WO2021068950A1 - 酰胺类化合物及其作为sting抑制剂的医药用途 - Google Patents

酰胺类化合物及其作为sting抑制剂的医药用途 Download PDF

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WO2021068950A1
WO2021068950A1 PCT/CN2020/120279 CN2020120279W WO2021068950A1 WO 2021068950 A1 WO2021068950 A1 WO 2021068950A1 CN 2020120279 W CN2020120279 W CN 2020120279W WO 2021068950 A1 WO2021068950 A1 WO 2021068950A1
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孙宏斌
王琛
尤燕平
孙立
洪泽
潘燕红
隋齐邦
臧永军
袁浩亮
温小安
许庆龙
柳军
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China Pharmaceutical University
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    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • 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
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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 ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • 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
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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 ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to a new type of amide compound or its pharmaceutically acceptable salt or solvate, which can act on transmembrane protein 173 (TMEM173), also known as STING (stimulator of interferon gene) ), as well as the preparation and its medical use.
  • TMEM173 transmembrane protein 173
  • STING stimulation of interferon gene
  • the present invention also relates to the use of the compound in the preparation of drugs for preventing or treating STING-mediated diseases.
  • PRRs pattern recognition receptors
  • PAMPs non-self pathogen-related molecular patterns
  • DAMPs damage-associated molecular patterns secreted by cells under abnormal conditions (stress, damage, aging, or death) will also be recognized by pattern recognition receptors to activate the immune system and promote Cell regeneration and repair after injury (Science, 2002, 296(5566): 301-305).
  • DNA in the cytoplasm plays an important role in the activation of the innate immune system (Curr Opin Immunol, 2018, 55: 31-37).
  • the DNA receptor protein cGAS (Cyclic AMP-GMP synthase) in the cytoplasm can recognize abnormally exposed cytoplasmic DNA molecules, and use ATP and GTP as substrates to catalyze the synthesis of 2',3'-cGAMP molecules (2'-3'/ 3'-5'cyclic GMP-AMP).
  • the signal molecules c-di-AMP and c-di-GMP formed in the metabolism of 2’, 3’-cGAMP and bacteria are called cyclic dinucleotides (CDNs).
  • CDNs molecules can specifically bind to the "V"-shaped pocket formed by the dimer of the endoplasmic reticulum regulatory protein STING (also known as TMEM173, MITA, ERIS or MPYS) (Nature, 2008, 455(7213): 674 -678; Nature, 2011, 478(7370): 515-518), thereby inducing the multimerization activation of STING protein (Cell, 2013, 154(4): 748-62).
  • STING also known as TMEM173, MITA, ERIS or MPYS
  • the multimerized STING protein transfers from the endoplasmic reticulum to the Golgi compartment, and in this process recruits the downstream kinase protein TBK1 and the transcription factor IRF3.
  • TBK1 catalyzes the phosphorylation of STING and IRF3 after autophosphorylation is activated (Nature, 2019 , 567(7748):394-398; Nature, 2019,569(7758):718-722).
  • Phosphorylated IRF3 further dimerizes into the nucleus to promote the expression of type I interferons and related immune factors (interferon stimulated genes, ISGs).
  • STING protein can also activate the NF- ⁇ B signaling pathway by recruiting TBK1 and TRAF6 molecules, and promote the expression of inflammatory factors such as TNF- ⁇ and IL-6 (J Virol, 2014, 88(10): 5328-41).
  • AGS syndrome (Aicardi-Goutines syndrome) is a rare systemic autoimmune disease caused by TREX1, RNASE H2, SAMHD1, ADAR or IFIH1 gene mutations (Am J Med Genet A, 2015, 167A(2): 296 -312).
  • TREX1 gene mutations have also been found in patients with systemic lupus erythematosus (SLE), and 50%-60% of SLE patients have high expression of type I interferon in the serum (Nat Rev Rheumatol, 2018, 14(4) :214-228). It was found in patients with Bloom syndrome that mutations in the BLM protein lead to the formation of micronuclei, which in turn activates the STING signaling pathway to induce high expression of IFNs and ISGs in the patient's serum (J Exp Med, 2019, 216(5): 1199-1213).
  • SAVI STING-associated vasculopathy with onset in infection
  • STING protein N Engl J Med, 2014, 371(6): 507-518
  • inflammation-related disease models such as skin cancer induction (Nat Commun, 2014, 5: 5166), tumor metastasis (Nature, 2018, 553(7689): 467-472), and progeria (Nature, 2017, 550(7676):402-406), sepsis (Shock, 2017, 47(5): 621-631), acute pancreatitis (Gastroenterology, 2018, 154(6): 1822-1835), Parkinson's disease ( Nature, 2018, 561(7722): 258-262), non-alcoholic fatty liver and liver fibrosis (Gastroenterology, 2018, 155(6): 1971-1984; Proceedings of the National Academy of Sciences, 2017, 114(46) ): 12196-12201), pneumonia (Nature Communications, 2018,
  • the present invention provides a novel amide compound or a pharmaceutically acceptable salt or ester or solvate thereof.
  • the amide compound of the present invention can be used as a novel small molecule inhibitor targeting STING, which can inhibit the activation of the STING signal pathway, and thus can be used to prepare drugs for preventing or treating STING-mediated diseases.
  • the invention also provides preparation methods, pharmaceutical combinations and medical uses of the amide compounds and intermediates thereof.
  • the present invention provides an amide compound represented by the following formula I or formula II or a pharmaceutically acceptable salt or ester or solvate thereof:
  • R a is substituted or unsubstituted C 1 -C 4 alkyl, cyclopropyl, trifluoromethyl, vinyl, substituted or unsubstituted aryl or heteroaryl, NH 2 , C 1 -C 4 alkyl Amino, hydroxy-C 1 -C 3 alkylamino or morpholinyl, the aryl or heteroaryl is phenyl, naphthyl, pyridyl, pyrazolyl, furyl, or thienyl, the substitution
  • the C 1 -C 4 alkyl group is substituted by one or two or three substituents independently selected from the following: F, Cl, NH 2 , OH, diethanolamine group, methanesulfonamide group, acetamide group, Aminoacetamido, pyrrolidin-1-yl, piperidin-1-yl, substituted piperidin-1-yl, piperazin-1-yl, substituted piperazin-1
  • R b is H, C 1 -C 3 alkyl or C 1 -C 3 alkylcarbonyl
  • R 2 is H, OH, C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkoxycarbonyl, C(O)OH, C(O)NH 2 or C (O)NHSO 2 CH 3 ;
  • R 3 is H, OH, C 1 -C 3 alkyl, COOCH 3 , COOH, CONH 2 , F, Cl, Br or I;
  • R 4 is H or C 1 -C 3 alkyl
  • Ar is phenyl or pyridyl
  • R 5 is substituted or unsubstituted phenyl,
  • the substituted phenyl group is substituted by one or two substituents independently selected from the following: F, Cl, Br, I, CN, NO 2 , NH 2 , OH, acetamido, CF 3 , CF 2 CF 3.
  • OCF 3 OCF 2 CF 3 , C(O)OH, C(O)NH 2 , C(O)NHOH, C 1 -C 3 alkyl, cyclopropyl, substituted or unsubstituted phenyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl or sulfamoyl;
  • R 6 and R 7 are each independently selected from: H, F, Cl, Br, CN, OH, NO 2 , CF 3 , OCF 3 , C 1 -C 3 alkoxy, morpholin-4-yl or substituted C 2 -C 3 alkoxy, the substituted C 2 -C 3 alkoxy refers to C 2 -C 3 alkyl group with halogen, NH 2 , OH, CN, carboxyl, carboxylate, methylsulfonyl , Pyrrolidin-1-yl, piperidin-1-yl, substituted piperidin-1-yl, piperazin-1-yl, substituted piperazin-1-yl, morpholin-4-yl, thiomorph Lin-1,1-dioxo-4-yl, N,N-dimethylamino, N,N-diethylamino, trimethylammonium, diethanolamine, nitrogen-containing aromatic heterocyclic group, phosphorus Amido or C 1 -C
  • every two of R 5 , R 6 and R 7 together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, A substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocyclic alkene ring.
  • the amide compound or a pharmaceutically acceptable salt or ester or solvate thereof that is, in the formula I or formula II:
  • R a is substituted or unsubstituted C 1 -C 4 alkyl, cyclopropyl, trifluoromethyl, vinyl, substituted or unsubstituted aryl or heteroaryl, NH 2 , C 1 -C 4 alkyl Amino, hydroxy-C 1 -C 3 alkylamino or morpholinyl, the aryl or heteroaryl is phenyl, naphthyl, pyridyl, pyrazolyl, furyl, or thienyl, the substitution
  • the C 1 -C 4 alkyl group is substituted by one or two or three substituents independently selected from the following: F, Cl, NH 2 , OH, diethanolamine group, methanesulfonamide group, acetamide group, Aminoacetamido, pyrrolidin-1-yl, piperidin-1-yl, substituted piperidin-1-yl, piperazin-1-yl, substituted piperazin-1
  • R b is H, C 1 -C 3 alkyl or C 1 -C 3 alkylcarbonyl
  • R 2 is H, OH, C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkoxycarbonyl, C(O)OH, C(O)NH 2 or C (O)NHSO 2 CH 3 ;
  • R 3 is H, OH, C 1 -C 3 alkyl, COOCH 3 , COOH, CONH 2 , F or Cl;
  • R 4 is H
  • Ar is phenyl or pyridyl
  • R 5 is substituted or unsubstituted phenyl,
  • the substituted phenyl group is substituted by one or two substituents independently selected from the following: F, Cl, Br, I, CN, NO 2 , NH 2 , OH, acetamido, CF 3 , CF 2 CF 3.
  • OCF 3 OCF 2 CF 3 , C(O)OH, C(O)NH 2 , C(O)NHOH, C 1 -C 3 alkyl, cyclopropyl, substituted or unsubstituted phenyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl or sulfamoyl;
  • R 6 and R 7 are each independently selected from: H, F, Cl, Br, CN, OH, NO 2 , CF 3 , OCF 3 , C 1 -C 3 alkoxy, morpholin-4-yl or substituted C 2 -C 3 alkoxy, the substituted C 2 -C 3 alkoxy refers to C 2 -C 3 alkyl group with halogen, NH 2 , OH, CN, carboxyl, carboxylate, methylsulfonyl , Piperidin-1-yl, substituted piperidin-1-yl, piperazin-1-yl, substituted piperazin-1-yl, morpholin-4-yl, thiomorpholine-1,1-di Oxo-4-yl, N,N-dimethylamino, diethanolamine, nitrogen-containing aromatic heterocyclic group, phosphoramido or C 1 -C 3 alkoxy;
  • every two of R 5 , R 6 and R 7 together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, A substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocyclic alkene ring.
  • the amide compound or a pharmaceutically acceptable salt or ester or solvate thereof is a benzamide compound represented by the following formula III or a pharmaceutically acceptable salt or ester or solvate thereof:
  • R a is substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted aryl or heteroaryl, NH 2 , C 1 -C 3 alkylamino, hydroxy-C 1 -C 3 alkylamino Or morphinyl, the aryl or heteroaryl is phenyl, naphthyl, pyridyl or thienyl, and the substituted C 1 -C 3 alkyl group is independently selected by one or two or three Substituted from the following substituents: F, NH 2 , OH or dimethylamino, the substituted aryl or heteroaryl group is substituted by one or two substituents independently selected from the following: C 1- C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, F, Cl, Br, I, CN, NO 2 , NH 2
  • R b is H, C 1 -C 3 alkyl or C 1 -C 3 alkylcarbonyl
  • R 2 is H, OH, C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkoxycarbonyl, C(O)OH, C(O)NH 2 or C (O)NHSO 2 CH 3 ;
  • R 3 is H, C 1 -C 3 alkyl, COOCH 3 , COOH, CONH 2 , F, Cl, Br or I;
  • R 4 is H or C 1 -C 3 alkyl
  • R 5 is substituted or unsubstituted phenyl,
  • the substituted phenyl group is substituted by one or two substituents independently selected from the following: F, Cl, Br, I, CN, NO 2 , NH 2 , OH, acetamido, CF 3 , CF 2 CF 3.
  • R 6 and R 7 are each independently selected from: H, F, Cl, Br, CN, NO 2 , CF 3 , OCF 3 or C 1 -C 3 alkoxy;
  • every two of R 5 , R 6 and R 7 together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, A substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocyclic alkene ring.
  • R a is substituted or unsubstituted C 1 -C 3 alkyl, substituted or unsubstituted aryl or heteroaryl, NH 2 , C 1 -C 3 alkylamino, hydroxy-C 1 -C 3 alkylamino Or morphinyl, the aryl or heteroaryl is phenyl, naphthyl, pyridyl or thienyl, and the substituted C 1 -C 3 alkyl group is independently selected by one or two or three Substituted from the following substituents: F, NH 2 , OH or dimethylamino, the substituted aryl or heteroaryl group is substituted by one or two substituents independently selected from the following: C 1- C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, C 1 -C 3 alkylsulfonyl, F, Cl, Br, I, CN, NO 2 , NH 2
  • R b is H, C 1 -C 3 alkyl or C 1 -C 3 alkylcarbonyl
  • R 2 is H, OH, C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkoxycarbonyl, C(O)OH, C(O)NH 2 or C (O)NHSO 2 CH 3 ;
  • R 3 is H, C 1 -C 3 alkyl, COOCH 3 , COOH, CONH 2 , F or Cl;
  • R 4 is H
  • R 5 is substituted or unsubstituted phenyl,
  • the substituted phenyl group is substituted by one or two substituents independently selected from the following: F, Cl, Br, I, CN, NO 2 , NH 2 , OH, acetamido, CF 3 , CF 2 CF 3.
  • R 6 and R 7 are each independently selected from: H, F, Cl, Br, CN, NO 2 , CF 3 , OCF 3 or C 1 -C 3 alkoxy;
  • every two of R 5 , R 6 and R 7 together with the atoms to which they are attached form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, A substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring or a substituted or unsubstituted heterocyclic alkene ring.
  • the amide compound also includes its metabolites, metabolic precursors or prodrugs.
  • the amide compound or a pharmaceutically acceptable salt or ester or solvate or metabolite or metabolic precursor or prodrug thereof is selected from any one of the compounds shown in Table 1 below:
  • the compounds of the present invention can also be used as pharmaceutical salts.
  • the salt may be the acid salt of at least one of the following acids: galactonic acid, D-glucuronic acid, glycerophosphoric acid, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5-naphthalene Disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecyl sulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, Malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, methanesulfonic acid, niacin, nitric acid, orotic acid, ox
  • the salt can also be a compound of the present invention and metal (including sodium, potassium, calcium, etc.) ions or pharmaceutically acceptable amines (including ethylenediamine, tromethamine, etc.), ammonium ions or choline.
  • metal including sodium, potassium, calcium, etc.
  • pharmaceutically acceptable amines including ethylenediamine, tromethamine, etc.
  • ammonium ions or choline can also be formulated into pharmaceutical compositions in the form of esters, prodrugs, N-oxides or their solvates.
  • the present invention includes all prodrugs of the compounds of the present invention, which can (directly or indirectly) provide the compounds of the present invention or their active metabolites or residues after being administered to the human or animal body.
  • the present invention includes various deuterated forms of the compounds of the present invention.
  • Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom.
  • the present invention provides the use of the amide compound of formula I or formula II or formula III or a pharmaceutically acceptable salt or ester or solvate thereof in the preparation of a medicament for inhibiting activation of the STING signal pathway.
  • the present invention provides the use of the amide compound of formula I or formula II or formula III or a pharmaceutically acceptable salt or ester or solvate thereof in the preparation of a medicine for preventing or treating STING-mediated diseases.
  • the STING-mediated diseases include one or more of infectious diseases, inflammatory diseases, autoimmune diseases, organ fibrotic diseases, cancer, and precancerous syndromes.
  • the present invention provides the use of the amide compound of formula I or formula II or formula III or a pharmaceutically acceptable salt or ester or solvate thereof in the preparation of immune adjuvant drugs.
  • the present invention is based on the crystal structure of the C-terminal domain of human STING protein (hSTING-CTD-139-379, PDB: 4EF5), using The Glide docking module in, has carried out computer-aided drug design and molecular docking research of active compounds.
  • the docking results indicate that the amide compound of the present invention may inhibit the activation of the STING signal pathway by directly binding to the STING protein and maintaining its dimer conformation in a resting state. Therefore, the amide compound of the present invention can be used to prepare drugs that inhibit the activation of the STING signal pathway and prepare drugs for preventing or treating STING-mediated diseases.
  • the compounds of the present invention can be used to prevent or treat infectious diseases, including: Mycobacterium tuberculosis infection, chlamydia infection, herpes virus (herpes simplex virus) infection, adenovirus infection, hepatitis B virus infection, orthomyxovirus infection and coronavirus infection.
  • infectious diseases including: Mycobacterium tuberculosis infection, chlamydia infection, herpes virus (herpes simplex virus) infection, adenovirus infection, hepatitis B virus infection, orthomyxovirus infection and coronavirus infection.
  • the compounds of the present invention can be used to prevent or treat inflammatory diseases, including: metabolic inflammation-related diseases (such as insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, myocardial Ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, ischemic encephalopathy, stroke, hemorrhagic encephalopathy, cerebral hemorrhage, cerebral edema, diabetic cardiomyopathy, diabetic nephropathy, diabetic retinopathy , Diabetic neuropathy and diabetic ulcer, non-alcoholic fatty liver, non-alcoholic steatohepatitis, alcoholic fatty liver, cirrhosis, gout, stroke or cerebral infarction, etc.), musculoskeletal inflammation (hands, wrists, elbows, shoulders) , Neck, knee, ankle and foot joint inflammation, such as osteoarthritis, rheumatoid arthritis
  • the compounds of the present invention can be used to prevent or treat autoimmune diseases. Including: Acardi syndrome (AGS), infantile-onset STING-associated vasculitis (SAVI), retinal vascular disease with cerebral protein dystrophy (RCVL), systemic lupus erythematosus (SLE), familial frostbite lupus ( CHBL), Behcet’s disease, Chagas’ disease, psoriasis, multiple sclerosis, scleroderma and Behcet’s disease, etc.
  • Acardi syndrome Acardi syndrome
  • SAVI infantile-onset STING-associated vasculitis
  • RCVL retinal vascular disease with cerebral protein dystrophy
  • SLE systemic lupus erythematosus
  • CHBL familial frostbite lupus
  • Behcet’s disease Chagas’ disease
  • psoriasis multiple sclerosis
  • scleroderma and Behcet’s disease etc.
  • the compounds of the present invention can be used to prevent or treat T cell-mediated hypersensitivity reactions with inflammatory components, including urticaria, skin allergies, allergic rhinitis, contact dermatitis, respiratory allergies, and the like.
  • the compounds of the present invention can be used to treat cancers in various tissues and organs of the body, including but not limited to lung, bone, pancreas, liver, kidney, head, uterus, ovary, stomach, colon, esophagus, small intestine, endocrine system, prostate, bladder, cervix , Cancer of the vagina.
  • liver cancer kidney cancer, cervical cancer, lung cancer, skin cancer, uterine cancer, adenocarcinoma, prostate cancer, sarcoma, osteosarcoma, thyroid cancer, non-small cell lung cancer, esophageal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia , Acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, neuroblastoma.
  • the compounds of the present invention can be used alone or in combination with other therapeutic agents.
  • immunomodulators the compounds of the present invention can be used in monotherapy or in combination with other therapeutic agents to treat STING-mediated diseases, including infectious diseases, inflammatory diseases, autoimmune diseases, cardiovascular and cerebrovascular diseases, cancer and cancer Pre-Syndrome.
  • the present invention includes a pharmaceutical composition for preventing or treating STING-mediated diseases, which contains a therapeutically effective amount of the amide compound of formula I or formula II or formula III or a pharmaceutically acceptable salt or ester thereof or Solvates or metabolites or metabolic precursors or prodrugs are used as active ingredients and pharmaceutically acceptable excipients.
  • the adjuvants that can be arbitrarily mixed can be changed according to the dosage form, administration form, and the like.
  • excipients include excipients, binders, disintegrating agents, lubricants, flavoring agents, flavoring agents, coloring agents or sweetening agents, and the like.
  • the pharmaceutical composition can be in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches, and other pharmacologically conventional preparations.
  • the preparation of the compounds of the present invention can be carried out with reference to the methods and synthetic routes described in the examples, or can be prepared by improved methods.
  • the present invention has the following advantages:
  • the newly designed and synthesized amide compound of the present invention is a new type of STING inhibitor.
  • the amide compound of the present invention or its pharmaceutically acceptable salt or ester or solvate can directly bind to the STING protein and maintain its The dimer conformation in the resting state significantly inhibits the activation of the STING signaling pathway, so it can be used to prepare drugs that inhibit the activation of the STING signaling pathway and prepare drugs for the prevention or treatment of STING-mediated diseases.
  • the amide compound of the present invention has the characteristics of strong STING inhibitory activity and high safety.
  • the amide compound of the present invention has simple structure, ingenious synthesis route design, cheap and easy-to-obtain raw materials, safe synthesis process, environmental protection, and easy large-scale production.
  • Figure 1 is a graph showing the inhibitory effect of compounds on the expression of IFN- ⁇ gene downstream of the STING signaling pathway in human primary foreskin fibroblasts (HFF) (q-PCR detection);
  • Figure 2 is a graph showing the inhibitory effect of compounds on IFN- ⁇ gene expression downstream of the STING signaling pathway in human monocytes (THP1) (q-PCR detection);
  • Figure 3 shows the effect of compound B-13 on the skin of the right ear and back of mice with imiquimod-induced psoriasis-like inflammation: control group, model group, B-13 250mg/kg group and B-13 500mg/kg group The appearance of mice;
  • Figure 4 shows the HE staining results of compound B-13 on the back skin tissue of mice with imiquimod-induced psoriasis-like inflammation: take the back skin of the mice for H&E staining, and measure the epidermal thickness for statistical analysis.
  • the scale is 100 ⁇ m (left : 100x, right: 200x), compared with the model group, *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001.
  • n 8;
  • Figure 5 shows the HE staining results of compound B-13 on the right ear tissue of mice with imiquimod-induced psoriasis-like inflammation: the mouse right ear tissue was taken for H&E staining, and the epidermal thickness was measured for statistical analysis.
  • Figure 13 is a schematic diagram of molecular docking between compound A-30 and STING protein.
  • the raw materials and equipment used in the specific embodiments of the present invention are all known products, which are obtained from the market.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR was measured with a (Bruker) nuclear magnetometer, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated acetone (Acetone-d 6 ), and the internal standard was four Methylsilane (TMS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Leyan, Glasgow Pharmaceutical, Aladdin, Anaiji and other companies.
  • the compound III-1 obtained above was dissolved in DMF (15 mL), K 2 CO 3 (2.0 g, 14.49 mmol), BnBr (1.2 mL, 11.59 mmol) were added, and the reaction was carried out at room temperature for 6 h. Dilute with water and extract with EtOAc (50mL ⁇ 2). The combined organic phases were washed sequentially with water (30mL) and saturated brine (20mL), dried over anhydrous Na 2 SO 4 , filtered, and evaporated under reduced pressure to obtain an oily substance. Add EtOAc (30mL), add saturated hydrogen chloride ethyl acetate solution (10mL) at room temperature, and react at room temperature for 2h.
  • Example 86 the compound III-13 was obtained by replacing III-6 with 1-bromo-2-chloro-4-trifluoromethylbenzene.
  • Example 86 the compound III-16 was prepared by substituting III-11 for III-15.
  • the compound III-16 obtained in the previous step was dissolved in DCM (5 mL), a DCM solution of boron tribromide (1M, 200 ⁇ L) was added, and the reaction was carried out at room temperature for 10 h. It was quenched by adding methanol (1 mL), the solvent was evaporated under reduced pressure, water (10 mL) and EtOAc (20 mL) were added, and the layers were separated.
  • Example 93 The compound D-1 (120mg, 0.24mmol) prepared in Example 93 was dissolved in THF (2mL) and MeOH (3mL), NaOH (53mg, 1.3mmol) in H 2 O (2mL) solution was added, and the temperature was raised to 70 React at °C for 4h. The solvent was evaporated under reduced pressure, 1N HCl was added to adjust the pH to 1-3, the solid was separated out, filtered with suction, the filter cake was washed with 1N HCl (4mL) and H 2 O (6mL) successively, and dried to constant weight to obtain a white solid, the compound D-2(78mg, 67%).
  • Example 94 The compound D-2 (55mg, 0.11mmol) prepared in Example 94 was dissolved in THF (2mL), SOCl 2 (100 ⁇ L) was added, and the temperature was raised to 70°C for 2h; cooled to room temperature, ammonia water (3mL) was added and reacted at room temperature overnight. The solvent was evaporated under reduced pressure and diluted with EtOAc (8 mL). The organic phase was washed with H 2 O (6 mL), 1N HCl (6 mL) and saturated brine (6 mL), dried, and the solvent was evaporated under reduced pressure. The residue was passed on silica gel.
  • the reaction solution was added with Et 2 O (15 mL), H 2 O (10 mL), and separated, the organic layer was washed with saturated brine, dried with anhydrous Na 2 SO 4 , filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a residue, brown oil
  • the liquid is IV-11.
  • reaction solution precipitated a solid, filtered with suction, the filter cake was washed with DCM, 1N HCl, H 2 O in turn, and dried to constant weight by infrared to obtain a white solid compound D-13 (25 mg, 57%).
  • ESI-MS m/z 520.2[MH] - .
  • Example 123 compound IV-17 was prepared by replacing IV-10 with IV-16.
  • reaction solution was evaporated under reduced pressure to remove the solvent, the residue was added with EtOAc (10 mL) and H 2 O (8 mL), and the layers were separated. The organic layer was washed with 1N HCl, saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was reduced. The solvent was removed by pressure evaporation, Et 2 O (2 mL) and petroleum ether (2 mL) were added to the residue, stirred, and filtered with suction to obtain compound IV-20 (156 mg, 81%) as a yellow solid.
  • the reaction solution was evaporated under reduced pressure to remove the solvent, the residue was added with 1N HCl (8mL) and EtOAc (10mL), the layers were separated, the organic layer was washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was evaporated under reduced pressure to obtain a residue
  • ESI-MS m/z 527.0[ MH] - .
  • reaction solution was added with saturated NaHCO 3 (50 mL) and DCM (50 mL), separated, the organic layer was washed with saturated brine, dried with anhydrous Na 2 SO 4 , filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a residue, which was subjected to silica gel column chromatography (DCM) purified to obtain the target, a pale yellow oily liquid, standing to precipitate out the solid compound IV-27 (3.47g, 34% for three steps).
  • DCM silica gel column chromatography
  • reaction solution was cooled to room temperature, H 2 O (20 mL) was added, stirred, filtered with suction, the filter cake was washed with water, and infrared dried to constant weight to obtain a brown solid, which was suspended in petroleum ether (20 mL) and EtOAc (5 mL), and stirred , Suction filtration, infrared drying of the filter cake to constant weight to obtain the target, a brown-yellow solid that is IV-28.
  • reaction solution precipitated a solid, filtered with suction, the filter cake was washed with DCM, 1N HCl, H 2 O in turn, and dried to constant weight by infrared to obtain a grayish solid compound D-40 (40 mg, 50%, two steps).
  • reaction solution was evaporated under reduced pressure to remove the organic solvent, the residue was diluted with H 2 O (4 mL), the diluted solution was adjusted to pH 3-4 with 1N HCl, and the solid was precipitated, filtered with suction, and the filter cake was washed with water to obtain a brown-yellow viscous solid Suspended it in acetone (6 mL), stirred and filtered with suction to obtain compound IV-32 (197 mg, 47%, two steps) as a pale yellow solid.
  • compound IV-42 was prepared by replacing IV-38 with methyl 2-nitro-4-bromobenzoate.
  • compound IV-45 was prepared by replacing IV-38 with methyl 3-hydroxy-4-bromobenzoate.
  • ESI-MS m/z 528.2[M+H] + .
  • the pH of the reaction solution was adjusted to 1-3 with 2N HCl, H 2 O (6 mL) and DCM (8 mL) were added, the layers were separated, the organic layer was washed with saturated brine, dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was evaporated under reduced pressure to remove the solvent
  • reaction solution precipitated a solid, and the filter cake was suction filtered, washed with DCM, 1N HCl, H 2 O, and dried to constant weight by infrared, to obtain a white solid compound D-53 (63 mg, 42%, two steps).
  • reaction solution was evaporated under reduced pressure to remove DCM, the residue was added with EtOAc (50mL) and 1N HCl (40mL), the layers were separated, the aqueous layer was extracted with EtOAc (30mL), the organic phases were combined, washed with 1N HCl, saturated brine, and anhydrous Na 2 SO 4 was dried, filtered, and the filtrate was evaporated under reduced pressure to obtain the residue, which was suspended in DCM (10 mL), stirred, filtered with suction, and the filter cake was infrared-dried to constant weight to obtain a yellow solid, compound IV-52 ( 1.35g, 55%).

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Abstract

本发明公开了一种酰胺类化合物及其作为STING抑制剂的医药用途，具体如式I或式II所示的化合物或其药学上可接受的盐或酯或溶剂化物，它们可用于制备具有抑制STING信号通路激活的STING抑制剂或药物以及用于制备预防或治疗STING介导的疾病的药物。

Description

酰胺类化合物及其作为STING抑制剂的医药用途 技术领域
本发明属于生物医药领域，具体涉及一类新型的酰胺类化合物或其药物上可接受的盐或溶剂化物，其可作用于跨膜蛋白173(TMEM173)，也称STING(干扰素基因的刺激剂)，以及制备和其医药用途，本发明还涉及该类化合物在制备预防或治疗STING介导的疾病的药物中的用途。
背景技术
机体的固有免疫系统的激活由表达在细胞膜上和细胞质中的模式识别受体(pattern recognition receptors,PRRs)识别非自身的病原体相关的分子模式(pathogen-associated molecular patterns,PAMPs)所介导。PRRs在识别PAMPs后，激活下游免疫信号的传导，促进炎症和免疫细胞因子的释放，进一步激活机体的适应性免疫系统协同杀伤并清除入侵的病原微生物(Cold Spring Harbor Symposia on Quantitative Biology,1989,54:1-13)。相似的，细胞在异常状态下(应激、受损、衰老或死亡)分泌的损伤相关的分子模式(damage-associated molecular patterns,DAMPs)也会被模式识别受体识别，进而激活免疫系统，促进细胞的再生以及损伤后的修复(Science,2002,296(5566):301-305)。
细胞质中的DNA作为经典的PAMP或DAMP分子在固有免疫系统的激活中发挥重要的作用(Curr Opin Immunol,2018,55:31-37)。细胞质中的DNA受体蛋白cGAS(Cyclic AMP-GMP synthase)能够识别异常暴露的胞浆DNA分子，并以ATP和GTP为底物催化合成2’,3’-cGAMP分子(2’-3’/3’-5’cyclic GMP-AMP)。2’,3’-cGAMP与细菌代谢中形成的信号分子c-di-AMP和c-di-GMP被称为环状二核苷酸类物质(cyclic dinucleotides,CDNs)。这些CDNs分子能特异性的结合到内质网上调控蛋白STING(也被称为TMEM173,MITA,ERIS或MPYS)二聚体形成的“V”形口袋内(Nature,2008,455(7213):674-678；Nature,2011,478(7370):515-518)，进而诱导STING蛋白的多聚化激活(Cell,2013,154(4):748-62)。多聚化的STING蛋白由内质网向高尔基体室转移，并在此过程中招募下游的激酶蛋白TBK1和转录因子IRF3，TBK1在自磷酸化激活后催化STING和IRF3的磷酸化(Nature,2019,567(7748):394-398；Nature,2019,569(7758):718-722)。磷酸化的IRF3进一步二聚化入核，促进I型干扰素(type I interferons)及其相关免疫因子的表达(interferon stimulated genes,ISGs)。此外，STING蛋白也能通过招募TBK1和TRAF6分子，激活NF-κB信号通路，促进TNF-α和IL-6等炎症因子的表达(J Virol,2014,88(10):5328-41)。
尽管STING介导的固有免疫信号通路的激活在机体抵抗病原微生物的入侵 过程中发挥重要的作用，持续的STING通路的激活会导致多种自身免疫疾病和炎症疾病的发生和发展(Nature Immunology,2017,18(7):716-724)。AGS综合症(Aicardi-Goutières syndrome)是一种由TREX1,RNASE H2,SAMHD1,ADAR或IFIH1基因突变引起的全身性的罕见的自身免疫疾病(Am J Med Genet A,2015,167A(2):296-312)。动物模型中研究发现核酸代谢酶TREX1,RNASE H2和SAMHD1的基因突变导致胞浆DNA聚集进而激活cGAS-STING信号通路，且进一步在疾病小鼠体内敲除STING蛋白的表达能显著改善疾病的进展(J Exp Med,2016,213(3):329-36；Proc Natl Acad Sci U S A,2015,112(42):E5699-705；Nature,2018,557(7703):57-61)。在系统性红斑狼疮(systemic lupus erythematosus,SLE)病人中也发现了TREX1基因的突变，且50％～60％的SLE病人血清中I型干扰素高表达(Nat Rev Rheumatol,2018,14(4):214-228)。在Bloom综合症病人中发现，BLM蛋白突变导致微核的形成，进而激活STING信号通路诱导病人的血清中IFNs和ISGs的高表达(J Exp Med,2019,216(5):1199-1213)。SAVI(STING-associated vasculopathy with onset in infancy)疾病是由STING蛋白中个别氨基酸的突变导致其异常激活诱导的全身性的自身免疫疾病(N Engl J Med,2014,371(6):507-518)。此外，在炎症相关的疾病模型中，如皮肤癌的诱发(Nat Commun,2014,5:5166)、肿瘤转移(Nature,2018,553(7689):467-472)、早衰症(Nature,2017,550(7676):402-406)、脓毒症(Shock,2017,47(5):621-631)、急性胰腺炎(Gastroenterology,2018,154(6):1822-1835)、帕金森疾病(Nature,2018,561(7722):258-262)、非酒精性脂肪肝及肝纤维化(Gastroenterology,2018,155(6):1971-1984；Proceedings of the National Academy of Sciences,2017,114(46):12196-12201)、肺炎(Nature Communications,2018,9(1))、慢性肾炎及肾纤维化(Cell Metabolism,2019,DOI:10.1016/j.cmet.2019.08.003)和缺血性再灌注损伤(Nature Medicine,2017,23(12):1481-1487)等，而抑制STING信号通路的激活能显著改善上述疾病的发生发展。总之，靶向STING蛋白的抑制剂的开发具有广泛的临床应用前景。
目前文献已报道的STING小分子抑制剂屈指可数，活性较弱且副作用较大(Cell Reports 2018,25,3405–3421；ACS Med.Chem.Lett.2019,10(1),92-97)。因此，研制新型的STING小分子抑制剂具有迫切的临床需求。
发明内容
发明目的：针对现有技术存在的问题，本发明提供一种新型酰胺类化合物或其药学上可接受的盐或酯或溶剂化物。本发明的酰胺类化合物可以作为靶向STING的新型小分子抑制剂，其可抑制STING信号通路的激活，因而可用于制备预防或治疗STING介导的疾病的药物。
本发明还提供所述酰胺类化合物及其中间体的制备方法、药物组合及其医药用途。
技术方案：为了实现上述目的，本发明提供如下式I或式II所示的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物：
Figure PCTCN2020120279-appb-000001
R 1是
Figure PCTCN2020120279-appb-000002
R a是取代或非取代的C 1-C 4烷基、环丙基、三氟甲基、乙烯基、取代或非取代的芳基或杂芳基、NH 2、C 1-C 4烷基氨基、羟基-C 1-C 3烷基氨基或吗啉基，所述芳基或杂芳基是苯基、萘基、吡啶基、吡唑基、呋喃基、或噻酚基，所述取代的C 1-C 4烷基是被一个或两个或三个独立地选自下列的取代基所取代：F、Cl、NH 2、OH、二乙醇胺基、甲磺酰胺基、乙酰胺基、氨基乙酰胺基、吡咯烷-1-基、哌啶-1-基、取代的哌啶-1-基、哌嗪-1-基、取代的哌嗪-1-基、吗啉-4-基、硫代吗啉-1,1-二氧代-4-基、N,N-二甲基氨基、羧基、羧酸酯基、甲酰胺基或氨基甲酰胺基，所述取代的芳基或杂芳基是被一个或两个独立地选自下列的取代基所取代：C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基、F、Cl、Br、I、CN、NO 2、NH 2、OH、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH或C(O)NH 2；
R b是H、C 1-C 3烷基或C 1-C 3烷基羰基；
R 2是H、OH、C 1-C 3烷氧基、C 1-C 3烷基羰基氧基、C 1-C 3烷氧羰基、C(O)OH、C(O)NH 2或C(O)NHSO 2CH 3；
R 3是H、OH、C 1-C 3烷基、COOCH 3、COOH、CONH 2、F、Cl、Br或I；
R 4是H或C 1-C 3烷基；
Ar是苯基或吡啶基；
R 5是取代或非取代的苯基、
Figure PCTCN2020120279-appb-000003
Figure PCTCN2020120279-appb-000004
所述取代的苯基是被一个或两个独立地选自下列的取代基所取代：F、Cl、Br、I、CN、NO 2、NH 2、OH、乙酰氨基、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH、C(O)NH 2、C(O)NHOH、 C 1-C 3烷基、环丙基、取代或非取代的苯基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基或氨磺酰基；
R 6和R 7各自独立地选自：H、F、Cl、Br、CN、OH、NO 2、CF 3、OCF 3、C 1-C 3烷氧基、吗啉-4-基或取代的C 2-C 3烷氧基，所述取代的C 2-C 3烷氧基是指C 2-C 3烷基被卤素、NH 2、OH、CN、羧基、羧酸酯基、甲磺酰基、吡咯烷-1-基、哌啶-1-基、取代的哌啶-1-基、哌嗪-1-基、取代的哌嗪-1-基、吗啉-4-基、硫代吗啉-1,1-二氧代-4-基、N,N-二甲基氨基、N,N-二乙基氨基、三甲基铵基、二乙醇胺基、含氮芳杂环基、磷酰胺基或C 1-C 3烷氧基；
或者，R 5、R 6和R 7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的环烷烯烃环、取代或非取代的杂环烷烃环或取代或非取代的杂环烯烃环。
在某些优选的实施方案中，所述的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物，即所述的式I或式II中：
R 1是
Figure PCTCN2020120279-appb-000005
R a是取代或非取代的C 1-C 4烷基、环丙基、三氟甲基、乙烯基、取代或非取代的芳基或杂芳基、NH 2、C 1-C 4烷基氨基、羟基-C 1-C 3烷基氨基或吗啉基，所述芳基或杂芳基是苯基、萘基、吡啶基、吡唑基、呋喃基、或噻酚基，所述取代的C 1-C 4烷基是被一个或两个或三个独立地选自下列的取代基所取代：F、Cl、NH 2、OH、二乙醇胺基、甲磺酰胺基、乙酰胺基、氨基乙酰胺基、吡咯烷-1-基、哌啶-1-基、取代的哌啶-1-基、哌嗪-1-基、取代的哌嗪-1-基、吗啉-4-基、硫代吗啉-1,1-二氧代-4-基、N,N-二甲基氨基、羧基、羧酸酯基、甲酰胺基或氨基甲酰胺基，所述取代的芳基或杂芳基是被一个或两个独立地选自下列的取代基所取代：C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基、F、Cl、Br、I、CN、NO 2、NH 2、OH、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH或C(O)NH 2；
R b是H、C 1-C 3烷基或C 1-C 3烷基羰基；
R 2是H、OH、C 1-C 3烷氧基、C 1-C 3烷基羰基氧基、C 1-C 3烷氧羰基、C(O)OH、C(O)NH 2或C(O)NHSO 2CH 3；
R 3是H、OH、C 1-C 3烷基、COOCH 3、COOH、CONH 2、F或Cl；
R 4是H；
Ar是苯基或吡啶基；
R 5是取代或非取代的苯基、
Figure PCTCN2020120279-appb-000006
Figure PCTCN2020120279-appb-000007
所述取代的苯基是被一个或两个独立地选自下列的取代基所取代：F、Cl、Br、I、CN、NO 2、NH 2、OH、乙酰氨基、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH、C(O)NH 2、C(O)NHOH、C 1-C 3烷基、环丙基、取代或非取代的苯基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基或氨磺酰基；
R 6和R 7各自独立地选自：H、F、Cl、Br、CN、OH、NO 2、CF 3、OCF 3、C 1-C 3烷氧基、吗啉-4-基或取代的C 2-C 3烷氧基，所述取代的C 2-C 3烷氧基是指C 2-C 3烷基被卤素、NH 2、OH、CN、羧基、羧酸酯基、甲磺酰基、哌啶-1-基、取代的哌啶-1-基、哌嗪-1-基、取代的哌嗪-1-基、吗啉-4-基、硫代吗啉-1,1-二氧代-4-基、N,N-二甲基氨基、二乙醇胺基、含氮芳杂环基、磷酰胺基或C 1-C 3烷氧基；
或者，R 5、R 6和R 7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的环烷烯烃环、取代或非取代的杂环烷烃环或取代或非取代的杂环烯烃环。
作为优选，所述酰胺类化合物或其药学上可接受的盐或酯或溶剂化物为如下式III所示的苯甲酰胺类化合物或其药学上可接受的盐或酯或溶剂化物：
Figure PCTCN2020120279-appb-000008
R 1是
Figure PCTCN2020120279-appb-000009
R a是取代或非取代的C 1-C 3烷基、取代或非取代的芳基或杂芳基、NH 2、C 1-C 3烷基氨基、羟基-C 1-C 3烷基氨基或吗啡啉基，所述芳基或杂芳基是苯基、萘基、吡啶基或噻酚基，所述取代的C 1-C 3烷基是被一个或两个或三个独立地选自下列的取代基所取代：F、NH 2、OH或二甲基氨基，所述取代的芳基或杂芳基是被一个或两个独立地选自下列的取代基所取代：C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基、F、Cl、Br、I、CN、NO 2、NH 2、OH、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH或C(O)NH 2；
R b是H、C 1-C 3烷基或C 1-C 3烷基羰基；
R 2是H、OH、C 1-C 3烷氧基、C 1-C 3烷基羰基氧基、C 1-C 3烷氧羰基、C(O)OH、C(O)NH 2或C(O)NHSO 2CH 3；
R 3是H、C 1-C 3烷基、COOCH 3、COOH、CONH 2、F、Cl、Br或I；
R 4是H或C 1-C 3烷基；
R 5是取代或非取代的苯基、
Figure PCTCN2020120279-appb-000010
Figure PCTCN2020120279-appb-000011
所述取代的苯基是被一个或两个独立地选自下列的取代基所取代：F、Cl、Br、I、CN、NO 2、NH 2、OH、乙酰氨基、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH、C(O)NH 2、C(O)NHOH、C 1-C 3烷基、取代或非取代的苯基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基或氨磺酰基；
R 6和R 7各自独立地选自：H、F、Cl、Br、CN、NO 2、CF 3、OCF 3或C 1-C 3烷氧基；
或者，R 5、R 6和R 7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的环烷烯烃环、取代或非取代的杂环烷烃环或取代或非取代的杂环烯烃环。
作为优选，所述式III化合物中：
R 1是
Figure PCTCN2020120279-appb-000012
R a是取代或非取代的C 1-C 3烷基、取代或非取代的芳基或杂芳基、NH 2、C 1-C 3烷基氨基、羟基-C 1-C 3烷基氨基或吗啡啉基，所述芳基或杂芳基是苯基、萘基、吡啶基或噻酚基，所述取代的C 1-C 3烷基是被一个或两个或三个独立地选自下列的取代基所取代：F、NH 2、OH或二甲基氨基，所述取代的芳基或杂芳基是被一个或两个独立地选自下列的取代基所取代：C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基、F、Cl、Br、I、CN、NO 2、NH 2、OH、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH或C(O)NH 2；
R b是H、C 1-C 3烷基或C 1-C 3烷基羰基；
R 2是H、OH、C 1-C 3烷氧基、C 1-C 3烷基羰基氧基、C 1-C 3烷氧羰基、C(O)OH、C(O)NH 2或C(O)NHSO 2CH 3；
R 3是H、C 1-C 3烷基、COOCH 3、COOH、CONH 2、F或Cl；
R 4是H；
R 5是取代或非取代的苯基、
Figure PCTCN2020120279-appb-000013
Figure PCTCN2020120279-appb-000014
所述取代的苯基是被一个或两个独立地选自下列的取代基所取代：F、Cl、Br、I、CN、NO 2、NH 2、OH、乙酰氨基、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH、C(O)NH 2、C(O)NHOH、C 1-C 3烷基、取代或非取代的苯基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基或氨磺酰基；
R 6和R 7各自独立地选自：H、F、Cl、Br、CN、NO 2、CF 3、OCF 3或C 1-C 3烷氧基；
或者，R 5、R 6和R 7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的环烷烯烃环、取代或非取代的杂环烷烃环或取代或非取代的杂环烯烃环。
在某些实施方案中，所述酰胺类化合物还包括其代谢产物、代谢前体或前药。
在某些更优选的实施方案中，所述酰胺类化合物或其药学上可接受的盐或酯或溶剂化物或代谢产物或代谢前体或前药自如下表1所示的任意一种化合物：
表1、化合物的结构与命名
Figure PCTCN2020120279-appb-000015
Figure PCTCN2020120279-appb-000016
Figure PCTCN2020120279-appb-000017
Figure PCTCN2020120279-appb-000018
Figure PCTCN2020120279-appb-000019
Figure PCTCN2020120279-appb-000020
Figure PCTCN2020120279-appb-000021
Figure PCTCN2020120279-appb-000022
Figure PCTCN2020120279-appb-000023
Figure PCTCN2020120279-appb-000024
Figure PCTCN2020120279-appb-000025
Figure PCTCN2020120279-appb-000026
Figure PCTCN2020120279-appb-000027
Figure PCTCN2020120279-appb-000028
Figure PCTCN2020120279-appb-000029
Figure PCTCN2020120279-appb-000030
Figure PCTCN2020120279-appb-000031
Figure PCTCN2020120279-appb-000032
Figure PCTCN2020120279-appb-000033
Figure PCTCN2020120279-appb-000034
Figure PCTCN2020120279-appb-000035
Figure PCTCN2020120279-appb-000036
Figure PCTCN2020120279-appb-000037
Figure PCTCN2020120279-appb-000038
Figure PCTCN2020120279-appb-000039
Figure PCTCN2020120279-appb-000040
Figure PCTCN2020120279-appb-000041
Figure PCTCN2020120279-appb-000042
Figure PCTCN2020120279-appb-000043
本发明的化合物也可作为药用盐使用。该盐可为下列酸中的至少一种的酸 盐：半乳糖二酸、D-葡糖醛酸、甘油磷酸、马尿酸、羟乙磺酸、乳糖酸、马来酸、1,5-萘二磺酸、萘-2-磺酸、新戊酸、对苯二甲酸、硫氰酸、胆酸、正十二烷基硫酸、苯磺酸、柠檬酸、D-葡萄糖，乙醇酸、乳酸、苹果酸、丙二酸、扁桃酸、磷酸、丙酸、盐酸、硫酸、酒石酸、琥珀酸、甲酸、氢碘酸、氢溴酸、甲烷磺酸、烟酸、硝酸、乳清酸、草酸、苦味酸、L-焦谷氨酸、糖精酸、水杨酸、龙胆酸、对甲苯磺酸、戊酸、棕榈酸、葵二酸、硬脂酸、月桂酸、乙酸、己二酸、碳酸、苯磺酸、乙烷二磺酸、乙基琥珀酸、富马酸、3-羟基萘-2-甲酸、1-羟基萘-2-甲酸、油酸、十一碳烯酸、抗坏血酸、樟脑酸、樟脑磺酸、二氯乙酸、乙烷磺酸。另一方面，该盐也可以是本发明的化合物与金属(包括钠、钾、钙等)离子或药学上可接受的胺(包括乙二胺、氨丁三醇等)、铵离子或胆碱形成的盐。本发明的化合物也可以按酯、前药形式、N-氧化物或其溶剂化物组成药物组合物。
本发明包括本发明化合物的所有前药，其在给予人或动物机体后能够(直接或者间接)提供本发明化合物或其活性代谢物或残余物。
本发明包括本发明化合物的各种氘代形式。与碳原子相连的每个可用氢原子可以独立的被氘原子取代。
本发明提供了所述式I或式II或式III的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物在制备抑制STING信号通路激活的药物中的用途。
本发明提供了所述式I或式II或式III酰胺类化合物或其药学上可接受的盐或酯或溶剂化物在制备预防或治疗STING介导的疾病的药物中的用途。
所述STING介导的疾病包括感染性疾病、炎性疾病、自身免疫性疾病、器官纤维化疾病、癌症和癌前期综合征中的一种或几种。
本发明提供了所述式I或式II或式III的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物在制备免疫佐剂药物中的用途。
本发明基于人源STING蛋白C端结构域的晶体结构(hSTING-CTD-139-379,PDB:4EF5)，使用
Figure PCTCN2020120279-appb-000044
中的Glide对接模块，进行了计算机辅助药物设计及活性化合物的分子对接研究。对接结果表明，本发明的酰胺类化合物可能通过直接结合STING蛋白并维持其静息状态下的二聚体构象而抑制STING信号通路的激活。因此，本发明的酰胺类化合物可用于制备抑制STING信号通路激活的药物以及制备预防或治疗STING介导的疾病的药物。
本发明化合物可以用于预防或治疗感染性疾病，包括：结核分枝杆菌感染、衣原体感染、疱疹病毒(单纯疱疹病毒)感染、腺病毒感染、乙肝病毒感染、正粘病毒感染和冠状病毒感染。
本发明化合物可以用于预防或治疗炎性疾病，包括：代谢性炎症相关疾病(如胰岛素抵抗、代谢综合征、1型或2型糖尿病、高脂血症、肥胖症、动脉粥样硬 化、心肌缺血、心肌梗死、心律失常、冠心病、高血压、心衰、心肌肥大、心肌炎、缺血性脑病、脑卒中、出血性脑病、脑溢血、脑水肿、糖尿病心肌病、糖尿病肾病、糖尿病视网膜病变、糖尿病神经病变和糖尿病溃疡、非酒精性脂肪肝、非酒精性脂肪性肝炎、酒精性脂肪肝、肝硬化、痛风、中风或脑梗死等)，肌肉骨骼肌炎症(手、腕、肘、肩、颈、膝盖、踝和脚关节炎症，例如骨关节炎、类风湿性关节炎、强直性脊柱炎、急性和慢性感染性关节炎等)，眼部炎症(角膜炎、巩膜炎、结膜炎等)，消化系统炎症(结肠炎、肝炎、胆管炎、胆囊炎、胰腺炎、胃炎、肠炎、炎症性肠病、直肠炎)，神经系统炎症(脑膜炎、神经性肌强直、多发性硬化、CNS血管炎)，脉管系统或者淋巴系统炎症(血管炎、淋巴管炎、静脉炎)，生殖系统炎症(宫颈炎、子宫内膜炎、附睾炎、睾丸炎、尿道炎)，呼吸系统炎症(肺炎、哮喘、慢性阻塞性肺病、慢性支气管炎、肺气肿、闭塞性细支气管炎、特发性肺纤维化、囊性纤维化肺病)，其他炎性病症包括阑尾炎、心肌炎、腮腺炎、牙龈炎、前列腺炎、腹膜炎、胸膜炎、血管炎、静脉炎、浮肿。
本发明化合物可以用于预防或治疗自身免疫性疾病。包括：艾卡尔迪综合征(AGS)、婴儿期发病的STING相关血管炎(SAVI)、伴有脑蛋白营养不良的视网膜血管病变(RCVL)、系统性红斑狼疮(SLE)、家族性冻疮狼疮(CHBL)、贝切特氏病、查加斯病、银屑病、多发性硬化症、硬皮症和白塞氏病等。
本发明化合物可以用于预防或治疗具有炎性组分的T细胞介导的超敏反应，包括荨麻疹、皮肤过敏、过敏性鼻炎、接触性皮炎和呼吸道过敏等。
本发明化合物可以用于治疗身体各组织器官的癌症，包括但不限于肺、骨、胰腺、肝、肾、头、子宫、卵巢、胃、结肠、食道、小肠、内分泌系统、前列腺、膀胱、宫颈、阴道的癌症。例如肝癌、肾癌、宫颈癌、肺癌、皮肤癌、子宫癌、腺癌、前列腺癌、肉瘤、骨肉瘤、甲状腺癌、非小细胞肺癌、食管癌、慢性髓细胞性白血病、慢性淋巴细胞性白血病、急性髓细胞性白血病、急性淋巴细胞性白血病、多发性骨髓瘤、恶性淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、神经母细胞瘤。
本发明化合物可单独使用或可与其他治疗剂组合使用。作为免疫调节剂，本发明的化合物可用于单一治疗或者与其它治疗剂组合使用以治疗STING介导的疾病，包括感染性疾病、炎性疾病、自身免疫性疾病、心脑血管疾病、癌症和癌前期综合征。
本发明包括了一种预防或治疗STING介导的疾病的药物组合物，其中含有治疗有效量的所述式I或式II或式III的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物或代谢产物或代谢前体或前药作为活性成份和药学上可接受的辅 料。可任意混合的辅料根据剂型、给药形式等可以改变。辅料的例子包括赋形剂、粘合剂、崩解剂、润滑剂、矫味剂、香味剂、着色剂或甜味剂等。所述药物组合物可以是胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂等制剂学上常规的制剂形式。
本发明化合物的制备可参照实施例中描述的方法及合成路线进行，或经过改进的方法来制备。
有益效果：与现有技术相比，本发明具有如下优点：
(1)本发明的全新设计合成的酰胺类化合物是一类新型的STING抑制剂，本发明的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物能通过直接结合STING蛋白并维持其静息状态下的二聚体构象而显著抑制STING信号通路的激活，因而可用于制备抑制STING信号通路激活的药物以及制备预防或治疗STING介导的疾病的药物。与现有的STING抑制剂相比，本发明的酰胺类化合物具有STING抑制活性强且安全性高的特点。
(2)本发明的酰胺类化合物结构简单，合成路线设计巧妙，原料便宜易得，合成工艺安全、环保，易于规模化生产。
附图说明
图1是化合物对人原代包皮成纤维细胞(HFF)STING信号通路下游IFN-β基因表达的抑制效应图(q-PCR检测)；
图2是化合物对人单核细胞(THP1)STING信号通路下游IFN-β基因表达的抑制效应图(q-PCR检测)；
图3是化合物B-13对咪喹莫特诱导银屑病样炎症小鼠右耳及背部皮肤的效应图：对照组、模型组、B-13 250mg/kg组和B-13 500mg/kg组小鼠的外观表现；
图4是化合物B-13对咪喹莫特诱导银屑病样炎症小鼠背部皮肤组织HE染色结果图：取小鼠背部皮肤进行H&E染色，并测量表皮厚度，进行统计分析，比例尺100μm(左：100x，右：200x)，与模型组相比，*p<0.05，**p<0.01，***p<0.001。n＝8；
图5是化合物B-13对咪喹莫特诱导银屑病样炎症小鼠右耳组织HE染色结果图：取小鼠右耳组织进行H&E染色，并测量表皮厚度，进行统计分析，比例尺100μm(左：100x，右：200x)，*p<0.05，**p<0.01，***p<0.001，n＝8；
图6是化合物B-13对咪喹莫特诱导银屑病样炎症小鼠体重的影响图：与对照组相比，*p<0.05，**p<0.01，***p<0.001，与模型组相比，#p<0.05，##p<0.01，###p<0.001，n＝8；
图7是化合物B-13对咪喹莫特诱导银屑病样炎症小鼠右耳厚度的影响图：与对照组相比，*p<0.05，**p<0.01，***p<0.001，与模型组相比，#p<0.05，##p<0.01， ###p<0.001，n＝8；
图8是化合物B-13对咪喹莫特诱导银屑病样炎症小鼠PASI打分结果图：与对照组相比，*p<0.05，**p<0.01，***p<0.001，与模型组相比，#p<0.05，##p<0.01，###p<0.001，n＝8；
图9是化合物B-13对咪喹莫特诱导银屑病样炎症小鼠血清中IFN-β水平的影响图：*p<0.05，**p<0.01，***p<0.001，n＝8；
图10是化合物B-13对咪喹莫特诱导银屑病样炎症小鼠血清中IL-17A水平的影响图：*p<0.05，**p<0.01，***p<0.001，n＝8；
图11是化合物B-13对咪喹莫特诱导银屑病样炎症小鼠后背皮肤组织相关炎症因子mRNA水平的影响图：*p<0.05，**p<0.01，***p<0.001，n＝8；
图12是化合物B-13对咪喹莫特诱导银屑病样炎症小鼠右耳组织相关炎症因子mRNA水平的影响图：*p<0.05，**p<0.01，***p<0.001，n＝8；
图13是化合物A-30与STING蛋白的分子对接示意图。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中,以下所述的实施例是为了更好的阐述本发明,并不是用来限制本发明的范围。在不背离本发明的精神和范围的前提下,可以对本发明进行各种变化和修饰。
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售获得。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR的测定是用(Bruker)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代丙酮(Acetone-d 6)，内标为四甲基硅烷(TMS)。
柱层析一般使用青岛海洋化工厂分厂硅胶200-300目硅胶为载体。
本发明的已知起始原料可以采用或按照本领域已知的方法合成，或可购买于乐研、毕得医药、阿拉丁、安耐吉等公司。
下列缩写(表2)可在本说明书使用：
表2.缩写表
Figure PCTCN2020120279-appb-000045
Figure PCTCN2020120279-appb-000046
Figure PCTCN2020120279-appb-000047
实施例1
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-3'-氨磺酰基[1,1'-联苯]-4-甲酰胺(化合物A-1)
Figure PCTCN2020120279-appb-000048
将化合物I-0(3-溴苯磺酰氯)(610mg,2.39mmol)的THF(2mL)溶液滴加到氨水(6mL)中，室温反应5h。反应液用EtOAc(20mL)提取，有机相依次用水(10mL)，饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得白色固体即化合物I-1(534mg,95％)。
将化合物I-1(238mg,1.01mmol)，对甲氧羰基苯硼酸(200mg,1.11mmol)，无水K 2CO 3(279mg,2.02mmol)，Pd(PPh 3) 4(58mg,0.05mmol)加入Toluene(Tol)(10mL)和MeOH(2mL)中，氮气氛围80℃，反应3h。冷却室温，过滤并用EtOAc洗涤滤饼，滤液减压蒸除溶剂，加入EtOAc(5mL)室温搅拌30min，过滤得淡黄色固体即化合物I-2(200mg,68％)。 1H NMR(300MHz,DMSO-d 6)δppm 8.07(s,1H),8.03(d,J＝8.5Hz,1H),7.81(d,J＝8.3Hz,1H),7.72(d,J＝7.6 Hz,1H),7.65(d,J＝7.7Hz,1H),7.44(dd,J＝7.7,7.7Hz 1H),3.88(s,1H).
