CN111848572A - Amide compound and preparation method and application thereof - Google Patents

Amide compound and preparation method and application thereof Download PDF

Info

Publication number
CN111848572A
CN111848572A CN201910357790.1A CN201910357790A CN111848572A CN 111848572 A CN111848572 A CN 111848572A CN 201910357790 A CN201910357790 A CN 201910357790A CN 111848572 A CN111848572 A CN 111848572A
Authority
CN
China
Prior art keywords
compound
cycloalkyl
alkyl radical
group
independently selected
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.)
Granted
Application number
CN201910357790.1A
Other languages
Chinese (zh)
Other versions
CN111848572B (en
Inventor
刘金明
任云
蔡家强
王利春
王晶翼
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.)
Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Original Assignee
Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sichuan Kelun Biotech Biopharmaceutical Co Ltd filed Critical Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority to CN201910357790.1A priority Critical patent/CN111848572B/en
Publication of CN111848572A publication Critical patent/CN111848572A/en
Application granted granted Critical
Publication of CN111848572B publication Critical patent/CN111848572B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Description

Amide compound and preparation method and application thereof
Technical Field
The invention relates to an amide compound, a pharmaceutical composition and a kit containing the same, a preparation method thereof and application of the amide compound in preparing drugs for treating STING-mediated related diseases.
Background
STING (Stimulator of interferon gene stimulating protein), also known as TMEM173, MPYS, MITA or ERIS, is an important signal molecule in immune responses. When STING is activated by stimulation with a ligand, such as a bacterial-derived Cyclic Dinucleotide (CDN), IRF3 and the NF- κ B signaling pathway are upregulated. Specifically, activated STING recruits TANK binding kinase (TBK1) in the cytoplasm, mediates phosphorylation of IRF3 by TBK1, resulting in the production of interferons and other cytokines. Interferons are a group of active proteins with multiple functions, and have the functions of regulating immune function, enhancing vaccine effect, resisting virus, inhibiting tumor cell proliferation, inducing tumor cell apoptosis and the like (Nature,2008,455, 674-678; Science Signaling,2012,5, ra 20). In addition, STING proteins are involved in various pathological and physiological processes such as tumor immunity, autoimmune inflammation, autophagy, and the like. STING-mediated type I interferon signaling pathways are key steps in tumor-specific T cell activation and tumor-infiltrating lymphocyte infiltration, whereas low STING expression promotes tumor immune tolerance and/or immune escape in various tumor tissues such as hepatocellular carcinoma, gastric cancer, and colorectal cancer. A large number of studies have shown that STING agonists have significant anti-tumor activity. For example, STING agonists (ADU-S100) are able to inhibit the growth of secondary graft tumors, reverse tumor immune tolerance phenomena for long periods of time, and inhibit tumor recurrence in mouse models.
Presently, the disclosed STING agonists are mainly compounds having cyclic dinucleotide analogue structures. MIW815(ADU-S100) has entered clinical stage 1, and the patient disease types recruited include Merkel cell carcinoma, parotid gland carcinoma, colorectal carcinoma, endometrial carcinoma, breast carcinoma, esophageal carcinoma, collecting duct carcinoma, ovarian carcinoma, Hodgkin' S lymphoma, vascular epithelial tumors, and skin-accessible advanced/metastatic solid tumors and lymphomas, among others.
In addition, there is a continuing body of research that discloses STING agonists of acyclic dinucleotide structure. For example, WO2018067423 discloses a class of benzothiophenes as STING agonists for the treatment of cell proliferation related diseases (such as cancer). WO2018234805, WO2018234807 and WO2018234808 also disclose a series of heterocyclic compounds that can modulate or activate human STING proteins for the treatment of various diseases, including cancer.
Therefore, the STING agonist has good application prospect in the pharmaceutical industry as a medicament. In order to achieve better tumor treatment effect and better meet market demand, development of a novel and efficient STING agonist is urgently needed.
Disclosure of Invention
On one hand, the invention provides compounds containing amido bonds, and the compounds have strong agonistic action on a STING signal path, so that the compounds have better tumor treatment effect. The compounds of the invention also have a number of advantageous properties, such as good physicochemical properties (e.g. solubility, physical and/or chemical stability) and good safety, among others. The compound is a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof:
Figure BDA0002045969190000011
Wherein the content of the first and second substances,
l is (C (R)5)2)m；
R1Each independently selected from H, halogen, cyano, -ORa、-SRa、-S(O)Ra、-S(O)2Ra、-NRaRb、-C(O)-NRaRb、-N(Ra)-C(O)-Rb、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Haloalkyl, cyano, hydroxy and C1-6An alkoxy group;
R2selected from H, halogen, cyano, -ORa、-NRaRb、C1-6Alkyl radical, C3-10Cycloalkyl and 3-10 membered heterocyclyl, said C1-6Alkyl radical, C3-10The cycloalkyl and 3-10 membered heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Haloalkyl, cyano, hydroxy and C1-6An alkoxy group;
R3selected from H, C1-6Alkyl radical, C3-10Cycloalkyl and 3-10 membered heterocyclyl, said C1-6Alkyl radical, C3-10Each cycloalkyl or 3-10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, C1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -N (R)a)(Rb)、-C(O)2Raand-S (O)2Ra；
R4Selected from H, C1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C 6-10Aryl, 5-10 membered heteroaryl, -OR6and-C (O)2R6Said C is1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more RcSubstitution;
Rceach independently selected from halogen, cyano, hydroxy, -NRaRb、-C(O)2Ra、C1-6Alkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, said C1-6Alkyl radical, C1-6Alkoxy and C1-6Haloalkoxy is each optionally substituted with one or more substituents independently selected from the group consisting of: cyano, -ORa、-NRaRb、-C(O)2Ra、C1-6Alkoxy and-S (O)2Ra；
R5Each independently selected from H, halogen, cyano, -ORa、-SRa、-NRaRb、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, C1-6Haloalkyl, cyano, hydroxy, C1-6Alkoxy and-ORa(ii) a Or two R5Together with the carbon atom to which they are attached form C3-10Cycloalkyl or 3-10 membered heterocyclyl; or any one of R5And R3Together with the atoms between them form a 3-10 membered heterocyclyl;
R6Selected from H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, -ORa、-SRa、-S(O)Ra、-S(O)2Ra、-NRaRb、-C(O)-Ra、-C(O)2Ra、-C(O)-NRaRb、-N(Ra)-C(O)-Rb、C1-6Alkyl radical, C1-6Haloalkyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl;
Raand RbEach independently selected from H, C1-6Alkyl radical, C3-10Cycloalkyl and C1-6Alkoxy radical, said C1-6Alkyl radical, C3-10Cycloalkyl and C1-6Each alkoxy group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and halogen;
or Ra、RbTogether with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl;
m is selected from 1, 2 and 3;
n is selected from 0, 1, 2, 3 and 4.
In another aspect, the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.
In another aspect, the invention provides a kit comprising a compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the invention.
In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use in the prevention or treatment of STING-mediated related diseases.
In another aspect, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention for the manufacture of a medicament for the prevention or treatment of STING-mediated related diseases.
In another aspect, the present invention provides a method for preventing or treating STING-mediated related diseases, comprising administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.
In another aspect, the present invention provides a method of preparing a compound of the invention, comprising the steps of:
Figure BDA0002045969190000031
wherein R is1、R2、R3、R4L and n are as defined above.
Definition of
Unless defined otherwise below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. Reference to the techniques used herein is intended to refer to those techniques commonly understood in the art, including those variations of or alternatives to those techniques that would be apparent to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
As used herein, the terms "comprises," "comprising," "has," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.
The term "alkyl" as used herein is defined as a straight or branched chain saturated aliphatic hydrocarbon group. For example, such asAs used herein, the term "C1-6Alkyl "refers to a straight or branched chain group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, or n-hexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen.
As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems, such as bicyclo [1.1.1]Pentyl, bicyclo [2.2.1]Heptyl, bicyclo [3.2.1]Octyl or bicyclo [5.2.0]Nonyl, decalinyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents. For example, the term "C3-6Cycloalkyl "refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) having 3 to 6 ring carbon atoms, optionally substituted with one or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.
