WO2019196780A1 - Novel indoleamine 2,3-dioxygenase inhibitor, preparation method therefor, and use thereof - Google Patents

Novel indoleamine 2,3-dioxygenase inhibitor, preparation method therefor, and use thereof Download PDF

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WO2019196780A1
WO2019196780A1 PCT/CN2019/081709 CN2019081709W WO2019196780A1 WO 2019196780 A1 WO2019196780 A1 WO 2019196780A1 CN 2019081709 W CN2019081709 W CN 2019081709W WO 2019196780 A1 WO2019196780 A1 WO 2019196780A1
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optionally substituted
compound
group
hydrogen
alkyl
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张龙
宋国伟
周凯松
李佳
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信达生物制药(苏州)有限公司
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Priority to CN201980023555.9A priority Critical patent/CN112004790A/en
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    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
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    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07F9/576—Six-membered rings
    • C07F9/60—Quinoline or hydrogenated quinoline ring systems

Definitions

  • the invention belongs to the field of medicinal chemistry, relates to a novel compound having an effective indoleamine 2,3-dioxygenase inhibiting function and good pharmacokinetic properties, a preparation method thereof, a pharmaceutical composition comprising the same, and Its medical use.
  • Indoleamine-2,3-dioxygenase is a monomeric enzyme containing heme found in the cell for the first time in 1967 by the Hayaishi group.
  • the cDNA encodes a protein. 403 amino acids with a molecular weight of 45 kDa, a rate-limiting enzyme that is catabolized along the tryptophan-kynurenine pathway and widely expressed in many mammalian tissues (Hayaishi O. et al., Science, 1969, 164: 389-396).
  • IDO-mediated tryptophan (Trp)-Kirurenine (Kyn) metabolic pathway is involved in tumor immune escape, and IDO also plays an important role in inducing tumor microenvironmental immune tolerance. The role.
  • Tryptophan is one of the essential amino acids in mammals and needs to be ingested in large quantities from food to maintain cell activation and proliferation, as well as the synthesis of proteins and some neurotransmitters. Therefore, lack of tryptophan can cause dysfunction of some important cells. IDO can catalyze the conversion of tryptophan to N-formyl kynurenine in vivo, resulting in insufficient tryptophan content in the body, which in turn leads to tumorigenesis. In addition, immunohistological studies have shown that the kynurenine metabolic pathway can lead to an increase in the neurogenic excitotoxin, which can lead to a variety of serious neurological diseases such as Alzheimer's disease (Guillemin GJet al., Neuropathol. And Appl. Neurobiol., 2005, 31: 395-404).
  • tryptophan metabolism rate-limiting enzymes There are two main types of tryptophan metabolism rate-limiting enzymes in mammals: tryptophan-2,3-dioxygenase (TDO) and IDO.
  • TDO tryptophan-2,3-dioxygenase
  • IDO IDO
  • Kotake et al. purified proteins from rabbit intestines and found that TDO was mainly expressed in mammalian liver. It has not been found to be closely related to the immune system.
  • TDO catalyzes the kynurenine metabolic pathway and converts tryptophan to N-formyl kynurenine (Higuchi K. et al., J. Biochem., 1937, 25:71-77; Shimizu T. et al ., J. Biol. Chem., 1978, 253: 4700-4706).
  • IDO the enzyme purified from the intestinal tract of rabbits was identified as IDO containing heme.
  • IDO is the only enzyme outside the liver that catalyzes the oxidative cleavage of purines in the tryptophan structure and catabolizes along the kynurenine pathway.
  • IDO is usually expressed in organs with more mucosa (such as lung, small intestine and large intestine, rectum, spleen, kidney, stomach, brain, etc.) and is widely distributed (Hayaishi O. et al., Proceedings of the tenth FEBS meeting, 1975, 131-144).
  • mucosa such as lung, small intestine and large intestine, rectum, spleen, kidney, stomach, brain, etc.
  • pathological conditions such as pregnancy, chronic infection, organ transplantation, tumors, etc.
  • the expression of IDO will increase significantly, and thus participate in mediating local immunosuppression.
  • IDO can inhibit local T cell immune responses in the tumor microenvironment by: tryptophan depletion, toxic metabolism, and induction of regulatory T cell proliferation. In many cases, it is overexpressed in tumors, thereby consuming local tryptophan and producing a large amount of metabolites such as kynurenine. In fact, in culture conditions without tryptophan or kynurenine, T cells undergo proliferation inhibition, decreased activity, and even apoptosis. There is a regulatory point in T cells that is very sensitive to tryptophan levels, which can consume tryptophan under the action of IDO, and arrest T cell proliferation in the middle of G1 phase, thereby inhibiting T cell proliferation and immune response.
  • T cells stop proliferating, they may not be stimulated again. This is the mechanism of immune function of IDO in vivo (Mellor A. et al., Biochem. Biophys. Res. Commun., 2005, 338(1): 20 -24; Le Rond S. et al., J. Exp. Med., 2002, 196(4): 447-457).
  • IDO inhibitors As a new immunotargeting drug, small molecule IDO inhibitors combined with immunological checkpoint inhibitors (ICI) have shown significantly improved efficacy and response rates in a variety of solid tumors, opening up for tumor immunotherapy A new window.
  • ICI immunological checkpoint inhibitors
  • a number of IDO inhibitor drug candidates have been in clinical research, and many patents have been applied, such as CN102164902A, US20080047579A1, WO2016/073770A1, WO2017/213919A1 and the like.
  • CN102164902A US20080047579A1, WO2016/073770A1, WO2017/213919A1
  • IDO inhibitors there is still a need to find compounds that overcome the shortcomings of existing inhibitors, have improved stability, pharmacodynamics, pharmacokinetics, etc. over existing inhibitors, or have found novelty for IDO family targets.
  • the present invention is directed to a novel series of compounds which have a modulatory or inhibitory effect on IDO activity, a process for the preparation of the series of compounds, a pharmaceutical composition comprising the series of compounds, and a pharmaceutical use of the series of compounds.
  • the invention provides a compound having the structure of formula I:
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and
  • A is NR 6 , N-OH, S or O;
  • R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
  • R 5a and R 5b are each independently hydrogen, halogen, hydroxy (-OH) or optionally substituted C 1 -C 6 alkyl; when R 5a and R 5b are simultaneously hydroxy, both are dehydrated to form a carbonyl group;
  • E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently halogen, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkyl; And each
  • At least one of R 1 and R 2 is optionally substituted C 2 -C 4 alkynyl, -SF 5 , -NHSO 2 NH 2 , -P(O)(CH 3 ) 2 or dialkoxyphosphoryl;
  • A is NR 6 , N-OH, S or O;
  • R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
  • R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
  • E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkan
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and
  • R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
  • R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
  • E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkan
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and
  • R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
  • E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkan
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and
  • A is optionally selected from NR 6 , N-OH, S or O;
  • R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
  • E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkan
  • the present invention provides a compound of the above formula I, which comprises:
  • the present invention provides a process for the preparation of a compound of the above formula I, which comprises the steps of:
  • the acylating reagent used in the step 1) of the above preparation method includes, but is not limited to, glacial acetic acid, acetic anhydride (or acetic anhydride), acetyl chloride, benzoic anhydride, benzoyl chloride, etc.
  • sulfonylation Reagents include, but are not limited to, formic acid anhydride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, p-toluenesulfonic anhydride, p-toluenesulfonyl chloride, and the like.
  • the introduction of the fragment E in the step 2) of the above production method is achieved by a coupling reaction.
  • Common coupling reactions include, but are not limited to, Suzuki Reaction, Heck Reaction, Stille Reaction, Sogonoshira Coupling, and Xiongtian Coupling Reaction ( Kumada Coupling reaction, Negishi Coupling, Hiyama Coupling, and the like.
  • the hydrogenation in the step 3) of the above production method is carried out by means of catalytic hydrogenation, metal hydride hydrogenation or hydroboration.
  • Catalysts commonly used in catalytic hydrogenation reactions include, but are not limited to, nickel catalysts (eg, Raney nickel), palladium catalysts (eg, palladium on carbon), platinum catalysts (eg, platinum carbon); reagents commonly found in metal hydride hydrogenation reactions include (but Not limited to) lithium hydride (LiH), sodium hydride (NaH), lithium aluminum hydride (LiAlH 4 ), etc.; common reagents in the hydroboration reaction include, but are not limited to, diborane (B 2 H 4 ), hydroboration Sodium (NaBH 4 ) and the like.
  • the present invention also provides a corresponding preparation method.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof, cis A reverse isomer, an isotope label, or a prodrug.
  • composition further comprises a pharmaceutically acceptable carrier.
  • the present invention provides a compound having the above formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label thereof Or a prodrug or a pharmaceutical composition as described above, which is used as an IDO inhibitor.
  • the present invention provides a compound having the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label thereof Or the use of a prodrug or the above pharmaceutical composition as an IDO inhibitor.
  • the present application provides a compound of the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-label thereof Or the use of a prodrug or a pharmaceutical composition as described above for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by IDO.
  • the present invention provides a method for preventing and/or treating a disease mediated at least in part by IDO, comprising the steps of: treating a therapeutically effective amount of a compound having the above structure of Formula I or a pharmaceutically acceptable compound thereof Accepted salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs or pharmaceutical compositions described above are administered to a patient in need thereof.
  • IDO includes, but is not limited to, cancer (eg, cervical cancer), neurodegenerative diseases (eg, Alzheimer's disease), viral infection (eg, AIDS), bacterial infection (eg, chain Cocci infection), eye diseases (such as cataracts), autoimmune diseases (such as rheumatoid arthritis), depression, anxiety, and psychological disorders.
  • cancer eg, cervical cancer
  • neurodegenerative diseases eg, Alzheimer's disease
  • viral infection eg, AIDS
  • bacterial infection eg, chain Cocci infection
  • eye diseases such as cataracts
  • autoimmune diseases such as rheumatoid arthritis
  • depression anxiety, and psychological disorders.
  • the present invention provides a pharmaceutical combination comprising the above compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof, cis A trans isomer, an isotopic label or prodrug or a pharmaceutical composition as described above and at least one additional cancer therapeutic.
  • the present invention provides a method for preventing and/or treating cancer comprising the steps of: administering a therapeutically effective amount of the above compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, hydrate thereof, Solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs or the above pharmaceutical compositions and at least one additional cancer therapeutic are administered to a patient in need thereof.
  • the above cancer includes, but is not limited to, brain cancer, liver cancer, gallbladder cancer, bronchial cancer, lung cancer, bladder cancer, ovarian cancer, cervical cancer, testicular cancer, lip cancer, tongue cancer, hypopharyngeal cancer, laryngeal cancer, esophagus Cancer, stomach cancer, intestinal cancer (eg colon cancer, rectal cancer), thyroid cancer, salivary gland cancer, pancreatic cancer, breast cancer, prostate cancer, blood cancer (or leukemia), lymphoma (or lymphoma), bone cancer and skin cancer.
  • cancer therapeutic agents include, but are not limited to, antispasmodic drugs (such as pentastatin, etc.), antipyrimidine drugs (such as fluorouracil), antifolate drugs (such as methotrexate), DNA polymerase inhibitors (such as Cytarabine, alkylating agents (such as cyclophosphamide), platinum complexes (such as cisplatin), DNA-killing antibiotics (such as mitomycin), topoisomerase inhibitors (such as camptothecin) Embedding DNA interference nucleic acid synthetic drugs (such as epirubicin), blocking raw material supply drugs (such as asparaginase), interfering with tubulin forming drugs (such as paclitaxel), interfering with ribosome functional drugs (such as harringtonine) ), cytokines (eg, IL-1), thymosin, tumor cell proliferative viruses (eg, adenovirus ONYX-015), and the like.
  • antispasmodic drugs
  • the present invention provides a novel structure of the compound of formula I, which can be used as a highly effective IDO inhibitor, and has various pharmacological activities such as anti-tumor, anti-neurodegenerative diseases (such as Alzheimer's disease), anti-inflammatory and the like.
  • the synthesis method is mild, the operation is simple and easy, and it is easy to derivatize, and is suitable for industrial scale production.
  • Figure 1 is a synthetic route of the compound 2 of the present invention.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of formula I having substantially no toxicity to an organism.
  • Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or an inorganic/organic base, such salts being referred to as acid addition salts or Base addition salt.
  • Common inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
  • Common organic acids include, but are not limited to, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid.
  • common inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide
  • common organic bases include, but are not limited to, diethylamine, triethylamine, ethambutol and the like.
  • hydrate means a substance formed by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with water by a non-covalent intermolecular force. Common hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, and the like.
  • solvate means a substance formed by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with at least one solvent molecule by a non-covalent intermolecular force.
  • solvate includes “hydrates.” Common solvates include, but are not limited to, hydrates, ethanolates, acetonates, and the like.
  • isomer refers to a compound having the same number of atoms and atom type and thus having the same molecular weight, but differing in the spatial arrangement or configuration of the atoms.
  • stereoisomer (also referred to as “an optical isomer”) means having a vertical asymmetric plane due to at least one chiral factor, including a chiral center, a chiral axis, a chiral surface, and the like. Thereby a stable isomer capable of rotating plane polarized light. Because of the presence of asymmetric centers and other chemical structures in the compounds of the invention that may result in stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Since the compounds of the present invention and salts thereof include asymmetric carbon atoms, they can exist as a single stereoisomeric form, a racemate, an enantiomer, and a mixture of diastereomers.
  • these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds can be prepared or isolated to give the pure stereoisomers, ie, single enantiomers or diastereomers, or single stereoisomers (purity ⁇ A mixture of 98%, ⁇ 95%, ⁇ 93%, ⁇ 90%, ⁇ 88%, ⁇ 85% or ⁇ 80%).
  • a single stereoisomer of a compound is prepared by synthesizing an optically active starting material having a desired chiral center, or by preparing a mixture of enantiomeric products, followed by separation or resolution.
  • enantiomer refers to a pair of stereoisomers that have a mirror image that does not overlap each other.
  • diastereomer or “diastereomer” refers to an optical isomer that does not form a mirror image of each other.
  • racemic mixture or “racemate” refers to a mixture of aliquots of a single enantiomer (ie, an equimolar amount of a mixture of two R and S enantiomers).
  • non-racemic mixture refers to a mixture of unequal portions of a single enantiomer. All stereoisomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • tautomer refers to structural isomers having different energies that are mutually transformable by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved.
  • proton tautomers include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization Isomerization of amide-imine alcohol, and the like. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
  • cis-trans isomer refers to a stereoisomer formed by an atom (or group) located on either side of a double bond or ring system due to a position relative to a reference plane; an atom in the cis isomer ( Or a group) is located on the same side of the double bond or ring system in which the atom (or group) is located on the opposite side of the double bond or ring system. Unless otherwise indicated, all cis and trans isomer forms of the compounds of the invention are within the scope of the invention.
  • isotopic label refers to a compound formed by replacing a particular atom in a structure with its isotope atom.
  • the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as 2 H(D), 3 H(T), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S and 37 Cl.
  • prodrug refers to a derivative compound that is capable of providing a compound of the invention, either directly or indirectly, after application to a patient.
  • Particularly preferred derivatizing compounds or prodrugs are compounds which, when administered to a patient, increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system) compound of.
  • site of action e.g., the lymphatic system
  • the term "independently” means that at least two groups (or ring systems) having the same or similar range of values present in the structure may have the same or different meanings in a particular situation.
  • substituent X and the substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl
  • substituent Y when the substituent X is hydrogen, the substituent Y may be either hydrogen or halogen. Hydroxy, cyano, alkyl or aryl;
  • the substituent Y is hydrogen, the substituent X may be either hydrogen, halogen, hydroxy, cyano, alkyl or aryl.
  • optionally substituted means that the group (or ring system) is present unsubstituted or substituted with at least one substituent (or substituted ring system).
  • substituents or substituted ring systems
  • halogen means four atoms of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • sulfonyl refers to a monovalent group formed by the loss of a hydroxy group of a sulfonic acid and attached to the parent nucleus via a single bond to the sulfur atom; common sulfonyl groups include, but are not limited to, methyl sulfonate An acyl group (-SO 2 CH 3 ), a trifluoromethylsulfonyl group (-SO 2 CF 3 ), a phenylsulfonyl group (-SO 2 Ph), an aminosulfonyl group (-SO 2 NH 2 ), or the like.
  • sulfonylamino refers to a monovalent group formed by the loss of a hydrogen atom on the amino group by a sulfonamide and attached to the parent nucleus via a single bond to the nitrogen atom; common sulfonylamino groups include (but Not limited to) methylsulfonylamino (-NHSO 2 CH 3 ), trifluoromethylsulfonylamino (-NHSO 2 CF 3 ), phenylsulfonylamino (-NHSO 2 Ph), sulfamoylamino (-NHSO) 2 NH 2 ) and so on.
  • phosphoroacyl refers to a monovalent group formed by the loss of a hydroxyl group by hypophosphorous acid and attached to the parent nucleus via a single bond to the phosphorus atom; common hypophosphoryl groups include, but are not limited to, two Methylphosphoryl (-P(O)(CH 3 ) 2 ), diphenylphosphoryl (-P(O)Ph 2 ), methylphenylphosphoryl (-P(O)(Ph) (CH 3 )), dialkoxyphosphoryl (-P(O)(OR) 2 ), and the like.
  • phosphoryl refers to a monovalent group formed by the loss of a hydroxyl group by a phosphoric acid and attached to a parent core through a single bond to a phosphorus atom.
  • alkyl refers to a monovalent straight or branched alkane group consisting of a carbon atom and a hydrogen atom, containing no unsaturation, and attached to the parent core through a single bond, preferably C 1 -C 6 alkyl, more preferably C 1 -C 4 alkyl; common alkyl groups include, but are not limited to, methyl (-CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), sec-butyl (-CH(CH 3 )CH 2 CH 3 ), Butyl (-CH 2 CH(CH 3 ) 2 ), tert-butyl (-C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), neopentyl (-CH) 2 C(CH
  • alkynyl refers to a monovalent straight or branched alkyne group consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond, and attached to the parent core through a single bond, preferably C 2 - C 6 alkynyl; common alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propyn-1-yl (ie propynyl) (-C ⁇ C-CH 3 ), 1- Butyn-1-yl (ie butynyl) Pentyn-1-yl 1,3-butadiyn-1-yl (-C ⁇ CC ⁇ CH), 1,4-pentadiyn-1-yl Wait.
  • alkoxy refers to a monovalent straight or branched chain which consists solely of carbon atoms, hydrogen atoms and oxygen atoms and which may contain unsaturation and which are linked by a single bond to the oxygen atom.
  • a C 1 -C 4 alkoxy group common alkoxy groups include, but are not limited to, methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy ( -OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ), n-butoxy (-OCH 2 CH 2 CH 2 CH 3 ), sec-butoxy (-OCH(CH 3 ) CH 2 CH 3 ), isobutoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy (-OC(CH 3 ) 3 ), n-pentyloxy (-OCH 2 CH 2 CH 2 CH 3 ), neopentyloxy (-OCH 2 CH 2 CH 2 CH 3
  • carbonyl refers to a divalent group consisting of only one carbon atom and one oxygen atom, a carbon atom and an oxygen atom are bonded by a double bond, and the carbon atoms in the structure are also bonded to each other through a single bond. The other two fragments.
  • alkanoyl refers to a monovalent straight or branched chain group consisting of only a carbon atom, a hydrogen atom and an oxygen atom, containing no unsaturation other than the carbonyl group in its structure, and passing through a carbonyl group.
  • a linked single bond is attached to the parent core, preferably a C 1 -C 4 alkanoyl group; common alkanoyl groups include, but are not limited to, formyl (-(O)CH), acetyl (-(O)CCH 3 ), positive Propionyl (-(O)CCH 2 CH 3 ), n-butyryl (-(O)CCH 2 CH 2 CH 3 ), isobutyryl (-(O)CCH(CH 3 ) 2 ), n-pentanoyl (- (O) CCH 2 CH 2 CH 2 CH 3 ), pivaloyl (-(O)CC(CH 3 ) 3 ), and the like.
  • common alkanoyl groups include, but are not limited to, formyl (-(O)CH), acetyl (-(O)CCH 3 ), positive Propionyl (-(O)CCH 2 CH 3 ), n-butyryl (-(O)CCH 2 CH 2 CH 3 ), iso
  • cycloalkyl refers to a monovalent monocyclic or polycyclic (including bridged and spiro form) non-aromatic ring system consisting of only carbon and hydrogen atoms, no unsaturation, and A single bond to the parent core; common cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl (also known as decalinyl, naphthyl) ), adamantyl and the like.
  • heterocyclyl refers to a monovalent monocyclic or polycyclic (including bridged and spiro form) non-aromatic ring system consisting of a carbon atom and a hetero atom selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus.
  • common heterocyclic groups include, but are not limited to, oxiranyl, oxetane-3-yl, azetidin-3-yl, tetrahydrofuran- 2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, piperidin-2-yl, piperidine Acridine-4-yl and the like.
  • aryl refers to a monovalent monocyclic or polycyclic (including fused form) aromatic ring system which consists of only carbon and hydrogen atoms and is attached to the parent nucleus by a single bond;
  • the group includes, but is not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthryl, fluorenyl, fluorenyl, fluorenyl, fluorenyl and the like.
  • heteroaryl refers to a monovalent monocyclic or polycyclic (including fused form) aromatic ring system consisting of a carbon atom and a hetero atom selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus, and Single bond to the parent core; common heterocyclic groups include, but are not limited to, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, anthracene Pyridyl, carbazolyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyridazinyl, fluorenyl , quinolyl, isoquinolyl, phenazinyl, phenoxazinyl, phenothiazine,
  • the present invention provides a compound of formula I:
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and
  • A is NR 6 , N-OH, S or O;
  • R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
  • R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
  • E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkan
  • R 1 and R 2 in the above compounds of formula I are each independently hydrogen, halo, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl
  • An optionally substituted C 3 -C 6 cycloalkyl group, an optionally substituted 3 to 6 membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group Or optionally substituted C 2 -C 4 alkynyl, hydrogen in R 1 , R 2 and/or hydrogen on the phenyl ring linking R 1 , R 2 may be optionally substituted by deuterium,
  • R 1 and R 2 in the above compound of formula I are each on two adjacent carbon atoms of the phenyl ring, R 1 and R 2 are bonded to each other to form a saturated 5-membered ring, a saturated 5-membered ring, a saturated 6-membered ring or an unsaturated 6-membered ring containing 0, 1 or 2 heteroatoms including O, N and S, wherein: a saturated 5-membered ring is a ring Pentane, pyrrolidine (ie tetrahydropyrrole), furan (ie tetrahydrofuran), thiophene (ie tetrahydrothiophene), imidazolidine (ie tetrahydroimidazole), pyrazolidine (ie tetrahydropyrazole), oxazole Alkane (ie tetrahydrooxazole), isooxazolidine (ie tetrahydro
  • a in the above formula I is NR 6 , N-OH, S or O;
  • R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl , optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl
  • the hydrogen in R 3 , R 6 is optionally substituted by deuterium, wherein: the optionally substituted C 1 -C 6 alkyl group is methyl, ethyl, hydroxymethyl, cyanomethyl, fluoromethyl, difluoro Methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, a-naphthylmethyl or ⁇ -naphthylmethyl; optionally substituted C 1 -C 6
  • R 3a and R 5b in the above compounds of formula I are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when R 5a and R 5b are simultaneously In the case of a hydroxyl group, the two are dehydrated to form a carbonyl group, wherein the optionally substituted C 1 -C 6 alkyl group is a methyl group, an ethyl group, a methylol group, a cyanomethyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group. .
  • E in the above formula I compound is one of the following fragments optionally substituted with at least one R 7 :
  • Each R 7 is each independently halogen, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl , -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 Independently hydrogen, halogen or optionally substituted C 1 -C 6 alkyl, wherein: for R 7 , the optionally substituted C 1 -C 6 alkyl is methyl, ethyl, hydroxymethyl, cyanide Methy
  • R 1 and R 2 in the compound of formula I above is optionally substituted C 2 -C 4 alkynyl, -SF 5 , -NHSO 2 NH 2 , -P(O (CH 3 ) 2 or dialkoxyphosphoryl;
  • A is NR 6 , N-OH, S or O;
  • R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl , optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl
  • the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
  • R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when R 5a and R 5b are simultaneously When it is a hydroxy group, the two are dehydrated to form
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1- C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3 to 6 membered heterocyclic, optionally substituted C 1 -C 4 alkoxy, optionally substituted C a 1- C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, a hydrogen in R 1 , R 2 and/or a hydrogen on the phenyl ring linking R 1 , R 2 may be optionally substituted by deuter
  • a in the above formula I is N-OH, and R 5a and R 5b are not simultaneously hydrogen;
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, - (CH 2 ) n SF 5 , —(CH 2 ) n NHSO 2 NH 2 , —(CH 2 ) n P(O)(CH 3 ) 2 , a sulfonyl group, a sulfonylamino group, an optionally substituted hypophosphoryl group, Optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3 to 6 membered heterocyclyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkanoyl or optionally substituted C 2 -C 4 alkynyl, hydrogen in R 1 , R 2 and/or benzene linking R 1 , R 2 and/
  • R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 Group, optionally substituted C 3 -C 6 cycloalkyl, and R 3, R 6 is optionally substituted by deuterium hydrogen;
  • E is optionally substituted with at least one R 7 5 to 12-membered aryl, heteroaryl, Aryl, cycloalkyl or heterocyclic; each R 7 is independently hydrogen, halo, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 ene , optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 )
  • R 5a and R 5b in the above formula I formula form a carbonyl group
  • R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , (CH 2 ) n NHSO 2 NH 2 , —(CH 2 ) n P(O)(CH 3 ) 2 , a sulfonyl group, a sulfonylamino group, an optionally substituted hypophosphoryl group, an optionally substituted phosphoryl group, optionally Substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3 to 6 membered heterocyclyl, optionally substituted C 1 -C 4 alkoxy, optionally Substituted C 1 -C 4 alkanoyl or optionally substituted C 2 -C 4 alkynyl, hydrogen in R 1 , R 2 and/or hydrogen on the
  • E in the above formula I compound is one of the following:
  • the above compound of formula I is a compound of formula Ia:
  • R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group).
  • Phosphoryl optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
  • the compound of formula I above is a compound of formula Ia-1 or a compound of formula Ia-2:
  • R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group).
  • Phosphoryl optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
  • the above compound of formula I is a compound of formula Ib:
  • R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group).
  • Phosphoryl optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
  • the compound of formula I above is a compound of formula Ib-1 or a compound of formula Ib-2:
  • R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group).
  • Phosphoryl optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
  • the above compound of formula I is a compound of formula Ic:
  • fragment E and the substituents R 1 , R 2 , R 3 , R 5a , R 5b and R 6 are as defined above.
  • the compound of formula I above is a compound of formula Ic-1 or a compound of formula Ic-2:
  • fragment E and the substituents R 1 , R 2 , R 3 , R 5a , R 5b and R 6 are as defined above.
  • the above compound of formula I is a compound of formula Id:
  • R 5a and R 5b are not hydrogen, and the fragment E and the substituents R 1 , R 2 , R 3 , R 5a and R 5b are as defined above.
  • the compound of formula I above is a compound of formula Id-1 or a compound of formula Id-2:
  • R 5a and R 5b are not hydrogen, and the fragment E and the substituents R 1 , R 2 , R 3 , R 5a and R 5b are as defined above.
  • the present invention provides a process for the preparation of a compound of formula I above, which comprises the steps of:
  • the acylating reagent used in the step 1) of the above preparation method includes, but is not limited to, glacial acetic acid, acetic anhydride (or acetic anhydride), acetyl chloride, benzoic anhydride, and benzoic acid.
  • the sulfonylating reagents include, but are not limited to, formic acid anhydride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, p-toluenesulfonic anhydride, p-toluenesulfonyl chloride, and the like. .
  • the introduction of Fragment E in step 2) of the above preparation process is achieved by a coupling reaction.
  • Common coupling reactions include, but are not limited to, Suzuki Reaction, Heck Reaction, Stille Reaction, Sogonoshira Coupling, and Xiongtian Coupling Reaction ( Kumada Coupling reaction, Negishi Coupling, Hiyama Coupling, and the like. It will be appreciated that those skilled in the art are familiar with the experimental conditions of the above coupling reactions.
  • the hydrogenation in step 3) of the above preparation process is achieved by catalytic hydrogenation, metal hydride hydrogenation or hydroboration.
  • Catalysts commonly used in catalytic hydrogenation reactions include, but are not limited to, nickel catalysts (eg, Raney nickel), palladium catalysts (eg, palladium on carbon), platinum catalysts (eg, platinum carbon); reagents commonly found in metal hydride hydrogenation reactions include (but Not limited to) lithium hydride (LiH), sodium hydride (NaH), lithium aluminum hydride (LiAlH 4 ), etc.; common reagents in the hydroboration reaction include, but are not limited to, diborane (B 2 H 4 ), hydroboration Sodium (NaBH 4 ) and the like.
  • the present invention also provides a corresponding preparation method comprising the following steps:
  • the above preparation method further comprises the following steps:
  • the chiral fragment R chiral is introduced into the compounds III-1 and III-2 obtained in the step 4), respectively, to obtain the compounds III'-1 and III'-2; the compound III'-1 is chirally resolved to obtain the compound III.
  • '-1-a and III'-1-b, compound III'-2 was chiralized to give compounds III'-2-a and III'-2-b; and then the chiral fragment R chiral was removed separately.
  • the chiral fragment R chiral is provided by a chiral auxiliary
  • the chiral auxiliary is a 4-substituted oxazolidinone compound, including but not limited to (S)-4-phenyl-2-oxazolidine Ketone, (R)-4-phenyl-2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone, (R)-4-benzyl-2-oxazolidinone, (S)-4-isopropyl-2-oxazolidinone, (R)-4-isopropyl-2-oxazolidinone, (S)-4-tert-butyl-2-oxazolidinone And (R)-4-tert-butyl-2-oxazolidinone.
