WO2018161960A1 - 乙型肝炎病毒表面抗原抑制剂 - Google Patents

乙型肝炎病毒表面抗原抑制剂 Download PDF

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Publication number
WO2018161960A1
WO2018161960A1 PCT/CN2018/078581 CN2018078581W WO2018161960A1 WO 2018161960 A1 WO2018161960 A1 WO 2018161960A1 CN 2018078581 W CN2018078581 W CN 2018078581W WO 2018161960 A1 WO2018161960 A1 WO 2018161960A1
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group
pharmaceutically acceptable
acceptable salt
mmol
compound according
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PCT/CN2018/078581
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English (en)
French (fr)
Inventor
孙飞
杜金华
胡彦宾
周丽莉
丁照中
陈曙辉
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福建广生堂药业股份有限公司
南京明德新药研发股份有限公司
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Priority to LTEPPCT/CN2018/078581T priority Critical patent/LT3590942T/lt
Priority to PL18763490T priority patent/PL3590942T3/pl
Application filed by 福建广生堂药业股份有限公司, 南京明德新药研发股份有限公司 filed Critical 福建广生堂药业股份有限公司
Priority to SI201830376T priority patent/SI3590942T1/sl
Priority to CA3055442A priority patent/CA3055442C/en
Priority to ES18763490T priority patent/ES2879930T3/es
Priority to JP2019548977A priority patent/JP6783424B2/ja
Priority to EP18763490.2A priority patent/EP3590942B1/en
Priority to EA201992082A priority patent/EA038122B9/ru
Priority to MX2019010736A priority patent/MX2019010736A/es
Priority to RS20210851A priority patent/RS62094B1/sr
Priority to CN201880001647.2A priority patent/CN109071564B/zh
Priority to KR1020197029437A priority patent/KR102087397B1/ko
Priority to DK18763490.2T priority patent/DK3590942T3/da
Priority to SG11201908101Y priority patent/SG11201908101YA/en
Priority to AU2018232071A priority patent/AU2018232071B2/en
Priority to US16/491,769 priority patent/US11008331B2/en
Priority to BR112019018650-6A priority patent/BR112019018650B1/pt
Publication of WO2018161960A1 publication Critical patent/WO2018161960A1/zh
Priority to IL269142A priority patent/IL269142B/en
Priority to PH12019502052A priority patent/PH12019502052A1/en
Priority to ZA2019/06252A priority patent/ZA201906252B/en
Priority to HRP20211331TT priority patent/HRP20211331T1/hr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel 10-oxo-6,10-dihydrobenzo[e]pyrido[1,2-c][1,3]oxazine-9-carboxylic acid derivative as a hepatitis B surface antigen inhibitor Specific to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition thereof for the treatment of hepatitis B virus application.
  • Hepatitis B is a disease caused by Hepatitis B Virus (HBV) infection in the body.
  • HBV Hepatitis B Virus
  • Hepatitis B virus is a hepadnavirus that mainly exists in hepatocytes and damages hepatocytes, causing inflammation, necrosis and fibrosis of hepatocytes.
  • Hepatitis B is divided into acute and chronic. Most people with acute hepatitis B can heal themselves through their own immune mechanisms.
  • CHB chronic hepatitis B
  • HCC liver cancer
  • HBsAg hepatitis B virus surface antigen
  • the surface antigen protein of hepatitis B virus plays a very important role in the process of HBV invasion into liver cells, and is of great significance for the prevention and treatment of HBV infection.
  • Surface antigen proteins include large (L), medium (M) and small (S) surface antigen proteins that share a common C-terminal S region. They are expressed from an open reading frame, the different lengths of which are determined by the three AUG start codons of the reading frame. These three surface antigen proteins include pre-S1/pre-S2/S, pre-S2/S and S domains.
  • the HBV surface antigen protein is integrated into the endoplasmic reticulum (ER) membrane and is initiated by the N-terminal signal sequence (Eble et al., 1987, 1990; Schmitt et al., 2004). They not only constitute the basic structure of the virion, but also form globular and filamentous subviral particles (SVPs, HBsAg), aggregated in ER, host ER and pre-Golgi apparatus (Huovila et al., 1992), SVP contains mostly S Surface antigen protein (Chisari et al., 1986). The L protein (Bruss, 1997, 2004) is critical in the morphogenesis of the virus and the interaction of the nucleocapsid, but is not necessary for the formation of SVP.