将化合物I-2(200mg,0.68mmol)溶于THF(4mL)和MeOH(4mL)，加入2N NaOH(3mL)，室温反应2h。用1N HCl调节pH至3-4，EtOAc(25mL)提取，有机相依次用水(10mL)，饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得白色固体即化合物I-3(179mg,94％)。
将2-氨基-4-硝基苯酚(15.0g,97.33mmol)，吡啶(11.8mL,146.00mmol)加入DCM(300mL)中，冰水浴下滴加4-氟苯磺酰氯(22.7g,116.80mmol)的DCM(150mL)溶液，滴毕室温反应8h。减压蒸除溶剂，加入EtOAc(400mL)和水(150mL)，摇匀分液，有机相依次用1N HCl(100mL)，水(100mL)，饱和食盐水(100mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得残留物，加入DCM(100mL)室温搅拌2h，过滤并用DCM(10mL)洗涤，得淡黄色固体即化合物I-4(20.5g,67％)。 1H NMR(300MHz,DMSO-d 6)δppm 11.35(s,1H),9.94(s,1H),8.05(d,J＝2.4Hz,1H),7.93(dd,J＝8.9,2.5Hz,1H),7.82(dd,J＝8.3,5.3Hz,2H),7.39(dd,J＝8.7,8.7Hz,2H),6.90(d,J＝9.0Hz,1H).
将化合物I-4(20.3g,65.01mmol)，10％Pd/C(1.1g)加入MeOH(200mL)中,H 2氛围反应12h。滤除Pd/C，MeOH洗涤滤饼，滤液减压蒸出溶剂得残留物，加入DCM(40mL)，室温搅拌2h，过滤并用DCM(3mL)洗涤，得淡黄色固体即化合物I-5(14.7g,80％)。
将化合物I-5(14.0g,49.59mmol)，咪唑(4.1g,59.51mmol)加入DCM(150mL)，冰水浴下滴加TBSCl(9.0g,59.51mmol)的DCM(50mL)溶液，滴毕室温反应12h。加入DCM(100mL)稀释，水洗(50mL×3)，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得淡棕色固体即化合物I-6(19.4g,98％)。 1H NMR(300MHz,CDCl 3)δppm 7.77(dd,J＝8.3,5.1Hz,1H),7.08(dd,J＝8.5,8.5Hz,1H),6.97(d,J＝2.0Hz,1H),6.78(s,1H),6.52(d,J＝8.5Hz,1H),6.28(dd,J＝8.6,2.2Hz,1H),3.48(s,1H),0.93(s,5H),0.09(s,3H).
将化合物I-3(177mg,0.64mmol)，DIPEA(0.16mL,0.96mmol)加入THF(4mL)中，加入HATU(291mg,0.77mmol)，室温反应1h后，加入化合物I-6(304mg,0.77mmol)，室温反应5h。加入EtOAc(20mL)，水(10mL)摇匀分液，有机相依次用1N HCl(10mL)，水(10mL)，饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，将所得残留物加入DCM(10mL)，Et 3N·3HF(0.15mL)，室温反应4h。过滤得红棕色固体，经硅胶柱层析(DCM/MeOH＝30/1)纯化，得类白色固体即化合物A-1(135mg,39％)。 1H NMR(300MHz,DMSO-d 6)δppm 10.17(s,1H),9.43(s,1H),9.32(s,1H),8.19(s,1H),8.09(d,J＝8.3Hz,2H),8.00(d,J＝7.8Hz,1H),7.92-7.79(m,5H),7.78-7.65(m,2H),7.51-7.41(m,3H), 7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 540.1[M-H] -.
实施例2
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-甲氧基-3'-氨磺酰基[1,1'-联苯]-4-甲酰胺(化合物A-2)
Figure PCTCN2020120279-appb-000049
参照实施例1的方法，将3-溴苯磺酰氯替换成2-甲氧基-5-溴苯磺酰氯，制得化合物A-2: 1H NMR(300MHz,DMSO-d 6)δppmδ10.10(s,1H),9.38(s,1H),9.27(s,1H),8.05(d,J＝2.3Hz,2H),8.02(s,1H),7.97(dd,J＝8.6,2.3Hz,1H),7.87-7.73(m,4H),7.70(d,J＝2.2Hz,1H),7.42(dd,J＝8.8,2.4Hz,1H),7.32-7.38(m,3H),7.17(s,2H),6.70(d,J＝8.8Hz,1H),3.97(s,3H).ESI-MS:m/z 570.1[M-H] -.
实施例3
4'–(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-[1,1'-联苯基]-4-羧酸甲酯(化合物A-3)
Figure PCTCN2020120279-appb-000050
参照实施例1的方法，将I-3替换成4'-(甲氧基羰基)-[1,1'-联苯基]-4-羧酸，制得化合物A-3: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.41(s,1H),9.31(s,1H),8.11-8.03(m,4H),7.91(m,4H),7.82(dd,J＝8.8,5.2Hz,2H),7.71(d,J＝2.2Hz,1H),7.43(dd,J＝8.6,2.2Hz,1H),7.33-7.39(m,2H),6.70(d,J＝8.7Hz,1H),3.89(s,3H).ESI-MS:m/z 519.1[M-H] -.
实施例4
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯基]-4,4'-二甲酰胺(化合物A-4)
Figure PCTCN2020120279-appb-000051
Figure PCTCN2020120279-appb-000052
将化合物I-7(500mg,2.28mmol)的THF(2mL)溶液室温下滴加至氨水(5mL)中，室温反应4h。加入水(20mL)和EtOAc(40mL)，摇匀分液，有机相依次用1N HCl(15mL)，水(20mL)，饱和食盐水(20mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得残留物得淡黄色固体即化合物I-8(300mg,66％)。
参照实施例1的方法,将I-1替换成I-8，制得化合物A-4: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.42(s,1H),9.31(s,1H),8.07-8.04(m,3H),8.01(d,J＝8.3Hz,2H),7.90(s,1H),7.88-7.78(m,4H),7.72(d,J＝2.4Hz,1H),7.47-7.31(m,4H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 504.1[M-H] -.
实施例5
2'-氯-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-5)
Figure PCTCN2020120279-appb-000053
参照实施例1的方法，将I-1替换成2-溴氯苯，制得化合物A-5: 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.41(s,1H),9.31(s,1H),8.01(d,J＝8.1Hz,2H),7.84(dd,J＝8.6,5.3Hz,2H),7.71(d,J＝2.1Hz,1H),7.65-7.52(m,3H),7.51-7.41(m,4H),7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 519.1[M+Na] +.
实施例6
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2'-(三氟甲氧基)-[1,1'-联苯]-4-甲酰胺(化合物A-6)
Figure PCTCN2020120279-appb-000054
参照实施例1的方法，将I-1替换成1-溴-2-(三氟甲氧基)苯，制得化合物A-6: 1H NMR(300MHz,DMSO-d 6)δppm 10.17(s,1H),9.42(s,1H),9.31(s,1H),8.03(d,J＝8.2Hz,2H),7.83(dd,J＝8.7,5.3Hz,2H),7.71(d,J＝2.2Hz,1H),7.67-7.49(m,6H),7.43(dd,J＝8.8,2.3Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7 Hz,1H).ESI-MS:m/z 569.2[M+Na] +.
实施例7
2',6'-二氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-7)
Figure PCTCN2020120279-appb-000055
参照实施例1的方法，将I-1替换成2-溴-1,3-二氟苯，制得化合物A-7: 1H NMR(300MHz,DMSO-d 6)δppm 10.17(s,1H),9.37(s,2H),8.02(d,J＝8.1Hz,2H),7.83(dd,J＝8.4,5.3Hz,2H),7.70(s,1H),7.60(d,J＝7.8Hz,2H),7.51(d,J＝8.1Hz,1H),7.47-7.18(m,5H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 497.2[M-H] -.
实施例8
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2'-甲氧基-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-8)
Figure PCTCN2020120279-appb-000056
参照实施例1的方法，将I-1替换成1-溴-2-甲氧基-4-(三氟甲基)苯，制得化合物A-8: 1H NMR(300MHz,DMSO-d 6)δppm 10.12(s,1H),9.34(s,2H),7.98(d,J＝8.2Hz,2H),7.83(dd,J＝8.7,5.2Hz,2H),7.70(d,J＝2.2Hz,1H),7.64(d,J＝8.1Hz,2H),7.57(d,J＝8.1Hz,1H),7.48-7.30(m,5H),6.70(d,J＝8.7Hz,1H),3.88(s,3H).ESI-MS:m/z 559.2[M-H] -.
实施例9
2'-氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-9)
Figure PCTCN2020120279-appb-000057
参照实施例1的方法，将I-1替换成1-溴-2-氟-4-(三氟甲基)苯，制得化合物A-9: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.36(s,2H),8.07(d,J＝8.1Hz,2H),7.89-7.80(m,4H),7.79-7.68(m,4H),7.43(dd,J＝8.9,2.3Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 547.2[M-H] -.
实施例10
2'-溴-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-10)
Figure PCTCN2020120279-appb-000058
参照实施例1的方法，将I-1替换成1-碘-2-溴-4-(三氟甲基)苯，制得化合物A-10: 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.36(s,2H),8.16(s,1H),8.03(d,J＝8.1Hz,2H),7.94-7.78(m,3H),7.71(s,1H),7.66(d,J＝7.9Hz,1H),7.58(d,J＝8.1Hz,2H),7.42(dd,J＝8.9,2.4Hz,1H),7.36(dd,J＝8.8,8.8Hz,2H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 607.1[M-H] -.
实施例11
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1':2',1″-三联苯]-4-甲酰胺(化合物A-11)
Figure PCTCN2020120279-appb-000059
参照实施例1的方法，将I-1替换成2-溴基-1,1'-联苯，制得化合物A-11: 1H NMR(300MHz,DMSO-d 6)δppm 10.03(s,1H),9.33(s,2H),7.89-7.75(m,3H),7.67(brs.,1H),7.58-7.31(m,7H),7.30-7.09(m,7H),6.68(d,J＝8.7Hz,1H).ESI-MS:m/z 537.2[M-H] -.
实施例12
4'-氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-12)
Figure PCTCN2020120279-appb-000060
将化合物I-9(200mg,1.11mmol)溶于THF(10mL)，加入NaOH(98mg,2.44mmol)，水(1mL)，加热回流3h。冷却室温，用1N HCl调节pH值至3-4，加入水(10mL)和EtOAc(30mL)，摇匀分液，有机相依次用水(10mL)，饱和食盐水洗涤(10mL)，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得残留物得白色固体即化合物I-10(174mg,95％)。
将化合物I-11(150mg,0.86mmol)，4-羧基苯硼酸(156mg,0.94mmol)，无水K 2CO 3(355mg,2.57mmol)，Pd(PPh 3) 4(50mg,0.04mmol)加入Toluene(Tol)(10mL)和MeOH(2mL)中，氮气氛围80℃，反应3h。冷却室温，减压蒸除溶剂，加入水(5mL)，用1N HCl调节pH值至3-4，过滤并水洗滤饼得灰白色固体即化合物I-12(154mg,83％)。
参照实施例1的方法，将I-3替换成I-12，制得化合物A-12: 1H NMR(300MHz,DMSO-d 6)δppm 10.11(s,1H),9.40(s,1H),9.30(s,1H),8.03(d,J＝8.3Hz,2H),7.87-7.74(m,6H),7.71(d,J＝2.4Hz,1H),7.42(dd,J＝8.8,2.4Hz,1H),7.38(d,J＝9.1Hz,2H),7.32(d,J＝9.0Hz,2H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 479.1[M-H] -.
实施例13
3-氯-4'-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-[1,1'-联苯基]-4-羧酸甲酯(化合物A-13)
Figure PCTCN2020120279-appb-000061
将化合物I-13(500mg,2.12mmol)溶于MeOH(5mL)，滴加氯化亚砜(0.77mL,10.62mmol)，室温反应10h。减压蒸除溶剂得残留物，加入水(15mL)和EtOAc(40mL)，摇匀分液，有机相依次用饱和NaHCO 3(10mL)水溶液，水(10mL)，饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得残留物得黄色液体即化合物I-14(500mg,95％)。
参照实施例12的方法，将I-11替换成I-14，制得化合物A-13: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.38(s,2H),8.08(d,J＝8.2Hz,2H),7.97(s,1H),7.94-7.90(m,3H),7.86-7.82(m,3H),7.73(d,J＝1.9Hz,1H),7.44(dd,J＝8.7,1.9Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.72(d,J＝8.7Hz,1H),3.89(s,3H). ESI-MS:m/z 553.2[M-H] -.
实施例14
4-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)苯甲酰胺(化合物A-14)
Figure PCTCN2020120279-appb-000062
参照实施例12的方法，将I-11替换成6-溴-1,4-苯并恶烷，制得化合物A-14: 1H NMR(300MHz,DMSO-d 6)δppm 10.09(s,1H),9.36(s,2H),7.99(d,J＝8.3Hz,2H),7.83(dd,J＝8.6,5.3Hz,2H),7.75(d,J＝8.3Hz,2H),7.71(d,J＝2.3Hz,1H),7.43(dd,J＝8.8,2.4Hz,1H),7.37(dd,J＝8.8Hz,2H),7.29-7.19(m,2H),6.97(d,J＝8.2Hz,1H),6.70(d,J＝8.7Hz,1H),4.29(brs.,4H).ESI-MS:m/z 519.2[M-H] -.
实施例15
4-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)苯甲酰胺(化合物A-15)
Figure PCTCN2020120279-appb-000063
参照实施例12的方法，将I-11替换成4-溴-1,2-亚甲二氧基苯，制得化合物A-15: 1H NMR(300MHz,DMSO-d 6)δppm 10.09(s,1H),9.41(s,1H),9.32(s,1H),7.99(d,J＝8.3Hz,2H),7.83(dd,J＝8.7,5.3Hz,2H),7.76(d,J＝8.3Hz,2H),7.71(d,J＝2.3Hz,1H),7.43(dd,J＝8.8,2.4Hz,1H),7.40-7.32(m,3H),7.26(d,J＝8.1Hz,1H),7.04(d,J＝8.1Hz,1H),6.70(d,J＝8.7Hz,1H),6.09(s,2H).ESI-MS:m/z 505.2[M-H] -.
实施例16
2'-氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-16)
Figure PCTCN2020120279-appb-000064
参照实施例12的方法，将I-11替换成1-溴-2-氟苯，制得化合物A-16: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.37(s,2H),8.04(d,J＝8.3Hz,2H), 7.84(dd,J＝8.8,5.2Hz,2H),7.72(d,J＝2.0Hz,2H),7.69(d,J＝1.1Hz,1H),7.61(td,J＝7.7,1.4Hz,1H),7.53-7.30(m,6H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 479.1[M-H] -.
实施例17
3'-氯-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-17)
Figure PCTCN2020120279-appb-000065
参照实施例12的方法，将I-11替换成1-溴-3-氯苯，制得化合物A-17: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.42(s,1H),9.31(s,1H),8.05(d,J＝8.4Hz,2H),7.91-7.80(m,5H),7.77-7.70(m,2H),7.54(dd,J＝7.7,7.7Hz,1H),7.51-7.46(m,1H),7.44(dd,J＝8.8,2.5Hz,1H),7.37(dd,J＝8.9,8.9Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 495.1[M-H] -.
实施例18
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-3',5'-双(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-18)
Figure PCTCN2020120279-appb-000066
参照实施例12的方法，将I-11替换成1-溴-3,5-双(三氟甲基)苯，制得化合物A-18: 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),9.44(s,1H),9.34(s,1H),8.44(s,2H),8.20-8.02(m,5H),7.85(dd,J＝8.8,5.2Hz,2H),7.74(d,J＝2.4Hz,1H),7.46(dd,J＝8.7,2.4Hz,1H),7.39(dd,J＝8.9,8.9Hz,2H),6.73(d,J＝8.7Hz,1H).ESI-MS:m/z 597.0[M-H] -.
实施例19
2',3'-二氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-19)
Figure PCTCN2020120279-appb-000067
参照实施例12的方法，将I-11替换成1-溴-2,3-二氟苯，制得化合物A-19: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.42(s,1H),9.31(s,1H),8.06(d, J＝8.3Hz,2H),7.84(dd,J＝8.8,5.3Hz,2H),7.77-7.68(m,3H),7.58-7.29(m,6H),6.72(d,J＝8.7Hz,1H).ESI-MS:m/z 497.0[M-H] -.
实施例20
2',3'-二氯-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-20)
Figure PCTCN2020120279-appb-000068
参照实施例12的方法，将I-11替换成1-溴-2,3-二氯苯，制得化合物A-20: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.36(s,2H),8.02(d,J＝8.2Hz,2H),7.84(dd,J＝8.7,5.3Hz,2H),7.72(dd,J＝5.9,3.4Hz,2H),7.58(d,J＝8.2Hz,2H),7.52-7.30(m,5H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 529.1[M-H] -.
实施例21
2'-溴-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-21)
Figure PCTCN2020120279-appb-000069
参照实施例12的方法，将I-11替换成1-碘-2-溴苯，制得化合物A-21: 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.41(s,1H),9.30(s,1H),8.00(d,J＝8.1Hz,2H),7.84(dd,J＝8.6,5.3Hz,2H),7.78(d,J＝7.9Hz,1H),7.71(d,J＝2.1Hz,1H),7.54(d,J＝8.1Hz,2H),7.50(d,J＝7.9Hz,1H),7.47-7.32(m,5H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 539.1[M-H] -.
实施例22
4-氟-N4'-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-3,4'-二甲酰胺(化合物A-22)
Figure PCTCN2020120279-appb-000070
Figure PCTCN2020120279-appb-000071
将化合物I-5(500mg,1.76mmol)，DIPEA(435μL,2.64mmol)，DMAP(43mg,0.325mmol)溶于DCM(8mL)中，加入TBDPSCl(582mg,2.11mmol)的DCM(3mL)溶液，室温反应3h。减压蒸除溶剂得残留物，加入2N HCl(30mL)，EtOAc(30mL×2)萃取，合并有机相，依次用2N HCl(30mL)，NH 4Cl溶液(30mL)，饱和食盐水(30mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得残留物褐色油状物质即化合物I-15(定量)。
参照实施例1的方法，将I-6替换成I-15，将I-3替换成3'-氨基甲酰基-4'-氟-[1,1'-联苯基]-4-羧酸，制得化合物A-22: 1H NMR(300MHz,DMSO-d 6)δppm10.13(s,1H),9.40(s,1H),9.30(s,1H),8.05(d,J＝8.2Hz,2H),7.98(dd,J＝6.8,2.1Hz,1H),7.94-7.80(m,6H),7.75-7.66(m,2H),7.47-7.31(m,4H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 522.1[M-H] -.
实施例23
4'-氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-3'-氨磺酰基[1,1'-联苯]-4-甲酰胺(化合物A-23)
Figure PCTCN2020120279-appb-000072
将化合物2-氟-5-溴苯磺酰氯(1.1g,4mmol)溶于THF(5mL)，加入氨水(14mL)，室温反应过夜。加入H 2O(40mL)，EtOAc(30mL)提取，有机相饱和食盐水(30mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得残留物白色固体即化合物I-17(910mg,89％)。
参照实施例1的方法，将I-6替换成I-15，将I-0替换成I-17，制得化合物A-23: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.41(s,1H),9.30(s,1H),8.19-8.00(m,4H),7.93-7.68(m,7H),7.62-7.52(m,1H),7.47-7.40(m,1H),7.37(dd,J＝8.7,8.7Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 558.1[M-H]-.
实施例24
N 4'-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-3,4'-二甲酰胺(化合物A-24)
Figure PCTCN2020120279-appb-000073
参照实施例22的方法，将2-氟-5-溴苯甲酸替换成2-溴苯甲酸，制得化合物A-24: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.46-9.26(m,2H),8.27-8.21(m,1H),8.18-8.11(m,1H),8.07(d,J＝8.2Hz,2H),7.96-7.87(m,4H),7.83(dd,J＝8.6,5.3Hz,2H),7.72(d,J＝2.1Hz,1H),7.59(dd,J＝7.7,7.7Hz,1H),7.49-7.41(m,2H),7.37(dd,J＝8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 504.2[M-H] -.
实施例25
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4-(噻吩-2-基)苯甲酰胺(化合物A-25)
Figure PCTCN2020120279-appb-000074
参照实施例23的方法，将I-17替换成2-溴噻吩，制得化合物A-25: 1H NMR(300MHz,DMSO-d 6)δppm 10.10(s,1H),9.45-9.28(m,2H),7.99(d,J＝8.3Hz,2H),7.87-7.77(m,4H),7.70(d,J＝2.3Hz,1H),7.67(d,J＝3.6Hz,1H),7.64(d,J＝5.1Hz,1H),7.45-7.42(m,1H),7.37(dd,J＝8.8,8.8Hz,2H),7.19(dd,J＝4.9,3.8Hz,1H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 491.1[M+Na] +.
实施例26
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4-(吡嗪-2-基)苯甲酰胺(化合物A-26)
Figure PCTCN2020120279-appb-000075
参照实施例23的方法，将I-17替换成2-溴吡嗪，制得化合物A-26: 1H NMR(300MHz,DMSO-d 6)δppm 10.20(s,1H),9.44-9.31(m,3H),8.80-8.75(m,1H),8.68(d,J＝2.5Hz,1H),8.30(d,J＝8.4Hz,2H),8.10(d,J＝8.4Hz,2H),7.83(dd,J＝8.8,5.2Hz,2H),7.72(d,J＝2.4Hz,1H),7.44(dd,J＝8.8,2.4Hz,1H),7.37(dd,J＝8.9Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 487.1[M+Na] +.
实施例27
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4-(嘧啶-2-基)苯甲酰胺(化合物A-27)
Figure PCTCN2020120279-appb-000076
参照实施例23的方法，将I-17替换成2-溴嘧啶，制得化合物A-27: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(d,J＝15.2Hz,1H),9.42(s,1H),9.31(s,1H),8.97(d,J＝4.8Hz,2H),8.51(d,J＝8.3Hz,2H),8.09(d,J＝8.3Hz,2H),7.84(dd,J＝8.7,5.3Hz,2H),7.72(d,J＝2.1Hz,1H),7.51(dd,J＝4.8,4.8Hz,1H),7.44(dd,J＝8.7,2.2Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 487.1[M+Na] +.
实施例28
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-3'-甲氧基-[1,1'-联苯]-4-甲酰胺(化合物A-28)
Figure PCTCN2020120279-appb-000077
参照实施例12的方法，将I-11替换成1-溴-3-甲氧基苯，制得化合物A-28: 1H NMR(300MHz,DMSO-d 6)δppm 10.12(s,1H),9.45-9.26(m,2H),8.03(d,J＝8.4Hz,2H),7.88-7.79(m,4H),7.72(d,J＝2.5Hz,1H),7.47-7.25(m,6H),6.99(dd,J＝8.1,1.8Hz,1H),6.70(d,J＝8.7Hz,1H),3.85(s,3H).ESI-MS:m/z 491.2[M-H] -.
实施例29
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-3'-(三氟甲氧基)-[1,1'-联苯]-4-甲酰胺(化合物A-29)
Figure PCTCN2020120279-appb-000078
参照实施例12的方法，将I-11替换成1-溴-3-三氟甲氧基苯，制得化合物A-29: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.45-9.27(m,2H),8.06(d,J＝8.3Hz,2H),7.88(d,J＝8.3Hz,2H),7.86-7.80(m,3H),7.77-7.73(m,1H),7.71(d,J＝2.4Hz,1H),7.65(dd,J＝8.0Hz,1H),7.47-7.41(m,2H),7.37(dd,J＝8.9Hz,2H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 545.1[M-H] -.
实施例30
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-30)
Figure PCTCN2020120279-appb-000079
参照实施例12的方法，将I-11替换成1-溴-4-三氟甲基苯，制得化合物A-30: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.39(s,1H),9.32(s,1H),8.08(d,J＝8.4Hz,2H),7.99(d,J＝8.2Hz,2H),7.94-7.80(m,6H),7.72(d,J＝2.5Hz,1H),7.43(dd,J＝8.7,2.5Hz,1H),7.37(dd,J＝8.9,8.9Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 529.1[M-H] -.
实施例31
4'-氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-3'-甲氧基-[1,1'-联苯]-4-甲酰胺(化合物A-31)
Figure PCTCN2020120279-appb-000080
参照实施例13的方法，将I-13替换成5-溴-2-氟苯酚，制得化合物A-31: 1H NMR(300MHz,DMSO-d 6)δppm 10.11(s,1H),9.43-9.29(m,2H),8.03(d,J＝8.2Hz,2H),7.90-7.77(m,4H),7.71(d,J＝2.0Hz,1H),7.53-7.26(m,6H),6.70(d,J＝8.7Hz,1H),3.96(s,3H).ESI-MS:m/z 509.1[M-H] -.
实施例32
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)喹啉-6-甲酰胺(化合物A-32)
Figure PCTCN2020120279-appb-000081
参照实施例1的方法，将I-3替换成喹啉-6-羧酸，制得化合物A-32: 1H NMR(300MHz,DMSO-d 6)δppm 10.33(s,1H),9.45(s,1H),9.33(s,1H),9.01(d,J＝4.1Hz,1H),8.60(s,1H),8.53(d,J＝8.2Hz,1H),8.24(d,J＝9.0Hz,1H),8.12(d,J＝8.8Hz,1H),7.84(dd,J＝7.9,5.4Hz,2H),7.74(d,J＝1.3Hz,1H),7.64(dd,J＝8.2,4.2Hz,1H),7.46(dd,J＝8.8,1.5Hz,1H),7.37(dd,J＝8.5Hz,2H),6.72(d,J＝8.7Hz,1H).ESI-MS:m/z 438.1[M+H] +.
实施例33
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-33)
Figure PCTCN2020120279-appb-000082
参照实施例1的方法，将I-3替换成4-苯基苯甲酸，制得化合物A-33: 1H NMR(300MHz,DMSO-d 6)δppm 10.12(s,1H),9.36(s,2H),8.04(d,J＝8.3Hz,2H),7.90-7.69(m,7H),7.58-7.32(m,6H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 461.1[M-H] -.
实施例34
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-甲酰胺(化合物A-34)
Figure PCTCN2020120279-appb-000083
将化合物I-18(336mg,2mmol)，K 2CO 3(838mg,6mmol)，1,2-二溴乙烷(173μL,2mmol)溶于DMSO(10mL)，升温至100℃反应10h。加入EtOAc(40mL)稀释，有机相依次用1N HCl(30mL)和饱和食盐水(30mL)洗涤，硅胶柱层析(石油醚/EtOAc＝25/1)纯化，减压蒸除溶剂，得无色油状物即化合物I-19(173mg,45％)。
将化合物I-19(173mg,0.89mmol)溶于THF(2mL)，MeOH(2mL)，加入NaOH(54mg,1.34mmol)的H 2O(2mL)溶液，升温至50℃反应1h。冷却至室温，减压蒸除有机溶剂得残留物，加入1N HCl调节pH至1-3，析出白色固体，抽滤，1N HCl(5mL)洗涤滤饼，干燥至恒重，得白色固体即化合物I-20(127mg,80％)。 1H NMR(300MHz,DMSO-d 6)δppm 12.63(s,1H),7.43(dd,J＝8.4,2.0Hz,1H),7.37(d,J＝2.0Hz,1H),6.93(d,J＝8.4Hz,1H),4.34-4.24(m,4H).
参照实施例1的方法，将I-3替换成I-20，制得化合物A-34: 1H NMR(300MHz,DMSO-d 6)δppm 9.86(s,1H),9.40-9.21(m,2H),7.82(dd,J＝8.8,5.2Hz,2H),7.66(d,J＝2.4Hz,1H),7.53-7.43(m,2H),7.42-7.30(m,3H),6.96(d,J＝8.3Hz,1H),6.67(d,J＝8.7Hz,1H),4.30(s,4H).ESI-MS:m/z 443.1[M-H] -.
实施例35
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2-萘甲酰胺(化合物A-35)
Figure PCTCN2020120279-appb-000084
参照实施例1的方法，将I-3替换成2-萘甲酸，制得化合物A-35: 1H NMR(300MHz,DMSO-d 6)δppm 10.25(s,1H),9.37(s,2H),8.55(s,1H),8.14-7.95(m,4H),7.84(dd,J＝8.6,5.3Hz,2H),7.74(d,J＝2.2Hz,1H),7.69-7.57(m,2H),7.46(dd,J＝8.7,2.2Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.72(d,J＝8.7Hz,1H).ESI-MS:m/z 435.1[M-H] -.
实施例36
4'-((3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-[1,1'-联苯基]-3-羧酸甲酯(化合物A-36)
Figure PCTCN2020120279-appb-000085
参照实施例13的方法，将I-13替换成3-溴苯甲酸，制得化合物A-36: 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.42(s,1H),9.32(s,1H),8.29-8.25(m,1H),8.11-7.98(m,4H),7.91-7.79(m,4H),7.72(d,J＝2.4Hz,1H),7.68(dd,J＝7.8,7.8Hz,1H),7.44(dd,J＝8.7,2.5Hz,1H),7.37(dd,J＝8.9,8.9Hz,2H),6.71(d,J＝8.8Hz,1H),3.91(s,3H).ESI-MS:m/z 519.2[M-H] -.
实施例37
4-氯-4'-((3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-[1,1'-联苯基]-3-羧酸甲酯(化合物A-37)
Figure PCTCN2020120279-appb-000086
参照实施例13的方法，将I-13替换成2-氯-5-溴苯甲酸，制得化合物A-37: 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.43(s,1H),9.33(s,1H),8.15(d,J＝2.1Hz,1H),8.06(d,J＝8.3Hz,2H),7.97(dd,J＝8.5,2.2Hz,1H),7.88(d,J＝8.3Hz,2H),7.83(dd,J＝8.8,5.4Hz,2H),7.74-7.68(m,2H),7.43(dd,J＝8.8,2.3Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.70(d,J＝8.7Hz,1H),3.91(s,3H).ESI-MS:m/z 553.1[M-H] -.
实施例38
4'-((3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-[1,1'-联苯基]-4-羧酸(化合物A-38)
Figure PCTCN2020120279-appb-000087
将化合物A-3(407mg,0.78mmol)加入水(3mL)、THF(3mL)、MeOH(3mL),NaOH(122mg,3.05mmol)，室温反应2h。用1N HCl调节pH至3-4，加水稀释，过滤并水洗；滤饼加入EtOAc(5mL)搅拌1h，过滤并用EtOAc(1mL)洗涤，得淡黄色固体即化合物A-38(262mg,66％)。 1H NMR(300MHz,DMSO-d 6)δppm 13.03(s,1H),10.15(s,1H),9.38(s,2H),8.06(dd,J＝8.2,1.9Hz,4H),7.89(d,J＝8.2Hz,4H),7.83(dd,J＝8.6,5.3Hz,2H),7.71(d,J＝2.2Hz,1H),7.43(dd,J＝8.7,2.2Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 505.1[M-H] -.
实施例39
3-氯-4'-((3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-[1,1'-联苯]-4-羧酸(化合物A-39)
Figure PCTCN2020120279-appb-000088
参照实施例38的方法，将A-3替换成A-13，制得化合物A-39: 1H NMR(300MHz,DMSO-d 6)δppm 13.43(s,1H),10.16(s,1H),9.41(s,1H),9.31(s,1H),8.07(d,J＝8.4Hz,2H),8.00-7.87(m,3H),8.00-7.88(m,3H),7.87-7.77(m,2H),7.71(d,J＝2.5Hz,1H),7.43(dd,J＝8.8,2.5Hz,1H),7.37(dd,J＝8.9,8.9Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 539.1[M-H] -.
实施例40
3-氯-4'-((3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-[1,1'-联苯]-3-羧酸(化合物A-40)
Figure PCTCN2020120279-appb-000089
参照实施例38的方法，将A-3替换成A-36，制得化合物A-40: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.62-9.17(m,2H),8.29-8.23(m,1H),8.07(d,J＝8.0Hz,2H),8.03-7.97(m,2H),7.93-7.80(m,4H),7.75-7.69(m,1H),7.64(dd,J＝7.7,7.7Hz,1H),7.43(dd,8.7,1.6Hz,1H),7.37(dd,J＝8.7,8.7Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 505.1[M-H] -.
实施例41
4-氯-4'-((3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-[1,1'-联苯基]-3-羧酸(化合物A-41)
Figure PCTCN2020120279-appb-000090
参照实施例38的方法，将A-3替换成A-37，制得化合物A-41: 1H NMR(300MHz,DMSO-d 6)δppm 13.54(s,1H),10.14(s,1H),9.40(s,1H),9.29(s,1H),8.11(d,J＝2.1Hz,1H),8.06(d,J＝8.3Hz,2H),7.96-7.78(m,5H),7.71(d,J＝2.3Hz,1H),7.67(d,J＝8.4Hz,1H),7.43(dd,J＝8.8,2.4Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 539.1[M-H] -.
