-1(0.5g, 2.4 mmol).
Step 2: m-2-1(0.5g, 2.4mmol) was added to concentrated sulfuric acid (5mL) under ice-bath conditions, followed by addition of potassium nitrate (0.5g, 4.9mmol), and after removing the ice-bath, the reaction was allowed to react at room temperature for 1 hour, after which the reaction mixture was poured into ice-water, extracted with EA, and purified with silica gel column (PE/EA 2:1) to give M-2(0.4 g).
Example 5: synthesis of S-7
Figure BDA0002312459850000161
Step 1: 4-fluoro-3-nitroaniline (0.78g, 5mmol) was dissolved in dichloromethane (10mL), acetyl chloride (0.78g, 10mmol) was added, the reaction was carried out at room temperature for 3 hours, the organic phase was washed with saturated brine, the organic phase was concentrated, and the product was purified with silica gel column (PE/EA ═ 2:1) to obtain S-6(0.82g, 4.1 mmol). MS (ESI) M/z 199[ M + H]+。
Step 2: to a solution of S-6(0.7g, 3.5mmol) in ethanol (8mL) were added N-t-butoxycarbonyl-1, 4-butanediamine (0.8g, 4.3mmol) and DIPEA (0.9g, 6.9mmol), and the mixture was reacted at 130 ℃ for 16 hours. The reaction mixture was concentrated and purified by silica gel column (EA/PE 1:1) to obtain S-7(0.9g, 2.5 mmol). MS (ESI) 367[ M + H ] M/z]+
Example 6: synthesis of S-8
Figure BDA0002312459850000162
Step 1: trans-1, 4-dibromo-2-butene (7.5g, 35mmol) was dissolved in DMF (20mL), added phthalimide potassium salt (2.16g, 12.6mmol) in portions, reacted at room temperature for 16h, poured into water, extracted with EA, and isolated on silica gel column to give S-8-1(1.83g, 6.6 mmol).
Step 2: s-8-1(1.83g, 6.6mmol) and urotropine (1.3g, 9.3mmol) were dissolved in chloroform (10ml), reacted at room temperature for 48h, filtered, and the filter cake was washed with chloroform and dried to give S-8-2(2.6g, 6.2 mmol).
And step 3: s-8-2(2.6g, 6.2mmol) was dissolved in ethanol (10mL), concentrated hydrochloric acid (5mL) was added, the reaction was carried out at 90 ℃ for 2h, cooled, filtered, and the filtrate was concentrated to give hydrochloride S-8-3(1.4g, 5.6 mmol). MS (ESI) M/z 217[ M + H ]]+
And 4, step 4: to a solution of S-3(0.45g, 1.3mmol) in ethanol (8mL) were added S-8-3(0.65g, 2.6mmol) and DIPEA (0.45g, 3.4mmol) and reacted at 130 ℃ for 16 h. The reaction mixture was concentrated and purified by silica gel column to give S-8(0.37g, 0.7 mmol). MS (ESI) M/z 524[ M + H ]]+
Example 7: synthesis of S-9
Figure BDA0002312459850000171
Step 1: to a solution of S-2(66mg, 0.31mmol) in DMF (3ml) were added 1, 3-dibromopropane (264mg, 1.31mmol) and potassium carbonate (260mg, 1.92mmol) in this order, reacted at 70 ℃ for 2h, poured into water, extracted with EA, the EA layer was washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography after spin-drying of the solvent to give S-9-1(75mg, 0.22 mmol).
Step 2: piperidine (53mg, 0.62mmol) and potassium carbonate (104mg, 0.775mmol) were added to a solution of S-9-1(105mg, 0.31mmol) in DMF (4mL), reacted at 65 ℃ for 3h, poured into water, EA extracted, the EA layer was washed with saturated brine, the EA layer was spin dried, and column chromatography gave S-9-2(86mg, 0.25 mmol). MS (ESI) M/z 342[ M + H ]]+
And step 3: adding S-9-2(86mg, 0.25mmol), S-8-3(126mg, 0.5mmol) and DIPEA (97mg, 0.75mmol) into ethanol (10mL), reacting at 120 deg.C for 16h, cooling, spin-drying, and purifying with columnChromatography gave S-9(64mg, 0.12 mmol). MS (ESI) M/z 522[ M + H ]]+.
Example 8: synthesis of S-10
Figure BDA0002312459850000181
Step 1: 2-bromopropane (210mg, 1.72mmol) and potassium carbonate (300mg, 2.22mmol) were added to a DMF (6mL) solution of S-2(190mg, 0.88mmol) in this order, reacted at 70 ℃ for 3 hours, poured into water, EA extracted, EA layer was washed with saturated brine, spin-dried, and column chromatography gave S-10-1 (170mg, 0.66 mmol).
Step 2: s-10-1(320mg, 1.18mmol), S-8-3(590mg, 2.36mmol) and DIPEA (380mg, 2.95mmol) were added to ethanol (15mL), reacted at 120 ℃ for 16h, cooled, spun dry, and column chromatographed to give S-10(407mg, 0.90 mmol). MS (ESI) M/z 439.2[ M + H ]]+
Example 9: synthesis of ZB-ST-1
Figure BDA0002312459850000182
Step 1: s-4(0.163g, 0.33mmol) was dissolved in 4mL of dichloromethane, 1mL of trifluoroacetic acid was added, and the solvent was directly spin-dried after 20 minutes of reaction at room temperature. The solid obtained by rotary drying was dissolved in ethanol (10mL), and M-1(0.1g, 0.49mmol) and DIPEA (78mg, 0.6mmol) were added and reacted at 130 ℃ for 16 hours. After cooling, a solid precipitated, which was filtered and washed with PE to give ZB-ST-1-1 (0.128g, 0.23 mmol). MS (ESI) M/z 566[ M + H ]]+。
And 2, step: ZB-ST-1-1(56mg, 0.1mmol) was dissolved in NMP (2mL), zinc powder (100mg, 1.5mmol) was added, a saturated aqueous ammonium chloride solution (0.1mL) was added, and the mixture was reacted at room temperature for 1 hour; then, a solution of T-1 in 1, 4-dioxane (0.5M, 0.2mL) was added and the reaction was carried out at room temperature for 0.5h, the zinc powder was filtered, water was added to the filtrate, a solid was precipitated and filtered, and the obtained solid was washed with water and dried to give ZB-ST-1-2(62mg, 0.07mmol) which was used in the next step.