As used herein, the term "alkoxy" means a group having an oxygen atom inserted at any reasonable position in the alkyl group (as defined above), e.g., C1-8Alkoxy radical, C1-6Alkoxy radical, C1-4Alkoxy or C1-3An alkoxy group. C1-6Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like, which may be optionally substituted with one or more (such as 1 to 3) identical or different substituents.
As used herein, the term "halo" or "halogen" group is defined to include fluorine, chlorine, bromine, or iodine.
As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) identical or different halogen atoms. For example, the term "C1-6Haloalkyl "meansHaloalkyl having 1 to 6 carbon atoms, e.g. -CF3、-C2F5、-CHF2、-CH2F、-CH2CF3、-CH2Cl or-CH2CH2CF3And the like.
As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic group, e.g., having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., 1, 2, 3, or 4) independently selected from N, O or S (O)p(wherein p is 0, 1 or 2), such as a 3-to 10-membered heterocyclic group, a 3-to 7-membered heterocyclic group, a 3-to 6-membered heterocyclic group, a 5-to 6-membered heterocyclic group and the like. Representative examples of heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, and the like.
As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused ring polycyclic aromatic group having a conjugated pi-electron system. For example, the term "C6-10Aryl "or" C6-10Aromatic ring "refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthyl (ring). Aryl is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g. halogen, -OH, -CN, -NO)2、C1-6Alkyl, etc.).
As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, for example having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular containing 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and, in addition, may be benzo-fused in each case. For example, the heteroaryl or heteroaromatic ring may be selected from thienyl (ring), furyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyrazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring), and the like, and benzo derivatives thereof; or pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), etc., and benzo derivatives thereof.
The term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency at the present time is not exceeded and the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
If a substituent is described as "optionally substituted with …", the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced individually and/or together with an independently selected substituent or not. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogen present) may each be replaced with an independently selected substituent or not.
If a substituent is described as "independently selected from" a group of groups, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, under reasonable conditions.
Unless indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.
When a bond of a substituent is shown through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.
The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the invention, exceptOne or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion into compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., hydrogen)2H、3H. Deuterium D, tritium T); isotopes of carbon (e.g. of11C、13C and14C) (ii) a Isotopes of chlorine (e.g. of chlorine)37Cl); isotopes of fluorine (e.g. of fluorine)18F) (ii) a Isotopes of iodine (e.g. of iodine)123I and125I) (ii) a Isotopes of nitrogen (e.g. of13N and15n); isotopes of oxygen (e.g. of15O、17O and18o); isotopes of phosphorus (e.g. of phosphorus) 32P); and isotopes of sulfur (e.g. of35S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in drug and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium (i.e. tritium3H) And carbon-14 (i.e.14C) Are particularly useful for this purpose because of their ease of incorporation and ease of detection. Using positron-emitting isotopes (e.g. of the type11C、18F、15O and13n) can be used to examine substrate receptor occupancy in Positron Emission Tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent employed previously. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g., D2O, acetone-d6Or DMSO-d6。
The term "stereoisomer" denotes an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., 1, 2, 3, or 4) asymmetric centers, they can result in racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as mixtures of two or more structurally different forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It is understood that the scope of this application encompasses all such isomers or mixtures thereof in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).
The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.
It will also be appreciated that certain compounds of the invention may be present in free form for use in therapy or, where appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to: pharmaceutically acceptable salts, solvates, metabolites or prodrugs thereof, which upon administration to a patient in need thereof are capable of providing, directly or indirectly, a compound of the present invention or a metabolite or residue thereof. Thus, when reference is made herein to "a compound of the invention," it is also intended to encompass the various derivative forms of the compounds described above.
Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. For a review of suitable Salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.
The compounds of the invention may be present in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural element of the crystal lattice of the compound a polar solvent, such as in particular water, methanol or ethanol. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric proportions.
Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, since the available lone pair is required for oxidation of the nitrogen to the oxide; one skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines with peroxy acids such as peracetic and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyldioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L.Gilchrist, Comprehensive Organic Synthesis, vol.7, pp 748-750; a.r.katitzky and a.j.boulton, eds., Academic Press; and G.W.H.Cheeseman and E.S.G.Werstuk, Advances in Heterocyclic Chemistry, vol.22, pp 390-.
Also included within the scope of the present invention are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by the process of contacting the compounds of the present invention with a mammal for a time sufficient to produce a metabolite thereof.
The present invention further includes within its scope prodrugs of the compounds of the present invention which are certain derivatives of the compounds of the present invention which may themselves have little or no pharmacological activity which, when administered into or onto the body, may be converted to the compounds of the present invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", volume 14, ACS Symposium Series (T.Higuchi and V.Stella) and "Bioreversible Carriers in Drug Design," PergamonPress,1987(E.B.Roche editions, American Pharmaceutical Association). Prodrugs of the invention may be prepared, for example, by substituting certain moieties known to those skilled in the art as "pro-moieties" (e.g., "Design of produgs", described in h. bundgaard (Elsevier, 1985)) for appropriate functional groups present in compounds of the invention.
The invention also encompasses compounds of the invention containing a protecting group. In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, as described in protective groups in Organic Chemistry, ed.j.f.w.mcomie, Plenum Press, 1973; and T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons,1991, which are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
The term "about" means within. + -. 10%, preferably within. + -. 5%, more preferably within. + -. 2% of the stated value.
Compound (I)
It is an object of the present invention to provide a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof:
Figure BDA0002045969190000051
wherein the content of the first and second substances,
l is (C (R)5)2)m；
R1Each independently selected from H, halogen, cyano, -OR a、-SRa、-S(O)Ra、-S(O)2Ra、-NRaRb、-C(O)-NRaRb、-N(Ra)-C(O)-Rb、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Haloalkyl, cyano, hydroxy and C1-6An alkoxy group;
R2selected from H, halogen, cyano, -ORa、-NRaRb、C1-6Alkyl radical, C3-10Cycloalkyl and 3-10 membered heterocyclyl, said C1-6Alkyl radical, C3-10The cycloalkyl and 3-10 membered heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Haloalkyl, cyano, hydroxy and C1-6An alkoxy group;
R3selected from H, C1-6Alkyl radical, C3-10Cycloalkyl and 3-10 membered heterocyclyl, said C1-6Alkyl radical, C3-10Each cycloalkyl or 3-10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, C1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -N (R)a)(Rb)、-C(O)2Raand-S (O)2Ra；
R4Selected from H, C1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, -OR6and-C (O)2R6Said C is1-6Alkyl radical, C 3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more RcSubstitution;
Rceach independently selected from halogen, cyano, hydroxy, -NRaRb、-C(O)2Ra、C1-6Alkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, said C1-6Alkyl radical, C1-6Alkoxy and C1-6Haloalkoxy is each optionally substituted with one or more substituents independently selected from the group consisting of: cyano, -ORa、-NRaRb、-C(O)2Ra、C1-6Alkoxy and-S (O)2Ra；