  • the chiral auxiliary group R chiral is introduced into the compounds III-1' and III-2', respectively, to obtain the compounds III'-1' and III'-2'; the compound III'-1' is induced by the chiral auxiliary group, and R 5b is introduced.
  • the group gives the compounds III'-1'-a and III'-1'-b, and the compound III'-2' is induced by a chiral auxiliary group, and the R 5b group is introduced to obtain the compound III'-2'-a and III.
  • '-2'-b; the chiral fragment R chiral is removed separately, and the compounds III"-1'-a and III"-1'-b and III" for reacting with the aniline compound in step 5) are obtained.
  • the chiral auxiliary group R chiral is a 4-substituted oxazolidinone compound, including but not limited to (S)-4-phenyl-2-oxazolidinone, (R)-4-phenyl -2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone, (R)-4-benzyl-2-oxazolidinone, (S)-4-isopropyl- 2-oxazolidinone, (R)-4-isopropyl-2-oxazolidinone, (S)-4-tert-butyl-2-oxazolidinone, (R)-4-tert-butyl -2-oxazolidinone and the like.
  • pharmaceutical composition refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier refers to a pharmaceutical excipient that is compatible with the pharmaceutically active ingredient and is not deleterious to the subject, including but not limited to diluents (or fillers), binders, disintegration Agents, lubricants, wetting agents, thickeners, glidants, flavoring agents, odorants, preservatives, antioxidants, pH adjusters, solvents, solubilizers, surfactants, and the like.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the above formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label thereof Or prodrug.
  • the above pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the present invention provides a compound of the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, or The use of a pharmaceutical composition as an IDO inhibitor.
  • the present application also provides a compound of the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, or Use of the above pharmaceutical composition for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by IDO.
  • IDO at least partially mediated by IDO
  • diseases in which at least a portion of IDO-related factors are involved in the pathogenesis including but not limited to cancer (eg, cervical cancer), neurodegenerative diseases (eg, Alz Haimo disease), viral infections (such as AIDS), bacterial infections (such as streptococcal infections), ocular diseases (such as cataracts), autoimmune diseases (such as rheumatoid arthritis), depression, anxiety, and psychological disorders .
  • cancer eg, cervical cancer
  • neurodegenerative diseases eg, Alz Haimo disease
  • viral infections such as AIDS
  • bacterial infections such as streptococcal infections
  • ocular diseases such as cataracts
  • autoimmune diseases such as rheumatoid arthritis
  • depression anxiety, and psychological disorders .
  • the present invention provides a method for preventing and/or treating a disease mediated at least in part by IDO, comprising the steps of: administering a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable salt, hydrate thereof, Solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs or pharmaceutical compositions described above are administered to a patient in need thereof.
  • terapéuticaally effective amount refers to a dose of a pharmaceutically active ingredient that is capable of inducing a biological or medical response in a cell, tissue, organ or organism (e.g., a patient).
  • administering means applying a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (for example, a pharmaceutical composition of the present invention) to a patient or a cell, tissue, organ, biological fluid or the like.
  • a pharmaceutically active ingredient such as a compound of the present invention
  • a pharmaceutical composition comprising a pharmaceutically active ingredient (for example, a pharmaceutical composition of the present invention)
  • Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.
  • the term "required for it” refers to the judgment of a doctor or other caregiver that the patient needs or will benefit from the prevention and/or treatment process, based on the judgment of the doctor or other caregiver in his area of expertise. Factors.
  • patient refers to a human or non-human animal (eg, a mammal).
  • the present invention provides a pharmaceutical combination comprising the above compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis and trans isomer thereof, isotope label Or a prodrug or a pharmaceutical composition as described above and at least one additional cancer therapeutic.
  • cancer refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, undesired ability to invade surrounding tissues, and/or the ability to establish new growth in ectopic.
  • Common cancers include (but are not limited to) brain cancer, liver cancer, gallbladder cancer, bronchial cancer, lung cancer, bladder cancer, ovarian cancer, cervical cancer, testicular cancer, lip cancer, tongue cancer, hypopharyngeal cancer, laryngeal cancer, esophageal cancer, Gastric cancer, intestinal cancer (eg colon cancer, rectal cancer), thyroid cancer, salivary gland cancer, pancreatic cancer, breast cancer, prostate cancer, blood cancer (or leukemia), lymphoma (or lymphoma), bone cancer and skin cancer.
  • cancer therapeutic agent refers to a pharmaceutical or pharmaceutical formulation that is effective in controlling and/or combating cancer.
  • Common cancer therapeutics include, but are not limited to, anticonvulsants (such as pentastatin, etc.), antipyrimidines (such as fluorouracil), antifolates (such as methotrexate), DNA polymerase inhibitors (such as arabinose).
  • Cytidine alkylating agents (such as cyclophosphamide), platinum complexes (such as cisplatin), DNA-killing antibiotics (such as mitomycin), topoisomerase inhibitors (such as camptothecin), embedding DNA interferes with nucleic acid synthesis drugs (such as epirubicin), prevents the supply of raw materials (such as asparaginase), interferes with tubulin-forming drugs (such as paclitaxel), interferes with ribosome-functional drugs (such as harringtonine), Cytokines (eg, IL-1), thymosin, tumor cell proliferative viruses (eg, adenovirus ONYX-015), and the like.
  • alkylating agents such as cyclophosphamide
  • platinum complexes such as cisplatin
  • DNA-killing antibiotics such as mitomycin
  • topoisomerase inhibitors such as camptothecin
  • embedding DNA interferes with nucleic acid synthesis drugs
  • the present invention provides a method for preventing and/or treating cancer comprising the steps of: administering a therapeutically effective amount of a compound of the above formula I or a pharmaceutically acceptable salt, hydrate, solvate thereof, or stereoisomer thereof A construct, tautomer, cis-trans isomer, isotopic label or prodrug or a pharmaceutical composition as described above, and at least one additional cancer therapeutic agent are administered to a patient in need thereof.
  • Example 1 Synthesis of Compounds 1 to 7 and 70 to 71.
  • S4 The product in S3 is separated and purified by silica gel column chromatography, and the mobile phase is petroleum ether/ethyl acetate (V/V: 10:1 to 1:1) to obtain the target compound 2-(cis-4-( Ethyl 6-fluoroquinolin-4-yl)cyclohexyl)propanoate.
  • S7 The product of S6 was purified by silica gel column chromatography, and the mobile phase was petroleum ether/ethyl acetate (V/V: 10:1 to 1:1) to obtain the target compound (4R)-3-((2S) -2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoyl)-4-phenyloxazolidin-2-one.
  • S8 The product of S7 (1.0 eq.) was dissolved in THF (0.25M) and water (1M), and aqueous solution of hydrogen peroxide (35 wt%, 4 eq.) was slowly added at 0 ° C, then lithium hydroxide (1.6 eq) was added.
  • the target compound isolated and purified in S7 is (S)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propionic acid, it can be obtained by a method similar to the above method ( S,Z)-N-(4-Chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionamidine (Compound 3).
  • the target compound isolated and purified in S4 is ethyl 2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propionate
  • a method similar to the above method can be used to obtain (R, Z)-N-(4-chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionamidine (Compound 4) and (S, Z)-N-(4-Chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionamidine (Compound 5).
  • N-(4-chlorophenyl)-2-(4-(6-fluoroquinoline) can be obtained by a method similar to the above.
  • 4-yl)cyclohexyl)propanoid compound 6
  • (R)-N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl) Propionin Compound 70.
  • ESI-MS m/z 410.17, [M+H] + .
  • the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-pentafluoroanisole.
  • the mass spectrometric data of the specific compound were as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-ethynylaniline.
  • the mass spectrometric data of the specific compound were as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-dimethylphosphoranilide.
  • the mass spectrometric data of the specific compound were as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-aminosulfonamidoaniline.
  • the mass spectrometric data of the specific compound were as follows:
  • the target compounds in each step were prepared by the method described in Example 6, and the target compounds were obtained by substituting the corresponding enantiomers.
  • the mass spectrometric data of the specific compounds were as follows:
  • the target compound in each step was prepared by the method described in Example 4 except that the target compound (amide compound) in S9 was not subjected to the carbonyl derivatization reaction in S10, and the mass spectrometric data of the specific compound were as follows:
  • the target compound in each step was prepared by the method described in Example 9, and the target compound was obtained by substituting each corresponding enantiomer.
  • the mass spectrometric identification data of the specific compound is as follows:
  • the target compounds in each step were prepared by the method described in Example 11, and the target compounds were obtained by substituting the corresponding enantiomers.
  • the mass spectrometric identification data of the specific compounds are as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 3-bromo-4-fluoroaniline.
  • the mass spectrometric data of the specific compound were as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 1-methyl-1H-indazole-5-yl.
  • Dimethyl borate, replacing p-chloroaniline in S9 with 3-chloro-4-fluoroaniline, the mass spectrometric identification data of specific compounds are as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 1-methyl-1H-indazole-5-yl.
  • Dimethyl borate, replacing p-chloroaniline in S9 with m-chloroaniline, the mass spectrometric identification data of specific compounds are as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with benzo[b]thiophen-5-ylborate.
  • the ester replace the p-chloroaniline in S9 with 3-chloro-4-fluoroaniline.
  • the target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 2-oxo-2H-chromene-6-yl.
  • Dimethyl borate, replacing p-chloroaniline in S9 with 3-chloro-4-fluoroaniline, the mass spectrometric identification data of specific compounds are as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 1-methyl-1H-indazole-5-yl. Dimethyl borate, replacing p-chloroaniline in S9 with 3,4-methylenedioxyaniline.
  • the mass spectrometric data of specific compounds are as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-chloro-2,3,5,6-deuterated aniline.
  • the mass spectrometric data of the specific compound were as follows. :
  • the target compound in each step was prepared by the method described in Example 8, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid B.
  • the mass spectrometric identification data of esters and specific compounds are as follows:
  • the target compound in each step was prepared by the method described in Example 7, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid.
  • the mass spectrometric identification data of esters and specific compounds are as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid
  • the mass spectrometric identification data of esters and specific compounds are as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid The ester is replaced by methylamine in S10.
  • the mass spectrometric data of the specific compound are as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid
  • the ester, the p-chloroaniline in S9 is replaced by N-methyl-p-chloroaniline, and the target compound (amide compound) in S9 is obtained, and the carbonyl derivatization reaction in S10 is not performed.
  • the mass spectrometric identification data of the specific compound are as follows:
  • Example 25 Synthesis of compounds 83 to 84.
  • the target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid
  • the ester, the p-chloroaniline in S9 is replaced by N-tridecylmethyl-p-chloroaniline, and the target compound (amide compound) in S9 is obtained, and the carbonyl derivatization reaction in S10 is not carried out, and the specific compound is identified by mass spectrometry.
  • Data are as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-propargylaniline or N-methyl-4-propargylaniline.
  • the identification data is as follows:
  • the target compound in each step was prepared by the method described in Example 23, except that 4-propargyl phenylamine or N-methyl-4-propargyl phenylamine in S9 was replaced with 4-pentafluorothiol.
  • aniline or N-methyl-4-pentafluorothiomethylaniline is as follows:
  • Example 28 Synthesis of compounds 97-100.
  • the target compound in each step was prepared by the method described in Example 2 except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-oxo-2-(4-oxo).
  • Ethyl acetate of cyclohexyl) the mass spectrometric identification data of specific compounds are as follows:
  • the target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-oxo-2-(4-oxo).
  • Ethyl acetate of cyclohexyl the mass spectrometric identification data of specific compounds are as follows:
  • Example 30 Investigation of the inhibitory activity of the compound against the indoleamine-2,3-dioxygenase (IDO) of HeLa cells.
  • HeLa (ATCC CCL-2) cells were obtained from ATCC and supplemented with 4.5 g/L glucose, 4.5 g/L L-glutamine and 4.5 g/L sodium L-pyruvate, 2 mM L-alanyl -L-glutamine dipeptide, 100 U/mL penicillin, 100 ⁇ g/mL streptomycin and 10% fetal bovine serum.
  • the cells were maintained in a humidified incubator at 37 ° C, 5% CO 2 .
  • Interferon gamma induces expression of IDO in Hela cells, a model used to test the inhibitory activity of compounds on indoleamine 2,3-dioxygenase (IDO).
  • the culture medium of Hela cells was RPMI-1640 containing 100 ⁇ M of L-tryptophan but no phenol red.
  • the stock solution of the test compound was prepared with dimethyl sulfoxide at a concentration of 10 mM. During the experiment, it was diluted with dimethyl sulfoxide to the highest concentration of the test, and then serially diluted with the medium for 3 times, generally diluted to 8 to 10 concentration points, and duplicate holes were set at each concentration point.
  • the final concentration of dimethyl sulfoxide was 0.5%, and each experiment contained the internal reference compound Epacadostat (INCB024360).
  • the specific procedure of the assay was as follows: 20,000 HeLa cells were added to each well in a 96-well culture plate and cultured overnight. After 24 h, interferon gamma (final concentration 50 ng/mL) and various concentrations of test compound and internal reference compound were added to the cultured cells. After 24 h, transfer 140 ⁇ L of supernatant/well to a new 96-well plate, add 10 ⁇ L of each of 6.1 N trichloroacetic acid per well, incubate at 50 ° C for 30 min to hydrolyze N-formyl-kynurenine to canine urine. Amino acid. The reaction mixture was centrifuged (2500 rpm, 10 min) to remove the precipitate.
  • A indicates ⁇ 10 nM
  • B indicates ⁇ 100 nM
  • C indicates ⁇ 1000 nM.
  • the novel structure of the compound of the formula I provided by the present invention can inhibit the indoleamine-2,3-dioxygenase (IDO) of HeLa cells, and the IC50 value can reach 100 nM or less. Individually even below 10nM, the effect is more significant, can be used as a highly effective IDO inhibitor for the prevention and / or treatment of diseases mediated at least in part by IDO, with anti-tumor and anti-neurodegenerative diseases (such as Alzhai Silent disease, anti-inflammatory and many other intended uses.
  • IDO indoleamine-2,3-dioxygenase
  • Example 31 Inhibitory activity of compounds against indoleamine-2,3-dioxygenase (IDO) of HeLa cells.
  • HeLa (ATCC CCL-2) cells were obtained from ATCC and cultured in EMEM (Eagle's Minimum Essential Medium; In 30-2003 TM medium, the medium contains Earle's balanced salt solution, non-essential amino acids, 2 mM L-glutamine, 1 mM sodium pyruvate and 1500 mg/L sodium bicarbonate, as follows:
  • Ave HC contains 10 ng/mL of IFN- ⁇ , no average reading of compounds
  • Cpd well contains 10 ng/mL of IFN- ⁇ and contains the reading value of the test compound
  • the compound 47 has an excellent inhibitory effect against HeLa cell guanamine-2,3-dioxygenase (IDO).
  • the IC 50 value reached below 1 nM;
  • Compound 52 had comparable HeLa cell indole-2,3-dioxygenase (IDO) inhibition compared to the control compound Epacadostat.
  • IDO HeLa cell indole-2,3-dioxygenase
  • These compounds are useful as potent IDO inhibitors for the prevention and/or treatment of diseases mediated at least in part by IDO, with anti-tumor, anti-neurodegenerative diseases (such as Alzheimer's disease), anti-inflammatory, etc. The intended use.

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Abstract

The present invention relates to the field of pharmaceutical chemistry. Disclosed are a novel indoleamine-2,3-dioxygenase (IDO) inhibitor, a preparation method therefor, and a use thereof. The IDO inhibitor in the present invention has a structure represented by formula (I) and has multiple pharmacological activities such as the prevention of cancers, the prevention of neurodegenerative diseases, and the prevention of inflammation.

Description

一种新型吲哚胺2，3-双加氧酶抑制剂及其制备方法和用途 Novel guanamine 2,3-dioxygenase inhibitor, preparation method and use thereof 技术领域Technical field
本发明属于药物化学领域，涉及一种具有有效的吲哚胺2，3-双加氧酶抑制功能和良好的药代动力学特性的新型化合物，其制备方法，包含其的药物组合物，及其医药用途。The invention belongs to the field of medicinal chemistry, relates to a novel compound having an effective indoleamine 2,3-dioxygenase inhibiting function and good pharmacokinetic properties, a preparation method thereof, a pharmaceutical composition comprising the same, and Its medical use.
背景技术Background technique
吲哚胺-2，3-双加氧酶(Indoleamine-2，3-dioxygenase，IDO)是1967年Hayaishi小组首次在细胞内发现的一种含有亚铁血红素的单体酶，cDNA编码蛋白由403个氨基酸组成，分子量为45kDa，是沿色氨酸-犬尿氨酸途径分解代谢的限速酶，并且在多种哺乳动物的组织中具有广泛的表达(Hayaishi O.et al.，Science，1969，164：389-396)。在肿瘤患者的细胞中，IDO介导的色氨酸(Tryptophan，Trp)-犬尿氨酸(Kynurenine，Kyn)代谢途径参与了肿瘤免疫逃逸，而IDO作为诱导肿瘤微环境免疫耐受也产生重要的作用。Indoleamine-2,3-dioxygenase (IDO) is a monomeric enzyme containing heme found in the cell for the first time in 1967 by the Hayaishi group. The cDNA encodes a protein. 403 amino acids with a molecular weight of 45 kDa, a rate-limiting enzyme that is catabolized along the tryptophan-kynurenine pathway and widely expressed in many mammalian tissues (Hayaishi O. et al., Science, 1969, 164: 389-396). In the cells of tumor patients, IDO-mediated tryptophan (Trp)-Kirurenine (Kyn) metabolic pathway is involved in tumor immune escape, and IDO also plays an important role in inducing tumor microenvironmental immune tolerance. The role.
色氨酸是哺乳动物体内的必需氨基酸之一，需要从食物中大量摄取，以维持细胞的活化和增殖，以及蛋白质和一些神经递质的合成。因此，色氨酸缺乏会导致一些重要细胞的功能失常。IDO在体内能够催化色氨酸转化为N-甲酰犬尿氨酸，造成体内色氨酸含量的不足，进而导致肿瘤的发生。此外，免疫组织学研究显示，犬尿氨酸代谢途径能够导致神经兴奋性毒素喹啉酸增多，还会导致阿尔茨海默病等多种严重的神经系统疾病(Guillemin G.J.et al.，Neuropathol.and Appl.Neurobiol.，2005，31：395-404)。Tryptophan is one of the essential amino acids in mammals and needs to be ingested in large quantities from food to maintain cell activation and proliferation, as well as the synthesis of proteins and some neurotransmitters. Therefore, lack of tryptophan can cause dysfunction of some important cells. IDO can catalyze the conversion of tryptophan to N-formyl kynurenine in vivo, resulting in insufficient tryptophan content in the body, which in turn leads to tumorigenesis. In addition, immunohistological studies have shown that the kynurenine metabolic pathway can lead to an increase in the neurogenic excitotoxin, which can lead to a variety of serious neurological diseases such as Alzheimer's disease (Guillemin GJet al., Neuropathol. And Appl. Neurobiol., 2005, 31: 395-404).
哺乳动物体内的色氨酸代谢限速酶主要有两种：色氨酸-2，3-双加氧酶(TDO)和IDO。1937年，Kotake等人从兔子的肠中纯化出蛋白，并且首次发现TDO主要在哺乳动物肝脏中表达，目前尚未发现其与免疫系统有密切联系。TDO能够催化犬尿氨酸代谢途径，使色氨酸转化为N-甲酰犬尿氨酸(Higuchi K.et al.，J.Biochem.，1937，25：71-77；Shimizu T.et al.，J.Biol.Chem.，1978，253：4700-4706)。1978年，从兔子肠道中纯化的酶被鉴定为含有亚铁血红素的IDO。IDO是肝脏外唯一可以催化色氨酸结构中的吲哚发生氧化裂解，并且沿犬尿氨酸途径分解代谢的酶。IDO通常在粘膜较多的器官(如肺、小肠和大肠、直肠、脾、肾、胃、脑等)中表达，分布比较广泛(Hayaishi O.et al.，Proceedings of the tenth FEBS meeting，1975，131-144)。在某些特殊情况或病理条件(如妊娠、慢性感染、器官移植、肿瘤等)下，IDO的表达会明显增加，进而参与介导局部的免疫抑制。There are two main types of tryptophan metabolism rate-limiting enzymes in mammals: tryptophan-2,3-dioxygenase (TDO) and IDO. In 1937, Kotake et al. purified proteins from rabbit intestines and found that TDO was mainly expressed in mammalian liver. It has not been found to be closely related to the immune system. TDO catalyzes the kynurenine metabolic pathway and converts tryptophan to N-formyl kynurenine (Higuchi K. et al., J. Biochem., 1937, 25:71-77; Shimizu T. et al ., J. Biol. Chem., 1978, 253: 4700-4706). In 1978, the enzyme purified from the intestinal tract of rabbits was identified as IDO containing heme. IDO is the only enzyme outside the liver that catalyzes the oxidative cleavage of purines in the tryptophan structure and catabolizes along the kynurenine pathway. IDO is usually expressed in organs with more mucosa (such as lung, small intestine and large intestine, rectum, spleen, kidney, stomach, brain, etc.) and is widely distributed (Hayaishi O. et al., Proceedings of the tenth FEBS meeting, 1975, 131-144). In certain special cases or pathological conditions (such as pregnancy, chronic infection, organ transplantation, tumors, etc.), the expression of IDO will increase significantly, and thus participate in mediating local immunosuppression.
研究表明，IDO在肿瘤微环境中可以通过以下几种方式来抑制局部T细胞免疫反应：色氨酸耗竭、毒性代谢和诱导调节性T细胞增殖。很多情况是在肿瘤中过度表达，从而消耗局部的色氨酸，产生大量的犬尿氨酸等代谢产物。事实上，在不含色氨酸或犬尿氨酸的培养条件下，T细胞会发生增殖抑制，活性降低，甚至凋亡。T细胞中存在一个对色氨酸水平非常敏感的调节点，其在IDO的作用下能够消耗色氨酸，使T细胞增殖停滞于G1期中期，从而抑制T细胞的增殖及免疫应答。而T细胞一旦停止增殖，可能就不会再接受刺激作用，这就是IDO在体内的免疫作用机制(Mellor A.et al.，Biochem.Biophys.Res.Commun.，2005，338(1)：20-24；Le Rond S.et al.，J.Exp.Med.，2002，196(4)：447-457)。Studies have shown that IDO can inhibit local T cell immune responses in the tumor microenvironment by: tryptophan depletion, toxic metabolism, and induction of regulatory T cell proliferation. In many cases, it is overexpressed in tumors, thereby consuming local tryptophan and producing a large amount of metabolites such as kynurenine. In fact, in culture conditions without tryptophan or kynurenine, T cells undergo proliferation inhibition, decreased activity, and even apoptosis. There is a regulatory point in T cells that is very sensitive to tryptophan levels, which can consume tryptophan under the action of IDO, and arrest T cell proliferation in the middle of G1 phase, thereby inhibiting T cell proliferation and immune response. Once T cells stop proliferating, they may not be stimulated again. This is the mechanism of immune function of IDO in vivo (Mellor A. et al., Biochem. Biophys. Res. Commun., 2005, 338(1): 20 -24; Le Rond S. et al., J. Exp. Med., 2002, 196(4): 447-457).
作为新的免疫靶向药物的小分子IDO抑制剂与免疫检验点抑制剂(immune checkpoint inhibitor，ICI)联用之后在多种实体瘤上表现出显著提高的疗效和反应率，为肿瘤免疫治疗打开了一扇新窗口。目前，已有多个IDO抑制剂候选药物正在临床研究中，并申请了许多专利，如CN102164902A、US20080047579A1、WO2016/073770A1、WO2017/213919A1等。然而，仍然需要发现一些能够克服现有抑制剂的缺点，比现有抑制剂在稳定性、药效学、药代动力学等方面具有改进的化合物，或者发现一些对IDO家族靶点具有新颖的作用模式或机制的抑制剂，以便于克服耐药，提高反应率。因此，开发新的改进的抑制剂或者与靶点具有不同作用模式的抑制剂，更深入地了解该类药物和IDO靶点蛋白与上下游信号通路之间的关系及其发挥抗肿瘤作用的机理将对肿瘤治疗具有重要意义，因此本领域尚需研发新型IDO抑制剂。As a new immunotargeting drug, small molecule IDO inhibitors combined with immunological checkpoint inhibitors (ICI) have shown significantly improved efficacy and response rates in a variety of solid tumors, opening up for tumor immunotherapy A new window. At present, a number of IDO inhibitor drug candidates have been in clinical research, and many patents have been applied, such as CN102164902A, US20080047579A1, WO2016/073770A1, WO2017/213919A1 and the like. However, there is still a need to find compounds that overcome the shortcomings of existing inhibitors, have improved stability, pharmacodynamics, pharmacokinetics, etc. over existing inhibitors, or have found novelty for IDO family targets. Inhibitors of action patterns or mechanisms to overcome drug resistance and increase response rates. Therefore, the development of new and improved inhibitors or inhibitors with different modes of action on the target, a deeper understanding of the relationship between the drug and IDO target protein and the upstream and downstream signaling pathways and its anti-tumor mechanism It will be of great significance for the treatment of tumors, so there is still a need to develop new IDO inhibitors in the field.
发明内容Summary of the invention
发明要解决的问题Problems to be solved by the invention
本发明旨在提供一系列对于IDO活性具有调节或抑制作用的新型化合物，该系列化合物的制备方法，包含该系列化合物的药物组合物，以及该系列化合物的医药用途。The present invention is directed to a novel series of compounds which have a modulatory or inhibitory effect on IDO activity, a process for the preparation of the series of compounds, a pharmaceutical composition comprising the series of compounds, and a pharmaceutical use of the series of compounds.
用于解决问题的方案Solution to solve the problem
第一方面，本发明提供了一种具有式I结构的化合物：In a first aspect, the invention provides a compound having the structure of formula I:
Figure PCTCN2019081709-appb-000001
Figure PCTCN2019081709-appb-000001
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，其中：Or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, wherein:
R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子； R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and R 2 are respectively located in the benzene ring When on one adjacent carbon atom, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 independently of each other. a hetero atom of O, N or S;
A为NR 6、N-OH、S或O； A is NR 6 , N-OH, S or O;
R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
R 5a和R 5b各自独立地为氢、卤素、羟基(-OH)或任选取代的C 1-C 6烷基；当R 5a和R 5b同时为羟基时，二者脱水形成羰基； R 5a and R 5b are each independently hydrogen, halogen, hydroxy (-OH) or optionally substituted C 1 -C 6 alkyl; when R 5a and R 5b are simultaneously hydroxy, both are dehydrated to form a carbonyl group;
E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently halogen, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkyl; And each m is independently 0, 1, 2 or 3.
进一步地，在上述具有式I结构的化合物中：Further, among the above compounds having the structure of formula I:
R 1、R 2至少有一个为任选取代的C 2-C 4炔基、-SF 5、-NHSO 2NH 2、-P(O)(CH 3) 2或二烷氧基次磷酰基； At least one of R 1 and R 2 is optionally substituted C 2 -C 4 alkynyl, -SF 5 , -NHSO 2 NH 2 , -P(O)(CH 3 ) 2 or dialkoxyphosphoryl;
A为NR 6、N-OH、S或O； A is NR 6 , N-OH, S or O;
R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
R 5a和R 5b各自独立地为氢、卤素、羟基或任选取代的C 1-C 6烷基；当R 5a和R 5b同时为羟基时，二者脱水形成羰基； R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkane And each m is independently 0, 1, 2 or 3.
进一步地，在上述具有式I结构的化合物中：Further, among the above compounds having the structure of formula I:
当A为NR 6时； When A is NR 6 ;
R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3- C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子； R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and R 2 are respectively located in the benzene ring When on one adjacent carbon atom, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 independently of each other. a hetero atom of O, N or S;
R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
R 5a和R 5b各自独立地为氢、卤素、羟基或任选取代的C 1-C 6烷基；当R 5a和R 5b同时为羟基时，二者脱水形成羰基； R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkane And each m is independently 0, 1, 2 or 3.
进一步地，在上述具有式I结构的化合物中：Further, among the above compounds having the structure of formula I:
当A为N-OH，且R 5a和R 5b不同时为氢时； When A is N-OH and R 5a and R 5b are not hydrogen at the same time;
R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子； R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and R 2 are respectively located in the benzene ring When on one adjacent carbon atom, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 independently of each other. a hetero atom of O, N or S;
R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkane And each m is independently 0, 1, 2 or 3.
进一步地，在上述具有式I结构的化合物中：Further, among the above compounds having the structure of formula I:
当R 5a和R 5b形成羰基时； When R 5a and R 5b form a carbonyl group;
R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子； R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and R 2 are respectively located in the benzene ring When on one adjacent carbon atom, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 independently of each other. a hetero atom of O, N or S;
A任意选自NR 6、N-OH、S或O； A is optionally selected from NR 6 , N-OH, S or O;
R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkane And each m is independently 0, 1, 2 or 3.