And step 3: ZB-ST-1-2(62mg,0.07mmol) was dissolved in acetonitrile (5mL), EDCI (30mg, 0.15mmol) and DIPEA (28mg, 0.21mmol) were added, and the mixture was heated to 70 ℃ and reacted for 1 h. The reaction was spun down and separated by reverse phase HPLC using acetonitrile (0.1% TFA)/water (0.1% TFA) as the mobile phase, which gave the example compound ZB-ST-1(7.5mg) after spin-drying under reduced pressure. MS (ESI) M/z 828[ M + H ]]+。1H NMR(400MHz,DMSO-d6)δ12.86(s,1H),8.11(s,1H), 8.01(s,1H),7.78(s,1H),7.65(s,1H),7.50–7.33(m,3H),6.63(s,1H),6.60(s, 1H),4.57(q,J＝7.2Hz,2H),4.52–4.34(m,4H),4.15(t,J＝6.0Hz,4H),3.53 (m,4H),2.45-2.30(m,4H),2.13(s,3H),2.11(s,3H),1.95–1.76(m,4H),1.35– 1.24(m,6H).
Example 10: synthesis of ZB-ST-4
Figure BDA0002312459850000191
Step 1: s-4(0.2g, 0.4mmol) was dissolved in 2ml of dichloromethane, and trifluoroacetic acid (0.5 ml) was added to react at room temperature for 20 minutes, after which the solvent was spun dry. The solid obtained by spin-drying was dissolved in ethanol (5ml), and M-2(0.2g, 0.78mmol) and DIPEA (120mg, 0.9mmol) were added and reacted at 130 ℃ for 16 hours. After cooling, it was dried and purified on silica gel (DCM/MeOH ═ 8:1) to give ZB-ST-4-1(0.2g, 0.35 mmol). MS (ESI) M/z 566[ M + H ]]+。
Step 2: ZB-ST-4-1(0.2g, 0.35mmol) was dissolved in NMP (3mL), and zinc powder (136mg, 2.1mmol) and a saturated ammonium chloride solution (0.1mL) were added to react at room temperature for 1 hour; then T-1 in 1, 4-dioxane (0.5M, 1.4mL) was added and the reaction was carried out at room temperature for 0.5h, the zinc powder was filtered, water was added to the organic phase of the filtrate, a solid precipitated, the filtrate was filtered, the resulting solid was washed with water and dried to give ZB-ST-4-2(0.116g, 0.13mmol) which was used directly in the next step.
And step 3: ZB-ST-4-2(0.116g, 0.13mmol) was added to acetonitrile (10mL), EDCI (0.08g, 0.22mmol) and DIPEA (0.043g, 0.33mmol) were added, and the reaction was heated to 70 ℃ for 1 h. Then the reaction solution is dried by spinning under reduced pressure and separated by reverse phase HPLC, the mobile phase is acetonitrile (containing 0.1% TFA)/water (containing 0.1% TFA), and the zB-ST-4 (after being dried by spinning under reduced pressure) is obtained24mg)。 MS(ESI)m/z＝828.4[M+H]+。1H NMR(600MHz,DMSO-d6)δ12.88(s,1H), 9.86(s,1H),8.00-7.88(m,3H),7.67(s,1H),7.50–7.34(m,3H),6.73(s,1H), 6.58(s,1H),4.55(q,J＝7.0Hz,2H),4.42–4.29(m,4H),4.17(t,J＝6.0Hz, 2H),4.11(m,2H),3.99-3.93(m,4H),3.41-3.35(m,2H),3.25–3.19(m,2H), 3.08-3.00(m,2H),2.14(s,3H),2.12(s,3H),2.08(m,2H),1.91–1.84(m,2H), 1.80-1.74(m,2H),1.29(t,J＝7.1Hz,3H),1.24-1.19(m,3H).
Example 11: synthesis of ZB-ST-5
Figure BDA0002312459850000201
Step 1: s-7(0.15g, 0.41mmol) was dissolved in dichloromethane (4mL), trifluoroacetic acid (1mL) was added, the reaction was carried out at room temperature for 1h, and the solvent was dried by spinning. The resulting compound was dissolved in ethanol (5mL), added with M-1(0.126g, 0.6mmol) and DIPEA (120mg, 0.9mmol), reacted at 130 ℃ for 16h, cooled, spin-dried, and purified by silica gel column to give ZB-ST-5-1(0.139 g). MS (ESI) M/z 437[ M + H ]]+。
Step 2: ZB-ST-5-1(0.139g, 0.32mmol) was dissolved in NMP (3mL), zinc powder (272mg, 4.2mmol) was added, a saturated ammonium chloride solution (0.1mL) was added, and the reaction was carried out at room temperature for 1 hour; then T-1 in 1, 4-dioxane (0.5M, 1.3mL) was added and the reaction was carried out at room temperature for 0.5h, the zinc powder was filtered, water was added to the organic phase, the filtrate was filtered, and the resulting solid was washed with water and dried to give ZB-ST-5-2(0.152g, 0.20 mmol). MS (ESI) M/z 767[ M + H ]]+
And step 3: ZB-ST-5-2(0.152g, 0.20mmol) was added to acetonitrile (10mL), EDCI (0.088g, 0.44mmol) and DIPEA (0.086g, 0.66mmol) were added, and the mixture was heated to 70 ℃ for 1 h. The reaction was spun down and separated by reverse phase HPLC with acetonitrile (0.1% TFA)/water (0.1% TFA) as the mobile phase, which gave ZB-ST-5(21mg, 0.031mmol) after spin-drying under reduced pressure. MS (ESI) M/z 699.3[ M + H ]]+。1H NMR(600MHz,DMSO-d6)δ12.64(s,1H),10.03(s, 1H),8.08(s,1H),7.85(d,J＝1.8Hz,1H),7.78(s,1H),7.45–7.33(m,3H), 6.66(s,1H),6.57(s,1H),4.56(q,J＝7.1Hz,2H),4.50-4.40(m,2H),4.20(t,J＝ 6.7Hz,2H),4.19-4.12(m,2H),2.12(s,3H),2.11(s,3H),2.04(s,3H),1.89– 1.85(m,2H),1.82–1.75(m,2H),1.31–1.28(m,3H).