R5Each independently selected from H, halogen, cyano, -ORa、-SRa、-NRaRb、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, C1-6Haloalkyl, cyano, hydroxy, C1-6Alkoxy and-ORa(ii) a Or two R5Together with the carbon atom to which they are attached form C3-10Cycloalkyl or 3-10 membered heterocyclyl; or any one of R5And R3Together with the atoms between them form a 3-10 membered heterocyclyl;
R6selected from H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C 6-10Aryl and 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, -ORa、-SRa、-S(O)Ra、-S(O)2Ra、-NRaRb、-C(O)-Ra、-C(O)2Ra、-C(O)-NRaRb、-N(Ra)-C(O)-Rb、C1-6Alkyl radical, C1-6Haloalkyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl;
Raand RbEach independently selected from H, C1-6Alkyl radical, C3-10Cycloalkyl and C1-6Alkoxy radical, said C1-6Alkyl radical, C3-10Cycloalkyl and C1-6Each alkoxy group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and halogen;
or Ra、RbTogether with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl;
m is selected from 1, 2 and 3;
n is selected from 0, 1, 2, 3 and 4.
According to some embodiments of the invention, R1Selected from H, halogen, CN and-ORa. In a preferred embodiment, R1is-ORa. In a more preferred embodiment, R1Selected from hydroxy and C optionally substituted by hydroxy1-6An alkoxy group. In a particularly preferred embodiment, R1Selected from the group consisting of hydroxy, methoxy and hydroxypropoxy.
According to some embodiments of the invention, R2Selected from H, halogen, C1-6Alkyl and C3-6Cycloalkyl radical, said C1-6Alkyl and C3-6Each cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 1-6Alkyl, cyano, hydroxy and C1-6An alkoxy group. In a preferred embodiment, R2Is H.
According to some embodiments of the invention, R3Selected from H, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6Each cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy、C1-3Alkoxy, -C (O)2Raand-S (O)2Ra. In a preferred embodiment, R3Selected from H and C1-3Alkyl radical, said C1-3Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: cyano, hydroxy, -C (O)2Raand-S (O)2Ra. In a more preferred embodiment, R3Selected from H and C1-3Alkyl radical, said C1-3Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: cyano, hydroxy, -C (O)2H and-S (O)2CH3. In a particularly preferred embodiment, R3Selected from the group consisting of H, methyl, ethyl, isopropyl, cyanoethyl, methylsulfonylethyl, hydroxyethyl, and carboxymethyl. For example, R3Selected from H and methyl.
According to some embodiments of the invention, R4Is optionally substituted by one or more C1-6Alkyl-substituted 5-6 membered heteroaryl (e.g., 5-6 membered nitrogen-containing heteroaryl), C1-6Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: cyano, -OR a、-C(O)2Raand-S (O)2Ra. In a preferred embodiment, R4Is optionally substituted by one or more C1-6Alkyl-substituted pyrazolyl radical, C1-6Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: cyano, hydroxy, -C (O)2H and-S (O)2CH3. In a more preferred embodiment, R4Selected from the group consisting of N-methylpyrazole, N-ethylpyrazole, N-isopropylpyrazole, N-cyanoethylpyrazole, N-methanesulfonylethylpyrazole, N-hydroxyethylpyrazole and N-carboxymethylpyrazole.
According to some embodiments of the invention, R4is-C (O)2R6Wherein R is6Is selected from C1-6Alkyl radical, C3-6Cycloalkyl and 5-6 membered heterocyclyl (e.g., 5-6 membered oxygen-containing heterocyclyl), C1-6Alkyl radical, C3-6Cycloalkyl and 5-6 membered heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting ofSubstituent group substitution: -ORa、-N(Ra)Rb、C6-10Aryl and-C (O)2Ra(ii) a Preferably, R6Is selected from C1-3Alkyl radical, C5-6Cycloalkyl and tetrahydropyranyl, said C1-3Alkyl radical, C5-6The cycloalkyl and tetrahydropyranyl groups are each optionally substituted with 1 to 4 substituents independently selected from: -OH, -NH2Phenyl and-C (O)2H; more preferably, R6Selected from the group consisting of methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, benzyl, hydroxyethyl, carboxymethyl, 2-carboxy-2-aminoethyl, and 2,3,4, 5-tetrahydroxytetrahydropyran-6-yl. For example, R 6Selected from methyl, ethyl and isopropyl.
According to some embodiments of the invention, R5Each independently selected from H and C1-6An alkyl group; or any one of R5And R3Together with the atoms between them, form a 5-6 membered heterocyclic group. In a preferred embodiment, R5Is H; or any one of R5And R3Together with the atoms between them, form a pyrrolidinyl group.
According to some embodiments of the invention, m is 1 or 2.
According to some embodiments of the invention, L is CH2Or (CH)2)2。
According to some embodiments of the invention, RaAnd RbEach independently selected from H, C1-6Alkyl and hydroxy C1-6An alkyl group.
According to some embodiments of the invention, n is 2.
In accordance with some embodiments of the present invention,
l is CH2；
R1Each independently selected from H, halogen, cyano, -ORa、-SRa、-S(O)Ra、-S(O)2Ra、-NRaRb、-C(O)-NRaRb、-N(Ra)-C(O)-Rb、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Haloalkyl, cyano, hydroxy and C1-6An alkoxy group;
R2selected from H, halogen, cyano, -OR a、-NRaRb、C1-6Alkyl radical, C3-10Cycloalkyl and 3-10 membered heterocyclyl, said C1-6Alkyl radical, C3-10The cycloalkyl and 3-10 membered heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Haloalkyl, cyano, hydroxy and C1-6An alkoxy group;
R3selected from H, C1-6Alkyl radical, C3-10Cycloalkyl and 3-10 membered heterocyclyl, said C1-6Alkyl radical, C3-10Each cycloalkyl or 3-10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, C1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -N (R)a)(Rb)、-C(O)2Raand-S (O)2Ra；
R4Selected from H, C1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl, said C1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-6 membered heteroaryl are each optionally substituted with one or more RcSubstitution;
Rceach independently selected from halogen, cyano, hydroxy, -NRaRb、-C(O)2Ra、C1-6Alkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, said C1-6Alkyl radical, C1-6Alkoxy and C1-6Haloalkoxy is each optionally substituted with one or more substituents independently selected from the group consisting of: cyano, -ORa、-NRaRb、-C(O)2Ra、C1-6Alkoxy and-S (O)2Ra；
RaAnd RbEach independently selected from H, C 1-6Alkyl radical, C3-10Cycloalkyl and C1-6Alkoxy radical, said C1-6Alkyl radical, C3-10Cycloalkyl and C1-6Each alkoxy group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and halogen;
or Ra、RbTogether with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl;
m is selected from 1, 2 and 3;
n is selected from 0, 1, 2, 3 and 4.
In accordance with some embodiments of the present invention,
l is CH2；
R1Each independently is-ORa；
R2Is H;
R3selected from H and C1-6Alkyl radical, said C1-6Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: cyano, hydroxy, -C (O)2Raand-S (O)2Ra；
R4Is a 5-6 membered heteroaryl group, said 5-6 membered heteroaryl group optionally substituted with one or more RcSubstitution;
Rceach independently selected from cyano, hydroxy, -C (O)2RaAnd C1-6Alkyl radical, said C1-6Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: cyano, -OH, -COOH and-S (O)2Ra；
RaEach independently selected from H and C1-6Alkyl radical, said C1-6Alkyl is optionally substituted by one or more substituents independently selected from hydroxy and halogenGeneration;
n is 2.
According to some embodiments of the invention, L is CH2；
R1Are both methoxy;
R2is H;
R3selected from H and C1-3Alkyl radical, said C1-3Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: cyano, hydroxy, -COOH and-S (O) 2-CH3；
R4Is a 5-6 membered heteroaryl group, said 5-6 membered heteroaryl group optionally substituted with one or more RcSubstitution;
Rceach independently selected from cyano, hydroxy and C1-3Alkyl radical, said C1-3Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: cyano, -OH, -COOH and-S (O)2-CH3；
n is 2.
According to some embodiments of the invention, the compounds of the invention have the structure of formula (II):
Figure BDA0002045969190000081
wherein R is1、R2、R3、R6L and n are as defined above;
preferably, in the compound of formula II,
l is (C (R)5)2)m；
R1Each independently is-ORa；
R2Is H;
R3selected from H, C1-6Alkyl radical, C3-10Cycloalkyl and 3-10 membered heterocyclyl, said C1-6Alkyl radical, C3-10Each cycloalkyl or 3-10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, C1-6Alkyl radical, C3-10Cycloalkyl, 3-to 10-memberedHeterocyclic group, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -N (R)a)(Rb)、-C(O)2Raand-S (O)2Ra；
R5Each independently of the other H and C1-6An alkyl group; or any one of R5And R3Together with the atoms between them form a 5-6 membered heterocyclyl;
R6is selected from C1-3Alkyl radical, C5-6Cycloalkyl and tetrahydropyranyl, said C1-3Alkyl radical, C5-6The cycloalkyl and tetrahydropyranyl groups are each optionally substituted with 1 to 4 substituents independently selected from: -OH, -NH 2Phenyl and-COOH;
Raand RbEach independently selected from H, C1-3Alkyl and hydroxy C1-3An alkyl group; and is
m is selected from 1, 2 and 3;
n is selected from 2, 3 and 4.
According to some embodiments of the invention, the compounds of the invention have the structure of formula (III):
Figure BDA0002045969190000082
wherein R is1、R2、R3、R6And n is as defined above;
preferably, in the compound of formula (III),
R1each independently is-ORa；
R2Is H;
R3selected from H, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6Each cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, C1-3Alkoxy, -C (O)2Raand-S (O)2Ra；