进一步地，在上述具有式I结构的化合物中：Further, among the above compounds having the structure of formula I:
E为下列片段之一：E is one of the following fragments:
Figure PCTCN2019081709-appb-000002
Figure PCTCN2019081709-appb-000002
第二方面，本发明提供了上述具有式I结构的化合物，其包括：In a second aspect, the present invention provides a compound of the above formula I, which comprises:
(1)(Z)-N-(4-氯苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(1) (Z)-N-(4-chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(2)(R，Z)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(2) (R,Z)-N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(3)(S，Z)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(3) (S,Z)-N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(4)(R，Z)-N-(4-氯苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(4) (R,Z)-N-(4-chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(5)(S，Z)-N-(4-氯苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(5) (S,Z)-N-(4-chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(6)N-(4-氯苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙脒；(6) N-(4-chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanone;
(7)(Z)-N-(4-氯苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-甲氧基丙脒；(7) (Z)-N-(4-chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-methoxypropionate;
(8)(Z)-N-(4-五氟化硫基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(8) (Z)-N-(4-pentafluorothiophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(9)(R，Z)-N-(4-五氟化硫基苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(9) (R,Z)-N-(4-Fluorothiophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxyl Bing
(10)(S，Z)-N-(4-五氟化硫基苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(10) (S,Z)-N-(4-Fluorothiophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxyl Bing
(11)(R，Z)-N-(4-五氟化硫基苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(11) (R,Z)-N-(4-Fluorothiophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxyl Bing
(12)(S，Z)-N-(4-五氟化硫基苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(12) (S,Z)-N-(4-Fluorothiophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxyl Bing
(13)N-(4-五氟化硫基苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙脒；(13) N-(4-pentafluorothiophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanone;
(14)(Z)-N-(4-五氟化硫基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-甲氧基丙脒；(14) (Z)-N-(4-pentafluorothiophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-methoxypropanone;
(15)(Z)-N-(4-乙炔基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(15) (Z)-N-(4-ethynylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(16)(R，Z)-N-(4-乙炔基苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(16) (R,Z)-N-(4-ethynylphenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(17)(S，Z)-N-(4-乙炔基苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(17) (S,Z)-N-(4-ethynylphenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionam;
(18)(R，Z)-N-(4-乙炔基苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(18) (R,Z)-N-(4-ethynylphenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionam;
(19)(S，Z)-N-(4-乙炔基苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(19) (S,Z)-N-(4-ethynylphenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionam;
(20)N-(4-乙炔基苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙脒；(20) N-(4-ethynylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanone;
(21)(Z)-N-(4-乙炔基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-甲氧基丙脒；(21) (Z)-N-(4-ethynylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-methoxypropionate;
(22)(Z)-N-(4-(二甲基次磷酰基)苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(22) (Z)-N-(4-(Dimethylphosphoryl)phenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate ;
(23)(R，Z)-N-(4-(二甲基次磷酰基)苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(23)(R,Z)-N-(4-(Dimethylphosphinyl)phenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N '-hydroxypropyl hydrazine;
(24)(S，Z)-N-(4-(二甲基次磷酰基)苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(24) (S,Z)-N-(4-(Dimethylphosphoryl)phenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N '-hydroxypropyl hydrazine;
(25)(R，Z)-N-(4-(二甲基次磷酰基)苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(25) (R,Z)-N-(4-(Dimethylphosphinyl)phenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N '-hydroxypropyl hydrazine;
(26)(S，Z)-N-(4-(二甲基次磷酰基)苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(26)(S,Z)-N-(4-(Dimethylphosphinyl)phenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N '-hydroxypropyl hydrazine;
(27)N-(4-(二甲基次磷酰基)苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙脒；(27) N-(4-(dimethylphosphoryl)phenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanone;
(28)(Z)-N-(4-(二甲基次磷酰基)苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-甲氧基丙脒；(28) (Z)-N-(4-(Dimethylphosphinyl)phenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-methoxy Bing
(29)(Z)-2-(4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)-N’-羟基丙脒；(29) (Z)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)-N'-hydroxypropionam;
(30)(R，Z)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)-N’-羟基丙脒；(30) (R,Z)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)-N'- Hydroxypropyl hydrazine;
(31)(S，Z)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)-N’-羟基丙脒；(31) (S,Z)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)-N'- Hydroxypropyl hydrazine;
(32)(R，Z)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)-N’-羟基丙脒；(32) (R,Z)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)-N'- Hydroxypropyl hydrazine;
(33)(S，Z)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)-N’-羟基丙脒；(33) (S,Z)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)-N'- Hydroxypropyl hydrazine;
(34)2-(4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)丙脒；(34) 2-(4-(6-Fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)propanone;
(35)(Z)-2-(4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)-N’-甲氧基丙脒；(35) (Z)-2-(4-(6-Fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)-N'-methoxypropionate ;
(36)2-(4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)丙酰胺；(36) 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)propanamide;
(37)(R)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)丙酰胺；(37) (R)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)propanamide;
(38)(S)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)丙酰胺；(38) (S)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)propanamide;
(39)(R)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)丙酰胺；(39) (R)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)propanamide;
(40)(S)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N-(4-(氨基磺酰氨基)苯基)丙酰胺；(40) (S)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N-(4-(aminosulfonylamino)phenyl)propanamide;
(41)N-(4-(二甲基次磷酰基)苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙酰胺；(41) N-(4-(dimethylphosphoryl)phenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(42)(R)-N-(4-(二甲基次磷酰基)苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(42) (R)-N-(4-(dimethylphosphoryl)phenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(43)(S)-N-(4-(二甲基次磷酰基)苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(43) (S)-N-(4-(dimethylphosphoryl)phenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(44)(R)-N-(4-(二甲基次磷酰基)苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(44) (R)-N-(4-(dimethylphosphoryl)phenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(45)(S)-N-(4-(二甲基次磷酰基)苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(45) (S)-N-(4-(dimethylphosphoryl)phenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(46)N-(4-乙炔基苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙酰胺；(46) N-(4-ethynylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(47)(R)-N-(4-乙炔基苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(47) (R)-N-(4-ethynylphenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(48)(S)-N-(4-乙炔基苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(48) (S)-N-(4-ethynylphenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(49)(R)-N-(4-乙炔基苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(49) (R)-N-(4-ethynylphenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(50)(S)-N-(4-乙炔基苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(50) (S)-N-(4-ethynylphenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(51)N-(4-五氟化硫基苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙酰胺；(51) N-(4-pentafluorothiophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(52)(R)-N-(4-五氟化硫基苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(52) (R)-N-(4-pentafluorothiophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(53)(S)-N-(4-五氟化硫基苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(53) (S)-N-(4-pentafluorothiophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(54)(R)-N-(4-五氟化硫基苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(54) (R)-N-(4-pentafluorothiophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(55)(S)-N-(4-五氟化硫基苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)丙酰胺；(55) (S)-N-(4-pentafluorothiophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(56)(Z)-N-(3-溴-4-氟苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(56) (Z)-N-(3-Bromo-4-fluorophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(57)(R，Z)-N-(3-溴-4-氟苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(57)(R,Z)-N-(3-Bromo-4-fluorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxyl Bing
(58)(S，Z)-N-(3-溴-4-氟苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(58)(S,Z)-N-(3-Bromo-4-fluorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxyl Bing
(59)(R，Z)-N-(3-溴-4-氟苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(59)(R,Z)-N-(3-Bromo-4-fluorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxyl Bing
(60)(S，Z)-N-(3-溴-4-氟苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(60)(S,Z)-N-(3-Bromo-4-fluorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxyl Bing
(61)(Z)-N-(3-氯-4-氟苯基)-2-(4-(1-甲基-1H-吲唑-5-基)环己基)-N’-羟基丙脒；(61)(Z)-N-(3-Chloro-4-fluorophenyl)-2-(4-(1-methyl-1H-indazol-5-yl)cyclohexyl)-N'-hydroxypropane脒
(62)(R，Z)-N-(3-氯-4-氟苯基)-2-(顺式-4-(1-甲基-1H-吲唑-5-基)环己基)-N’-羟基丙脒；(62)(R,Z)-N-(3-Chloro-4-fluorophenyl)-2-(cis-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)- N'-hydroxypropyl hydrazine;
(63)(S，Z)-N-(3-氯-4-氟苯基)-2-(顺式-4-(1-甲基-1H-吲唑-5-基)环己基)-N’-羟基丙脒；(63)(S,Z)-N-(3-Chloro-4-fluorophenyl)-2-(cis-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)- N'-hydroxypropyl hydrazine;
(64)(R，Z)-N-(3-氯-4-氟苯基)-2-(反式-4-(1-甲基-1H-吲唑-5-基)环己基)-N’-羟基丙脒；(64) (R,Z)-N-(3-Chloro-4-fluorophenyl)-2-(trans-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)- N'-hydroxypropyl hydrazine;
(65)(S，Z)-N-(3-氯-4-氟苯基)-2-(反式-4-(1-甲基-1H-吲唑-5-基)环己基)-N’-羟基丙脒；(65)(S,Z)-N-(3-Chloro-4-fluorophenyl)-2-(trans-4-(1-methyl-1H-indazol-5-yl)cyclohexyl)- N'-hydroxypropyl hydrazine;
(66)(Z)-N-(3-氯苯基)-2-(4-(1-甲基-1H-吲唑-5-基)环己基)-N’-羟基丙脒；(66) (Z)-N-(3-chlorophenyl)-2-(4-(1-methyl-1H-indazol-5-yl)cyclohexyl)-N'-hydroxypropionate;
(67)(Z)-N-(3-氯-4-氟苯基)-2-(4-(苯并[b]噻吩-5-基)环己基)-N’-羟基丙脒；(67) (Z)-N-(3-chloro-4-fluorophenyl)-2-(4-(benzo[b]thiophen-5-yl)cyclohexyl)-N'-hydroxypropionam;
(68)(Z)-N-(3-氯-4-氟苯基)-2-(4-(2-氧代-2H-色烯-6-基)环己基)-N’-羟基丙脒；(68) (Z)-N-(3-Chloro-4-fluorophenyl)-2-(4-(2-oxo-2H-chromen-6-yl)cyclohexyl)-N'-hydroxypropane脒
(69)(Z)-N-(苯并[d][1，3]二氧杂环戊烷-5-基)-2-(4-(1-甲基-1H-吲唑-5-基)环己基)-N’-羟基丙脒；(69) (Z)-N-(Benzo[d][1,3]dioxol-5-yl)-2-(4-(1-methyl-1H-indazole-5-) ()cyclohexyl)-N'-hydroxypropionate;
(70)(R)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙脒；(70) (R)-N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanone;
(71)(R，Z)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-甲氧基丙脒；(71)(R,Z)-N-(4-Chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-methoxypropionate ;
(72)(R，Z)-N-(4-氯-2，3，5，6-氘代苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-甲氧基丙脒；(72) (R,Z)-N-(4-Chloro-2,3,5,6-nonanoylphenyl)-2-(cis-4-(6-fluoroquinolin-4-yl) ring Hexyl)-N'-methoxypropionate;
(73)N-(4-乙炔基苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)乙酰胺；(73) N-(4-ethynylphenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide;
(74)N-(4-(二甲基次磷酰基)苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)乙酰胺；(74) N-(4-(dimethylphosphoryl)phenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide;
(75)N-(4-(二甲基次磷酰基)苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)乙酰胺；(75) N-(4-(dimethylphosphoryl)phenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide;
(76)N-(4-氯苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)乙脒；(76) N-(4-chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamidine;
(77)N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)乙脒；(77) N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamidine;
(78)N-(4-乙炔基苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)乙酰胺；(78) N-(4-ethynylphenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide;
(79)(Z)-N-(4-氯苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-甲基乙脒；(79) (Z)-N-(4-chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-methylacetamidine;
(80)(Z)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-甲基乙脒；(80) (Z)-N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-methylacetamidine;
(81)N-(4-氯苯基)-N-甲基-2-(反式-4-(6-氟喹啉-4-基)环己基)乙酰胺；(81) N-(4-chlorophenyl)-N-methyl-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide;
(82)N-(4-氯苯基)-N-甲基-2-(顺式-4-(6-氟喹啉-4-基)环己基)乙酰胺；(82) N-(4-chlorophenyl)-N-methyl-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide;
(83)N-(4-氯苯基)-N-三氘代甲基-2-(反式-4-(6-氟喹啉-4-基)环己基)乙酰胺；(83) N-(4-chlorophenyl)-N-trideuteromethyl-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide;
(84)N-(4-氯苯基)-N-三氘代甲基-2-(顺式-4-(6-氟喹啉-4-基)环己基)乙酰胺；(84) N-(4-chlorophenyl)-N-trideuteromethyl-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)acetamide;
(85)(Z)-N-(4-炔丙基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(85) (Z)-N-(4-propargylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(86)N-(4-炔丙基苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙脒；(86) N-(4-propargylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanone;
(87)(Z)-N-(4-炔丙基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-甲氧基丙脒；(87) (Z)-N-(4-propargylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-methoxypropanone;
(88)N-(4-炔丙基苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙酰胺；(88) N-(4-propargylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(89)N-(4-炔丙基苯基)-2-(4-(6-氟喹啉-4-基)环己基)硫代丙酰胺；(89) N-(4-propargylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)thiopropionamide;
(90)N-(4-炔丙基苯基)-N-甲基-2-(4-(6-氟喹啉-4-基)环己基)丙酰胺；(90) N-(4-propargylphenyl)-N-methyl-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(91)(Z)-N-(4-五氟化硫基甲基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒；(91) (Z)-N-(4-pentafluorothiomethylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionate;
(92)N-(4-五氟化硫基甲基苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙脒；(92) N-(4-pentafluorothiomethylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoid;
(93)(Z)-N-(4-五氟化硫基甲基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-甲氧基丙脒；(93) (Z)-N-(4-Fluorothiomethylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-methoxypropane脒
(94)N-(4-五氟化硫基甲基苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙酰胺；(94) N-(4-sulfosylthiophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(95)N-(4-五氟化硫基甲基苯基)-2-(4-(6-氟喹啉-4-基)环己基)硫代丙酰胺；(95) N-(4-pentafluoromethylphenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)thiopropionamide;
(96)N-(4-五氟化硫基甲基苯基)-N-甲基-2-(4-(6-氟喹啉-4-基)环己基)丙酰胺；(96) N-(4-pentafluoromethylphenyl)-N-methyl-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide;
(97)(Z)-N-(4-五氟化硫基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-2-氧代-N’-羟基乙脒；(97) (Z)-N-(4-Fluorothiophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-2-oxo-N'-hydroxyl Acetylene
(98)N-(4-五氟化硫基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-2-氧代乙脒；(98) N-(4-pentafluorothiophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-2-oxoethyl hydrazine;
(99)(Z)-N-(4-五氟化硫基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-2-氧代-N’-甲氧基乙脒；(99) (Z)-N-(4-Fluorothiophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-2-oxo-N'-A Oxyacetam
(100)N-(4-五氟化硫基苯基)-2-(4-(6-氟喹啉-4-基)环己基)-2-氧代乙酰胺；(100) N-(4-pentafluorothiophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-2-oxoacetamide;
(101)N-(4-氯苯基)-2-(4-(6-氟喹啉-4-基)环己基)-2-氧代乙酰胺。(101) N-(4-Chlorophenyl)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)-2-oxoacetamide.
第三方面，本发明提供了上述具有式I结构的化合物的制备方法，其包括下列步骤：In a third aspect, the present invention provides a process for the preparation of a compound of the above formula I, which comprises the steps of:
1)将化合物VI与磺酰化试剂反应，得到化合物V；1) reacting compound VI with a sulfonylating reagent to obtain compound V;
Figure PCTCN2019081709-appb-000003
Figure PCTCN2019081709-appb-000003
2)向化合物V中引入片段E，得到化合物IV；2) introducing a fragment E into the compound V to obtain a compound IV;
Figure PCTCN2019081709-appb-000004
Figure PCTCN2019081709-appb-000004
3)将化合物IV氢化，得到化合物III；3) hydrogenation of compound IV to give compound III;
Figure PCTCN2019081709-appb-000005
Figure PCTCN2019081709-appb-000005
4)将化合物III与苯胺类化合物反应，得到化合物II；4) reacting compound III with an aniline compound to obtain compound II;
Figure PCTCN2019081709-appb-000006
Figure PCTCN2019081709-appb-000006
5)向化合物II中引入片段A，得到具有式I结构的化合物；5) introducing a fragment A into the compound II to obtain a compound having the structure of the formula I;
Figure PCTCN2019081709-appb-000007
Figure PCTCN2019081709-appb-000007
其中：片段A和E以及取代基R 1、R 2、R 3、R 5a和R 5b的定义如上所述。 Wherein: the definitions of the fragments A and E and the substituents R 1 , R 2 , R 3 , R 5a and R 5b are as described above.
进一步地，上述制备方法的步骤1)中所使用的酰化试剂包括(但不限于)冰醋酸、醋酐(或称乙酸酐)、乙酰氯、苯甲酸酐、苯甲酰氯等，磺酰化试剂包括(但不限于)甲酸酸酐、甲磺酰氯、三氟甲磺酸酐、三氟甲磺酰氯、苯磺酸酐、苯磺酰氯、对甲苯磺酸酐、对甲苯磺酰氯等。Further, the acylating reagent used in the step 1) of the above preparation method includes, but is not limited to, glacial acetic acid, acetic anhydride (or acetic anhydride), acetyl chloride, benzoic anhydride, benzoyl chloride, etc., sulfonylation Reagents include, but are not limited to, formic acid anhydride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, p-toluenesulfonic anhydride, p-toluenesulfonyl chloride, and the like.
进一步地，上述制备方法的步骤2)中片段E的引入通过偶联反应来实现。常见的偶联反应包括(但不限于)铃木反应(Suzuki Reaction)、赫克反应(Heck Reaction)、斯蒂尔反应(Stille Reaction)、菌头偶联反应(Sogonoshira Coupling)、熊田偶联反应(Kumada Coupling)反应、根岸偶联反应(Negishi Coupling)、桧山偶联反应(Hiyama Coupling)等。Further, the introduction of the fragment E in the step 2) of the above production method is achieved by a coupling reaction. Common coupling reactions include, but are not limited to, Suzuki Reaction, Heck Reaction, Stille Reaction, Sogonoshira Coupling, and Xiongtian Coupling Reaction ( Kumada Coupling reaction, Negishi Coupling, Hiyama Coupling, and the like.
进一步地，上述制备方法的步骤3)中的氢化通过催化氢化、金属氢化物氢化或硼氢化的方式来实现。催化氢化反应中常见的催化剂包括(但不限于)镍催化剂(例如兰尼镍)、钯催化剂(例如钯碳)、铂催化剂(例如铂碳)；金属氢化物氢化反应中常见的试剂包括(但不限于)氢化锂(LiH)、氢化钠(NaH)、四氢铝锂(LiAlH 4)等；硼氢化反应中常见的试剂包括(但不限于)乙硼烷(B 2H 4)、硼氢化钠(NaBH 4)等。 Further, the hydrogenation in the step 3) of the above production method is carried out by means of catalytic hydrogenation, metal hydride hydrogenation or hydroboration. Catalysts commonly used in catalytic hydrogenation reactions include, but are not limited to, nickel catalysts (eg, Raney nickel), palladium catalysts (eg, palladium on carbon), platinum catalysts (eg, platinum carbon); reagents commonly found in metal hydride hydrogenation reactions include (but Not limited to) lithium hydride (LiH), sodium hydride (NaH), lithium aluminum hydride (LiAlH 4 ), etc.; common reagents in the hydroboration reaction include, but are not limited to, diborane (B 2 H 4 ), hydroboration Sodium (NaBH 4 ) and the like.
除此以外，当上述式I化合物具有特定构型时，本发明还提供了相应的制备方法。In addition to this, when the above compound of the formula I has a specific configuration, the present invention also provides a corresponding preparation method.
第四方面，本发明提供了一种药物组合物，其包含上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药。In a fourth aspect, the present invention provides a pharmaceutical composition comprising the above compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof, cis A reverse isomer, an isotope label, or a prodrug.
进一步地，上述药物组合物还包含药学上可接受的载体。Further, the above pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
第五方面，本发明提供了上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物，其用作IDO抑制剂。In a fifth aspect, the present invention provides a compound having the above formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label thereof Or a prodrug or a pharmaceutical composition as described above, which is used as an IDO inhibitor.
第六方面，本发明提供了上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物用作IDO抑制剂的用途。In a sixth aspect, the present invention provides a compound having the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label thereof Or the use of a prodrug or the above pharmaceutical composition as an IDO inhibitor.
第七方面，本申请提供了上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物在制备用于预防和/或治疗至少部分由IDO介导的疾病的药物中的用途。In a seventh aspect, the present application provides a compound of the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope-label thereof Or the use of a prodrug or a pharmaceutical composition as described above for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by IDO.
第八方面，本发明提供了一种用于预防和/或治疗至少部分由IDO介导的疾病的方法，其包括下列步骤：将治疗有效量的上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物施用于对其有需求的患者。In an eighth aspect, the present invention provides a method for preventing and/or treating a disease mediated at least in part by IDO, comprising the steps of: treating a therapeutically effective amount of a compound having the above structure of Formula I or a pharmaceutically acceptable compound thereof Accepted salts, hydrates, solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs or pharmaceutical compositions described above are administered to a patient in need thereof.
进一步地，上述至少部分由IDO介导的疾病包括(但不限于)癌症(例如宫颈癌)、神经退行性疾病(例如阿尔茨海默病)、病毒感染(例如AIDS)、细菌感染(例如链球菌感染)、眼部疾病(例如白内障)、自身免疫性疾病(例如类风湿性关节炎)、抑郁症、焦虑症以及心理障碍。Further, the above-mentioned at least partially mediated by IDO includes, but is not limited to, cancer (eg, cervical cancer), neurodegenerative diseases (eg, Alzheimer's disease), viral infection (eg, AIDS), bacterial infection (eg, chain Cocci infection), eye diseases (such as cataracts), autoimmune diseases (such as rheumatoid arthritis), depression, anxiety, and psychological disorders.
第九方面，本发明提供了一种药物联合形式，其包含上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物以及至少一种额外的癌症治疗剂。In a ninth aspect, the present invention provides a pharmaceutical combination comprising the above compound having the structure of Formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof, cis A trans isomer, an isotopic label or prodrug or a pharmaceutical composition as described above and at least one additional cancer therapeutic.
第十方面，本发明提供了一种用于预防和/或治疗癌症的方法，其包括下列步骤：将治疗有效量的上述具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物以及至少一种额外的癌症治疗剂施用于对其有需求的患者。In a tenth aspect, the present invention provides a method for preventing and/or treating cancer comprising the steps of: administering a therapeutically effective amount of the above compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, hydrate thereof, Solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs or the above pharmaceutical compositions and at least one additional cancer therapeutic are administered to a patient in need thereof.
进一步地，上述癌症包括(但不限于)脑癌、肝癌、胆囊癌、支气管癌、肺癌、膀胱癌、卵巢 癌、宫颈癌、睾丸癌、唇癌、舌癌、下咽癌、喉癌、食管癌、胃癌、肠癌(例如结肠癌、直肠癌)、甲状腺癌、唾液腺癌、胰腺癌、乳腺癌、前列腺癌、血癌(或称白血病)、淋巴癌(或称淋巴瘤)、骨癌和皮肤癌。Further, the above cancer includes, but is not limited to, brain cancer, liver cancer, gallbladder cancer, bronchial cancer, lung cancer, bladder cancer, ovarian cancer, cervical cancer, testicular cancer, lip cancer, tongue cancer, hypopharyngeal cancer, laryngeal cancer, esophagus Cancer, stomach cancer, intestinal cancer (eg colon cancer, rectal cancer), thyroid cancer, salivary gland cancer, pancreatic cancer, breast cancer, prostate cancer, blood cancer (or leukemia), lymphoma (or lymphoma), bone cancer and skin cancer.
进一步地，上述癌症治疗剂包括(但不限于)抗嘌呤药(例如喷司他丁等)、抗嘧啶药(例如氟尿嘧啶)、抗叶酸药(例如甲氨蝶呤)、DNA多聚酶抑制剂(如阿糖胞苷)、烷化剂(如环磷酰胺)、铂类配合物(例如顺铂)、破坏DNA的抗生素(例如丝裂霉素)、拓扑异构酶抑制剂(例如喜树碱)、嵌入DNA干扰核酸合成药(例如表柔比星)、阻止原料供应药(例如门冬酰胺酶)、干扰微管蛋白形成药(例如紫杉醇)、干扰核糖体功能药(例如三尖杉酯碱)、细胞因子(例如IL-1)、胸腺肽、肿瘤细胞增殖病毒(如腺病毒ONYX-015)等。Further, the above cancer therapeutic agents include, but are not limited to, antispasmodic drugs (such as pentastatin, etc.), antipyrimidine drugs (such as fluorouracil), antifolate drugs (such as methotrexate), DNA polymerase inhibitors (such as Cytarabine, alkylating agents (such as cyclophosphamide), platinum complexes (such as cisplatin), DNA-killing antibiotics (such as mitomycin), topoisomerase inhibitors (such as camptothecin) Embedding DNA interference nucleic acid synthetic drugs (such as epirubicin), blocking raw material supply drugs (such as asparaginase), interfering with tubulin forming drugs (such as paclitaxel), interfering with ribosome functional drugs (such as harringtonine) ), cytokines (eg, IL-1), thymosin, tumor cell proliferative viruses (eg, adenovirus ONYX-015), and the like.
发明的效果Effect of the invention
本发明提供了一种结构新颖的式I化合物，其可以作为高效的IDO抑制剂，具有抗肿瘤、抗神经退行性疾病(如阿尔茨海默病)、抗炎等多种药理活性。合成方法温和，操作简单易行，易于衍生化，适合工业放大量生产。The present invention provides a novel structure of the compound of formula I, which can be used as a highly effective IDO inhibitor, and has various pharmacological activities such as anti-tumor, anti-neurodegenerative diseases (such as Alzheimer's disease), anti-inflammatory and the like. The synthesis method is mild, the operation is simple and easy, and it is easy to derivatize, and is suitable for industrial scale production.
附图说明DRAWINGS
图1为本发明的化合物2的合成路线。Figure 1 is a synthetic route of the compound 2 of the present invention.
具体实施方式detailed description
在进一步描述本发明之前，应当理解，本发明不限于本文中所述的特定实施方案；还应该理解，本文中所使用的术语仅用于描述而非限制特定实施方案。The present invention is not limited to the specific embodiments described herein; it is understood that the terminology used herein is for the purpose of description and not limitation.
[术语定义][Definition of Terms]
除非另有说明，下列术语的含义如下。Unless otherwise stated, the following terms have the following meanings.
“药学上可接受的盐”是指对生物体基本上无毒性的具有式I结构的化合物的盐。药学上可接受的盐通常包括(但不限于)本发明的化合物与药学上可接受的无机/有机酸或无机/有机碱反应而形成的盐，此类盐又被称为酸加成盐或碱加成盐。常见的无机酸包括(但不限于)盐酸、氢溴酸、硫酸、磷酸等，常见的有机酸包括(但不限于)三氟乙酸、柠檬酸、马来酸、富马酸、琥珀酸、酒石酸、乳酸、丙酮酸、草酸、甲酸、乙酸、苯甲酸、甲磺酸、苯磺酸、对甲苯磺酸等，常见的无机碱包括(但不限于)氢氧化钠、氢氧化钾、氢氧化钙、氢氧化钡等，常见的有机碱包括(但不限于)二乙胺、三乙胺、乙胺丁醇等。"Pharmaceutically acceptable salt" refers to a salt of a compound of formula I having substantially no toxicity to an organism. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or an inorganic/organic base, such salts being referred to as acid addition salts or Base addition salt. Common inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc. Common organic acids include, but are not limited to, trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid. , lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., common inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide Commonly used organic bases include, but are not limited to, diethylamine, triethylamine, ethambutol and the like.
术语“水合物”是指由本发明的化合物或其药学上可接受的盐与水通过非共价分子间作用力结合而形成的物质。常见的水合物包括(但不限于)半水合物、一水合物、二水合物、三水合物等。The term "hydrate" means a substance formed by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with water by a non-covalent intermolecular force. Common hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, and the like.
术语“溶剂化物”是指由本发明的化合物或其药学上可接受的盐与至少一种溶剂分子通过非共价分子间作用力结合而形成的物质。术语“溶剂化物”包括“水合物”。常见的溶剂化物包括(但不限于)水合物、乙醇合物、丙酮合物等。The term "solvate" means a substance formed by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with at least one solvent molecule by a non-covalent intermolecular force. The term "solvate" includes "hydrates." Common solvates include, but are not limited to, hydrates, ethanolates, acetonates, and the like.
术语“异构体”是指具有相同原子数和原子类型因而具有相同分子量，但原子的空间排列或构型不同的化合物。The term "isomer" refers to a compound having the same number of atoms and atom type and thus having the same molecular weight, but differing in the spatial arrangement or configuration of the atoms.