Example 12: synthesis of ZB-ST-6
Figure BDA0002312459850000211
Step 1: s-8(100mg, 0.19mmol) was dissolved in methanol (5mL), aqueous methylamine (2mL) was added, the reaction was carried out at 50 ℃ for 2h, cooled, diluted with water, extracted with dichloromethane 3 times, the organic phases were combined, dried over anhydrous sodium sulfate and the solvent was spin dried under reduced pressure. The resulting crude product was dissolved in ethanol (7mL), and M-1(0.084g, 0.4mmol) and DIPEA (80mg, 0.6mmol) were added, followed by reaction at 130 ℃ for 16 hours, followed by cooling, spin-drying of the solvent under reduced pressure, and purification with silica gel column to give ZB-ST-6-1(54mg, 0.09 mmol). MS (ESI) M/z 564.2[ M + H ]]+
And 2, step: ZB-ST-6-1(54mg, 0.09mmol) was dissolved in NMP (3mL), zinc powder (136mg, 2.1mmol) was added, a saturated ammonium chloride solution (0.1mL) was added, and the reaction was carried out at room temperature for 1 hour; then, a solution of T-1 in 1, 4-dioxane (0.5M, 0.36mL) was added thereto, the mixture was reacted at room temperature for 0.5h, the zinc powder was filtered, water was added to the organic phase of the filtrate, a solid was precipitated, the filtrate was filtered, and the obtained solid was washed with water and dried to obtain ZB-ST-6-2(0.035g, 0.04 mmol).
And step 3: ZB-ST-6-2(0.035g, 0.04mmol) was added to acetonitrile (3mL), EDCI (0.04g) and DIPEA (0.08g) were added, and the reaction mixture was heated to 70 ℃ and reacted for 1 hour. The solvent was spun down under reduced pressure and separated by reverse phase HPLC with acetonitrile (containing 0.1% TFA)/water (containing 0.1% TFA) as the mobile phase to give ZB-ST-6(10mg, 0.012mmol) after spin-down under reduced pressure. MS (ESI) M/z 826.4[ M + H ]]+。1H NMR(600MHz,DMSO)δ12.88(brs,1H),9.82(s,1H),8.11(s,1H),7.95(s, 1H),7.79(s,1H),7.67(d,J＝0.9Hz,1H),7.44(s,1H),7.36(d,J＝0.9Hz,2H), 6.66(s,1H),6.58(s,1H),6.21(dt,J＝15.4,5.1Hz,1H),5.69–5.59(m,1H), 5.05(d,J＝4.4Hz,2H),4.67(d,J＝4.4Hz,2H),4.57(q,J＝7.1Hz,2H), 4.46-4.38(m,2H),4.23(t,J＝6.0Hz,2H),4.02-3.96(m,2H),3.65(t,J＝12.0 Hz,2H),3.45(d,J＝11.8Hz,2H),3.34–3.25(m,2H),3.15-3.05(m,2H),2.24– 2.16(m,2H),2.14(s,3H),2.136(s,3H),1.31(t,J＝7.1Hz,3H),1.23(t,J＝7.1 Hz,3H).
Example 13: synthesis of ZB-ST-7
Figure BDA0002312459850000221
Step 1: s-9(110mg, 0.21mmol) was dissolved in methanol (4mL), aqueous methylamine (2mL) was added, the reaction was carried out at 50 ℃ for 2h, cooled, diluted with water, extracted with dichloromethane 3 times, the organic phases were combined, dried over anhydrous sodium sulfate and the solvent was dried by rotary drying. The crude product was directly dissolved in ethanol (7mL), and M-1(0.092g, 0.45mmol) and DIPEA (80mg, 0.6mmol) were added to react at 130 ℃ for 16 hours, followed by cooling, spin-drying and silica gel column purification to obtain ZB-ST-7-1(89 mg). MS (ESI) M/z 562.2[ M + H ]]+.
Step 2: ZB-ST-7-1(89mg, 0.16mmol) was dissolved in NMP (3mL), and zinc powder (104mg, 1.6mmol) and a saturated ammonium chloride solution (0.1mL) were added to react at room temperature for 1 hour; then, a solution of T-1 in 1, 4-dioxane (0.5M, 0.64mL) was added thereto, the mixture was reacted at room temperature for 0.5h, the zinc powder was filtered, water was added to the organic phase to precipitate a solid, the solid was filtered, washed with water and dried to obtain ZB-ST-7-2(0.073g, 0.08 mmol).
And step 3: ZB-ST-7-2(0.073g, 0.08mmol) was added to acetonitrile (5mL), EDCI (0.032g, 0.16mmol) and DIPEA (0.045g, 0.35mmol) were added, and the mixture was heated to 70 ℃ for 1 h. After spin-drying the solvent, the fractions were separated by reverse phase HPLC using acetonitrile (0.1% TFA)/water (0.1% TFA) as the mobile phase and spin-dried under reduced pressure to give ZB-ST-7(21mg, 0.025 mmol). MS (ESI) M/z 824.4[ M + H ]]+。1H NMR(600MHz,DMSO-d6)δ12.89(s,1H),9.29(s, 1H),7.95(s,1H),7.66(s,1H),7.360(s,1H),7.358(s,1H),7.19(s,1H),7.11(s, 1H),7.02(s,1H),6.58(s,1H),6.25–6.16(m,1H),5.71–5.61(m,1H),5.05(d, J＝4.2Hz,2H),4.74–4.64(m,2H),4.57(m,2H),4.22(t,J＝6.1Hz,2H), 2.87-2.80(m,2H),2.26–2.08(m,8H),1.83–1.76(m,2H),1.73-1.60(m,4H), 1.31(t,J＝7.2Hz,3H),1.25(t,J＝7.2Hz,3H).
Example 14: synthesis of ZB-ST-8
Figure BDA0002312459850000231
Step 1: s-10(130mg) was dissolved in methanol (4mL), 0.3 mL of hydrazine hydrate was added, and after 2 hours at room temperature, the mixture was diluted with water, extracted with dichloromethane 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure. The resulting crude product was dissolved in ethanol (6mL), M-1(0.123g, 0.60mmol) and DIPEA (117mg, 0.9mmol) were added and reacted at 130 ℃ for 16 h. After cooling the reaction solution, the solvent was dried under reduced pressure and purified by silica gel column (DCM/MeOH ═ 8:1) to give ZB-ST-8-1(76mg, 0.16 mmol).
Step 2: ZB-ST-8-1(76mg, 0.16mmol) was dissolved in NMP (3mL), zinc powder (104mg, 1.6mmol) was added, a saturated ammonium chloride solution (0.1mL) was added, the reaction mixture was reacted at room temperature for 1 hour, a 1, 4-dioxane solution of T-1 (0.5M, 0.64mL) was added, the reaction mixture was reacted at room temperature for 0.5 hour, the zinc powder was filtered, water was added to the filtrate, a solid was precipitated, the obtained solid was filtered, washed with water and dried to obtain ZB-ST-8-2(57mg, 0.07mmol), which was used in the next step as it was.