实施例42
3-氯-N 4'-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-N 4-羟基-[1,1'-联苯基]-4,4'-二甲酰胺(化合物A-42)
Figure PCTCN2020120279-appb-000091
将化合物A-39(70mg,0.13mmol)溶于THF(2mL)，加入N-甲基吗啉(39mg,0.39mmol)，滴加氯甲酸乙酯(34mg,0.31mmol)的THF(1mL)溶液，室 温反应0.5h。过滤并THF(1mL)洗涤滤饼，将滤液滴加到50％(w/w)NH 2OH(2mL)水溶液中，反应0.5h。加入水(10mL)和EtOAc(20mL)分液，有机相依次用1N HCl(10mL)，水(10mL)，饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得白色固体，硅胶柱层析(DCM/MeOH＝10/1)得化合物A-42(17mg,24％)。 1H NMR(300MHz,DMSO-d 6)δppm 11.03(s,1H),10.15(s,1H),9.31(s,3H),8.10-8.00(m,2H),7.89(d,J＝8.4Hz,3H),7.83(dd,J＝8.8,5.5Hz,2H),7.80-7.75(m,1H),7.52(d,J＝7.9Hz,1H),7.42(dd,J＝8.9,2.0Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 554.1[M-H] -.
实施例43
N 4-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-N 4'-羟基-[1,1'-联苯基]-4,4'-二甲酰胺(化合物A-43)
Figure PCTCN2020120279-appb-000092
参照实施例42的方法，将A-39替换成A-38，制得化合物A-43: 1H NMR(300MHz,DMSO-d 6)δppm 10.12(s,1H),9.28(brs.,2H),8.05(d,J＝8.2Hz,2H),7.93-7.78(m,6H),7.69(d,J＝1.8Hz,1H),7.39(d,J＝7.4Hz,1H),7.34(dd,J＝8.8,8.8Hz,2H),6.69(d,J＝8.7Hz,1H).ESI-MS:m/z 520.1[M-H] -.
实施例44
N 4'-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-N 3-羟基-[1,1'-联苯]-3,4'-二甲酰胺(化合物A-44)
Figure PCTCN2020120279-appb-000093
参照实施例42的方法，将A-39替换成A-40，制得化合物A-44: 1H NMR(300MHz,DMSO-d 6)δppmδ10.12(s,1H),9.54-9.11(m,2H),8.14-8.10(m,1H),8.06(d,J＝8.0Hz,2H),7.94-7.78(m,6H),7.69(d,J＝1.3Hz,1H),7.59(dd,J＝7.6,7.6Hz,1H),7.44-7.30(m,3H),6.69(d,J＝8.6Hz,1H).ESI-MS:m/z 520.2[M-H] -.
实施例45
4'-((3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-3-羟基-[1,1'-联苯]-4-羧酸(化合物A-45)
Figure PCTCN2020120279-appb-000094
将化合物2-羟基-4-溴苯甲酸(I-21)(1.3g,6.0mmol)溶于DMF(15mL)，加入K 2CO 3(2.5g,18.0mmol)，滴加BnBr(1.6mL,13.2mmol)，室温反应过夜。加入H 2O(150mL)，EtOAc(50mL)提取，有机相依次用NaOAc溶液(40mL),饱和食盐水(40mL)洗涤,无水Na 2SO 4干燥,过滤，减压蒸除溶剂，得棕黄色固体即化合物I-22(2.34g,98％)。
将化合物I-22(1.4g,3.5mmol)，4-硼酸苯甲酸(640mg,3.85mmol)，K 2CO 3(1.45g,10.5mmol)，Pd(PPh 3) 4(202mg,0.175mmol)混合于Tol(20mL)、MeOH(8mL)，氮气氛围下升温至80℃反应4h。减压蒸除有机溶剂，加入1N HCl(60mL)，EtOAc(50mL)，摇匀后抽滤，收集有机相，水相EtOAc(20mL)提取，合并有机相，饱和食盐水(40mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得残留物，加入DCM/EtOAc＝1:5(15mL)搅拌1h，抽滤，得灰白色固体即化合物I-23(900mg,58％)。 1H NMR(300MHz,DMSO-d 6)δppm 13.04(s,1H),8.05(d,J＝8.3Hz,2H),7.88(d,J＝8.4Hz,2H),7.84(d,J＝8.1Hz,1H),7.61-7.28(m,12H),5.35(s,2H),5.33(s,2H).
将化合物I-23(710mg,1.62mmol)溶于THF(2mL)、DCM(10mL)中，加入HATU(740mg,1.94mmol)，室温反应2h，加入I-6(706mg,1.78mmol)，反应2h。减压蒸除有机溶剂，加入饱和氯化铵水溶液(50mL)，EtOAc(20mL×3)萃取；合并有机相，依次用饱和氯化铵水溶液(30mL)，饱和食盐水(30mL)洗涤，硅胶柱层析(DCM)，减压蒸除溶剂，得黄棕色油状液体即化合物I-24，直接用于下一步反应。
将化合物I-24溶于DCM(10mL)中，加入TEA·3HF(210μL)，室温反应过 夜。减压蒸除溶剂，残余物经硅胶柱层析(DCM/MeOH＝100/1)纯化，得粉白色固体即化合物I-25(400mg,35％,two steps)。
将化合物I-25(100mg,0.14mmol)，甲酸铵(180mg,2.8mmol)混于MeOH(7mL)，加入10％Pd/C(10mg)，升温至80℃反应3h。硅藻土抽滤,母液硅胶柱层析(DCM/MeOH＝15/1(+AcOH))，减压蒸除溶剂，残余物经无水乙醚(3mL)打浆,抽滤，得墨绿色固体即化合物A-45(17mg,23％)。 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.42(s,1H),9.31(s,1H),8.05(d,J＝8.3Hz,2H),7.93-7.80(m,5H),7.71(d,J＝2.1Hz,1H),7.43(dd,J＝9.0,2.2Hz,1H),7.40-7.29(m,4H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 521.1[M-H] -.
实施例46
3'-氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-羟基-[1,1'-联苯基]-4-甲酰胺(化合物A-46)
Figure PCTCN2020120279-appb-000095
参照实施例45的方法，将I-21替换成2-氟-4-溴苯酚，最终通过Pd/C催化脱苄，制得化合物A-46: 1H NMR(300MHz,DMSO-d 6)δppm 10.22-10.00(m,2H),9.49-9.21(m,2H),8.00(d,J＝8.3Hz,2H),7.83(dd,J＝8.7,5.3Hz,2H),7.77(d,J＝8.3Hz,2H),7.71(d,J＝2.2Hz,1H),7.60(dd,J＝12.7,1.8Hz,1H),7.47-7.40(m,2H),7.37(dd,J＝8.9,8.9Hz,2H),7.06(dd,J＝8.8,8.8Hz,1H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 495.1.1[M-H] -.
实施例47
4'-((3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-4-羟基-[1,1'-联苯]-3-羧酸(化合物A-47)
Figure PCTCN2020120279-appb-000096
参照实施例45的方法，将I-21替换成2-羟基-5-溴苯甲酸，最终通过Pd/C催化脱苄，制得化合物A-47: 1H NMR(300MHz,DMSO-d 6)δppm 12.49(s,1H),10.10(s,1H),9.40(s,1H),9.30(s,1H),8.13(d,J＝1.8Hz,1H),8.02(d,J＝8.2Hz,1H),7.92(dd,J＝8.6,1.9Hz,1H),7.83(dd,J＝8.5,5.4Hz,1H),7.78(d,J＝8.2Hz,1H),7.43(dd,J＝9.0,2.0Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),7.08(d,J＝8.6Hz, 1H).ESI-MS:m/z 521.1[M-H] -.
实施例48
N 4'-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4-羟基-[1,1'-联苯基]-3,4'-二甲酰胺(化合物A-48)
Figure PCTCN2020120279-appb-000097
将化合物I-26(500mg,2.30mmol)，K 2CO 3(954mg,6.91mmol)加入DMF(4mL)，加入BnBr(0.60mL,5.06mmol)，室温反应2h。加入水(20mL)和EtOAc(50mL)分液，有机相依次用水(10mL)，饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得残留物即化合物I-27。
将上述所得残留物I-27溶于THF(5mL)，MeOH(5mL)，2N NaOH(5mL)，室温反应5h。减压蒸除溶剂，1N HCl调节pH至3-4，加入水(20mL)和EtOAc(50mL)分液，有机相依次用水(10mL)，饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝30/1)纯化，得化合物I-28。
将上述所得化合物I-28溶于DCM(5mL)，加1滴DMF，滴加草酰氯(0.50mL)，室温反应4h。减压蒸除溶剂，残留物用THF(2mL)溶解，滴加氨水(5mL)，室温反应2h。加入水(10mL)和EtOAc(30mL)分液，有机相依次用水(10mL)，饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，向残留物加入EtOAc(1mL)和石油醚(20mL)析出白色固体，过滤，得白色固体即化合物I-29(77mg,11％)。
参照实施例45的方法,将I-22替换成I-29,最终通过Pd/C催化脱苄，制得化合物A-48: 1H NMR(300MHz,DMSO-d 6)δppm 13.21(s,1H),10.09(s,1H),9.40(s,1H),9.31(s,1H),8.64(s,1H),8.29(s,1H),8.15-7.95(m,3H),7.94-7.76(m,5H),7.71(d,J＝1.7Hz,1H),7.44(dd,J＝8.7,2.0Hz,1H),7.37(dd,J＝9.0,9.0Hz,2H),7.01(d,J＝8.6Hz,1H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 520.2[M-H] -.
实施例49
N 4'-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-3-羟基-[1,1'-联苯基]-4,4'-二甲酰胺(化合物A-49)
Figure PCTCN2020120279-appb-000098
参照实施例38的方法,将A-3替换成I-25,得化合物I-30。
参照实施例42的方法,将A-39替换成I-30,制得化合物I-31: 1H NMR(300MHz,DMSO-d 6)δppm 10.67(s,1H),10.13(s,1H),9.36(s,2H),9.15(s,1H),8.05(d,J＝8.2Hz,2H),7.89-7.79(m,4H),7.72(d,J＝2.3Hz,1H),7.65(d,J＝7.9Hz,1H),7.55(d,J＝7.2Hz,2H),7.50(s,1H),7.47-7.29(m,7H),6.71(d,J＝8.7Hz,1H),5.39(s,2H).
将化合物I-31(45mg)，10％Pd/C(5mg)加入THF(5mL),H 2氛围室温反应10h。过滤，减压蒸除溶剂，残留物经硅胶柱层析纯化(DCM/MeOH＝10/1)，得化合物A-49(7mg,19％): 1H NMR(300MHz,DMSO-d 6)δppm 13.18(s,1H),10.13(s,1H),9.34(s,2H),8.46(s,1H),8.04(d,J＝8.3Hz,1H),7.97(d,J＝8.2Hz,1H),7.91-7.77(m,4H),7.71(d,J＝2.3Hz,1H),7.43(dd,J＝8.9,2.4Hz,1H),7.37(dd,J＝8.9,8.9Hz,2H),7.28(d,J＝9.0Hz,2H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 520.2[M-H] -.
实施例50
N 4'-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-N 4,3-二羟基-[1,1'-联苯基]-4,4'-二甲酰胺(化合物A-50)
Figure PCTCN2020120279-appb-000099
Figure PCTCN2020120279-appb-000100
参照实施例45的方法,将I-22替换成I-31,最终通过Pd/C催化脱苄，制得化合物A-50: 1H NMR(300MHz,DMSO-d 6)δppm 12.44(s,1H),11.54(s,1H),10.14(s,1H),9.38(s,3H),8.04(d,J＝8.2Hz,2H),7.89-7.84(m,2H),7.83-7.87(m,3H),7.71(d,J＝2.1Hz,1H),7.43(d,J＝9.0Hz,1H),7.37(dd,J＝8.8Hz,2H),7.31-7.23(m,2H),6.70(d,J＝8.8Hz,1H).ESI-MS:m/z 536.2[M-H] -.
实施例51
3',5'-二氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-51)
Figure PCTCN2020120279-appb-000101
将化合物2,4-二氟溴苯(97mg,0.5mmol)，I-10(113mg,0.55mmol)，K 2CO 3(207mg,0.5mmol)，Pd(PPh 3) 4(30mg,0.025mmol)混溶于Tol(8mL)、MeOH(2mL)中，氮气氛围下升温至80℃反应4h。减压蒸除溶剂，加入1N HCl调节pH至1-3，搅拌，抽滤，水洗涤，干燥至恒重，石油醚/EtOAc＝2:1(6mL)打浆，抽滤，得白色固体即化合物I-33(90mg,77％).
将化合物I-33(80mg,0.34mmol)溶于DCM(5mL)、THF(1mL)中，加入草酰氯(100μL)，DMF(1drop)，室温反应3h。减压蒸除溶剂，将残留物溶于无水DCM(2mL)中制成酰氯的DCM溶液，在冰浴条件将其下加至I-6(135.5mg,0.34mmol)，DIPEA(100μL)的DCM(2mL)溶液中，室温反应。将反应液减压蒸除溶剂，残余物经硅胶柱层析(石油醚：EtOAc＝5：1)纯化，得化合物I-34，直接投下一步反应。
将化合物I-34溶于DCM(5mL)中，加入TEA·3HF(100μL)，室温下反应5 h，析出白色固体，抽滤，滤饼依次用DCM(3mL)、1N HCl(5mL)和H 2O(10mL)洗涤，干燥至恒重，得白色固体即化合物A-51(92mg,54％)。 1H NMR(300MHz,DMSO-d 6)δ10.15(s,1H),9.45-9.26(m,2H),8.05(d,J＝8.2Hz,2H),7.91(d,J＝8.3Hz,2H),7.83(dd,J＝8.6,5.3Hz,2H),7.71(d,J＝2.1Hz,1H),7.60-7.52(m,2H),7.43(dd,J＝8.8,2.2Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),7.33-7.24(m,1H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 521.1[M+Na] +.
实施例52
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-硝基[1,1'-联苯]-4-甲酰胺(化合物A-52)
Figure PCTCN2020120279-appb-000102
参照实施例51的方法，将I-32替换成4-溴硝基苯，制得化合物A-52: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.42(s,1H),9.31(s,1H),8.34(d,J＝8.7Hz,2H),8.08(dd,J＝10.6,8.7Hz,4H),7.95(d,J＝8.3Hz,2H),7.83(dd,J＝8.7,5.3Hz,2H),7.72(d,J＝2.2Hz,1H),7.44(dd,J＝8.8,2.3Hz,1H),7.37(t,J＝8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 506.1[M-H] -.
实施例53
4-(苯并[c][1,2,5]恶二唑-5-基)-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)苯甲酰胺(化合物A-53)
Figure PCTCN2020120279-appb-000103
将化合物4-溴-2-硝基苯胺(325mg,1.5mmol)，KOH(252mg,4.5mmol)混溶于EtOH(15mL)中，升温至60℃反应2h。冷却至室温，冰浴下加入NaOCl(4mL)，反应30min后抽滤，滤饼用EtOH(10mL)洗涤，减压蒸除溶剂，加入EtOAc(20mL)稀释，饱和食盐水(15mL)洗涤，无水Na 2SO 4干燥，过滤，加压蒸除溶剂，得黄色固体即化合物I-36(280mg,87％)。
将化合物I-36(280mg,1.3mmol)溶于EtOH(8mL)中，加入PPh 3(446mg,1.3mmol)，升温至70℃反应6h。将反应液减压蒸除溶剂，残余物经硅胶柱层析(石油醚/DCM＝10/1)纯化,得化合物I-37的粗品，直接投下一步反应。
参照实施例51的方法，将I-32替换成化合物I-37，制得化合物A-53: 1H NMR(300MHz,DMSO-d 6)δppm 10.20(s,1H),9.44-9.31(m,2H),8.46-8.42(m,1H),8.20(d,J＝9.4Hz,1H),8.14-8.00(m,5H),7.83(dd,J＝8.4,5.4Hz,2H),7.73(d,J＝1.9Hz,1H),7.44(dd,J＝8.7,2.0Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 503.1[M-H] -.
实施例54
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-(5-甲基-1,2,4-恶二唑-3-基)-[1,1'-联苯]-4-甲酰胺(化合物A-54)
Figure PCTCN2020120279-appb-000104
将化合物4-溴苯腈(364mg,2mmol)，50％(w/w)羟胺水溶液混溶于EtOH(6mL),升温至80℃反应1.5h。减压蒸除溶剂，加入正己烷(10mL)，再减压蒸除溶剂，得白色固体即化合物I-39，直接用于下一步反应。
将化合物I-39溶于DMSO(6mL)中，加入NaOH(120mg,3mmol)，乙酸甲酯(250μL)，室温反应过夜。加入EtOAc(20mL)稀释，分别用1N HCl(15mL)，H 2O(15mL)，NH 4Cl水溶液(15mL)，饱和食盐水(15mL)洗涤，干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚/DCM＝1/1)纯化，得白色固体即化合物I-40(290mg,61％,two steps)。
参照实施例51的方法，将I-32替换成I-40，制得化合物A-54: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.43-9.26(m,2H),8.12(d,J＝8.3Hz,2H),8.08(d,J＝8.3Hz,2H),7.97(d,J＝8.3Hz,2H),7.91(d,J＝8.3Hz,2H),7.84(dd,J＝8.6,5.3Hz,2H),7.72(d,J＝2.1Hz,1H),7.44(dd,J＝8.8,2.1Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7Hz,1H),2.69(s,3H).ESI-MS:m/z 567.2[M+Na] +.
实施例55
4'-氰基-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-55)
Figure PCTCN2020120279-appb-000105
参照实施例51的方法，将I-32替换成4-溴苯腈，制得化合物A-55: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.43(s,1H),9.33(s,1H),8.08(d,J＝8.2Hz,2H),8.02-7.95(m,4H),7.91(d,J＝8.2Hz,2H),7.83(dd,J＝8.5,5.3Hz,2H),7.72(d,J＝2.0Hz,1H),7.44(dd,J＝8.7,2.1Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 510.2[M+Na] +.
实施例56
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2-硝基-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-56)
Figure PCTCN2020120279-appb-000106
参照实施例1的方法，将I-3替换成2-硝基-4'-(三氟甲基)-[1,1'-联苯基]-4-羧酸，制得化合物A-56: 1H NMR(300MHz,DMSO-d 6)δppm 10.41(s,1H),9.50(s,1H),9.35(s,1H),8.61(s,1H),8.35(d,J＝8.0Hz,1H),7.92-7.80(m,4H),7.77(d,J＝8.0Hz,1H),7.71(d,J＝2.2Hz,1H),7.66(d,J＝8.1Hz,2H),7.45(d,J＝8.8Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.73(d,J＝8.8Hz,1H).ESI-MS:m/z 574.1[M-H] -.
实施例57
4-(苯并[d]噻唑-2-基-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)苯甲酰胺(化合物A-57)
Figure PCTCN2020120279-appb-000107
参照实施例51的方法，将I-32替换成2-溴苯并[d]噻唑，制得化合物A-57: 1H NMR(300MHz,DMSO-d 6)δppm 10.26(s,1H),9.45(s,1H),9.32(s,1H),8.29-8.17(m,3H),8.16-8.08(m,3H),7.84(dd,J＝8.8,5.3Hz,2H),7.72(d,J＝2.2Hz,1H),7.63-7.55(m,1H),7.55-7.47(m,1H),7.44(dd,J＝8.7,2.3Hz,1H),7.37(dd,J＝8.9,8.9Hz,2H),6.72(d,J＝8.7Hz,1H).ESI-MS:m/z 518.1[M-H] -.
实施例58
4'–((3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-[1,1'-联苯基]-2-羧酸甲酯(化合物A-58)
Figure PCTCN2020120279-appb-000108
参照实施例51的方法，将I-32替换成2-溴苯甲酸甲酯，制得化合物A-58: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),9.40(s,1H),9.29(s,1H),7.98(d,J＝8.2Hz,2H),7.88-7.78(m,3H),7.71(d,J＝2.3Hz,1H),7.67(ddd,J＝7.6,7.6,1.1Hz,1H),7.58-7.51(m,1H),7.50-7.46(m,1H),7.46-7.40(m,3H),7.37(dd,J＝8.9,8.9Hz,2H),3.62(s,3H).ESI-MS:m/z 543.2[M+Na] +.
实施例59
2'-氰基-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-59)
Figure PCTCN2020120279-appb-000109
参照实施例51的方法，将I-32替换成2-溴苯腈，制得化合物A-59: 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),9.42(s,1H),9.31(s,1H),8.08(d,J＝8.3Hz,2H),8.03-7.97(m,1H),7.88-7.80(m,3H),7.77-7.67(m,4H),7.64(ddd,J＝7.7,7.7,1.0Hz,1H),7.44(dd,J＝8.8,2.5Hz,1H),7.37(dd,J＝8.9,8.9Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 510.1[M+Na] +.
实施例60
N-3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-60)
Figure PCTCN2020120279-appb-000110
参照实施例51的方法，将I-32替换成1-溴-2-三氟甲基苯，制得化合物A-60: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.41(s,1H),9.30(s,1H),7.99(d,J＝8.1Hz,2H),7.90-7.80(m,3H),7.79-7.73(m,1H),7.71(d,J＝2.2Hz,1H),7.69-7.62(m,1H),7.51-7.41(m,4H),7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 553.1[M+Na] +.
实施例61
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-(三氟甲氧基)-[1,1'-联苯]-4-甲酰胺(化合物A-61)
Figure PCTCN2020120279-appb-000111
参照实施例51的方法，将I-32替换成1-溴-4-三氟甲氧基苯，制得化合物A-61: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.46–9.27(m,2H),8.05(d,J＝8.1Hz,2H),7.89(d,J＝8.6Hz,2H),7.86–7.77(m,4H),7.71(d,J＝1.8Hz,1H),7.50(d,J＝8.3Hz,2H),7.43(dd,J＝8.9,2.0Hz,1H),7.37(dd,J＝8.8Hz,2H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 569.2[M+Na] +.
实施例62
3',5'-二氯-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-62)
Figure PCTCN2020120279-appb-000112
将化合物2,4-二氯溴苯(97mg,0.5mmol)，4-甲氧羰基苯硼酸(91mg,0.55mmol)，K 2CO 3(207mg,1.5mmol)，Pd(PPh 3) 4(30mg,0.025mmol)混溶于甲苯(8mL)、MeOH(2mL)中，氮气氛围升温至80℃反应4h。减压蒸除溶剂，残余物经硅胶柱层析(石油醚/DCM(1/1):EtOAc＝40:1)纯化，得化合物I-42，直接用于下一步反应。
将化合物I-42溶于MeOH(6mL)、THF(3mL)中，加入NaOH(45mg)的H 2O(3mL)溶液，升温至50℃反应3h。减压蒸除溶剂，加入1N HCl调节pH至1-3，析出白色固体，抽滤，水洗涤，干燥至恒重，得白色固体即化合物I-43(120mg,90％)。
参照实施例51的方法，将I-33替换成I-43，制得化合物A-62: 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.45-9.29(m,2H),8.05(d,J＝8.2Hz,2H),7.91(d,J＝8.3Hz,2H),7.83(dd,J＝8.3,3.4Hz,4H),7.72(d,J＝2.1Hz,1H),7.67-7.64(m,1H),7.43(dd,J＝8.8,2.2Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 529.1[M-H] -.
实施例63
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2'-硝基[1,1'-联苯]-4-甲酰胺(化合物A-63)
Figure PCTCN2020120279-appb-000113
参照实施例62的方法，将I-41替换成1-溴-2-硝基苯，制得化合物A-63: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.43(s,1H),9.32(s,1H),8.08-8.02(m,1H),8.00(d,J＝8.2Hz,2H),7.88-7.77(m,3H),7.74-7.65(m,2H),7.64-7.58(m,1H),7.49(d,J＝8.2Hz,2H),7.43(dd,J＝9.0,2.3Hz,1H),7.37(dd,J＝8.9,8.9Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 506.2[M-H] -.
实施例64
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2'-(5-甲基-1,2,4-恶二唑-3-基)-[1,1'-联苯]-4-甲酰胺(化合物A-64)
Figure PCTCN2020120279-appb-000114
参照实施例54中I-40的合成方法，将I-38替换成I-44，制得化合物I-45。
参照实施例62的方法，将I-41替换成I-45，制得化合物A-64: 1H NMR(300MHz,DMSO-d 6)δppm 10.11(s,1H),9.45-9.27(m,2H),7.91(d,J＝8.3Hz,2H),7.87-7.78(m,3H),7.70(d,J＝2.5Hz,1H),7.67(dd,J＝7.5,1.4Hz,1H),7.59(ddd,J＝7.6,7.6,1.2Hz,1H),7.56-7.50(m,1H),7.46-.31(m,5H),6.70(d,J＝8.7Hz,1H),2.56(s,3H).ESI-MS:m/z 567.2[M+Na] +.
实施例65
4'-((3-((4-氟苯基)磺酰氨基)-4-羟基苯基)氨基甲酰基)-[1,1'-联苯基]-2-羧酸(化合物A-65)
Figure PCTCN2020120279-appb-000115
Figure PCTCN2020120279-appb-000116
将化合物2-溴苯甲酸(401mg,2mmol),K 2CO 3(552mg,4mmol)混于DMF(12mL)，加入BnBr(261μL,2.2mmol)，升温至75℃反应2h。加入EtOAc(30mL)稀释反应液，有机相分别用H 2O(20mL)、1N HCl(20mL)和饱和食盐水(20mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得无色油状液体即化合物I-47(562mg,96％)。
参照实施例62的方法，将I-41替换成I-47，制得化合物I-48。
将化合物I-48(415mg,0.58mmol)溶于THF(15mL)，加入10％Pd/C(70mg)，氢气氛围下室温反应5h。硅藻土抽滤，将滤液减压蒸除溶剂，残余物经硅胶柱层析(DCM/MeOH＝200/1)纯化，得化合物I-49。
将化合物I-49溶于DCM(8mL)，加入TEA·3HF(200μL)，室温反应过夜。减压蒸除DCM，加入EtOAc(15mL)稀释，分别用1N HCl(10mL)和饱和食盐水洗涤(10mL)，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，残余物用DCM/EtOAc(5mL/0.5mL)打浆，抽滤，滤饼干燥至恒重，得白色固体即化合物A-65(150mg,51％)。 1H NMR(300MHz,DMSO-d 6)δppm 12.83(s,1H),10.13(s,1H),9.64-8.96(m,2H),7.96(d,J＝8.2Hz,2H),7.89-7.77(m,3H),7.72(d,J＝2.4Hz,1H),7.61(ddd,7.4,7.4,1.1Hz,1H),7.55-7.49(m,1H),7.37(dd,J＝8.9Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 505.2[M-H] -.
实施例66
2'-乙酰氨基-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-66)
Figure PCTCN2020120279-appb-000117
参照实施例62中I-42的合成方法，将I-41替换成1-溴-2-硝基苯，制得化合物I-50。
将化合物I-50(292mg,1.14mmol)溶于THF(8mL)，加入10％Pd/C(30mg)， 氢气氛围下室温反应过夜。硅藻土抽滤，将滤液减压蒸除溶剂，得残留物即化合物I-51。
将化合物I-51溶于无水DCM(5mL)，加入DIPEA(300μL)，AcCl(200μL)，室温反应2.5h。将反应液减压蒸除溶剂，残余物经硅胶柱层析(石油醚：EtOAc＝10:1)纯化，得白色固体即化合物I-52(181mg,59％)。
参照实施例62的方法,将I-42替换成I-52，制得化合物A-66: 1H NMR(300MHz,DMSO-d 6)δppm 10.11(s,1H),9.44-9.25(m,3H),8.00(d,J＝8.2Hz,2H),7.84(dd,J＝8.7,5.3Hz,2H),7.72(d,J＝2.2Hz,1H),7.58-7.29(m,9H),6.70(d,J＝8.7Hz,1H),1.90(s,3H).ESI-MS:m/z 518.2[M-H] -.
实施例67
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-3-甲氧基-[1,1'-联苯]-4-甲酰胺(化合物A-67)
Figure PCTCN2020120279-appb-000118
将化合物II-0(200mg,0.92mmol)溶于DMF(4mL)，加入无水K 2CO 3(382mg,2.77mmol)，碘甲烷(127μL,2.03mmol)，室温反应5h。加入水(10mL)和EtOAc(20mL)，分液，有机相分别用水(10mL)，饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得油状物即化合物II-1(184mg,81％)。
将化合物II-1(184mg,0.75mmol)，苯硼酸(100mg,0.83mmol)，无水K 2CO 3(188mg,1.36mmol)，Pd(PPh 3) 4(40mg,0.04mmol)加入Tol(10mL)和MeOH(2mL)中，氮气氛围80℃反应3h。冷却室温，加入水(10mL)和EtOAc(20mL)，分液，有机相分别用1N HCl(10mL)、水(10mL)和饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得油状物即化合物II-2。
将化合物I1-2溶于THF(2mL)和MeOH(2mL)，加入2N NaOH(2mL)，室温反应2h。用1N HCl调节pH至3-4，EtOAc(20mL)提取，有机相分别用水(10mL)和饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶 剂，得白色固体即化合物II-3(133mg,78％)。 1H NMR(300MHz,DMSO-d 6)δppm13.00(s,1H),7.62(d,J＝9.4Hz,2H),7.51(d,J＝7.8Hz,2H),7.47-7.30(m,4H),3.82(s,3H).
将化合物II-3(125mg,0.55mmol)，DIPEA(0.14mL,0.83mmol)加入THF(4mL)中，加入HATU(250mg,0.66mmol)，室温反应1h后，加入化合物I-6(239mg,0.60mmol)室温反应5h。加入EtOAc(30mL)，水(10mL)摇匀分液，有机相分别用1N HCl(10mL)、水(10mL)和饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，将所得残留物加入DCM(10mL)，Et 3N .3HF(0.15mL)，室温反应4h，有固体析出，过滤，用DCM(1mL)、1N HCl(2mL)和水(4mL)洗涤滤饼，干燥，得类白色固体即化合物A-67(210mg,78％)。 1H NMR(300MHz,DMSO-d 6)δppm 10.09(s,1H),9.37(s,2H),7.83(dd,J＝8.3,5.4Hz,2H),7.70(d,J＝1.6Hz,1H),7.63(d,J＝7.6Hz,2H),7.53(d,J＝7.5Hz,2H),7.48-7.31(m,7H),6.71(d,J＝8.7Hz,1H),3.87(s,3H).ESI-MS:m/z 491.1[M-H] -.
实施例68
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2-甲氧基-[1,1'-联苯]-4-甲酰胺(化合物A-68)
Figure PCTCN2020120279-appb-000119
参照实施例67的方法，将II-0替换成3-羟基-4-溴苯甲酸，制得化合物A-68: 1H NMR(300MHz,DMSO-d 6)δppm 9.91(s,1H),9.34(s,2H),7.83(dd,J＝8.5,5.3Hz,2H),7.76(d,J＝7.4Hz,2H),7.71(d,J＝7.9Hz,1H),7.66(d,J＝2.1Hz,1H),7.51(dd,J＝7.4Hz,2H),7.43(d,J＝7.2Hz,1H),7.41-7.29(m,5H),6.69(d,J＝8.7Hz,1H),4.00(s,3H).ESI-MS:m/z 491.1[M-H] -.
实施例69
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2-甲氧基-[1,1'-联苯]-4-甲酰胺(化合物A-69)
Figure PCTCN2020120279-appb-000120
将化合物II-5(165mg,0.70mmol)，苯硼酸(94mg,0.77mmol)，无水K 2CO 3 (290mg,2.10mmol)，Pd(PPh 3) 4(40mg,0.03mmol)加入甲苯(10mL)和MeOH(2mL)中，氮气氛围80℃反应3h。冷却至室温，减压蒸除溶剂，加入水(5mL)，用1N HCl调节pH值至3-4，过滤，用水洗滤饼，得橘红色固体即化合物II-6(142mg,87％)。
参照实施例67的方法，将II-3替换成II-6，制得化合物A-69: 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),9.41(s,2H),8.12(s,1H),7.97(d,J＝8.0Hz,1H),7.83(dd,J＝7.3,5.3Hz,2H),7.70(s,1H),7.56(d,J＝8.0Hz,1H),7.53-7.31(m,8H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 519.1[M+Na] +.
实施例70
N-(3-((4-氟苯基)磺酰胺基)-4-羟基苯基)喹啉-3-甲酰胺(化合物A-70)
Figure PCTCN2020120279-appb-000121
参照实施例1的方法，将I-3替换成喹啉-3-羧酸，制得化合物A-70: 1H NMR(300MHz,DMSO-d 6)δppm 10.44(s,1H),9.49-9.38(m,2H),9.34(s,1H),8.93(s,1H),8.20-8.08(m,2H),7.94-7.86(m,1H),7.84dd,J＝8.3,5.3Hz,2H),7.79-7.69(m,2H),7.47(dd,J＝8.6,1.6Hz,1H),7.37(dd,J＝8.7,8.7Hz,2H),6.73(d,J＝8.7Hz,1H).ESI-MS:m/z 436.1[M-H] -.
实施例71
3,5-二氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-71)
Figure PCTCN2020120279-appb-000122
参照实施例69的方法，将II-5替换成2,6-二氟苯甲酸，制得化合物A-71: 1H NMR(300MHz,DMSO-d 6)δppm 10.60(s,1H),9.50(s,1H),9.38(s,1H),7.82(dd,J＝10.1,8.1Hz,4H),7.62(s,1H),7.60-7.56(m,2H),7.55-7.44(m,3H),7.42-7.31(m,3H),6.72(d,J＝8.7Hz,1H).ESI-MS:m/z 521.1[M+Na] +.
实施例72
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4-苯基-1-萘甲酰胺(化合物A-72)
Figure PCTCN2020120279-appb-000123
参照实施例69的方法，将II-5替换成4-溴萘甲酸，制得化合物A-72: 1H NMR (300MHz,DMSO-d 6)δppm 10.42(s,1H),9.43(s,1H),9.34(s,1H),8.23(d,J＝8.3Hz,1H),7.92-7.81(m,3H),7.76(d,J＝7.3Hz,1H),7.71(d,J＝2.2Hz,1H),7.67-7.44(m,9H),7.39(dd,J＝8.8,8.8Hz,2H),6.74(d,J＝8.7Hz,1H).ESI-MS:m/z 535.2[M+Na] +.
实施例73
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-2-硝基-[1,1'-联苯]-4-甲酰胺(化合物A-73)
Figure PCTCN2020120279-appb-000124
参照实施例69的方法，将II-5替换成3-硝基-4-溴苯甲酸，制得化合物A-73: 1H NMR(300MHz,DMSO-d 6)δppm 10.37(s,1H),9.49(s,1H),9.35(s,1H),8.52(d,J＝0.7Hz,1H),8.30(d,J＝8.1Hz,1H),7.83(dd,J＝8.6,5.3Hz,2H),7.77–7.67(m,2H),7.58–7.31(m,8H),6.73(d,J＝8.7Hz,1H).ESI-MS:m/z 506.1[M-H] -.
实施例74
N-(4-羟基-3-((4-(甲基磺酰基)苯基)磺酰氨基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-1)
Figure PCTCN2020120279-appb-000125
参照实施例1的方法，将4-氟苯磺酰氯替换成4-甲磺酰基苯磺酰氯，制得化合物B-1: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),9.66(s,1H),9.45(s,1H),8.10(d,J＝8.4Hz,2H),8.03(dd,J＝8.2,3.3Hz,4H),7.82(d,J＝8.3Hz,2H),7.76(d,J＝7.5Hz,2H),7.71(d,J＝2.2Hz,1H),7.51(dd,J＝7.4,7.4Hz,2H),7.46-7.40(m,2H),6.72(d,J＝8.7Hz,1H),3.27(s,3H).ESI-MS:m/z 521.1[M-H] -.
实施例75
N-(4-羟基-3-((4-(甲氧基)苯基)磺酰氨基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-2)
Figure PCTCN2020120279-appb-000126
参照实施例1的方法，将4-氟苯磺酰氯替换成4-甲氧基苯磺酰氯，制得化合物B-2: 1H NMR(300MHz,DMSO-d 6)δppm 10.11(s,1H),9.18(s,2H),8.04(d,J ＝8.2Hz,2H),7.82(d,J＝8.2Hz,2H),7.79-7.66(m,5H),7.51(dd,J＝7.4,7.4Hz,2H),7.46-7.36(m,2H),7.03(d,J＝8.8Hz,2H),6.70(d,J＝8.7Hz,1H),3.80(s,3H).ESI-MS:m/z 473.2[M-H] -.
实施例76
N-(4-羟基-3-((4-(三氟甲基)苯基)磺酰氨基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-3)
Figure PCTCN2020120279-appb-000127
参照实施例1的方法，将4-氟苯磺酰氯替换成4-三氟甲基苯磺酰氯，制得化合物B-3: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),9.63(s,1H),9.43(s,1H),8.04(d,J＝8.2Hz,2H),7.96(dd,J＝8.5,8.5Hz,4H),7.82(d,J＝8.2Hz,2H),7.76(d,J＝7.5Hz,2H),7.72(d,J＝2.1Hz,1H),7.51(dd,J＝7.4,7.4Hz,2H),7.48-7.38(m,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 511.2[M-H] -.
实施例77
N-(3-((4-氨基甲酰基苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-4)
Figure PCTCN2020120279-appb-000128
参照实施例1的方法，将4-氟苯磺酰氯替换成4-甲氧羰基苯磺酰氯，制得化合物I-55。
将化合物I-55(890mg,2.53mmol)加入氨水(20mL)，室温反应15h。浓盐酸调节pH至3-4，EtOAc(50mL)提取，有机相依次用水(20mL)和饱和食盐水(20mL)洗涤，无水Na 2SO 4干燥，减压蒸除溶剂，向残留物加入EtOAc(15mL)搅拌1h,过滤，干燥，得黄色固体即化合物I-56(760mg,89％)。
参照实施例1的方法,将I-4替换成I-56,制得化合物B-4: 1H NMR(300MHz,DMSO-d 6)δppm 10.12(s,1H),9.42(s,1H),9.38(s,1H),8.10(s,1H),8.04(d,J＝8.3Hz,2H),7.97(d,J＝8.4Hz,2H),7.85(d,J＝8.5Hz,2H),7.82(d,J＝8.4Hz,2H),7.77-7.74(m,3H),7.56-7.47(m,3H),7.46-7.35(m,2H),6.70(d,J＝8.7Hz,1H).ESI-MS:m/z 486.2[M-H] -.
实施例78
N-(3-((3-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-5)
Figure PCTCN2020120279-appb-000129
将化合物III-0(1.5g,19.73mmol)溶于THF(50mL)，TEA(5.4mL,38.92mmol)，室温下滴加(Boc) 2O(7.4g,34.06mmol)的THF(25mL)，升温60℃反应3h。加水(30mL)稀释，EtOAc(30mL×2)提取，合并有机相依次用水(20mL)，饱和食盐水(20mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，所得残留物溶于THF(20mL)和MeOH(20mL)中，加入2N NaOH(10mL)，室温反应1.5h。用1N HCl调节反应液pH至5-6，EtOAc(30mL×2)提取，合并有机相，依次用水(20mL)和饱和食盐水(20mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得残留物即化合物III-1(3.42g)。
将上述所得化合物III-1溶于DMF(15mL)，加入K 2CO 3(2.0g,14.49mmol)，BnBr(1.2mL,11.59mmol)，室温反应6h。加水稀释，EtOAc(50mL×2)提取，合并有机相依次用水(30mL)和饱和食盐水(20mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得油状物，加入EtOAc(30mL)，室温下加入饱和氯化氢乙酸乙酯溶液(10mL)，室温反应2h。过滤，用EtOAc(5mL)洗涤滤饼，得白色固体即化合物III-2(1.96g,72％)。 1H NMR(300MHz,DMSO-d 6)δppm 8.92(brs.,3H),7.74(s,1H),7.55-7.27(m,7H),5.29(s,2H).
将4-苯基苯甲酸(847mg,4.27mmol)加入SOCl 2(4mL)，升温65℃反应5h。减压蒸除SOCl 2，加入THF(10mL)溶解备用；将化合物III-2(1.0g,3.56mmol)溶于THF(20mL)，DIPEA(1.78mL,10.68mmol)，室温下加入上述备用液，室温反应1h。用1N HCl调节反应液pH至3-4，EtOAc(50mL×2)提取，合并有机相，依次用水(20mL)和饱和食盐水(20mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，所得残留物加入EtOAc(20mL)，室温搅拌1h，过滤，滤饼用 EtOAc(2mL)洗涤，得黄色固体即化合物III-3(1.4g,93％)。 1H NMR(300MHz,DMSO-d 6)δppm 10.52(s,1H),8.45(s,1H),8.07(d,J＝8.2Hz,2H),8.01(dd,J＝9.0,2.0Hz,1H),7.85(d,J＝8.1Hz,2H),7.76(d,J＝7.3Hz,2H),7.61-7.31(m,9H),5.31(s,2H).
将化合物III-3(1.4g,3.30mmol)加入THF(30mL)，MeOH(30mL)，H 2氛围室温反应24h。过滤用MeOH(10mL)洗涤，减压蒸除溶剂，得灰色固体即化合物III-4(0.89g,89％)。
将化合物III-4(50mg,0.16mmol)加入THF(3mL)，吡啶(20μL,0.25mmol)，室温下滴加3-氟苯磺酰氯(26μL,0.20mmol)，室温反应4h。用1N HCl调节反应液pH至3-4，EtOAc(20mL)提取，有机相依次用水(10mL)和饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝50/1)纯化，得类白固体即化合物B-5(28mg,37％)。 1H NMR(300MHz,DMSO-d 6)δppm 10.11(s,1H),9.46(s,2H),8.04(d,J＝8.3Hz,2H),7.82(d,J＝8.3Hz,2H),7.76(d,J＝7.4Hz,2H),7.72(d,J＝2.3Hz,1H),7.65-7.55(m,3H),7.55-7.46(m,3H),7.42(dd,J＝8.6,6.2Hz,2H),6.72(d,J＝8.7Hz,1H).ESI-MS:m/z 461.1[M-H] -.
实施例79
N-(4-羟基-3-(吗啉-4-磺酰氨基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-6)
Figure PCTCN2020120279-appb-000130
参照实施例78的方法，将3-氟苯磺酰氯替换成吗啉磺酰氯，制得化合物B-6: 1H NMR(300MHz,acetone-d 6)δppm 9.52(s,1H),8.80(s,1H),8.09(d,J＝8.4Hz,2H),7.96(d,J＝2.5Hz,1H),7.79(d,J＝8.4Hz,2H),7.73(dd,J＝7.2,1.4Hz,2H),7.68(s,1H),7.60(dd,J＝8.7,2.5Hz,1H),7.50(dd,J＝7.4,7.4Hz,2H),7.45-7.37(m,1H),6.93(d,J＝8.7Hz,1H),3.62(t,J＝4.6Hz,4H),3.23(t,J＝4.6Hz,4H).ESI-MS:m/z 452.2[M-H] -.
实施例80
N-(3-((2-氯苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-7)
Figure PCTCN2020120279-appb-000131
参照实施例78的方法，将3-氟苯磺酰氯替换成2-氯苯磺酰氯，制得化合物B-7: 1H NMR(300MHz,DMSO-d 6)δppm 10.09(s,1H),9.57(s,1H),9.23(s,1H), 8.02(d,J＝8.3Hz,2H),7.96(dd,J＝7.8,1.0Hz,1H),7.81(d,J＝8.4Hz,2H),7.76(d,J＝7.4Hz,2H),7.66(dd,J＝9.2,1.9Hz,2H),7.64-7.57(m,1H),7.57-7.37(m,5H),6.73(d,J＝8.7Hz,1H).ESI-MS:m/z 477.1[M-H] -.
实施例81
N-(3-((4-硝基苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-8)
Figure PCTCN2020120279-appb-000132
参照实施例78的方法，将3-氟苯磺酰氯替换成4-硝基苯磺酰氯，制得化合物B-8: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),9.76(s,1H),9.40(s,1H),8.37(d,J＝8.7Hz,2H),8.02(dd,J＝8.0,8.0Hz,4H),7.82(d,J＝8.2Hz,2H),7.76(d,J＝7.4Hz,2H),7.70(d,J＝2.2Hz,1H),7.57-7.37(m,4H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 488.2[M-H] -.
实施例82
N-(3-((4-氯苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-9)
Figure PCTCN2020120279-appb-000133
参照实施例78的方法，将3-氟苯磺酰氯替换成4-氯苯磺酰氯，制得化合物B-9: 1H NMR(300MHz,DMSO-d 6)δppm 10.12(s,1H),9.42(s,1H),9.40(s,1H),8.04(d,J＝8.0Hz,2H),7.82(d,J＝8.1Hz,2H),7.80-7.73(m,4H),7.71(d,J＝2.0Hz,1H),7.61(d,J＝8.1Hz,2H),7.51(dd,J＝7.6,7.6Hz,2H),7.47-7.38(m,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 477.2[M-H] -.
实施例83
N-(3-((4-溴苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-10)
Figure PCTCN2020120279-appb-000134
参照实施例78的方法，将3-氟苯磺酰氯替换成4-溴苯磺酰氯，制得化合物B-10: 1H NMR(300MHz,DMSO-d 6)δppm 10.12(s,1H),9.42(s,1H),9.40(s,1H),8.04(d,J＝8.2Hz,2H),7.82(d,J＝8.2Hz,2H),7.79-7.65(m,7H),7.51(dd,J＝7.5,7.5Hz,2H),7.47-7.38(m,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 521.1[M-H] -.
实施例84
N-(3-((2,6-二氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-11)
Figure PCTCN2020120279-appb-000135
参照实施例78的方法，将3-氟苯磺酰氯替换成2,6-二氟苯磺酰氯，制得化合物B-11: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),9.74(s,1H),9.43(s,1H),8.03(d,J＝8.3Hz,2H),7.81(d,J＝8.3Hz,2H),7.75(d,J＝7.4Hz,2H),7.71-7.60(m,2H),7.56-7.37(m,4H),7.21(dd,J＝9.0,9.0Hz,2H),6.72(d,J＝8.8Hz,1H).ESI-MS:m/z 503.1[M+Na] +.