R6Is selected from C1-3Alkyl radical, C5-6Cycloalkyl and tetrahydropyranyl, said C1-3Alkyl radical, C5-6The cycloalkyl and tetrahydropyranyl groups are each optionally substituted with 1 to 4 substituents independently selected from: -OH, -NH2Phenyl and-COOH;
Raeach independently selected from H, C1-6Alkyl and hydroxy C1-6An alkyl group; and is
n is selected from 2, 3 and 4.
According to some embodiments of the invention, the compounds of the invention have the structure of formula (III-1):
Figure BDA0002045969190000091
wherein R is1、R2、R3And R6As defined above;
preferably, in the compound of the formula (III-1),
R1each independently is-ORa；
R2Is H;
R3selected from H, C1-3Alkyl and C3-6Cycloalkyl radical, said C 1-3Alkyl and C3-6Each cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, C1-3Alkoxy, -C (O)2Raand-S (O)2Ra；
R6Is selected from C1-3Alkyl radical, C5-6Cycloalkyl and tetrahydropyranyl, said C1-3Alkyl radical, C5-6The cycloalkyl and tetrahydropyranyl groups are each optionally substituted with 1 to 4 substituents independently selected from: -OH, -NH2Phenyl and-COOH; and is
RaEach independently selected from H, C1-6Alkyl and hydroxy C1-6Alkyl, preferably, RaEach independently selected from H, C1-3Alkyl and hydroxy C1-3An alkyl group.
According to some embodiments of the invention, the compound of the invention is selected from:
Figure BDA0002045969190000092
Figure BDA0002045969190000101
preparation method
The present invention also relates to a process for preparing a compound of formula (II-a), said process comprising the steps of:
Figure BDA0002045969190000102
wherein R is1、R2、R3、R4L and n are as defined above.
Step (1): reacting compound IN-1 with methyl thioglycolate to obtain compound IN-2;
the reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, acetonitrile, and any combination thereof, preferably N, N-dimethylformamide.
The reaction is preferably carried out in the presence of a suitable base. The base may be selected from diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, preferably potassium carbonate.
The reaction is carried out at a suitable temperature, preferably from 25 to 100 ℃.
The reaction is carried out for a suitable time, for example 2 to 8 hours.
Step (2): subjecting the compound IN-2 to hydrolysis reaction to obtain a compound IN-3;
the reaction is preferably carried out in a suitable solvent. The solvent may be selected from tetrahydrofuran, methanol, ethanol, water and any combination thereof, and is preferably a mixed solvent of methanol and water.
The reaction is preferably carried out in the presence of a suitable base. The base may be selected from lithium hydroxide, sodium hydroxide, preferably sodium hydroxide.
The reaction is carried out at a suitable temperature, preferably from 25 to 60 ℃.
The reaction is carried out for a suitable time, for example 2 to 8 hours.
And (3): reacting compound IN-3 with compound IN-4 to obtain compound I;
the reaction is preferably carried out in a suitable organic solvent. The organic solvent may be selected from the group consisting of tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, dichloromethane, and any combination thereof, preferably tetrahydrofuran.
The reaction is preferably carried out in the presence of a suitable condensing agent. The condensing agent can be selected from dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, HATU, benzotriazole-N, N, N, N-tetramethylurea hexafluorophosphate, 1H-benzotriazole-1-oxytripyrrolidinyl hexafluorophosphate, preferably HATU.
The reaction is preferably carried out in the presence of a suitable organic base. The organic base may be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine, preferably diisopropylethylamine.
The reaction is carried out at a suitable temperature, preferably from 25 to 60 ℃.
The reaction is carried out for a suitable time, for example 2 to 8 hours.
Pharmaceutical composition and kit
It is another object of the present invention to provide a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, and one or more pharmaceutically acceptable carriers.
It is another object of the present invention to provide a kit comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.
By "pharmaceutically acceptable carrier" in the context of the present invention is meant a diluent, adjuvant, excipient, or vehicle that is administered together with a therapeutic agent and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may be employed in the pharmaceutical compositions or formulations of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
The pharmaceutical composition may, for example, be in the form of a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation, and the like. The solid preparation is, for example, tablets, capsules, powders, granules or suppositories, and the like, and the liquid preparation is, for example, solutions, suspensions or injections. The composition can also be in the form of liposome, microsphere, etc. In particular, the pharmaceutical composition is in a form of a formulation suitable for oral administration.
Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition may also optionally contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's pharmaceutical sciences (1990).
The pharmaceutical compositions of the present invention may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by injection (e.g. intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.
For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms. Such dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
The compound of the invention may be present in the pharmaceutical composition in an amount or amount of from about 0.001mg to about 1000mg, suitably 0.01-800mg, preferably 0.05-500mg, more preferably 0.1-350mg, especially 0.5-100 mg.
In some embodiments, the present invention provides a method of making a pharmaceutical composition of the present invention, the method comprising combining a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, with one or more pharmaceutically acceptable carriers.
Methods of treatment and uses
It is another object of the present invention to provide a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention for use in activating STING signaling pathway.
Another object of the present invention is to provide a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use in the prevention or treatment of STING-mediated related diseases.
Another object of the present invention is to provide a use of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or the pharmaceutical composition of the present invention for the preparation of a medicament for the prevention or treatment of STING-mediated related diseases.
It is another object of the present invention to provide a method for preventing or treating STING-mediated related diseases, which comprises administering to a subject in need thereof a prophylactically or therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.
According to some embodiments of the invention, the STING-mediated associated disease is a tumor, preferably the disease is cancer.
The term "effective amount" as used herein refers to an amount sufficient to achieve a desired prophylactic or therapeutic effect, e.g., to achieve alleviation of one or more symptoms associated with the disease being treated.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition being alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.
The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is from about 0.0001 to about 50mg per kg body weight per day, e.g., from about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70kg human, this may amount to about 0.007 mg/day to about 3500 mg/day, e.g., about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels not higher than the lower limit of the aforesaid range may be sufficient, while in other cases still larger doses may be employed without causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.
As used herein, unless otherwise specified, the term "treating" or "treatment" means reversing, alleviating, inhibiting the progression of, or preventing such a disorder or condition, or one or more symptoms of such a disorder or condition, to which such term applies.
As used herein, "individual" includes a human or non-human animal. Exemplary human individuals include human individuals (referred to as patients) having a disease (e.g., a disease described herein) or normal individuals. "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
Detailed Description
In order to make the objects and technical solutions of the present invention clearer, embodiments of the present invention will be described in detail below with reference to examples. It will be understood by those skilled in the art that the following examples are illustrative of the present invention only and should not be taken as limiting the scope of the invention. The examples, in which the specific conditions are not specified, were conducted under the conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
The structure of the compound is determined by nuclear magnetic resonance1H NMR) or Mass Spectrometry (MS).1The H NMR analyzer is a JEOL Eclipse 400 NMR spectrometer, and the measuring solvent is deuterated methanol (CD)3OD), deuterated chloroform (CDCl)3) Or hexadeutero dimethyl sulfoxide (DMSO-d)6) Internal standard is Tetramethylsilane (TMS), and chemical shifts () are given in parts per million (ppm).
The measurement instrument for MS was an agilent (esi) mass spectrometer, manufacturer: agilent, model: agilent 6120B.