And step 3: ZB-ST-8-2(57mg, 0.070mmol) was added to acetonitrile (5mL), followed by EDCI (0.06g) and DIPEA (0.1g), and the reaction was heated to 70 ℃ for 1 h. The solvent was then spun down under reduced pressure and separated by reverse phase HPLC with acetonitrile (0.1% TFA)/water (0.1% TFA) as the mobile phase to give ZB-ST-8(16mg, 0.022mmol) after spin-drying under reduced pressure. MS (ESI) M/z 741.3 [ M + H ]]+。1H NMR(600MHz,DMSO)δ12.83(brs,1H),8.04(s,1H),7.95(s, 1H),7.77(s,1H),7.62(d,J＝1.1Hz,1H),7.37(s,1H),7.33(s,2H),6.64(s,1H), 6.58(s,1H),6.08(dt,J＝15.4,5.7Hz,1H),5.81–5.72(m,1H),5.01(d,J＝5.3 Hz,2H),4.87-4.78(m,1H),4.69(d,J＝5.8Hz,2H),4.57(q,J＝7.1Hz,2H), 4.43(q,J＝6.6Hz,2H),2.15(s,3H),2.13(s,3H),1.31(t,J＝7.1Hz,3H), 1.26-1.22(m,9H).
Example 15: synthesis of S-11
Figure BDA0002312459850000241
Step 1: bromomethylcyclopropane (250mg) and potassium carbonate (300mg, 2.22mmol) were added to a DMF (6mL) solution of S-2(190mg) in this order, reacted at 70 ℃ for 3h, poured into water, extracted with EA, the EA layer was washed with saturated brine, dried over anhydrous sodium sulfate, solvent was spin-dried under reduced pressure, and column chromatography was performed to give S-11-1.
Step 2: s-11-1(320mg), S-8-3(590mg) and DIPEA (460mg) were added to ethanol (20mL), and the reaction mixture was reacted at 120 ℃ for 16 hours, cooled, and subjected to column chromatography under reduced pressure to give S-11(182 mg). MS (ESI) M/z 451.2[ M + H ]]+.
Example 16: synthesis of S-12
Figure BDA0002312459850000251
Step 1: to a solution of S-2(190mg) in DMF (6mL) were added 3-iodooxetane (350mg) and potassium carbonate (300mg, 2.22mmol) in this order, reacted at 70 ℃ for 3h, poured into water, extracted with EA, the EA layer was washed with saturated brine, dried under reduced pressure and subjected to column chromatography to give 95 mg of S-12-1.
Step 2: s-12-1(320mg, 1.18mmol), S-8-3(590mg, 2.36mmol) and DIPEA (380mg, 2.95mmol) were added to ethanol (20mL), reacted at 120 ℃ for 16h, cooled, the solvent was spin-dried under reduced pressure, and column chromatography gave 175 mg of S-12. MS (ESI) M/z 453.2[ M + H ]]+.
Example 17: synthesis of S-13
Figure BDA0002312459850000252
Step 1: to a solution of S-2(190mg) in DMF (6mL) were added 4-methylbenzenesulfonic acid (oxetan-3-yl) methyl ester (CAS: 1395417-57-8, 400mg) and potassium carbonate (300mg) in this order, reacted at 70 ℃ for 8 hours, poured into water, extracted with EA, and the EA layer was washed with saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography after spin-drying the solvent under reduced pressure to give 120mg of S-13-1.
Step 2: to ethanol (20mL) was added S-13-1(320mg), S-8-3(590mg) and DIPEA (430mg) were reacted at 120 ℃ for 16 hours, cooled, and then the solvent was spin-dried under reduced pressure, and column chromatography was performed to give S-13. MS (ESI) M/z 467.2[ M + H ]]+.
Example 18: synthesis of ZB-ST-11
Figure BDA0002312459850000261
Step 1: s-11(130mg) was dissolved in methanol (6mL), aqueous methylamine solution (2mL) was added, the reaction was carried out at 50 ℃ for 2h, cooling, dilution with water, extraction with dichloromethane 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure. The resulting crude product was dissolved in ethanol (6mL), and M-1(0.123g) and DIPEA (117mg) were added to react at 130 ℃ for 16 hours, after cooling, the solvent was dried under reduced pressure, and the mixture was purified by silica gel column to obtain ZB-ST-11-1(45 mg).
Step 2: ZB-ST-11-1(70mg) was dissolved in NMP (3mL), and zinc powder (104mg) and a saturated ammonium chloride solution (0.1mL) were added to the solution to react at room temperature for 1 hour; then, a solution of T-1 in 1, 4-dioxane (0.5M, 0.64mL) was added to the reaction solution, the reaction was continued at room temperature for 0.5h, the zinc powder was filtered, water was added to the filtrate to precipitate a solid, the solid was filtered, and the obtained solid was washed with water and dried to obtain ZB-ST-11-2 which was used in the next step.
And step 3: ZB-ST-11-2(50mg) was added to acetonitrile (6mL), EDCI (0.06g) and DIPEA (0.1g) were added, and the mixture was heated to 70 ℃ to react for 1 hour. The solvent of the reaction mixture was dried by spinning under reduced pressure and separated by reverse phase HPLC, the mobile phase was acetonitrile (containing 0.1% TFA)/water (containing 0.1% TFA), and then dried under reduced pressure to obtain ZB-ST-11. MS (ESI) M/z 753.3[ M + H ]]+。
Example 19: synthesis of ZB-ST-12
Figure BDA0002312459850000271
Step 1: s-12(120mg) is dissolved in methanol (6mL), methylamine water solution (2mL) is added, reaction is carried out for 2h at 50 ℃, after cooling to room temperature, water is added for dilution, dichloromethane is used for extraction for 3 times, organic phases are combined, anhydrous sodium sulfate is used for drying, and the solvent is dried by spinning under reduced pressure. The resulting crude product was dissolved in ethanol (6mL), and M-1(0.123g) and DIPEA (117mg) were added to react at 130 ℃ for 16 hours, after cooling to room temperature, the solvent was dried under reduced pressure, and the mixture was purified by silica gel column to give ZB-ST-12-1(51 mg).
Step 2: ZB-ST-12-1(73mg) was dissolved in NMP (3mL), zinc powder (104mg) was added, a saturated ammonium chloride solution (0.1mL) was added, and the mixture was reacted at room temperature for 1 hour; a solution of T-1 in 1, 4-dioxane (0.5M, 0.64mL) was then added and the reaction continued at room temperature for 0.5 h. Filtering zinc powder, adding water into the filtrate to precipitate solid, filtering, washing the obtained solid with water, and drying to obtain ZB-ST-12-2 which can be used in the next step without purification.