实施例85
N-(4-羟基-3-(甲基磺酰氨基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-12)
Figure PCTCN2020120279-appb-000136
参照实施例78的方法，将3-氟苯磺酰氯替换成甲磺酰氯，制得化合物B-12: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.69(s,1H),8.70(s,1H),8.05(d,J＝8.2Hz,2H),7.82(d,J＝8.2Hz,2H),7.76(d,J＝7.3Hz,2H),7.67(d,J＝2.0Hz,1H),7.58-7.37(m,4H),6.87(d,J＝8.7Hz,1H),2.98(s,3H).ESI-MS:m/z 381.1[M-H] -.
实施例86
N-(4-羟基-3-(甲基磺酰氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-13)
Figure PCTCN2020120279-appb-000137
将化合物4-氨基-2-硝基苯酚(462mg,3mmol)，DIPEA(1mL,6mmol)混溶 于DCM(15mL)中，加入TBSCl(678mg,4.5mmol)，室温反应4h。减压蒸除有机溶剂，加入EtOAc(25mL)稀释,分别用1N HCl(15mL)和饱和食盐水(15mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸去溶剂，所得残留物静置析出棕色固体，加入正己烷(10mL)搅拌，抽滤，得黄色固体即化合物III-7(637mg,79％)。
将化合物4-三氟甲基溴苯(450mg,2mmol)，4-硼酸苯甲酸(365mg,2.2mmol)，K 2CO 3(828mg,6mmol)，Pd(PPh 3) 4(115mg,0.1mmol)混溶于Tol(20mL)、MeOH(3mL)中，氮气氛围升温至80℃反应4h。减压蒸除溶剂，残留物加入1N HCl调节pH至1-3，搅拌，抽滤，水洗涤，干燥至恒重，得棕色固体。将所得固体加入无水乙醚/EtOAc(10mL/0.5mL)，搅拌，抽滤，得黄色固体即化合物III-9(427mg,79％)。
将化合物III-9(420mg,1.58mmol)溶于DCM(8mL)和THF(2mL)中，加入草酰氯(200μL,2.37mmol)，DMF(1滴)，室温搅拌3h。减压蒸除溶剂，将残留物溶于无水THF中制得酰氯THF(2mL)溶液备用，将备用液在冰浴条件下加至III-7(424mg,1.58mmol)和DIPEA(400μL,2.37mmol)的THF(4mL)溶液中，室温反应过夜。减压蒸除溶剂，加入无水乙醚/EtOAc(5mL/0.5mL)，搅拌，抽滤，无水乙醚(2mL)洗涤，得黄色固体即化合物III-10。
将化合物III-10溶于THF(15mL)、MeOH(10mL)中，加入10％Pd/C(50mg)，氢气氛围下室温反应2d。硅藻土抽滤，滤饼用DCM(5mL)和MeOH(5mL)洗涤，将滤液减压蒸除溶剂，残留物加入无水乙醚(5mL)，搅拌，抽滤，得土黄色固体即化合物III-11(284mg,43％)。
将化合物III-11(84mg,0.2mmol)，吡啶(100μL)溶于DCM(5mL)，加入甲基磺酰氯(50μL)，室温反应2.5h。减压蒸除有机溶剂，残留物加入EtOAc(8mL)稀释，有机相依次用1N HCl(6mL)和饱和食盐水(6mL)洗涤，干燥，减压蒸除溶剂，残余物经硅胶柱层析(石油醚/EtOAc＝5/1)纯化，得化合物III-12，直接用于下一步反应。
将化合物III-12溶于DCM(5mL)中，加入100μL TEA·3HF，室温反应4h，析出白色固体，抽滤，滤饼依次用DCM(1mL)、1N HCl(3mL)和H 2O(3mL)洗涤，干燥至恒重，得白色固体即化合物B-13(46mg,51％). 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.71(s,1H),8.71(s,1H),8.09(d,J＝8.3Hz,2H),7.99(d,J＝8.2Hz,2H),7.90(d,J＝8.4Hz,2H),7.86(d,J＝8.4Hz,2H),7.67(d,J＝2.2Hz,1H),7.53(dd,J＝8.7,2.4Hz,1H),6.87(d,J＝8.8Hz,1H),2.98(s,3H).ESI-MS:m/z 449.1[M-H] -.
实施例87
N-(4-羟基-3-((4-硝基苯基)磺酰氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺 (化合物B-14)
Figure PCTCN2020120279-appb-000138
参照实施例86的方法，将甲磺酰氯替换成4-硝基苯磺酰氯，制得化合物B-14: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.77(s,1H),9.42(s,1H),8.37(d,J＝8.7Hz,2H),8.07(d,J＝8.3Hz,2H),8.03-7.96(m,4H),7.90(d,J＝8.4Hz,2H),7.86(d,J＝8.5Hz,2H),7.70(d,J＝2.3Hz,1H),7.47(dd,J＝8.7,2.4Hz,1H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 556.1[M-H] -.
实施例88
N-(4-羟基-3-(萘-2-亚磺酰氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-15)
Figure PCTCN2020120279-appb-000139
参照实施例86的方法，将甲磺酰氯替换成2-萘磺酰氯，制得化合物B-15: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.45-9.27(m,2H),8.44(s,1H),8.13-8.03(m,4H),8.03-7.96(m,3H),7.93-7.79(m,6H),7.72-7.58(m,2H),7.43-7.34(m,1H),6.65(d,J＝8.7Hz,1H).ESI-MS:m/z 561.2[M-H] -.
实施例89
4-([1,1'-联苯基]-4-甲酰胺基)-2-(N-((4-氟苯基)磺酰基)乙酰氨基)苯基乙酸酯(化合物C-1)
Figure PCTCN2020120279-appb-000140
将化合物A-33(456mg,0.99mmol)溶于THF(10mL)，加入DIPEA(1.0mL,6.05mmol)，室温下滴加乙酰氯(204μL,2.37mmol)，室温反应10h。用水(10mL)淬灭，EtOAc(30mL)提取，有机相分别用1N HCl(10mL)、水(10mL)和饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，所得残留固 体加入EtOAc(2mL)溶解，滴加石油醚(6mL)，大量白色固体析出，过滤，得化合物C-1(500mg,93％)。 1H NMR(300MHz,DMSO-d 6)δppm 10.58(s,1H),8.14-8.05(m,4H),8.03(d,J＝2.3Hz,1H),7.99(dd,J＝8.8,2.5Hz,1H),7.88(d,J＝8.4Hz,2H),7.78(d,J＝7.2Hz,2H),7.61-7.48(m,4H),7.48-7.39(m,2H),2.15(s,3H),1.87(s,3H).ESI-MS:m/z 545.2[M-H] -.
实施例90
4-([1,1'-联苯基]-4-甲酰胺基)-2-((4-氟苯基)磺酰氨基)苯基乙酸酯(化合物C-2)
Figure PCTCN2020120279-appb-000141
将化合物A-33(200mg,0.43mmol)溶于THF(5mL)，加入吡啶(52μL,0.65mmol)，室温下滴加乙酰氯(37μL,0.52mmol)，室温反应10h。用水(10mL)淬灭，EtOAc(30mL)提取，有机相依次用1N HCl(10mL)、水(10mL)和饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得白色固体，经硅胶柱层析(DCM/MeOH＝10/1)纯化，得白色固体即化合物C-2(76mg,35％)。 1H NMR(300MHz,DMSO-d 6)δppm 10.39(s,1H),10.01(s,1H),8.06(d,J＝8.3Hz,2H),7.96(d,J＝2.2Hz,1H),7.86-7.8(m,4H),7.77(d,J＝7.4Hz,2H),7.62(dd,J＝8.8,2.3Hz,1H),7.52(dd,J＝7.4,7.4Hz,2H),7.44(d,J＝5.3Hz,1H),7.40(dd,J＝7.9,7.9Hz,2H),7.01(d,J＝8.8Hz,1H),2.14(s,3H).ESI-MS:m/z 461.1[M-CH 3CO] -.
实施例91
2'-氯-N-(4-羟基-3-(甲基磺酰氨基)苯基)-N-甲基-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物C-3)
Figure PCTCN2020120279-appb-000142
Figure PCTCN2020120279-appb-000143
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯制得化合物III-13。
将NaH(16mg,0.398mmol)，干燥DMF(2mL)混合，室温下滴加化合物III-13(100mg,0.181mmol)的DMF(2mL)溶液，室温反应1h，加入碘甲烷(25μL,0.398mmol)室温反应1h。加入水(10mL)和EtOAc(20mL)，分液，有机相依次用1N HCl(10mL)、水(10mL)和饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得残留固体即化合物III-14，直接用于下一步反应。
向上述所得化合物III-14加入无水乙醇(10mL)，铁粉(200mg)，饱和氯化铵水溶液(4mL)，升温80℃反应3h。冷却室温，加入EtOAc(20mL)稀释，过滤，并EtOAc(10mL)洗涤滤饼，合并有机相，减压蒸除溶剂，加入水(10mL)和EtOAc(20mL)，分液，有机相依次用水(10mL)和饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得残留固体即化合物III-15，直接用于下一步反应。
参照实施例86的方法，将III-11替换成III-15制得化合物III-16。
将上步所得化合物III-16溶于DCM(5mL)，加入三溴化硼的DCM溶液(1M,200μL)，室温反应10h。加入甲醇(1mL)淬灭，减压蒸除溶剂，加入水(10mL)和EtOAc(20mL)，分液，有机相依次用水(10mL)和饱和食盐水(10mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，所得残留固体经硅胶柱层析(DCM/MeOH＝80/1)纯化，得白色固体即化合物C-3(32mg,36％)。 1H NMR(300MHz,-d 6)δppm 9.99(s,1H),8.65(s,1H),7.96(s,1H),7.77(d,J＝8.2Hz,1H),7.55(d,J＝8.0Hz,1H),7.42-7.27(m,4H),7.05(d,J＝1.8Hz,1H),6.93(dd,J＝8.4,2.2Hz,1H),6.78(d,J＝8.5Hz,1H),3.32(s,3H),2.73(s,3H).HRMS(ESI):m/z calcd for C 22H 19ClF 3N 2O 4S[M+H] +499.0701,found 499.0706.
实施例92
N-(3-((4-氟-N-甲基苯基)磺酰氨基)-4-甲氧基苯基)-[1,1'-联苯]-4-甲酰胺(化合 物C-4)
Figure PCTCN2020120279-appb-000144
N-(3-((4-氟-N-甲基苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物C-5)
Figure PCTCN2020120279-appb-000145
将化合物A-33(100mg,0.216mmol)，K 2CO 3(120mg,0.864mmol)混溶于丙酮(4mL)中，向其中加入CH 3I(30μL)，室温反应8h。抽滤，滤饼用EtOAc(6mL)洗涤，合并有机相，减压蒸除溶剂，残余物经硅胶柱层析(DCM/EtOAc＝200/1)纯化，得白色固体即化合物C-4(23mg,22％). 1H NMR(300MHz,DMSO-d 6)δppm 10.27(s,1H),8.06(d,J＝7.9Hz,2H),7.91-7.67(m,8H),7.57-7.38(m,5H),7.01(d,J＝8.9Hz,1H),3.41(s,3H),3.14(s,3H).ESI-MS:m/z 489.2[M-H] -；当用DCM/MeOH＝400:1洗脱时，得化合物C-5，白色固体(37mg,36％). 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.44(s,1H),8.04(d,J＝6.9Hz,2H),7.91-7.69(m,6H),7.66-7.57(m,2H),7.55-7.34(m,5H),6.80(d,J＝8.2Hz,1H),3.15(s,3H).ESI-MS:m/z 475.2[M-H] -.
实施例93
4-([1,1'-联苯基]-4-甲酰胺基)-2-((4-氟苯基)磺酰氨基)苯甲酸甲酯(化合物D-1)
Figure PCTCN2020120279-appb-000146
Figure PCTCN2020120279-appb-000147
将化合物2-氨基-4-硝基苯甲酸(638mg,3.5mmol)，Na 2CO 3(1.5g,14mmol)混于H 2O(16mL)，加入4-氟苯磺酰氯(1.4g,7mmol)，室温反应过夜后升温至75℃反应5h。冷却至室温,加入HCl调节pH至1-2，抽滤，滤饼依次用1N HCl(6mL)和H 2O(8mL)洗涤，干燥至恒重，用正己烷/无水乙醚(10mL/1mL)打浆，抽滤，得黄棕色固体即化合物IV-2。
将化合物IV-2(830mg,2.44mmol)溶于THF(8mL)中，缓慢加入SOCl 2(1mL),DMF(1滴),升温至75℃反应1.5h。冷却至室温，加入MeOH(6mL)，室温反应30min。将反应液减压蒸除溶剂，残余物经硅胶柱层析(DCM)纯化，得黄色固体即化合物IV-3。 1H NMR(300MHz,DMSO-d 6)δppm 10.53(s,1H),8.20-8.13(m,1H),8.06-8.00(m,2H),7.87(dd,J＝8.7,5.1Hz,2H),7.42(dd,J＝8.8，8.8Hz,2H),3.82(s,3H).
将化合物IV-3溶于EtOH(12mL)中，加入SnCl 2·2H 2O(1.91g)，升温至80℃反应1h。冷却至室温,减压蒸除溶剂，残留物加入EtOAc(20mL)稀释，加入NaHCO 3水溶液(15mL)，析出固体，抽滤，滤饼用EtOAc(10mL)洗涤，有机相依次用醋酸铵水溶液(15mL)和饱和食盐水洗涤(15mL)，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得油状液体即化合物IV-4(550mg,70％)。
将化合物4-苯基苯甲酸(277mg,1.4mmol)溶于THF(7mL)，加入草酰氯(156μL,1.82mmol)，DMF(1滴)，室温反应3h。减压蒸除溶剂，残留物溶于无水THF(3mL)中备用，将备用液在冰浴条件下加至IV-4(550mg,1.7mmol)，DIPEA(350μL,2.1mmol)的THF(3mL)溶液中，室温反应过夜。反应液减压蒸除溶剂，残余物经硅胶柱层析((石油醚/DCM(1/1)):EtOAc＝50:1)纯化,所得产物用无水乙醚/DCM(8mL/1mL)打浆，抽滤，干燥至恒重，得白色絮状固体即化合物D-1(381mg,52％). 1H NMR(300MHz,DMSO-d 6)δppm 10.69(s,1H),10.64(s,1H),8.24(d,J＝1.9Hz,1H),8.08(d,J＝8.4Hz,2H),7.99(dd,J＝8.9,5.1Hz,2H),7.91-7.84(m,3H),7.80-7.74(m,2H),7.65(dd,J＝8.8,2.0Hz,1H),7.52(dd,J＝7.4,7.4Hz,2H),7.47-7.39(m,3H),3.82(s,3H).HRMS(ESI):m/z calcd for C 27H 22FN 2O 5S[M+H] +505.1228,found 505.1236.
实施例94
4-([1,1'-联苯基]-4-基氨基甲酰基)-2-((4-氟苯基)磺酰氨基)苯甲酸(化合物D-2)
Figure PCTCN2020120279-appb-000148
将实施例93制得的化合物D-1(120mg,0.24mmol)溶于THF(2mL)和MeOH(3mL)中，加入NaOH(53mg,1.3mmol)的H 2O(2mL)溶液，升温至70℃反应4h。减压蒸除溶剂，加入1N HCl调节pH至1-3，析出固体，抽滤，滤饼依次用1N HCl(4mL)和H 2O(6mL)洗涤，干燥至恒重，得白色固体即化合物D-2(78mg,67％). 1H NMR(300MHz,DMSO-d 6)δppm 10.58(s,1H),8.17(d,J＝1.2Hz,1H),8.06(d,J＝8.3Hz,2H),7.96(dd,J＝8.6,5.2Hz,2H),7.90-7.82(m,3H),7.76(d,J＝7.4Hz,2H),7.55-7.47(m,3H),7.46-7.42(m,1H),7.39(dd,J＝8.8,8.8Hz,2H).ESI-MS:m/z 489.1[M-H] -.
实施例95
N-(4-氨基甲酰基-3-((4-氟苯基)磺酰氨基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-3)
Figure PCTCN2020120279-appb-000149
将实施例94制得的化合物D-2(55mg,0.11mmol)溶于THF(2mL)，加入SOCl 2(100μL)，升温至70℃反应2h；冷却至室温，加入氨水(3mL)，室温反应过夜。减压蒸除溶剂，加入EtOAc(8mL)稀释，有机相依次用H 2O(6mL)、1N HCl(6mL)和饱和食盐水(6mL)洗涤，干燥，减压蒸除溶剂，残余物经硅胶柱层析(DCM/MeOH＝150/1)纯化，所得产物加入无水乙醚(4mL)打浆，抽滤，滤饼用无水乙醚(1.5mL)洗涤，干燥至恒重，得白色固体即化合物D-3(28mg,51％)。 1H NMR(300MHz,DMSO-d 6)δppm 12.57(s,1H),10.60(s,1H),8.29-8.22 (m,1H),8.20(d,J＝1.8Hz,1H),8.08(d,J＝8.3Hz,2H),7.93(dd,J＝8.8,5.1Hz,2H),7.86(d,J＝8.3Hz,2H),7.83-7.71(m,4H),7.59(dd,J＝8.8,1.8Hz,1H),7.52(dd,J＝7.4,7.4Hz,2H),7.47-7.36(m,3H).ESI-MS:m/z 488.2[M-H] -.
实施例96
N-(4-羟基-3-脲基苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-4)
Figure PCTCN2020120279-appb-000150
将2-硝基-4-氨基苯酚(1.0g,6.5mmol)和DIPEA(1.6ml,9.75mmol)溶于DCM(20mL)，加入TBDPSCl(2.32g,8.4mmol)，室温反应过夜。减压蒸除溶剂，残留物加入EtOAc(40mL)稀释，有机相依次用NH 4Cl水溶液(20mL)、1N HCl(20mL)和饱和食盐水(20mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，残留物用正己烷/无水乙醚(20mL/3mL)打浆，过滤，得黄棕色固体即化合物IV-6(2.24g,87％)。
将4-苯基苯甲酸(1.18g,6mmol)溶于DCM(25mL)，加入草酰氯(634μL,7.4mmol)，DMF(1滴)，室温反应5h。减压蒸除溶剂，将残留物溶于无水DCM备用,将备用液在冰浴条件下加至IV-6和DIPEA(1.5mL)的DCM溶液中，室温反应3h。减压蒸除溶剂，残留物加入EtOAc/Et 2O(3mL/15mL)打浆，抽滤，干燥至恒重，得黄色固体即化合物IV-7，直接用于下一步反应。
将化合物IV-7溶于MeOH(30mL)和THF(10mL)，加入10％Pd/C(300mg),氢气氛围下室温反应过夜。硅藻土抽滤，将滤液减压蒸除溶剂，残留物用EtOAc/Et 2O(2mL/15mL)打浆，抽滤，干燥至恒重，得土黄色固体即化合物IV-8(1.5g,49％)。
将化合物IV-8(100mg,0.184mmol)，TEA(40μL,0.276mmol)溶于DCM(5mL)，加入氯甲酸苯酯(70μL)，室温反应5h。减压蒸除溶剂，残留物加入EtOAc(10mL)稀释，有机相依次用NH 4Cl水溶液(6mL)、1N HCl(6mL)和饱和食盐水 (6mL)洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，得残留物即化合物IV-9,直接用于下一步反应。
将化合物IV-9溶于DMSO(1.5mL)，加入氨水(3mL)，室温反应过夜。加入EtOAc(8mL)稀释，依次用NH 4Cl水溶液(6mL)、1N HCl(6mL)、饱和食盐水(6mL)洗涤，有机相硅胶柱层析(DCM/MeOH＝30/1(+AcOH))，减压蒸除溶剂，残留物用DCM(3mL)打浆，抽滤，干燥至恒重，得白色固体即化合物D-4(10mg,14％)。 1H NMR(300MHz,DMSO-d 6)δppm 10.06(s,1H),9.81(s,1H),8.16(d,J＝2.1Hz,1H),8.06(s,1H),8.05-8.01(m,2H),7.85-7.69(m,4H),7.51(dd,J＝7.4Hz,2H),7.46-7.37(m,1H),7.26(dd,J＝8.5,2.2Hz,1H),6.76(d,J＝8.6Hz,1H),6.22(s,2H).ESI-MS:m/z 370.1[M+Na] +.
实施例97
N-(4-羟基-3-(3-(2-羟乙基)脲基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-5)
Figure PCTCN2020120279-appb-000151
参照实施例96的方法，将氨水替换成2-羟基乙胺，制得化合物D-5: 1H NMR(300MHz,DMSO-d 6)δppm 10.04(s,1H),9.73(s,1H),8.18(d,J＝2.2Hz,1H),8.10-8.00(m,3H),7.78(dd,J＝14.5,7.8Hz,4H),7.56-7.47(m,2H),7.46-7.37(m,1H),7.24(dd,J＝8.6,2.2Hz,1H),6.92(t,J＝5.4Hz,1H),6.75(d,J＝8.6Hz,1H),4.70(t,J＝5.1Hz,1H),3.45(q,J＝5.5Hz,2H),3.16(q,J＝5.5Hz,2H).ESI-MS:m/z 430.1[M+K] +.
实施例98
2-氟-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-74)
Figure PCTCN2020120279-appb-000152
参照实施例69的方法，将II-5替换成3-氟-4-溴苯甲酸，苯硼酸替换成4-三氟甲基苯硼酸，制得化合物A-74: 1H NMR(300MHz,DMSO-d 6)δppm 10.21(s,1H),9.46(s,1H),9.32(s,1H),8.00-7.80(m,8H),7.77(dd,J＝7.9,7.9Hz,1H),7.71(d,J＝2.3Hz,1H),7.43(dd,J＝8.8,2.5Hz,1H),7.37(dd,J＝8.9,8.9Hz,2H),6.72(d,J＝8.7Hz,1H).HRMS(ESI):m/z calcd for C 26H 18F 5N 2O 4S[M+H] +549.0902,found 549.0910.
实施例99
N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-3-甲氧基-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-75)
Figure PCTCN2020120279-appb-000153
参照实施例69的方法，将II-5替换成2-甲氧基-4-溴苯甲酸，苯硼酸替换成4-三氟甲基苯硼酸，制得化合物A-75: 1H NMR(300MHz,DMSO-d 6)δppm 9.95(s,1H),9.35(s,2H),8.00(d,J＝8.1Hz,2H),7.84(dd,J＝8.4,8.4Hz,4H),7.73(d,J＝7.9Hz,1H),7.66(d,J＝2.3Hz,1H),7.46(s,1H),7.39(dd,J＝15.2,6.3Hz,3H),7.34(dd,J＝6.2,2.1Hz,1H),6.70(d,J＝8.7Hz,1H),4.00(s,3H).ESI-MS:m/z 559.3[M-H] -.
实施例100
2'-氯-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-76)
Figure PCTCN2020120279-appb-000154
参照实施例51的方法，将I-32替换成1-溴-2-氯苯，制得化合物A-76: 1H NMR(300MHz,DMSO-d 6)δppm 10.17(s,1H),9.42(s,1H),9.31(s,1H),8.01(d,J＝8.2Hz,2H),7.84(dd,J＝8.7,5.3Hz,2H),7.71(d,J＝2.3Hz,1H),7.65-7.54(m,3H),7.51-7.41(m,4H),7.37(dd,J＝8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 495.1[M-H] -.
实施例101
3'-三氟甲基-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物A-77)
Figure PCTCN2020120279-appb-000155
参照实施例51的方法，将I-32替换成1-溴-3-三氟甲基苯，制得化合物A-77: 1H NMR(300MHz,DMSO-d 6)δppm 10.17(s,1H),9.46-9.21(m,2H),8.13-8.04(m,4H),7.92(d,J＝8.2Hz,2H),7.88-7.70(m,5H),7.44(dd,J＝8.9,2.3Hz,1H),7.37(dd,J＝8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 529.3[M-H] -.
实施例102
3'-溴-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物 A-78)
Figure PCTCN2020120279-appb-000156
参照实施例51的方法，将I-32替换成1-碘-3-溴苯，制得化合物A-78: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.48-9.27(m,2H),8.05(d,J＝8.3Hz,2H),7.98-7.93(m,1H),7.90-7.80(m,4H),7.80-7.75(m,1H),7.71(s,1H),7.66-7.59(m,1H),7.52-7.41(m,2H),7.37(dd,J＝8.8Hz,2H),6.76-6.63(m,1H).ESI-MS:m/z 539.2[M-H] -.
实施例103
3'-氯-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-79)
Figure PCTCN2020120279-appb-000157
参照实施例62的方法，将I-41替换成1-溴-3-氯-4-三氟甲基苯，制得化合物A-79: 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.52-9.23(m,2H),8.16-8.12(m,1H),8.08(d,J＝8.3Hz,2H),8.01-7.92(m,4H),7.83(dd,J＝8.7,5.3Hz,2H),7.72(d,J＝2.2Hz,1H),7.44(dd,J＝8.7,2.3Hz,1H),7.37(dd,J＝8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 563.1[M-H] -.
实施例104
2'-氯-N-(3-((4-氟苯基)磺酰氨基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物A-80)
Figure PCTCN2020120279-appb-000158
参照实施例62的方法，将I-41替换成1-溴-2-氯-4-三氟甲基苯，制得化合物A-80: 1H NMR(300MHz,DMSO-d 6)δppm 10.20(s,1H),9.43(s,1H),9.32(s,1H),8.13-7.98(m,3H),7.90-7.80(m,3H),7.75-7.67(m,2H),7.63(d,J＝8.2Hz,2H),7.43(dd,J＝8.7,2.5Hz,1H),7.37(dd,J＝8.8Hz,2H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 563.1[M-H] -.
实施例105
2'-氯-N-(4-羟基-3-(甲基磺酰氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-16)
Figure PCTCN2020120279-appb-000159
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，制得化合物B-16: 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),9.72(s,1H),8.71(s,1H),8.11-7.99(m,3H),7.84(d,J＝7.7Hz,1H),7.70(d,J＝8.0Hz,1H),7.67(d,J＝2.4Hz,1H),7.63(d,J＝8.2Hz,2H),7.53(dd,J＝8.7,2.4Hz,1H),6.88(d,J＝8.7Hz,1H),2.98(s,3H).ESI-MS:m/z 483.1[M-H] -.
实施例106
2'-氯-N-(3-(乙基磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-17)
Figure PCTCN2020120279-appb-000160
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成乙磺酰氯制得化合物B-17: 1H NMR(300MHz,DMSO-d 6)δppm 10.21(s,1H),9.71(s,1H),8.66(s,1H),8.12-7.99(m,2H),7.84(d,J＝8.2Hz,1H),7.70(d,J＝8.2Hz,1H),7.63(d,J＝8.2Hz,2H),7.52(dd,J＝8.7,2.3Hz,1H),6.86(d,J＝8.7Hz,1H),3.07(q,J＝7.3Hz,2H),1.27(t,J＝7.3Hz,3H).ESI-MS:m/z 497.1[M-H] -.
实施例107
2'-氯-N-(4-羟基-3-(乙烯基磺酰氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-18)
Figure PCTCN2020120279-appb-000161
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成2-氯乙磺酰氯制得化合物B-18: 1H NMR(300MHz,DMSO-d 6)δppm 10.21(s,1H),9.67(s,1H),8.88(s,1H),8.09-8.01(m,3H),7.84(d,J＝7.8Hz,1H),7.70(d,J＝7.9Hz,1H),7.67(d,J＝2.1Hz,1H),7.63(d,J＝8.2Hz,2H),7.49(dd,J＝8.6,2.2Hz,1H),6.83(d,J＝8.8Hz,1H),6.75(dd,J＝16.8,9.9Hz,1H),6.06(d,J＝16.6Hz,1H),5.97(d,J＝10.0Hz,1H).ESI-MS:m/z 495.1[M-H] -.
实施例108
N-(4-羟基3-(丙基磺胺基)苯基)-2'-氯-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化 合物B-19)
Figure PCTCN2020120279-appb-000162
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成丙磺酰氯制得化合物B-19: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.67(s,1H),8.67(s,1H),8.11-7.94(m,3H),7.81(d,J＝8.7Hz,1H),7.67(d,J＝8.2Hz,1H),7.65-7.55(m,3H),7.48(d,J＝8.2Hz,1H),6.82(d,J＝8.5Hz,1H),3.05-2.97(m,2H),1.82-1.65(m,2H),0.93(t,J＝7.5Hz,3H).ESI-MS:m/z 511.1[M-H] -.
实施例109
2'-氯-N-(4-羟基-3-((三氟甲基)磺酰氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-20)
Figure PCTCN2020120279-appb-000163
参照实施例1的方法，将4-氟苯磺酰氯替换成三氟甲磺酰氯，I-1替换成1-溴-2-氯-4-三氟甲基苯，制得化合物B-20: 1H NMR(300MHz,DMSO-d 6)δppm11.18(s,1H),10.26(s,1H),9.93(s,1H),8.10-8.00(m,4H),7.84(d,J＝8.3Hz,1H),7.75-7.67(m,3H),7.67-7.58(m,4H),6.92(d,J＝8.8Hz,1H).ESI-MS:m/z 537.0[M-H] -.
实施例110
N-(4-羟基-3-(苯磺胺基)苯基)-2'-氯--4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-21)
Figure PCTCN2020120279-appb-000164
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成苯磺酰氯制得化合物B-21: 1H NMR(300MHz,DMSO-d 6)δppm 10.25-10.11(s,1H),9.44(s,1H),9.24(s,1H),8.15-7.95(m,3H),7.88-7.76(m,3H),7.71(d,J＝9.7Hz,2H),7.66-7.56(m,3H),7.56-7.48(m,2H),7.41(d,J＝8.7Hz,1H),6.70(d,J＝8.8Hz,1H).ESI-MS:m/z 545.1[M-H] -.
实施例111
2'-氯-N-(4-羟基-3-(噻吩-2-磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺 (化合物B-22)
Figure PCTCN2020120279-appb-000165
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成2-噻吩磺酰氯制得化合物B-22: 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),9.49(s,1H),9.39(s,1H),8.11-7.99(m,3H),7.88(dd,J＝4.9,1.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.75(d,J＝2.3Hz,1H),7.71(d,J＝8.0Hz,1H),7.63(d,J＝8.2Hz,2H),7.56(dd,J＝3.6,1.0Hz,1H),7.47(dd,J＝8.7,2.3Hz,1H),7.12(dd,J＝4.8,3.9Hz,1H),6.75(d,J＝8.8Hz,1H).ESI-MS:m/z 551.1[M-H] -.
实施例112
2'-氯-N-(3-((5-氯噻吩)-2-亚磺酰氨基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-23)
Figure PCTCN2020120279-appb-000166
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成5-氯-2-噻吩磺酰氯制得化合物B-23: 1H NMR(300MHz,DMSO-d 6)δppm10.23(s,1H),9.67(s,1H),9.57(s,1H),8.10-7.99(m,3H),7.84(d,J＝8.1Hz,1H),7.74-7.67(m,2H),7.63(d,J＝8.3Hz,2H),7.50(dd,J＝11.0,4.7Hz,1H),7.39(d,J＝4.0Hz,1H),7.19(d,J＝4.0Hz,1H),6.78(d,J＝8.7Hz,1H).ESI-MS:m/z 585.0[M-H] -.
实施例113
2'-氯-N-(4-羟基-3-(吡啶-3-磺酰氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-24)
Figure PCTCN2020120279-appb-000167
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成3-吡啶磺酰氯制得化合物B-24: 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),9.63(s,1H),9.48(s,1H),8.91(s,1H),8.77(d,J＝4.5Hz,1H),8.12(d,J＝7.6Hz,1H),8.09-7.99(m,3H),7.84(d,J＝7.7Hz,1H),7.78-7.67(m,2H),7.63(d,J＝7.9Hz,2H),7.58(dd,J＝7.5,5.7Hz,1H),7.47(d,J＝8.4Hz,1H),6.71(d,J＝8.7Hz,1H).ESI-MS:m/z 546.1[M-H] -.
实施例114
N-(4-羟基-3-丙酰胺苯基)-2'-氯-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-25)
Figure PCTCN2020120279-appb-000168
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成丙酰氯制得化合物B-25: 1H NMR(300MHz,DMSO-d 6)δppm 10.20(s,1H),9.61(s,1H),9.28(s,1H),8.21-8.12(m,1H),8.06(d,J＝8.2Hz,2H),8.04-8.00(m,1H),7.84(d,J＝8.0Hz,1H),7.70(d,J＝8.0Hz,1H),7.62(d,J＝8.2Hz,2H),7.39(dd,J＝8.5,2.0Hz,1H),6.84(d,J＝8.6Hz,1H),2.42(dd,J＝14.9,7.4Hz,2H),1.10(t,J＝7.5Hz,3H).ESI-MS:m/z 461.1[M-H] -.
实施例115
N-(3-丁胺基-4-羟基苯基)-2'-氯-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物B-26)
Figure PCTCN2020120279-appb-000169
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成丁酰氯制得化合物B-26: 1H NMR(300MHz,DMSO-d 6)δppm 10.20(s,1H),9.60(s,1H),9.31(s,1H),8.19-8.11(m,1H),8.11-8.00(m,3H),7.84(d,J＝8.3Hz,1H),7.71(d,J＝7.9Hz,1H),7.62(d,J＝8.1Hz,2H),7.40(d,J＝8.5Hz,1H),6.84(d,J＝8.8Hz,1H),2.39(t,J＝7.3Hz,2H),1.71-1.54(m,2H),0.93(t,J＝7.3Hz,3H).ESI-MS:m/z 475.1[M-H] -.
实施例116
N-(5-(2'-氯-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺基)-2-羟基苯基)呋喃-2-甲酰胺(化合物B-27)
Figure PCTCN2020120279-appb-000170
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成2-呋喃甲酰氯制得化合物B-27: 1H NMR(300MHz,DMSO-d 6)δppm 10.26(s,1H),9.92(s,1H),9.18(s,1H),8.34(d,J＝1.9Hz,1H),8.07(d,J＝8.1Hz,2H),8.04-8.00(m,1H),7.97-7.93(m,1H),7.84(d,J＝8.1Hz,1H),7.71(d,J＝8.0Hz, 1H),7.63(d,J＝8.1Hz,2H),7.48(dd,J＝8.6,1.9Hz,1H),7.32(d,J＝3.3Hz,1H),6.92(d,J＝8.7Hz,1H),6.75-6.70(m,1H).ESI-MS:m/z 499.1[M-H] -.
实施例117
N-(5-(2'-氯-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺基)-2-羟基苯基)噻吩-2-甲酰胺(化合物B-28)
Figure PCTCN2020120279-appb-000171
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成2-噻吩甲酰氯制得化合物B-28: 1H NMR(300MHz,DMSO-d 6)δppm 10.24(s,1H),9.62(s,1H),9.59(s,1H),8.04(dd,J＝14.5,6.5Hz,5H),7.88-7.80(m,2H),7.71(d,J＝7.9Hz,1H),7.63(d,J＝8.2Hz,2H),7.49(dd,J＝8.7,2.3Hz,1H),7.26-7.19(m,1H),6.91(d,J＝8.7Hz,1H).ESI-MS:m/z 515.1[M-H] -.
实施例118
N-(5-(2'-氯-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺基)-2-羟基苯基)吡啶甲酰胺(化合物B-29)
Figure PCTCN2020120279-appb-000172
参照实施例86的方法，将III-6替换成1-溴-2-氯-4-三氟甲基苯，甲磺酰氯替换成2-吡啶甲酰氯制得化合物B-29: 1H NMR(300MHz,DMSO-d 6)δppm 10.50(s,1H),10.29(s,1H),10.19(s,1H),8.83-8.80(m,1H),8.76(d,J＝4.3Hz,1H),8.21(d,J＝7.7Hz,1H),8.14-8.06(m,3H),8.05-8.01(m,1H),7.84(d,J＝8.0Hz,1H),7.76-7.67(m,2H),7.63(d,J＝8.0Hz,2H),7.48(dd,J＝8.8,1.6Hz,1H),6.94(d,J＝8.6Hz,1H).ESI-MS:m/z 510.1[M-H] -.
实施例119
N-(3-乙酰氨基-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-30)
Figure PCTCN2020120279-appb-000173
参照实施例78的方法，将3-氟苯磺酰氯替换成乙酰氯，制得化合物B-30: 1H NMR(300MHz,DMSO-d 6)δppm 10.12(s,1H),9.59(s,1H),9.36(s,1H),8.11(s,1H),8.05(d,J＝8.2Hz,2H),7.81(d,J＝8.2Hz,2H),7.75(d,J＝7.4Hz,2H),7.51(dd,J＝7.4,7.4Hz,2H),7.46-7.32(m,2H),6.83(d,J＝8.6Hz,1H),2.05(d,J＝ 38.1Hz,3H).ESI-MS:m/z 345.1[M-H] -.
实施例120
N-(3-(4-氟苯甲酰氨基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物B-31)
Figure PCTCN2020120279-appb-000174
参照实施例78的方法，将3-氟苯磺酰氯替换成4-氟苯甲酰氯，制得化合物B-31: 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.65(s,1H),9.61(s,1H),8.15-8.02(m,5H),7.82(d,J＝8.2Hz,2H),7.76(d,J＝7.4Hz,2H),7.56-7.46(m,3H),7.43(d,J＝7.3Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.93(d,J＝8.7Hz,1H).ESI-MS:m/z 425.2[M-H] -.
实施例121
N-(4-羟基-3-(氨磺酰基氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-6)
Figure PCTCN2020120279-appb-000175
参照实施例86的方法，将甲基磺酰氯替换成氨基磺酰氯制得化合物D-6: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.49(s,1H),8.09(d,J＝8.1Hz,2H),7.99(d,J＝8.1Hz,2H),7.92-7.83(m,4H),7.79(s,1H),7.72(d,J＝1.7Hz,1H),7.41(dd,J＝8.7,1.8Hz,1H),6.95(s,2H),6.83(d,J＝8.7Hz,1H).ESI-MS:m/z 371.0[M-SO 2NH 2] -.
实施例122
N-(3-(环丙烷磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-7)
Figure PCTCN2020120279-appb-000176
参照实施例86的方法，将甲基磺酰氯替换成环丙磺酰氯制得化合物D-7: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.59(s,1H),8.63(s,1H),8.09(d,J＝8.4Hz,2H),7.99(d,J＝8.1Hz,2H),7.88(dd,J＝11.7,8.5Hz,4H),7.74(d,J＝2.4Hz,1H),7.50(dd,J＝8.7,2.5Hz,1H),6.86(d,J＝8.7Hz,1H),2.73-2.58(m,1H),0.98-0.89(m,4H).ESI-MS:m/z 475.1[M-H] -.
实施例123
N-(3-((3-氟丙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-8)
Figure PCTCN2020120279-appb-000177
将化合物IV-10(1-氟-3-溴丙烷)(423mg,3mmol),硫脲(251mg,3.3mmol)混溶于MeCN(7mL)中,升温至85℃反应12h。反应液冷却至室温，在冰浴条件下依次加入2N HCl(1mL),NCS(2g,15mmol),室温反应30min。反应液加入Et 2O(15mL),H 2O(10mL),分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，棕黄色油状液体即IV-11。
参照实施例86的方法，将甲基磺酰氯替换成IV-11制得化合物D-8: 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.76(s,1H),8.90(s,1H),8.09(d,J＝8.1Hz,2H),7.99(d,J＝8.2Hz,2H),7.90(d,J＝8.3Hz,2H),7.86(d,J＝8.4Hz,2H),7.67(d,J＝1.8Hz,1H),7.54(dd,J＝8.6,1.8Hz,1H),6.87(d,J＝8.7Hz,1H),4.62(t,J＝6.0Hz,1H),4.46(t,J＝6.0Hz,1H),3.24-3.08(m,2H),2.25-2.04(m,2H).ESI-MS:m/z 495.1[M-H] -.
实施例124
N-(3-((3-氯丙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-9)
Figure PCTCN2020120279-appb-000178
参照实施例86的方法，将甲基磺酰氯替换成3-氯丙磺酰氯制得化合物D-9: 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.77(s,1H),8.93(s,1H),8.09(d,J＝8.3Hz,2H),7.99(d,J＝8.1Hz,2H),7.88(dd,J＝12.0,8.4Hz,4H),7.67(d,J＝2.2Hz,1H),7.54(dd,J＝8.7,2.2Hz,1H),6.87(d,J＝8.7Hz,1H),3.75(t,J＝6.5Hz,2H),3.24-3.11(m,2H),2.29-2.12(m,2H).ESI-MS:m/z 535.1[M+Na] +.
实施例125
N-(3-((2-(二甲基氨基)乙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-10)
Figure PCTCN2020120279-appb-000179
将化合物III-11(470mg,0.97mmol),吡啶(241μL,3mmol)混溶于DCM(10mL)中，向其中缓慢滴加2-氯乙烷磺酰氯(210μL,2mmol),室温反应3.5h。反应液减压蒸除溶剂得残留物，经硅胶柱层析(石油醚:DCM(1:1)/EtOAc＝30/1)纯化得目标物，棕红色固体即化合物IV-12(414mg,74％)。
将化合物IV-12(80mg,0.14mmol),二甲胺盐酸盐(25mg,0.3mmol),DIPEA(50μL,0.3mmol)混溶于MeOH(4mL)中，室温反应1h。反应液减压蒸除溶剂，残留物加入DCM(5mL)溶解，向其中滴加TEA·3HF(50μL)，室温反应3.5h。反应液析出固体，抽滤，滤饼用少量MeOH洗涤，红外干燥至恒重得类白色固体即化合物D-10(64mg,90％). 1H NMR(300MHz,DMSO-d 6)δppm10.19(s,1H),8.09(d,J＝8.3Hz,2H),7.99(d,J＝8.1Hz,2H),7.88(dd,J＝11.7,8.4Hz,4H),7.69(d,J＝2.2Hz,1H),7.52(dd,J＝8.7,2.2Hz,1H),6.86(d,J＝8.7Hz,1H),3.34-3.24(m,2H),2.84(t,J＝7.0Hz,2H),2.25(s,6H).ESI-MS:m/z 506.2[M-H] -.
实施例126
N-(3-((2-(双(2-(2-羟乙基)氨基)乙基)磺酰胺基)-4-羟苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-11)
Figure PCTCN2020120279-appb-000180
将化合物IV-12(80mg,0.14mmol),二乙醇胺(40μL,0.4mmol)混溶于MeOH(4mL)中，室温反应过夜。反应液减压蒸除有机溶剂，残留物加入MeOH(3mL)溶解，向其中缓慢滴加conc.HCl(15drops),室温搅拌5.5h。反应液析出固体，抽滤，滤饼用少量MeOH洗涤，红外干燥至恒重得类白色固体即化合物D-11(45mg,53％). 1H NMR(300MHz,DMSO-d 6)δppm 10.24(s,1H),10.03(s, 1H),9.97(brs,1H),9.36(s,1H),8.11(d,J＝8.2Hz,2H),7.99(d,J＝8.1Hz,2H),7.88(dd,J＝11.7,8.4Hz,4H),7.70(d,J＝2.0Hz,1H),7.57(dd,J＝8.7,2.1Hz,1H),6.97(d,J＝8.8Hz,1H),5.33(s,2H),3.93-3.74(m,4H),3.74-3.59(m,4H),3.48-3.21(m,4H).ESI-MS:m/z 566.2[M-H] -.
实施例127
N-(3-((2-氨基乙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-12)
Figure PCTCN2020120279-appb-000181
将化合物IV-12(350mg,0.607mmol),二苄胺(200μL,1.04mmol)混溶于MeOH(11mL)中，室温反应过夜，升温至70℃反应5h。反应液减压蒸除溶剂，残留物经硅胶柱层析(石油醚:DCM(1:1)/EtOAc＝25/1)纯化得目标物，将其溶于MeOH(10mL)中,缓慢滴加conc.HCl(9drops),室温搅拌，反应液析出固体，抽滤得白色固体即IV-13(334mg,68％)。
将化合物IV-13(334mg,0.41mmol)混于MeOH(12mL)中，加入Pd/C(50mg),氢气氛围升温至50℃反应5h。反应液冷却至室温，硅藻土抽滤，滤液减压蒸除有机溶剂得残留物，将其混悬于EtOAc(3mL)中，搅拌，抽滤得白色固体即化合物IV-14(213mg,82％)。
将化合物IV-14(30mg,0.048mmol)溶于DCM(3mL)和MeOH(1mL)中，向其中缓慢滴加TEA·3HF(20μL)，室温反应3h。反应液减压蒸除有机溶剂，残留物混悬于MeOH(2.5mL)，搅拌，抽滤得白色固体即化合物D-12(20mg,81％). 1H NMR(300MHz,DMSO-d 6)δppm 10.21(s,1H),8.28(brs,3H),8.11(d,J＝8.2Hz,2H),7.98(d,J＝8.1Hz,2H),7.93-7.80(m,4H),7.67(d,J＝1.3Hz,1H),7.59(dd,J＝8.8,1.9Hz,1H),6.88(d,J＝8.7Hz,1H),3.45-3.33(m,2H),3.28-3.13(m,2H).ESI-MS:m/z 478.1[M-H] -.
实施例128
N-(4-羟基-3-((2-(甲基磺酰胺基)乙基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-13)
Figure PCTCN2020120279-appb-000182
将化合物IV-14(50mg,0.079mmol)，DIPEA(30μL)混溶于DCM(3mL)中，向其中缓慢滴加MsCl(15μL)，室温反应3h。反应液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝100/1)纯化得目标物。将其溶于DCM(5mL)中,向其中缓慢滴加TEA·3HF(20μL)，室温反应3.5h。反应液析出固体，抽滤，滤饼依次用DCM，1N HCl，H 2O洗涤，红外干燥至恒重得白色固体即化合物D-13(25mg,57％). 1H NMR(300MHz,DMSO-d 6)δppm 10.20(s,1H),9.80(s,1H),9.04(s,1H),8.09(d,J＝7.9Hz,2H),7.99(d,J＝8.0Hz,2H),7.88(dd,J＝12.0,8.4Hz,4H),7.69-7.64(m,1H),7.55(d,J＝8.7Hz,1H),7.16(s,1H),6.88(d,J＝8.7Hz,1H),3.46-3.38(m,2H),3.30-3.24(m,2H),2.93(s,3H).ESI-MS:m/z 556.1[M-H] -.