术语“立体异构体”(或称“旋光异构体”)是指由于具有至少一个手性因素(包括手性中心、手性轴、手性面等)而导致具有垂直的不对称平面，从而能够使平面偏振光旋转的稳定异构体。由于本发明化合物中存在可能导致立体异构的不对称中心以及其他化学结构，因此本发明也包括这些立体异构体及其混合物。由于本发明的化合物及其盐包括不对称碳原子，因而能够以单一立体异构体形式、外消旋物、对映异构体和非对映异构体的混合物形式存在。通常，这些化合物能够以外消旋混合物的形式制备。然而，如果需要的话，可以将这类化合物制备或分离后得到纯的立体异构体，即单一对映异构体或非对映异构体，或者单一立体异构体富集化(纯度≥98％、≥95％、≥93％、≥90％、≥88％、≥85％或≥80％)的混合物。如下文中所述，化合物的单一立体异构体是由含有所需手性中心的旋光起始原料合成制备得到的，或者是通过制备得到对映异构体产物的混合物之后再分离或拆分制备得到的，例如转化为非对映异构体的混合物之后再进行分离或重结晶、色谱处理、使用手性拆分试剂，或者在手性 色谱柱上将对映异构体进行直接分离。具有特定立体化学的起始化合物既可以商购得到，也可以按照下文中描述的方法制备再通过本领域熟知的方法拆分得到。术语“对映异构体”是指彼此具有不能重叠的镜像的一对立体异构体。术语“非对映异构体”或“非对映体”是指彼此不构成镜像的旋光异构体。术语“外消旋混合物”或“外消旋物”是指含有等份的单一对映异构体的混合物(即两种R和S对映体的等摩尔量混合物)。术语“非外消旋混合物”是指含有不等份的单一对映异构体的混合物。除非另外指出，本发明的化合物的所有立体异构体形式都在本发明的范围之内。The term "stereoisomer" (also referred to as "an optical isomer") means having a vertical asymmetric plane due to at least one chiral factor, including a chiral center, a chiral axis, a chiral surface, and the like. Thereby a stable isomer capable of rotating plane polarized light. Because of the presence of asymmetric centers and other chemical structures in the compounds of the invention that may result in stereoisomers, the present invention also includes such stereoisomers and mixtures thereof. Since the compounds of the present invention and salts thereof include asymmetric carbon atoms, they can exist as a single stereoisomeric form, a racemate, an enantiomer, and a mixture of diastereomers. Generally, these compounds can be prepared in the form of a racemic mixture. However, if desired, such compounds can be prepared or isolated to give the pure stereoisomers, ie, single enantiomers or diastereomers, or single stereoisomers (purity ≥ A mixture of 98%, ≥95%, ≥93%, ≥90%, ≥88%, ≥85% or ≥80%). As described hereinafter, a single stereoisomer of a compound is prepared by synthesizing an optically active starting material having a desired chiral center, or by preparing a mixture of enantiomeric products, followed by separation or resolution. The resulting, for example, is converted to a mixture of diastereomers followed by separation or recrystallization, chromatography, using a chiral resolving reagent, or direct separation of the enantiomers on a chiral column. Starting compounds having specific stereochemistry are either commercially available or can be prepared by methods described below and resolved by methods well known in the art. The term "enantiomer" refers to a pair of stereoisomers that have a mirror image that does not overlap each other. The term "diastereomer" or "diastereomer" refers to an optical isomer that does not form a mirror image of each other. The term "racemic mixture" or "racemate" refers to a mixture of aliquots of a single enantiomer (ie, an equimolar amount of a mixture of two R and S enantiomers). The term "non-racemic mixture" refers to a mixture of unequal portions of a single enantiomer. All stereoisomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
术语“互变异构体”(或称“互变异构形式”)是指具有不同能量的可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(或称质子转移互变异构体)包括(但不限于)通过质子迁移来进行的互相转化，如酮-烯醇异构化、亚胺-烯胺异构化、酰胺-亚胺醇异构化等。除非另外指出，本发明的化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" (also referred to as "tautomeric form") refers to structural isomers having different energies that are mutually transformable by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton transfer, such as keto-enol isomerization, imine-enamine isomerization Isomerization of amide-imine alcohol, and the like. All tautomeric forms of the compounds of the invention are within the scope of the invention unless otherwise indicated.
术语“顺反异构体”是指位于双键或环系两侧的原子(或基团)因相对于参考平面的位置不同而形成的立体异构体；在顺式异构体中原子(或基团)位于双键或环系的同侧，在反式异构体中原子(或基团)位于双键或环系的异侧。除非另外指出，本发明的化合物的所有顺反异构体形式都在本发明的范围之内。The term "cis-trans isomer" refers to a stereoisomer formed by an atom (or group) located on either side of a double bond or ring system due to a position relative to a reference plane; an atom in the cis isomer ( Or a group) is located on the same side of the double bond or ring system in which the atom (or group) is located on the opposite side of the double bond or ring system. Unless otherwise indicated, all cis and trans isomer forms of the compounds of the invention are within the scope of the invention.
术语“同位素标记物”是指将结构中的特定原子替换为其同位素原子而形成的化合物。除非另外指出，本发明的化合物中包括H、C、N、O、F、P、S、Cl的各种同位素，如 2H(D)、 3H(T)、 13C、 14C、 15N、 17O、 18O、 18F、 31P、 32P、 35S、 36S和 37Cl。 The term "isotopic label" refers to a compound formed by replacing a particular atom in a structure with its isotope atom. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as 2 H(D), 3 H(T), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S and 37 Cl.
术语“前药”是指在适用于患者后能够直接或间接地提供本发明的化合物的衍生化合物。特别优选的衍生化合物或前药是在施用于患者时可以提高本发明的化合物的生物利用度的化合物(例如，更易吸收入血)，或者促进母体化合物向作用位点(例如，淋巴系统)递送的化合物。除非另外指出，本发明的化合物的所有前药形式都在本发明的范围之内，且各种前药形式是本领域熟知的。The term "prodrug" refers to a derivative compound that is capable of providing a compound of the invention, either directly or indirectly, after application to a patient. Particularly preferred derivatizing compounds or prodrugs are compounds which, when administered to a patient, increase the bioavailability of the compounds of the invention (e.g., are more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system) compound of. Unless otherwise indicated, all prodrug forms of the compounds of the invention are within the scope of the invention, and various prodrug forms are well known in the art.
术语“各自独立地”是指结构中存在的取值范围相同或相近的至少两个基团(或环系)可以在特定情形下具有相同或不同的含义。例如，取代基X和取代基Y各自独立地为氢、卤素、羟基、氰基、烷基或芳基，则当取代基X为氢时，取代基Y既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基；同理，当取代基Y为氢时，取代基X既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基。The term "independently" means that at least two groups (or ring systems) having the same or similar range of values present in the structure may have the same or different meanings in a particular situation. For example, when the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, when the substituent X is hydrogen, the substituent Y may be either hydrogen or halogen. Hydroxy, cyano, alkyl or aryl; Similarly, when the substituent Y is hydrogen, the substituent X may be either hydrogen, halogen, hydroxy, cyano, alkyl or aryl.
术语“任选取代的”是指基团(或环系)以未取代或采用至少一个取代基(或取代环系)取代的方式存在。当基团(或环系)被至少一个取代基(或取代环系)取代时，这些取代基(或取代环系)之间可以相同或不同。The term "optionally substituted" means that the group (or ring system) is present unsubstituted or substituted with at least one substituent (or substituted ring system). When a group (or ring system) is substituted with at least one substituent (or a substituted ring system), these substituents (or substituted ring systems) may be the same or different.
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)、碘(I)四种原子。The term "halogen" means four atoms of fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
术语“磺酰基”是指一价的基团，其由磺酸失去羟基后形成，并且通过一个与硫原子相连的单键连接至母核；常见的磺酰基包括(但不限于)甲基磺酰基(-SO 2CH 3)、三氟甲基磺酰基(-SO 2CF 3)、苯基磺酰基(-SO 2Ph)、氨基磺酰基(-SO 2NH 2)等。 The term "sulfonyl" refers to a monovalent group formed by the loss of a hydroxy group of a sulfonic acid and attached to the parent nucleus via a single bond to the sulfur atom; common sulfonyl groups include, but are not limited to, methyl sulfonate An acyl group (-SO 2 CH 3 ), a trifluoromethylsulfonyl group (-SO 2 CF 3 ), a phenylsulfonyl group (-SO 2 Ph), an aminosulfonyl group (-SO 2 NH 2 ), or the like.
术语“磺酰氨基”是指一价的基团，其由磺酰胺失去氨基上的氢原子后形成，并且通过一个与氮原子相连的单键连接至母核；常见的磺酰氨基包括(但不限于)甲基磺酰氨基(-NHSO 2CH 3)、三氟甲基磺酰氨基(-NHSO 2CF 3)、苯基磺酰氨基(-NHSO 2Ph)、氨基磺酰氨基(-NHSO 2NH 2)等。 The term "sulfonylamino" refers to a monovalent group formed by the loss of a hydrogen atom on the amino group by a sulfonamide and attached to the parent nucleus via a single bond to the nitrogen atom; common sulfonylamino groups include (but Not limited to) methylsulfonylamino (-NHSO 2 CH 3 ), trifluoromethylsulfonylamino (-NHSO 2 CF 3 ), phenylsulfonylamino (-NHSO 2 Ph), sulfamoylamino (-NHSO) 2 NH 2 ) and so on.
术语“次磷酰基”是指一价的基团，其由次磷酸失去羟基后形成，并且通过一个与磷原子相连的单键连接至母核；常见的次磷酰基包括(但不限于)二甲基次磷酰基(-P(O)(CH 3) 2)、二苯基次磷酰基(-P(O)Ph 2)、甲基苯基次磷酰基(-P(O)(Ph)(CH 3))、二烷氧基次磷酰基(-P(O)(OR) 2)等。 The term "phosphoroacyl" refers to a monovalent group formed by the loss of a hydroxyl group by hypophosphorous acid and attached to the parent nucleus via a single bond to the phosphorus atom; common hypophosphoryl groups include, but are not limited to, two Methylphosphoryl (-P(O)(CH 3 ) 2 ), diphenylphosphoryl (-P(O)Ph 2 ), methylphenylphosphoryl (-P(O)(Ph) (CH 3 )), dialkoxyphosphoryl (-P(O)(OR) 2 ), and the like.
术语“磷酰基”是指一价的基团，其由磷酸失去羟基后形成，并且通过一个与磷原子相连的单键连接至母核。The term "phosphoryl" refers to a monovalent group formed by the loss of a hydroxyl group by a phosphoric acid and attached to a parent core through a single bond to a phosphorus atom.
术语“烷基”是指一价的直链或支链的烷烃基团，其由碳原子和氢原子构成，不含有不饱和度，并且通过一个单键连接至母核，优选C 1-C 6烷基，更优选C 1-C 4烷基；常见的烷基包括(但不限于)甲基(-CH 3)、乙基(-CH 2CH 3)、正丙基(-CH 2CH 2CH 3)、异丙基(-CH(CH 3) 2)、正丁基(-CH 2CH 2CH 2CH 3)、仲丁基(-CH(CH 3)CH 2CH 3)、异丁基(-CH 2CH(CH 3) 2)、叔丁基(-C(CH 3) 3)、正戊基(-CH 2CH 2CH 2CH 2CH 3)、新戊基(-CH 2C(CH 3) 3)等。 The term "alkyl" refers to a monovalent straight or branched alkane group consisting of a carbon atom and a hydrogen atom, containing no unsaturation, and attached to the parent core through a single bond, preferably C 1 -C 6 alkyl, more preferably C 1 -C 4 alkyl; common alkyl groups include, but are not limited to, methyl (-CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), sec-butyl (-CH(CH 3 )CH 2 CH 3 ), Butyl (-CH 2 CH(CH 3 ) 2 ), tert-butyl (-C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 ), neopentyl (-CH) 2 C(CH 3 ) 3 ) and the like.
术语“烯基”是指一价的直链或支链的烯烃基团，其仅由碳原子和氢原子构成，含有至少一个双键，并且通过一个单键连接至母核，优选C 2-C 6烯基；常见的烯基包括(但不限于)乙烯基(-CH＝CH 2)、1-丙烯-1-基(-CH＝CH-CH 3)、1-丁烯-1-基(-CH＝CH-CH 2-CH 3)、1-戊烯-1-基(-CH＝CH-CH 2-CH 2-CH 3)、1，3-丁二烯-1-基(-CH＝CH-CH＝CH 2)、1，4-戊二烯-1-基(-CH＝CH-CH 2-CH＝CH 2)等。 The term "alkenyl" refers to a monovalent straight or branched olefinic group consisting solely of carbon atoms and hydrogen atoms, containing at least one double bond, and attached to the parent core through a single bond, preferably C 2 - C 6 alkenyl; common alkenyl groups include, but are not limited to, vinyl (-CH=CH 2 ), 1-propen-1-yl (-CH=CH-CH 3 ), 1-buten-1-yl (-CH=CH-CH 2 -CH 3 ), 1-penten-1-yl (-CH=CH-CH 2 -CH 2 -CH 3 ), 1,3-butadien-1-yl (- CH=CH-CH=CH 2 ), 1,4-pentadien-1-yl (-CH=CH-CH 2 -CH=CH 2 ), and the like.
术语“炔基”是指一价的直链或支链的炔烃基团，其仅由碳原子和氢原子构成，含有至少一个三键，并且通过一个单键连接至母核，优选C 2-C 6炔基；常见的炔基包括(但不限于)乙炔基(-C≡CH)、1-丙炔-1-基(即丙炔基)(-C≡C-CH 3)、1-丁炔-1-基(即丁炔基)
Figure PCTCN2019081709-appb-000008
戊炔-1-基
Figure PCTCN2019081709-appb-000009
1，3-丁二炔-1-基(-C≡C-C≡CH)、1，4-戊二炔-1-基
Figure PCTCN2019081709-appb-000010
等。 The term "alkynyl" refers to a monovalent straight or branched alkyne group consisting solely of carbon atoms and hydrogen atoms, containing at least one triple bond, and attached to the parent core through a single bond, preferably C 2 - C 6 alkynyl; common alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propyn-1-yl (ie propynyl) (-C≡C-CH 3 ), 1- Butyn-1-yl (ie butynyl)
Figure PCTCN2019081709-appb-000008
Pentyn-1-yl
Figure PCTCN2019081709-appb-000009
1,3-butadiyn-1-yl (-C≡CC≡CH), 1,4-pentadiyn-1-yl
Figure PCTCN2019081709-appb-000010
Wait.
术语“烷氧基”是指一价的直链或支链的基团，其仅由碳原子、氢原子和氧原子构成，可以含有不饱和度，并且通过一个与氧原子相连的单键连接至母核，优选C 1-C 4烷氧基；常见的烷氧基包括(但不限于)甲氧基(-OCH 3)、乙氧基(-OCH 2CH 3)、正丙氧基(-OCH 2CH 2CH 3)、异丙氧基(-OCH(CH 3) 2)、正丁氧基(-OCH 2CH 2CH 2CH 3)、仲丁氧基(-OCH(CH 3)CH 2CH 3)、异丁氧基(-OCH 2CH(CH 3) 2)、叔丁氧基(-OC(CH 3) 3)、正戊氧基(-OCH 2CH 2CH 2CH 2CH 3)、新戊氧基(-OCH 2C(CH 3) 3)等。 The term "alkoxy" refers to a monovalent straight or branched chain which consists solely of carbon atoms, hydrogen atoms and oxygen atoms and which may contain unsaturation and which are linked by a single bond to the oxygen atom. To the core, preferably a C 1 -C 4 alkoxy group; common alkoxy groups include, but are not limited to, methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy ( -OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ), n-butoxy (-OCH 2 CH 2 CH 2 CH 3 ), sec-butoxy (-OCH(CH 3 ) CH 2 CH 3 ), isobutoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy (-OC(CH 3 ) 3 ), n-pentyloxy (-OCH 2 CH 2 CH 2 CH 2 CH 3 ), neopentyloxy (-OCH 2 C(CH 3 ) 3 ), and the like.
术语“羰基”是指二价的基团，其仅由一个碳原子和一个氧原子构成，碳原子和氧原子之间通过双键连接，并且自身结构中的碳原子还分别通过单键连接至其他两个片段。The term "carbonyl" refers to a divalent group consisting of only one carbon atom and one oxygen atom, a carbon atom and an oxygen atom are bonded by a double bond, and the carbon atoms in the structure are also bonded to each other through a single bond. The other two fragments.
术语“烷酰基”是指一价的直链或支链的基团，其仅由碳原子、氢原子和氧原子构成，除自身结构中的羰基以外不含有不饱和度，并且通过一个与羰基相连的单键连接至母核，优选C 1-C 4烷酰基；常见的烷酰基包括(但不限于)甲酰基(-(O)CH)、乙酰基(-(O)CCH 3)、正丙酰基(-(O)CCH 2CH 3)、正丁酰基(-(O)CCH 2CH 2CH 3)、异丁酰基(-(O)CCH(CH 3) 2)、正戊酰基(-(O)CCH 2CH 2CH 2CH 3)、新戊酰基(-(O)CC(CH 3) 3)等。 The term "alkanoyl" refers to a monovalent straight or branched chain group consisting of only a carbon atom, a hydrogen atom and an oxygen atom, containing no unsaturation other than the carbonyl group in its structure, and passing through a carbonyl group. A linked single bond is attached to the parent core, preferably a C 1 -C 4 alkanoyl group; common alkanoyl groups include, but are not limited to, formyl (-(O)CH), acetyl (-(O)CCH 3 ), positive Propionyl (-(O)CCH 2 CH 3 ), n-butyryl (-(O)CCH 2 CH 2 CH 3 ), isobutyryl (-(O)CCH(CH 3 ) 2 ), n-pentanoyl (- (O) CCH 2 CH 2 CH 2 CH 3 ), pivaloyl (-(O)CC(CH 3 ) 3 ), and the like.
术语“环烷基”是指一价的单环或多环(包含桥环和螺环形式)的非芳香族环系，其仅由碳原子和氢原子构成，不含有不饱和度，并且通过一个单键连接至母核；常见的环烷基包括(但不限于)环丙基、环丁基、环戊基、环己基、十氢萘基(又称为十氢化萘基、萘烷基)、金刚烷基等。The term "cycloalkyl" refers to a monovalent monocyclic or polycyclic (including bridged and spiro form) non-aromatic ring system consisting of only carbon and hydrogen atoms, no unsaturation, and A single bond to the parent core; common cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthyl (also known as decalinyl, naphthyl) ), adamantyl and the like.
术语“杂环基”是指一价的单环或多环(包含桥环和螺环形式)的非芳香族环系，其由碳原子及选自氮、氧、硫和磷的杂原子构成，并且通过一个单键连接至母核；常见的杂环基包括(但不限于)环氧乙烷基、氧杂环丁烷-3-基、氮杂环丁烷-3-基、四氢呋喃-2-基、吡咯烷-1-基、吡咯烷-2-基、四氢-2H-吡喃-2-基、四氢-2H-吡喃-4-基、哌啶-2-基、哌啶-4-基等。The term "heterocyclyl" refers to a monovalent monocyclic or polycyclic (including bridged and spiro form) non-aromatic ring system consisting of a carbon atom and a hetero atom selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus. And is attached to the parent core by a single bond; common heterocyclic groups include, but are not limited to, oxiranyl, oxetane-3-yl, azetidin-3-yl, tetrahydrofuran- 2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, piperidin-2-yl, piperidine Acridine-4-yl and the like.
术语“芳基”是指一价的单环或多环(包含稠合形式)的芳香族环系，其仅有碳原子和氢原子构成，并且通过一个单键连接至母核；常见的芳基包括(但不限于)苯基、萘基、蒽基、菲基、苊基、薁基、芴基、茚基、芘基等。The term "aryl" refers to a monovalent monocyclic or polycyclic (including fused form) aromatic ring system which consists of only carbon and hydrogen atoms and is attached to the parent nucleus by a single bond; The group includes, but is not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, anthryl, fluorenyl, fluorenyl, fluorenyl, fluorenyl and the like.
术语“杂芳基”是指一价的单环或多环(包含稠合形式)的芳香族环系，其由碳原子及选自氮、氧、硫和磷的杂原子构成，并且通过一个单键连接至母核；常见的杂环基包括(但不限于)苯并吡咯基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、苯并噻唑基、吖啶基、咔唑基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、吡唑基、异噁唑基、异噻唑基、吲唑基、吲嗪基、吲哚基、喹啉基、异喹啉基、吩嗪基、吩噁嗪基、吩噻嗪基、蝶啶基、嘌呤基、吡嗪基、嘧啶基、哒嗪基、吡啶基、三唑基、四唑基等。The term "heteroaryl" refers to a monovalent monocyclic or polycyclic (including fused form) aromatic ring system consisting of a carbon atom and a hetero atom selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus, and Single bond to the parent core; common heterocyclic groups include, but are not limited to, benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, anthracene Pyridyl, carbazolyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyridazinyl, fluorenyl , quinolyl, isoquinolyl, phenazinyl, phenoxazinyl, phenothiazine, pteridinyl, fluorenyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, triazolyl, tetra Azolyl and the like.
[通式化合物][complex compound]
本发明提供了一种式I化合物：The present invention provides a compound of formula I:
Figure PCTCN2019081709-appb-000011
Figure PCTCN2019081709-appb-000011
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素 标记物或前药，其中：Or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, wherein:
R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子； R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and R 2 are respectively located in the benzene ring When on one adjacent carbon atom, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 independently of each other. a hetero atom of O, N or S;
A为NR 6、N-OH、S或O； A is NR 6 , N-OH, S or O;
R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
R 5a和R 5b各自独立地为氢、卤素、羟基或任选取代的C 1-C 6烷基；当R 5a和R 5b同时为羟基时，二者脱水形成羰基； R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkane And each m is independently 0, 1, 2 or 3.
在本发明的一些实施方案中，上述式I化合物中的R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3，其中：卤素为氟、氯或溴；磺酰基为氨基磺酰基、甲基磺酰基或三氟甲基磺酰基；任选取代的C 1-C 4烷基为甲基、乙基、正丙基、烯丙基(-CH 2-CH＝CH 2)(即乙烯基取代的甲基)、炔丙基
Figure PCTCN2019081709-appb-000012
(即乙炔基取代的甲基)、羟甲基(-CH 2-OH)、氰甲基(-CH 2-CN)、氟甲基(-CH 2F)、二氟甲基(-CHF 2)或三氟甲基(-CF 3)；任选取代的C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基；任选取代的3至6元杂环基为环氧乙烷基、氧杂环丁烷-3-基、氮杂环丁烷-3-基、四氢呋喃-2-基、吡咯烷-1-基、吡咯烷-2-基、四氢-2H-吡喃-2-基、四氢-2H-吡喃-4-基、哌啶-2-基或哌啶-4-基；任选取代的C 1-C 4烷氧基为甲氧基、氟甲氧基(-OCH 2F)、二氟甲氧基(-OCHF 2)、三氟甲氧基(-OCF 3)、乙氧基、2-羟基乙氧基(-OCH 2CH 2OH)、2-氨基乙氧基(-OCH 2CH 2NH 2)、异丙氧基或叔丁氧基；任选取代的C 1-C 4烷酰基为甲酰基、氨基甲酰基(-C(O)NH 2)、甲氧基甲酰基(-C(O)OCH 3)或苯甲酰基(-C(O)Ph)；任选取代的C 2-C 4炔基为乙炔基、1-丙炔-1-基或1-丁炔-1-基。 In some embodiments of the invention, R 1 and R 2 in the above compounds of formula I are each independently hydrogen, halo, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl An optionally substituted C 3 -C 6 cycloalkyl group, an optionally substituted 3 to 6 membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group Or optionally substituted C 2 -C 4 alkynyl, hydrogen in R 1 , R 2 and/or hydrogen on the phenyl ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 Or 3, wherein: halogen is fluorine, chlorine or bromine; sulfonyl group is aminosulfonyl group, methylsulfonyl group or trifluoromethylsulfonyl group; optionally substituted C 1 -C 4 alkyl group is methyl group, ethyl group, N-propyl, allyl (-CH 2 -CH=CH 2 ) (ie vinyl-substituted methyl), propargyl
Figure PCTCN2019081709-appb-000012
(ie ethynyl substituted methyl), hydroxymethyl (-CH 2 -OH), cyanomethyl (-CH 2 -CN), fluoromethyl (-CH 2 F), difluoromethyl (-CHF 2 Or a trifluoromethyl group (-CF 3 ); an optionally substituted C 3 -C 6 cycloalkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group; an optionally substituted 3 to 6 membered heterocyclic ring The base is oxiranyl, oxetan-3-yl, azetidin-3-yl, tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, tetrahydrogen -2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, piperidin-2-yl or piperidin-4-yl; optionally substituted C 1 -C 4 alkoxy group Oxyl, fluoromethoxy (-OCH 2 F), difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), ethoxy, 2-hydroxyethoxy (-OCH 2 CH 2 OH), 2-aminoethoxy (-OCH 2 CH 2 NH 2 ), isopropoxy or t-butoxy; optionally substituted C 1 -C 4 alkanoyl is formyl or carbamoyl ( -C(O)NH 2 ), methoxycarbonyl (-C(O)OCH 3 ) or benzoyl (-C(O)Ph); optionally substituted C 2 -C 4 alkynyl is ethynyl , 1-propyn-1-yl or 1-butyn-1-yl.
在本发明的一些实施方案中，当上述式I化合物中的R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2相互连接成饱和的5元环、不饱和的5元环、饱和的6元环或不饱和6元环，这些环中包含0、1或2个杂原子，这些杂原子包括O、N和S，其中：饱和的5元环为环戊烷、吡咯烷(即四氢吡咯)、呋喃烷(即四氢呋喃)、噻吩烷(即四氢噻吩)、咪唑烷(即四氢咪唑)、吡唑烷(即四氢吡唑)、噁唑烷(即四氢噁唑)、异噁唑烷(即四氢异噁唑)、噻唑烷(即四氢噻唑)、异噻唑烷(即四氢异噻唑)、1，3-二氧杂环戊烷或1，3-二硫杂环戊烷；不饱和的5元环为环戊烯、2，3-二氢-1H-吡咯、2，3-二氢呋喃、2，3-二氢噻吩、1，3-二氧杂环戊烯或1，3-二硫杂环戊烯；饱和的6元环为环己烷、哌啶、哌嗪、四氢吡喃、1，3-二噁烷(即1，3-二氧六环)、1，4-二噁烷(即1，4-二氧六环)、四氢硫代吡喃、1，3-二噻烷(即1，3-二硫六环)或1，4-二噻烷(即1，4-二硫六环)；不饱和的6元环为环己烯、1，3-环己二烯、1，2，3，4-四氢吡啶、1，2，3，6-四氢吡啶、3，4-二氢-2H-吡喃或3，4-二氢-2H-硫代吡喃。 In some embodiments of the invention, when R 1 and R 2 in the above compound of formula I are each on two adjacent carbon atoms of the phenyl ring, R 1 and R 2 are bonded to each other to form a saturated 5-membered ring, a saturated 5-membered ring, a saturated 6-membered ring or an unsaturated 6-membered ring containing 0, 1 or 2 heteroatoms including O, N and S, wherein: a saturated 5-membered ring is a ring Pentane, pyrrolidine (ie tetrahydropyrrole), furan (ie tetrahydrofuran), thiophene (ie tetrahydrothiophene), imidazolidine (ie tetrahydroimidazole), pyrazolidine (ie tetrahydropyrazole), oxazole Alkane (ie tetrahydrooxazole), isooxazolidine (ie tetrahydroisoxazole), thiazolidine (ie tetrahydrothiazole), isothiazolidine (ie tetrahydroisothiazole), 1,3-dioxe Pentane or 1,3-dithiolane; unsaturated 5-membered ring is cyclopentene, 2,3-dihydro-1H-pyrrole, 2,3-dihydrofuran, 2,3-dihydrogen Thiophene, 1,3-dioxolene or 1,3-dithietene; saturated 6-membered ring is cyclohexane, piperidine, piperazine, tetrahydropyran, 1,3-two Oxane (ie, 1,3-dioxane), 1,4-dioxane (ie, 1,4-dioxane), tetrahydrothiopyran, 1,3- Dithiane (ie, 1,3-dithiocyclo) or 1,4-dithiane (ie, 1,4-dithiocyclo); unsaturated 6-membered ring is cyclohexene, 1,3-ring Hexadiene, 1,2,3,4-tetrahydropyridine, 1,2,3,6-tetrahydropyridine, 3,4-dihydro-2H-pyran or 3,4-dihydro-2H-sulfur Depyran.
在本发明的一些实施方案中，上述式I化合物中的A为NR 6、N-OH、S或O；R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代，其中：任选取代的C 1-C 6烷基为甲基、乙基、羟甲基、氰甲基、氟甲基、二氟甲基、三氟甲基、环丙基甲基、环戊基甲基、环己基甲基、苄基、α- 萘基甲基或β-萘基甲基；任选取代的C 1-C 6烷氧基为甲氧基、乙氧基、异丙氧基、叔丁氧基、氟甲氧基、二氟甲氧基或三氟甲氧基；任选取代的C 2-C 6烯基为乙烯基、丙烯基、2-氰基乙烯基(-CH＝CH-CN)、2-氟乙烯基(-CH＝CHF)、2，2-二氟乙烯基(-CH＝CF 2)或1，2，2-三氟乙烯基(-CF＝CF 2)；任选取代的C 2-C 6炔基为乙炔基、1-丙炔-1-基或1-丁炔-1-基；任选取代的C 3-C 6环烷基为环丙基、环丁基、环戊基或环己基。 In some embodiments of the invention, A in the above formula I is NR 6 , N-OH, S or O; R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl , optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl And the hydrogen in R 3 , R 6 is optionally substituted by deuterium, wherein: the optionally substituted C 1 -C 6 alkyl group is methyl, ethyl, hydroxymethyl, cyanomethyl, fluoromethyl, difluoro Methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, a-naphthylmethyl or β-naphthylmethyl; optionally substituted C 1 -C 6 alkoxy is methoxy, ethoxy, isopropoxy, tert-butoxy, fluoromethoxy, difluoromethoxy or trifluoromethoxy; optionally substituted C 2 -C 6 olefin The base is vinyl, propenyl, 2-cyanovinyl (-CH=CH-CN), 2-fluorovinyl (-CH=CHF), 2,2-difluorovinyl (-CH=CF 2 ) Or 1,2,2-trifluorovinyl (-CF=CF 2 ); optionally substituted C 2 -C 6 alkynyl is ethynyl, 1-propyn-1-yl or 1-butyn-1- Base; optionally substituted C 3 -C 6 naphthenic The group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
在本发明的一些实施方案中，上述式I化合物中的R 3a和R 5b各自独立地为氢、卤素、羟基或任选取代的C 1-C 6烷基；当R 5a和R 5b同时为羟基时，二者脱水形成羰基，其中：任选取代的C 1-C 6烷基为甲基、乙基、羟甲基、氰甲基、氟甲基、二氟甲基或三氟甲基。 In some embodiments of the invention, R 3a and R 5b in the above compounds of formula I are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when R 5a and R 5b are simultaneously In the case of a hydroxyl group, the two are dehydrated to form a carbonyl group, wherein the optionally substituted C 1 -C 6 alkyl group is a methyl group, an ethyl group, a methylol group, a cyanomethyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group. .