And step 3: ZB-ST-12-2(53mg) was added to acetonitrile (3mL), followed by EDCI (0.06g) and DIPEA (0.1g), and the reaction was heated to 70 ℃ to continue the reaction for 1 h. The reaction was then spun down and separated by reverse phase HPLC using acetonitrile (0.1% TFA)/water (0.1% TFA) as the mobile phase to afford ZB-ST-12 after spin-drying under reduced pressure. MS (ESI) M/z 755.3[ M + H ]]+。
Example 20: synthesis of ZB-ST-13
Figure BDA0002312459850000281
Step 1: s-13(124mg) was dissolved in methanol (6mL), an aqueous methylamine solution (2mL) was added, the reaction was carried out at 50 ℃ for 2 hours, after cooling, water was added for dilution, methylene chloride was extracted 3 times, the organic phases were combined, dried over anhydrous sodium sulfate, and then the solvent was spin-dried under reduced pressure. The resulting crude product was dissolved in ethanol (6mL), and M-1(0.123g) and DIPEA (117mg) were added to react at 130 ℃ for 16 hours, after cooling, the solvent was dried under reduced pressure, and the mixture was purified by silica gel column to obtain ZB-ST-13-1.
Step 2: ZB-ST-13-1(68mg) was dissolved in NMP (3mL), and zinc powder (104mg) and a saturated ammonium chloride solution (0.1mL) were added to the solution to react at room temperature for 1 hour; then T-1 in 1, 4-dioxane (0.5M, 0.64mL) was added and the reaction continued at room temperature for 0.5h, the zinc powder was filtered, water was added to the organic phase filtrate, a solid precipitated, filtered, the resulting solid washed with water and dried to give ZB-ST-13-2, which was used in the next step without purification.
And step 3: ZB-ST-13-2(56mg) was added to acetonitrile (5mL), EDCI (0.06g) and DIPEA (0.09 g) were added, and the mixture was heated to 70 ℃ to react for 1 hour. The reaction was spin-dried under reduced pressure and separated by reverse phase HPLC using acetonitrile (containing 0.1% TFA)/water (containing 0.1% TFA) as the mobile phase to give ZB-ST-13 after spin-drying under reduced pressure. MS (ESI) M/z 769.4[ M + H ]]+。
Example 21: synthesis of S-14
Figure BDA0002312459850000291
Step 1: (R) -3-hydroxytoluenesulfonic acid ester (260mg), potassium iodide (30mg) and potassium carbonate (300mg) were sequentially added to a DMF (6mL) solution of S-2(190mg), reacted at 70 ℃ for 12 hours, poured into water, EA extracted, EA layer washed with saturated brine, dried over anhydrous sodium sulfate, and then the organic phase was spin-dried under reduced pressure and column chromatography was performed to give S-14-1(67 mg).
Step 2: s-14-1(270mg), S-8-3(590mg) and DIPEA (380mg) were added to ethanol (30mL), the reaction mixture was reacted at 120 ℃ for 16 hours, cooled to room temperature, the solvent was dried under reduced pressure, and column chromatography was performed to give S-14. MS (ESI) M/z 467.2[ M + H ]]+.
Example 22: synthesis of S-15
Figure BDA0002312459850000292
Step 1: (S) -3-hydroxytoluenesulfonic acid ester (260mg), potassium iodide (30mg) and potassium carbonate (300mg) were sequentially added to a DMF (6mL) solution of S-2(190mg), reacted at 70 ℃ for 12 hours, poured into water, EA extracted, EA layer washed with saturated brine, solvent dried by spinning and column chromatography to give S-15-1(77 mg).
And 2, step: s-15-1(270mg), S-8-3(590mg) and DIPEA (380mg) were added to ethanol (30mL), reacted at 120 ℃ for 16h, cooled, and then the solvent was spin-dried under reduced pressure, and column chromatography was performed to give S-15. MS (ESI) M/z 467.2[ M + H ]]+.
Example 23: synthesis of S-16
Figure BDA0002312459850000301
Step 1: 2-oxaspiro [3.3] heptane-6-ol (140mg), triphenylphosphine (450mg) and diisopropyl azodicarboxylate (350mg) were added in this order to a tetrahydrofuran (20mL) solution of S-2(220mg), and after nitrogen substitution protection, the mixture was reacted at 50 ℃ for 12 hours, the solvent was spin-dried under reduced pressure and column chromatography was performed to give S-16-1(62 mg).
Step 2: s-16-1(300mg), S-8-3(590mg) and DIPEA (380mg) were added to ethanol (30mL), and the reaction mixture was reacted at 120 ℃ for 16 hours, followed by cooling, spin-drying of the solvent, and column chromatography to give S-16. MS (ESI) M/z 493[ M + H ]]+.
Example 24: synthesis of S-17
Figure BDA0002312459850000302
Step 1: tetrahydropyran-4-ol (150mg), triphenylphosphine (450mg) and diisopropyl azodicarboxylate (350mg) were added to a tetrahydrofuran (20mL) solution of S-2(220mg) in this order, and after nitrogen substitution protection, the reaction was carried out at 50 ℃ for 12 hours, and after the solvent was spin-dried under reduced pressure, column chromatography was carried out directly to give S-17-1.
Step 2: s-17-1(27mg), S-8-3(59mg) and DIPEA (38mg) were added to ethanol (5mL), reacted at 120 ℃ for 16 hours, cooled, and then the solvent was spin-dried, and column chromatography was performed to give S-17. MS (ESI) M/z 481.2[ M + H ]]+.
Example 25: synthesis of ZB-ST-14
Figure BDA0002312459850000311
Step 1: s-14(120mg) was dissolved in methanol (6mL), and aqueous methylamine solution (2mL) was added to react at 50 ℃ for 2h, cooled, diluted with water, extracted 3 times with dichloromethane, the organic phases combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure. The resulting crude product was dissolved in ethanol (6mL), and M-1(0.123g) and DIPEA (117mg) were added to react at 130 ℃ for 16 hours, after cooling, the solvent was spin-dried under reduced pressure, and the mixture was purified by silica gel column to give ZB-ST-14-1.