实施例129
N-(3-((2-乙酰氨基乙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-14)
Figure PCTCN2020120279-appb-000183
参照实施例123的方法，将MsCl替换成AcCl制得化合物D-14: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.65(s,1H),8.93(s,1H),8.09(d,J＝8.2Hz,2H),8.04-7.94(m,3H),7.88(dd,J＝11.8,8.4Hz,4H),7.67(d,J＝2.1Hz,1H),7.53(dd,J＝8.7,2.0Hz,1H),6.87(d,J＝8.7Hz,1H),3.53-3.41(m,2H),3.25-3.15(m,2H),1.78(s,3H).ESI-MS:m/z 520.2[M-H] -.
实施例130
N-(4-羟基-3-((2-(4-甲基哌嗪-1-基)乙基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-15)
Figure PCTCN2020120279-appb-000184
参照实施例125的方法，将二甲氨基盐酸盐替换成N-甲基哌嗪制得化合物D-15: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),8.09(d,J＝8.3Hz,2H),7.99(d,J＝8.2Hz,2H),7.88(dd,J＝11.8,8.4Hz,4H),7.68(d,J＝2.4Hz,1H),7.51(dd,J＝8.7,2.4Hz,1H),6.86(d,J＝8.7Hz,1H),3.32-3.22(m,2H),2.82-2.71(m,2H),2.46-2.27(m,8H),2.15(s,3H).ESI-MS:m/z 561.2[M-H] -.
实施例131
N-(4-羟基-3-((2-(哌嗪-1-基)乙基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-16)
Figure PCTCN2020120279-appb-000185
参照实施例126的方法，将二乙醇胺替换成1-叔丁氧羰基哌嗪制得化合物D-16: 1H NMR(300MHz,DMSO-d 6)δppm 10.23(s,1H),9.98(s,1H),9.46(brs,2H),9.25(s,1H),8.11(d,J＝8.3Hz,2H),7.99(d,J＝8.2Hz,2H),7.88(dd,J＝11.7,8.5Hz,4H),7.70(d,J＝2.4Hz,1H),7.57(dd,J＝8.8,2.3Hz,1H),6.94(d,J＝8.8Hz,1H),3.67-3.18(m,12H).ESI-MS:m/z 547.2[M-H] -.
实施例132
N-(3-((2-(4-(4-氨基哌啶-1-基)乙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺二盐酸盐(化合物D-17)
Figure PCTCN2020120279-appb-000186
参照实施例126的方法，将二乙醇胺替换成4-Boc氨基哌啶制得化合物D-17: 1H NMR(300MHz,DMSO-d 6)δppm 10.98(brs,1H),10.24(s,1H),10.03(s,1H),9.37(s,1H),8.34(brs,3H),8.11(d,J＝8.1Hz,2H),7.99(d,J＝8.1Hz,2H),7.94-7.81(m,4H),7.70(d,J＝1.7Hz,1H),7.59(dd,J＝8.6,1.2Hz,1H),6.96(d,J＝8.6Hz,1H),3.76-3.43(m,6H),3.30-3.21(m,1H),3.19-3.02(m,2H),2.22-2.06(m,2H),2.04-1.86(m,2H).ESI-MS:m/z 561.2[M-H] -.
实施例133
N-(3-((2-(2-氨基乙酰氨基)乙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-18)
Figure PCTCN2020120279-appb-000187
将化合物IV-14(90mg,0.174mmol),N-Boc Gly(32mg,0.183mmol),EDCI(50mg,0.261mmol),HOBt(35mg,0.261mmol),DIPEA(60μL,0.384mmol)混溶于THF(5mL)中，室温反应3h后向其中加入TEA·3HF(50μL)，室温反应过夜。反应液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝30/1)纯化得目标物即化合物IV-15。
将化合物IV-15溶于MeOH(5mL)中,向其中缓慢滴加conc.HCl(8drops),升温至50℃反应3.5h。反应液冷却至室温，静置析出固体，抽滤，滤饼少量MeOH洗涤，红外干燥至恒重得白色固体即化合物D-18(22mg,22％,three steps). 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),8.95(s,1H),8.59(t,J＝5.4Hz,1H),8.10(d,J＝8.4Hz,2H),7.99(d,J＝8.2Hz,2H),7.88(dd,J＝11.5,8.5Hz,4H),7.70(d,J＝2.4Hz,1H),7.53(dd,J＝8.8,2.4Hz,1H),6.92(d,J＝8.8Hz,1H),3.63-3.54(m,2H),3.52(s,2H),3.28-3.18(m,2H).ESI-MS:m/z 535.1[M-H] -.
实施例134
3-(N-(2-羟基-5-(4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺基)苯基)氨磺酰基)丙酸甲酯(化合物D-19)
Figure PCTCN2020120279-appb-000188
参照实施例86的方法，将甲基磺酰氯替换成3-(氯磺酰基)丙酸甲酯制得化合物D-19: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.76(s,1H),9.03(s,1H),8.09(d,J＝8.3Hz,2H),7.99(d,J＝8.2Hz,2H),7.88(dd,J＝12.1,8.4Hz,4H),7.65(d,J＝2.4Hz,1H),7.55(dd,J＝8.7,2.4Hz,1H),6.87(d,J＝8.7Hz,1H),3.62(s,3H),3.33(t,J＝7.4Hz,2H),2.85(t,J＝7.4Hz,2H).ESI-MS:m/z 521.1[M-H] -.
实施例135
3-(N-(2-羟基-5-(4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺基)苯基)氨磺酰基)丙酸(化合物D-20)
Figure PCTCN2020120279-appb-000189
将化合物D-19(100mg,0.191mmol)溶于THF(4mL)和MeOH(1mL)中，向其中滴加2N NaOH(0.5mL),室温反应40min。反应液用1N HCl调节pH至3-4，加入H 2O(8mL)和EtOAc(8mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝20/1(+AcOH))纯化得目标物，白色固体即化合物D-20(21mg,26％). 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),8.09(d,J＝8.3Hz,2H),7.99(d,J＝8.2Hz,2H),7.88(dd,J＝11.7,8.5Hz,4H),7.65(d,J＝2.4Hz,1H),7.54(dd,J＝8.8,2.5Hz,1H),6.87(d,J＝8.7Hz,1H),3.26(t,J＝7.6Hz,2H),2.71(t,J＝7.6Hz,2H).ESI-MS:m/z 507.1[M-H] -.
实施例136
N-(4-羟基-3-((3-羟丙基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-21)
Figure PCTCN2020120279-appb-000190
将化合物D-19(45mg,0.086mmol)溶于THF(4mL)中，向其中加入LiAlH 4(10mg),室温反应20min。反应液加入1drop H 2O淬灭，1N HCl调节pH至3-4，加入H 2O(6mL)和EtOAc(8mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝40/1)纯化得目标物，白色固体即化合物D-21(26mg,61％). 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.66(s,1H),8.64(s,1H),8.08(d,J＝8.4Hz,2H),7.98(d,J＝8.1Hz,2H),7.87(dd,J＝11.4,8.5Hz,4H),7.68(d,J＝2.5Hz,1H),7.52(dd,J＝8.7,2.5Hz,1H),6.86(d,J＝8.8Hz,1H),4.57(s,1H),3.51-3.42(m,2H),3.16-3.06 (m,2H),1.94-1.81(m,2H).ESI-MS:m/z 493.1[M-H] -.
实施例137
N-(3-((3-氨基-3-氧丙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-22)
Figure PCTCN2020120279-appb-000191
将化合物D-19(50mg,0.096mmol)混悬于NH 3·H 2O(4mL)中，室温反应2d。反应液用conc.HCl调节pH至3-4，加入H 2O(6mL)和EtOAc(8mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝20/1(+AcOH))纯化得目标物，土黄色固体即化合物D-22(10mg,21％). 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),8.09(d,J＝8.3Hz,2H),7.99(d,J＝8.1Hz,2H),7.88(dd,J＝9.2,9.2Hz,4H),7.58(d,J＝1.7Hz,1H),7.43(d,J＝8.7Hz,2H),6.91(s,1H),6.79(d,J＝8.6Hz,1H),3.19(t,J＝8.2Hz,2H),2.56(t,J＝8.2Hz,2H).ESI-MS:m/z 506.1[M-H] -.
实施例138
4-(N-(2-羟基-5-(4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺基)苯基)氨磺酰基)丁酸甲酯(化合物D-23)
Figure PCTCN2020120279-appb-000192
参照实施例123的方法，将IV-10替换成4-溴丁酸甲酯制得化合物D-23: 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.73(s,1H),8.82(s,1H),8.09(d,J＝8.2Hz,2H),8.00(d,J＝8.1Hz,2H),7.88(dd,J＝11.8,8.4Hz,4H),7.67(d,J＝2.1Hz,1H),7.54(dd,J＝8.7,2.1Hz,1H),6.87(d,J＝8.7Hz,1H),3.59(s,3H),3.19-3.05(m,2H),2.49-2.43(m,2H),2.10-1.93(m,2H).ESI-MS:m/z 535.1[M-H] -.
实施例139
4-(N-(2-羟基-5-(4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺基)苯基)氨磺酰基)丁酸(化合物D-24)
Figure PCTCN2020120279-appb-000193
参照实施例135的方法，将D-19替换成D-23制得化合物D-24: 1H NMR(300MHz,DMSO-d 6)δppm 10.17(s,1H),8.09(d,J＝8.1Hz,2H),7.99(d,J＝8.0Hz,2H),7.88(dd,J＝11.0,8.6Hz,4H),7.66(d,J＝1.8Hz,1H),7.53(d,J＝8.6Hz,1H),6.86(d,J＝8.7Hz,1H),3.10(t,7.1Hz,2H),2.38(t,J＝7.1Hz,2H),2.05-1.88(dt,J＝14.4,7.1Hz,1H).ESI-MS:m/z 521.1[M-H] -.
实施例140
N-(4-羟基-3-((4-羟基丁基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-25)
Figure PCTCN2020120279-appb-000194
参照实施例136的方法，将D-19替换成D-23制得化合物D-25: 1H NMR(300MHz,DMSO-d 6)δppm 10.20(s,1H),9.73(s,1H),8.69(s,1H),8.09(d,J＝8.1Hz,2H),7.99(d,J＝7.8Hz,2H),7.88(dd,J＝11.1,8.6Hz,4H),7.66(d,J＝0.9Hz,1H),7.52(dd,J＝7.9,0.7Hz,1H),6.86(d,J＝8.7Hz,1H),4.43(s,1H),3.39(t,J＝6.0Hz,2H),3.13-3.03(m,2H),1.87-1.71(m,2H),1.57-1.43(m,2H).ESI-MS:m/z 507.1[M-H] -.
实施例141
N-(3-((3-氨基丙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-26)
Figure PCTCN2020120279-appb-000195
将化合物3-溴丙胺氢溴酸盐(500mg,2.28mmol),DIPEA(944mL,5.71mmol)混悬于DCM(10mL)中，向其中缓慢滴加CbzCl(487mL,3.426mmol),室温反应1h。反应液减压蒸除溶剂，残留物加入EtOAc(30mL)稀释，稀释液依次 用1N HCl,H 2O,饱和NaHCO 3(aq.)，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得残留物，无色油状液体即IV-16(701mg,Quant.)。
参照实施例123的方法，将IV-10替换成IV-16制得化合物IV-17。
将化合物IV-17(84mg,0.134mmol)溶于THF(5mL)中,向其中加入Pd/C(10mg),氢气氛围升温至50℃反应8h。反应液硅藻土抽滤，滤液减压蒸除溶剂，残留物混悬于DCM(4mL)中,搅拌，抽滤，滤饼用少量DCM洗涤，红外干燥至恒重得白色固体即D-26(57mg,86％). 1H NMR(300MHz,DMSO-d 6)δppm 10.11(s,1H),8.10(d,J＝8.3Hz,2H),8.00(d,J＝8.2Hz,2H),7.89(dd,J＝9.0,9.0Hz,4H),7.61(d,J＝2.4Hz,1H),7.38(dd,J＝8.6,2.3Hz,1H),6.79(d,J＝8.6Hz,1H),5.34(s,2H),3.08(t,J＝6.8Hz,2H),2.73(t,J＝6.8Hz,2H),1.93-1.78(dt,J＝14.9,6.8Hz,1H).ESI-MS:m/z 492.1[M-H] -.
实施例142
N-(3-((4-氨基-4-氧丁基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-27)
Figure PCTCN2020120279-appb-000196
参照实施例137的方法，将D-19替换成D-23制得化合物D-27: 1H NMR(300MHz,DMSO-d 6)δppm 10.05(s,1H),8.08(d,J＝8.3Hz,2H),7.99(d,J＝8.2Hz,2H),7.87(dd,J＝8.5,8.5Hz,4H),7.53(d,J＝2.0Hz,1H),7.33(d,J＝7.5Hz,1H),7.24(s,1H),6.73(d,J＝8.6Hz,1H),6.70(s,1H),2.96(t,J＝7.4Hz,2H),2.17(t,J＝7.4Hz,1H),1.90(dt,J＝15.0,7.4Hz,1H).ESI-MS:m/z 520.0[M-H] -.
实施例143
2'-氯-N-(4-羟基-3-(氨磺酰基氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-28)
Figure PCTCN2020120279-appb-000197
将化合物III-13(1.88g,3.4mmol)，还原铁粉(1.9g,34mmol)，NH 4Cl(1.83g,34mmol)混溶于无水乙醇(30mL)和H 2O(10mL)中，升温至80℃反应2h。反 应液冷却室温，加入EtOAc(20mL)稀释，稀释液经硅藻土抽滤，滤液减压蒸除有机溶剂，残留物加入水(30mL)和EtOAc(40mL)，分液，有机层依饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂，残留物混悬于石油醚(20mL)中，搅拌，抽滤，红外干燥得灰白色固体即化合物IV-18(1.66g,94％)。
参照实施例86的方法，将III-11替换成IV-18，甲基磺酰氯替换为氨基磺酰氯制得化合物D-28： 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.49(s,1H),8.06(d,J＝8.3Hz,2H),8.03(s,1H),7.84(d,J＝8.1Hz,1H),7.80(s,1H),7.75-7.68(m,2H),7.62(d,J＝8.3Hz,2H),7.41(dd,J＝8.7,2.4Hz,1H),6.95(s,2H),6.83(d,J＝8.7Hz,1H).ESI-MS:m/z 484.1[M-H] -.
实施例144
2'-氯-N-(3-((2-(二甲基氨基)乙基)磺酰胺基)-4-羟苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-29)
Figure PCTCN2020120279-appb-000198
参照实施例125的方法，将III-11替换成IV-18制得化合物D-29： 1H NMR(300MHz,DMSO-d 6)δppm 10.21(s,1H),8.05(d,J＝8.3Hz,2H),8.03(s,1H),7.84(d,J＝8.3Hz,1H),7.74-7.67(m,2H),7.63(d,J＝8.2Hz,2H),7.51(dd,J＝8.7,2.4Hz,1H),6.85(d,J＝8.7Hz,1H),3.25(t,J＝7.1Hz,2H),2.73(t,J＝7.1Hz,2H),2.17(s,6H).ESI-MS:m/z 540.1[M-H] -.
实施例145
2'-氯-N-(3-(((3-氯丙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-30)
Figure PCTCN2020120279-appb-000199
参照实施例124的方法，将III-11替换成IV-18制得化合物D-30： 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),9.78(s,1H),8.94(s,1H),8.09-8.01(m,3H),7.84(d,J＝8.1Hz,1H),7.71(d,J＝8.1Hz,1H),7.67(d,J＝2.3Hz,1H),7.63(d,J＝8.2Hz,2H),7.54(dd,J＝8.7,2.4Hz,1H),6.87(d,J＝8.7Hz,1H),3.75(t,J＝6.6Hz,2H),3.25-3.13(m,2H),2.30-2.13(m,2H).ESI-MS:m/z 545.1[M-H] -.
实施例146
3-(N-(5-(2'-氯-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺基)-2-羟基苯基)氨磺酰基)丙 酸(化合物D-31)
Figure PCTCN2020120279-appb-000200
参照实施例134和135的方法，将III-11替换成IV-18制得化合物D-31： 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),8.06(d,J＝8.3Hz,2H),8.03(s,1H),7.84(d,J＝7.8Hz,1H),7.71(d,J＝8.0Hz,1H),7.67-7.63(m,2H),7.61(s,1H),7.53(dd,J＝8.7,2.3Hz,1H),6.86(d,J＝8.7Hz,1H),3.25(t,7.6Hz,2H),2.64(t,J＝7.6Hz,2H).ESI-MS:m/z 541.1[M-H] -.
实施例147
2'-氯-N-(4-羟基-3-((2-吗啉代乙基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-32)
Figure PCTCN2020120279-appb-000201
参照实施例125的方法，将III-11替换成IV-18，二甲氨基盐酸盐替换成吗啡啉制得化合物D-32： 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),9.83(s,1H),8.81(s,1H),8.12-7.99(m,3H),7.84(d,J＝7.9Hz,1H),7.76-7.67(m,2H),7.63(d,J＝8.1Hz,2H),7.51(d,J＝8.6Hz,1H),6.87(d,J＝8.7Hz,1H),3.61-3.50(m,4H),3.37-3.25(m,2H),2.85-2.71(m,2H),2.47-2.31(m,4H).ESI-MS:m/z 582.1[M-H] -.
实施例148
2'-氯-N-(4-羟基-3-((2-(4-苯基哌嗪-1-基)乙基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-33)
Figure PCTCN2020120279-appb-000202
参照实施例125的方法，将III-11替换成IV-18，二甲氨基盐酸盐替换成1-苯基哌嗪制得化合物D-33： 1H NMR(300MHz,Pyridine-d 5)δppm 11.14(s,1H),8.67-8.60(m,1H),8.35(d,J＝8.1Hz,2H),8.18-8.08(m,1H),7.92(s,1H),7.64(d,J＝8.0Hz,1H),7.58-7.54(m,2H),7.46(d,J＝8.1Hz,1H),7.36-7.26(m,3H),7.01-6.84(m,3H),3.79(t,J＝7.1Hz,2H),3.24-3.11(m,6H),2.60-2.50(m,4H).ESI-MS:m/z 657.2[M-H] -.
实施例149
2'-氯-N-(4-羟基-3-((2-(4-(甲基磺酰基)哌嗪-1-基)乙基)磺酰胺基)苯基)-4'-(三 氟甲基)-[1,1'-联苯基]-4-甲酰胺(化合物D-34)
Figure PCTCN2020120279-appb-000203
参照实施例125的方法，将III-11替换成IV-18，二甲氨基盐酸盐替换成1-(甲基磺酰基)哌嗪制得化合物D-34： 1H NMR(300MHz,Acetone-d 6)δppm 9.61(s,1H),8.13(d,J＝8.1Hz,2H),7.92(s,1H),7.88-7.84(m,1H),7.81(d,J＝8.1Hz,1H),7.70(d,J＝8.0Hz,1H),7.67-7.60(m,3H),6.96(d,J＝8.7Hz,1H),3.43(t,J＝6.5Hz,2H),3.25-3.13(m,4H),2.97(t,J＝6.4Hz,2H),2.80(s,3H),2.66-2.55(m,4H).ESI-MS:m/z 659.1[M-H] -.
实施例150
2'-氯-N-(4-羟基-3-((2-(4-羟基哌啶-1-基)乙基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-35)
Figure PCTCN2020120279-appb-000204
参照实施例125的方法，将III-11替换成IV-18，二甲氨基盐酸盐替换成4-羟基哌啶制得化合物D-35： 1H NMR(300MHz,DMSO-d 6)δppm 10.21(s,1H),8.12-8.00(m,3H),7.84(d,J＝8.1Hz,1H),7.75-7.66(m,2H),7.63(d,J＝8.2Hz,2H),7.51(dd,J＝8.7,2.3Hz,1H),6.86(d,J＝8.7Hz,1H),4.56(s,1H),3.56-3.41(m,1H),3.39-3.25(m,2H),2.90-2.67(m,4H),2.27-2.07(m,2H),1.77-1.63(m,2H),1.51-1.33(m,2H).ESI-MS:m/z 596.2[M-H] -.
实施例151
2'-氯-N-(4-羟基-3-((2-(4-甲基哌嗪-1-基)乙基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-36)
Figure PCTCN2020120279-appb-000205
参照实施例125的方法，将III-11替换成IV-18，二甲氨基盐酸盐替换成N-甲基哌嗪制得化合物D-36： 1H NMR(300MHz,DMSO-d 6)δppm 10.21(s,1H),8.09-8.00(m,3H),7.84(d,J＝8.1Hz,1H),7.74-7.66(m,2H),7.63(d,J＝8.2Hz,2H),7.51(dd,J＝8.7,2.3Hz,1H),6.86(d,J＝8.7Hz,1H),3.38(t,J＝7.3Hz,2H),2.77(t,J＝7.3Hz,2H),2.46-2.26(m,8H),2.16(s,3H).ESI-MS:m/z 595.2[M-H] -.
实施例152
2'，3'-二氯-N-(4-羟基-3-(甲基磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物 D-37)
Figure PCTCN2020120279-appb-000206
将化合物2,3-二氯苯硼酸(169mg,0.877mmol)，4-碘苯甲酸(200mg,0.806mmol)，无水K 2CO 3(334mg,2.419mmol)，Pd(PPh 3) 4(47mg,0.04mmol)混悬于Tol(15mL)和MeOH(3mL)中，氮气氛围升温至80℃反应4h。反应液减压蒸除溶剂，残留物加入1N HCl调节pH至1-3，搅拌，抽滤，滤饼用水洗涤，红外干燥至恒重得棕色固体。将其混悬于Et 2O/EtOAc(5mL/0.5mL)中，搅拌，抽滤得黄色固体即化合物IV-19(200mg,93％). 1H NMR(300MHz,DMSO-d 6)δppm 13.05(s,1H),8.03(d,J＝8.2Hz,2H),7.71(dd,J＝7.8,1.5Hz,1H),7.56(d,J＝8.2Hz,2H),7.50-7.38(m,2H).
将化合物IV-19(105mg,0.391mmol)混悬于DCM(5mL)中，冰浴条件下向其中缓慢滴加(COCl) 2(48μL,0.560mmol)，DMF(1drop)，室温反应3h。反应液减压蒸除溶剂，残留物加入DCM(2mL)制得酰氯溶液，冰浴条件下将其加至III-7(100mg,0.373mmol)和DIPEA(93μL,0.560mmol)的DCM(2mL)溶液中，室温反应1.5h。反应液减压蒸除溶剂，残留物加入EtOAc(10mL)和H 2O(8mL)，分液，有机层依次用1N HCl，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物加入Et 2O(2mL)和石油醚(2mL)，搅拌，抽滤得黄色固体即化合物IV-20(156mg,81％)。
将化合物IV-20(156mg,0.3mmol)，还原铁粉(84mg,1.5mmol)，饱和NH 4Cl(aq.)(2mL)混悬于EtOH(10mL)中，升温至80℃反应2h。反应液冷却至室温，加入EtOAc(10mL)稀释，稀释液经硅藻土抽滤，滤饼用EtOAc(10mL)洗涤，合并有机相，减压蒸除有机溶剂，残留物加入H 2O(10mL)和EtOAc(20mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，棕黄色固体即化合物IV-21(111mg,76％)。
将化合物IV-21(110mg,0.226mmol)，吡啶(22μL,0.271mmol)，DIPEA(56μL,0.339mmol)混溶于DCM(5mL)中，向其中缓慢滴加MsCl(21μL)，室温反 应1.5h。反应液减压蒸除溶剂，残留物加入1N HCl(8mL)和EtOAc(10mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，经硅胶柱层析(石油醚/EtOAc＝6/1)纯化得目标物。将其溶于DCM(5mL)中，向其中缓慢滴加TEA·3HF(80μL)，室温反应4h。反应液减压蒸除溶剂，残留物加入1N HCl(6mL)和EtOAc(10mL)，分液，有机层用饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物混悬于DCM(2mL)中，搅拌，抽滤，滤饼红外干燥至恒重得类白色固体即化合物D-37(38mg,37％). 1H NMR(300MHz,DMSO-d 6)δppm 10.20(s,1H),9.70(s,1H),8.70(s,1H),8.03(d,J＝8.2Hz,2H),7.71(dd,J＝7.6,1.2Hz,1H),7.67(d,J＝1.3Hz,1H),7.58(d,J＝8.2Hz,2H),7.55-7.45(m,2H),7.45-7.40(m,1H),6.87(d,J＝8.8Hz,1H),2.98(s,3H).ESI-MS:m/z 449.0[M-H] -.
实施例153
2'-溴-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-38)
Figure PCTCN2020120279-appb-000207
将化合物2-溴-1-碘-4-三氟甲基苯(1.0g,2.85mmol)，4-甲氧羰基苯硼酸(564mg,3.14mmol)，无水K 2CO 3(1.18g,8.55mmol)，Pd(PPh 3) 4(165mg,0.14mmol)混悬于Tol(30mL)和MeOH(5mL)中，氮气氛围升温至80℃反应3h。反应液减压蒸除溶剂，残留物加入EtOAc(30mL)和H 2O(20mL)，分液，有机层依次用1N HCl，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚/EtOAc＝30/1)纯化得目标物，白色固体即化合物IV-22(373mg,36％). 1H NMR(300MHz,DMSO-d 6)δppm 8.16(s,1H),8.07(d,J＝8.1Hz,2H),7.87(d,J＝7.9Hz,1H),7.65(d,J＝8.1Hz,1H),7.60(d,J＝8.1Hz,2H),3.90(s,3H).
将化合物IV-22(120mg,0.33mmol)溶于THF(5mL)和MeOH(2mL)中，向其中加入2N NaOH(3mL)，室温反应2h。反应液减压蒸除有机溶剂，残留物加H 2O(6mL)稀释，稀释液用1N HCl调节pH至3-4，向其中加入EtOAc(8mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO4干燥，过滤，滤液减压蒸除溶剂， 残留物混悬于石油醚(5mL)中，搅拌，抽滤，滤饼红外干燥至恒重得白色固体即化合物IV-23(84mg,78％)。
参照实施例152的方法，将IV-19替换成IV-23制得化合物D-38: 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),9.70(s,1H),8.71(s,1H),8.16(s,1H),8.05(d,J＝8.2Hz,2H),7.88(d,J＝7.9Hz,1H),7.69-7.64(m,2H),7.59(d,J＝8.2Hz,2H),7.53(dd,J＝8.8,2.4Hz,1H),6.87(d,J＝8.7Hz,1H),2.98(s,3H).ESI-MS:m/z 527.0[M-H] -.
实施例154
N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'：2'，1″-三苯基]-4-甲酰胺(化合物D-39)
Figure PCTCN2020120279-appb-000208
将化合物IV-22(250mg,0.707mmol)，苯硼酸(102mg,0.84mmol)，无水K 2CO 3(290mg,2.1mmol)，Pd(PPh 3) 4(40mg,0.035mmol)混悬于Tol(12mL)和MeOH(2mL)中，氮气氛围升温至80℃反应5h。反应液冷却室温，加入H 2O(8mL)和EtOAc(12mL)，分液，有机层依次用1N HCl，饱和食盐水洗涤，无水NaSO 4干燥，过滤，滤液减压蒸除溶剂，残留物溶于THF(5mL)和MeOH(2mL)中，向其中加入2N NaOH(3mL)，室温反应2h。反应液减压蒸除有机溶剂，残留物加入H 2O(5mL)稀释，稀释液用1N HCl调节pH至3-4，析出固体，搅拌，抽滤，滤饼用水洗涤，红外干燥至恒重得灰色固体。经硅胶柱层析(DCM/MeOH＝50/1)纯化得目标物，白色固体即化合物IV-24(158mg,66％,two steps)。
参照实施例152的方法，将IV-19替换成IV-24制得化合物D-39: 1H NMR(300MHz,DMSO-d 6)δppm 10.09(s,1H),9.68(s,1H),8.68(s,1H),7.90-7.82(m,3H),7.73(s,1H),7.70(d,J＝8.1Hz,1H),7.62(d,J＝2.1Hz,1H),7.48(dd,J＝8.7,2.3Hz,1H),7.34-7.25(m,5H),7.23-7.16(m,2H),6.85(d,J＝8.8Hz,1H),2.97(s,3H).ESI-MS:m/z 525.1[M-H] -.
实施例155
N-(4-羟基-3-(甲基磺酰胺基)苯基)-4-(2-(三氟甲基)-1H-苯并[d]咪唑-6-基)苯 甲酰胺(化合物D-40)
Figure PCTCN2020120279-appb-000209
将化合物2-氨基-4-硝基苯酚(5g,32.4mmol)，吡啶(4mL,48.6mmol)混溶于DCM(50mL)中，冰浴条件下缓慢滴加MsCl(3mL,39mmol)的DCM(25mL)溶液，室温反应过夜。向反应液中滴加conc.HCl(4mL)，搅拌，减压蒸除有机溶剂，残留物加入EtOAc(70mL)和1N HCl(50mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物加入EtOH(40mL)，向其中滴加NaOH(1.3g)的H 2O(15mL)溶液，升温至80℃反应4h。反应液减压蒸除有机溶剂，残留物缓慢滴加conc.HCl调节pH至1-3，析出固体，抽滤，水洗涤，红外干燥至恒重得棕黄色固体即化合物IV-25。
将化合物IV-25溶于THF(45mL)和MeOH(30mL)中，加入Pd/C(600mg)，氢气氛围室温反应过夜。反应液经硅藻土抽滤，滤液减压蒸除溶剂得残留物即化合物IV-26(4.45g)。
将化合物IV-26，DIPEA(5.5mL,33.3mmol)混溶于DCM(50mL)中，冰浴条件下滴加TBSCl(4.34g,28.8mmol)的DCM(15mL)溶液，室温反应3h。反应液加入饱和NaHCO 3(50mL)和DCM(50mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，经硅胶柱层析(DCM)纯化得目标物，淡黄色油状液体，静置析出固体即化合物IV-27(3.47g,34％for three steps). 1H NMR(300MHz,DMSO-d 6)δppm 7.93(s,1H),6.65-6.57(m,2H),6.29(dd,J＝8.5,2.8Hz,1H),4.75(s,2H),2.98(s,3H),0.96(s,9H).
将化合物4-溴-2-硝基苯胺(1.0g,4.61mmol)，对甲氧羰基苯硼酸(912mg,5.07mmol)，无水K 2CO 3(1.9g,13.82mmol)，Pd(PPh 3) 4(266mg,0.23mmol)混悬于Tol(20mL)和MeOH(4mL)中，氮气氛围升温至80℃反应5h。反应液 冷却室温，加入H 2O(20mL)，搅拌，抽滤，滤饼水洗涤，红外干燥至恒重得棕色固体，将其混悬于石油醚(20mL)和EtOAc(5mL)中，搅拌，抽滤，滤饼红外干燥至恒重得目标物，棕黄色固体即IV-28。
将化合物IV-28溶于THF(15mL)和MeOH(5mL)中，加入Pd/C(100mg)，氢气氛围升温至50℃反应8h。反应液冷却至室温，硅藻土抽滤，滤液减压蒸除溶剂，残留物混悬于石油醚(20mL)和EtOAc(5mL)中，搅拌，抽滤，滤饼红外干燥至恒重得目标物，棕色固体即IV-29(920mg,82％,two steps)。
将化合物IV-29(201mg,0.83mmol)溶于CF 3COOH(3mL)中，回流反应2.5h。反应液冷却至室温，用饱和Na 2CO 3(aq.)调节pH至9-10，加入EtOAc(15mL)，分液，有机层依次用H 2O，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物混悬于石油醚(5mL)和DCM(2mL)中，搅拌，抽滤得灰白色固体即化合物IV-30(220mg,83％). 1H NMR(300MHz,DMSO-d 6)δppm 14.11(s,1H),8.06(d,J＝8.2Hz,2H),7.97-7.85(m,3H),7.84-7.67(m,2H),3.89(s,3H).
将化合物IV-30(216mg,0.675mmol)溶于THF(2mL)和MeOH(2mL)中，向其中加入2N NaOH(aq.)(1mL)，室温反应过夜后升温至50℃反应3h。反应液减压蒸除有机溶剂，残留物加入H 2O(4mL)稀释，稀释液用1N HCl调节pH至3-4，析出固体，抽滤，滤饼水洗涤，红外干燥至恒重得灰白色固体即化合物IV-31(200mg,97％)。
将化合物IV-31(50mg,0.163mmol)，HATU(75mg,0.196mmol)，DIPEA(54μL,0.326mmol)混悬于THF(5mL)中，室温反应3h后加入IV-27(52mg,0.163mmol)，室温反应8h后升温至60℃反应1.5h。反应液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝80/1)纯化得目标物。将其溶于DCM(5mL)中，向其中滴加TEA·3HF(60μL)，室温反应4h。反应液析出固体，抽滤，滤饼依次用DCM，1N HCl，H 2O洗涤，红外干燥至恒重得土灰色固体即化合物D-40(40mg,50％,two steps). 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.68(s,1H),8.68(s,1H),8.09(s,1H),8.08-8.01(m,2H),7.93-7.75(m,4H),7.68(d,J＝2.4Hz,1H),7.54(dd,J＝8.7,2.5Hz,1H),6.88(d,J＝8.7Hz,1H),2.99(s,3H).ESI-MS:m/z 489.1[M-H] -.
实施例156
N-(4-羟基-3-(甲基磺酰胺基)苯基)-4-(2-甲基-1H-苯并[d]咪唑-6-基)苯甲酰胺(化合物D-41)
Figure PCTCN2020120279-appb-000210
Figure PCTCN2020120279-appb-000211
将化合物IV-29(400mg,1.65mmol)，乙酰乙酸乙酯(209μL,1.65mmol)，无水FeCl 3(35mg,0.215mmol)混悬于EtOH(15mL)中，回流反应1h。反应液冷却至室温，减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝30/1)纯化得目标物。将其溶于THF(4mL)和MeOH(2mL)中，向其中加入2N NaOH(aq.)(2mL)，升温至60℃反应4h。反应液减压蒸除有机溶剂，残留物加入H 2O(4mL)稀释，稀释液用1N HCl调节pH至3-4，析出固体，抽滤，滤饼水洗涤，得棕黄色粘稠状固体，将其混悬于丙酮(6mL)中，搅拌，抽滤，得淡黄色固体即化合物IV-32(197mg,47％,two steps)。
参照实施例155的方法，将IV-31替换成IV-32制得化合物D-41: 1H NMR(300MHz,DMSO-d 6)δppm 14.37(s,1H),10.18(s,1H),9.74(s,1H),8.73(s,1H),8.09(d,J＝7.8Hz,2H),8.01(s,1H),7.89(d,J＝7.9Hz,2H),7.81(s,2H),7.67(s,1H),7.54(d,J＝8.6Hz,1H),6.89(d,J＝8.7Hz,1H),2.98(s,3H),2.76(s,3H).ESI-MS:m/z 435.2[M-H] -.
实施例157
N-(4-羟基-3-(甲基磺酰胺基)苯基)-4-(1-甲基-1H-吲唑-5-基)苯甲酰胺(化合物D-42)
Figure PCTCN2020120279-appb-000212
将化合物IV-33(5-溴-1-甲基-1H-吲唑)(106mg,0.5mmol)，对甲氧羰基苯硼酸(99mg,0.55mmol)，无水K 2CO 3(207mg,1.5mmol)，Pd(PPh 3) 4(30mg,0.025mmol)混悬于Tol(6mL)和MeOH(1mL)中，氩气氛围升温至80℃反应6h。反应液冷却室温，减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝200/1)纯化得目标物即化合物IV-34。
将化合物IV-34溶于THF(2mL)和MeOH(3mL)中，向其中加入NaOH(95mg,2.4mmol)的H 2O(2mL)溶液，室温反应4h。反应液减压蒸除有机溶剂，残留物加入H 2O(3mL)稀释，稀释液用1N HCl调节pH至1-3，析出固体，抽滤，滤饼水洗涤，红外干燥至恒重得黄色固体，将其混悬于MeOH(3mL)中，搅拌，抽滤得目标物即化合物IV-35(102mg,81％,two steps)。
将化合物IV-35(70mg,0.278mmol)混悬于THF(2mL)和DCM(2mL)中，冰浴条件下向其中缓慢滴加(COCl) 2(50μL,0.556mmol)，DMF(1drop)，室温反应过夜。反应液减压蒸除溶剂，残留物加入DCM(3mL)制得酰氯溶液，冰浴条件下将其加至IV-27(88mg,0.278mmol)和DIPEA(92μL,0.556mmol)的DCM(3mL)溶液中，室温反应2.5h。反应液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝200/1)纯化得目标物即化合物IV-36。
将化合物IV-36溶于DCM(3mL)中，向其中缓慢滴加TEA·3HF(50μL)，室温反应4h。反应液析出固体，抽滤，滤饼依次用DCM，1N HCl，H 2O洗涤，红外干燥至恒重，得类白色固体即化合物D-42(24mg,20％,two steps). 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),8.13-8.02(m,4H),7.95(d,J＝8.1Hz,2H),7.86(d,J＝8.4Hz,1H),7.70-7.64(m,1H),7.54(d,J＝8.4Hz,2H),6.88(d,J＝8.7Hz,1H),4.13(s,3H),2.99(s,3H).ESI-MS:m/z 435.2[M-H] -.
实施例158
N-(4-羟基-3-(甲基磺酰胺基)苯基)-4-(1-甲基-1H-吡唑-4-基)苯甲酰胺(化合物D-43)
Figure PCTCN2020120279-appb-000213
将化合物4-溴-1-甲基-1H-吡唑(447mg,2.78mmol)，对甲氧羰基苯硼酸(500mg,2.78mmol)，无水Cs 2CO 3(1.8g,5.56mmol)，Pd(dppf)Cl 2·DCM(114mg,0.139mmol)混悬于Dioxane(15mL)和H 2O(1mL)中，氩气氛围升温至100℃反应4h。反应液冷却室温，加入MeOH(3mL)和EtOAc(10mL)稀释，稀释液滤去不溶物，滤液加入H 2O(10mL)和EtOAc(15mL)，分液，有机层依次用H 2O，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物混悬于石油醚(15mL)和EtOAc(4mL)中，搅拌，抽滤，红外干燥至恒重，得淡黄色固体 即IV-37(294mg,49％)。
参照实施例155的方法，将IV-30替换成IV-37制得化合物D-43: 1H NMR(300MHz,DMSO-d 6)δppm 10.00(s,1H),9.61(s,1H),8.62(s,1H),8.25(s,1H),7.96(s,2H),7.94(s,1H),7.70(d,J＝8.3Hz,2H),7.65(d,J＝2.2Hz,1H),7.51(dd,J＝8.7,2.4Hz,1H),6.87(d,J＝8.7Hz,1H),3.89(s,3H),2.99(s,3H).ESI-MS:m/z 385.1[M-H] -.
实施例159
N-(4-羟基-3-(甲基磺酰胺基)苯基)-3-((甲基磺酰基)甲基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-44)
Figure PCTCN2020120279-appb-000214
将化合物IV-38(2-甲基-4-溴苯甲酸甲酯)(458mg,2mmol)，对三氟甲基基苯硼酸(380mg,2.2mmol)，无水K 2CO 3(828mg,6mmol)，Pd(PPh 3) 4(116mg,0.1mmol)混悬于Tol(15mL)和MeOH(3mL)中，氩气氛围升温至80℃反应5h。冷却室温，反应液用1N HCl调节pH至1-3，加入H 2O(25mL)和EtOAc(30mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚/EtOAc＝50/1)纯化得目标物即化合物IV-39。
将化合物IV-39，AIBN(66mg,0.4mmol)，NBS(374mg,2.1mmol)混溶于CCl 4(15mL)中，升温至80℃反应2h。反应液冷却至室温，减压蒸除溶剂，残留物经硅胶柱层析(石油醚/EtOAc＝10/1)纯化得残留物，将其混悬于正己烷(6mL)中，搅拌，抽滤得白色固体即化合物IV-40(390mg,52％,two steps)。
将化合物IV-40(100mg,0.265mmol)，甲基亚磺酸钠(54mg,0.530mmol)混溶于DMF(4mL)中，室温反应3.5h。向反应液中加入H 2O(10mL)，搅拌，抽滤，水洗涤，红外干燥得类白色固体，将其混悬于Et 2O(4mL)中，搅拌，抽滤得白色固体即化合物IV-41(90mg,91％)。
参照实施例157的方法，将IV-34替换成IV-41制得化合物D-44: 1H NMR(300MHz,DMSO-d 6)δppm 10.39(s,1H),7.99-7.97(m,1H),7.96-7.92(m,2H),7.92-7.86(m,3H),7.78(d,J＝8.0Hz,1H),7.60(d,J＝2.4Hz,1H),7.49(dd,J＝8.7,2.4Hz,1H),6.87(d,J＝8.7Hz,1H),4.93(s,2H),2.98(s,3H),2.95(s,3H).ESI-MS: m/z 541.1[M-H] -.
实施例160
N-(4-羟基-3-(甲基磺酰胺基)苯基)-3-(甲基磺酰胺基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-45)
Figure PCTCN2020120279-appb-000215
参照实施例159的方法，将IV-38替换成2-硝基-4-溴苯甲酸甲酯制得化合物IV-42。
将化合物IV-42(300mg,0.92mmol)溶于THF(5mL)和MeOH(5mL)中，加入Pd/C(30mg)，氢气氛围室温反应4h。反应液经硅藻土抽滤，滤液减压蒸除溶剂得残留物，淡黄色固体即化合物IV-43。
将化合物IV-43溶于吡啶(3.5mL)中，向其中滴加MsCl(100mL,1.33mmol)，室温反应过夜。反应液倾倒入conc.HCl(6mL)和饱和NH 4Cl(aq.)(10mL)的混合液中，析出固体，搅拌，抽滤，滤饼依次用1N HCl，水洗涤，红外干燥至恒重得目标物，橘黄色固体即化合物IV-44(314mg,91％,two steps)。
参照实施例157的方法，将IV-34替换成IV-44制得化合物D-45: 1H NMR(300MHz,DMSO-d 6)δppm 10.62(s,1H),10.45(s,1H),9.81(s,1H),8.75(s,1H),8.04(d,J＝8.1Hz,1H),7.92(dd,J＝18.7,8.2Hz,4H),7.83(s,1H),7.67-7.58(m,2H),7.48(d,J＝8.2Hz,1H),6.89(d,J＝8.7Hz,1H),3.21(s,3H),2.98(s,3H).ESI-MS:m/z 542.1[M-H] -.
实施例161
N-(4-羟基-3-(甲基磺酰胺基)苯基)-2-(2-羟基乙氧基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-46)
Figure PCTCN2020120279-appb-000216
Figure PCTCN2020120279-appb-000217
参照实施例159的方法，将IV-38替换成3-羟基-4-溴苯甲酸甲酯制得化合物IV-45。
将化合物IV-45(70mg,0.236mmol)，2-溴乙醇(44mg,0.354mmol)，无水K 2CO 3(65mg,0.472mmol)混悬于丙酮(4mL)和DMSO(1.5mL)中，升温至70℃反应10h。反应液冷却至室温，加入1N HCl(10mL)和EtOAc(15mL)，分液，有机层依次用1N HCl，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，将其溶于THF(3mL)和MeOH(5mL)中，向其中加入2N NaOH(aq.)(1.5mL)，室温反应1.5h。反应液减压蒸除有机溶剂，残留物加入H 2O(3mL)稀释，稀释液1N HCl调节pH至3-4，析出固体，抽滤，水洗涤，红外干燥至恒重得淡棕色固体即化合物IV-46(60mg,78％,two steps)。
参照实施例155的方法，将IV-31替换成IV-46制得化合物D-46: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.72(s,1H),8.72(s,1H),7.87(d,J＝8.3Hz,2H),7.78(d,J＝8.4Hz,2H),7.71-7.63(m,3H),7.57-7.47(m,2H),6.88(d,J＝8.7Hz,1H),4.84(s,1H),4.18(t,J＝4.9Hz,2H),3.77-3.67(m,2H),2.98(s,3H).ESI-MS:m/z 509.2[M-H] -.
实施例162
N-(4-羟基-3-(甲基磺酰胺基)苯基)-2-(3-吗啉代丙氧基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-47)
Figure PCTCN2020120279-appb-000218
将化合物IV-45(400mg,1.35mmol)，1,3-二溴丙烷(1.36g,6.75mmol)，无水K 2CO 3(932mg,6.75mmol)混悬于丙酮(15mL)中，回流反应3h。反应液冷却至室温，滤去不溶物，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚/EtOAc＝40/1)纯化得目标物，白色固体即化合物IV-47(520mg,89％)。
将化合物IV-47(100mg,0.24mmol)，吗啉(25μL,0.29mmol)，无水K 2CO 3 (50mg,0.36mmol)混悬于DMF(2mL)中，升温至80℃反应1h。反应液冷却至室温，加入EtOAc(10mL)和H 2O(10mL)，分液，有机层依次用1N HCl，H 2O，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，将其溶于THF(3mL)和MeOH(3mL)中，向其中加入2N NaOH(aq.)(1.0mL)，室温反应3h。反应液减压蒸除有机溶剂，残留物加入H 2O(4mL)稀释，稀释液用1N HCl调节pH至3-4，析出固体，抽滤，水洗涤，红外干燥得残留物，将其混悬于石油醚(1mL)和EtOAc(2mL)中，搅拌，抽滤，得白色固体即化合物IV-48(79mg,74％,two steps). 1H NMR(300MHz,DMSO-d 6)δppm 13.14(s,1H),10.89(s,1H),7.90-7.77(m,4H),7.72-7.62(m,2H),7.52(d,J＝7.8Hz,1H),4.19(t,J＝5.9Hz,2H),3.99-3.87(m,2H),3.84-3.70(m,2H),3.48-3.36(m,2H),3.19-2.91(m,4H),2.26-2.10(m,2H).