在本发明的一些实施方案中，上述式I化合物中的E为任选被至少一个R 7取代的下列片段之一： In some embodiments of the invention, E in the above formula I compound is one of the following fragments optionally substituted with at least one R 7 :
Figure PCTCN2019081709-appb-000013
Figure PCTCN2019081709-appb-000013
每一个R 7各自独立地为卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基，其中：对于R 7而言，任选取代的C 1-C 6烷基为甲基、乙基、羟甲基、氰甲基、氟甲基、二氟甲基、三氟甲基、环丙基甲基、环戊基甲基、环己基甲基、苄基、α-萘基甲基或β-萘基甲基；任选取代的C 2-C 6烯基为乙烯基、丙烯基、2-氰基乙烯基、2-氟乙烯基、2，2-二氟乙烯基或1，2，2-三氟乙烯基；任选取代的C 2-C 6炔基为乙炔基、1-丙炔-1-基或1-丁炔-1-基；对于R 4而言，卤素为氟、氯或溴，任选取代的C 1-C 6烷基为甲基、乙基、羟甲基、氰甲基、氟甲基、二氟甲基或三氟甲基；且m为0、1、2或3。 Each R 7 is each independently halogen, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl , -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 Independently hydrogen, halogen or optionally substituted C 1 -C 6 alkyl, wherein: for R 7 , the optionally substituted C 1 -C 6 alkyl is methyl, ethyl, hydroxymethyl, cyanide Methyl, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, alpha-naphthylmethyl or beta-naphthylmethyl The optionally substituted C 2 -C 6 alkenyl group is vinyl, propenyl, 2-cyanovinyl, 2-fluorovinyl, 2,2-difluorovinyl or 1,2,2-trifluoroethylene The optionally substituted C 2 -C 6 alkynyl group is ethynyl, 1-propyn-1-yl or 1-butyn-1-yl; for R 4 , halogen is fluorine, chlorine or bromine, optionally substituted C 1 -C 6 alkyl is methyl, ethyl, hydroxymethyl, cyanomethyl, fluoromethyl, bis Methyl or trifluoromethyl; and m is 2 or 3.
在本发明的一些实施方案中，上述式I化合物中的R 1、R 2至少有一个为任选取代的C 2-C 4炔基、-SF 5、-NHSO 2NH 2、-P(O)(CH 3) 2或二烷氧基次磷酰基；A为NR 6、N-OH、S或O；R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代；R 5a和R 5b各自独立地为氢、卤素、羟基或任选取代的C 1-C 6烷基；当R 5a和R 5b同时为羟基时，二者脱水形成羰基；E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 In some embodiments of the invention, at least one of R 1 and R 2 in the compound of formula I above is optionally substituted C 2 -C 4 alkynyl, -SF 5 , -NHSO 2 NH 2 , -P(O (CH 3 ) 2 or dialkoxyphosphoryl; A is NR 6 , N-OH, S or O; R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl , optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl And the hydrogen in R 3 , R 6 is optionally substituted by deuterium; R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when R 5a and R 5b are simultaneously When it is a hydroxy group, the two are dehydrated to form a carbonyl group; E is a 5- to 12-membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen Halogen, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N( R 4) 2, -NH- (CR 4 R 4) m -CO 2 H -NH- (CR 4 R 4) m -C (O) NH 2; each R 4 is independently hydrogen, halo or optionally substituted C 1 -C 6 alkyl; and each m is independently 0, 1, 2 or 3.
在本发明的一些实施方案中，上述式I化合物中的A为NR 6时；R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子；R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代；R 5a和R 5b各自独立地为氢、卤素、羟基或任选取代的C 1-C 6烷基；当R 5a和R 5b同时为羟基时，二者脱水形成羰基；E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、 -(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 In some embodiments of the invention, when A in the above formula I is NR 6 ; R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1- C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3 to 6 membered heterocyclic, optionally substituted C 1 -C 4 alkoxy, optionally substituted C a 1- C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, a hydrogen in R 1 , R 2 and/or a hydrogen on the phenyl ring linking R 1 , R 2 may be optionally substituted by deuterium, and n Is 0, 1, 2 or 3; when R 1 and R 2 are respectively located on two adjacent carbon atoms of the benzene ring, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5- or 6-membered a ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 heteroatoms each independently of O, N or S; R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 Alkyl group, and R 3, R 6 is hydrogen, optionally substituted with deuterium; R 5a and R 5b are each independently hydrogen, halogen, hydroxy, or optionally substituted C 1 -C 6 alkyl group; and when R 5a and R When 5b is a hydroxy group, both are dehydrated to form a carbonyl group; E is a 5- to 12-membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently Is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m - N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, Halogen or optionally substituted C 1 -C 6 alkyl; and each m is independently 0, 1, 2 or 3.
在本发明的一些实施方案中，上述式I化合物中的A为N-OH，且R 5a和R 5b不同时为氢时；R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子；R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代；E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 In some embodiments of the invention, A in the above formula I is N-OH, and R 5a and R 5b are not simultaneously hydrogen; R 1 and R 2 are each independently hydrogen, halogen, cyano, - (CH 2 ) n SF 5 , —(CH 2 ) n NHSO 2 NH 2 , —(CH 2 ) n P(O)(CH 3 ) 2 , a sulfonyl group, a sulfonylamino group, an optionally substituted hypophosphoryl group, Optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3 to 6 membered heterocyclyl, optionally substituted C 1 -C 4 alkoxy, optionally substituted C 1 -C 4 alkanoyl or optionally substituted C 2 -C 4 alkynyl, hydrogen in R 1 , R 2 and/or benzene linking R 1 , R 2 The hydrogen on the ring is optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and R 2 are respectively on two adjacent carbon atoms of the phenyl ring, R 1 and R 2 are optionally linked to each other. a saturated or unsaturated 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 heteroatoms each independently of O, N or S; R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 Group, optionally substituted C 3 -C 6 cycloalkyl, and R 3, R 6 is optionally substituted by deuterium hydrogen; E is optionally substituted with at least one R 7 5 to 12-membered aryl, heteroaryl, Aryl, cycloalkyl or heterocyclic; each R 7 is independently hydrogen, halo, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 ene , optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkyl; and each m is independently 0, 1, 2 or 3.
在本发明的一些实施方案中，上述式I化合物中的R 5a和R 5b形成羰基时；R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子；A任意选自NR 6、N-OH、S或O；R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代；E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 In some embodiments of the invention, when R 5a and R 5b in the above formula I formula form a carbonyl group; R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , (CH 2 ) n NHSO 2 NH 2 , —(CH 2 ) n P(O)(CH 3 ) 2 , a sulfonyl group, a sulfonylamino group, an optionally substituted hypophosphoryl group, an optionally substituted phosphoryl group, optionally Substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3 to 6 membered heterocyclyl, optionally substituted C 1 -C 4 alkoxy, optionally Substituted C 1 -C 4 alkanoyl or optionally substituted C 2 -C 4 alkynyl, hydrogen in R 1 , R 2 and/or hydrogen on the phenyl ring linking R 1 , R 2 may be optionally substituted by deuterium And n is 0, 1, 2 or 3; when R 1 and R 2 are respectively located on two adjacent carbon atoms of the benzene ring, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5 element Or a 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 heteroatoms each independently of O, N or S; A is optionally selected from NR 6 , N-OH, S or O; 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally Substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium; E is 5 optionally substituted by at least one R 7 Up to 12-membered aryl, heteroaryl, cycloalkyl or heterocyclic; each R 7 is independently hydrogen, halo, hydroxy, cyano, optionally substituted C 1 -C 6 alkyl, optionally Substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH -(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkyl; and each m is independently 0, 1, 2 or 3.
在本发明的一些实施方案中，上述式I化合物中的E为下列片段之一：In some embodiments of the invention, E in the above formula I compound is one of the following:
Figure PCTCN2019081709-appb-000014
Figure PCTCN2019081709-appb-000014
在本发明的一些优选的实施方案中，上述式I化合物为式Ia化合物：In some preferred embodiments of the invention, the above compound of formula I is a compound of formula Ia:
Figure PCTCN2019081709-appb-000015
Figure PCTCN2019081709-appb-000015
其中：R 1和R 2中的至少一个为五氟化硫基、磺酰氨基(优选氨基磺酰氨基)、任选取代的次磷 酰基(优选二甲基次磷酰基、二烷氧基次磷酰基)、任选取代的C 2-C 4炔基(优选乙炔基)或任选取代的C 1-C 4烷基(优选炔丙基)，片段E以及取代基R 3、R 5a和R 5b如上所定义。 Wherein: at least one of R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group). Phosphoryl), optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
在本发明的一些更优选的实施方案中，上述式I化合物为式Ia-1化合物或式Ia-2化合物：In some more preferred embodiments of the invention, the compound of formula I above is a compound of formula Ia-1 or a compound of formula Ia-2:
Figure PCTCN2019081709-appb-000016
Figure PCTCN2019081709-appb-000016
其中：R 1和R 2中的至少一个为五氟化硫基、磺酰氨基(优选氨基磺酰氨基)、任选取代的次磷酰基(优选二甲基次磷酰基、二烷氧基次磷酰基)、任选取代的C 2-C 4炔基(优选乙炔基)或任选取代的C 1-C 4烷基(优选炔丙基)，片段E以及取代基R 3、R 5a和R 5b如上所定义。 Wherein: at least one of R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group). Phosphoryl), optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
在本发明的一些优选的实施方案中，上述式I化合物为式Ib化合物：In some preferred embodiments of the invention, the above compound of formula I is a compound of formula Ib:
Figure PCTCN2019081709-appb-000017
Figure PCTCN2019081709-appb-000017
其中：R 1和R 2中的至少一个为五氟化硫基、磺酰氨基(优选氨基磺酰氨基)、任选取代的次磷酰基(优选二甲基次磷酰基、二烷氧基次磷酰基)、任选取代的C 2-C 4炔基(优选乙炔基)或任选取代的C 1-C 4烷基(优选炔丙基)，片段E以及取代基R 3、R 5a和R 5b如上所定义。 Wherein: at least one of R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group). Phosphoryl), optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
在本发明的一些更优选的实施方案中，上述式I化合物为式Ib-1化合物或式Ib-2化合物：In some more preferred embodiments of the invention, the compound of formula I above is a compound of formula Ib-1 or a compound of formula Ib-2:
Figure PCTCN2019081709-appb-000018
Figure PCTCN2019081709-appb-000018
其中：R 1和R 2中的至少一个为五氟化硫基、磺酰氨基(优选氨基磺酰氨基)、任选取代的次磷酰基(优选二甲基次磷酰基、二烷氧基次磷酰基)、任选取代的C 2-C 4炔基(优选乙炔基)或任选取代的C 1-C 4烷基(优选炔丙基)，片段E以及取代基R 3、R 5a和R 5b如上所定义。 Wherein: at least one of R 1 and R 2 is a sulfur pentafluoride group, a sulfonylamino group (preferably a sulfamoylamino group), an optionally substituted hypophosphoryl group (preferably a dimethyl hypophosphoryl group, a dialkoxy group). Phosphoryl), optionally substituted C 2 -C 4 alkynyl (preferably ethynyl) or optionally substituted C 1 -C 4 alkyl (preferably propargyl), fragment E and substituents R 3 , R 5a and R 5b is as defined above.
在本发明的一些优选的实施方案中，上述式I化合物为式Ic化合物：In some preferred embodiments of the invention, the above compound of formula I is a compound of formula Ic:
Figure PCTCN2019081709-appb-000019
Figure PCTCN2019081709-appb-000019
其中：片段E以及取代基R 1、R 2、R 3、R 5a、R 5b和R 6如上所定义。 Wherein: the fragment E and the substituents R 1 , R 2 , R 3 , R 5a , R 5b and R 6 are as defined above.
在本发明的一些更优选的实施方案中，上述式I化合物为式Ic-1化合物或式Ic-2化合物：In some more preferred embodiments of the invention, the compound of formula I above is a compound of formula Ic-1 or a compound of formula Ic-2:
Figure PCTCN2019081709-appb-000020
Figure PCTCN2019081709-appb-000020
其中：片段E以及取代基R 1、R 2、R 3、R 5a、R 5b和R 6如上所定义。 Wherein: the fragment E and the substituents R 1 , R 2 , R 3 , R 5a , R 5b and R 6 are as defined above.
在本发明的一些优选的实施方案中，上述式I化合物为式Id化合物：In some preferred embodiments of the invention, the above compound of formula I is a compound of formula Id:
Figure PCTCN2019081709-appb-000021
Figure PCTCN2019081709-appb-000021
其中：R 5a和R 5b中的至少一个不为氢，且片段E以及取代基R 1、R 2、R 3、R 5a和R 5b如上所定义。 Wherein: at least one of R 5a and R 5b is not hydrogen, and the fragment E and the substituents R 1 , R 2 , R 3 , R 5a and R 5b are as defined above.
在本发明的一些更优选的实施方案中，上述式I化合物为式Id-1化合物或式Id-2化合物：In some more preferred embodiments of the invention, the compound of formula I above is a compound of formula Id-1 or a compound of formula Id-2:
Figure PCTCN2019081709-appb-000022
Figure PCTCN2019081709-appb-000022
其中：R 5a和R 5b中的至少一个不为氢，且片段E以及取代基R 1、R 2、R 3、R 5a和R 5b如上所定义。 Wherein: at least one of R 5a and R 5b is not hydrogen, and the fragment E and the substituents R 1 , R 2 , R 3 , R 5a and R 5b are as defined above.
另外，本发明还提供了上述式I化合物，其具体结构及名称如下表所示：In addition, the present invention also provides the above compound of formula I, the specific structure and name of which are shown in the following table:
Figure PCTCN2019081709-appb-000023
Figure PCTCN2019081709-appb-000023
Figure PCTCN2019081709-appb-000024
Figure PCTCN2019081709-appb-000024
Figure PCTCN2019081709-appb-000025
Figure PCTCN2019081709-appb-000025
Figure PCTCN2019081709-appb-000026
Figure PCTCN2019081709-appb-000026
Figure PCTCN2019081709-appb-000027
Figure PCTCN2019081709-appb-000027
Figure PCTCN2019081709-appb-000028
Figure PCTCN2019081709-appb-000028
Figure PCTCN2019081709-appb-000029
Figure PCTCN2019081709-appb-000029
Figure PCTCN2019081709-appb-000030
Figure PCTCN2019081709-appb-000030
Figure PCTCN2019081709-appb-000031
Figure PCTCN2019081709-appb-000031
Figure PCTCN2019081709-appb-000032
Figure PCTCN2019081709-appb-000032
[制备方法][Preparation]
本发明提供了上述式I化合物的制备方法，其包括下列步骤：The present invention provides a process for the preparation of a compound of formula I above, which comprises the steps of:
1)将化合物VI与磺酰化试剂反应，得到化合物V；1) reacting compound VI with a sulfonylating reagent to obtain compound V;
Figure PCTCN2019081709-appb-000033
Figure PCTCN2019081709-appb-000033
2)向化合物V中引入片段E，得到化合物IV；2) introducing a fragment E into the compound V to obtain a compound IV;
Figure PCTCN2019081709-appb-000034
Figure PCTCN2019081709-appb-000034
3)将化合物IV氢化，得到化合物III；3) hydrogenation of compound IV to give compound III;
Figure PCTCN2019081709-appb-000035
Figure PCTCN2019081709-appb-000035
4)将化合物III与苯胺类化合物反应，得到化合物II；4) reacting compound III with an aniline compound to obtain compound II;
Figure PCTCN2019081709-appb-000036
Figure PCTCN2019081709-appb-000036
5)向化合物II中引入片段A，得到具有式I结构的化合物；5) introducing a fragment A into the compound II to obtain a compound having the structure of the formula I;
Figure PCTCN2019081709-appb-000037
Figure PCTCN2019081709-appb-000037
其中：片段A和E以及取代基R 1、R 2、R 3、R 5a和R 5b的定义如上所述。 Wherein: the definitions of the fragments A and E and the substituents R 1 , R 2 , R 3 , R 5a and R 5b are as described above.
在本发明的一些实施方案中，上述制备方法的步骤1)中所使用的酰化试剂包括(但不限于)冰醋酸、醋酐(或称乙酸酐)、乙酰氯、苯甲酸酐、苯甲酰氯等，磺酰化试剂包括(但不限于)甲酸酸酐、甲磺酰氯、三氟甲磺酸酐、三氟甲磺酰氯、苯磺酸酐、苯磺酰氯、对甲苯磺酸酐、对甲苯磺酰氯等。In some embodiments of the present invention, the acylating reagent used in the step 1) of the above preparation method includes, but is not limited to, glacial acetic acid, acetic anhydride (or acetic anhydride), acetyl chloride, benzoic anhydride, and benzoic acid. The sulfonylating reagents include, but are not limited to, formic acid anhydride, methanesulfonyl chloride, trifluoromethanesulfonic anhydride, trifluoromethanesulfonyl chloride, benzenesulfonic anhydride, benzenesulfonyl chloride, p-toluenesulfonic anhydride, p-toluenesulfonyl chloride, and the like. .
在本发明的一些实施方案中，上述制备方法的步骤2)中片段E的引入通过偶联反应来实现。常见的偶联反应包括(但不限于)铃木反应(Suzuki Reaction)、赫克反应(Heck Reaction)、斯蒂尔反应(Stille Reaction)、菌头偶联反应(Sogonoshira Coupling)、熊田偶联反应(Kumada Coupling)反应、根岸偶联反应(Negishi Coupling)、桧山偶联反应(Hiyama Coupling)等。可以理解的是，本领域技术人员己熟知上述偶联反应的实验条件。In some embodiments of the invention, the introduction of Fragment E in step 2) of the above preparation process is achieved by a coupling reaction. Common coupling reactions include, but are not limited to, Suzuki Reaction, Heck Reaction, Stille Reaction, Sogonoshira Coupling, and Xiongtian Coupling Reaction ( Kumada Coupling reaction, Negishi Coupling, Hiyama Coupling, and the like. It will be appreciated that those skilled in the art are familiar with the experimental conditions of the above coupling reactions.
在本发明的一些实施方案中，上述制备方法的步骤3)中的氢化通过催化氢化、金属氢化物氢化或硼氢化的方式来实现。催化氢化反应中常见的催化剂包括(但不限于)镍催化剂(例如兰尼镍)、钯催化剂(例如钯碳)、铂催化剂(例如铂碳)；金属氢化物氢化反应中常见的试剂包括(但不限于)氢化锂(LiH)、氢化钠(NaH)、四氢铝锂(LiAlH 4)等；硼氢化反应中常见的试剂包括(但不限于)乙硼烷(B 2H 4)、硼氢化钠(NaBH 4)等。 In some embodiments of the invention, the hydrogenation in step 3) of the above preparation process is achieved by catalytic hydrogenation, metal hydride hydrogenation or hydroboration. Catalysts commonly used in catalytic hydrogenation reactions include, but are not limited to, nickel catalysts (eg, Raney nickel), palladium catalysts (eg, palladium on carbon), platinum catalysts (eg, platinum carbon); reagents commonly found in metal hydride hydrogenation reactions include (but Not limited to) lithium hydride (LiH), sodium hydride (NaH), lithium aluminum hydride (LiAlH 4 ), etc.; common reagents in the hydroboration reaction include, but are not limited to, diborane (B 2 H 4 ), hydroboration Sodium (NaBH 4 ) and the like.
当上述式I化合物具有特定构型时，本发明还提供了相应的制备方法，其包括下列步骤：When the above compound of formula I has a specific configuration, the present invention also provides a corresponding preparation method comprising the following steps:
1)将化合物VI与磺酰化试剂反应，得到化合物V；1) reacting compound VI with a sulfonylating reagent to obtain compound V;
Figure PCTCN2019081709-appb-000038
Figure PCTCN2019081709-appb-000038
2)向化合物V中引入片段E，得到化合物IV；2) introducing a fragment E into the compound V to obtain a compound IV;
Figure PCTCN2019081709-appb-000039
Figure PCTCN2019081709-appb-000039
3)将化合物IV氢化，得到化合物III；3) hydrogenation of compound IV to give compound III;
Figure PCTCN2019081709-appb-000040
Figure PCTCN2019081709-appb-000040
4)将化合物III进行手性拆分，得到化合物III-1和III-2；4) chiral resolution of compound III to give compounds III-1 and III-2;
Figure PCTCN2019081709-appb-000041
Figure PCTCN2019081709-appb-000041
5)将化合物III-1和III-2分别与苯胺类化合物反应，得到化合物II-1和II-2；5) reacting compounds III-1 and III-2 with an aniline compound, respectively, to obtain compounds II-1 and II-2;
Figure PCTCN2019081709-appb-000042
Figure PCTCN2019081709-appb-000042
6)分别向化合物II-1和II-2中引入片段A，得到化合物I-1和化合物I-2；6) introducing the fragment A into the compound II-1 and II-2, respectively, to obtain the compound I-1 and the compound I-2;
Figure PCTCN2019081709-appb-000043
Figure PCTCN2019081709-appb-000043
其中：片段A和E以及取代基R 1、R 2、R 3、R 5a和R 5b的定义如上所述。 Wherein: the definitions of the fragments A and E and the substituents R 1 , R 2 , R 3 , R 5a and R 5b are as described above.
另外，当上述式I化合物中与取代基R 5a和R 5b连接的碳原子为手性碳原子时，上述制备方法还包括下列步骤： Further, when the carbon atom bonded to the substituents R 5a and R 5b in the above compound of the formula I is a chiral carbon atom, the above preparation method further comprises the following steps:
分别向在步骤4)中得到的化合物III-1和III-2中引入手性片段R chiral，得到化合物III’-1和III’-2；化合物III’-1经手性拆分，得到化合物III’-1-a和III’-1-b，化合物III’-2经手性拆分，得到化合物III’-2-a和III’-2-b；再分别脱除手性片段R chiral，得到用于在步骤5)中与苯胺类化合物反应的化合物III”-1-a和III”-1-b以及III”-2-a和III”-2-b； The chiral fragment R chiral is introduced into the compounds III-1 and III-2 obtained in the step 4), respectively, to obtain the compounds III'-1 and III'-2; the compound III'-1 is chirally resolved to obtain the compound III. '-1-a and III'-1-b, compound III'-2 was chiralized to give compounds III'-2-a and III'-2-b; and then the chiral fragment R chiral was removed separately. Compounds III"-1-a and III"-1-b and III"-2-a and III"-2-b for reacting with aniline compounds in step 5);
Figure PCTCN2019081709-appb-000044
Figure PCTCN2019081709-appb-000044
其中：手性片段R chiral由手性助剂提供，手性助剂为4位取代的噁唑烷酮类化合物，包括(但不限于)(S)-4-苯基-2-噁唑烷酮、(R)-4-苯基-2-噁唑烷酮、(S)-4-苄基-2-噁唑烷酮、(R)-4-苄基-2-噁唑烷酮、(S)-4-异丙基-2-噁唑烷酮、(R)-4-异丙基-2-噁唑烷酮、(S)-4-叔丁基-2-噁唑烷酮、(R)-4-叔丁基-2-噁唑烷酮等。 Wherein: the chiral fragment R chiral is provided by a chiral auxiliary, and the chiral auxiliary is a 4-substituted oxazolidinone compound, including but not limited to (S)-4-phenyl-2-oxazolidine Ketone, (R)-4-phenyl-2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone, (R)-4-benzyl-2-oxazolidinone, (S)-4-isopropyl-2-oxazolidinone, (R)-4-isopropyl-2-oxazolidinone, (S)-4-tert-butyl-2-oxazolidinone And (R)-4-tert-butyl-2-oxazolidinone.
或者采用下述制备方法，其包括下列步骤：Or adopt the following preparation method, which includes the following steps:
分别向化合物III-1’和III-2’中引入手性辅基R chiral，得到化合物III’-1’和III’-2’；化合物III’-1’经手 性辅基诱导，引入R 5b基团，得到化合物III’-1’-a和III’-1’-b，化合物III’-2’经手性辅基诱导，引入R 5b基团，得到化合物III’-2’-a和III’-2’-b；再分别脱除手性片段R chiral，得到用于在步骤5)中与苯胺类化合物反应的化合物III”-1’-a和III”-1’-b以及III”-2’-a和III”-2’-b； The chiral auxiliary group R chiral is introduced into the compounds III-1' and III-2', respectively, to obtain the compounds III'-1' and III'-2'; the compound III'-1' is induced by the chiral auxiliary group, and R 5b is introduced. The group gives the compounds III'-1'-a and III'-1'-b, and the compound III'-2' is induced by a chiral auxiliary group, and the R 5b group is introduced to obtain the compound III'-2'-a and III. '-2'-b; the chiral fragment R chiral is removed separately, and the compounds III"-1'-a and III"-1'-b and III" for reacting with the aniline compound in step 5) are obtained. -2'-a and III"-2'-b;
Figure PCTCN2019081709-appb-000045
Figure PCTCN2019081709-appb-000045
其中：手性辅基R chiral为4位取代的噁唑烷酮类化合物，包括(但不限于)(S)-4-苯基-2-噁唑烷酮、(R)-4-苯基-2-噁唑烷酮、(S)-4-苄基-2-噁唑烷酮、(R)-4-苄基-2-噁唑烷酮、(S)-4-异丙基-2-噁唑烷酮、(R)-4-异丙基-2-噁唑烷酮、(S)-4-叔丁基-2-噁唑烷酮、(R)-4-叔丁基-2-噁唑烷酮等。 Wherein: the chiral auxiliary group R chiral is a 4-substituted oxazolidinone compound, including but not limited to (S)-4-phenyl-2-oxazolidinone, (R)-4-phenyl -2-oxazolidinone, (S)-4-benzyl-2-oxazolidinone, (R)-4-benzyl-2-oxazolidinone, (S)-4-isopropyl- 2-oxazolidinone, (R)-4-isopropyl-2-oxazolidinone, (S)-4-tert-butyl-2-oxazolidinone, (R)-4-tert-butyl -2-oxazolidinone and the like.
[药物组合物][pharmaceutical composition]
术语“药物组合物”是指可以用作药物的组合物，其包含药物活性成分(API)以及可选的一种或多种药学上可接受载体。术语“药学上可接受的载体”是指与药物活性成分相容并且对受试者无害的药用辅料，包括(但不限于)稀释剂(或称填充剂)、粘合剂、崩解剂、润滑剂、润湿剂、增稠剂、助流剂、矫味剂、矫嗅剂、防腐剂、抗氧化剂、pH调节剂、溶剂、助溶剂、表面活性剂等。The term "pharmaceutical composition" refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient that is compatible with the pharmaceutically active ingredient and is not deleterious to the subject, including but not limited to diluents (or fillers), binders, disintegration Agents, lubricants, wetting agents, thickeners, glidants, flavoring agents, odorants, preservatives, antioxidants, pH adjusters, solvents, solubilizers, surfactants, and the like.
本发明提供了一种药物组合物，其包含上述式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药。The present invention provides a pharmaceutical composition comprising a compound of the above formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label thereof Or prodrug.
在本发明的一些实施方案中，上述药物组合物还包含药学上可接受的载体。In some embodiments of the invention, the above pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
[医药用途][medical use]
无论是上述式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，还是上述药物组合物，都能够对因干扰素γ诱导Hela细胞而表达的IDO表现出抑制活性，针对IDO的IC 50值能够达到100nM以下，个别甚至达到10nM以下，抑制活性较为显著，可以用作IDO抑制剂。因此，本发明提供了上述式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物用作IDO抑制剂的用途。 Whether it is a compound of the above formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, or a pharmaceutical composition as described above All of them can exhibit inhibitory activity against IDO expressed by interferon γ-induced Hela cells, and the IC 50 value for IDO can reach 100 nM or less, and even up to 10 nM or less, and the inhibitory activity is remarkable, and it can be used as an IDO inhibitor. Accordingly, the present invention provides a compound of the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, or The use of a pharmaceutical composition as an IDO inhibitor.
另外，本申请还提供了上述式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物在制备用于预防和/或治疗至少部分由IDO介导的疾病的药物中的用途。In addition, the present application also provides a compound of the above formula I, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, or Use of the above pharmaceutical composition for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by IDO.
术语“至少部分由IDO介导的疾病”是指发病机理中至少包含一部分与IDO有关的因素的疾病，这些疾病包括(但不限于)癌症(例如宫颈癌)、神经退行性疾病(例如阿尔茨海默病)、病毒感染(例如AIDS)、细菌感染(例如链球菌感染)、眼部疾病(例如白内障)、自身免疫性疾病(例如类风湿性关节炎)、抑郁症、焦虑症以及心理障碍。The term "at least partially mediated by IDO" refers to diseases in which at least a portion of IDO-related factors are involved in the pathogenesis, including but not limited to cancer (eg, cervical cancer), neurodegenerative diseases (eg, Alz Haimo disease), viral infections (such as AIDS), bacterial infections (such as streptococcal infections), ocular diseases (such as cataracts), autoimmune diseases (such as rheumatoid arthritis), depression, anxiety, and psychological disorders .
[治疗方法][treatment method]
本发明提供了一种用于预防和/或治疗至少部分由IDO介导的疾病的方法，其包括下列步骤：将治疗有效量的上述式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物施用于对其有需求的患者。The present invention provides a method for preventing and/or treating a disease mediated at least in part by IDO, comprising the steps of: administering a therapeutically effective amount of a compound of formula I above, or a pharmaceutically acceptable salt, hydrate thereof, Solvates, stereoisomers, tautomers, cis-trans isomers, isotopic labels or prodrugs or pharmaceutical compositions described above are administered to a patient in need thereof.
术语“治疗有效量”是指能够诱发细胞、组织、器官或生物体(例如患者)产生生物或医学反应 的药物活性成分的剂量。The term "therapeutically effective amount" refers to a dose of a pharmaceutically active ingredient that is capable of inducing a biological or medical response in a cell, tissue, organ or organism (e.g., a patient).
术语“施用”是指将药物活性成分(比如本发明的化合物)或包含药物活性成分的药物组合物(例如本发明的药物组合物)应用于患者或其细胞、组织、器官、生物流体等部位，以便使药物活性成分或药物组合物与患者或其细胞、组织、器官、生物流体等部位接触的过程。常见的施用方式包括(但不限于)口服施用、皮下施用、肌内施用、腹膜下施用、眼部施用、鼻部施用、舌下施用、直肠施用、阴道施用等。The term "administering" means applying a pharmaceutically active ingredient (such as a compound of the present invention) or a pharmaceutical composition comprising a pharmaceutically active ingredient (for example, a pharmaceutical composition of the present invention) to a patient or a cell, tissue, organ, biological fluid or the like. The process of contacting a pharmaceutically active ingredient or pharmaceutical composition with a patient or a cell, tissue, organ, biological fluid or the like. Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.