Step 2: ZB-ST-14-1(75mg) was dissolved in NMP (3mL), followed by addition of zinc powder (104mg) and a saturated aqueous ammonium chloride solution (0.1mL) and reaction at room temperature for 1 hour; then, a solution of T-1 in 1, 4-dioxane (0.5M, 0.64mL) was added and the reaction was carried out at room temperature for 0.5 hour, followed by filtering the zinc powder, adding water to the organic phase of the filtrate, filtering, washing the resulting solid with water, and drying to obtain ZB-ST-14-2, which was used in the next step without purification.
And step 3: ZB-ST-14-2(50mg) was added to acetonitrile (3mL), EDCI (0.6 g) and DIPEA (0.1g) were added, and the mixture was heated to 70 ℃ and reacted for 1 hour. The reaction was spun down and separated by reverse phase HPLC using acetonitrile (0.1% TFA)/water (0.1% TFA) as the mobile phase, and then dried under reduced pressure to give ZB-ST-14. MS (ESI) M/z 769.3[ M + H ]]+。
Example 26: synthesis of ZB-ST-15
Figure BDA0002312459850000321
Step 1: s-15(120mg) was dissolved in methanol (6mL), aqueous methylamine solution (2mL) was added, the reaction was carried out at 50 ℃ for 2 hours, cooling, dilution with water was carried out, extraction was carried out 3 times with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was spin-dried under reduced pressure. The resulting crude product was dissolved in ethanol (6mL), and M-1(0.123g) and DIPEA (117mg) were added to react at 130 ℃ for 16 hours, after cooling, the solvent was spin-dried under reduced pressure, and the mixture was purified by silica gel column to obtain ZB-ST-15-1.
And 2, step: ZB-ST-15-1(75mg) was dissolved in NMP (3mL), followed by addition of zinc powder (104mg) and a saturated aqueous ammonium chloride solution (0.1mL) and reaction at room temperature for 1 hour; then T-1 in 1, 4-dioxane (0.5M, 0.64mL) was added and the reaction was carried out at room temperature for 0.5 hour, then the zinc powder was filtered, water was added to the organic phase of the filtrate, the filtrate was filtered, and the resulting solid was washed with water and dried to give ZB-ST-15-2 which was used in the next step without purification.
And 3, step 3: ZB-ST-15-2(50mg) was added to acetonitrile (3mL), EDCI (0.06g) and DIPEA (0.1g) were added, and the mixture was heated to 70 ℃ and reacted for 1 hour. The reaction solution is dried by spinning, separated by reversed phase HPLC and flowedThe phase was acetonitrile (containing 0.1% TFA)/water (containing 0.1% TFA), and spin-dried under reduced pressure to give ZB-ST-15. MS (ESI) M/z 769.3[ M + H ]]+。
Example 27: synthesis of ZB-ST-16
Figure BDA0002312459850000331
Step 1: s-16(135mg) was dissolved in methanol (6mL), and aqueous methylamine solution (2mL) was added to react at 50 ℃ for 2 hours, followed by cooling, dilution with water, extraction with dichloromethane 3 times, combination of the organic phases, drying over anhydrous sodium sulfate, and spin-drying the solvent under reduced pressure. The resulting crude product was dissolved in ethanol (6mL), and M-1(0.123g) and DIPEA (117mg) were added to react at 130 ℃ for 16 hours, after cooling, the solvent was spin-dried under reduced pressure, and the mixture was purified by silica gel column to obtain ZB-ST-16-1.
Step 2: ZB-ST-16-1(75mg) was dissolved in NMP (3mL), followed by addition of zinc powder (104mg) and a saturated aqueous ammonium chloride solution (0.1mL) and reaction at room temperature for 1 hour; then T-1 in 1, 4-dioxane (0.5M, 0.64mL) was added and the reaction was carried out at room temperature for 0.5 hour, then the zinc powder was filtered, water was added to the organic phase of the filtrate, the filtrate was filtered, and the resulting solid was washed with water and dried to give ZB-ST-16-2 which was used in the next step without purification.
And step 3: ZB-ST-16-2(50mg) was added to acetonitrile (3mL), EDCI (0.06g) and DIPEA (0.1g) were added, and the mixture was heated to 70 ℃ to react for 1 hour. The reaction was spun down and separated by reverse phase HPLC using acetonitrile (0.1% TFA)/water (0.1% TFA) as the mobile phase, and then dried under reduced pressure to give ZB-ST-16. MS (ESI) M/z 795.4[ M + H ]]+。
Example 28: synthesis of ZB-ST-17
Figure BDA0002312459850000341
Step 1: s-17(127mg) was dissolved in methanol (6mL), and aqueous methylamine solution (2mL) was added to react at 50 ℃ for 2 hours, followed by cooling, dilution with water, extraction with dichloromethane 3 times, combination of the organic phases, drying over anhydrous sodium sulfate, and spin-drying the solvent under reduced pressure. The resulting crude product was dissolved in ethanol (6mL), and M-1(0.123g) and DIPEA (117mg) were added to react at 130 ℃ for 16 hours, after cooling, the solvent was dried by rotary evaporation under reduced pressure, and the resulting mixture was purified with silica gel column to obtain ZB-ST-17-1.
Step 2: ZB-ST-17-1(75mg) was dissolved in NMP (3mL), and zinc powder (104mg) and a saturated aqueous ammonium chloride solution (0.1mL) were added to the solution and reacted at room temperature for 1 hour; then, a solution of T-1 in 1, 4-dioxane (0.5M, 0.64mL) was added and the reaction was carried out at room temperature for 0.5 hour, followed by filtering the zinc powder, adding water to the organic phase of the filtrate, filtering, washing the resulting solid with water, and drying to obtain ZB-ST-17-2, which was used in the next step without purification.
And step 3: ZB-ST-17-2(50mg) was added to acetonitrile (3mL), EDCI (0.06g) and DIPEA (0.1g) were added, and the mixture was heated to 70 ℃ and reacted for 1 hour. The reaction was spun down and separated by reverse phase HPLC using acetonitrile (0.1% TFA)/water (0.1% TFA) as the mobile phase to afford ZB-ST-17 after spin-drying under reduced pressure. MS (ESI) M/z 783.4[ M + H ]]+。
Example 29: activation Effect of Compounds on the type I Interferon pathway (ISG) in human-derived THP1-Blue-ISG cells
1. The experimental method comprises the following steps:
20 μ L of a compound diluted with physiological saline was added to each well of a 96-well cell culture plate, and the positive control compound was ADU-S100 at a concentration of 50 μ M. The vehicle control group was added with 20. mu.L of 1% DMSO-containing physiological saline. THP1-Blue-ISG cell count, adjusting cell concentration to 5X 105mL, add 180. mu.l of cells per well for incubation. Thus, the final volume of each test well was 200. mu.L, DMSO content was 0.1%, and the test concentration of the compound was 10. mu.M. The positive control compound is ADU-S100, the final concentration is 10 mu M, and the positive control compound is incubated for 24 hours for detection;
after 24 hours, 20. mu.L of the culture solution per well was put into a new 96-well plate, 180. mu.L of color development solution Quanti-Blue was added, the plate was placed in an incubator at 37 ℃ and after 0.5 to 2 hours, the OD650 value was measured, and the experiment was repeated 2 times.