参照实施例157的方法，将IV-35替换成IV-48制得化合物D-47: 1H NMR(300MHz,DMSO-d 6)δppm 10.51(s,1H),10.19(s,1H),9.77(s,1H),8.74(s,1H),7.88-7.76(m,4H),7.74-7.63(m,3H),7.57-7.47(m,2H),6.89(d,J＝8.7Hz,1H),4.28-4.13(m,2H),3.96-3.54(m,4H),3.36-3.28(m,4H),3.17-3.03(m,2H),2.98(s,3H),2.23-2.00(m,2H).ESI-MS:m/z 594.2[M+H] +.
实施例163
N-(4-羟基-3-(甲基磺酰胺基)苯基)-2-(3-(4-甲基哌嗪-1-基)丙氧基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺二盐酸盐(化合物D-48)
Figure PCTCN2020120279-appb-000219
参照实施例162的方法，将吗啡啉替换成N-甲基哌嗪制得化合物D-48: 1H NMR(300MHz,DMSO-d 6)δppm 11.65(s,2H),10.20(s,1H),9.78(s,1H),8.74(s,1H),7.89-7.78(m,4H),7.75-7.64(m,3H),7.58-7.47(m,2H),6.90(d,J＝8.7Hz,1H),4.24(t,J＝5.0Hz,2H),3.80-3.47(m,8H),3.24-3.08(m,2H),2.99(s,3H),2.81(s,3H),2.24-2.06(m,2H).ESI-MS:m/z 607.3[M+H] +.
实施例164
N-(4-羟基-3-(甲基磺酰胺基)苯基)-2-(2-吗啉代乙氧基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-49)
Figure PCTCN2020120279-appb-000220
Figure PCTCN2020120279-appb-000221
将化合物IV-45(55mg,0.186mmol)，4-(2-溴乙基)吗啡啉氢溴酸盐(76mg,0.28mmol)，无水K 2CO 3(77mg,0.51mmol)混悬于丙酮(4mL)中，回流反应3h。反应液冷却至室温，加入EtOAc(10mL)和H 2O(8mL)，分液，有机层用饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，将其溶于THF(3mL)和MeOH(1mL)中，向其中加入2N NaOH(aq.)(1.0mL)，室温反应4h。反应液减压蒸除有机溶剂，残留物加入H 2O(5mL)稀释，稀释液用1N HCl调节pH至3-4，析出固体，抽滤，水洗涤，红外干燥至恒重得白色固体即化合物IV-48(72mg,90％,two steps)。
参照实施例155的方法，将IV-31替换成IV-49制得化合物D-49: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),9.73(s,1H),8.72(s,1H),7.81(dd,J＝16.6,8.0Hz,4H),7.71-7.60(m,3H),7.56-7.46(m,2H),6.88(d,J＝8.7Hz,1H),4.25(t,J＝4.2Hz,2H),3.61-3.45(m,4H),2.98(s,3H),2.70(t,J＝4.2Hz,2H),2.46-2.23(m,4H).ESI-MS:m/z 580.2[M+H] +.
实施例165
2-(2-(二甲基氨基)乙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-50)
Figure PCTCN2020120279-appb-000222
将化合物IV-45(50mg,0.169mmol)，二甲氨基氯乙烷盐酸盐(32mg,0.219mmol)，Cs 2CO 3(138mg,0.423mmol)混悬于DMF(3mL)中，升温至80℃反应18h。反应液冷却至室温，加入EtOAc(10mL)和H 2O(10mL)，分液，有机层用饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，将其溶于THF(4mL)和MeOH(2mL)中，向其中加入2N NaOH(aq.)(1.5mL)，室温反应4h。反应液减压蒸除有机溶剂，残留物加入H 2O(5mL)稀释，稀释液用1N HCl调节pH至3-4，析出固体，抽滤，水洗涤，红外干燥至恒重，得白色固 体即化合物IV-50(31mg,47％,two steps)。
参照实施例157的方法，将IV-35替换成IV-50制得化合物D-50: 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.74(s,1H),8.75(s,1H),7.87-7.76(m,4H),7.75-7.63(m,3H),7.57-7.46(m,2H),6.88(dd,J＝8.7,1.3Hz,1H),4.35(t,J＝4.5Hz,2H),3.09(t,J＝4.5Hz,2H),2.98(s,3H),2.49(s,6H).ESI-MS:m/z 528.2[M+H] +.
实施例166
N-(4-羟基-3-((2-脲基乙基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-51)
Figure PCTCN2020120279-appb-000223
将化合物IV-14(90mg,0143mmol)，DIPEA(60μL,0.358mmol)混溶于DCM(5mL)中，冰浴条件下向其中缓慢滴加氯甲酸苯酯(27μL,0.214mmol)，室温反应30min。反应液加入1N HCl(6mL)和EtOAc(10mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物溶于DCM(5mL)中，向其中滴加TEA·3HF(55μL)，室温反应过夜。反应液析出固体，抽滤，滤饼DCM洗涤，红外干燥至恒重，得白色固体即化合物IV-51(71mg,81％)。
将化合物IV-51混溶于混悬于EtOH(5mL)和NH 3·H 2O(3mL)中，升温至85℃反应3h。反应液冷却至室温，减压蒸除有机溶剂，残留物加入饱和NH 4Cl(aq.)(10mL)和EtOAc(10mL)，分液，水层用EtOAc(8mL)提取，合并有机相，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝10/1)纯化得目标物，将其混悬于DCM(3mL)，搅拌，抽滤，滤饼依次用少量MeOH洗涤，红外干燥至恒重，得棕色固体即化合物D-51(13mg,21％). 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.75(s,1H),8.88(s,1H),8.09(d,J＝8.1Hz,2H),7.99(d,J＝8.1Hz,2H),7.94-7.83(m,4H),7.68-7.65(m,1H),7.54(dd,J＝8.7,1.5Hz,1H),6.87(d,J＝8.7Hz,1H),6.07(t,J＝5.7Hz,1H),5.59(s,2H),3.47-3.38(m,2H),3.16(t,J＝6.5Hz,2H).ESI-MS:m/z 521.2[M-H] -.
实施例167
3-(N-(5-(2'-氯-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺基)-2-羟基苯基)氨磺酰基)丙酸甲酯(化合物D-52)
Figure PCTCN2020120279-appb-000224
参照实施例134的方法，将III-11替换成IV-18制得化合物D-52： 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),8.10-8.01(m,3H),7.84(d,J＝8.2Hz,1H),7.71(d,J＝8.1Hz,1H),7.67-7.60(m,3H),7.55(dd,J＝8.8,2.5Hz,1H),6.87(d,J＝8.7Hz,1H),3.62(s,3H),3.36-3.26(m,2H),2.85(t,J＝7.5Hz,2H).ESI-MS:m/z555.2[M-H] -.
实施例168
N-(3-((4-氟苯基)磺酰胺基)-4-羟基苯基)-[1,1'-联苯]-4-磺酰胺(化合物D-53)
Figure PCTCN2020120279-appb-000225
将化合物I-6(119mg,0.3mmol)和吡啶(100μL)混溶于DCM(4mL)中，向其中缓慢加入对联苯磺酰氯(78mg,0.31mmol)，室温反应2h。反应液2N HCl调节pH至1-3，加入H 2O(6mL)和DCM(8mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚/EtOAc＝5/1)纯化得目标物。将其溶于DCM(5mL)中，向其中缓慢滴加TEA·3HF(50μL)，室温反应1h。反应液析出固体，抽滤滤饼依次用DCM，1N HCl，H 2O洗涤，红外干燥至恒重，得白色固体即化合物D-53(63mg,42％,two steps). 1H NMR(300MHz,DMSO-d 6)δppm 9.86(s,1H),9.43(s,1H),9.25(s,1H),7.82(d,J＝8.5Hz,2H),7.75-7.67(m,4H),7.64(dd,J＝8.8,5.2Hz,2H),7.53-7.38(m,3H),7.27(dd,J＝8.9,8.9Hz,2H),7.06(d,J＝2.5Hz,1H),6.69(dd,J＝8.6,2.6Hz,1H),6.56(d,J＝8.6Hz,1H).ESI-MS:m/z 521.1[M+Na] +.
实施例169
N-(4-羟基-3-(甲基磺酰胺基)苯基)-[1,1'-联苯]-4-磺酰胺(化合物D-54)
Figure PCTCN2020120279-appb-000226
参照实施例168的方法，将I-6替换成IV-27制得化合物D-54: 1H NMR(300MHz,DMSO-d 6)δppm 9.87(s,1H),9.77(s,1H),8.62(s,1H),7.82(d,J＝8.3Hz,2H),7.75(d,J＝8.5Hz,2H),7.72-7.66(m,2H),7.54-7.37(m,3H),7.04(d,J＝2.0Hz,1H),6.82-6.70(m,2H),2.83(s,3H).ESI-MS:m/z 441.1[M+Na] +.
实施例170
N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-磺酰胺(化合物D-55)
Figure PCTCN2020120279-appb-000227
将化合物2-氨基-4-硝基苯甲醚(1.68g,10mmol)和吡啶(1.6mL,20mmol)混溶于DCM(15mL)中，冰浴条件下向其中缓慢滴加MsCl(1.2mL,15mmol)，室温反应2.5h。反应液减压蒸除DCM，残留物加入EtOAc(50mL)和1N HCl(40mL)，分液，水层EtOAc(30mL)提取，合并有机相，依次用1N HCl，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，将其混悬于DCM(10mL)中，搅拌，抽滤，滤饼红外干燥至恒重，得黄色固体即化合物IV-52(1.35g,55％)。
将化合物IV-52溶于THF(10mL)和MeOH(15mL)中，向其中加入Pd/C(140mg)，氢气氛围室温反应5h。反应液经硅藻土抽滤，滤液减压蒸除溶剂得残留物，灰白色固体即化合物IV-53(1.15g,80％)。
将化合物IV-53(231mg,1.07mmol)和吡啶(200μL)混溶于DCM(9mL)中，向其中缓慢加入4-溴苯磺酰氯(179mg,0.7mmol)，室温反应2h。反应液减压蒸除有机溶剂，残留物加入1N HCl(8mL)和EtOAc(12mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物混悬于Et 2O(5mL)中，搅拌，抽滤，滤饼红外干燥至恒重，得粉色固体即化合物IV-54(262mg,86％). 1H NMR(300MHz,DMSO-d 6)δppm 10.04(s,1H),8.85(s,1H),7.75(d,J＝ 8.5Hz,2H),7.60(d,J＝8.5Hz,2H),7.07(d,J＝2.3Hz,1H),6.95(d,J＝8.8Hz,1H),6.84(dd,J＝8.7,2.3Hz,1H),3.74(s,3H),2.86(s,3H).
将化合物IV-54(87mg,0.2mmol)，4-三氟甲基苯硼酸(42mg,0.22mmol)，无水K 2CO 3(83mg,0.6mmol)，Pd(PPh 3) 4(12mg,0.01mmol)混悬于Tol(5mL)和MeOH(1.5mL)中，氩气氛围升温至80℃反应3.5h。反应液冷却至室温，减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝50/1)纯化得目标物，将其混悬于DCM(2mL)中，搅拌，抽滤，滤饼DCM洗涤，红外干燥至恒重，得白色固体即化合物IV-55(66mg,66％). 1H NMR(300MHz,DMSO-d 6)δppm 10.08(s,1H),8.85(s,1H),7.99-7.78(m,8H),7.12(d,J＝2.0Hz,1H),7.01-6.87(m,2H),3.74(s,3H),2.84(s,3H).
将化合物IV-55(50mg,0.1mmol)混悬于DCM(5mL)中，冰浴条件下向其中缓慢滴加BBr 3(60μL)，室温反应2h。反应液加入MeOH(1mL)淬灭，减压蒸除有机溶剂，残留物经硅胶柱层析(DCM/MeOH＝100/1)纯化得目标物，将其混悬于DCM(3mL)，搅拌，抽滤，滤饼DCM洗涤，红外干燥至恒重，得白色固体即化合物D-55(41mg,84％). 1H NMR(300MHz,DMSO-d 6)δppm 9.92(s,1H),9.78(s,1H),8.64(s,1H),7.98-7.74(m,8H),7.03(d,J＝2.0Hz,1H),6.82-6.69(m,2H),2.83(s,3H).ESI-MS:m/z 509.0[M+Na] +.
实施例171
N-(3-((3-氯丙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-磺酰胺(化合物D-56)
Figure PCTCN2020120279-appb-000228
将化合物III-7(805mg,3mmol)和吡啶(784μL,9mmol)混溶于DCM(35mL)中，向其中缓慢加入4-溴苯磺酰氯(860mg,3.36mmol)，室温反应过夜。反应液用2N HCl调节pH至3-4，加入H 2O(12mL)和DCM(20mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物混悬于Et 2O(6mL)和正己烷(10mL)中，搅拌，抽滤，滤饼红外干燥至恒重，得棕黄色 固体即化合物IV-56(1.2g,82％)。
将化合物IV-56(876mg,1.87mmol)，4-三氟甲基苯硼酸(391mg,2.06mmol)，无水K 2CO 3(775mg,5.62mmol)，Pd(PPh 3) 4(120mg,0.1mmol)混悬于Tol(20mL)和MeOH(3mL)中，氩气氛围升温至80℃反应4.5h。反应液冷却至室温，加入H 2O(10mL)和EtOAc(20mL)，conc.HCl调节pH至1-3，分液，水层EtOAc(20mL)提取，合并有机相，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/EtOAc＝200/1)纯化得目标物，将其溶于DCM(10mL)中，向其中加入TEA·3HF(300μL)，室温反应2h。反应液减压蒸除有机溶剂，残留物加入MeOH(5mL)，搅拌，抽滤，滤饼少量MeOH洗涤，红外干燥至恒重，得黄色固体即化合物IV-57. 1H NMR(300MHz,DMSO-d 6)δppm 10.56(brs,2H),8.00-7.90(m,4H),7.89-7.79(m,4H),7.60(d,J＝2.6Hz,1H),7.30(dd,J＝8.9,2.6Hz,1H),7.05(d,J＝8.9Hz,1H).
将化合物IV-57溶于THF(12.5mL)和MeOH(7.5mL)中，向其中加入Pd/C(70mg)，氢气氛围室温反应过夜。反应液经硅藻土抽滤，滤液减压蒸除溶剂得残留物，灰绿固体即化合物IV-58(610mg,80％,three steps)。
将化合物IV-58(60mg,0.137mmol)溶于吡啶(1mL)中，向其中缓慢滴加3-氯丙磺酰氯(20μL,0.164mmol)，室温反应3.5h。反应液加入EtOAc(10mL)和H 2O(5mL)稀释，稀释液用conc.HCl调节pH至1-3，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝100/1)纯化得目标物，将其混悬于Et 2O(5mL)中，搅拌，抽滤，红外干燥至恒重，得类白色固体即化合物D-56(55mg,73％). 1H NMR(300MHz,DMSO-d 6)δppm 9.92(s,1H),9.85(s,1H),8.86(s,1H),7.97-7.73(m,8H),7.06-7.01(m,1H),6.84-6.69(m,2H),3.65(t,J＝6.5Hz,2H),3.08-2.98(m,2H),2.15-2.02(m,2H).ESI-MS:m/z 571.1[M+Na] +.
实施例172
N-(4-羟基-3-((3-羟丙基)磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-磺酰胺(化合物D-57)
Figure PCTCN2020120279-appb-000229
参照实施例123的方法，将IV-10替换成3-苄氧基溴丙烷(3.0mmol)制得化合物IV-59，将其溶于DCM(3mL)中制得IV-59的DCM溶液。
将化合物IV-58(100mg,0.245mmol)溶于DCM(3mL)和THF(0.5mL)中，向其中缓慢滴加IV-59的DCM溶液(1.5mL)，室温反应过夜。反应液减压蒸除有机溶剂，残留物加入EtOAc(10mL)和1N HCl(8mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝200/1)纯化得目标物，将其溶于THF(3mL)和MeOH(2.5mL)中，向其中加入Pd/C(10mg)，氢气氛围室温反应过夜。反应液硅藻土抽滤，滤液减压蒸除溶剂，残留物混悬于EtOAc(0.5mL)和Et 2O(5mL)中，搅拌，抽滤，红外干燥至恒重，得灰白色固体即化合物D-57(27mg,21％,two steps). 1H NMR(300MHz,DMSO-d 6)δppm 9.90(s,1H),9.77(s,1H),8.62(s,1H),8.00-7.75(m,8H),7.07(d,J＝1.6Hz,1H),6.80-6.68(m,2H),4.58(t,J＝4.4Hz,1H),3.43-3.34(m,2H),3.00-2.91(m,2H),1.84-1.70(m,2H).ESI-MS:m/z 553.2[M+Na] +.
实施例173
4'-氟-N-(4-羟基-3-(甲基磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-58)
Figure PCTCN2020120279-appb-000230
参照实施例157的方法，将IV-33替换成4-氟溴苯制得化合物D-58: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.68(s,1H),8.71(s,1H),8.04(d,J＝8.4Hz,2H),7.87-7.76(m,4H),7.66(d,J＝2.4Hz,1H),7.52(dd,J＝8.7,2.5Hz,1H),7.33(dd,J＝8.9,8.9Hz,2H),6.87(d,J＝8.7Hz,1H),2.98(s,3H).ESI-MS:m/z423.1[M+Na] +.
实施例174
4'-氟-N-(4-羟基-3-((3-羟丙基)磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-59)
Figure PCTCN2020120279-appb-000231
将化合物4-氟溴苯(875mg,5mmol)，对甲氧羰基苯硼酸(990mg,5.5mmol)，无水K 2CO 3(2.1g,15mmol)，Pd(PPh 3) 4(289mg,0.25mmol)混溶于Tol(35mL)和MeOH(5mL)中，氩气氛围升温至80℃反应5h。反应液减压蒸除溶剂，残留物加入H 2O(10mL)稀释，稀释液用1N HCl调节pH至6-7，加入EtOAc(30mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚:DCM(1:1)/EtOAc＝100/1)纯化得目标物。将其溶于THF(15mL)和MeOH(10mL)中，加入NaOH(782mg,19.5mmol)的H 2O(7mL)溶液，升温至60℃反应2h。反应液冷却至室温，减压蒸除有机溶剂，残留物加入H 2O(8mL)稀释，2N HCl调节pH至1-3，析出固体，搅拌，抽滤，水洗涤，红外干燥至恒重，得白色固体即化合物IV-61(1.0g,92％,two steps)。
将化合物IV-61(700mg,3.24mmol)混悬于DCM(15mL)中，向其中依次滴加(COCl) 2(417μL,4.86mmol)，DMF(1drop)，室温反应6h。反应液减压蒸除溶剂，残留物复溶于DCM(6mL)中制得酰氯溶液，冰浴条件下将其加至III-7(1.02g,3.24mmol)和DIPEA(803μL,4.86mmol)的DCM(8mL)溶液中，室温反应1.5h。反应液减压蒸除溶剂，残留物加入1N HCl(20mL)和EtOAc(40mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物混悬于正己烷(10mL)和DCM(1mL)中，搅拌，抽滤，红外干燥至恒重，得黄色固体即化合物IV-62。
将化合物IV-62溶于THF(20mL)和MeOH(16mL)中，向其中加入Pd/C(120mg)，氢气氛围室温反应过夜。反应液硅藻土抽滤，滤液减压蒸除溶剂，残留物混悬于正己烷(8mL)中，搅拌，抽滤，得黄色固体即化合物IV-63(997mg,70％,two steps)。
参照实施例86的方法，将III-11替换成IV-63，甲基磺酰氯替换成IV-59，最后经Pd/C脱苄基制得化合物D-59(30mg,75％): 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.69(s,1H),8.69(s,1H),8.04(d,J＝8.2Hz,2H),7.88-7.77(m,4H),7.67(d,J＝2.1Hz,1H),7.52(dd,J＝8.6,2.3Hz,1H),7.33(dd,J＝8.8,8.8Hz,2H),6.85(d,J＝8.6Hz,1H),4.67-4.57(m,1H),3.55-3.42(m,2H),3.14-3.05(m,2H),1.93-1.80(m,2H).ESI-MS:m/z 467.2[M+Na] +.
实施例175
4'-氟-N-(4-羟基-3-((2-(4-甲基哌嗪-1-基)乙基)磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-60)
Figure PCTCN2020120279-appb-000232
参照实施例130的方法，将III-11替换成IV-63制得化合物D-60: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),9.82(brs,2H),8.04(d,J＝8.4Hz,2H),7.88-7.75(m,4H),7.68(d,J＝2.4Hz,1H),7.50(dd,J＝8.7,2.5Hz,1H),7.33(dd,J＝8.9,8.9Hz,2H),6.86(d,J＝8.7Hz,1H),3.27(t,J＝7.3Hz,2H),2.76(t,J＝7.3Hz,2H),2.46-2.25(m,8H),2.15(s,3H).ESI-MS:m/z 513.3[M+H] +.
实施例176
N-(4-羟基-3-(甲基磺酰胺基)苯基)-2',3'-二甲氧基-[1,1'-联苯]-4-甲酰胺(化合物D-61)
Figure PCTCN2020120279-appb-000233
将化合物2-溴-6-甲氧基苯酚(406mg,2mmol)和无水K 2CO 3(552mg,4mmol)混悬于丙酮(12mL)中，向其中滴加MeI(250μL,4mmol)，升温至60℃反应6h后室温搅拌过夜。反应液滤去不溶物，滤液减压蒸除溶剂，残留物加入EtOAc(15mL)和1N HCl(10mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，黄色油状液体即化合物IV-64。
参照实施例157的方法，将IV-33替换成IV-64制得化合物D-61: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.68(s,1H),8.69(s,1H),7.99(d,J＝7.9Hz,2H),7.71-7.65(m,1H),7.60(d,J＝7.9Hz,2H),7.55-7.48(m,1H),7.23-7.07(m,2H),7.01-6.92(m,1H),6.87(d,J＝8.8Hz,1H),3.86(s,3H),3.57(s,3H),2.98(s,3H).ESI-MS:m/z 465.2[M+Na] +.
实施例177
2',3'-二氟-N-(4-羟基-3-(甲基磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-62)
Figure PCTCN2020120279-appb-000234
参照实施例157的方法，将IV-33替换成2,3-二氟溴苯制得化合物D-62: 1H NMR(300MHz,DMSO-d 6)δppm 10.20(s,1H),9.23(brs,2H),8.06(d,J＝8.2Hz,2H),7.72(d,J＝7.6Hz,2H),7.66(d,J＝2.0Hz,1H),7.58-7.47(m,2H),7.47-7.39(m,1H),7.39-7.29(m,1H),6.87(d,J＝8.7Hz,1H),2.98(s,3H).HRMS(ESI):m/z calcd for C 20H 16F 2N 2O 4S[M+Na] +441.06911,found 441.06919.
实施例178
2'-氟-N-(4-羟基-3-(甲基磺酰胺基)苯基)-3'-甲氧基-[1,1'-联苯]-4-甲酰胺(化合物D-63)
Figure PCTCN2020120279-appb-000235
参照实施例157的方法，将IV-33替换成3-溴-2-氟苯甲醚制得化合物D-63: 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.24(brs,2H),8.03(d,J＝8.2Hz,2H),7.76-7.59(m,3H),7.57-7.47(m,1H),7.31-7.17(m,2H),7.16-7.05(m,1H),6.87(d,J＝8.7Hz,1H),3.89(s,3H),2.98(s,3H).HRMS(ESI):m/z calcd for C 21H 19FN 2O 5S[M+H] +431.10715,found 431.10654.
实施例179
3'-氟-N-(4-羟基-3-(甲基磺酰胺基)苯基)-2'-甲氧基-[1,1'-联苯]-4-甲酰胺(化合物D-64)
Figure PCTCN2020120279-appb-000236
参照实施例157的方法，将IV-33替换成2-溴-6-氟苯甲醚制得化合物D-64: 1H NMR(300MHz,DMSO-d 6)δppm 10.17(s,1H),9.70(s,1H),8.70(s,1H),8.02(d,J＝8.0Hz,2H),7.74-7.60(m,3H),7.53(d,J＝8.7Hz,1H),7.39-7.29(m,1H),7.29-7.15(m,2H),6.87(d,J＝8.7Hz,1H),3.70(s,3H),2.98(s,3H).HRMS(ESI):m/z calcd for C 21H 19FN 2O 5S[M+H] +431.10715,found 431.10707.
实施例180
4'-氯-N-(4-羟基-3-(甲基磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-65)
Figure PCTCN2020120279-appb-000237
参照实施例157的方法，将IV-33替换成4-氯溴苯制得化合物D-65: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.37(brs,2H),8.05(d,J＝8.2Hz,2H),7.81(dd,J＝9.0,9.0Hz,4H),7.66(d,J＝2.2Hz,1H),7.61–7.47(m,3H),6.87(d,J＝8.7Hz,1H),2.98(s,3H).HRMS(ESI):m/z calcd for C 20H 17ClN 2O 4S[M+H] +417.06703,found 417.06689.
实施例181
3'-乙氧基-N-(4-羟基-3-(甲基磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-66)
Figure PCTCN2020120279-appb-000238
参照实施例157的方法，将IV-33替换成3-溴苯乙醚制得化合物D-66: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),8.94(brs,2H),8.03(d,J＝8.1Hz,2H),7.82(d,J＝8.1Hz,2H),7.66(s,1H),7.52(d,J＝8.6Hz,1H),7.47-7.34(m,1H),7.34-7.18(m,2H),6.97(d,J＝7.8Hz,1H),6.87(d,J＝8.7Hz,1H),4.13(q,J＝6.9Hz,2H),2.99(s,3H),1.37(t,J＝6.9Hz,3H).HRMS(ESI):m/z calcd for C 22H 22N 2O 5S[M+H] +427.13222,found 427.13202.
实施例182
2-(2-(2-(1,1-二氧硫代吗啉代)乙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-67)
Figure PCTCN2020120279-appb-000239
将PPh 3(393mg,1.5mmol)，咪唑(204mg,3mmol)混溶于THF(6mL)中，向其中加入I 2(381mg,1.5mmol)的THF(3mL)溶液，室温反应30min后向加入4-(2-羟乙基)硫代吗啉-1,1-二氧化物(179mg,1.0mmol)的THF(3mL)溶液，室温反应过夜。反应液加入EtOAc(15mL)和饱和Na 2S 2O4(aq.)(15mL)，分液，水层EtOAc(10mL)提取，合并有机相，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，白色固体即化合物IV-65。
参照实施例164的方法，将4-(2-溴乙基)吗啡啉氢溴酸盐替换成IV-65制得化合物D-67: 1H NMR(300MHz,DMSO-d 6)δppm 10.23(s,1H),9.78(s,1H),8.74(s,1H),7.90-7.62(m,7H),7.51(d,J＝7.5Hz,2H),6.90(d,J＝8.8Hz,1H),4.52(s,2H),3.73-3.37(m,10H),2.98(s,3H).HRMS(ESI):m/z calcd for C 27H 29F 3N 3O 7S 2[M+H] +628.13935,found 628.13891.
实施例183
2-(3-(4,4-二氟哌啶-1-基)丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-68)
Figure PCTCN2020120279-appb-000240
Figure PCTCN2020120279-appb-000241
将化合物4,4-二氟哌啶盐酸盐(315mg,2mmol)，1,3-二溴丙烷(2.02g,10mmol)，无水K 2CO 3(1.38g,10mmol)混悬于丙酮(10mL)中，升温至70℃反应6h。反应液滤去不溶物，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝150/1)纯化得目标物，无色油状液体即化合物IV-66(328mg,68％)。
参照实施例164的方法，将4-(2-溴乙基)吗啡啉氢溴酸盐替换成IV-66制得化合物D-68: 1H NMR(300MHz,DMSO-d 6)δppm 11.01(s,1H),10.19(s,1H),9.77(s,1H),8.73(s,1H),7.88-7.79(m,4H),7.75-7.66(m,3H),7.56-7.48(m,2H),6.90(d,J＝8.7Hz,1H),4.24(t,J＝5.9Hz,2H),3.65-3.49(m,2H),3.25-3.04(m,4H),2.98(s,3H),2.47-2.12(m,6H).HRMS(ESI):m/z calcd for C 29H 30F 5N 3O 5S[M+H] +628.18991,found 628.18897.
实施例184
2-(3-(4-乙酰基哌嗪-1-基)丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-69)
Figure PCTCN2020120279-appb-000242
将化合物1-乙酰哌嗪(385mg,3mmol)，1,3-二溴丙烷(3.0g,15mmol)，K 2CO 3(2.07g,15mmol)混溶于丙酮(15mL)中，升温至70℃反应3h，室温搅拌过夜。反应液滤去不溶物，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝50/1)纯化得目标物，无色油状液体即化合物IV-67(532mg,71％)。
将化合物IV-45(130mg,0.44mmol)，IV-67(150mg,0.60mmol)，无水Cs 2CO 3(220mg,0.68mmol)混悬于丙酮(8mL)中，升温至70℃反应30min。反应液冷却至室温，滤去不溶物，滤液减压蒸除溶剂得残留物，将其溶于THF(4mL)和MeOH(3mL)中，向其中加NaOH(130mg)的H 2O(1mL)溶液，室温反应5h。反应液减压蒸除有机溶剂，加入H 2O(3mL)稀释，稀释液用2N HCl调节pH至 1-3，析出固体，抽滤，水洗涤，红外干燥至恒重，得淡黄色固体即化合物IV-68(Quant.)。
参照实施例157的方法，将IV-35替换成IV-68制得化合物D-69: 1H NMR(300MHz,DMSO-d 6)δppm 10.72(s,1H),10.20(s,1H),9.78(s,1H),8.74(s,1H),7.89-7.78(m,4H),7.76-7.65(m,3H),7.58-7.47(m,2H),6.90(d,J＝8.7Hz,1H),4.49-4.35(m,1H),4.31-4.19(m,2H),4.06-3.85(m,1H),3.60-3.40(m,3H),3.23-3.12(m,2H),3.11-2.79(m,3H),2.98(s,3H),2.29-2.12(m,2H),2.04(s,3H).HRMS(ESI):m/z calcd for C 30H 34F 3N 4O 6S[M+H] +635.21457,found 635.21395.
实施例185
(3-((4-((4-羟基-3-(甲基磺酰胺基)苯基)氨基甲酰基)-4'-(三氟甲基)-[1,1'-联苯]-2-基)氧基)丙基)氨基磷酸二甲酯(化合物D-70)
Figure PCTCN2020120279-appb-000243
将化合物3-溴丙胺氢溴酸盐(438mg,2mmol)，无水K 2CO 3(690mg,5mmol)混悬于丙酮(12mL)中，向其中缓慢滴加氯磷酸二甲酯(400μL,3.7mmol)，室温反应过夜。反应液滤去不溶物，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝100/1)纯化得目标物，黄色油状液体即化合物IV-69(152mg,31％)。
将化合物IV-45(95mg,0.32mmol)，IV-69，Cs 2CO 3(220mg,0.68mmol)混悬于丙酮(7mL)中，升温至70℃反应30min。反应液冷却至室温，滤去不溶物，滤液减压蒸除溶剂得残留物，将其溶于THF(3mL)，MeOH(3mL)和H 2O(1mL)中，向其中加入LiOH·H 2O(94mg)，室温反应2h。反应液减压蒸除有机溶剂，加入H 2O(4mL)稀释，稀释液用2N HCl调节pH至1-3，加入EtOAc(8mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，减压蒸除溶剂得残留物，将其混悬于Et 2O(3mL)，搅拌，抽滤，滤饼红外干燥至恒重，得白色固体即化合物IV-70(115mg,80％,two steps). 1H NMR(300MHz,DMSO-d 6)δppm13.07(s,1H),7.84-7.75(m,4H),7.70-7.60(m,2H),7.49(d,J＝7.9Hz,1H),5.05-4.91(m,1H),4.13(t,J＝5.9Hz,2H),3.51(s,3H),3.48(s,3H),2.92-2.80(m, 2H),1.86-1.75(m,2H).
参照实施例155的方法，将IV-31替换成IV-70得化合物D-70: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.73(s,1H),8.77(s,1H),7.90-7.75(m,4H),7.73-7.62(m,3H),7.58-7.44(m,2H),6.88(d,J＝8.8Hz,1H),5.09-4.94(m,1H),4.17(s,2H),3.52(s,3H),3.49(s,3H),2.99(s,3H),2.92-2.80(m,2H),1.94-1.73(m,2H).HRMS(ESI):m/z calcd for C 26H 28F 3N 3O 8PS[M-H] -630.12923,found 630.12849.
实施例186
2-(3-(1H-1,2,4-三唑-1-基)丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-71)
Figure PCTCN2020120279-appb-000244
参照实施例184的方法，将1-乙酰哌嗪替换成1,2,4-三氮唑制得化合物IV-71: 1H NMR(300MHz,DMSO-d 6)δppm 13.09(s,1H),8.44(s,1H),7.94(s,1H),7.89-7.76(m,4H),7.70-7.63(m,1H),7.62-7.57(m,1H),7.50(d,J＝7.9Hz,1H),4.26(t,J＝6.8Hz,2H),4.08(t,J＝6.0Hz,2H),2.30-2.13(m,2H).
参照实施例155的方法，将IV-31替换成IV-71得化合物D-71: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),8.45(s,1H),7.95(s,1H),7.90-7.78(m,4H),7.72-7.61(m,3H),7.56-7.44(m,2H),6.88(d,J＝8.7Hz,1H),4.28(t,J＝6.8Hz,2H),4.12(t,J＝6.0Hz,2H),2.98(s,3H),2.31-2.16(m,2H).HRMS(ESI):m/z calcd for C 26H 23F 3N 5O 5S[M-H] -574.13775,found 574.13673.
实施例187
4-((4-((4-羟基-3-(甲基磺酰胺基)苯基)氨基甲酰基)-4'-(三氟甲基)-[1,1'-联苯]-2-基)氧基)叔丁基酯(化合物D-72)
Figure PCTCN2020120279-appb-000245
Figure PCTCN2020120279-appb-000246
将叔丁醇钾(202mg,1.8mmol)混悬于Et 2O(5mL)中，冰浴下向其中滴加4-溴丁酰氯(173μL,1.5mmol)，室温反应12h。反应液加入H 2O(8mL)和EtOAc(10mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，得残留物即化合物IV-72。
将化合物IV-72，IV-45(148mg,0.5mmol),无水Cs 2CO 3(244mg,0.75mmol)混悬于丙酮(7mL)中，升温至70℃反应5h。反应液冷却至室温，1N HCl调剂pH至3-4，加入H 2O(8mL)和EtOAc(10mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚/EtOAc＝30/1)纯化得目标物。将其溶于THF(2mL)和MeOH(1.5mL)中，向其中加入NaOH(55mg)的H 2O(0.5mL)溶液，室温反应2h。反应液减压蒸除有机溶剂，残留物加入H 2O(8mL)和EtOAc(12mL)，1N HCl调剂pH至3-4，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝200/1)纯化，得白色固体即化合物IV-73(86mg,40％,two steps). 1H NMR(300MHz,CDCl 3)δppm 7.81(dd,J＝7.9,1.4Hz,1H),7.72-7.64(m,5H),7.42(d,J＝7.9Hz,1H),4.10(t,J＝6.2Hz,2H),2.32(t,J＝7.3Hz,2H),2.10-1.94(m,2H),1.43(s,9H).
参照实施例155的方法，将IV-31替换成IV-73制得化合物D-74: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.72(s,1H),8.72(s,1H),7.87-7.73(m,4H),7.70-7.61(m,3H),7.56-7.46(m,2H),6.88(d,J＝8.7Hz,1H),4.12(t,J＝6.1Hz,2H),2.98(s,3H),2.28(t,J＝7.3Hz,2H),1.96-1.85(m,2H),1.36(s,9H).HRMS(ESI):m/z calcd for C 29H 31F 3N 2NaO 7S[M+Na] +631.16963,found 631.16966.
实施例188
2-(3-氰基丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-73)
Figure PCTCN2020120279-appb-000247
参照实施例184的方法，将IV-67替换成4-溴丁腈制得化合物D-73: 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.26(brs,2H),7.84-7.76(m,4H),7.72-7.63(m,3H),7.56-7.47(m,2H),6.88(d,J＝8.7Hz,1H),4.19(t,J＝6.0Hz,2H),2.98(s,3H),2.56(t,J＝7.1Hz,2H),2.09-1.95(m,2H).HRMS(ESI):m/z calcd for C 25H 22F 3N 3NaO 5S[M+Na] +556.11245,found 556.11221.
实施例189
2-(3-氟丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-74)
Figure PCTCN2020120279-appb-000248
参照实施例184的方法，将IV-67替换成1-溴-3-氟丙烷制得化合物D-74: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.72(s,1H),8.73(s,1H),7.90-7.71(m,4H),7.73-7.61(m,2H),7.56-7.45(m,2H),6.87(d,J＝8.7Hz,1H),4.60(t,J＝5.8Hz,1H),4.45(t,J＝5.8Hz,1H),4.22(t,J＝6.1Hz,2H),2.97(s,3H),2.19-2.00(m,2H).HRMS(ESI):m/z calcd for C 24H 23F 4N 2O 5S[M+H] +527.12583,found 527.12610.
实施例190
2-(3-氨基丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-75)
Figure PCTCN2020120279-appb-000249
参照实施例184的方法，将IV-67替换成3-(Boc-氨基)丙基溴制得化合物IV-74。
参照实施例155的方法，将IV-31替换成IV-74，最后经EtOH·HCl脱Boc制得化合物D-75: 1H NMR(300MHz,DMSO-d 6)δppm 10.21(s,1H),9.78(s,1H),8.74(s,1H),7.90(s,3H),7.84-7.77(m,4H),7.74-7.66(m,3H),7.56-7.46(m,2H),6.90(d,J＝8.7Hz,1H),4.23(t,J＝6.0Hz,2H),2.98(s,3H),2.92-2.80(m,2H),2.11-1.92(m,2H).HRMS(ESI):m/z calcd for C 24H 25F 3N 3O 5S[M+H] +524.14615,found 524.14575.
实施例191
N-(4-羟基-3-(甲基磺酰胺基)苯基)-2-(3-羟基丙氧基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-76)
Figure PCTCN2020120279-appb-000250
参照实施例161的方法，将2-溴乙醇替换成3-溴-1-丙醇制得化合物D-76: 1H  NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.72(s,1H),8.71(s,1H),7.86-7.75(m,4H),7.72-7.61(m,3H),7.55-7.46(m,2H),6.88(d,J＝8.7Hz,1H),4.51(s,1H),4.19(t,J＝6.1Hz,2H),3.51(t,J＝6.1Hz,2H),2.98(s,3H),1.97-1.77(m,2H).HRMS(ESI):m/z calcd for C 24H 24F 3N 2O 6S[M+H] +525.1302,found 525.1308.
实施例192
N-(4-羟基-3-(甲基磺酰胺基)苯基)-2-(3-(甲基磺酰基)丙氧基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-77)
Figure PCTCN2020120279-appb-000251
将化合物3-甲砜基-1-丙醇(228mg,1.65mmol)，NaOH(90mg,2.25mmol)混溶于THF(2mL)和H 2O(2mL)中，向其中缓慢滴加TsCl(286mg,1.5mmol)的THF(3mL)溶液，室温反应2h。反应液加入1N HCl(3mL)和EtOAc(6mL)，分液，水层EtOAc提取(8mL x 2)，合并有机相，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，得白色固体即化合物IV-75(273mg,62％)。
参照实施例184的方法，将IV-67替换成IV-75制得化合物D-77: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.14(brs,2H),7.89-7.76(m,4H),7.73-7.60(m,3H),7.58-7.45(m,2H),6.88(d,J＝8.7Hz,1H),4.24(t,J＝6.0Hz,2H),3.23-3.11(m,2H),2.98(s,3H),2.97(s,3H),2.23-2.07(m,2H).HRMS(ESI):m/z calcd for C 25H 25F 3N 2NaO 7S 2[M+Na] +609.09475,found 609.09448.
实施例193
N-(4-羟基-3-((2-(4-甲基哌嗪-1-基)乙基)磺酰胺基)苯基)-6-(4-(三氟甲基)苯基)烟酰胺(化合物D-78)
Figure PCTCN2020120279-appb-000252
将化合物6-溴烟酸甲酯(1.54g,7.13mmol)，对三氟甲基基苯硼酸(1.49g,7.84mmol)，无水K 2CO 3(3.0g,21.4mmol)，Pd(PPh 3) 4(247mg,0.214mmol)混 悬于Tol(30mL)和MeOH(5mL)中，氩气氛围升温至80℃反应5h。冷却室温，反应液加入H 2O(25mL)，1N HCl调节pH至1-3，加入EtOAc(45mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚:DCM(1:1)/EtOAc＝100/1)纯化，得化合物IV-76。
将化合物IV-76溶于THF(20mL)和MeOH(20mL)中，向其中加入NaOH(800mg,20mmol)的H 2O(10mL)溶液，室温反应过夜。反应液减压蒸除有机溶剂，残留物加入H 2O(15mL)稀释，稀释液用1N HCl调节pH至1-3，析出固体，搅拌，抽滤，滤饼红外干燥至恒重，得白色固体即化合物IV-77(1.56g,71％,two steps). 1H NMR(300MHz,DMSO-d 6)δppm 13.49(s,1H),9.19(d,J＝1.5Hz,1H),8.47-8.34(m,3H),8.22(d,J＝8.3Hz,1H),7.90(d,J＝8.3Hz,2H).
参照实施例152的方法，将IV-19替换成IV-77制得化合物IV-78。
参照实施例130的方法，将III-11替换成IV-78制得化合物D-78: 1H NMR(300MHz,DMSO-d 6)δppm 10.35(s,1H),9.22(s,1H),8.47-8.36(m,3H),8.24(d,J＝8.3Hz,1H),7.90(d,J＝8.4Hz,2H),7.68(d,J＝2.3Hz,1H),7.51(dd,J＝8.8,2.2Hz,1H),6.88(d,J＝8.7Hz,1H),3.31-3.21(m,2H),2.83-2.71(m,2H),2.46-2.24(m,8H),2.15(s,3H).HRMS(ESI):m/z calcd for C 26H 29F 3N 5O 4S[M+H] +564.18869,found 564.19027.
实施例194
N-(4-羟基-3-(甲基磺酰胺基)苯基)-6-(4-(三氟甲基)苯基)烟酰胺(化合物D-79)
Figure PCTCN2020120279-appb-000253
参照实施例157的方法，将IV-35替换成IV-78制得化合物D-79: 1H NMR(300MHz,DMSO-d 6)δppm 10.36(s,1H),9.23(s,1H),8.48-8.38(m,3H),8.25(d,J＝8.3Hz,1H),7.90(d,J＝8.2Hz,2H),7.67(d,J＝2.0Hz,1H),7.53(dd,J＝8.7,1,8Hz,1H),6.89(d,J＝8.7Hz,1H),2.99(s,3H).HRMS(ESI):m/z calcd for C 20H 17F 3N 3O 4S[M+H] +452.0886,found 452.0892.
实施例195
N-(4-羟基-3-(甲基磺酰胺基)苯基)-5-(4-(三氟甲基)苯基)吡啶啉酰胺(化合物D-80)
Figure PCTCN2020120279-appb-000254
参照实施例193和194的方法，将6-溴烟酸甲酯替换成5-溴吡啶-2-羧酸甲酯制得化合物D-80: 1H NMR(300MHz,DMSO-d 6)δppm 10.56(s,1H),9.70(s,1H), 9.07(s,1H),8.74(s,1H),8.42(d,J＝8.1Hz,1H),8.24(d,J＝8.1Hz,1H),8.07(d,J＝7.9Hz,2H),7.91(d,J＝8.0Hz,2H),7.87-7.77(m,1H),7.59(d,J＝8.7Hz,1H),6.88(d,J＝8.6Hz,1H),3.01(s,3H).HRMS(ESI):m/z calcd for C 20H 17F 3N 3O 4S[M+H] +452.0886,found 452.0891.
实施例196
N-(3-((3-氯丙基)磺酰胺基)-4-羟基苯基)-6-(4-(三氟甲基)苯基)烟酰胺(化合物D-81)
Figure PCTCN2020120279-appb-000255
参照实施例124的方法，将III-11替换成IV-78制得化合物D-81: 1H NMR(300MHz,DMSO-d 6)δppm 10.35(s,1H),9.83(s,1H),9.22(d,J＝1.9Hz,1H),8.95(s,1H),8.50-8.34(m,3H),8.24(d,J＝8.3Hz,1H),7.90(d,J＝8.3Hz,2H),7.67(d,J＝2.4Hz,1H),7.54(dd,J＝8.7,2.4Hz,1H),6.89(d,J＝8.7Hz,1H),3.75(t,J＝6.6Hz,2H),3.24-3.11(m,2H),2.30-2.13(m,2H).HRMS(ESI):m/z calcd for C 22H 20ClF 3N 3O 4S[M+H] +514.08097,found 514.08047.