术语“对其有需求”是指医生或其他护理人员对患者需要或者将要从预防和/或治疗过程中获益的判断，该判断的得出基于医生或其他护理人员在其专长领域中的各种因素。The term "required for it" refers to the judgment of a doctor or other caregiver that the patient needs or will benefit from the prevention and/or treatment process, based on the judgment of the doctor or other caregiver in his area of expertise. Factors.
术语“患者”(或称受试者)是指人类或非人类的动物(例如哺乳动物)。The term "patient" (or subject) refers to a human or non-human animal (eg, a mammal).
[联合用药][combination]
本发明提供了一种药物联合形式，其包含上述式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物以及至少一种额外的癌症治疗剂。The present invention provides a pharmaceutical combination comprising the above compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis and trans isomer thereof, isotope label Or a prodrug or a pharmaceutical composition as described above and at least one additional cancer therapeutic.
术语“癌症”是指以失控的或失调的细胞增殖、减少的细胞分化、不适宜的侵入周围组织的能力和/或在异位建立新生长的能力为特征的细胞障碍。常见的癌症包括(但不限于)脑癌、肝癌、胆囊癌、支气管癌、肺癌、膀胱癌、卵巢癌、宫颈癌、睾丸癌、唇癌、舌癌、下咽癌、喉癌、食管癌、胃癌、肠癌(例如结肠癌、直肠癌)、甲状腺癌、唾液腺癌、胰腺癌、乳腺癌、前列腺癌、血癌(或称白血病)、淋巴癌(或称淋巴瘤)、骨癌和皮肤癌。The term "cancer" refers to a cellular disorder characterized by uncontrolled or dysregulated cell proliferation, reduced cell differentiation, undesired ability to invade surrounding tissues, and/or the ability to establish new growth in ectopic. Common cancers include (but are not limited to) brain cancer, liver cancer, gallbladder cancer, bronchial cancer, lung cancer, bladder cancer, ovarian cancer, cervical cancer, testicular cancer, lip cancer, tongue cancer, hypopharyngeal cancer, laryngeal cancer, esophageal cancer, Gastric cancer, intestinal cancer (eg colon cancer, rectal cancer), thyroid cancer, salivary gland cancer, pancreatic cancer, breast cancer, prostate cancer, blood cancer (or leukemia), lymphoma (or lymphoma), bone cancer and skin cancer.
术语“癌症治疗剂”是指能够有效控制和/或对抗癌症的药物组合物或药物制剂。常见的癌症治疗剂包括(但不限于)抗嘌呤药(例如喷司他丁等)、抗嘧啶药(例如氟尿嘧啶)、抗叶酸药(例如甲氨蝶呤)、DNA多聚酶抑制剂(如阿糖胞苷)、烷化剂(如环磷酰胺)、铂类配合物(例如顺铂)、破坏DNA的抗生素(例如丝裂霉素)、拓扑异构酶抑制剂(例如喜树碱)、嵌入DNA干扰核酸合成药(例如表柔比星)、阻止原料供应药(例如门冬酰胺酶)、干扰微管蛋白形成药(例如紫杉醇)、干扰核糖体功能药(例如三尖杉酯碱)、细胞因子(例如IL-1)、胸腺肽、肿瘤细胞增殖病毒(如腺病毒ONYX-015)等。The term "cancer therapeutic agent" refers to a pharmaceutical or pharmaceutical formulation that is effective in controlling and/or combating cancer. Common cancer therapeutics include, but are not limited to, anticonvulsants (such as pentastatin, etc.), antipyrimidines (such as fluorouracil), antifolates (such as methotrexate), DNA polymerase inhibitors (such as arabinose). Cytidine), alkylating agents (such as cyclophosphamide), platinum complexes (such as cisplatin), DNA-killing antibiotics (such as mitomycin), topoisomerase inhibitors (such as camptothecin), embedding DNA interferes with nucleic acid synthesis drugs (such as epirubicin), prevents the supply of raw materials (such as asparaginase), interferes with tubulin-forming drugs (such as paclitaxel), interferes with ribosome-functional drugs (such as harringtonine), Cytokines (eg, IL-1), thymosin, tumor cell proliferative viruses (eg, adenovirus ONYX-015), and the like.
另外，本发明提供了一种用于预防和/或治疗癌症的方法，其包括下列步骤：将治疗有效量的上述式I化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者上述药物组合物以及至少一种额外的癌症治疗剂施用于对其有需求的患者。Further, the present invention provides a method for preventing and/or treating cancer comprising the steps of: administering a therapeutically effective amount of a compound of the above formula I or a pharmaceutically acceptable salt, hydrate, solvate thereof, or stereoisomer thereof A construct, tautomer, cis-trans isomer, isotopic label or prodrug or a pharmaceutical composition as described above, and at least one additional cancer therapeutic agent are administered to a patient in need thereof.
以下将结合具体的实施例来进一步阐述本发明。应当理解，这些实施例仅用于说明本发明，而并不旨在限制本发明的范围。如果下列实施例中的实验方法未注明具体条件，则通常按照常规条件或生产厂商所建议的条件。除非另外说明，下列实施例中出现的百分比和份数均以重量计算。The invention will now be further elucidated in connection with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. If the experimental methods in the following examples do not specify specific conditions, they are usually in accordance with conventional conditions or conditions recommended by the manufacturer. The percentages and parts appearing in the following examples are by weight unless otherwise stated.
实施例1：化合物1～7及70～71的合成。Example 1: Synthesis of Compounds 1 to 7 and 70 to 71.
S1：将2-(4-氧代环己基)丙酸乙酯(1.0eq.)溶于二氯甲烷中，降温至-20℃，加入三氟甲磺酸酐(2.0eq.)，再缓慢滴加三乙胺(2.0eq.)的二氯甲烷溶液；滴加完毕后，升温至室温，反应3h；反应结束后，将反应液旋干，石油醚洗涤2次，得到固体产物，即目标化合物2-(4-(三氟甲磺酰氧基)-3-环己烯-1-基)丙酸乙酯，直接用于下一步反应。S1: Ethyl 2-(4-oxocyclohexyl)propanoate (1.0 eq.) was dissolved in dichloromethane, cooled to -20 ° C, trifluoromethanesulfonic anhydride (2.0 eq.) was added, and then slowly dripped Add a solution of triethylamine (2.0 eq.) in dichloromethane; after the addition is completed, the temperature is raised to room temperature and reacted for 3 hours; after the reaction is completed, the reaction solution is spun dry and washed with petroleum ether twice to obtain a solid product, which is a target compound. Ethyl 2-(4-(trifluoromethanesulfonyloxy)-3-cyclohexen-1-yl)propanoate was used directly in the next reaction.
S2：将S1中的产物(1.0eq.)、6-氟喹啉-4-基硼酸二甲酯(1.2eq.)、碳酸钠(2.5eq.)、溴化钾(1.1eq.)溶于1，4-二氧六环/水(V/V＝10∶1)中(0.25M)，然后加入四(三苯基膦)钯(5mol％)；将反应液加热至80～90℃，反应16h；反应结束后，将反应液浓缩，用乙酸乙酯/水稀释，分离有机相，MgSO 4干燥，过滤，浓缩，固体经柱层析纯化，得到目标化合物2-(4-(6-氟喹啉-4-基)-3-环己烯-1-基)丙酸乙酯。ESI-MS：m/z 328.16，[M+H] +。 S2: The product of S1 (1.0 eq.), dimethyl 6-fluoroquinolin-4-ylborate (1.2 eq.), sodium carbonate (2.5 eq.), potassium bromide (1.1 eq.) were dissolved. 1,4-dioxane/water (V/V=10:1) (0.25 M), then tetrakis(triphenylphosphine)palladium (5 mol%); the reaction solution was heated to 80-90 ° C, the reaction for 16 h; after completion of the reaction, the reaction solution was concentrated / water, diluted with ethyl acetate, the organic phase separated, dried MgSO 4, filtered, concentrated and solid was purified by column chromatography to give the title compound 2- (4- (6- Ethyl fluoroquinolin-4-yl)-3-cyclohexen-1-yl)propanoate. ESI-MS: m/z 328.16, [M+H] + .
S3：将S2中的产物(1.0eq.)溶于乙醇中(0.1～0.3M)，向反应体系中充入氮气，加入钯碳催化剂(10wt％)；体系采用氢气置换，然后在氢气氛围中反应，TLC检测直至原料消失；反应结束后，将反应液过滤，浓缩，得到目标化合物2-(4-(6-氟喹啉-4-基)环己基)丙酸乙酯。ESI-MS：m/z 330.28，[M+H] +。 S3: The product (1.0 eq.) in S2 is dissolved in ethanol (0.1-0.3 M), the reaction system is filled with nitrogen, and a palladium-carbon catalyst (10 wt%) is added; the system is replaced with hydrogen, and then in a hydrogen atmosphere. The reaction was confirmed by TLC until the disappearance of the starting material. After the reaction was completed, the reaction mixture was filtered and concentrated to give ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoate as the title compound. ESI-MS: m/z 330.28, [M+H] + .
S4：将S3中的产物进行硅胶柱层析分离纯化，流动相为石油醚/乙酸乙酯(V/V∶10∶1～1∶1)，得到目标化合物2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酸乙酯。S4: The product in S3 is separated and purified by silica gel column chromatography, and the mobile phase is petroleum ether/ethyl acetate (V/V: 10:1 to 1:1) to obtain the target compound 2-(cis-4-( Ethyl 6-fluoroquinolin-4-yl)cyclohexyl)propanoate.
S5：将S4中的产物(1.0eq.)加入到氢氧化锂(2eq.)的水溶液中，反应2h；加入盐酸(1M)，调节pH值至2；加入乙酸乙酯，萃取3次，合并有机相，浓缩；于0℃加入草酰氯(2.0eq.)，搅拌，反应2h；反应结束后，将反应液浓缩，得到目标化合物2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酰氯，直接用于下一步反应。S5: The product in S4 (1.0 eq.) was added to an aqueous solution of lithium hydroxide (2 eq.) for 2 h; hydrochloric acid (1 M) was added to adjust the pH to 2; ethyl acetate was added, extracted 3 times, and combined. The organic phase was concentrated. Oxalyl chloride (2.0 eq.) was added at 0 ° C, stirred and reacted for 2 h. After the reaction was completed, the reaction mixture was concentrated to give the title compound 2-( cis-4-(6-fluoroquinoline-4). -Based on cyclohexyl)propionyl chloride, used directly in the next reaction.
S6：将S5中的产物(1.0eq.)溶于四氢呋喃中(0.25M)，加入(S)-4-苯基噁唑烷-2-酮，降温至-78℃，缓慢加入正丁基锂(1.3eq.)的正己烷溶液(2.5M)，于-78℃搅拌15min，然后移至冰浴中，继续反应3h；向反应体系中加入饱和氯化铵溶液，淬灭反应，加入乙酸乙酯萃取3次，饱和食盐水洗涤，MgSO 4干燥，过滤，浓缩，得到固体产物，即目标化合物(4R)-3-(2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酰基)-4-苯基噁唑烷-2-酮。ESI-MS：m/z 447.20，[M+H] +。 S6: The product in S5 (1.0 eq.) was dissolved in tetrahydrofuran (0.25 M), (S)-4-phenyloxazolidin-2-one was added, the temperature was lowered to -78 ° C, and n-butyllithium was slowly added. (1.3 eq.) in n-hexane solution (2.5 M), stir at -78 ° C for 15 min, then transferred to an ice bath, continue the reaction for 3 h; add saturated ammonium chloride solution to the reaction system, quench the reaction, add acetic acid The ester was extracted 3 times, washed with saturated brine, dried with MgSO 4 , filtered, and evaporated to give the title compound ( 4 s) Cyclohexyl)propionyl)-4-phenyloxazolidin-2-one. ESI-MS: m/z 447.20, [M+H] + .
S7：将S6中的产物进行硅胶柱层析分离纯化，流动相为石油醚/乙酸乙酯(V/V∶10∶1～1∶1)，得到目标化合物(4R)-3-((2S)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酰基)-4-苯基噁唑烷-2-酮。S7: The product of S6 was purified by silica gel column chromatography, and the mobile phase was petroleum ether/ethyl acetate (V/V: 10:1 to 1:1) to obtain the target compound (4R)-3-((2S) -2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoyl)-4-phenyloxazolidin-2-one.
S8：将S7中的产物(1.0eq.)溶于THF(0.25M)和水(1M)中，于0℃缓慢加入双氧水(35wt％，4eq.)的水溶液，然后加入氢氧化锂(1.6eq.)的水溶液(2.7M)，升温至室温，TLC检测直至原料消失；向反应体系中加入亚硫酸钠溶液，淬灭反应，加入HCl(1M)，调节pH值至5～6，加入乙酸乙酯和二氯甲烷萃取，合并有机相，MgSO 4干燥，浓缩，经硅胶柱层析分离纯化，得到目标化合物(R)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酸。ESI-MS：m/z 302.15，[M+H] +。 S8: The product of S7 (1.0 eq.) was dissolved in THF (0.25M) and water (1M), and aqueous solution of hydrogen peroxide (35 wt%, 4 eq.) was slowly added at 0 ° C, then lithium hydroxide (1.6 eq) was added. .) aqueous solution (2.7M), warmed to room temperature, TLC detection until the disappearance of the starting material; adding sodium sulfite solution to the reaction system, quenching the reaction, adding HCl (1M), adjusting the pH to 5-6, adding ethyl acetate and extracted with dichloromethane, the organic phases were combined, dried MgSO 4, and concentrated, purification by silica gel column chromatography to give the title compound (R) -2- (cis-4- (6-fluoro-quinolin-4-yl) rings Hexyl) propionic acid. ESI-MS: m/z 302.15, [M+H] + .
S9：向S8中的产物(1.0eq.)中加入丙基磷酸酐(50wt％，1.5eq.)的乙酸乙酯溶液，然后加入吡啶(3eq.)的乙酸乙酯溶液(0.1M)，反应10min后，加入对氯苯胺(1.5eq.)，TLC检测直至原料消失；反应结束后，向体系中加入水、氢氧化钠(10eq.)的水溶液(1M)，采用乙酸乙酯萃取3次，合并有机相，MgSO 4干燥，浓缩，经过硅胶柱色谱层析分离纯化，得到目标化合物(R)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酰胺。ESI-MS：m/z 411.16，[M+H] +。 S9: To a solution of the product (1.0 eq.) in S8, a solution of propylphosphonic anhydride (50 wt%, 1.5 eq.) in ethyl acetate was added, followed by a solution of pyridine (3 eq.) in ethyl acetate (0.1 M). After 10 min, p-chloroaniline (1.5 eq.) was added, and TLC was detected until the starting material disappeared. After the reaction was completed, water, sodium hydroxide (10 eq.) aqueous solution (1 M) was added to the system, and extracted with ethyl acetate three times. The organic phases were combined, dried MgSO 4, concentrated and purified by silica gel column chromatography separation after, to give the title compound (R) -N- (4- chlorophenyl) -2- (cis-4- (6-fluoro-quinoline 4-yl)cyclohexyl)propanamide. ESI-MS: m/z 411.16, [M+H] + .
S10：将S9中的产物(1.0eq.)溶于四氢呋喃(0.25M)中，降温至-20℃，依次加入二氯亚砜(2.0eq.)、三氯氧磷(2.0eq.)和五氯化磷(2.0eq.)，搅拌反应3h，TLC检测直至原料消失；反应结束后，将反应液浓缩，采用甲基叔丁基醚洗涤，得到中间体粗品；将中间体粗品(1.0eq.)和水合羟胺(50wt％，5.0eq.)加入到95％乙醇中(0.2M)，于60℃反应16h；反应结束后，加入水和乙酸乙酯萃取，合并有机相，浓缩，经硅胶柱层析分离纯化，洗脱剂为二氯甲烷/甲醇(V/V＝10∶1)，得到白色固体，即为(R，Z)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒(化合物2)。ESI-MS：m/z426.17，[M+H] +。 S10: The product of S9 (1.0 eq.) was dissolved in tetrahydrofuran (0.25 M), cooled to -20 ° C, and then thionyl chloride (2.0 eq.), phosphorus oxychloride (2.0 eq.) and Phosphorus chloride (2.0 eq.), stirred for 3 h, TLC detection until the disappearance of the starting material; after the reaction was completed, the reaction mixture was concentrated and washed with methyl t-butyl ether to give a crude intermediate; crude intermediate (1.0 eq. And hydrated hydroxylamine (50 wt%, 5.0 eq.) was added to 95% ethanol (0.2 M), and reacted at 60 ° C for 16 h; after the reaction was completed, water and ethyl acetate were added for extraction, and the organic phases were combined, concentrated, and passed through silica gel column Chromatography separation and purification, the eluent is dichloromethane / methanol (V / V = 10:1) to give a white solid, which is (R,Z)-N-(4-chlorophenyl)-2-(cis 4-(6-Fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropanthene (Compound 2). ESI-MS: m/z 426.17, [M+H] + .
若S7中分离纯化的目标化合物为(S)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙酸，则采用类似于上法的方法可以制得(S，Z)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒(化合物3)。If the target compound isolated and purified in S7 is (S)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)propionic acid, it can be obtained by a method similar to the above method ( S,Z)-N-(4-Chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionamidine (Compound 3).
若省略S7，则采用类似于上法的方法可以制得(Z)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒(化合物1)。If S7 is omitted, (Z)-N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl can be obtained by a method similar to the above. )-N'-hydroxypropionamidine (Compound 1).
若S4中分离纯化的目标化合物为2-(反式-4-(6-氟喹啉-4-基)环己基)丙酸乙酯，则采用类似于上法的方法可以制得(R，Z)-N-(4-氯苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒(化合物4)和(S，Z)-N-(4-氯苯基)-2-(反式-4-(6-氟喹啉-4-基)环己基)-N’-羟基丙脒(化合物5)。If the target compound isolated and purified in S4 is ethyl 2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)propionate, a method similar to the above method can be used to obtain (R, Z)-N-(4-chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionamidine (Compound 4) and (S, Z)-N-(4-Chlorophenyl)-2-(trans-4-(6-fluoroquinolin-4-yl)cyclohexyl)-N'-hydroxypropionamidine (Compound 5).
若将化合物1的制备方法中S10所使用的羟胺替换为氨水，则采用类似于上法的方法可以制得N-(4-氯苯基)-2-(4-(6-氟喹啉-4-基)环己基)丙脒(化合物6)和(R)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)丙脒(化合物70)。ESI-MS：m/z 410.17，[M+H] +。 If the hydroxylamine used in S10 in the preparation method of the compound 1 is replaced with ammonia water, N-(4-chlorophenyl)-2-(4-(6-fluoroquinoline) can be obtained by a method similar to the above. 4-yl)cyclohexyl)propanoid (compound 6) and (R)-N-(4-chlorophenyl)-2-(cis-4-(6-fluoroquinolin-4-yl)cyclohexyl) Propionin (Compound 70). ESI-MS: m/z 410.17, [M+H] + .
若将化合物1的制备方法中S10所使用的羟胺替换为甲氧基胺，则采用类似于上法的方法可以制得(Z)-N-(4-氯苯基)-2-(4-(6-氟喹啉-4-基)环己基)-N’-甲氧基丙脒(化合物7)和(R，Z)-N-(4-氯苯基)-2-(顺式-4-(6-氟喹啉-4-基)环己基)-N’-甲氧基丙脒(化合物71)。ESI-MS：m/z 440.18，[M+H] +。 If the hydroxylamine used in S10 in the preparation method of the compound 1 is replaced with a methoxyamine, (Z)-N-(4-chlorophenyl)-2-(4-) can be obtained by a method similar to the above. (6-fluoroquinolin-4-yl)cyclohexyl)-N'-methoxypropanthene (compound 7) and (R,Z)-N-(4-chlorophenyl)-2-(cis- 4-(6-Fluoroquinolin-4-yl)cyclohexyl)-N'-methoxypropanthene (Compound 71). ESI-MS: m/z 440.18, [M+H] + .
实施例2：化合物8～14的合成。Example 2: Synthesis of compounds 8 to 14.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S9中的对氯苯胺替换为4-五氟化硫基苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-pentafluoroanisole. The mass spectrometric data of the specific compound were as follows:
化合物8～12：ESI-MS：m/z 518.16，[M+H] +。化合物13：ESI-MS：m/z 502.17，[M+H] +。化合物14：ESI-MS：m/z 532.18，[M+H] +。 Compounds 8-12: ESI-MS: m/z 518.16, [M+H] + . Compound 13: ESI-MS: m / z 502.17, [M + H] +. Compound 14: ESI-MS: m/z 532.18, [M+H] + .
实施例3：化合物15～21的合成。Example 3: Synthesis of compounds 15-21.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S9中的对氯苯胺替换为4-乙炔基苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-ethynylaniline. The mass spectrometric data of the specific compound were as follows:
化合物15～19：ESI-MS：m/z 416.21，[M+H] +。化合物20：ESI-MS：m/z 400.21，[M+H] +。化合物21：ESI-MS：m/z 430.22，[M+H] +。 Compound 15 ~ 19: ESI-MS: m / z 416.21, [M + H] +. Compound 20: ESI-MS: m / z 400.21, [M + H] +. Compound 21: ESI-MS: m/z 430.22, [M+H] + .
实施例4：化合物22～28的合成。Example 4: Synthesis of compounds 22-28.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S9中的对氯苯胺替换为4-二甲基次磷酰基苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-dimethylphosphoranilide. The mass spectrometric data of the specific compound were as follows:
化合物22～26：ESI-MS：m/z 468.21，[M+H] +。化合物27：ESI-MS：m/z 452.22，[M+H] +。化合物28：ESI-MS：m/z 482.23，[M+H] +。 Compound 22 ~ 26: ESI-MS: m / z 468.21, [M + H] +. Compound 27: ESI-MS: m / z 452.22, [M + H] +. Compound 28: ESI-MS: m / z 482.23, [M + H] +.
实施例5：化合物29～35的合成。Example 5: Synthesis of compounds 29-35.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S9中的对氯苯胺替换为4-氨基磺酰氨基苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-aminosulfonamidoaniline. The mass spectrometric data of the specific compound were as follows:
化合物29～33：ESI-MS：m/z 486.19，[M+H] +。化合物34：ESI-MS：m/z 470.19，[M+H] +。化合物35：ESI-MS：m/z 500.21，[M+H] +。 Compounds 29 to 33: ESI-MS: m/z 486.19, [M+H] + . Compound 34: ESI-MS: m/z 470.19, [M+H] + . Compound 35: ESI-MS: m / z 500.21, [M + H] +.
实施例6：化合物37的合成。Example 6: Synthesis of Compound 37.
Figure PCTCN2019081709-appb-000046
Figure PCTCN2019081709-appb-000046
S1：向1，4-二氧杂螺[4.5]癸-8-酮(100g，0.64mol)的甲苯(1000mL)溶液中加入2-(三苯基-λ 5-亚磷酰基)乙酸乙酯(267.7g，0.768mol)，将反应混合物加热至100℃，保持6h，然后真空浓缩，得到粗产物，通过硅胶柱色谱法(洗脱液∶石油醚/乙酸乙酯＝10∶1)纯化粗产物，得到黄色油状物，即为2-(1，4-二氧杂螺[4.5]癸烷-8-亚基)乙酸乙酯(115g，80％产率)。ESI-MS：m/z 227.12，[M+1] +。 S1: To a solution of 1,4-dioxaspiro[4.5]decan-8-one (100 g, 0.64 mol) in toluene (1000 mL), ethyl 2-(triphenyl-λ 5 -phosphoryl)acetate (267.7 g, 0.768 mol), the reaction mixture was heated to 100 ° C for 6 h then concentrated in vacuo to afford crude crystals. The product was obtained as a yellow oil to ethyl 2-(4-dioxaspiro[4.5]decane-8-ylidene) (l. ESI-MS: m/z 227.12, [M+1] + .
Figure PCTCN2019081709-appb-000047
Figure PCTCN2019081709-appb-000047
S2：向化合物2-(1，4-二氧杂螺[4.5]癸烷-8-亚基)乙酸乙酯(115g，509mmol)的EtOH(500mL)溶液中加入10％钯碳(5.7g)，将得到的混合物在H 2气球下在室温下氢化24h，过滤反应混合物并浓缩，得到无色油状物，即为2-(1，4-二氧杂螺[4.5]癸烷-8-基)乙酸乙酯(4.99g，75％收率)。ESI-MS：m/z229.14，[M+1] +。 S2: To a solution of the compound 2-(1,4-dioxaspiro[4.5]decane-8-ylidene) ethyl acetate (115 g, 509 mmol) in EtOH (500 mL) The resulting mixture was hydrogenated at room temperature for 24 h under H 2 balloon. The reaction mixture was filtered and concentrated to give crystals, md. Ethyl acetate (4.99 g, 75% yield). ESI-MS: m/z 229.14, [M+1] + .
Figure PCTCN2019081709-appb-000048
Figure PCTCN2019081709-appb-000048
S3：向化合物2-(1，4-二氧杂螺[4.5]癸烷-8-基)乙酸乙酯(110g，482mmol)的丙酮(4000ml)溶液中加入1M盐酸水溶液(120mL)，将得到的混合物在室温下搅拌15h，使用蒸发器除去有机溶剂，将剩余的水溶液用乙酸乙酯萃取两次，用饱和盐水洗涤有机层，然后经硫酸钠干燥，浓缩，得到无色油状物，即为2-(4-氧代环己基)乙酸乙酯(50g，60％收率)。ESI-MS：m/z 185.11，[M+1] +。 S3: To a solution of ethyl 2-(1,4-dioxaspiro[4.5]decane-8-yl)acetate (110 g, 482 mmol) in EtOAc (EtOAc) The mixture was stirred at room temperature for 15 h, EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Ethyl 2-(4-oxocyclohexyl)acetate (50 g, 60% yield). ESI-MS: m/z 185.11, [M+1] + .
Figure PCTCN2019081709-appb-000049
Figure PCTCN2019081709-appb-000049
S4：向化合物2-(4-氧代环己基)乙酸乙酯(10.6g，57.5mmol)和2-二叔丁基-4-甲基吡啶(17.7g，69.1mmol)的无水CH 2Cl 2(500ml)溶液中加入Tf 2O(8.35ml，50mmol)，添加后将其在室温下搅拌过夜，反应混合物从橙色变为绿色，同时加入Tf 2O，30分钟后形成悬浮液，过滤悬浮液，蒸发滤液，将粗制混合物溶解在CH 2Cl 2(200ml)中并过滤，将滤液用盐水洗涤，浓缩有机层并通过硅胶柱(洗脱液∶石油醚/乙酸乙酯＝20∶1至10∶1)纯化，得到化合物2-(4-(三氟甲磺酰氧基)环己-3-烯基)乙酸乙酯(10.4g，57％收率)。ESI-MS：m/z 317.06，[M+1] +。 S4: ethyl 2-(4-oxocyclohexyl)acetate (10.6 g, 57.5 mmol) and 2-di-tert-butyl-4-methylpyridine (17.7 g, 69.1 mmol) in anhydrous CH 2 Cl 2 (500 ml) was added Tf 2 O (8.35 ml, 50 mmol), and after stirring, it was stirred at room temperature overnight, the reaction mixture was changed from orange to green, and Tf 2 O was added thereto, and after 30 minutes, a suspension was formed, and the suspension was filtered. solution, the filtrate was evaporated, the crude mixture was dissolved in CH 2 Cl 2 (200ml) and filtered, the filtrate was washed with brine and the organic layer was concentrated and purified by silica gel column chromatography (eluent: petroleum ether / ethyl acetate = 20 Purification by 10:1) gave the compound 2-(4-(trifluoromethanesulfonyloxy)cyclohex-3-enyl)acetate (10.4 g, 57% yield). ESI-MS: m/z 317.06, [M+1] + .
Figure PCTCN2019081709-appb-000050
Figure PCTCN2019081709-appb-000050
S5：向2-(4-(三氟甲磺酰氧基)环己-3-烯基)乙酸乙酯(10.4g，32.9mmol)和双(频哪醇合)二硼(10.0g，39.5mmol，1.2eq)的二恶烷(200mL)溶液中加入KOAc(4.8g，49.4mmol，1.5eq)和Pd(dppf)Cl 2(2.4g，3.29mmol，0.1eq)，向反应混合物中加入N 2气，然后加热至110℃并搅拌过夜，然后向反应混合物中加入水(400ml)和乙酸乙酯(600ml)，分离各层，用乙酸乙酯(600ml)萃取水层，将合并的有机层用盐水(500ml)洗涤，并用无水硫酸钠干燥，蒸发混合物并通过柱色谱(洗脱液∶石油醚/乙酸乙酯＝100∶1)纯化，得到2-(4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)环己-3-烯基)乙酸乙酯(4.1g，42％收率)。ESI-MS：m/z 295.20，[M+1] +。 S5: ethyl 2-(4-(trifluoromethanesulfonyloxy)cyclohex-3-enyl)acetate (10.4 g, 32.9 mmol) and bis(pinacol) diboron (10.0 g, 39.5) mmol, 1.2eq) in dioxane (200mL) was added KOAc (4.8g, 49.4mmol, 1.5eq) and a solution of Pd (dppf) Cl 2 (2.4g , 3.29mmol, 0.1eq), the reaction mixture was added N 2 gas, then heated to 110 ° C and stirred overnight, then water (400 ml) and ethyl acetate (600 ml) were added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ethyl acetate (600 ml). It was washed with brine (500 ml) and dried over anhydrous sodium sulfate. , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyl)acetate (4.1 g, 42% yield). ESI-MS: m/z 295.20, [M+1] + .