The preparation method of the high performance liquid chromatograph comprises the following steps:
the instrument model is as follows: agilent 1260; a chromatographic column: waters SunAire Prep C18OBD (19 mm. times.150 mm. times.5.0 μm); temperature of the chromatographic column: 25 ℃; flow rate: 20.0 mL/min; detection wavelength: 214 nm; elution gradient: (0 min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% aqueous formic acid.
Thin layer chromatography silica gel plate (TLC) an aluminum plate (20X 20cm) from Merck was used, and the specification for separation and purification by thin layer chromatography was GF 254(1mm) from Nicotiana.
The reaction was monitored by Thin Layer Chromatography (TLC) or LC-MS; the developer system used included: dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system, and the volume ratio of the solvent is regulated according to different polarities of the compounds or by adding triethylamine and the like.
The microwave reaction was carried out using a Biotage Initiator + (400W, RT-300 ℃ C.) microwave reactor.
The column chromatography generally uses 200-300 mesh silica gel as a carrier. The eluent system comprises: the volume ratio of the solvent is adjusted according to different polarities of the compounds in a dichloromethane and methanol system and a petroleum ether and ethyl acetate system, and a small amount of triethylamine can be added for adjustment.
In the examples, the reaction temperature is room temperature (20 ℃ to 35 ℃);
the reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Texas Chemical, and the like.
In the conventional syntheses as well as in the examples and intermediate syntheses, the meanings of the abbreviations are shown in the following table.
Abbreviations Means of
TLC Thin layer chromatography
LC-MS Liquid chromatography-mass spectrometry
DIPEA N, N-diisopropylethylamine
HATU 2- (7-benzotriazole oxide) -N, N, N, N-tetramethyluronium hexafluorophosphate
DMF N, N-dimethylformamide
CD3OD Deuterated methanol
CDCl3 Deuterated chloroform
DMSO-d6 Hexahydro-deuterated dimethyl sulfoxide
TMS Tetramethylsilane
NMR Nuclear magnetic resonance
MS Mass spectrometry
s Single peak (singlet)
d Double peak (doublet)
t Triple peak (triplet)
q Quartet (quartz)
dd Double two peak (double)
m Multiplet (multiplex)
br Broad peak (broad)
J Coupling constant
Hz Hertz's scale
Intermediate preparation example 1: preparation of 5, 6-dimethoxybenzo [ b ] thiophene-2-carboxylic acid
Figure BDA0002045969190000131
The first step is as follows: preparation of methyl 5, 6-dimethoxybenzo [ b ] thiophene-2-carboxylate
6-Fluoroveratraldehyde (10.0g,54.3mmol) was dissolved in DMF (200mL), methyl thioglycolate (6.9g,65.2mmol) and potassium carbonate (22.5g,162.9mmol) were added, and the mixture was heated to 60 ℃ for 15 hours. The reaction mixture was slowly poured into water (1000mL), stirred for 2 hours, filtered and the solid was washed with water (500mL) to give methyl 5, 6-dimethoxybenzo [ b ] thiophene-2-carboxylate (12.0g, yield: 87.6%) after drying in vacuo at 60 ℃.
MS m/z(ESI):253.0[M+H]+。
The second step is that: preparation of 5, 6-dimethoxybenzo [ b ] thiophene-2-carboxylic acid
Methyl 5, 6-dimethoxybenzo [ b ] thiophene-2-carboxylate (12.0g,47.6mmol) was dissolved in methanol (100mL) and water (20mL), and after adding sodium hydroxide (3.8g,95.1mmol), the reaction was carried out at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure at 40 ℃ to remove a part of methanol, the residue was added to water (500mL), pH was adjusted to 3 with dilute hydrochloric acid, filtered and the solid was washed with water (500mL), and dried under vacuum at 60 ℃ to obtain the title compound (8.0g, yield: 70.6%).
MS m/z(ESI):239.0[M+H]+。
Example 1: preparation of methyl 3- (5, 6-dimethoxybenzo [ b ] thiophene-2-carboxamido) propionate (Compound 3)
Figure BDA0002045969190000141
5, 6-Dimethoxybenzo [ b ] thiophene-2-carboxylic acid (500.0mg,2.1mmol) and methyl 3-aminopropionate hydrochloride (325mg,2.3mmol) were dissolved in tetrahydrofuran (10mL), HATU (1.6g,4.2mmol) and DIPEA (814mg,6.3mmol) were added, and the mixture was heated to 60 ℃ for 4 hours. The reaction solution was poured into water (100mL), extracted three times with ethyl acetate (25mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatography to give the title compound (250mg, yield: 35%).
MS m/z(ESI):324.1[M+H]+。
1H-NMR(400MHz,DMSO-d6):8.73-8.71(m,1H),7.89(s,1H),7.56(s,1H),7.39(s,1H),3.84-3.83(m,6H),3.62(s,3H),3.51-3.46(m,2H),2.63-2.60(m,2H)。
Example 2: preparation of (S) -1- (5, 6-dimethoxybenzo [ b ] thiophene-2-carbonyl) pyrrolidine-2-carboxylic acid methyl ester (Compound 1)
Figure BDA0002045969190000142
Using the synthetic route of example 1, the starting material methyl 3-aminopropionate hydrochloride was replaced with L-proline methyl ester hydrochloride to give the title compound (72mg, yield: 39.3%).
MS m/z(ESI):350.1[M+H]+。
1H-NMR(400MHz,DMSO-d6):7.91(s,1H),7.57(s,1H),7.44(s,1H),4.53-4.50(m,1H),3.97-3.94(m,2H),3.85-3.82(m,6H),3.66(s,3H),3.31-3.22(m,1H),2.08-2.00(m,2H),1.94-1.86(m,1H)。
Example 3: preparation of (S) -1- (5, 6-dimethoxybenzo [ b ] thiophene-2-carbonyl) pyrrolidine-3-carboxylic acid methyl ester (Compound 2)
Figure BDA0002045969190000143
Using the synthetic route of example 1, the starting material methyl 3-aminopropionate hydrochloride was replaced with methyl (S) -pyrrolidine-3-carboxylate to give the title compound (72mg, yield: 39.3%).
MS m/z(ESI):350.1[M+H]+。
1H-NMR(400MHz,DMSO-d6):7.82(s,1H),7.55(s,1H),7.46-7.42(m,1H),4.07-3.89(m,2H),3.84-3.82(m,6H),3.76-3.71(m,1H),3.66(s,3H),3.60-3.56(m,1H),3.31-3.25(m,1H),2.26-2.08(m,2H)。
Example 4: preparation of ethyl 3- (5, 6-dimethoxybenzo [ b ] thiophene-2-carboxamido) propionate (Compound 4)
Figure BDA0002045969190000151
The first step is as follows: preparation of 3- (5, 6-dimethoxybenzo [ b ] thiophene-2-carboxamido) propionic acid
Methyl 3- (5, 6-dimethoxybenzo [ b ] thiophene-2-carboxamido) propionate (compound 3, 2.7g,8.4mmol) was dissolved in methanol (60mL) and water (10mL), and after addition of sodium hydroxide (2.5g,62.5mmol), the reaction was carried out at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure at 40 ℃ to remove a part of methanol, the residue was added to water (150mL), pH was adjusted to 3 with dilute hydrochloric acid, filtered and the solid was washed with water (150mL), and dried under vacuum at 60 ℃ to obtain the title compound (2.0g, yield: 77.4%).
MS m/z(ESI):310.1[M+H]+。
The second step is that: preparation of ethyl 3- (5, 6-dimethoxybenzo [ b ] thiophene-2-carboxamido) propionate
3- (5, 6-Dimethoxybenzo [ b ] thiophene-2-carboxamido) propionic acid (100.0mg, 323.3. mu. mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (93.0mg, 484.9. mu. mol) and 4-dimethylaminopyridine (59.2mg, 484.9. mu. mol) were dissolved in tetrahydrofuran (5mL) and ethanol (1mL) and reacted at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure at 40 ℃ to remove the solvent, and the concentrate was purified by preparative high performance liquid chromatography to give the title compound (41mg, yield: 34.8%).
MS m/z(ESI):338.1[M+H]+。
1H-NMR(400MHz,CDCl3):7.63(s,1H),7.24(s,1H),7.19(s,1H),6.84-6.81(m,1H),4.21-4.16(m,2H),3.96-3.94(m,6H),3.75-3.71(m,2H),2.68-2.65(m,2H),1.30-1.25(m,3H)。
Example 5: preparation of propyl 3- (5, 6-dimethoxybenzo [ b ] thiophene-2-carboxamido) propionate (Compound 5)
Figure BDA0002045969190000152
Using the synthetic route of example 4, the reaction material ethanol of the second step was replaced with n-propanol to give the title compound (52mg, yield: 36.2%).
MS m/z(ESI):352.1[M+H]+。
1H-NMR(400MHz,DMSO-d6):8.72-8.70(m,1H),7.88(s,1H),7.55(s,1H),7.39(s,1H),4.01-3.98(m,2H),3.84-3.3.81(m,6H),3.51-3.46(m,2H),2.62-2.59(m,2H),1.60-1.53(m,2H),0.88-0.85(m,3H)。
Example 6: preparation of isopropyl 3- (5, 6-dimethoxybenzo [ b ] thiophene-2-carboxamido) propionate (Compound 6)
Figure BDA0002045969190000153
Using the synthetic route of example 4, the reaction material ethanol of the second step was replaced with isopropanol to give the title compound (56mg, yield: 35.3%).
MS m/z(ESI):352.1[M+H]+。
1H-NMR(400MHz,CDCl3):7.63(s,1H),7.25(s,1H),7.20(s,1H),6.81(s,1H),5.09-5.03(m,1H),3.97-3.94(m,6H),3.72-3.70(m,2H),2.64-2.61(m,2H),1.27-1.23(m,6H)。
Example 7: preparation of cyclopentyl 3- (5, 6-dimethoxybenzo [ b ] thiophene-2-carboxamido) propionate (Compound 7)
Figure BDA0002045969190000161
Using the synthetic route of example 4, the reaction material ethanol of the second step was replaced with cyclopentanol to give the title compound (42mg, yield: 32.3%).
MS m/z(ESI):378.1[M+H]+。
1H-NMR(400MHz,CDCl3):7.63(s,1H),7.25(s,1H),7.20(s,1H),6.83-6.80(m,1H),5.24-5.20(m,1H),3.97-3.95(m,6H),3.78-3.69(m,2H),2.64-2.61(m,2H),1.92-1.83(m,2H),1.75-1.59(m,6H)。
Example 8: preparation of cyclohexyl 3- (5, 6-dimethoxybenzo [ b ] thiophene-2-carboxamido) propionate (Compound 8)
Figure BDA0002045969190000162
Using the synthetic route of example 4, the reaction material ethanol of the second step was replaced with cyclohexanol to obtain the title compound (38mg, yield: 30.2%).
MS m/z(ESI):392.1[M+H]+。
1H-NMR(400MHz,CDCl3):7.63(s,1H),7.25(s,1H),7.20(s,1H),6.82-6.79(m,1H),4.84-4.78(m,1H),3.97-3.95(m,6H),3.75-3.70(m,2H),2.66-2.63(m,2H),1.88-1.85(m,2H),1.75-1.70(m,3H),1.48-1.23(m,5H)。
Example 9: preparation of benzyl 3- (5, 6-dimethoxybenzo [ b ] thiophene-2-carboxamido) propionate (Compound 9)
Figure BDA0002045969190000163
Using the synthetic route of example 4, the reaction material ethanol of the second step was replaced with benzyl alcohol to give the title compound (62mg, yield: 37.5%).