Experimental results the ability of a compound to induce secretion of the type I interferon pathway (ISG) was evaluated as Fold Change (Fold Change) and calculated as follows:
fold-compound OD 650/vehicle control OD 650.
2. Results of the experiment
As shown in Table 1, the compounds of the present disclosure have the function of inducing secretion of type I interferon pathway at 10. mu.M in human-derived THP1-Blue-ISG cells, and the activity of some compounds at 10. mu.M concentration is equivalent to that of the positive compound ADU-S100.
Table 1: the disclosed compounds have activation effect on type I interferon pathway in human-derived THP1-Blue-ISG cells
Compound numbering Multiple (10 μ M)
ADU-S100* 19.41
ZB-ST-1 >15
ZB-ST-4 2.12
ZB-ST-6 9.56
ZB-ST-7 16.69
ZB-ST-8 16.85
ZB-ST-11 >10
ZB-ST-12 >10
ZB-ST-13 >10
ZB-ST-14 >10
ZB-ST-15 >10
ZB-ST-16 >10
*ADU-S100 is a positive compound (Corrales, L.; Glickman, L.H.; McWhitter, S.M.; Kanne, D.B.; Sivick, K.E.; Katibah, G.E.; Woo, S.R.; Lemmens, E.; Banda, T.; Leong, J.J.; Metchette, K.; Dubensky, T.W.Jr.; Gajewski, T.F.direct action of STING in the tumor microelectron deletion to cell and system tumor regression and immunity. cell 2015,11 (7)), 1018-
Example 30: effect of Compounds on activation of type I Interferon pathway in murine Raw-lucia cells
1. The experimental method comprises the following steps:
raw-lucia cell count, adjusting cell concentration to 5X 105PermL, 180. mu.L of cells per well were added for incubation. After the cells are attached to the wall, 20. mu.L of a compound diluted with physiological saline is added to each well of a 96-well cell culture plate, the concentration of the compound is 50. mu.M/100. mu.M, the positive control compound is DMXAA, the concentration is 50. mu.M, the solvent control group is 20. mu.L of physiological saline containing 1% DMSO, and 3 duplicate wells are respectively arranged. Detection was performed by incubation for 24 hours.
After 24 hours, 20. mu.L of the culture broth per well was transferred to a new bottom-transmitting 96-well plate, and the luciferase assay reagent QUANTI-Luc was addedTM 50μL，Fluorescence was measured immediately (protected from light) and the experiment was repeated 2 times.
Experimental results the ability of a compound to induce secretion of the type I interferon pathway was evaluated as Fold Change (Fold Change) and calculated as follows:
fold-compound fluorescence/vehicle group fluorescence.
2. Results of the experiment
The experimental results of the cell level are shown in a table 2, the compound disclosed by the invention has the function of inducing the secretion of the type I interferon pathway in murine Raw-lucia cells, and the activity of part of the compound at the concentration of 50 mu M is close to that of the positive compound DMXAA.
Table 2: effect of Compounds of the disclosure on activation of the type I Interferon pathway (ISG) in murine Raw-lucia cells
Compound numbering Multiple (50 μ M) Multiple (100. mu.M)
DMXAA* 23.54 NA
ZB-ST-6 10.22 NA
ZB-ST-7 2.63 8.62
ZB-ST-8 14.51 21.72
*DMXAA is a positive compound (Shirey, K.A.; Nhu, Q.M.; Yim, K.C.; Roberts, Z.J.; Teijaro, J.R.; Farber, D.L.; Blanco, J.C.; Vogel, S.N.the anti-tumor agent, 5, 6-dimethylxanthone-4-acetic acid (DMXAA), induced IFN-beta-mediated anti-viral activity in vitro and in vivo. J.Leukoc.biol.2011,89(3): 351-.

Claims (13)

1. A heterocyclic compound represented by the general formula I, a pharmaceutically acceptable salt thereof, or an isotopically labeled compound thereof:
Figure FDA0003664937200000011
wherein the heterocyclic compound shown in the general formula I is selected from compounds shown in a formula II, namely, X in a general formula 12、X3、X4Are all C:
Figure FDA0003664937200000012
ring A is selected from the group consisting of 0 to 2RAAn optionally substituted 5-membered aromatic heterocycle;
RAselected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk；-C(O)NRaRbOr S (O)2NRaRb；
B ring selected from
Figure FDA0003664937200000013
C ring selected from
Figure FDA0003664937200000014
RB1、RB2、RB3、RC1、RC2、RC3Each independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6A cycloalkyl group;
R2、R3、R4are independently selected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk、-C(O)NRaRbOr S (O)2NRaRb；
R5、R5’Each independently selected from hydrogen and C1～C6An alkyl group;
Ra、Rb、Rd、Reeach independently selected from hydrogen, C1～C6Alkyl, or C3～C6A cycloalkyl group;
Rxselected from hydrogen, halogen, by 0-4RhOptionally substituted C1～C6Alkyl, -O (CH)2)mRc、-NRfRg、-C(O)Rf、-CO2Rf、-C(O)NRfRg、-NRfC(O)Rg；
Rc、Rf、RgEach independently selected from hydrogen and 0-4RhOptionally substituted C1～C6Alkyl, with 0 to 4RiAn optionally substituted 6-to 10-membered aromatic ring, substituted with 0 to 4RiOptionally substituted 5-to 10-membered aromatic heterocycle, substituted with 0 to 4RiOptionally substituted 3-to 10-memberedCycloalkyl group, a group represented by 0 to 4RiAn optionally substituted 3-to 8-membered non-aromatic heterocyclic group, or 5-to 10-membered cycloalkenyl group;
Rhindependently selected from halogen, -ORj、-NRjRk、-C(O)Rj、-CO2Rj、-C(O)NRjRk、-NRjC(O)Rk0 to 4RiAn optionally substituted 6-to 10-membered aromatic ring, substituted with 0 to 4RiOptionally substituted 5-to 10-membered aromatic heterocycle substituted with 0 to 4RiOptionally substituted 3-to 10-membered cycloalkyl, substituted with 0 to 4RiAn optionally substituted 3-to 8-membered non-aromatic heterocyclic group, or 5-to 10-membered cycloalkenyl group;
Riindependently selected from halogen, hydroxy, amino, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen-substituted C1～C6Alkyl, hydroxy substituted C1～C6Alkyl, amino substituted C1～C6Alkyl, cyano;
or two RiAnd the ring atoms to which they are attached form a 3-to 8-membered saturated or unsaturated ring;
m is 0 to 6;
Rjindependently selected from hydrogen, C1～C6Alkyl or C3～C6A cycloalkyl group;
Rkindependently selected from hydrogen, hydroxy, amino, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen-substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, or halogen substituted C3～C6A cycloalkyl group;
l is selected from 0 to 4RnOptionally substituted C4～C6Alkylene of (a) with 0 to 4RnOptionally substituted C4～C6Alkenylene group of (A) is substituted by 0-4RnOptionally substituted C4～C6Alkynylene of (a); wherein, optionally substituted C4～C6Alkylene of (A)Radical, optionally substituted C4～C6Alkenylene of (2), optionally substituted C4～C6Of alkynylene of (a) — CH2-、-CHRn-or-C (R)n)2May be substituted by-O-, -S-, -NRm-substitution;
Rmselected from hydrogen, C1～C6Alkyl radical, C3～C6A cycloalkyl group;
Rnselected from halogen, hydroxy, amino, C1～C6Alkyl radical, C1～C6Alkoxy radical, C1～C6Alkylamino, halogen-substituted C1～C6An alkyl group.