Figure PCTCN2019081709-appb-000051
Figure PCTCN2019081709-appb-000051
S6：向2-(4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)环己-3-烯基)乙酸乙酯(3.5g，11.9mmol)和4-氯-6-氟喹啉(2.8g，15.5mmol)在二恶烷(40mL)和水(10mL)的混合溶剂中的混合物中加入K 2CO 3(2.2g，15.5mmol)和Pd(dppf)Cl 2(0.9g，1.19mmol)，向反应混合物中加入N 2气，然后加热至105℃并搅拌过夜，浓缩反应混合物，用水稀释残余物，用乙酸乙酯(200ml)萃取水层两次，将合并的有机层用盐水(200ml)洗涤，并用无水硫酸钠干燥，蒸发混合物并通过柱色谱法纯化(洗脱剂∶石油醚/乙酸乙酯＝10∶1至2∶1)，得到2-(4-(6-氟喹啉-4-基)环己-3-烯基)乙酸乙酯(2.6g，70％收率)。ESI-MS：m/z 314.15，[M+1] +。 S6: To 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enyl)acetate Addition of K 2 CO 3 (3.5 g, 11.9 mmol) and 4-chloro-6-fluoroquinoline (2.8 g, 15.5 mmol) in a mixture of dioxane (40 mL) and water (10 mL) 2.2 g, 15.5 mmol) and Pd(dppf)Cl 2 (0.9 g, 1.19 mmol), N 2 gas was added to the reaction mixture, then heated to 105 ° C and stirred overnight, the reaction mixture was concentrated, and the residue was diluted with water. Ethyl acetate (200 ml) was extracted with EtOAc (EtOAc)EtOAc. From 10:1 to 2:1), ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohex-3-enyl)acetate (2.6 g, 70% yield). ESI-MS: m/z 314.15, [M+1] + .
Figure PCTCN2019081709-appb-000052
Figure PCTCN2019081709-appb-000052
S7：向2-(4-(6-氟喹啉-4-基)环己-3-烯基)乙酸乙酯(2.7g，8.6mmol)的EtOH(20mL)溶液中加入10％钯碳(0.3g)，将得到的混合物在H 2气球下在室温下氢化3d，过滤反应混合物并浓缩，得到无色油状物，即为2-(4-(6-氟喹啉-4-基)环己基)乙酸乙酯(2.5g，92.5％产率)。ESI-MS：m/z 316.16，[M+1] +。 S7: To a solution of ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohex-3-enyl)acetate (2.7 g, 8.6 mmol) in EtOAc (20 mL) 0.3 g), the resulting mixture was hydrogenated at room temperature for 3 d under H 2 balloon, filtered, and concentrated to give a colorless oil (2-(4-(6-fluoroquinolin-4-yl)). Ethyl acetate (2.5 g, 92.5% yield). ESI-MS: m/z 316.16, [M+1] + .
Figure PCTCN2019081709-appb-000053
Figure PCTCN2019081709-appb-000053
S8：向2-(4-(6-氟喹啉-4-基)环己基)乙酸乙酯(3.8g，12mmol)在MeOH(40mL)和H 2O(10mL)的混合溶剂中的混合物中加入LiOH(1100mg，24mmol)，将混合物在50℃下搅拌1h，将反应混合物倒入水(200mL)中，用乙酸酸化至pH＝6，用乙酸乙酯(3×200mL)萃取，有机相经无水硫酸钠干燥并真空浓缩，得到粗产物，通过硅胶柱色谱法(洗脱液∶CH 2Cl 2∶MeOH＝50∶1至10∶1)纯化，得到白色泡沫，即为2-(4-(6-氟喹啉-4-基)环己基)乙酸(3.2g，93％产率)。ESI-MS：m/z 288.13，[M+1] +。 S8: To a mixture of ethyl 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetate (3.8 g, 12 mmol) in MeOH (40 mL) and H ? LiOH (1100 mg, 24 mmol) was added, and the mixture was stirred at 50 ° C for 1 h, then the mixture was poured into water (200 mL), acidified to pH=6 with ethyl acetate (3×200 mL) dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product which was purified by silica gel column chromatography (eluent :CH 2 Cl 2 :MeOH = 50:1 to 1) to give a white foam, i.e. 2- (4 -(6-Fluoroquinolin-4-yl)cyclohexyl)acetic acid (3.2 g, 93% yield). ESI-MS: m/z 288.13, [M+1] + .
Figure PCTCN2019081709-appb-000054
Figure PCTCN2019081709-appb-000054
S9：在0℃下，向2-(4-(6-氟喹啉-4-基)环己基)乙酸(3.0g，10.4mmol)和三乙胺(2.10g，20.9mmol)的THF(100mL)混合物中加入新戊酰氯(1.53g，12.6mmol)，将混合物在该温度下搅拌1h；在另一个干燥烧瓶中，在0℃下，向(R)-4-苯基恶唑烷-2-酮(2.2g，13.6mmol)的THF(50mL)溶液中加入 HMDSLi(13.6mL，13.6mmol)，将混合物在该温度下搅拌3h，然后将其逐滴注入上述反应瓶中；在0℃下搅拌3h后，用水溶液淬灭，用乙酸乙酯(3×100mL)萃取NH 4Cl，有机相用无水硫酸钠干燥，真空浓缩，得到粗产物，经硅胶柱层析纯化(洗脱剂∶石油醚∶乙酸乙酯＝2∶1至1∶1)，得到白色固体，即为化合物(R)-3-(2-(4-(6-氟喹啉-4-基)环己基)乙酰基)-4-苯基恶唑烷-2-酮(4.05g，89％收率)。ESI-MS：m/z433.18，[M+1] +。 1H-NMR(400MHz，CDCl 3)：δ8.80(d，J＝4.5Hz，1H)，8.11(dd，J＝9.1，5.7Hz，1H)，7.63(dd，J＝10.5，2.5Hz，1H)，7.48-7.43(m，1H)，7.40-7.30(m，6H)，5.47-5.44(m，1H)，4.71(t，J＝8.9Hz，1H)，4.31-4.28(m，1H)，3.20-3.11(m，3H)，2.49-2.46(m，1H)，1.82-1.67(m，6H)。 S9: 2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetic acid (3.0 g, 10.4 mmol) and triethylamine (2.10 g, 20.9 mmol) in THF (100 mL) To the mixture was added pivaloyl chloride (1.53 g, 12.6 mmol), and the mixture was stirred at this temperature for 1 h; in another dry flask, at 0 ° C, to (R)-4-phenyloxazolidine-2 To a solution of the ketone (2.2 g, 13.6 mmol) in THF (50 mL), HM EtOAc (13.6 mL, 13.6 mmol), and the mixture was stirred at this temperature for 3 h and then poured into the above reaction flask at 0 ° C; after stirring for 3h under, quenched with aqueous with ethyl acetate (3 × 100mL) and extracted NH 4 Cl, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (eluent : petroleum ether: ethyl acetate = 2:1 to 1:1) to give a white solid as the compound (R)-3-(2-(4-(6-fluoroquinolin-4-yl)cyclohexyl) Acetyl)-4-phenyloxazolidin-2-one (4.05 g, 89% yield). ESI-MS: m/z 433.18, [M+1] + . 1 H-NMR (400 MHz, CDCl 3 ): δ 8.80 (d, J = 4.5 Hz, 1H), 8.11 (dd, J = 9.1, 5.7 Hz, 1H), 7.63 (dd, J = 10.5, 2.5 Hz, 1H), 7.48-7.43 (m, 1H), 7.40-7.30 (m, 6H), 5.47-5.44 (m, 1H), 4.71 (t, J = 8.9 Hz, 1H), 4.31-4.28 (m, 1H) , 3.20-3.11 (m, 3H), 2.49-2.46 (m, 1H), 1.82-1.67 (m, 6H).
Figure PCTCN2019081709-appb-000055
Figure PCTCN2019081709-appb-000055
S10：在-30℃和N 2保护下，向(R)-3-(2-(4-(6-氟喹啉-4-基)环己基)乙酰基)-4-苯基恶唑烷-2-酮(3.0g，6.94mmol)的THF(150mL)混合物中加入HMDSLi(21mL，20.8mmol)，将反应混合物在该温度下搅拌1h，然后向混合物中加入MeI(6mL，55.52mmol)，将反应物搅拌3h，然后倒入水溶液中，用乙酸乙酯(2×200mL)萃取NH 4Cl(100mL)，有机相用无水硫酸钠干燥，真空浓缩，得到粗产物，经硅胶柱层析纯化(洗脱剂∶石油醚∶乙酸乙酯＝2∶1至1∶1)，得到白色固体，即为(R)-3-((R)-2-(4-(6-氟喹啉-4-基)环己基)丙酰基)-4-苯基恶唑烷-2-酮(2.2g，71％收率)。 1H-NMR(400MHz，CDCl3)：δ8.81(d，J＝4.6Hz，1H)，8.10(dd，J＝9.2，5.7Hz，1H)，7.65(dd，J＝10.6，2.7Hz，1H)，7.47-7.42(m，1H)，7.41-7.29(m，6H)，5.47(dd，J＝8.8，3.8Hz，1H)，4.69(t，J＝8.9Hz，1H)，4.38-4.30(m，1H)，4.26(dd，J＝8.9，3.9Hz，1H)，3.26-3.21(m，1H)，2.18-2.15(m，1H)，1.93-1.64(m，8H)，1.09(d，J＝6.9Hz，3H)。 S10: (R)-3-(2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)acetyl)-4-phenyloxazolidine at -30 ° C under N 2 protection To a mixture of -2- ketone (3.0 g, 6.94 mmol) in THF (150 mL), HM EtOAc (EtOAc &lt;RTI ID=0.0&gt; the reaction was stirred for 3h, then poured into an aqueous solution, extracted with ethyl acetate (2 × 200mL) and extracted NH 4 Cl (100mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product was purified by silica gel column chromatography Purification (eluent: petroleum ether: ethyl acetate = 2:1 to 1:1) to give a white solid (R)-3-((R)-2-(4-(6-fluoroquinoline) 4-yl)cyclohexyl)propanoyl)-4-phenyloxazolidin-2-one (2.2 g, 71% yield). 1 H-NMR (400 MHz, CDCl 3 ): δ 8.81 (d, J = 4.6 Hz, 1H), 8.10 (dd, J = 9.2, 5.7 Hz, 1H), 7.65 (dd, J = 10.6, 2.7 Hz, 1H) ), 7.47-7.42 (m, 1H), 7.41-7.29 (m, 6H), 5.47 (dd, J = 8.8, 3.8 Hz, 1H), 4.69 (t, J = 8.9 Hz, 1H), 4.38-4.30 ( m,1H), 4.26 (dd, J=8.9, 3.9 Hz, 1H), 3.26-3.21 (m, 1H), 2.18-2.15 (m, 1H), 1.93-1.64 (m, 8H), 1.09 (d, J = 6.9 Hz, 3H).
Figure PCTCN2019081709-appb-000056
Figure PCTCN2019081709-appb-000056
S11：在0℃下，向(R)-3-((R)-2-(4-(6-氟喹啉-4-基)环己基)丙酰基)-4-苯基恶唑烷-2-酮(1.2g，2.69mmol)在THF/H 2O(30mL/30mL)的混合物中加入H 2O 2(6mL)和LiOH(226mg，5.50mmol)，将混合物在室温下搅拌过夜，将反应混合物倒入水(100mL)中，用Na 2SO 3淬灭，用乙酸乙酯(3×200mL)萃取，有机相经无水硫酸钠干燥并真空浓缩，得到粗产物，通过硅胶柱色谱法(洗脱液∶CH 2Cl 2∶MeOH＝10∶1)纯化，得到白色泡沫，即为(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)丙酸(400mg，50％收率)。ESI-MS：m/z 302.15，[M+1] +。 S11: (R)-3-((R)-2-(4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoyl)-4-phenyloxazolidine at 0 °C 2- one (1.2g, 2.69mmol) was added H 2 O 2 (6mL) and LiOH in a mixture of THF / H 2 O (30mL / 30mL) in (226mg, 5.50mmol), and the mixture was stirred overnight at room temperature, the reaction mixture was poured into water (100 mL), the mixture was extracted with ethyl acetate (3 × 200mL) with Na 2 SO 3 and quenched, the organic phase dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude product was purified by silica gel column chromatography (Eluent: CH 2 Cl 2 : MeOH = 10:1) was purified to give white foam as (R)-2-((1s,4S)-4-(6-fluoroquinolin-4-yl) Cyclohexyl)propionic acid (400 mg, 50% yield). ESI-MS: m/z 302.15, [M+1] + .
Figure PCTCN2019081709-appb-000057
Figure PCTCN2019081709-appb-000057
S12：在0℃下，向化合物(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)丙酸(50mg，0.166mmol)和三乙胺(34mg，0.332mmol)的THF(5mL)混合物中加入新戊酰氯(22mg，0.183mmol)，将混合物在该温度下搅拌1h，然后加入化合物N-(4-氨基苯基)磺酰胺(50mg，0.166mmol)，将所得混合物加热至50℃过夜，浓缩，通过制备HPLC纯化后冻干，得到白色固体，即为化合物37(9.8mg，12％收率)。ESI-MS：m/z 471.18，[M+1] +。 1H-NMR(400MHz，DMSO-d 6)：δ9.88(s，1H)，9.28(s，1H)，8.96(d，J＝4.0Hz，1H)，8.16(dd，J＝8.0Hz，4.0Hz，1H)，8.10(dd，J＝12.0Hz，4.0Hz，1H)，7.78-7.73(m，1H)，7.68(d，J＝4.0Hz，1H)，7.52(d，J＝8.0Hz，2H)，7.10(d，J＝8.0Hz，2H)，6.97(brs，2H)，2.86-2.83(m，1H)，1.99-1.66(m，10H)，1.15(d，J＝8.0Hz，3H)。 S12: Compound (R)-2-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid (50 mg, 0.166 mmol) and triethylamine at 0 °C (5 mg, 0.332 mmol) in THF (5 mL) was added EtOAc (EtOAc, m. The resulting mixture was heated to 50.degree. C., EtOAc (m.) ESI-MS: m/z 471.18, [M+1] + . 1 H-NMR (400MHz, DMSO -d 6): δ9.88 (s, 1H), 9.28 (s, 1H), 8.96 (d, J = 4.0Hz, 1H), 8.16 (dd, J = 8.0Hz, 4.0 Hz, 1H), 8.10 (dd, J = 12.0 Hz, 4.0 Hz, 1H), 7.78-7.73 (m, 1H), 7.68 (d, J = 4.0 Hz, 1H), 7.52 (d, J = 8.0 Hz) , 2H), 7.10 (d, J = 8.0 Hz, 2H), 6.97 (brs, 2H), 2.86-2.83 (m, 1H), 1.99-1.66 (m, 10H), 1.15 (d, J = 8.0 Hz, 3H).
实施例7：化合物36，38～40的合成。Example 7: Synthesis of compound 36, 38-40.
参照实施例6中记载的方法制备各个步骤中的目标化合物，采用各自对应的对映异构体替换得到目标化合物，具体化合物的质谱鉴定数据如下：The target compounds in each step were prepared by the method described in Example 6, and the target compounds were obtained by substituting the corresponding enantiomers. The mass spectrometric data of the specific compounds were as follows:
化合物36，38～40：ESI-MS：m/z 471.18，[M+H] +。 Compound 36, 38-40: ESI-MS: m/z 471.18, [M+H] + .
实施例8：化合物41～45的合成。Example 8: Synthesis of compounds 41 to 45.
参照实施例4中记载的方法制备各个步骤中的目标化合物，区别在于得到S9中的目标化合物(酰胺类化合物)之后不再进行S10中的羰基衍生化反应，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 4 except that the target compound (amide compound) in S9 was not subjected to the carbonyl derivatization reaction in S10, and the mass spectrometric data of the specific compound were as follows:
化合物41～45：ESI-MS：m/z 453.20，[M+H] +。 Compounds 41 to 45: ESI-MS: m/z 453.20, [M+H] + .
实施例9：化合物47的合成。Example 9: Synthesis of Compound 47.
参照实施例6中步骤S1-S11，获得(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)丙酸。Referring to steps S1-S11 of Example 6, (R)-2-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid was obtained.
Figure PCTCN2019081709-appb-000058
Figure PCTCN2019081709-appb-000058
在室温下，向(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)丙酸(150mg，0.33mmol)和4-乙炔基苯胺(117mg，0.66mmol)的乙酸乙酯(5mL)混合物中加入T3P(2mL，50％乙酸乙酯溶液)和吡啶(0.1mL)，然后将混合物在50℃下搅拌过夜，将反应混合物倒入水溶液中，用NaHCO 3(30mL)中和，用乙酸乙酯(3×50mL)萃取，有机相用无水硫酸钠干燥，真空浓缩，得到粗产物，通过制备HPLC纯化后冻干，得到白色固体，即为化合物47(20.4mg，15％收率)。ESI-MS：m/z 401.20，[M+H] +。 1H-NMR(400MHz，DMSO-d 6)：δ10.21(s，1H)，9.03(d，J＝4.0Hz，1H)，8.21(dd，J＝8.0Hz，4Hz，1H)，8.17(dd，J＝12.0Hz，4Hz，1H)，7.84-7.77(m，1H)，7.77(d，J＝4.0Hz，1H)，7.68(d，J＝8.0Hz，2H)，7.43(d，J＝8.0Hz，2H)，4.08(s，1H)，3.50-3.47(m，1H)，2.93-2.89(m，1H)，1.99-1.81(m，9H)，1.15(d，J＝8.0Hz，3H)。 To (R)-2-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid (150 mg, 0.33 mmol) and 4-ethynylaniline (117 mg) at room temperature T3P (2 mL, 50% ethyl acetate solution) and pyridine (0.1 mL) were added to a mixture of ethyl acetate (5 mL), and then the mixture was stirred at 50 ° C overnight, and the mixture was poured into an aqueous solution. , (3 × 50mL) and extracted with NaHCO 3 (30mL) and extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, after purification by preparative HPLC and lyophilized to give a white solid, i.e. Compound 47 (20.4 mg, 15% yield). ESI-MS: m/z 401.20, [M+H] + . 1 H-NMR (400 MHz, DMSO-d 6 ): δ 10.21. (s, 1H), 9.03 (d, J = 4.0 Hz, 1H), 8.21. (dd, J = 8.0 Hz, 4 Hz, 1H), 8.17 ( Dd, J = 12.0 Hz, 4 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.77 (d, J = 4.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 4.08 (s, 1H), 3.50-3.47 (m, 1H), 2.93-2.89 (m, 1H), 1.99-1.81 (m, 9H), 1.15 (d, J = 8.0 Hz, 3H).
实施例10：化合物46，48～50的合成。Example 10: Synthesis of Compound 46, 48-50.
参照实施例9中记载的方法制备各个步骤中的目标化合物，采用各自对应的对映异构体替换得到目标化合物，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 9, and the target compound was obtained by substituting each corresponding enantiomer. The mass spectrometric identification data of the specific compound is as follows:
化合物46，48～50：ESI-MS：m/z 401.20，[M+H] +。 Compound 46, 48-50: ESI-MS: m/z 401.20, [M+H] + .
实施例11：化合物52的合成。Example 11: Synthesis of Compound 52.
参照实施例6中步骤S1-S11，获得(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)丙酸。Referring to steps S1-S11 of Example 6, (R)-2-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid was obtained.
Figure PCTCN2019081709-appb-000059
Figure PCTCN2019081709-appb-000059
在室温下，向(R)-2-((1s，4S)-4-(6-氟喹啉-4-基)环己基)丙酸和4-(五氟化硫基)苯胺(109mg，0.50mmol)的乙酸乙酯(5mL)混合物中加入T3P(1.5mL，50％乙酸乙酯溶液)和吡啶(0.5mL)，然后将混合物在0℃下搅拌过夜，将反应混合物倒入水溶液中，用NaHCO 3(30mL)中和，用乙酸乙酯(3×50mL)萃取，有机相用无水硫酸钠干燥，真空浓缩，得到粗产物，通过制备HPLC纯化后冻干，得到白色固体，即为化合物52(21mg，39.5％产率)。ESI-MS：m/z 503.15，[M+H] +。 1H-NMR(400MHz，DMSO-d6)：δ8.78(d，J＝4.0Hz，1H)，8.10(dd，J＝12.0Hz，4Hz，1H)，7.81(dd，J＝12.0Hz，4Hz，1H)，7.80-7.74(m，4H)，7.62-7.57(m，2H)，3.47-3.44(m，1H)，2.94-2.88(m，1H)，2.19-2.09(m，3H)，1.93-1.81(m，8H)，1.30(d，J＝8.0Hz，3H)。 To (R)-2-((1s,4S)-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanoic acid and 4-(thiosulfonium thio)aniline (109 mg, at room temperature T3P (1.5 mL, 50% ethyl acetate solution) and pyridine (0.5 mL) were added to a mixture of ethyl acetate (5 mL), and then the mixture was stirred at 0 ° C overnight, and the mixture was poured into an aqueous solution. , (3 × 50mL) extracted with NaHCO 3 (30mL) and ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and concentrated in vacuo to give the crude product, after purification by preparative HPLC and lyophilized to give a white solid, i.e. Compound 52 (21 mg, 39.5% yield). ESI-MS: m/z 503.15, [M+H] + . 1 H-NMR (400 MHz, DMSO-d6): δ 8.78 (d, J = 4.0 Hz, 1H), 8.10 (dd, J = 12.0 Hz, 4 Hz, 1H), 7.81 (dd, J = 12.0 Hz, 4 Hz) , 1H), 7.80-7.74 (m, 4H), 7.62-7.57 (m, 2H), 3.47-3.44 (m, 1H), 2.94-2.88 (m, 1H), 2.19-2.09 (m, 3H), 1.93 -1.81 (m, 8H), 1.30 (d, J = 8.0 Hz, 3H).
实施例12：化合物51，53～55的合成。Example 12: Synthesis of compound 51, 53-55.
参照实施例11中记载的方法制备各个步骤中的目标化合物，采用各自对应的对映异构体替换得到目标化合物，具体化合物的质谱鉴定数据如下：The target compounds in each step were prepared by the method described in Example 11, and the target compounds were obtained by substituting the corresponding enantiomers. The mass spectrometric identification data of the specific compounds are as follows:
化合物51，53～55：ESI-MS：m/z 503.15，[M+H] +。 Compound 51, 53-55: ESI-MS: m/z 503.15, [M+H] + .
实施例13：化合物56～60的合成。Example 13: Synthesis of compounds 56-60.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S9中的对氯苯胺替换为3-溴-4-氟苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 3-bromo-4-fluoroaniline. The mass spectrometric data of the specific compound were as follows:
化合物56～60：ESI-MS：m/z 488.11，[M+H] +。 Compounds 56 to 60: ESI-MS: m/z 488.11, [M+H] + .
实施例14：化合物61～65的合成。Example 14: Synthesis of compounds 61-65.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S2中的6-氟喹啉-4-基硼酸二甲酯替换为1-甲基-1H-吲唑-5-基硼酸二甲酯，将S9中的对氯苯胺替换为3-氯-4-氟苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 1-methyl-1H-indazole-5-yl. Dimethyl borate, replacing p-chloroaniline in S9 with 3-chloro-4-fluoroaniline, the mass spectrometric identification data of specific compounds are as follows:
化合物61～65：ESI-MS：m/z 429.18，[M+H] +。 Compound 61 ~ 65: ESI-MS: m / z 429.18, [M + H] +.
实施例15：化合物66的合成。Example 15: Synthesis of Compound 66.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S2中的6-氟喹啉-4-基硼酸二甲酯替换为1-甲基-1H-吲唑-5-基硼酸二甲酯，将S9中的对氯苯胺替换为间氯苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 1-methyl-1H-indazole-5-yl. Dimethyl borate, replacing p-chloroaniline in S9 with m-chloroaniline, the mass spectrometric identification data of specific compounds are as follows:
化合物66：ESI-MS：m/z 411.19，[M+H] +。 Compound 66: ESI-MS: m / z 411.19, [M + H] +.
实施例16：化合物67的合成。Example 16: Synthesis of Compound 67.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S2中的6-氟喹啉-4-基硼酸二甲酯替换为苯并[b]噻吩-5-基硼酸二甲酯，将S9中的对氯苯胺替换为3-氯-4-氟苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with benzo[b]thiophen-5-ylborate. For the ester, replace the p-chloroaniline in S9 with 3-chloro-4-fluoroaniline. The mass spectrometric identification data of the specific compound are as follows:
化合物67：ESI-MS：m/z 431.13，[M+H] +。 Compound 67: ESI-MS: m / z 431.13, [M + H] +.
实施例17：化合物68的合成。Example 17: Synthesis of Compound 68.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S2中的6-氟喹啉-4-基硼酸二甲酯替换为2-氧代-2H-色烯-6-基硼酸二甲酯，将S9中的对氯苯胺替换为3-氯-4-氟苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 2-oxo-2H-chromene-6-yl. Dimethyl borate, replacing p-chloroaniline in S9 with 3-chloro-4-fluoroaniline, the mass spectrometric identification data of specific compounds are as follows:
化合物68：ESI-MS：m/z 443.15，[M+H] +。 Compound 68: ESI-MS: m / z 443.15, [M + H] +.
实施例18：化合物69的合成。Example 18: Synthesis of Compound 69.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S2中的6-氟喹啉-4-基硼酸二甲酯替换为1-甲基-1H-吲唑-5-基硼酸二甲酯，将S9中的对氯苯胺替换为3，4-亚甲二氧基苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the dimethyl 6-fluoroquinolin-4-ylborate in S2 was replaced with 1-methyl-1H-indazole-5-yl. Dimethyl borate, replacing p-chloroaniline in S9 with 3,4-methylenedioxyaniline. The mass spectrometric data of specific compounds are as follows:
化合物69：ESI-MS：m/z 421.22，[M+H] +。 Compound 69: ESI-MS: m / z 421.22, [M + H] +.
实施例19：化合物72的合成。Example 19: Synthesis of Compound 72.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S9中的对氯苯胺替换为4-氯-2，3，5，6-氘代苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-chloro-2,3,5,6-deuterated aniline. The mass spectrometric data of the specific compound were as follows. :
化合物72：ESI-MS：m/z 444.21，[M+H] +。 Compound 72: ESI-MS: m / z 444.21, [M + H] +.
实施例20：化合物73和78的合成。Example 20: Synthesis of compounds 73 and 78.
参照实施例8中记载的方法制备各个步骤中的目标化合物，区别在于将S1中的2-(4-氧代环己基)丙酸乙酯替换为2-(4-氧代环己基)乙酸乙酯，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 8, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid B. The mass spectrometric identification data of esters and specific compounds are as follows:
化合物73和78：ESI-MS：m/z 386.18，[M+H] +。 Compounds 73 and 78: ESI-MS: m/z 386.18, [M+H] + .
实施例21：化合物74～75的合成。Example 21: Synthesis of compounds 74-75.
参照实施例7中记载的方法制备各个步骤中的目标化合物，区别在于将S1中的2-(4-氧代环己基)丙酸乙酯替换为2-(4-氧代环己基)乙酸乙酯，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 7, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid. The mass spectrometric identification data of esters and specific compounds are as follows:
化合物74～75：ESI-MS：m/z 439.19，[M+H] +。 Compounds 74-75: ESI-MS: m/z 437.19, [M+H] + .
实施例22：化合物76～77的合成。Example 22: Synthesis of compounds 76-77.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S1中的2-(4-氧代环己基)丙酸乙酯替换为2-(4-氧代环己基)乙酸乙酯，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid The mass spectrometric identification data of esters and specific compounds are as follows:
化合物76～77：ESI-MS：m/z 396.16，[M+H] +。 Compounds 76-77: ESI-MS: m/z 396.16, [M+H] + .
实施例23：化合物79～80的合成。Example 23: Synthesis of compounds 79-80.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S1中的2-(4-氧代环己基) 丙酸乙酯替换为2-(4-氧代环己基)乙酸乙酯，将S10中的羟胺替换为甲胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid The ester is replaced by methylamine in S10. The mass spectrometric data of the specific compound are as follows:
化合物79～80：ESI-MS：m/z 410.17，[M+H] +。 Compounds 79-80: ESI-MS: m/z 410.17, [M+H] + .
实施例24：化合物81～82的合成。Example 24: Synthesis of compounds 81-82.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S1中的2-(4-氧代环己基)丙酸乙酯替换为2-(4-氧代环己基)乙酸乙酯，将S9中的对氯苯胺替换为N-甲基对氯苯胺，得到S9中的目标化合物(酰胺类化合物)之后不再进行S10中的羰基衍生化反应，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid The ester, the p-chloroaniline in S9 is replaced by N-methyl-p-chloroaniline, and the target compound (amide compound) in S9 is obtained, and the carbonyl derivatization reaction in S10 is not performed. The mass spectrometric identification data of the specific compound are as follows:
化合物81～82：ESI-MS：m/z 411.16，[M+H] +。 Compounds 81-82: ESI-MS: m/z 411.16, [M+H] + .
实施例25：化合物83～84的合成。Example 25: Synthesis of compounds 83 to 84.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S1中的2-(4-氧代环己基)丙酸乙酯替换为2-(4-氧代环己基)乙酸乙酯，将S9中的对氯苯胺替换为N-三氘代甲基对氯苯胺，得到S9中的目标化合物(酰胺类化合物)之后不再进行S10中的羰基衍生化反应，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-(4-oxocyclohexyl)acetic acid The ester, the p-chloroaniline in S9 is replaced by N-tridecylmethyl-p-chloroaniline, and the target compound (amide compound) in S9 is obtained, and the carbonyl derivatization reaction in S10 is not carried out, and the specific compound is identified by mass spectrometry. Data are as follows:
化合物83～84：ESI-MS：m/z 414.17，[M+H] +。 Compounds 83-84: ESI-MS: m/z 414.17, [M+H] + .