  • SVPs globular and filamentous subviral particles
  • SVPs are non-infectious due to their lack of nucleocapsids. SVPs are heavily involved in disease progression, especially in response to hepatitis B virus. In the blood of infected people, the amount of SVPs is at least 10,000 times the number of viruses (Bruns et al., 1998; Ganem and Prince, 2004). It traps the immune system and weakens the body's immune response to hepatitis B virus.
  • HBsAg also inhibits human innate immunity, inhibits the production of cytokines induced by polysaccharides (LPS) and IL-2 (Vanlandschoot et al., 2002), inhibits dendritic cell DC function and LPS against ERK-1/2 and c- The N-terminal interference kinase-1/2 induces activity in monocytes (Op den Brouw et al., 2009). It is worth noting that disease progression in cirrhosis and hepatocellular carcinoma is also largely associated with persistent secretion of HBsAg (Chisari et al., 1989; Wang et al., 2004; Yang et al., 2009; Wu et al. , 2014). These findings suggest that HBsAg plays an important role in the development of chronic hepatitis.
  • anti-HBV drugs are mainly immunomodulators (interferon- ⁇ and peginterferon- ⁇ -2 ⁇ ) and antiviral drugs (lamivudine, adefovir dipivoxil, entecavir, Bivudine, tenofovir, clafidine, etc.).
  • antiviral therapeutic drugs belong to nucleotides, and their mechanism of action is to inhibit the synthesis of HBV DNA, and can not directly reduce the level of HBsAg.
  • nucleotides show that HBsAg clearance is similar to natural observations (Janssen et al. Lancet (2005), 365, 123-129; Marcellin et al. N. Engl. J. Med. (2004) , 351, 1206-1217; Buster et al. Hepatology (2007), 46, 388-394).
  • WO2016128335A1 discloses a series of 2-oxo-6,7-dihydrobenzo[a]quinolizine 3-carboxylic acid derivatives for the treatment or prevention of hepatitis B virus infection (the general structure is as follows),
  • the series of fused ring compounds still have the problems of strong molecular rigidity, insufficient solubility, and easy aromatization. Therefore, for clinical applications, the demand for more medicinal drugs still exists.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from H, OH, CN, NH 2 or is selected from C 11-5 alkyl, C 1-5 heteroalkyl, C 2-5 alkynyl optionally substituted by 1, 2 or 3 R a C 3-6 alkyl group and a 3 to 6 membered heterocycloalkyl group;
  • R 2 is selected from H, halogen, or is selected from C 1 - 3 alkyl and C 1-3 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • n is selected from 0, 1, 2, 3, 4 and 5;
  • A is selected from the group consisting of 1, 2 or 3 R substituted: phenyl or 5- to 6-membered heteroaryl;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • R is selected from the group consisting of H, F, Cl, Br, OH, CH 3 , CH 3 O, CF 3 , CHF 2 , CH 2 F.
  • R 1 is selected from the group consisting of: H, OH, CH 3 , CHF 2 , CH 3 O,
  • R 2 is selected from H, F, Cl, Br, or is selected from the group consisting of: 1 , 3 or 3, R: CH 3 , CH 3 CH 2 , CH 3 O, CH 3 CH 2 O,
  • R 2 is selected from the group consisting of Cl and CH 3 O.
  • the above A is selected from the group consisting of phenyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, optionally substituted by 1, 2 or 3 R.
  • the above A is selected from the group consisting of, optionally substituted by 1, 2 or 3 R:
  • the above A is selected from the group consisting of:
  • the above A is selected from the group consisting of:
  • the above m is 3.
  • R 2 is selected from the group consisting of Cl and CH 3 O.
  • R 1 is CH 3 O.
  • the above m is one.
  • R 2 is Cl
  • the above A is selected from the group consisting of, optionally substituted by 1, 2 or 3 R:
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 , A, R, m are as defined above.
  • the above compound or a pharmaceutically acceptable salt thereof selected from the group consisting of
  • the present invention also provides a compound or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the above claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a medicament for treating hepatitis B.