MS m/z(ESI):400.1[M+H]+。
1H-NMR(400MHz,CDCl3):7.55(s,1H),7.37-7.33(m,5H),7.25(s,1H),7.19(s,1H),6.72(t,J＝6.0Hz,1H),5.17(s,2H),3.97(s,3H),3.95(s,3H),3.77-3.72(m,2H),2.74-2.71(m,2H)。
Example 10: preparation of methyl 3- (N-methyl-5, 6-dimethoxy-benzo [ b ] thiophene-2-carboxamido) propionate (Compound 10)
Figure BDA0002045969190000171
5, 6-Dimethoxybenzo [ b ] thiophene-2-carboxylic acid (1.0g,4.2mmol) and methyl 3-methylaminopropionate (737.5mg,6.3mmol) were dissolved in tetrahydrofuran (15mL), HATU (3.2g,8.4mmol) and N, N-diisopropylethylamine (1.6g,12.6mmol) were added, and the mixture was heated to 60 ℃ and reacted for 4 hours. The reaction solution was poured into water (100mL), extracted three times with ethyl acetate (25mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatography to give the title compound (0.75g, yield: 52.9%).
MS m/z(ESI):338.1[M+H]+。
1H-NMR(400MHz,DMSO-d6):7.66(s,1H),7.55(s,1H),7.41(s,1H),3.84-3.82(m,6H),3.74(s,2H),3.61(s,3H),3.19(s,3H),2.71-2.68(m,2H)。
Example 11: preparation of ethyl 3- (N-methyl-5, 6-dimethoxy-benzo [ b ] thiophene-2-carboxamido) propionate (Compound 11)
Figure BDA0002045969190000172
The first step is as follows: preparation of 3- (N-methyl-5, 6-dimethoxy-benzo [ b ] thiophene-2-carboxamido) propionic acid
Methyl 3- (N-methyl-5, 6-dimethoxy-benzo [ b ] thiophene-2-carboxamido) propionate (1.2g,3.6mmol) was dissolved in methanol (60mL) and water (10mL), and after addition of sodium hydroxide (1.1g,26.7mmol), the mixture was reacted at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure at 40 ℃ to remove a part of methanol, the residue was added to water (200mL), adjusted to pH 3 with dilute hydrochloric acid, filtered and the solid was washed with water (150mL), and dried under vacuum at 60 ℃ to obtain the title compound (0.98g, yield: 84.2%).
MS m/z(ESI):324.1[M+H]+。
The second step is that: preparation of ethyl 3- (N-methyl-5, 6-dimethoxy-benzo [ b ] thiophene-2-carboxamido) propionate
3- (N-methyl-5, 6-dimethoxy-benzo [ b ] thiophene-2-carboxamido) propionic acid (100.0mg, 309.2. mu. mol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (89.0mg, 463.8. mu. mol) and 4-dimethylaminopyridine (39.5mg, 463.8. mu. mol) were dissolved in tetrahydrofuran (5mL) and ethanol (1mL) and reacted at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure at 40 ℃ to remove the solvent, and the concentrate was purified by preparative high performance liquid chromatography to give the title compound (35mg, yield: 36.5%).
MS m/z(ESI):352.1[M+H]+。
1H-NMR(400MHz,CDCl3):7.47(s,1H),7.25(s,1H),7.21(s,1H),4.16(q,J＝7.2Hz,2H),3.97(s,3H),3.95(s,3H),3.88-3.85(m,2H),3.28(s,3H),2.74-2.71(m,2H),1.27(t,J＝7.2Hz,3H)。
Example 12: preparation of isopropyl 3- (N-methyl-5, 6-dimethoxy-benzo [ b ] thiophene-2-carboxamido) propionate (Compound 12)
Figure BDA0002045969190000173
Using the synthetic route of example 11, the reaction material ethanol of the second step was replaced with isopropanol to give the title compound (42mg, yield: 37.8%).
MS m/z(ESI):366.1[M+H]+。
1H-NMR(400MHz,CDCl3):7.47(s,1H),7.25(s,1H),7.20(s,1H),5.06-5.00(m,1H),3.96(s,3H),3.94(s,3H),3.86(s,2H),3.28(s,3H),2.70(s,2H),1.25-1.24(m,6H)。
Example 13: preparation of ethyl 3- (N-methyl-6-hydroxy-5-methoxy-benzo [ b ] thiophene-2-carboxamido) propionate (Compound 13)
Figure BDA0002045969190000181
Ethyl 3- (N-methyl-5, 6-dimethoxy-benzo [ b ] thiophene-2-carboxamido) propionate (220mg, 626.1. mu. mol) was dissolved in methylene chloride (10mL), and after slowly adding aluminum trichloride (840mg,6.3mmol) with stirring in an ice bath, it was allowed to stand at room temperature for 20 hours to react. The reaction solution was concentrated under reduced pressure at 40 ℃ to remove the solvent, the residue was added to water (30mL), adjusted to pH 3 with dilute hydrochloric acid, extracted three times with ethyl acetate (25mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatography to give the title compound (80mg, yield: 36.0%).
MS m/z(ESI):338.1[M+H]+。
1H-NMR(400MHz,DMSO-d6):9.25(s,1H),7.58(s,1H),7.50(s,1H),7.23(s,1H),4.07(q,J＝7.2Hz,2H),3.85(s,3H),3.73(s,2H),3.18(s,3H),2.68-2.65(m,2H),1.17(t,J＝7.2Hz,3H)。
Example 14: preparation of ethyl 3- (N-methyl-6- (3-hydroxypropoxy) -5-methoxy-benzo [ b ] thiophene-2-carboxamido) propionate (Compound 14)
Figure BDA0002045969190000182
Ethyl 3- (N-methyl-6-hydroxy-5-methoxy-benzo [ b ] thiophene-2-carboxamido) propionate (500mg,1.5mmol) and 3-bromopropanol (309.0mg,2.2mmol) were dissolved in acetone (10mL), and after potassium carbonate (409.0mg,3.0mmol) and potassium iodide (49.2mg, 296.4. mu. mol) were added in this order, the temperature was raised to 60 ℃ to react for 15 hours. The reaction solution was concentrated under reduced pressure at 40 ℃ to remove the solvent, the residue was added to water (100mL), extracted three times with ethyl acetate (25mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure, and the concentrate was purified by preparative high performance liquid chromatography to give the title compound (500mg, yield: 81.0%).
MS m/z(ESI):396.1[M+H]+。
1H-NMR(400MHz,DMSO-d6):7.65(s,1H),7.55(s,1H),7.41(s,1H),4.58-4.55(m,1H),4.12-4.04(m,4H),3.82(s,3H),3.75(s,2H),3.58(q,J＝6.0Hz,2H),3.19(s,3H),2.69-2.66(m,2H),1.94-1.88(m,2H),1.18(t,J＝7.6Hz,3H)。
Example 15: preparation of N-methyl-N- ((1-methyl-1H-pyrazol-3-yl) methyl) -5, 6-dimethoxy-benzo [ b ] thiophene-2-carboxamide (Compound 23)
Figure BDA0002045969190000183
Using the synthetic route of example 1, the starting material methyl 3-aminopropionate hydrochloride was replaced with N-methyl-1- (1-methyl-1H-pyrazol-3-yl) methylamine to give the title compound (78mg, yield: 38.3%).
MS m/z(ESI):346.1[M+H]+。
1H-NMR(400MHz,DMSO-d6):7.72(s,1H),7.67(s,1H),7.56(s,1H),7.39(s,1H),6.19(s,1H),4.65(s,2H),3.83-3.80(m,9H),3.11(s,3H)。
Biological assay
Control compound 1 used in the following experimental examples:
Figure BDA0002045969190000191
synthesized according to the prior art; control compound 2: ADU-S100(1638750-96-5) was purchased from MCE.
EXAMPLE 1 agonism of Compounds on STING-mediated Interferon (IFN) signaling pathway
The experiment is carried out by using THP1-BlueTMThe activity of SEAP (secreted embryonic alkaline phosphatase) reporter gene regulated by IFN regulatory factor (interferon regulatory factor) was measured in ISG cells (invitrogen) to evaluate the agonism of test compounds at the cellular level on STING-mediated IFN signaling pathway.
THP1-Blue in logarithmic growth phaseTMISG cells (InvivoGen) were centrifuged and resuspended in cell culture medium to a density of 2X 106Each/ml was inoculated at 50. mu.L/well into a 96-well cell culture plate (Corning). Control compounds 1, 2 and the compound of the invention stock solution were gradient diluted with cell culture medium to 2 working concentration dilutions at concentrations of 200, 66.67, 22.22, 7.41, 2.47, 0.82, 0.27 and 0 μ M, 50 μ L/well compound 2 working concentration dilution was added to 96-well plates (50 μ L of 2% DMSO medium was added to negative control wells), and the plates were placed in a cell incubator for incubation for 16 h. After completion of cell incubation, 10. mu.L of the cell culture supernatant was transferred to a 96-well plate, and 90. mu.L/well of QUANTI-blue (InvivoGen) solution was added thereto, incubated at 37 ℃ for 3 hours, and the absorbance value (OD) at 620nm was read using a microplate reader 620nm). EC was calculated by Graphpad Prism software fitting50The experimental results are shown in table one.
TABLE I test Compounds for agonism of STING-mediated Interferon (IFN) signaling pathway
Compound numbering EC50(μM) Emax(OD620nm)
3 0.62 1.99
4 1.28 2.06
5 1.24 1.86
9 2.04 1.87
10 0.98 1.81
11 1.09 2.15
12 0.40 2.12
13 0.54 1.63
14 1.81 2.04
Control Compound 1 4.95 1.49
Control Compound 2 3.88 2.03
Remarking: EC (EC)50Refers to OD produced by compound stimulation620nmValue up to EmaxHalf the time the concentration of the compound; emaxRefers to the highest OD produced by stimulation of a compound620nmThe value is obtained.
The results show that the compounds of the present invention (especially compounds 3, 10, 12 and 13, etc.) are directed to THP1-BlueTMSTING-mediated Interferon (IFN) signaling pathways in ISG cells have strong agonistic effects.
EXAMPLE 2 agonism of Compounds on IFN- β, a downstream cytokine from STING
This experiment evaluated the agonistic effect of compounds on STING proteins at the cellular level by detecting changes in the downstream cytokine IFN- β of STING using ELISA detection.
THP-1 cells (Nanjing Kebai) in logarithmic growth phase were centrifuged and resuspended in cell culture medium to a density of 8X 106cells/mL, 250 μ Ι/well cell suspension was seeded into 24-well cell culture plates (Corning); the test compound was diluted to 2 × working solution concentration with cell culture medium. Mu.l of the test compound dilution was added to a 24-well plate (250. mu.l of 2% DMSO culture medium was added to the negative control wells) and mixed well with the cells, and the 24-well plate was placed in a cell incubator and incubated for 8 h. After the incubation is finished, centrifuging for 5min at the rotating speed of 300g, and collecting supernatant; sucking 100 μ l of cell culture solution, incubating primary antibody and HRP-labeled secondary antibody according to the procedure of Human IFN- β ELISA kit (PBL-41410), developing color, and reading absorbance (OD) at 450nm 450nm). IFN- β concentrations were calculated from standard curves using Graphpadprism software.