实施例26：化合物85～90的合成。Example 26: Synthesis of compounds 85-90.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S9中的对氯苯胺替换为4-炔丙基苯胺或N-甲基-4-炔丙基苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the p-chloroaniline in S9 was replaced with 4-propargylaniline or N-methyl-4-propargylaniline. The identification data is as follows:
化合物85：ESI-MS：m/z430.22，[M+H] +。化合物86：ESI-MS：m/z414.23，[M+H] +。化合物87：ESI-MS：m/z444.24，[M+H] +。化合物88：ESI-MS：m/z415.21，[M+H] +。化合物89：ESI-MS：m/z 431.19，[M+H] +。化合物90：ESI-MS：m/z 429.23，[M+H] +。 Compound 85: ESI-MS: m/z 430.22, [M+H] + . Compound 86: ESI-MS: m / z414.23, [M + H] +. Compound 87: ESI-MS: m / z444.24, [M + H] +. Compound 88: ESI-MS: m / z415.21, [M + H] +. Compound 89: ESI-MS: m/z 431.19, [M+H] + . Compound 90: ESI-MS: m / z 429.23, [M + H] +.
实施例27：化合物91～96的合成。Example 27: Synthesis of compounds 91-96.
参照实施例23中记载的方法制备各个步骤中的目标化合物，区别在于将S9中的4-炔丙基苯胺或N-甲基-4-炔丙基苯胺替换为4-五氟化硫基甲基苯胺或N-甲基-4-五氟化硫基甲基苯胺，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 23, except that 4-propargyl phenylamine or N-methyl-4-propargyl phenylamine in S9 was replaced with 4-pentafluorothiol. For the mass spectrometric identification data of specific compounds, aniline or N-methyl-4-pentafluorothiomethylaniline is as follows:
化合物91：ESI-MS：m/z 532.18，[M+H] +。化合物92：ESI-MS：m/z 516.18，[M+H] +。化合物93：ESI-MS：m/z 546.19，[M+H] +。化合物94：ESI-MS：m/z 517.17，[M+H] +。化合物95：ESI-MS：m/z 533.14，[M+H] +。化合物96：ESI-MS：m/z 531.18，[M+H] +。 Compound 91: ESI-MS: m / z 532.18, [M + H] +. Compound 92: ESI-MS: m / z 516.18, [M + H] +. Compound 93: ESI-MS: m / z 546.19, [M + H] +. Compound 94: ESI-MS: m/z 517.17, [M+H] + . Compound 95: ESI-MS: m / z 533.14, [M + H] +. Compound 96: ESI-MS: m / z 531.18, [M + H] +.
实施例28：化合物97～100的合成。Example 28: Synthesis of compounds 97-100.
参照实施例2中记载的方法制备各个步骤中的目标化合物，区别在于将S1中的2-(4-氧代环己基)丙酸乙酯替换为2-氧代-2-(4-氧代环己基)乙酸乙酯，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 2 except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-oxo-2-(4-oxo). Ethyl acetate of cyclohexyl), the mass spectrometric identification data of specific compounds are as follows:
化合物97：ESI-MS：m/z 518.13，[M+H] +。化合物98：ESI-MS：m/z 502.13，[M+H] +。化合物99：ESI-MS：m/z 532.14，[M+H] +。化合物100：ESI-MS：m/z 503.11，[M+H] +。 Compound 97: ESI-MS: m / z 518.13, [M + H] +. Compound 98: ESI-MS: m / z 502.13, [M + H] +. Compound 99: ESI-MS: m/z 532.14, [M+H] + . Compound 100: ESI-MS: m / z 503.11, [M + H] +.
实施例29：化合物101的合成。Example 29: Synthesis of Compound 101.
参照实施例1中记载的方法制备各个步骤中的目标化合物，区别在于将S1中的2-(4-氧代环己基)丙酸乙酯替换为2-氧代-2-(4-氧代环己基)乙酸乙酯，具体化合物的质谱鉴定数据如下：The target compound in each step was prepared by the method described in Example 1, except that the ethyl 2-(4-oxocyclohexyl)propionate in S1 was replaced with 2-oxo-2-(4-oxo). Ethyl acetate of cyclohexyl), the mass spectrometric identification data of specific compounds are as follows:
化合物101：ESI-MS：m/z 411.12，[M+H] +。 Compound 101: ESI-MS: m / z 411.12, [M + H] +.
实施例30：化合物针对HeLa细胞吲哚胺-2，3-双加氧酶(IDO)的抑制活性考察。Example 30: Investigation of the inhibitory activity of the compound against the indoleamine-2,3-dioxygenase (IDO) of HeLa cells.
从ATCC获得HeLa(ATCC CCL-2)细胞，并补充4.5g/L的葡萄糖、4.5g/L的L-谷氨酰胺和4.5g/L的L-丙酮酸钠、2mM的L-丙氨酰-L-谷氨酰胺二肽、100U/mL的青霉素、100μg/mL的链霉素和10％胎牛血清。将细胞维持在37℃，5％CO 2的潮湿培养箱中。干扰素γ可诱导Hela细胞表达IDO，这一模型被用来测试化合物对吲哚胺2，3-双加氧酶(IDO)的抑制活性。Hela细胞的培养液为含100μM的L-色氨酸，但不含酚红的RPMI-1640。待测化合物的贮备溶液用二甲基亚砜配制，浓度为10mM。实验时，用二甲基亚砜稀释至试验最高浓度，再用培养基进行3倍系列稀释，一般稀释成8到10个浓度点，每个浓度点设复孔。二甲基亚砜的终浓度为0.5％，每次实验均包含内参化合物Epacadostat(INCB024360)。 HeLa (ATCC CCL-2) cells were obtained from ATCC and supplemented with 4.5 g/L glucose, 4.5 g/L L-glutamine and 4.5 g/L sodium L-pyruvate, 2 mM L-alanyl -L-glutamine dipeptide, 100 U/mL penicillin, 100 μg/mL streptomycin and 10% fetal bovine serum. The cells were maintained in a humidified incubator at 37 ° C, 5% CO 2 . Interferon gamma induces expression of IDO in Hela cells, a model used to test the inhibitory activity of compounds on indoleamine 2,3-dioxygenase (IDO). The culture medium of Hela cells was RPMI-1640 containing 100 μM of L-tryptophan but no phenol red. The stock solution of the test compound was prepared with dimethyl sulfoxide at a concentration of 10 mM. During the experiment, it was diluted with dimethyl sulfoxide to the highest concentration of the test, and then serially diluted with the medium for 3 times, generally diluted to 8 to 10 concentration points, and duplicate holes were set at each concentration point. The final concentration of dimethyl sulfoxide was 0.5%, and each experiment contained the internal reference compound Epacadostat (INCB024360).
试验的具体程序如下：在96孔培养板上每孔加入20000个Hela细胞，过夜培养。24h后，将干扰 素γ(终浓度为50ng/mL)和不同浓度的待测化合物和内参化合物加入到培养的细胞中。24h后，将140μL上清液/孔转移至一个新的96孔板中，每孔加入6.1N三氯乙酸各10μL，50℃孵育30min，使N-甲酰基-犬尿氨酸水解为犬尿氨酸。将反应混合物离心(2500rpm，10min)，以去除沉淀物。将上清液100μL转移至另一个新的96孔板中，每孔加入2％(w/v)的p-(二甲基氨基)苯甲醛(p-DMBA)/冰醋酸溶液各100μL，用BioTek Synergy H1酶标仪(Molecular Devices)读取490nm处的吸光值。分析已读取的原始数据，计算受试化合物的不同浓度点对IDO酶活性的抑制，采用GraphPad Prism软件对抑制百分比数据进行非线性拟合分析，得到化合物的半数抑制浓度IC 50值，结果见下表。 The specific procedure of the assay was as follows: 20,000 HeLa cells were added to each well in a 96-well culture plate and cultured overnight. After 24 h, interferon gamma (final concentration 50 ng/mL) and various concentrations of test compound and internal reference compound were added to the cultured cells. After 24 h, transfer 140 μL of supernatant/well to a new 96-well plate, add 10 μL of each of 6.1 N trichloroacetic acid per well, incubate at 50 ° C for 30 min to hydrolyze N-formyl-kynurenine to canine urine. Amino acid. The reaction mixture was centrifuged (2500 rpm, 10 min) to remove the precipitate. Transfer 100 μL of the supernatant to another new 96-well plate, add 2 μg/w of p-(dimethylamino)benzaldehyde (p-DMBA)/glacial acetic acid solution to each well, using 100 μL each. The BioTek Synergy H1 microplate reader (Molecular Devices) reads the absorbance at 490 nm. The raw data read was analyzed, and the inhibition of IDO enzyme activity by different concentration points of the test compound was calculated. The half-inhibition concentration IC 50 value of the compound was obtained by GraphPad Prism software. The following table.
表1.本发明的化合物对IDO酶活性的抑制效果Table 1. Inhibitory effects of the compounds of the invention on IDO enzyme activity
编号Numbering 化合物Compound IC 50 IC 50
11 化合物5Compound 5 AA
22 化合物6Compound 6 AA
33 化合物61Compound 61 AA
44 化合物66Compound 66 AA
55 化合物68Compound 68 BB
66 化合物69Compound 69 BB
77 化合物72Compound 72 BB
88 化合物82Compound 82 BB
99 化合物83Compound 83 BB
1010 化合物84Compound 84 BB
1111 内参化合物Internal reference compound BB
注：A表示＜10nM；B表示＜100nM；C表示＜1000nM。Note: A indicates <10 nM; B indicates <100 nM; C indicates <1000 nM.
由表1中的结果可知，本发明提供的一系列结构新颖的式I化合物能够针对HeLa细胞吲哚胺-2，3-双加氧酶(IDO)产生抑制效果，IC50值均可达到100nM以下，个别甚至达到10nM以下，效果较为显著，可以作为高效的IDO抑制剂，用于至少部分由IDO介导的疾病的预防和/或治疗，具有抗肿瘤、抗神经退行性疾病(如阿尔茨海默病)、抗炎等多种预期用途。From the results in Table 1, it can be seen that the novel structure of the compound of the formula I provided by the present invention can inhibit the indoleamine-2,3-dioxygenase (IDO) of HeLa cells, and the IC50 value can reach 100 nM or less. Individually even below 10nM, the effect is more significant, can be used as a highly effective IDO inhibitor for the prevention and / or treatment of diseases mediated at least in part by IDO, with anti-tumor and anti-neurodegenerative diseases (such as Alzhai Silent disease, anti-inflammatory and many other intended uses.
实施例31：化合物针对HeLa细胞吲哚胺-2，3-双加氧酶(IDO)的抑制活性考察。Example 31: Inhibitory activity of compounds against indoleamine-2,3-dioxygenase (IDO) of HeLa cells.
从ATCC获得HeLa(ATCC CCL-2)细胞，培养在EMEM(Eagle′s Minimum Essential Medium；
Figure PCTCN2019081709-appb-000060
30-2003 TM)培养基中，该培养基含有Earle’s的平衡盐溶液、非必需氨基酸、2mM的L-谷氨酰胺、1mM的丙酮酸钠和1500mg/L的碳酸氢钠，具体操作如下： HeLa (ATCC CCL-2) cells were obtained from ATCC and cultured in EMEM (Eagle's Minimum Essential Medium;
Figure PCTCN2019081709-appb-000060
In 30-2003 TM medium, the medium contains Earle's balanced salt solution, non-essential amino acids, 2 mM L-glutamine, 1 mM sodium pyruvate and 1500 mg/L sodium bicarbonate, as follows:
1.将Hela细胞接种到96孔板(Corning；3599)中：1. Inoculate Hela cells into 96-well plates (Corning; 3599):
1)从烧瓶中移除培养基。1) Remove the medium from the flask.
2)用PBS冲洗细胞。2) Rinse the cells with PBS.
3)将TrypLE溶液加入烧瓶中，使细胞脱落；用含有10％FBS的新鲜培养基洗涤细胞一次，然后以1000rpm离心5分钟。3) The TrypLE solution was added to the flask to cause the cells to fall off; the cells were washed once with fresh medium containing 10% FBS, and then centrifuged at 1000 rpm for 5 minutes.
4)吸出细胞上清液，加入1mL培养基，重悬细胞并计数细胞。4) Aspirate the cell supernatant, add 1 mL of medium, resuspend the cells and count the cells.
5)对于100μL适当生长培养基中的Hela细胞，以每孔4500个细胞的密度接种细胞。5) For 100 μL of HeLa cells in appropriate growth medium, cells were seeded at a density of 4500 cells per well.
6)将细胞在37℃，5％CO 2下孵育过夜。 6) Incubate the cells overnight at 37 ° C, 5% CO 2 .
2.化合物准备和化合物处理：2. Compound preparation and compound treatment:
1)在DMSO中制备10mM化合物原液。1) A 10 mM compound stock solution was prepared in DMSO.
2)然后进行3倍连续稀释9个剂量；将5μL化合物加入到45μL培养基中作为中间稀释液(10倍稀释，含10％DMSO)。2) Three doses of serial dilution were then performed; 5 μL of the compound was added to 45 μL of the medium as an intermediate dilution (10-fold dilution, containing 10% DMSO).
3)向每个孔补充96μL新鲜生长培养基，以产生196μL的总培养基体积；将2μL化合物从中间稀释板加入到测定板中的细胞中，然后在37℃，5％CO 2下孵育。 3) 96 μL of fresh growth medium was added to each well to produce a total medium volume of 196 μL; 2 μL of the compound was added from the intermediate dilution plate to the cells in the assay plate, and then incubated at 37 ° C, 5% CO 2 .
4)在每个孔中加入2μL的人IFN-γ溶液，使最终浓度为15ng/mL，总体积为200μL；最终的DMSO浓度为0.1％。4) 2 μL of human IFN-γ solution was added to each well to give a final concentration of 15 ng/mL in a total volume of 200 μL; the final DMSO concentration was 0.1%.
5)将细胞在37℃，5％CO 2培养箱中孵育48小时。 5) Incubate the cells for 48 hours at 37 ° C in a 5% CO 2 incubator.
3.IDO/犬尿氨酸测定和数据分析：3. IDO / kynurenine determination and data analysis:
1)在37℃，5％CO 2培养箱中再孵育72小时后，将每孔140μL上清液转移到新的96孔板中。 1) After further incubation for 72 hours at 37 ° C in a 5% CO 2 incubator, 140 μL of supernatant per well was transferred to a new 96-well plate.
2)将10μL的6.1N三氯乙酸混合到各孔中，然后将板密封并在50℃下孵育30分钟。2) 10 μL of 6.1 N trichloroacetic acid was mixed into each well, and then the plate was sealed and incubated at 50 ° C for 30 minutes.
3)然后将板以4000rpm离心5分钟。3) The plate was then centrifuged at 4000 rpm for 5 minutes.
4)将每孔100μL上清液转移到另一个96孔测定板中，并与100μL的6％(w/v)对二甲基氨基苯甲醛混合。4) 100 μL of the supernatant per well was transferred to another 96-well assay plate and mixed with 100 μL of 6% (w/v) p-dimethylaminobenzaldehyde.
5)使用EnSpire微孔板检测仪在OD480nm处读取吸光值。5) Read the absorbance at OD 480 nm using an EnSpire microplate reader.
4.数据分析：4. Data analysis:
1)计算每个筛选板的HC(高对照：10ng/mL的IFN-γ)和LC(低对照：无IFN-γ)的平均数据。1) Calculate the average data of HC (high control: 10 ng/mL IFN-γ) and LC (low control: no IFN-γ) per screening plate.
2)化合物孔的抑制百分比(％)＝100×(ave HC-cpd well)/(ave HC-ave LC)，其中：2) Percent inhibition (%) of compound pores = 100 × (ave HC-cpd well) / (ave HC-ave LC), wherein:
ave HC：含有10ng/mL的IFN-γ，无化合物的平均读值；Ave HC: contains 10 ng/mL of IFN-γ, no average reading of compounds;
cpd well：含有10ng/mL的IFN-γ，并含有待测化合物的读值；Cpd well: contains 10 ng/mL of IFN-γ and contains the reading value of the test compound;
ave LC：无10ng/mL的IFN-γ，无化合物的平均读值。Ave LC: no 10 ng/mL IFN-γ, no mean reading of compounds.
3)使用GraphPad Prism 6软件计算IC 50，并绘制化合物的效应-剂量曲线。 3) using the software GraphPad Prism 6 calculated IC 50, and draw effect of the compound - dose curve.
表2.本发明的化合物对IDO酶活性的抑制效果Table 2. Inhibitory effects of the compounds of the invention on IDO enzyme activity
Figure PCTCN2019081709-appb-000061
Figure PCTCN2019081709-appb-000061
*参见文献：ACS Medicinal Chemistry Letters，2017，8(5)，486-491.*See literature: ACS Medicinal Chemistry Letters, 2017, 8(5), 486-491.
由表2中的结果可知，本发明提供的一系列结构新颖的式I化合物中，化合物47具有能够针对HeLa细胞吲哚胺-2，3-双加氧酶(IDO)产生优异的抑制效果，IC 50值达到了1nM以下；化合物52与对照化合物Epacadostat相比，具有相当的HeLa细胞吲哚胺-2，3-双加氧酶(IDO)抑制效果。这些化合物均可以作为高效的IDO抑制剂，用于至少部分由IDO介导的疾病的预防和/或治疗，具有抗肿瘤、抗神经退行性疾病(如阿尔茨海默病)、抗炎等多种预期用途。 From the results in Table 2, it is understood that among the series of novel compounds of the formula I provided by the present invention, the compound 47 has an excellent inhibitory effect against HeLa cell guanamine-2,3-dioxygenase (IDO). The IC 50 value reached below 1 nM; Compound 52 had comparable HeLa cell indole-2,3-dioxygenase (IDO) inhibition compared to the control compound Epacadostat. These compounds are useful as potent IDO inhibitors for the prevention and/or treatment of diseases mediated at least in part by IDO, with anti-tumor, anti-neurodegenerative diseases (such as Alzheimer's disease), anti-inflammatory, etc. The intended use.

Claims (15)

  1. 一种具有式I结构的化合物：A compound having the structure of formula I:
    Figure PCTCN2019081709-appb-100001
    Figure PCTCN2019081709-appb-100001
    或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药，其中：Or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotope label or prodrug thereof, wherein:
    R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子； R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and R 2 are respectively located in the benzene ring When on one adjacent carbon atom, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 independently of each other. a hetero atom of O, N or S;
    A为NR 6、N-OH、S或O； A is NR 6 , N-OH, S or O;
    R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
    R 5a和R 5b各自独立地为氢、卤素、羟基或任选取代的C 1-C 6烷基；当R 5a和R 5b同时为羟基时，二者脱水形成羰基； R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
    E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkane And each m is independently 0, 1, 2 or 3.
  2. 根据权利要求1所述的具有式I结构的化合物，其特征在于：A compound of the formula I according to claim 1 wherein:
    R 1、R 2至少有一个为任选取代的C 2-C 4炔基、-SF 5、-NHSO 2NH 2、-P(O)(CH 3) 2或二烷氧基次磷酰基； At least one of R 1 and R 2 is optionally substituted C 2 -C 4 alkynyl, -SF 5 , -NHSO 2 NH 2 , -P(O)(CH 3 ) 2 or dialkoxyphosphoryl;
    A为NR 6、N-OH、S或O； A is NR 6 , N-OH, S or O;
    R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
    R 5a和R 5b各自独立地为氢、卤素、羟基或任选取代的C 1-C 6烷基；当R 5a和R 5b同时为羟基时，二者脱水形成羰基； R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
    E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkyl And each m is independently 0, 1, 2 or 3.
  3. 根据权利要求1所述的具有式I结构的化合物，其特征在于：A compound of the formula I according to claim 1 wherein:
    当A为NR 6时； When A is NR 6 ;
    R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且 n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元 或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子； R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and R 2 are respectively located in the benzene ring When on one adjacent carbon atom, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 independently of each other. a hetero atom of O, N or S;
    R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
    R 5a和R 5b各自独立地为氢、卤素、羟基或任选取代的C 1-C 6烷基；当R 5a和R 5b同时为羟基时，二者脱水形成羰基； R 5a and R 5b are each independently hydrogen, halogen, hydroxy or optionally substituted C 1 -C 6 alkyl; when both R 5a and R 5b are hydroxy, both are dehydrated to form a carbonyl group;
    E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkane And each m is independently 0, 1, 2 or 3.
  4. 根据权利要求1所述的具有式I结构的化合物，其特征在于：A compound of the formula I according to claim 1 wherein:
    当A为N-OH，且R 5a和R 5b不同时为氢时； When A is N-OH and R 5a and R 5b are not hydrogen at the same time;
    R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子； R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and R 2 are respectively located in the benzene ring When on one adjacent carbon atom, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 independently of each other. a hetero atom of O, N or S;
    R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
    E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R4) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkyl And each m is independently 0, 1, 2 or 3.
  5. 根据权利要求1所述的具有式I结构的化合物，其特征在于：A compound of the formula I according to claim 1 wherein:
    当R 5a和R 5b形成羰基时； When R 5a and R 5b form a carbonyl group;
    R 1和R 2各自独立地为氢、卤素、氰基、-(CH 2) nSF 5、-(CH 2) nNHSO 2NH 2、-(CH 2) nP(O)(CH 3) 2、磺酰基、磺酰氨基、任选取代的次磷酰基、任选取代的磷酰基、任选取代的C 1-C 4烷基、任选取代的C 3-C 6环烷基、任选取代的3至6元杂环基、任选取代的C 1-C 4烷氧基、任选取代的C 1-C 4烷酰基或任选取代的C 2-C 4炔基，R 1、R 2中的氢和/或连接R 1、R 2的苯环上的氢任选被氘取代，且n为0、1、2或3；当R 1和R 2分别位于苯环的两个相邻碳原子上时，R 1和R 2任选相互连接成饱和的或不饱和的5元或6元环，且5元或6元环任选包含0、1或2个各自独立地为O、N或S的杂原子； R 1 and R 2 are each independently hydrogen, halogen, cyano, -(CH 2 ) n SF 5 , -(CH 2 ) n NHSO 2 NH 2 , -(CH 2 ) n P(O)(CH 3 ) 2 , sulfonyl, sulfonylamino, optionally substituted hypophosphoryl, optionally substituted phosphoryl, optionally substituted C 1 -C 4 alkyl, optionally substituted C 3 -C 6 cycloalkyl, any a substituted 3- to 6-membered heterocyclic group, an optionally substituted C 1 -C 4 alkoxy group, an optionally substituted C 1 -C 4 alkanoyl group or an optionally substituted C 2 -C 4 alkynyl group, R 1 Hydrogen in R 2 and/or hydrogen on the benzene ring linking R 1 , R 2 may be optionally substituted by deuterium, and n is 0, 1, 2 or 3; when R 1 and R 2 are respectively located in the benzene ring When on one adjacent carbon atom, R 1 and R 2 are optionally bonded to each other to form a saturated or unsaturated 5- or 6-membered ring, and the 5- or 6-membered ring optionally contains 0, 1 or 2 independently of each other. a hetero atom of O, N or S;
    A任意选自NR 6、N-OH、S或O； A is optionally selected from NR 6 , N-OH, S or O;
    R 3和R 6各自独立地为氢、任选取代的C 1-C 6烷基、任选取代的C 1-C 6烷氧基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 6环烷基，且R 3、R 6中的氢任选被氘取代； R 3 and R 6 are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally a substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 6 cycloalkyl group, and the hydrogen in R 3 , R 6 is optionally substituted by deuterium;
    E为任选被至少一个R 7取代的5至12元的芳基、杂芳基、环烷基或杂环基；每一个R 7各自独立地为氢、卤素、羟基、氰基、任选取代的C 1-C 6烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、-(CR 4R 4) m-CO 2H、-(CR 4R 4) m-C(O)NH 2、-(CR 4R 4) m-C(O)NHR 4、-(CR 4R 4) m-N(R 4) 2、-NH-(CR 4R 4) m-CO 2H或-NH-(CR 4R 4) m-C(O)NH 2；每一个R 4各自独立地为氢、卤素或任选取代的C 1-C 6烷基；且每一个m各自独立地为0、1、2或3。 E is a 5 to 12 membered aryl, heteroaryl, cycloalkyl or heterocyclic group optionally substituted by at least one R 7 ; each R 7 is independently hydrogen, halogen, hydroxy, cyano, optionally Substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, -(CR 4 R 4 ) m -CO 2 H, -(CR 4 R 4 ) m -C(O)NH 2 , -(CR 4 R 4 ) m -C(O)NHR 4 , -(CR 4 R 4 ) m -N(R 4 ) 2 , -NH-(CR 4 R 4 ) m -CO 2 H or -NH-(CR 4 R 4 ) m -C(O)NH 2 ; each R 4 is independently hydrogen, halogen or optionally substituted C 1 -C 6 alkane And each m is independently 0, 1, 2 or 3.
  6. 根据权利要求1所述的具有式I结构的化合物，其特征在于：A compound of the formula I according to claim 1 wherein:
    E为下列片段之一：E is one of the following fragments:
    Figure PCTCN2019081709-appb-100002
    Figure PCTCN2019081709-appb-100002
  7. 根据权利要求1所述的具有式I结构的化合物，其包括：A compound of formula 1 according to claim 1 comprising:
    Figure PCTCN2019081709-appb-100003
    Figure PCTCN2019081709-appb-100003
    Figure PCTCN2019081709-appb-100004
    Figure PCTCN2019081709-appb-100004
    Figure PCTCN2019081709-appb-100005
    Figure PCTCN2019081709-appb-100005
    Figure PCTCN2019081709-appb-100006
    Figure PCTCN2019081709-appb-100006
    Figure PCTCN2019081709-appb-100007
    Figure PCTCN2019081709-appb-100007
    Figure PCTCN2019081709-appb-100008
    Figure PCTCN2019081709-appb-100008
    Figure PCTCN2019081709-appb-100009
    Figure PCTCN2019081709-appb-100009
  8. 根据权利要求1所述的具有式I结构的化合物的制备方法，其包括下列步骤：A method of preparing a compound of formula I according to claim 1 comprising the steps of:
    1)将化合物VI与磺酰化试剂反应，得到化合物V；1) reacting compound VI with a sulfonylating reagent to obtain compound V;
    Figure PCTCN2019081709-appb-100010
    Figure PCTCN2019081709-appb-100010
    2)向化合物V中引入片段E，得到化合物IV；2) introducing a fragment E into the compound V to obtain a compound IV;
    Figure PCTCN2019081709-appb-100011
    Figure PCTCN2019081709-appb-100011
    3)将化合物IV氢化，得到化合物III；3) hydrogenation of compound IV to give compound III;
    Figure PCTCN2019081709-appb-100012
    Figure PCTCN2019081709-appb-100012
    4)将化合物III与苯胺类化合物反应，得到化合物II；4) reacting compound III with an aniline compound to obtain compound II;
    Figure PCTCN2019081709-appb-100013
    Figure PCTCN2019081709-appb-100013
    5)向化合物II中引入片段A，得到具有式I结构的化合物；5) introducing a fragment A into the compound II to obtain a compound having the structure of the formula I;
    Figure PCTCN2019081709-appb-100014
    Figure PCTCN2019081709-appb-100014
    其中：片段A和E以及取代基R 1、R 2、R 3、R 5a和R 5b的定义如权利要求1中所述。 Wherein: the definitions of the fragments A and E and the substituents R 1 , R 2 , R 3 , R 5a and R 5b are as defined in claim 1.
  9. 一种药物组合物，其包含根据权利要求1至7中任一项所述的具有式I结构的化合物或其药学上 可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药。A pharmaceutical composition comprising a compound of the formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof, according to any one of claims 1 to 7 A conformation, a cis-trans isomer, an isotope label, or a prodrug.
  10. 根据权利要求1至7中任一项所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者根据权利要求9所述的药物组合物，其用作IDO抑制剂。A compound having the structure of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer or cis-trans isomer thereof An isotopic label or prodrug or a pharmaceutical composition according to claim 9 for use as an IDO inhibitor.
  11. 根据权利要求1至7中任一项所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者根据权利要求9所述的药物组合物用作IDO抑制剂的用途。A compound having the structure of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer or cis-trans isomer thereof Use of an isotopic label or prodrug or a pharmaceutical composition according to claim 9 as an IDO inhibitor.
  12. 根据权利要求1至7中任一项所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者根据权利要求9所述的药物组合物在制备用于预防和/或治疗至少部分由IDO介导的疾病的药物中的用途。A compound having the structure of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer or cis-trans isomer thereof Use of an isotopic label or prodrug or a pharmaceutical composition according to claim 9 for the manufacture of a medicament for the prevention and/or treatment of a disease mediated at least in part by IDO.
  13. 一种用于预防和/或治疗至少部分由IDO介导的疾病的方法，其包括下列步骤：将治疗有效量的根据权利要求1至7中任一项所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者根据权利要求9所述的药物组合物施用于对其有需求的患者。A method for preventing and/or treating a disease mediated at least in part by IDO, comprising the steps of: treating a therapeutically effective amount of a compound having the structure of Formula I according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug thereof or a pharmaceutical composition according to claim 9 Patients who have a need for it.
  14. 一种药物联合形式，其包含根据权利要求1至7中任一项所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者根据权利要求9所述的药物组合物以及至少一种额外的癌症治疗剂。A pharmaceutical combination comprising a compound having the structure of Formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer thereof A construct, cis-trans isomer, isotopic label or prodrug or a pharmaceutical composition according to claim 9 and at least one additional cancer therapeutic.
  15. 一种用于预防和/或治疗癌症的方法，其包括下列步骤：将治疗有效量的根据权利要求1至7中任一项所述的具有式I结构的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、顺反异构体、同位素标记物或前药或者根据权利要求9所述的药物组合物以及至少一种额外的癌症治疗剂施用于对其有需求的患者。A method for the prevention and/or treatment of cancer comprising the step of: administering a therapeutically effective amount of a compound of the formula I according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof , hydrate, solvate, stereoisomer, tautomer, cis-trans isomer, isotopic label or prodrug or pharmaceutical composition according to claim 9 and at least one additional cancer therapeutic Apply to patients who need it.
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