实施例197
3-(N-(2-羟基-5-(6-(4-(三氟甲基)苯基)烟酰胺基)苯基)氨磺酰基)丙酸甲酯(化合物D-82)
Figure PCTCN2020120279-appb-000256
将化合物IV-77(6-(4-(三氟甲基)苯基)烟酸)(992mg,3.71mmol)混悬于DCM(15mL)中，冰浴条件下向其中缓慢滴加(COCl) 2(477μL,5.57mmol)，DMF(1drop)，室温反应5h。反应液减压蒸除溶剂，残留物加入DCM(6mL)制得酰氯溶液，冰浴条件下将其加至III-7(996mg,3.71mmol)和DIPEA(920μL,5.57mmol)的DCM(12mL)溶液中，室温反应40min。反应液减压蒸除溶剂，残留物加入1N HCl(15mL)和EtOAc(30mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物混悬于Et 2O(6mL)和正己烷(12mL) 中，搅拌，抽滤，红外干燥至恒重，得黄色固体即化合物IV-79(1.73g,90％)。
将化合物IV-79(767mg,1.48mmol)溶于DCM(15mL)和MeOH(3mL)中，向其中滴加TEA·3HF(380μL)，室温反应2h。反应液减压蒸除溶剂，残留物混悬于DCM(8mL)，搅拌，抽滤，滤饼少量MeOH洗涤，红外干燥至恒重，得黄色固体。将其溶于THF(12mL)和MeOH(12mL)中，向其中加入Pd/C(70mg)，氢气氛围室温反应过夜。反应液经硅藻土抽滤，滤液减压蒸除溶剂，残留物混悬于石油醚(4mL)和EtOAc(4mL)中，搅拌，抽滤，得灰绿色固体即化合物IV-80(428mg,77％,two steps)。
将化合物IV-80(150mg,0.4mmol)，吡啶(200μL)混溶于THF(7mL)中，向其中滴加3-(氯磺酰基)丙酸甲酯(90mg，0.48mmol)，室温反应4h。反应液加入1N HCl(10mL)和EtOAc(10mL)，分液，有机层依次用1N HCl，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(DCM/MeOH＝60/1)纯化得目标物。将其混悬于Et 2O(4mL)中，搅拌，抽滤，得灰白色固体即化合物D-82(69mg,33％). 1H NMR(300MHz,DMSO-d 6)δppm10.36(s,1H),9.86(s,1H),9.22(s,1H),9.03(s,1H),8.52-8.36(m,3H),8.25(d,J＝8.3Hz,1H),7.90(d,J＝8.3Hz,2H),7.65(d,J＝2.1Hz,1H),7.55(dd,J＝8.7,2.4Hz,1H),6.88(d,J＝8.8Hz,1H),3.62(s,3H),3.35-3.25(m,2H),2.85(t,J＝7.5Hz,2H).HRMS(ESI):m/z calcd for C 23H 20F 3N 3NaO 6S[M+Na] +546.09171,found 546.09102.
实施例198
N-(4-羟基-3-((3-羟丙基)磺酰胺基)苯基)-6-(4-(三氟甲基)苯基)烟酰胺(化合物D-83)
Figure PCTCN2020120279-appb-000257
参照实施例136的方法，将D-19替换成D-82制得化合物D-83: 1H NMR(300MHz,DMSO-d 6)δppm 10.36(s,1H),9.72(s,1H),9.22(d,J＝1.8Hz,1H),8.78(s,1H),8.48-8.35(m,3H),8.25(d,J＝8.3Hz,1H),7.90(d,J＝8.4Hz,2H),7.67(d,J＝2.4Hz,1H),7.52(dd,J＝8.7,2.4Hz,1H),6.87(d,J＝8.7Hz,1H),4.60(s,1H),3.47(t,J＝6.2Hz,2H),3.17-3.04(m,2H),1.96-1.79(m,2H).HRMS(ESI):m/z calcd for C 22H 20F 3N 3NaO 5S[M+Na] +518.09680,found 518.09640.
实施例199
N-(4-羟基-3-(氨磺酰基氨基)苯基)-6-(4-(三氟甲基)苯基)烟酰胺(化合物D-84)
Figure PCTCN2020120279-appb-000258
参照实施例197的方法，将3-(氯磺酰基)丙酸甲酯替换成氨基磺酰氯制得化合物D-84: 1H NMR(300MHz,DMSO-d 6)δppm 10.33(s,1H),9.54(s,1H),9.22(d,J＝2.0Hz,1H),8.48-8.34(m,3H),8.24(d,J＝8.4Hz,1H),7.90(d,J＝8.4Hz,2H),7.80(s,1H),7.72(d,J＝2.3Hz,1H),7.41(dd,J＝8.8,2.3Hz,1H),6.96(s,2H),6.84(d,J＝8.7Hz,1H).HRMS(ESI):m/z calcd for C 19H 16F 3N 4O 4S[M+H] +453.0839,found 453.0846.
实施例200
6-(4-氯苯基)-N-(4-羟基-3-((2-(4-甲基哌嗪-1-基)乙基)磺酰胺基)苯基)烟酰胺(化合物D-85)
Figure PCTCN2020120279-appb-000259
参照实施例193的方法，将对三氟甲基苯硼酸替换成4-氯苯硼酸制得化合物IV-81。
参照实施例130的方法，将III-11替换成IV-81制得化合物D-85: 1H NMR(300MHz,DMSO-d 6)δppm 10.31(s,1H),9.71(brs,2H),9.17(d,J＝1.8Hz,1H),8.39(dd,J＝8.4,2.1Hz,1H),8.21(d,J＝8.6Hz,2H),8.15(d,J＝8.3Hz,1H),7.67(d,J＝2.3Hz,1H),7.60(d,J＝8.6Hz,2H),7.50(dd,J＝8.7,2.3Hz,1H),6.87(d,J＝8.7Hz,1H),3.32-3.20(m,2H),2.85-2.68(m,2H),2.46-2.36(m,4H),2.35-2.26(m,4H),2.15(s,3H).HRMS(ESI):m/z calcd for C 25H 28ClN 5O 4S[M+H] +530.16233,found 530.16201.
实施例201
6-(4-氯苯基)-N-(4-羟基-3-((3-羟丙基)磺酰胺基)苯基)烟酰胺(化合物D-86)
Figure PCTCN2020120279-appb-000260
参照实施例86和136的方法，将III-11替换成IV-81，甲基磺酰氯替换成3-(氯磺酰基)丙酸甲酯氯制得化合物D-86: 1H NMR(300MHz,DMSO-d 6)δppm 10.31(s,1H),9.17(s,1H),8.39(dd,J＝8.3,1.7Hz,1H),8.21(d,J＝8.5Hz,2H),8.15(d,J＝8.4Hz,1H),7.66(d,J＝2.0Hz,1H),7.60(d,J＝8.5Hz,2H),7.51(dd,J＝8.8,2.0Hz,1H),6.86(d,J＝8.7Hz,1H),3.46(t,J＝6.1Hz,2H),3.09(m,2H),1.95-1.81(m,2H).HRMS(ESI):m/z calcd for C 21H 21ClN 3O 5S[M+H] +462.0885,found 462.0894.
实施例202
6-(4-氯苯基)-N-(4-羟基-3-(氨磺酰基氨基)苯基)烟酰胺(化合物D-87)
Figure PCTCN2020120279-appb-000261
参照实施例86的方法，将III-11替换成IV-81，甲基磺酰氯替换成氨基磺酰氯制得化合物D-87: 1H NMR(300MHz,DMSO-d 6)δppm 10.30(s,1H),9.55(s,1H),9.18(s,1H),8.39(dd,J＝8.3,1.8Hz,1H),8.21(d,J＝8.5Hz,2H),8.15(d,J＝8.3Hz,1H),7.80(s,1H),7.72(d,J＝2.0Hz,1H),7.60(d,J＝8.5Hz,2H),7.41(dd,J＝8.8,1.7Hz,1H),6.97(s,2H),6.83(d,J＝8.6Hz,1H).HRMS(ESI):m/z calcd for C 18H 16ClN 4O 4S[M+H] +419.0575,found 419.0577.
实施例203
4'-氯-N-(4-羟基-3-((2-(4-甲基哌嗪-1-基)乙基)磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-88)
Figure PCTCN2020120279-appb-000262
参照实施例174的方法，将4-氟溴苯替换成4-氯溴苯制得化合物IV-82:
参照实施例130的方法，将III-11替换成IV-82制得化合物D-88: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.65(brs,2H),8.05(d,J＝8.4Hz,2H),7.82(d,J＝8.9Hz,2H),7.79(d,J＝8.9Hz,2H).7.67(d,J＝2.4Hz,1H),7.56(d,J＝8.5Hz,2H),7.50(dd,J＝8.7,2.4Hz,1H),6.86(d,J＝8.7Hz,1H),3.42-3.17(m,2H),2.81-2.71(m,2H),2.45-2.36(m,4H),2.35-2.27(m,4H),2.14(s,3H).HRMS(ESI):m/z calcd for C 26H 29ClN 4O 4S[M+H] +529.16708,found 529.16692.
实施例204
4'-氯-N-(4-羟基-3-(氨磺酰基氨基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-89)
Figure PCTCN2020120279-appb-000263
参照实施例86的方法，将III-11替换成IV-82，甲基磺酰氯替换成氨基磺酰氯制得化合物D-89: 1H NMR(300MHz,DMSO-d 6)δppm 10.12(s,1H),9.48(s,1H),8.06(d,J＝8.4Hz,2H),7.88-7.75(m,5H),7.72(d,J＝2.4Hz,1H),7.56(d,J＝8.5Hz,2H),7.41(dd,J＝8.7,2.4Hz,1H),6.96(s,2H),6.83(d,J＝8.7Hz,1H). HRMS(ESI):m/z calcd for C 19H 17ClN 3O 4S[M+H] +418.0623,found 418.0627.
实施例205
N-(3-((氯甲基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-90)
Figure PCTCN2020120279-appb-000264
参照实施例86的方法，将甲基磺酰氯替换成氯甲磺酰氯制得化合物D-90: 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.73(s,1H),9.47(s,1H),8.08(d,J＝8.2Hz,2H),7.99(d,J＝8.1Hz,2H),7.90(d,J＝8.4Hz,2H),7.86(d,J＝8.3Hz,2H),7.65(d,J＝2.0Hz,1H),7.55(dd,J＝8.7,2.1Hz,1H),6.87(d,J＝8.7Hz,1H),4.93(s,2H).HRMS(ESI):m/z calcd for C 21H 16ClF 3N 2O 4S[M+H] +485.05442,found 485.05385.
实施例206
2-(3-(1,1-二氧硫代吗啉代)丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-91)
Figure PCTCN2020120279-appb-000265
参照实施例184的方法，将1-乙酰基哌嗪替换成1,1-二氧化硫代吗啉制得化合物D-91: 1H NMR(300MHz,DMSO-d 6)δppm 10.17(s,1H),9.75(s,1H),8.71(s,1H),7.87-7.78(m,4H),7.74-7.64(m,3H),7.57-7.47(m,2H),6.89(d,J＝8.7Hz,1H),4.22(t,J＝6.0Hz,2H),3.63-3.34(m,10H),2.98(s,3H),2.22-2.10(m,2H).HRMS(ESI):m/z calcd for C 28H 30F 3N 3O 7S 2[M+H] +642.15500,found 642.15469.
实施例207
4'-氯-N-(3-(环丙烷磺酰胺基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-92)
Figure PCTCN2020120279-appb-000266
参照实施例86的方法，将III-11替换成IV-82，甲基磺酰氯替换成环丙基磺酰氯制得化合物D-92: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.58(s,1H),8.62(s,1H),8.05(d,J＝8.3Hz,2H),7.83(d,J＝8.8Hz,1H),7.80(d,J＝8.9Hz,1H),7.73(d,J＝2.4Hz,1H),7.56(d,J＝8.5Hz,2H),7.49(dd,J＝8.7,2.5Hz,1H),6.85(d,J＝8.7Hz,1H),2.69-2.56(m,1H),0.97-0.89(m,4H).HRMS(ESI):m/z calcd for C 22H 20ClN 2O 4S[M+H] +443.0827,found 443.0832.
实施例208
6-(4-氯苯基)-N-(3-(环丙烷磺酰胺基)-4-羟基苯基)烟酰胺(化合物D-93)
Figure PCTCN2020120279-appb-000267
参照实施例86的方法，将III-11替换成IV-81，甲基磺酰氯替换成环丙基磺酰氯制得化合物D-93: 1H NMR(300MHz,DMSO-d 6)δppm 10.31(s,1H),9.18(d,J＝2.0Hz,1H),8.39(dd,J＝8.3,2.0Hz,1H),8.22(d,J＝8.5Hz,2H),8.16(d,J＝8.4Hz,1H),7.72(d,J＝2.2Hz,1H),7.60(d,J＝8.5Hz,2H),7.49(dd,J＝8.7,2.3Hz,1H),6.87(d,J＝8.7Hz,1H),2.69-2.57(m,1H),0.97-0.89(m,4H).HRMS(ESI):m/z calcd for C 21H 19ClN 3O 4S[M+H] +444.0779,found 444.0787.
实施例209
6-(4-(二氟甲基)苯基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)烟酰胺(化合物D-94)
Figure PCTCN2020120279-appb-000268
将化合物4-溴-α,α-二氟甲苯(1.24g,6mmol)，联硼酸频那醇酯(1.83g,7.2mmol)，KOAc(1.2g,12mmol)，PdCl 2(dppf)·DCM(245mg,0.3mmol)混溶于二氧六环(40mL)中，升温至80℃反应8h。反应液冷却至室温，减压蒸除溶剂，残留物加入EtOAc(40mL)和H 2O(30mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，经硅胶柱层析(石油醚/EtOAc＝60/1)纯化，得无色油状物质即化合物IV-83(1.06g,70％)。
参照实施例194的方法，将对-三氟甲基苯硼酸替换成IV-83制得化合物IV-84.
参照实施例157的方法，将IV-35替换成IV-84制得化合物D-94: 1H NMR(300MHz,DMSO-d 6)δppm 10.34(s,1H),9.20(d,J＝1.6Hz,1H),8.41(dd,J＝8.3,2.1Hz,1H),8.32(d,J＝8.0Hz,2H),8.20(d,J＝8.4Hz,1H),7.73(d,J＝8.2Hz,2H),7.66(d,J＝2.3Hz,1H),7.53(dd,J＝8.7,2.4Hz,1H),7.13(t,J＝55.9Hz,1H),6.89(d,J＝8.7Hz,1H),2.98(s,3H).HRMS(ESI):m/z calcd for C 20H 18F 2N 3O 4S[M+H] +434.0981,found 434.0986.
实施例210
N-(3-(环丙烷磺酰胺基)-4-羟基苯基)-6-(4-(三氟甲基)苯基)烟酰胺(化合物D-95)
Figure PCTCN2020120279-appb-000269
参照实施例86的方法，将III-11替换成IV-78，甲基磺酰氯替换成环丙磺酰氯制得化合物D-95: 1H NMR(300MHz,DMSO-d 6)δppm 10.34(s,1H),9.66(s,1H),9.22(d,J＝1.8Hz,1H),8.64(s,1H),8.46-8.34(m,3H),8.24(d,J＝8.3Hz,1H),7.90(d,J＝8.4Hz,2H),7.73(d,J＝2.4Hz,1H),7.49(dd,J＝8.7,2.5Hz,1H),6.87(d,J＝8.7Hz,1H),2.69-2.58(m,1H),1.01-0.89(m,4H).HRMS(ESI):m/z calcd for C 22H 19F 3N 3O 4S[M+H] +478.1043,found 478.1048.
实施例211
4'-环丙基-N-(4-羟基-3-(甲基磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-96)
Figure PCTCN2020120279-appb-000270
参照实施例157的方法，将IV-33替换成4-溴环丙基苯制得化合物D-96: 1H NMR(300MHz,DMSO-d 6)δppm 10.11(s,1H),9.09(brs,2H),8.02(d,J＝8.3Hz,2H),7.78(d,J＝8.3Hz,2H),7.69-7.58(m,3H),7.52(dd,J＝8.7,2.3Hz,1H),7.20(d,J＝8.2Hz,2H),6.87(d,J＝8.7Hz,1H),2.98(s,3H),2.04-1.91(m,1H),1.06-0.95(m,2H),0.78-0.68(m,2H).HRMS(ESI):m/z calcd for C 23H 23N 2O 4S[M+H] +423.1373,found 423.1379.
实施例212
4'-(二氟甲基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-97)
Figure PCTCN2020120279-appb-000271
参照实施例157的方法，将IV-33替换成4-溴-α,α-二氟甲苯制得化合物D-97: 1H NMR(300MHz,DMSO-d 6)δppm 10.17(s,1H),9.49(s,1H),8.88(s,1H),8.07(d,J＝8.3Hz,2H),7.96-7.82(m,4H),7.75-7.64(m,3H),7.53(dd,J＝8.7,2.5Hz,1H),7.11(t,J＝55.9Hz,1H),6.87(d,J＝8.7Hz,1H),2.98(s,3H).HRMS(ESI):m/z calcd for C 21H 19F 2N 2O 4S[M+H] +433.1028,found 433.1033.
实施例213
2-(3-(二甲基氨基)丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-98)
Figure PCTCN2020120279-appb-000272
参照实施例184的方法，将IV-67替换成3-溴-N,N-二甲基-1-丙胺氢溴酸盐制得化合物D-98: 1H NMR(300MHz,DMSO-d 6)δppm 10.19(s,1H),9.93(s,1H),9.76(s,1H),8.73(s,1H),7.88-7.77(m,4H),7.75-7.65(m,3H),7.56-7.46(m,2H),6.89(d,J＝8.7Hz,1H),4.21(t,J＝5.9Hz,2H),3.15-3.05(m,2H),2.98(s,3H),2.74(s,6H),2.19-2.05(m,2H).HRMS(ESI):m/z calcd for C 26H 29F 3N 3O 5S[M+H] +552.1775,found 552.1776.
实施例214
3-(3-氟丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-99)
Figure PCTCN2020120279-appb-000273
将化合物4-溴-2-羟基苯甲酸甲酯(2.52g,10.9mmol)，4-三氟甲基苯硼酸(2.28g,12.0mmol)，无水K 2CO 3(4.5g,32.7mmol)，Pd(PPh 3) 4(370mg,0.327mmol)混溶于Tol(40mL)和MeOH(5mL)中，氩气氛围升温至80℃反应5h。反应液冷却室温，加入H 2O(20mL)和EtOAc(50mL)稀释，稀释液conc.HCl调节pH至1-3，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚/DCM＝1/1)纯化得目标物，将其混悬于正己烷(20mL)和EtOAc(1mL)中，搅拌，抽滤，得淡黄色固体即化合物IV-85(1.46g,45％): 1H NMR(300MHz,CDCl 3)δppm 10.83(s,1H),7.92(d,J＝8.3Hz,1H),7.76-7.69(m,4H),7.22(d,J＝1.6Hz,1H),7.12(dd,J＝8.3,1.7Hz,1H),3.99(s,3H).
参照实施例189的方法，将IV-45替换成IV-85制得化合物D-99: 1H NMR(300MHz,DMSO-d 6)δppm 9.97(s,1H),9.68(s,1H),8.70(s,1H),8.00(d,J＝8.0Hz,2H),7.85(d,J＝8.1Hz,2H),7.77(d,J＝7.9Hz,1H),7.62(d,J＝2.1Hz,1H),7.53-7.47(m,1H),7.46-7.38(m,2H),6.86(d,J＝8.6Hz,1H),4.73(d,J＝5.8Hz,1H),4.57(t,J＝5.5Hz,1H),4.37(t,J＝5.8Hz,2H),2.98(s,3H),2.32-2.13(m,2H).HRMS(ESI):m/z calcd for C 24H 23F 4N 2O 5S[M+H] +527.1258,found 527.1260.
实施例215
3-(3-氨基丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-100)
Figure PCTCN2020120279-appb-000274
参照实施例190的方法，将IV-45替换成IV-85制得化合物D-100: 1H NMR(300MHz,DMSO-d 6)δppm 10.08(s,1H),9.76(s,1H),8.78(s,1H),8.04-7.79(m,7H),7.71(d,J＝7.7Hz,1H),7.67-7.63(m,1H),7.50-7.38(m,3H),6.89(d,J＝8.7Hz,1H),4.40-4.31(m,2H),3.07-2.96(m,2H),2.98(s,3H),2.16-2.02(m,2H).HRMS(ESI):m/z calcd for C 24H 25F 3N 3O 5S[M+H] +524.1462,found 524.1465.
实施例216
N-(4-羟基-3-(甲基磺酰胺基)苯基)-3-(3-羟基丙氧基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-101)
Figure PCTCN2020120279-appb-000275
参照实施例191的方法，将IV-45替换成IV-85制得化合物D-101: 1H NMR(300MHz,DMSO-d 6)δppm 10.01(s,1H),9.67(s,1H),8.70(s,1H),8.00(d,J＝8.1Hz,2H),7.91-7.80(m,3H),7.65(d,J＝2.4Hz,1H),7.49-7.47(m,1H),7.45-7.37(m,2H),6.87(d,J＝8.7Hz,1H),4.62(s,1H),4.35(t,J＝6.0Hz,2H),3.69-3.58(m,2H),2.99(s,3H),2.06-1.90(m,2H).HRMS(ESI):m/z calcd for C 24H 24F 3N 2O 6S[M+H] +525.1302,found 525.1307.
实施例217
3-(3-(二甲基氨基)丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-102)
Figure PCTCN2020120279-appb-000276
参照实施例213的方法，将IV-45替换成IV-85制得化合物D-102: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.93(s,1H),9.79(s,1H),8.78(s,1H),7.99(d,J＝8.1Hz,2H),7.86(d,J＝8.4Hz,2H),7.74-7.66(m,2H),7.52-7.40(m,3H),6.90(d,J＝8.7Hz,1H),4.35(t,J＝5.7Hz,2H),3.22(t,J＝7.1Hz,2H),2.98(s,3H),2.73(s,6H),2.27-2.15(m,2H).HRMS(ESI):m/z calcd for C 26H 29F 3N 3O 5S[M+H] +552.1775,found 552.1780.
实施例218
3-羟基-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-103)
Figure PCTCN2020120279-appb-000277
将化合物IV-85(89mg,0.3mmol)，无水Cs 2CO 3(147mg,0.45mmol)混悬于丙酮(7mL)中，向其中滴加BnBr(43μL,0.36mmol)，升温至50℃反应1h。反应液冷却至室温，滤去不溶物，滤液减压蒸出溶剂，残留物溶于THF(3mL)和MeOH(3mL)中，向其中滴加2N NaOH(1mL)，升温至50℃反应2h。反应液减压蒸除有机溶剂，残留物加入H 2O(3mL)稀释，稀释液1N HCl调节pH至1-3，析出固体，搅拌，抽滤，水洗涤，红外干燥至恒重，得白色固体即化合物IV-86(110mg,98％)。
参照实施例157的方法，将IV-34替换成IV-86，最后经Pd/C脱苄基制得化合物103: 1H NMR(300MHz,DMSO-d 6)δppm 12.25(s,1H),10.33(s,1H),9.81(s,1H),8.74(s,1H),8.12(d,J＝8.3Hz,1H),7.95(d,J＝8.3Hz,2H),7.84(d,J＝8.4Hz,2H),7.59(d,J＝2.4Hz,1H),7.44(dd,J＝8.7,2.5Hz,1H),7.38-7.29(m,2H),6.90(d,J＝8.7Hz,1H),2.99(s,3H).HRMS(ESI):m/z calcd for C 21H 18F 3N 2O 5S[M+H] +467.0883,found 467.0889.
实施例219
N-(4-羟基-3-(甲基磺酰胺基)苯基)-2'-(2-甲氧基乙氧基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-104)
Figure PCTCN2020120279-appb-000278
将化合物2-溴-5-三氟甲基苯酚(271mg,1.12mmol),无水Cs 2CO 3(547mg,1.68mmol)，2-溴乙基甲基醚(187mg,1.35mmol)混悬于丙酮(9mL)中，升温至60℃反应1h。反应液冷却至室温，滤去不溶物，滤液减压蒸出溶剂得残留物即化合物IV-87，直接用于下一步。
参照实施例157的方法，将IV-33替换成IV-87制得化合物D-104: 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.70(s,1H),8.70(s,1H),8.01(d,J＝8.4Hz,2H),7.73(d,J＝8.3Hz,2H),7.66(d,J＝2.4Hz,1H),7.60(d,J＝7.9Hz,1H),7.53(dd,J＝8.8,2.5Hz,1H),7.48–7.39(m,2H),6.87(d,J＝8.7Hz,1H),4.33–4.25(m,2H),3.69–3.62(m,2H),3.28(s,3H),2.98(s,3H).HRMS(ESI):m/z calcd for C 24H 24F 3N 2O 6S[M+H] +525.1302,found 525.1306.
实施例220
2-羟基-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-105)
Figure PCTCN2020120279-appb-000279
参照实施例218的方法，将IV-85替换成IV-45，最后经Pd/C脱苄基制得化合物D-105: 1H NMR(300MHz,DMSO-d 6)δppm 10.19-10.07(m,2H),9.68(s,1H),8.70(s,1H),7.83(d,J＝8.4Hz,2H),7.78(d,J＝8.6Hz,2H),7.64(d,J＝2.2Hz,1H),7.56-7.43(m,4H),6.86(d,J＝8.7Hz,1H),2.98(s,3H).HRMS(ESI):m/z calcd for C 21H 18F 3N 2O 5S[M+H] +467.0883,found 467.0886.
实施例221
N-(3-((4-(二甲基氨基)丁基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-106)
Figure PCTCN2020120279-appb-000280
将1,4-丁磺酸内酯(272mg,2mmol)溶于2M二甲胺THF溶液(5mL)中，室温反应9h。反应液减压蒸出溶剂，残留物加入Et 2O(5mL)，搅拌，抽滤，得白色固体即化合物IV-88(138mg,38％)。
将化合物IV-88(130mg,0.72mmol)分批加至氯化亚砜(4mL)中，升温至80℃反应4h。反应液减压蒸出溶剂得淡黄色油状物质即化合物IV-89(Quant.)。ESI-MS:m/z 196.1[M+MeOH-HCl+H] +.
参照实施例86的方法，将甲基磺酰氯替换成IV-89制得化合物D-106: 1H NMR(300MHz,DMSO-d 6)δppm 10.22(s,1H),9.69(brs,2H),8.10(d,J＝8.1Hz,2H),7.99(d,J＝8.2Hz,2H),7.94-.82(m,4H),7.70(d,J＝2.0Hz,1H),7.51(dd,J＝8.7,2.1Hz,1H),6.90(d,J＝8.7Hz,1H),3.12(t,J＝6.9Hz,2H),2.99-2.87(m,2H), 2.65(s,6H),1.86-1.65(m,4H).HRMS(ESI):m/z calcd for C 26H 29F 3N 3O 4S[M+H] +536.1825,found 536.1831.
实施例222
N-(4-羟基-3-(甲基磺酰胺基)苯基)-2-吗啉代-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-107)
Figure PCTCN2020120279-appb-000281
将化合物3-氟-4-硝基苯甲酸甲酯(400mg,2mmol)，吗啡啉(522mg,6mmol)混溶于MeCN(10mL)中，室温反应5h。反应液减压蒸出溶剂，残留物加入EtOAc(15mL)和1N HCl(10mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸出溶剂得残留物即化合物IV-90。
将IV-90溶于THF(10mL)和MeOH(8mL)中，加入Pd/C(50mg)，氢气氛围室温反应过夜。反应液硅藻土抽滤，滤液减压蒸出溶剂，得黄色固体即化合物IV-91(462mg,97％,two steps)。
将化合物IV-91(236mg,1mmol)溶于MeCN(10mL)中，向其中加入 tBuONO(240μL,2mmol)和CuBr 2(268mg,1.2mmol)，室温反应2h。反应液加入EtOAc(15mL)和1N HCl(10mL)，分液，有机层依次用饱和NaHCO 3，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸出溶剂得棕红色油状液体即化合物IV-92(273mg,91％)，直接用于下一步。
将化合物IV-92，4-三氟甲基苯硼酸(190mg,1.0mmol)，无水K 2CO 3(414mg,3.0mmol)，Pd(PPh 3) 4(60mg,0.05mmol)混溶于Tol(12mL)和MeOH(2mL)中，氩气氛围升温至80℃反应5h。反应液冷却室温，加入H 2O(6mL)和EtOAc(12mL)，1N HCl调剂pH至3-4，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚/EtOAc＝30/1)纯化得目标物。将其溶于THF(3mL)和MeOH(3mL)中，向其中滴加2N NaOH(1.5mL)，升温至60℃反应2h。反应液减压蒸出溶剂，残留物加入H 2O(5mL)稀释，1N HCl调剂pH至1-3，析出固体，搅拌，抽滤，水洗涤，红外干燥至恒重，得淡黄色固体即化合物IV-93(145mg,45％,three steps)。 1H NMR(300MHz,DMSO-d 6)δppm 13.03(s,1H),7.91(d,J＝8.1Hz,2H),7.82(d,J＝8.3Hz,2H),7.72-7.68(m,1H),7.66-7.62(m,1H),7.39(d,J＝7.9Hz,1H),3.58-3.47(m,4H), 2.83-2.71(m,4H).
参照实施例157的方法，将IV-35替换成IV-93制得化合物D-107: 1H NMR(300MHz,DMSO-d 6)δppm 10.12(s,1H),9.70(s,1H),8.69(s,1H),7.92(d,J＝8.1Hz,1H),7.82(d,J＝8.3Hz,1H),7.71(dd,J＝7.9,1.0Hz,1H),7.67-7.61(m,1H),7.50(dd,J＝8.7,2.4Hz,1H),7.40(d,J＝7.9Hz,1H),6.88(d,J＝8.7Hz,1H),3.59-3.49(m,4H),2.98(s,1H),2.85-2.77(m,4H).HRMS(ESI):m/z calcd for C 25H 25F 3N 3O 5S[M+H] +536.1462,found 536.1470.
实施例223
N-(3-((3-(二甲基氨基)丙基)磺酰胺基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-108)
Figure PCTCN2020120279-appb-000282
参照实施例221的方法，将1,4-丁磺酸内酯替换成1,3-丙磺酸内酯制得化合物D-108: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.73(brs,2H),8.09(d,J＝8.3Hz,2H),7.99(d,J＝8.1Hz,2H),7.94-7.82(m,4H),7.68(d,J＝2.3Hz,1H),7.52(dd,J＝8.6,2.4Hz,1H),6.86(d,J＝8.7Hz,1H),3.14-3.02(m,2H),2.33(t,J＝6.8Hz,2H),2.12(s,5H),1.96-1.81(m,2H).HRMS(ESI):m/z calcd for C 25H 27F 3N 3O 4S[M+H] +522.1669,found 522.1675.
实施例224
2-(3-(4,4-二氟哌啶-1-基)丙氧基)-4'-氟-N-(4-羟基-3-(甲基磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-109)
Figure PCTCN2020120279-appb-000283
将化合物4-溴-3-羟基苯甲酸甲酯(693mg,3.0mmol)，4-氟苯硼酸(462mg,3.3mmol)，无水K 2CO 3(1.24g,9.0mmol)，PdCl 2(dppf)·DCM(73mg,0.09mmol)混悬于Tol(15mL)和MeOH(3mL)中，氩气氛围升温至80℃反应5h。反应液冷却室温，减压蒸除溶剂，残留物加入H 2O(15mL)和EtOAc(30mL)，1N HCl调节pH至1-3，分液，有机层饱和食盐水洗涤，无水Na 2SO4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚:DCM(1:1)/EtOAc＝20/1)纯化，得目标物，将其混悬于正己烷(15mL)和Et 2O(6mL)中，搅拌，抽滤，红外干燥至 恒重，得白色固体即化合物IV-94(600mg,81％)。
参照实施例184的方法，将IV-45替换成IV-94，IV-67替换成IV-66制得化合物D-109: 1H NMR(300MHz,DMSO-d 6)δppm 10.74(s,1H),10.14(s,1H),9.75(s,1H),8.72(s,1H),7.73-7.58(m,5H),7.54-7.44(m,2H),7.30(dd,J＝8.9,8.9Hz,2H),6.89(d,J＝8.7Hz,1H),4.29-4.14(m,2H),3.69-3.55(m,2H),3.26-3.05(m,4H),2.98(s,3H),2.48-2.10(m,6H).HRMS(ESI):m/z calcd for C 28H 31F 3N 3O 5S[M+H] +578.1931,found 578.1939.
实施例225
N-(3-(环丙烷磺酰胺基)-4-羟基苯基)-2',3'-二氟-[1,1'-联苯]-4-甲酰胺(化合物D-110)
Figure PCTCN2020120279-appb-000284
参照实施例174的方法，将4-氟溴苯替换成2,3-二氟溴苯制得化合物IV-95。
参照实施例86的方法，将III-11替换成IV-95，甲基磺酰氯替换成环丙磺酰氯制得化合物D-110: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.55(s,1H),8.65(s,1H),8.06(d,J＝8.2Hz,2H),7.81-7.67(m,3H),7.60-7.25(m,4H),6.85(d,J＝8.7Hz,1H),2.72-2.58(m,1H),1.01-0.84(m,4H).HRMS(ESI):m/z calcd for C 22H 19F 2N 2O 4S[M+H] +445.1028,found 445.1034.
实施例226
3',4'-二氟-N-(4-羟基-3-(甲基磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-111)
Figure PCTCN2020120279-appb-000285
参照实施例157的方法，将IV-33替换成3,4-二氟溴苯制得化合物D-111: 1H NMR(300MHz,DMSO-d 6)δppm 10.15(s,1H),9.69(s,1H),8.70(s,1H),8.05(d,J＝8.3Hz,2H),8.00-7.80(m,3H),7.78-7.48(m,4H),6.87(d,J＝8.7Hz,1H),2.98(s,3H).HRMS(ESI):m/z calcd for C 20H 17F 2N 2O 4S[M+H] +419.0872,found 419.0879.
实施例227
N-(3-(环丙烷磺酰胺基)-4-羟基苯基)-2-(3-(4,4-二氟哌啶-1-基)丙氧基)-4'-氟-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-112)
Figure PCTCN2020120279-appb-000286
参照实施例155的方法，将甲基磺酰氯替换成环丙磺酰氯制得化合物IV-96。
参照实施例224的方法，将IV-27替换成IV-96制得化合物D-112: 1H NMR(300MHz,DMSO-d 6)δppm 11.16(s,1H),10.14(s,1H),9.66(s,1H),8.65(s,1H),7.73(d,J＝2.2Hz,1H),7.71-7.58(m,4H),7.51-7.43(m,2H),7.30(dd,J＝8.8,8.8Hz,2H),6.87(d,J＝8.7Hz,1H),4.21(t,J＝5.9Hz,2H),3.66-3.51(m,2H),3.25-3.03(m,4H),2.69-2.58(m,1H),2.45-2.11(m,6H),0.98-0.87(m,4H).HRMS(ESI):m/z calcd for C 30H 33F 3N 3O 5S[M+H] +604.2088,found 604.2099.
实施例228
3-(3-(4,4-二氟哌啶-1-基)丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-113)
Figure PCTCN2020120279-appb-000287
参照实施例184的方法，将IV-45替换成IV-85，IV-67替换成IV-66制得化合物D-113: 1H NMR(300MHz,DMSO-d 6)δppm 10.89(s,1H),10.06(s,1H),9.75(s,1H),8.76(s,1H),8.00(d,J＝8.1Hz,2H),7.85(d,J＝8.4Hz,2H),7.71(d,J＝7.9Hz,1H),7.62(d,J＝2.4Hz,1H),7.56-7.35(m,3H),6.89(d,J＝8.7Hz,1H),4.45-4.29(m,2H),3.68-3.47(m,2H),3.14-3.02(m,2H),2.99(s,3H),2.46-2.17(m,6H).HRMS(ESI):m/z calcd for C 29H 31F 5N 3O 5S[M+H] +628.1899,found 628.1905.
实施例229
N-(4-羟基-3-((1-甲基-1H-吡唑)-4-磺酰胺基)苯基)-6-(4-(三氟甲基)苯基)烟酰胺(化合物D-114)
Figure PCTCN2020120279-appb-000288
参照实施例86的方法，将III-11替换成IV-78，甲基磺酰氯替换成1H-吡唑-4-磺酰氯制得化合物D-114: 1H NMR(300MHz,DMSO-d 6)δppm 10.34(s,1H),9.22(s,1H),8.48-8.36(m,3H),8.25(d,J＝8.4Hz,1H),8.19(s,1H),7.91(d,J＝8.2Hz,2H),7.75(d,J＝1.9Hz,1H),7.72(s,1H),7.41(d,J＝8.7Hz,1H),6.77(d,J＝ 8.7Hz,1H),3.84(s,3H).HRMS(ESI):m/z calcd for C 23H 19F 3N 5O 4S[M+H] +518.1104,found 518.1110.
实施例230
N-(3-(环丙烷磺酰胺基)-4-羟基苯基)-4'-氟-[1,1'-联苯]-4-甲酰胺(化合物D-115)
Figure PCTCN2020120279-appb-000289
参照实施例86的方法，将III-11替换成IV-63，甲基磺酰氯替换成环丙磺酰氯制得化合物D-115: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),9.59(s,1H),8.64(s,1H),8.05(d,J＝8.4Hz,2H),7.86-7.76(m,4H),7.73(d,J＝2.4Hz,1H),7.49(dd,J＝8.7,2.4Hz,1H),7.34(dd,J＝8.9,8.9Hz,2H),6.85(d,J＝8.7Hz,1H),2.73-2.54(m,1H),1.03-0.88(m,4H).HRMS(ESI):m/z calcd for C 22H 20FN 2O 4S[M+H] +427.1122,found 427.1130.
实施例231
4'-氟-N-(4-羟基-3-(氨磺酰基氨基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-116)
Figure PCTCN2020120279-appb-000290
参照实施例86的方法，将III-11替换成IV-63，甲基磺酰氯替换成氨基磺酰氯制得化合物D-116: 1H NMR(300MHz,DMSO-d 6)δppm 10.11(s,1H),9.48(s,1H),8.05(d,J＝8.2Hz,2H),7.86-7.77(m,5H),7.73(d,1H),7.41(dd,J＝8.6,2.2Hz,1H),7.33(dd,J＝8.8,8.8Hz,2H),6.95(s,2H),6.83(d,J＝8.6Hz,1H).HRMS(ESI):m/z calcd for C 19H 17FN 3O 4S[M+H] +402.0918,found 402.0924.
实施例232
6-(4-氟苯基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)烟酰胺(化合物D-117)
Figure PCTCN2020120279-appb-000291
参照实施例193的方法，将对三氟甲基苯硼酸替换成4-氟苯硼酸制得化合物IV-97。
参照实施例86的方法，将III-11替换成IV-97制得化合物D-117: 1H NMR(300MHz,DMSO-d 6)δppm 10.31(s,1H),9.74(s,1H),9.17(d,J＝1.9Hz,1H),8.71(s, 1H),8.38(dd,J＝8.4,2.2Hz,1H),8.25(dd,J＝8.8,5.6Hz,2H),8.13(d,J＝8.4Hz,1H),7.67(d,J＝2.4Hz,1H),7.53(dd,J＝8.7,2.4Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.89(d,J＝8.7Hz,1H),2.99(s,3H).HRMS(ESI):m/z calcd for C 19H 17FN 3O 4S[M+H]+402.0918,found 402.0922.
实施例233
N-(3-(环丙烷磺酰胺基)-4-羟基苯基)-6-(4-氟苯基)烟酰胺(化合物D-118)
Figure PCTCN2020120279-appb-000292
参照实施例86的方法，将III-11替换成IV-97，甲基磺酰氯替换成环丙磺酰氯制得化合物D-118: 1H NMR(300MHz,DMSO-d 6)δppm 10.29(s,1H),9.64(s,1H),9.17(s,1H),8.64(s,1H),8.38(dd,J＝8.3,2.0Hz,1H),8.25(dd,J＝8.6,5.7Hz,2H),8.13(d,J＝8.3Hz,1H),7.73(d,J＝2.2Hz,1H),7.49(dd,J＝8.7,2.2Hz,1H),7.37(dd,J＝8.8,8.8Hz,2H),6.87(d,J＝8.7Hz,1H),2.70-2.57(m,1H),0.99-0.89(m,4H).HRMS(ESI):m/z calcd for C 21H 19FN 3O 4S[M+H] +428.1075,found 428.1081.
实施例234
4'-氟-N-(3-(((3-氟丙基)磺酰胺基)-4-羟基苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-119)
Figure PCTCN2020120279-appb-000293
参照实施例86的方法，将III-11替换成IV-63，甲基磺酰氯替换成IV-11制得化合物D-119: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.74(s,1H),8.90(s,1H),8.05(d,J＝8.3Hz,2H),7.86-7.73(m,4H),7.67(d,J＝2.5Hz,1H),7.54(dd,J＝8.7,2.4Hz,1H),7.39-7.27(m,2H),6.87(d,J＝8.7Hz,1H),4.62(t,J＝6.0Hz,1H),4.47(t,J＝6.0Hz,1H),3.21-3.09(m,2H),2.29-2.03(m,2H).HRMS(ESI):m/z calcd for C 22H 21F 2N 2O 4S[M+H] +447.1185,found 447.1191.
实施例235
4'-氟-N-(4-羟基-3-(吗啉-4-磺酰胺基)苯基)-[1,1'-联苯]-4-甲酰胺(化合物D-120)
Figure PCTCN2020120279-appb-000294
参照实施例86的方法，将III-11替换成IV-63，甲基磺酰氯替换成吗啉磺酰氯制得化合物D-120: 1H NMR(300MHz,DMSO-d 6)δppm 10.14(s,1H),9.77(s, 1H),8.80(s,1H),8.04(d,J＝8.3Hz,2H),7.87-7.73(m,5H),7.48(dd,J＝8.7,2.4Hz,1H),7.40-7.27(m,2H),6.84(d,J＝8.7Hz,1H),3.61-3.54(m,4H),3.15-3.07(m,4H).HRMS(ESI):m/z calcd for C 23H 23FN 3O 5S[M+H] +472.1337,found 472.1344.
实施例236
2-(3-(3,3-二氟哌啶-1-基)丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-121)
Figure PCTCN2020120279-appb-000295
参照实施例184的方法，将1-乙酰基哌嗪替换成3,3-二氟哌啶盐酸盐制得化合物D-121: 1H NMR(300MHz,DMSO-d 6)δppm 10.99(s,1H),10.23(s,1H),9.82(s,1H),8.76(s,1H),7.87-7.77(m,4H),7.75-7.65(m,3H),7.56-7.47(m,2H),6.91(d,J＝8.7Hz,1H),4.28-4.16(m,2H),3.98-3.05(m,6H),2.98(s,3H),2.33-1.78(m,6H).HRMS(ESI):m/z calcd for C 29H 31F 5N 3O 5S[M+H] +628.1899,found 628.1893.
实施例237
N-(3-((N,N-二甲基氨磺酰基)氨基)-4-羟基苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-122)
Figure PCTCN2020120279-appb-000296
参照实施例86的方法，将甲基磺酰氯替换成二甲氨基磺酰氯制得化合物D-122: 1H NMR(300MHz,DMSO-d 6)δppm 10.18(s,1H),9.68(s,1H),8.58(s,1H),8.08(d,J＝8.3Hz,2H),7.99(d,J＝8.2Hz,2H),7.94-7.83(m,4H),7.74(d,J＝2.4Hz,1H),7.47(dd,J＝8.7,2.4Hz,1H),6.83(d,J＝8.7Hz,1H),2.72(s,6H).HRMS(ESI):m/z calcd for C 22H 21F 3N 3O 4S[M+H] +480.1199,found 480.1206.
实施例238
N-(4-羟基-3-((N-异丁基氨磺酰基)氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-123)
Figure PCTCN2020120279-appb-000297
将化合物异丁胺(2.9mL,30mmol)溶于DCM(20mL)中，-10℃条件下向下其中缓慢滴加ClSO 3H(654mL,10mmol)，滴毕后室温反应0.5h。反应液析出固 体，加入H 2O(1mL)，搅拌，抽滤，滤饼Et 2O(5mL)洗涤，红外干燥得黏状固体，将其溶于PhH(15mL)中，向其中加入PCl 5(2.05g,10mmol)，升温至80℃反应2h，反应液减压蒸除溶剂，得化合物IV-98。
参照实施例86的方法，将甲基磺酰氯替换成IV-98制得化合物D-123: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),9.53(s,1H),8.13-8.05(m,3H),7.99(d,J＝8.2Hz,2H),7.94-7.83(m,4H),7.73(d,J＝2.3Hz,1H),7.41(dd,J＝8.7,2.3Hz,1H),7.10(t,J＝6.0Hz,1H),6.82(d,J＝8.7Hz,1H),2.73(t,J＝6.4Hz,2H),1.76-1.60(m,1H),0.80(d,J＝6.7Hz,6H).HRMS(ESI):m/z calcd for C 24H 25F 3N 3O 4S[M+H] +508.1512,found 508.1519
实施例239
N-(4-羟基-3-(甲基磺酰胺基)苯基)-6-苯基烟酰胺(化合物D-124)
Figure PCTCN2020120279-appb-000298
参照实施例193的方法，将4-三氟甲基苯硼酸替换苯硼酸制得化合物IV-99。
参照实施例157的方法，将IV-35替换成IV-99制得化合物D-124: 1H NMR(300MHz,DMSO-d 6)δppm 10.31(s,1H),9.72(s,1H),9.18(d,J＝1.6Hz,1H),8.73(s,1H),8.38(dd,J＝8.3,2.1Hz,1H),8.25-8.09(m,3H),7.67(d,J＝2.3Hz,1H),7.61-7.46(m,4H),6.89(d,J＝8.7Hz,1H),2.99(s,3H).HRMS(ESI):m/z calcd for C 19H 18N 3O 4S[M+H] +384.1013,found 384.1013.
实施例240
3-(3-(3,3-二氟哌啶-1-基)丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-125)
Figure PCTCN2020120279-appb-000299
参照实施例184的方法，将1-乙酰基哌嗪替换成3,3-二氟哌啶盐酸盐，IV-45替换成IV-85制得化合物D-125: 1H NMR(300MHz,DMSO-d 6)δppm 10.55(s,1H),10.04(s,1H),9.78(s,1H),8.80(s,1H),7.99(d,J＝8.2Hz,2H),7.86(d,J＝8.3Hz,2H),7.69(d,J＝7.8Hz,1H),7.65(d,J＝2.3Hz,1H),7.55-7.40(m,3H),6.89(d,J＝8.8Hz,1H),4.39-4.27(m,2H),3.99-3.79(m,1H),3.35-3.16(m,2H),3.09-2.83(m,4H),2.36-1.64(m,6H).ESI-MS:m/z 626.3[M-H] -.