Claims (13)

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof:
Figure FDA0002045969180000011
wherein the content of the first and second substances,
l is (C (R)5)2)m；
R1Each independently selected from H, halogen, cyano, -ORa、-SRa、-S(O)Ra、-S(O)2Ra、-NRaRb、-C(O)-NRaRb、-N(Ra)-C(O)-Rb、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Haloalkyl, cyano, hydroxy and C1-6An alkoxy group;
R2selected from H, halogen, cyano, -ORa、-NRaRb、C1-6Alkyl radical, C3-10Cycloalkyl and 3-10 membered heterocyclyl, said C1-6Alkyl radical, C3-10The cycloalkyl and 3-10 membered heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C1-6Haloalkyl, cyano, hydroxy and C1-6An alkoxy group;
R3selected from H, C1-6Alkyl radical, C3-10Cycloalkyl and 3-10 membered heterocyclyl, said C1-6Alkyl radical, C3-10Each cycloalkyl or 3-10 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, C 1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -N (R)a)(Rb)、-C(O)2Raand-S (O)2Ra；
R4Selected from H, C1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, -OR6and-C (O)2R6Said C is1-6Alkyl radical, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more RcSubstitution;
Rceach independently selected from halogen, cyano, hydroxy, -NRaRb、-C(O)2Ra、C1-6Alkyl radical, C1-6Alkoxy and C1-6Haloalkoxy, said C1-6Alkyl radical, C1-6Alkoxy and C1-6Haloalkoxy is each optionally substituted with one or more substituents independently selected from the group consisting of: cyano, -ORa、-NRaRb、-C(O)2Ra、C1-6Alkoxy and-S (O)2Ra；
R5Each independently selected from H, halogen, cyano, -ORa、-SRa、-NRaRb、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C1-6Alkyl radical, C3-6Cycloalkyl, 3-6 membered heterocyclyl, C6-10Aryl, 5-10 membered heteroaryl, C1-6Haloalkyl, cyano, hydroxy, C1-6Alkoxy and-OR a(ii) a Or two R5Together with the carbon atom to which they are attached form C3-10Cycloalkyl or 3-10 membered heterocyclyl; or any one of R5And R3Together with atomic co-shape between themTo a 3-10 membered heterocyclic group;
R6selected from H, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-to 10-membered heteroaryl, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, -ORa、-SRa、-S(O)Ra、-S(O)2Ra、-NRaRb、-C(O)-Ra、-C(O)2Ra、-C(O)-NRaRb、-N(Ra)-C(O)-Rb、C1-6Alkyl radical, C1-6Haloalkyl, C3-10Cycloalkyl, 3-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl;
Raand RbEach independently selected from H, C1-6Alkyl radical, C3-10Cycloalkyl and C1-6Alkoxy radical, said C1-6Alkyl radical, C3-10Cycloalkyl and C1-6Each alkoxy group is optionally substituted with one or more substituents independently selected from the group consisting of hydroxy and halogen;
or Ra、RbTogether with the nitrogen atom to which they are attached form a 3-7 membered heterocyclyl;
m is selected from 1, 2 and 3;
n is selected from 0, 1, 2, 3 and 4.
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,
R4Is optionally substituted by one or more C1-6Alkyl-substituted 5-6 membered heteroaryl, said C1-6Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: cyano, -ORa、-C(O)2Raand-S (O)2Ra；
Preferably, R4Is optionally substituted by one or more C1-6Alkyl-substituted pyrazolyl radical, C1-6Alkyl is optionally substituted with one or more substituents independently selected from the group consisting of: cyano, hydroxy, -C (O)2H and-S (O)2CH3。
3. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,
R4is-C (O)2R6Wherein R is6Is selected from C1-6Alkyl radical, C3-6Cycloalkyl and 5-6 membered heterocyclyl, said C1-6Alkyl radical, C3-6The cycloalkyl and 5-6 membered heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of: -ORa、-NRaRb、C6-10Aryl and-C (O)2Ra(ii) a Preferably, R6Is selected from C1-6Alkyl radical, C5-6Cycloalkyl and tetrahydropyranyl, said C1-6Alkyl radical, C5-6The cycloalkyl and tetrahydropyranyl groups are each optionally substituted with 1 to 4 substituents independently selected from: -OH, -NH2Phenyl and-C (O)2H。
4. The compound of claim 1 or 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (II):
Figure FDA0002045969180000021
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,
R5each independently selected from H and C1-6An alkyl group; or any one of R5And R3Together with the atoms between them form a 5-6 membered heterocyclyl;
preferably, R5Is H; or any one of R5And R3Together with the atoms between them, form a pyrrolidinyl group.
6. The compound of claim 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (III):
Figure FDA0002045969180000022
7. the compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound has the structure of formula (III-1):
Figure FDA0002045969180000031
8. the compound of any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein,
R1is-ORa；
R2Is H;
R3selected from H, C1-3Alkyl and C3-6Cycloalkyl radical, said C1-3Alkyl and C3-6Each cycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, cyano, hydroxy, C1-3Alkoxy, -C (O)2Raand-S (O)2Ra；
R6Is selected from C1-3Alkyl radical, C5-6Cycloalkyl and tetrahydropyranyl, said C1-3Alkyl radical, C5-6The cycloalkyl and tetrahydropyranyl groups are each optionally substituted with 1 to 4 substituents independently selected from: -OH, -NH2Phenyl and-C (O)2H; and is
RaAnd RbEach independently selected from H, C1-6Alkyl and hydroxy C1-6An alkyl group.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, wherein the compound is selected from the group consisting of:
Figure FDA0002045969180000032
Figure FDA0002045969180000041
10. a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
11. A kit comprising a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, or a pharmaceutical composition according to claim 10.
12. Use of a compound according to any one of claims 1-9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 10, for the manufacture of a medicament for the prevention or treatment of a STING-mediated related disease, wherein the medicament is preferably administered by oral, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal route, wherein the STING-mediated related disease is preferably a tumor.
13. A process for preparing a compound according to any one of claims 1-9, comprising the steps of:
Figure FDA0002045969180000042
wherein R is1、R2、R3、R4L and n are as defined in claim 1;
step (1): reacting compound IN-1 with methyl thioglycolate to obtain compound IN-2;
Step (2): subjecting the compound IN-2 to hydrolysis reaction to obtain a compound IN-3;
and (3): compound IN-3 is reacted with compound IN-4 to give compound I.
CN201910357790.1A 2019-04-30 2019-04-30 Amide compound and preparation method and application thereof Active CN111848572B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910357790.1A CN111848572B (en) 2019-04-30 2019-04-30 Amide compound and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910357790.1A CN111848572B (en) 2019-04-30 2019-04-30 Amide compound and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN111848572A true CN111848572A (en) 2020-10-30
CN111848572B CN111848572B (en) 2023-03-31