2. The heterocyclic compound, a pharmaceutically acceptable salt thereof, or an isotopically labeled compound according to claim 1, wherein the heterocyclic compound of formula I is selected from compounds of formula III:
Figure FDA0003664937200000031
ring A is selected from the group consisting of 0 to 2RAAn optionally substituted thiophene ring;
RB1、RB2、RB3、RC1、RC2、RC3each independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6A cycloalkyl group;
R2、R3、R4are independently selected from hydrogen, -ORd、-NRdReHalogen, -CN, -C (O) ORd、C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk、-C(O)NRaRbOr S (O)2NRaRb；
Ra、Rb、Rd、Re、Rj、Rk、RA、R5、R5’、RxAnd L is as defined in claim 1.
3. The heterocyclic compound, a pharmaceutically acceptable salt thereof, or an isotopically labeled compound according to claim 1, wherein the heterocyclic compound represented by formula I is selected from compounds represented by formula IV:
Figure FDA0003664937200000032
RB1、RB2、RB3、RC1、RC2、RC3each independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6A cycloalkyl group;
R5、R5’、Rxand L is as defined in claim 1.
4. The heterocyclic compound, a pharmaceutically acceptable salt thereof, or an isotopically labeled compound according to claim 1, wherein the heterocyclic compound of formula I is selected from compounds of formula V:
Figure FDA0003664937200000041
RB1、RB2、RB3、RC1、RC2、RC3each independently selected from hydrogen and C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6A cycloalkyl group;
R5、R5’、Rxthe same as defined in claim 1.
5. The heterocyclic compound, a pharmaceutically acceptable salt thereof, or an isotopically labeled compound according to claim 1, wherein the heterocyclic compound of formula I is selected from compounds of formula VI:
Figure FDA0003664937200000042
Rxis selected from-O (CH)2)mRc；
m and RcThe same as defined in claim 1.
6. A heterocyclic compound, a pharmaceutically acceptable salt thereof, or an isotopically labeled compound thereof, wherein the heterocyclic compound is selected from the group consisting of compounds represented by formula VII:
Figure FDA0003664937200000043
a ring is selected from the group consisting of 0 to 2RAAn optionally substituted thiophene ring;
R2、R3、R4are independently selected from hydrogen, -ORd、-NRdReHalogen, -CN, C (O) ORd、C1～C6Alkyl, halogen substituted C1～C6Alkyl radical, C3～C6Cycloalkyl, halogen substituted C3～C6Cycloalkyl, -NRjC(O)Rk、-C(O)NRaRbOr S (O)2NRaRb；
Ra、Rb、Rd、Re、Rj、RkEach independently selected from hydrogen and C1～C6An alkyl group;
RA、R5、R5’、Rxl is as defined in claim 1,
B. the C rings are each independently selected from 0 to 4R1Optionally substituted benzene ring, substituted with 0-4R1An optionally substituted 5-6 membered aromatic heterocycle.
7. The heterocyclic compound, the pharmaceutically acceptable salt thereof, or the isotopically labeled compound according to claim 1, wherein
The heterocyclic compound shown in the general formula I is selected from the following compounds:
Figure FDA0003664937200000051
Figure FDA0003664937200000061
Figure FDA0003664937200000071
。
8. a pharmaceutical composition comprising the heterocyclic compound of any one of claims 1 to 7, a pharmaceutically acceptable salt thereof, or an isotopically labeled compound, and a pharmaceutically acceptable adjuvant.
9. Use of the heterocyclic compound of any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or an isotopically labeled compound thereof or the pharmaceutical composition of claim 8 for the preparation of a medicament for activating STING class.
10. Use of the heterocyclic compound of any one of claims 1 to 7, its pharmaceutically acceptable salt or isotopically labeled compound or the pharmaceutical composition of claim 8 for the preparation of a medicament for the treatment of a disease associated with STING activity.
11. Use according to claim 10, characterized in that: the diseases related to STING activity are one or more of diseases related to inflammatory diseases, autoimmune diseases, infectious diseases, cancer and precancerous syndrome.
12. Use of a heterocyclic compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or an isotopically labeled compound or a pharmaceutical composition according to claim 8 in the manufacture of a medicament for the treatment of an inflammatory, autoimmune, infectious, cancer or pre-cancerous syndrome.
13. Use of a heterocyclic compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt thereof or an isotopically labeled compound or a pharmaceutical composition according to claim 8 in the preparation of an immunoadjuvant.
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Citations (5)

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CN109563081A (en) * 2016-04-07 2019-04-02 葛兰素史克知识产权开发有限公司 It can be used as the heterocycleamide class of protein modulators
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CN109071514A (en) * 2016-04-07 2018-12-21 葛兰素史密斯克莱知识产权发展有限公司 Heterocycleamide as protein modulator
CN109563081A (en) * 2016-04-07 2019-04-02 葛兰素史克知识产权开发有限公司 It can be used as the heterocycleamide class of protein modulators
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