实施例241
N-(3-(环丙烷磺酰胺基)-4-羟基苯基)-3-(3-(4,4-二氟哌啶-1-基)丙氧基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-126)
Figure PCTCN2020120279-appb-000300
参照实施例228的方法，将IV-27替换成IV-96制得化合物D-126: 1H NMR(300MHz,DMSO-d 6)δppm 10.52(s,1H),10.07(s,1H),9.66(s,1H),8.70(s,1H),8.00(d,J＝8.1Hz,2H),7.86(d,J＝8.2Hz,2H),7.77-7.63(m,2H),7.52-7.39(m,3H),6.86(d,J＝8.7Hz,1H),4.41-4.26(m,2H),3.67-3.51(m,2H),3.17-2.96(m,2H),2.69-2.57(m,1H),2.47-2.13(m,6H),0.98-0.84(m,4H).ESI-MS:m/z 652.3[M-H] -.
实施例242
4-羟基-3-(甲基磺酰胺基)-N-(4'-(三氟甲基)-[1,1'-联苯]-4-基)苯甲酰胺(化合物E-1)
Figure PCTCN2020120279-appb-000301
将化合物4-溴硝基苯(1.01g,5.0mmol)，4-三氟甲基苯硼酸(1.04g,5.5mmol)，无水K 2CO 3(2.07g,15mmol)，Pd(PPh 3) 4(115mg,0.1mmol)混溶于Tol(30mL)和MeOH(5mL)中，氩气氛围升温至80℃反应5h。反应液冷却室温，加入H 2O(20mL)和EtOAc(50mL)，conc.HCl调节pH至1-3，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，残留物经硅胶柱层析(石油醚/EtOAc＝50/1)纯化得目标物，淡黄色固体即化合物V-1。
将化合物V-1溶于THF(10mL)和MeOH(10mL)中，加入Pd/C(135mg)，氢气氛围室温反应过夜。反应液经硅藻土抽滤，滤液减压蒸除溶剂，得灰白色固体即化合物V-2(1.1g,80％,two steps). 1H NMR(300MHz,CDCl 3)δ7.68-7.58(m, 4H),7.43(d,J＝8.5Hz,2H),6.77(d,J＝8.5Hz,2H),3.78(brs,2H).
将化合物3-硝基-4-羟基苯甲酸(550mg,3mmol)，无水K 2CO 3(1.7g,12mmol)混悬于DMF(25mL)中，向其中滴加BnBr(890mL,7.5mmol)，滴毕后升温至70℃反应8h。反应液冷却至室温，加入H 2O(80mL)和EtOAc(60mL)，conc.HCl调节pH至1-3，分液，水层EtOAc(40mL)提取，合并有机相，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，得淡黄色油状物质即化合物V-3. 1H NMR(300MHz,CDCl 3)δ8.55(d,J＝2.0Hz,1H),8.21(dd,J＝8.8,2.1Hz,1H),7.51-7.33(m,10H),7.17(d,J＝8.8Hz,1H),5.38(s,2H),5.33(s,2H).
将化合物V-3，还原铁粉(840mg,15mmol)混溶于EtOH(15mL)和饱和NH 4Cl(aq.)(5mL)中，升温至80℃反应3h。反应液冷却至室温，加入EtOAc(20mL)稀释，稀释液经硅藻土抽滤，滤液减压蒸除溶剂，残留物加入EtOAc(40mL)和饱和NaHCO 3(aq.)(30mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂，得黄色油状物质即化合物V-4。
将化合物V-4，吡啶(480μL)混溶于DCM(15mL)中，向其中滴加MsCl(300μL,3.9mmol)，室温反应过夜。反应液减压蒸除溶剂，残留物加入EtOAc(35mL)和1N HCl(25mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，经硅胶柱层析(石油醚:DCM(1:1)/EtOAc＝40/1)纯化得目标物。将其溶解于THF(15mL)和MeOH(10mL)中，加入2N NaOH(7mL)，升温至60℃反应3h。反应液冷却至室温，减压蒸除有机溶剂，残留物加入H 2O(6mL)，1N HCl调节pH至1-3，析出固体，搅拌，抽滤，滤饼水洗涤，红外干燥至恒重，得白色固体即化合物V-6(767mg,80％,four steps). 1H NMR(300MHz,DMSO-d 6)δppm 12.77(s,1H),9.16(s,1H),7.85(d,J＝2.1Hz,1H),7.78(dd,J＝8.6,2.1Hz,1H),7.59-7.52(m,2H),7.46-7.30(m,3H),7.24(d,J＝8.7Hz,1H),5.26(s,2H),2.92(s,3H).
将化合物V-6(48mg,0.15mmol)混悬于DCM(6mL)中，冰浴条件下向其中缓慢滴加(COCl) 2(40μL,0.46mmol)，DMF(1drop)，室温反应4h。反应液减压蒸除溶剂，残留物加入DCM(3mL)制得酰氯溶液，冰浴条件下将其加至V-2(40mg,0.15mmol)和DIPEA(80μL,0.48mmol)的DCM(3mL)溶液中，室温反应1h。反应液析出固体，抽滤，滤饼MeOH(1mL)洗涤，红外干燥至恒重得白色固体即化合物V-7。
将化合物V-7溶于THF(8mL)和MeOH(4mL)中，加入Pd/C(8mg)，氢气氛围室温反应过夜。反应液经硅藻土抽滤，滤液减压蒸除溶剂得残留物，将其混悬于MeOH(3mL)中，搅拌，抽滤，红外干燥，得白色固体即化合物E-1(33mg, 49％,two steps). 1H NMR(300MHz,DMSO-d 6)δppm 10.62(s,1H),10.21(s,1H),8.92(s,1H),7.97-7.85(m,5H),7.85-7.71(m,5H),7.00(d,J＝8.5Hz,1H),3.00(s,3H).HRMS(ESI):m/z calcd for C 21H 18F 3N 2O 4S[M+H] +451.0934,found 451.0936.
实施例243
N-([[1,1'-联苯]-4-基]-3-((4-氟苯基)磺酰胺基)-4-羟基苯甲酰胺(化合物E-2)
Figure PCTCN2020120279-appb-000302
将化合物3-硝基-4-羟基苯甲酸(274mg,1.5mmol)，无水K 2CO 3(830mg,6.0mmol)混悬于DMF(11mL)中，向其中滴加BnBr(410mL,3.3mmol)，滴毕后升温至70℃反应2h。反应液冷却至室温，加入H 2O(40mL)和EtOAc(30mL)，分液，有机层依次用1N HCl，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物。将其溶于THF(4mL)和MeOH(6mL)中，向其中加入NaOH(180mg,4.5mmol)的H 2O(3mL)溶液，升温至50℃反应4h。反应液减压蒸除有机溶剂，残留物加入H 2O(3mL)，1N HCl调节pH至1-3，析出固体，搅拌，抽滤，滤饼水洗涤，红外干燥至恒重，得黄色固体即化合物V-8(354mg,86％,two steps)。
将化合物V-8(350mg,1.28mmol)混悬于DCM(7mL)和THF(2mL)中，冰浴条件下向其中缓慢滴加(COCl) 2(170μL,1,92mmol)，DMF(1drop)，室温反应4h。反应液减压蒸除溶剂，残留物加入DCM(4mL)制得酰氯溶液，冰浴条件下将其加至联苯胺(238mg,1.40mmol)和DIPEA(320μL,1.92mmol)的DCM(6mL)溶液中，室温反应5h。反应液析出固体，抽滤，滤饼DCM(5mL)洗涤，红外干燥至恒重得土绿色固体即化合物V-9。将其溶解于THF(5mL)和MeOH(10mL)中，加入Pd/C(80mg)，氢气氛围室温反应过夜。反应液经硅藻土抽滤，滤液减压蒸除溶剂得残留物，将其混悬于Et 2O(4mL)中，搅拌，抽滤，得灰色固体即化合物V-10(202mg,52％,two steps)。
将化合物V-10(61mg,0.2mmol)，吡啶(50μL,0.6mmol)混溶于THF(6mL)中，向其中加入4-氟苯磺酰氯(57mg,0.3mmol)，室温反应5h。反应液加入1N HCl(8mL)和EtOAc(10mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，经硅胶柱层析(DCM/MeOH＝100/1)纯化， 得目标物，将其混悬于Et 2O(2mL)中，搅拌，抽滤，红外干燥，得白色固体即化合物E-2(15mg,16％). 1H NMR(300MHz,DMSO-d 6)δppm 10.21(s,1H),10.12(s,1H),9.58(s,1H),7.90-7.82(m,3H),7.78(dd,J＝8.5,5.3Hz,2H),7.73-7.61(m,5H),7.50-7.41(m,2H),7.41-7.29(m,3H),6.82(d,J＝8.4Hz,1H).ESI-MS:m/z485.2[M+Na] +.HRMS(ESI):m/z calcd for C 25H 20FN 2O 4S[M+H] +463.1122,found 463.1130.
实施例244
3,4-二羟基-5-(甲基磺酰胺基)-N-(4'-(三氟甲基)-[1,1'-联苯]-4-基)苯甲酰胺(化合物E-3)
Figure PCTCN2020120279-appb-000303
将化合物香草酸甲酯(2.52g,15mmol)溶于AcOH(15mL)中，向其中缓慢滴加发烟HNO 3(1mL,24mmol)，滴毕后室温反应30min。反应液析出固体，抽滤，滤饼石油醚(30mL)洗涤，红外干燥，得黄色固体即化合物V-11(1.5g,45％)。
将化合物V-11(830mg,3.65mmol)，无水Cs 2CO 3(1.2g,3.68mmol)混悬于DMF(15mL)中，向其中滴加MeI(500μL,8.03mmol)，滴毕后升温至55℃反应12h。反应液加入H 2O(40mL)，1N HCl调节pH至1-3，EtOAc(30mL×2)提取水相，合并有机相，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，经硅胶柱层析(石油醚/EtOAc＝20/1)纯化，得白色固体即化合物IV-12(741mg,84％)。
将化合物V-12(585mg,2.43mmol)溶解于THF(8mL)和MeOH(6mL)中，向其中加入2N NaOH(4mL)，升温至60℃反应2h。反应液减压蒸除有机溶剂，残留物加入H 2O(6mL)，1N HCl调节pH至1-3，析出固体，抽滤，滤饼水洗涤，红外干燥至恒重，得黄色固体即化合物V-13(500mg,90％)。 1H NMR(300MHz,DMSO-d 6)δppm 13.51(s,1H),7.91(d,J＝1.6Hz,1H),7.79(d,J＝1.7Hz,1H),3.97(s,3H),3.94(s,3H).
将化合物IV-13(495mg,2.18mmol)混悬于DCM(20mL)中，冰浴条件下向其中滴加2M BBr 3(4mL)，室温反应过夜。反应液析出固体，抽滤，滤饼DCM (2mL)洗涤，红外干燥，得黄色固体即化合物V-14(306mg,70％)。
将化合物IV-14，无水K 2CO 3(1.06g,7.7mmol)混悬于DMF(15mL)中，向其中滴加BnBr(730μL,6.1mmol)，滴毕后升温至70℃反应4h，室温搅拌过夜。反应液加入H 2O(40mL)，1N HCl调节pH至1-3，EtOAc(20mL×2)提取水相，合并有机相，饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，经硅胶柱层析(石油醚/EtOAc＝50/1)纯化，得化合物V-15。
将化合物V-15，还原铁粉(320mg,5.71mmol)，饱和NH 4Cl(aq.)(3mL)混溶于EtOH(10mL)中，升温至80℃反应3h。反应液冷却至室温，加入EtOAc(10mL)稀释，稀释液经硅藻土抽滤，滤液减压蒸除有机溶剂，残留物加入H 2O(10mL)，饱和NaHCO 3(5mL)和EtOAc(20mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得淡黄色固体即化合物V-16(339mg,50％，two steps). 1H NMR(300MHz,CDCl 3)δ7.54-7.30(m,15H),7.19(d,J＝1.7Hz,1H),7.14(d,J＝1.8Hz,1H),5.32(s,2H),5.15(s,2H),5.08(s,2H),3.85(s,2H).
参照实施例242的方法，将V-4替换成V-16制得化合物E-3: 1H NMR(300MHz,DMSO-d 6)δppm 10.20(s,1H),9.87(s,1H),9.56(s,1H),8.88(s,1H),7.95-7.88(m,4H),7.80(d,J＝8.5Hz,2H),7.75(d,J＝8.7Hz,2H),7.44(d,J＝1.9Hz,1H),7.35(d,J＝2.0Hz,1H),2.99(s,3H).HRMS(ESI):m/z calcd for C 21H 18F 3N 2O 5S[M+H] +467.0883,found 467.0882.
实施例245
3,4-二羟基-5-(甲基磺酰胺基)-N-(4'-(三氟甲氧基)-[1,1'-联苯]-4-基)苯甲酰胺(化合物E-4)
Figure PCTCN2020120279-appb-000304
参照实施例242的方法，将4-三氟甲基苯硼酸替换成4-三氟甲氧基苯硼酸制得化合物V-17。
参照实施例242的方法，将V-4替换成V-16，将V-2替换成V-17制得化合物E-4: 1H NMR(300MHz,DMSO-d 6)δppm 10.16(s,1H),9.87(s,1H),9.56(s,1H),8.89(s,1H),7.87(d,J＝8.6Hz,2H),7.79(d,J＝8.7Hz,2H),7.67(d,J＝8.0Hz,1H),7.47-7.41(m,3H),7.34(d,J＝1.9Hz,1H),2.99(s,3H).HRMS(ESI):m/z calcd for C 21H 18F 3N 2O 6S[M+H] +483.0832,found 469.0830.
实施例246
3-氟-4-羟基-5-(甲基磺酰胺基)-N-(4'-(三氟甲基)-[1,1'-联苯]-4-基)苯甲酰胺(化合物E-5)
Figure PCTCN2020120279-appb-000305
将化合物3-氟-4-羟基苯甲酸甲酯(340mg,2mmol)溶于AcOH(6mL)中，向其中缓慢滴加发烟HNO 3(125μL,3.0mmol)，滴毕后室温反应5h。反应液加入H 2O(15mL)，析出固体，搅拌，抽滤，滤饼水洗涤，红外干燥至恒重，得黄色固体即化合物V-18(370mg,86％). 1H NMR(300MHz,DMSO-d 6)δppm 8.26-8.22(m,1H),7.99(dd,J＝10.9,2.0Hz,1H),3.86(s,3H).
将化合物V-18(172mg,0.8mmol)，无水K 2CO 3(220mg,1.6mmol)混悬于DMF(6mL)中，向其中滴加BnBr(200μL,1.6mmol)，滴毕后升温至70℃反应5h，室温搅拌过夜。反应液加入H 2O(25mL)，1N HCl调节pH至1-3，加入EtOAc(20mL)，分液，有机层饱和食盐水洗涤，无水Na 2SO 4干燥，过滤，滤液减压蒸除溶剂得残留物，经硅胶柱层析(石油醚/EtOAc＝50/1)纯化，得黄色固体即化合物V-19(197mg,80％)。
参照实施例242的方法，将V-3替换成V-19制得化合物E-5: 1H NMR(300MHz,DMSO-d 6)δppm 10.85(s,1H),10.27(s,1H),9.22(s,1H),8.02-7.71(m,10H),3.05(s,3H).HRMS(ESI):m/z calcd for C 21H 17F 4N 2O 4S[M+H] +469.0840,found 469.0838.
实施例247
2-氟-4-羟基-5-(甲基磺酰胺基)-N-(4'-(三氟甲基)-[1,1'-联苯]-4-基)苯甲酰胺(化合物E-6)
Figure PCTCN2020120279-appb-000306
参照实施例246的方法，将3-氟-4-羟基苯甲酸甲酯替换成2-氟-4-羟基苯甲酸甲酯制得化合物E-6: 1H NMR(300MHz,DMSO-d 6)δppm 11.01(s,1H),10.27(s,1H),8.98(s,1H),7.95-7.70(m,8H),7.53(d,J＝7.9Hz,1H),6.79(d,J＝11.6Hz,1H),2.99(s,3H).HRMS(ESI):m/z calcd for C 21H 17F 4N 2O 4S[M+H] +469.0840,found 469.0839.
实施例248
N-(4-羟基-3-(甲基磺酰胺基)苯基)-3-(3-吗啉代丙氧基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-127)
Figure PCTCN2020120279-appb-000307
参照实施例184的方法，将IV-45替换成IV-85，IV-67替换成N-(3-氯丙基)吗啉制得化合物D-127: 1H NMR(300MHz,DMSO-d 6)δppm 10.51(s,1H),10.07(s,1H),9.78(s,1H),8.80(s,1H),7.99(d,J＝8.1Hz,2H),7.86(d,J＝8.4Hz,2H),7.69(d,J＝7.9Hz,1H),7.62(d,J＝2.3Hz,1H),7.53-7.38(m,3H),6.89(d,J＝8.7Hz,1H),4.34(t,J＝5.4Hz,2H),3.95-3.82(m,2H),3.82-3.65(m,2H),3.43-3.19(m,4H),2.98(s,3H),2.96-2.86(m,2H),2.30-2.18(m,2H).ESI-MS:m/z 594.3[M+H] +.
实施例249
3-(3-(4-氰基哌啶-1-基)丙氧基)-N-(4-羟基-3-(甲基磺酰胺基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺盐酸盐(化合物D-128)
Figure PCTCN2020120279-appb-000308
参照实施例184的方法，将IV-45替换成IV-85，N-乙酰基哌嗪替换成4-氰基盐酸盐哌啶制得化合物D-128: 1H NMR(300MHz,DMSO-d 6)δppm10.64-10.40(m,1H),10.11-10.03(m,1H),9.82-9.75(m,1H),8.87-8.76(m,1H),8.00(d,J＝8.1Hz,2H),7.85(d,J＝8.2Hz,2H),7.76-7.58(m,2H),7.56-7.38(m,3H),6.91(d,J＝8.5Hz,1H),4.46-4.29(m,2H),3.57-3.41(m,2H),3.26-3.13(m,2H),3.00(s,3H),3.07-2.71(m,3H),2.33-1.97(m,6H).ESI-MS:m/z 617.3[M+H] +.
实施例250
N-(4-羟基-3-((N-异丙基氨磺酰基)氨基)苯基)-4'-(三氟甲基)-[1,1'-联苯]-4-甲酰胺(化合物D-129)
Figure PCTCN2020120279-appb-000309
参照实施例238的方法，将异丁胺替换成异丙胺制得化合物D-129: 1H NMR(300MHz,DMSO-d 6)δppm 10.13(s,1H),9.55(s,1H),8.09(d,J＝8.3Hz,2H),8.04-7.95(m,3H),7.93-7.81(m,4H),7.76(d,1H),7.38(dd,J＝8.5,2.0Hz,1H),7.06(d,J＝7.5Hz,1H),6.82(d,J＝8.6Hz,1H),3.56-3.37(m,1H),1.04(d,J＝6.5Hz,6H).ESI-MS:m/z 492.2[M-H] -.
实施例251
化合物对人原代包皮成纤维细胞(HFF)STING信号通路的抑制活性评价
实验原理：2’,3’-cGAMP能特异性地结合到内质网上的STING蛋白二聚体形成的“V”形口袋内，进而诱导STING蛋白的多聚化激活。多聚化的STING蛋白由内质网向高尔基体室转移，并在此过程中招募下游的激酶蛋白TBK1和转录因子IRF3，TBK1在自磷酸化激活后催化STING和IRF3的磷酸化。磷酸化的IRF3进一步二聚化入核，促进I型干扰素(如IFN-β)基因的表达。因此，通过检测化合物对2'3'-cGAMP刺激HFF细胞后IFN-β基因表达水平的影响可间接评判化合物是否是STING抑制剂。
实验方法：HFF细胞在培养板中贴壁生长，待细胞长至80％丰度时开始化合物的孵育，分别孵育待测化合物(化合物溶于DMSO中，化合物在培养基中的初筛终浓度：1和10μM；IC 50测试浓度：5，2.5，1.25，0.625，0.3125，0.15625，0.078125，0.039μM)过夜。空白对照组只加DMSO，阳性对照组采用文献报导的STING抑制剂Astin C(Cell Reports 2018,25,3405–3421)。孵育完成后用含有2'3'-cGAMP刺激物的洋地黄皂苷溶液(2'3'-cGAMP终浓度：1μg/mL)处理细胞，使2'3'-cGAMP分子进入细胞质中，进而激活内质网上的STING蛋白，2'3'-cGAMP刺激细胞3小时后收取细胞，检测IFN-β基因的表达。
细胞中总RNA的抽提过程如下：1)取适量的细胞和组织用TRIzol(Invitrogen)充分裂解后加入氯仿萃取裂解液中的RNA，4℃ 12000g 15min离心；2)上清溶液中加入异丙醇将溶液中的RNA沉淀下来；3)RNA沉淀用75％的乙醇洗去杂质；4)RNA干燥透明后用适量的DEPC水55℃溶解，OD260处检测RNA浓度。总RNA抽提完成后即可用于后续的荧光定量PCR检测目的基因的表达，实验步骤如下：RNA与引物Oligo dT混合后在反转录酶的作用下转录成cDNA，cDNA与IFN-β基因的引物以及DNA聚合酶和荧光燃料FastStart Universal SYBR GREEN MASTER MIX(Roche)混合后，在ABI QuantStudio 3仪器中进行扩增和检测，GAPDH为基因表达的内参，2-ΔΔCT法进行相对定量计算目的基因的表达。检测目的基因使用的引物序列见表3：
表3.qPCR primer sequences for human
名称 序列
Gapdh正向引物 5’-CGGAGTCAACGGATTTGGTC-3’
Gapdh反向引物 5’-GACAAGCTTCCCGTTCTCAG-3’
Ifn-β正向引物 5’-ATTGCCTCAAGGACAGGATG-3’
Ifn-β反向引物 5’-GGCCTTCAGGTAATGCAGAA-3’
化合物在1和10μM浓度下对2'3'-cGAMP刺激后STING信号通路的抑制率依据IFN-β基因表达倍数计算得到：{100-100*[IFN-β(给药组+cGAMP)/IFN-β(DMSO空白组+cGAMP)]}％；IC 50值测定：每种化合物设置8个浓度梯度，实验得到不同浓度的抑制率，然后在软件中计算化合物的IC 50值。
实验结果如图1和表4所示。
表4.化合物对HFF细胞STING信号通路下游IFN-β基因表达的抑制作用
Figure PCTCN2020120279-appb-000310
Figure PCTCN2020120279-appb-000311
Figure PCTCN2020120279-appb-000312
Figure PCTCN2020120279-appb-000313
Figure PCTCN2020120279-appb-000314
Figure PCTCN2020120279-appb-000315
Figure PCTCN2020120279-appb-000316
Figure PCTCN2020120279-appb-000317
Figure PCTCN2020120279-appb-000318
Figure PCTCN2020120279-appb-000319
Figure PCTCN2020120279-appb-000320
Figure PCTCN2020120279-appb-000321
实验结果(图1和表4)表明，本发明的酰胺类化合物可显著抑制由2'3'-cGAMP刺激诱导的HFF细胞STING信号通路下游IFN-β基因的表达，有很多化合物在1μM浓度下的抑制率大于90％(如：化合物A-8、A-9、A-10、A-11、A-20、A-21、A-30、A-61、A-74、A-79、A-80、B-8、B-13、B-16、B-17、B-19、B-21、B-22、B-23、D-8、D-95、D-103、D-109、D-113、D-123、E-3、E-4)， 显著优于阳性对照化合物(Astin C:1μM浓度下的抑制率＝12.95％)，部分化合物的IC 50值达到纳摩尔水平(如：A-20、A-30、A-61、B-2、B-10、B-12、B-13、D-95、D-113、D-121、E-3、E-4)。本发明中的其他化合物也都显示了显著的STING信号通路抑制活性。这说明本发明的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物可以作为靶向STING的新型小分子抑制剂，可有效抑制STING信号通路的激活。
实施例252
化合物对人单核细胞(THP1)STING信号通路的抑制活性评价
本研究所使用的细胞系为人单核细胞(THP1)。细胞使用含有10％灭活胎牛血清(BI)及100U/mL盘尼西林和100μg/mL链霉素(BI)的1640培养基(BI)培养。
化合物对THP1细胞活力的影响：使用EnoGene的Cell Counting kit-8(CCK8)试剂盒检测。实验过程如下：1)将细胞以8000个/孔提前一天点至96孔板内；2)第二天孵育不同浓度(0.1μM，1μM，10μM)的化合物48h；3)化合物孵育完成后每孔加入20μL的CCK8工作液反应4h后，在450nm的波长处检测吸光值并计算化合物对细胞活力的影响。实验结果表明，本发明的绝大部分化合物均无明显细胞毒性。
化合物对THP1细胞STING信号通路的抑制活性评价：THP1细胞用含0.5％胎牛血清的1640培养基稀释浓度至8×10 5个/孔，种至6孔板内。1和10μM的化合物提前处理细胞6小时，利用FuGENE 6 Transfection Reagent(Promega)将10μg/mL 2'3'-cGAMP转染细胞，刺激12小时后，检测IFN-β基因的表达水平。
细胞中总RNA的抽提过程如下：1)取适量的细胞用TRIzol(Invitrogen)充分裂解后，加入氯仿萃取裂解液中的RNA，4℃ 12000g 15分钟离心；2)上层水相溶液中加入相同体积异丙醇将溶液中的RNA沉淀下来；3)RNA沉淀用1mL75％的乙醇洗去杂质；4)RNA干燥透明后用适量的DEPC水55℃溶解，OD260处检测RNA浓度。总RNA抽提完成后即可用于后续的荧光定量PCR检测目的基因的表达，实验步骤如下：RNA与引物Oligo dT混合后在反转录酶试剂盒的作用下转录成cDNA，cDNA与IFN-β基因的引物以及DNA聚合酶和荧光染料FastStart Universal SYBR GREEN MASTER MIX(Roche)混合后，在ABI QuantStudio 3仪器中进行扩增和检测，GAPDH为基因表达的内参，2 -ΔΔCT法进行相对定量计算目的基因的表达。
化合物在1和10μM浓度下对2'3'-cGAMP刺激后STING信号通路的抑制率依据IFN-β基因表达倍数计算得到:{100-100*[IFN-β(给药组+cGAMP)/IFN-β(DMSO空白组+cGAMP)]}％；
实验结果如图2和表5所示。
表5.化合物对THP1细胞STING信号通路下游IFN-β基因表达的抑制作用
Figure PCTCN2020120279-appb-000322
Figure PCTCN2020120279-appb-000323
Figure PCTCN2020120279-appb-000324
Figure PCTCN2020120279-appb-000325
Figure PCTCN2020120279-appb-000326
Figure PCTCN2020120279-appb-000327
实验结果(图2和表5)表明，本发明的酰胺类化合物可显著抑制由2'3'-cGAMP刺激诱导的THP1细胞STING信号通路下游IFN-β基因的表达，有很多化合物在1μM浓度下的抑制率大于90％(如：化合物D-6、D-7、D-9、D-21、 D-25、D-28、D-30、D-33、D-36、、D-37、D-38、D-39、D-47、D-58、D-62、D-65、D-66、D-68、D-79、D-80、D-81、D-84)，部分化合物的IC 50值达到纳摩尔水平(如：、D-6、D-9、D-15、D-21、D-65、D-68、D-79、D-81)。本发明中的其他化合物也都显示了显著的STING信号通路抑制活性。这说明本发明的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物可以作为靶向STING的新型小分子抑制剂，可有效抑制STING信号通路的激活。
实施例253
化合物B-13对咪喹莫特乳膏所致小鼠银屑病模型的影响
为验证本发明化合物对自身免疫性疾病的作用，采用咪喹莫特乳膏所致小鼠银屑病模型验证化合物的药效。
实验动物：Balb/c雌性小鼠，8周龄，购自浙江维通利华实验动物有限公司。
受试药物配置：将1mL乙醚加入到10g羊毛脂和10g凡士林中，37℃下加热溶解。称取1000mg化合物B-13溶于3.5mL DMSO，500mg化合物B-13溶于2mL DMSO，溶解后加入到羊毛脂与凡士林的混合液中，加入3mL乙醇搅拌均匀，继续加热若干分钟。将0.05g尼泊金甲酯和0.02g尼泊金丙溶于0.4mL乙醚后加入到混合物中，200μL乙醚刷洗1-2次。88℃加热60min。室温搅拌至凝，配制成500mg/kg、250mg/kg化合物B-13软膏，同时配制不含化合物的对照软膏。
造模给药：将小鼠随机分为空白组(Control组)、模型组(Model组)、500mg/kg化合物B-13给药组和250mg/kg化合物B-13给药组，每组10只。小鼠背部脱毛，露出2cm×3cm的皮肤区域。脱毛后适应3天。5％咪喹莫特(Imiquimod,IMQ)乳膏62.5mg/只涂抹右耳及后背，每天一次，造模5天。同时给予给药组500mg/kg、250mg/kg化合物B-13软膏，对照组以及模型组动物对照软膏，0.2g/只，每天2次，共给药5天。每天称重，测量小鼠右耳厚度，拍摄后背照片并进行PASI(银屑病皮损面积和严重程度指数)打分。待给药结束后眼眶取血，并取皮肤和右耳组织，进行下一步实验验证。
实验结果(图3～12)表明，化合物B-13可以有效减轻咪喹莫特乳膏所致银屑病情况。减少模型小鼠后背鳞屑及右耳厚度，降低后背及右耳组织表皮厚度，减少组织中的炎性浸润、棘层增厚以及角质分化过度的情况。同时能够显著降低血清IL-17A、IFN-β水平以及IL-1β、TNF-α、IL-6等炎症因子mRNA水平，缓解炎症症状。说明化合物B-13具有显著的抗炎功效，可抑制银屑病动物模型中炎症因子的释放，且对银屑病具有显著疗效。这提示化合物B-13可用于预防和治疗自身免疫性疾病、器官移植排斥、感染性疾病和炎症性疾病。本发明的其他化合物也具有类似的疗效。
实施例254
分子对接研究
本发明基于人源STING蛋白C端结构域的晶体结构(hSTING-CTD-139-379,PDB:4EF5)，使用
Figure PCTCN2020120279-appb-000328
中的Glide对接模块，进行了计算机辅助的药物设计及分子对接研究。首先，使用Protein Preparation模块对蛋白进行处理，修补缺失的氨基酸侧链和loop结构，去除不必要的溶剂水分子，加氢，赋予OPLS_2005力场，并进行能量优化。然后在Receptor Grid Generation模块中，根据关键性氨基酸残基，如Tyr167，Ser241，Ser243，Gln260等，生成结合位点的格点文件。再利用ligand preparation模块对所设计的小分子结构进行处理，赋予OPLS_2005力场，中性pH值下产生其离子化状态，并进行能量优化。最后在Ligand Docking模块中利用XP(extra precision)精度进行分子对接，配体构象柔性采样，根据Glide docking score进行排序，输出对接结果。
对接结果(图13)表明，本发明的酰胺类化合物(以表1中的化合物A-30为例)可反相平行地结合在STING二聚体表面，A-30中的联苯环结合在二聚体口袋的底部，4-氟-苯磺胺基团延伸到蛋白二聚体口袋的顶部。与apo-STING-CTD蛋白的结晶结构相似，STING-CTD(149-379)与A-30结合后仍维持“V”字型的二聚体结构。且此结合方式明显不同于2’3’-cGAMP与STING-CTD蛋白的“并肩排列”的结合方式(Nature,2019,567(7748):389-393)。也就是说，在与化合物A-30结合后，STING蛋白的空间构象并未发生显著变化，仍维持其在静息状态下的二聚体构象。进一步的对接分析表明，A-30通过与STING蛋白二聚体口袋内的特定氨基酸形成氢键和π-π堆积作用而稳定在口袋内。同时，A-30结构中的酰胺NH与Tyr167氨基酸侧链的酚羟基氧形成氢键。A-30结构中的联苯环与蛋白Tyr167氨基酸侧链的苯环形成π-π堆积作用。A-30结构中的酚羟基与周围的Ser241和Leu259氨基酸形成氢键作用而稳定。而A-30中的磺胺键能进一步与Ser241，Ser243氨基酸侧链上的羟基形成氢键作用。据此，本发明的酰胺类化合物可能通过直接结合STING蛋白并维持其静息状态下的二聚体构象而抑制STING信号通路的激活。本发明中的其他化合物与A30的作用机制类似。
综上所述，本发明的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物可以作为靶向STING的新型小分子抑制剂，可有效抑制STING信号通路的激活，因而可用于制备预防或治疗STING介导的疾病的药物。
实施例255
片剂
将实施例86中制得的化合物B-13(50g)、羟丙甲基纤维素E(150g)、淀粉(200g)、聚维酮K30适量和硬脂酸镁(1g)混合，制粒，压片。
此外，可以根据药典2015版常规制剂法，将实施例1～250制得的化合物赋予不同的药物辅料制成胶囊剂、散剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂等。

Claims (12)

  1. 如下式I或式II所示的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物：
    Figure PCTCN2020120279-appb-100001
    R 1是
    Figure PCTCN2020120279-appb-100002
    R a是取代或非取代的C 1-C 4烷基、环丙基、三氟甲基、乙烯基、取代或非取代的芳基或杂芳基、NH 2、C 1-C 4烷基氨基、羟基-C 1-C 3烷基氨基或吗啉基，所述芳基或杂芳基是苯基、萘基、吡啶基、吡唑基、呋喃基、或噻酚基，所述取代的C 1-C 4烷基是被一个或两个或三个独立地选自下列的取代基所取代：F、Cl、NH 2、OH、二乙醇胺基、甲磺酰胺基、乙酰胺基、氨基乙酰胺基、吡咯烷-1-基、哌啶-1-基、取代的哌啶-1-基、哌嗪-1-基、取代的哌嗪-1-基、吗啉-4-基、硫代吗啉-1,1-二氧代-4-基、N,N-二甲基氨基、羧基、羧酸酯基、甲酰胺基或氨基甲酰胺基，所述取代的芳基或杂芳基是被一个或两个独立地选自下列的取代基所取代：C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基、F、Cl、Br、I、CN、NO 2、NH 2、OH、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH或C(O)NH 2；
    R b是H、C 1-C 3烷基或C 1-C 3烷基羰基；
    R 2是H、OH、C 1-C 3烷氧基、C 1-C 3烷基羰基氧基、C 1-C 3烷氧羰基、C(O)OH、C(O)NH 2或C(O)NHSO 2CH 3；
    R 3是H、OH、C 1-C 3烷基、COOCH 3、COOH、CONH 2、F、Cl、Br或I；
    R 4是H或C 1-C 3烷基；
    Ar是苯基或吡啶基；
    R 5是取代或非取代的苯基、
    Figure PCTCN2020120279-appb-100003
    Figure PCTCN2020120279-appb-100004
    所述取代的苯基是被一个或两个独立地选自下列的取代基所取代：F、Cl、Br、I、CN、NO 2、NH 2、OH、乙酰氨基、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH、C(O)NH 2、C(O)NHOH、C 1-C 3烷基、环丙基、取代或非取代的苯基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基或氨磺酰基；
    R 6和R 7各自独立地选自：H、F、Cl、Br、CN、OH、NO 2、CF 3、OCF 3、C 1-C 3 烷氧基、吗啉-4-基或取代的C 2-C 3烷氧基，所述取代的C 2-C 3烷氧基是指C 2-C 3烷基被卤素、NH 2、OH、CN、羧基、羧酸酯基、甲磺酰基、吡咯烷-1-基、哌啶-1-基、取代的哌啶-1-基、哌嗪-1-基、取代的哌嗪-1-基、吗啉-4-基、硫代吗啉-1,1-二氧代-4-基、N,N-二甲基氨基、N,N-二乙基氨基、三甲基铵基、二乙醇胺基、含氮芳杂环基、磷酰胺基或C 1-C 3烷氧基；
    或者，R 5、R 6和R 7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的环烷烯烃环、取代或非取代的杂环烷烃环或取代或非取代的杂环烯烃环。
  2. 根据权利要求1所述的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物，其特征在于，所述的式I或式II中：
    R 1是
    Figure PCTCN2020120279-appb-100005
    R a是取代或非取代的C 1-C 4烷基、环丙基、三氟甲基、乙烯基、取代或非取代的芳基或杂芳基、NH 2、C 1-C 4烷基氨基、羟基-C 1-C 3烷基氨基或吗啉基，所述芳基或杂芳基是苯基、萘基、吡啶基、吡唑基、呋喃基、或噻酚基，所述取代的C 1-C 4烷基是被一个或两个或三个独立地选自下列的取代基所取代：F、Cl、NH 2、OH、二乙醇胺基、甲磺酰胺基、乙酰胺基、氨基乙酰胺基、吡咯烷-1-基、哌啶-1-基、取代的哌啶-1-基、哌嗪-1-基、取代的哌嗪-1-基、吗啉-4-基、硫代吗啉-1,1-二氧代-4-基、N,N-二甲基氨基、羧基、羧酸酯基、甲酰胺基或氨基甲酰胺基，所述取代的芳基或杂芳基是被一个或两个独立地选自下列的取代基所取代：C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基、F、Cl、Br、I、CN、NO 2、NH 2、OH、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH或C(O)NH 2；
    R b是H、C 1-C 3烷基或C 1-C 3烷基羰基；
    R 2是H、OH、C 1-C 3烷氧基、C 1-C 3烷基羰基氧基、C 1-C 3烷氧羰基、C(O)OH、C(O)NH 2或C(O)NHSO 2CH 3；
    R 3是H、OH、C 1-C 3烷基、COOCH 3、COOH、CONH 2、F或Cl；
    R 4是H；
    Ar是苯基或吡啶基；
    R 5是取代或非取代的苯基、
    Figure PCTCN2020120279-appb-100006
    Figure PCTCN2020120279-appb-100007
    所述取代的苯基是被一个或两个独立地选自下列的取代基所取代：F、Cl、Br、I、CN、NO 2、NH 2、OH、乙酰氨基、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH、C(O)NH 2、C(O)NHOH、C 1-C 3烷 基、环丙基、取代或非取代的苯基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基或氨磺酰基；
    R 6和R 7各自独立地选自：H、F、Cl、Br、CN、OH、NO 2、CF 3、OCF 3、C 1-C 3烷氧基、吗啉-4-基或取代的C 2-C 3烷氧基，所述取代的C 2-C 3烷氧基是指C 2-C 3烷基被卤素、NH 2、OH、CN、羧基、羧酸酯基、甲磺酰基、哌啶-1-基、取代的哌啶-1-基、哌嗪-1-基、取代的哌嗪-1-基、吗啉-4-基、硫代吗啉-1,1-二氧代-4-基、N,N-二甲基氨基、二乙醇胺基、含氮芳杂环基、磷酰胺基或C 1-C 3烷氧基；
    或者，R 5、R 6和R 7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的环烷烯烃环、取代或非取代的杂环烷烃环或取代或非取代的杂环烯烃环。
  3. 根据权利要求1所述的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物，其特征在于，所述酰胺类化合物或其药学上可接受的盐或酯或溶剂化物为如下式III所示的苯甲酰胺类化合物或其药学上可接受的盐或酯或溶剂化物：
    Figure PCTCN2020120279-appb-100008
    R 1是
    Figure PCTCN2020120279-appb-100009
    R a是取代或非取代的C 1-C 3烷基、取代或非取代的芳基或杂芳基、NH 2、C 1-C 3烷基氨基、羟基-C 1-C 3烷基氨基或吗啡啉基，所述芳基或杂芳基是苯基、萘基、吡啶基或噻酚基，所述取代的C 1-C 3烷基是被一个或两个或三个独立地选自下列的取代基所取代：F、NH 2、OH或二甲基氨基，所述取代的芳基或杂芳基是被一个或两个独立地选自下列的取代基所取代：C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基、F、Cl、Br、I、CN、NO 2、NH 2、OH、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH或C(O)NH 2；
    R b是H、C 1-C 3烷基或C 1-C 3烷基羰基；
    R 2是H、OH、C 1-C 3烷氧基、C 1-C 3烷基羰基氧基、C 1-C 3烷氧羰基、C(O)OH、C(O)NH 2或C(O)NHSO 2CH 3；
    R 3是H、C 1-C 3烷基、COOCH 3、COOH、CONH 2、F、Cl、Br或I；
    R 4是H或C 1-C 3烷基；
    R 5是取代或非取代的苯基、
    Figure PCTCN2020120279-appb-100010
    Figure PCTCN2020120279-appb-100011
    所述取代的苯基是被一个或两个独立地选自下列的取代基所取代：F、Cl、Br、I、CN、NO 2、NH 2、OH、乙酰氨基、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH、C(O)NH 2、C(O)NHOH、C 1-C 3烷基、取代或非取代的苯基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基或氨磺酰基；
    R 6和R 7各自独立地选自：H、F、Cl、Br、CN、NO 2、CF 3、OCF 3或C 1-C 3烷氧基；
    或者，R 5、R 6和R 7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的环烷烯烃环、取代或非取代的杂环烷烃环或取代或非取代的杂环烯烃环。
  4. 根据权利要求3所述的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物，其特征在于，所述式III化合物中：
    R 1是
    Figure PCTCN2020120279-appb-100012
    R a是取代或非取代的C 1-C 3烷基、取代或非取代的芳基或杂芳基、NH 2、C 1-C 3烷基氨基、羟基-C 1-C 3烷基氨基或吗啡啉基，所述芳基或杂芳基是苯基、萘基、吡啶基或噻酚基，所述取代的C 1-C 3烷基是被一个或两个或三个独立地选自下列的取代基所取代：F、NH 2、OH或二甲基氨基，所述取代的芳基或杂芳基是被一个或两个独立地选自下列的取代基所取代：C 1-C 3烷基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基、F、Cl、Br、I、CN、NO 2、NH 2、OH、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH或C(O)NH 2；
    R b是H、C 1-C 3烷基或C 1-C 3烷基羰基；
    R 2是H、OH、C 1-C 3烷氧基、C 1-C 3烷基羰基氧基、C 1-C 3烷氧羰基、C(O)OH、C(O)NH 2或C(O)NHSO 2CH 3；
    R 3是H、C 1-C 3烷基、COOCH 3、COOH、CONH 2、F或Cl；
    R 4是H；
    R 5是取代或非取代的苯基、
    Figure PCTCN2020120279-appb-100013
    Figure PCTCN2020120279-appb-100014
    所述取代的苯基是被一个或两个独立地选自下列的取代基所取代：F、Cl、Br、I、CN、NO 2、NH 2、OH、乙酰氨基、CF 3、CF 2CF 3、OCF 3、OCF 2CF 3、C(O)OH、C(O)NH 2、C(O)NHOH、C 1-C 3烷基、取代或非取代的苯基、C 1-C 3烷氧基、C 1-C 3烷氧羰基、C 1-C 3烷基磺酰基或氨 磺酰基；
    R 6和R 7各自独立地选自：H、F、Cl、Br、CN、NO 2、CF 3、OCF 3或C 1-C 3烷氧基；
    或者，R 5、R 6和R 7之中每两个与它们所连接到的原子一起形成取代或非取代的苯环、取代或非取代的杂芳环、取代或非取代的环烷烃环、取代或非取代的环烷烯烃环、取代或非取代的杂环烷烃环或取代或非取代的杂环烯烃环。
  5. 根据权利要求1-4任一所述的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物，其特征在于，所述酰胺类化合物还包括其代谢产物、代谢前体或前药。
  6. 根据权利要求1～4任一所述的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物，其特征在于，所述酰胺类化合物或其药学上可接受的盐或酯或溶剂化物或代谢产物或代谢前体或前药选自如下任意一种化合物：
    Figure PCTCN2020120279-appb-100015
    Figure PCTCN2020120279-appb-100016
    Figure PCTCN2020120279-appb-100017
    Figure PCTCN2020120279-appb-100018
    Figure PCTCN2020120279-appb-100019
    Figure PCTCN2020120279-appb-100020
    Figure PCTCN2020120279-appb-100021
    Figure PCTCN2020120279-appb-100022
    Figure PCTCN2020120279-appb-100023
    Figure PCTCN2020120279-appb-100024
    Figure PCTCN2020120279-appb-100025
    Figure PCTCN2020120279-appb-100026
    Figure PCTCN2020120279-appb-100027
    Figure PCTCN2020120279-appb-100028
    Figure PCTCN2020120279-appb-100029
    Figure PCTCN2020120279-appb-100030
    Figure PCTCN2020120279-appb-100031
    Figure PCTCN2020120279-appb-100032
    Figure PCTCN2020120279-appb-100033
    Figure PCTCN2020120279-appb-100034
    Figure PCTCN2020120279-appb-100035
    Figure PCTCN2020120279-appb-100036
    Figure PCTCN2020120279-appb-100037
    Figure PCTCN2020120279-appb-100038
    Figure PCTCN2020120279-appb-100039
    Figure PCTCN2020120279-appb-100040
    Figure PCTCN2020120279-appb-100041
    Figure PCTCN2020120279-appb-100042
    Figure PCTCN2020120279-appb-100043
  7. 一种权利要求1-4任一项所述的酰胺类化合物或其药学上可接受的盐或酯 或溶剂化物在制备抑制STING信号通路激活的药物中的用途。
  8. 一种权利要求1-4任一项所述的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物在制备预防或治疗STING介导的疾病的药物中的用途。
  9. 根据权利要求8所述的用途，所述STING介导的疾病包括感染性疾病、炎性疾病、自身免疫性疾病、器官纤维化疾病、癌症或癌期综合征。
  10. 一种权利要求1-4任一项所述的酰胺类化合物或其药学上可接受的盐或酯或溶剂化物在制备免疫佐剂药物中的用途。
  11. 一种预防或治疗STING介导的疾病的药物组合物，其包含如权利要求1-4任一项所述的酰胺类化合物或其药学上可接受的盐或酯或溶剂化合物或代谢产物或代谢前体或前药作为活性成分和药学上可接受的辅料。
  12. 根据权利要求11所述的药物组合物，其特征在于，所述药物组合物为胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
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