Family

ID=72965510

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910357790.1A Active CN111848572B (en) 2019-04-30 2019-04-30 Amide compound and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN111848572B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024067709A1 (en) * 2022-09-30 2024-04-04 苏州阿尔脉生物科技有限公司 Pyridinylamide derivative, pharmaceutical composition comprising same, and medical use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1901902A (en) * 2003-10-09 2007-01-24 阿托恩药品公司 Thiophene and benzothiophene hydroxamic acid derivatives
US20180093964A1 (en) * 2016-10-04 2018-04-05 Merck Sharp & Dohme Corp. BENZO[b]THIOPHENE COMPOUNDS AS STING AGONISTS

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1901902A (en) * 2003-10-09 2007-01-24 阿托恩药品公司 Thiophene and benzothiophene hydroxamic acid derivatives
US20180093964A1 (en) * 2016-10-04 2018-04-05 Merck Sharp & Dohme Corp. BENZO[b]THIOPHENE COMPOUNDS AS STING AGONISTS

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
REGISTRY: "RN 2033264-94-5、RN 1575143-94-0等", 《REGISTRY》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024067709A1 (en) * 2022-09-30 2024-04-04 苏州阿尔脉生物科技有限公司 Pyridinylamide derivative, pharmaceutical composition comprising same, and medical use thereof

Also Published As

Publication number Publication date
CN111848572B (en) 2023-03-31

Similar Documents

Publication Publication Date Title
CN109665968B (en) Fused ring compound, preparation method and application thereof
JP5820921B2 (en) 1,2-disubstituted heterocyclic compounds
WO2020094104A1 (en) Nitrogen-containing fused heterocyclic shp2 inhibitor compound, preparation method, and use
KR101982912B1 (en) Fused heterocyclic compound, preparation method therefor, pharmaceutical composition, and uses thereof
CN113518776B (en) Benzothiophene compound and preparation method and application thereof
CN111315747A (en) Dihydropyrazolone pyrimidine compound and preparation method and application thereof
CN112898284B (en) Compound for inhibiting RNA helicase DHX33 and application thereof
CN112430234A (en) Novel KRAS G12C protein inhibitor and preparation method and application thereof
CN112424200A (en) Iminosulfones compound as bromodomain protein inhibitor, pharmaceutical composition and medical application thereof
CN117460737A (en) Heteroaromatic compounds, method for the production and use thereof
KR102238012B1 (en) Carboline derivatives, bromodomain inhibitors
EP3936509A1 (en) Fgfr4 kinase inhibitor, preparation method therefor and use thereof
EP3929185A1 (en) Nitrogen-containing fused cyclic compound, preparation method therefor and use thereof
JP2022542162A (en) Heterocyclic amide compound and its production method and use
CN111848572B (en) Amide compound and preparation method and application thereof
CN111848573B (en) Benzothiophene amide compound and preparation method and application thereof
CN116120296A (en) Polycyclic compound, pharmaceutical composition containing polycyclic compound, preparation method and application of polycyclic compound
WO2019080724A1 (en) Nucleoside phosphate compound and preparation method therefor and use thereof
RU2712140C2 (en) Compositions for treating fibrosis and fibrosis-related conditions
JP7329052B2 (en) Fluorine-containing substituted benzothiophene compounds and pharmaceutical compositions and applications thereof
KR20230154194A (en) Oxadiazolyl dihydropyrano[2,3-b]pyridine inhibitor of HIPK2 for the treatment of renal fibrosis
CN114555565A (en) Nitrogen-containing heterocyclic compound, preparation method and application thereof
JP7349572B2 (en) Crosslinked ring-fused formylpyridine derivatives and their applications
CN118108716A (en) Benzothiophene compound and preparation method and application thereof
CN110724076B (en) Para-aryldiamide compound, pharmaceutical composition containing same, preparation method and application thereof

Legal Events

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