  • the present invention creatively designs and synthesizes a novel series of compounds having a six-membered oxynital as a core structure.
  • the compound of the invention overcomes the defect that the six-membered ring nitrogen oxyacetal core structure may be unstable and easily hydrolyzed in the acidic environment of the body through ingenious design. It has been confirmed by relevant experiments that the compound of the present invention has good stability in a certain temperature range and acid range. Further, after creatively replacing a carbon atom with an oxygen atom, the activity of the series of compounds of the present invention can be well maintained relative to the prior art. This was verified in an in vitro inhibition experiment on hepatitis B surface antigen activity.
  • the design of the oxygen atom replacing the carbon atom prevents the mother nucleus from being dehydrogenated and aromatized by the presence of the carbon atom, and the water solubility of the compound of the present invention is improved, so that more excellent drug-forming properties can be obtained.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Ketone substitution does not occur on the aryl group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • a substitution reaction for example, an affinity substitution reaction.
  • representative leaving groups include chlorine, bromine; sulfonate groups such as tosylate, p-toluenesulfonate, and the like.
  • protecting group includes, but is not limited to, “amino protecting group”, “hydroxy protecting group”.
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl; arylmethyl groups such as benzyl (Bn) and the like.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • Step B Dissolve 1-2 (20.00 g, 92.33 mmol) in N,N-dimethylformamide (60 mL), and add benzyl bromide (14.26 ml, 120.03 mmol) and potassium carbonate (33.18 g) with stirring. , 240.06 mmol), controlled at 25 to 30 degrees Celsius. The system was stirred at 25 to 30 degrees Celsius for 48 hours. After completion of the reaction, ethyl acetate (200 ml) and water (500 ml) were added to the mixture, and the organic layer was separated. The organic phase was washed with water (50 mL*2)
  • Step D Dissolve 1-4 (15 g, 51.25 mmol) in dichloromethane (150 mL) and add oxalyl chloride (9.76 g, 76.88 mmol) and N,N-dimethyl Amide (394.26 ⁇ L, 5.13 mmol). The system was stirred at 25 degrees Celsius for 2 hours. The solvent was concentrated under reduced pressure to give 1-5.
  • Step E Lithium hexamethyldisilazide (1 mol/L, 101.06 ml) was added dropwise to 1-5 (15.72 g, 50.53 mmol) and 2-acetyl-3- at minus 70 °C. Ethyl dimethylaminoacrylate (7.8 g, 42.11 mmol) in tetrahydrofuran (93 mL).
  • Step G 1-7 (3 g, 9.27 mmol) was dissolved in N,N-dimethylformamide (60 ml), and potassium carbonate (10.25 g, 74.16 mmol) and dibromotoluene (6.59 g). , 27.81 mmol), the system was stirred at 100 ° C for 32 hours. The reaction mixture was quenched with EtOAc (EtOAc) The organic phase was combined, washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 1-8.
  • Step H 1-8 (100.00 mg, 242.81 ⁇ mol) was dissolved in methanol (2 mL) and water (1 mL), sodium hydroxide (19.42 mg, 485.62 micromoles) was added and stirred at 25 ° C for 16 hours.
  • the reaction solution was adjusted to pH 3 with 1 mol/L hydrochloric acid, and extracted with dichloromethane (15 ml*2).
  • the combined organic layers were washed with brine, dried over sodium sulfate
  • Step A 1-8 (1.60 g, 3.89 mmol) was dissolved in dichloromethane (160 ml), boron tribromide (2.25 ml, 23.34 mmol) was added dropwise at 70 ° C, and stirred at 25 ° C. hour. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc.
  • Step B 2-2 (1.20 g, 3.25 mmol) was dissolved in methanol (30 ml), thionyl chloride (2.36 ml, 32.50 mmol) was added at 0 ° C, and the reaction was stirred at 50 ° C for 16 hours. . The system was concentrated under reduced pressure. EtOAc was evaporated.
  • Step C 2-3 (100.00 mg, 260.57 ⁇ mol), 3-bromo-2,2-dimethyl-1-propanol (65.29 mg, 390.86 ⁇ mol), sodium iodide (7.81 mg, 52.11 Micromolar, potassium carbonate was mixed in N,N-dimethylformamide (2 ml) and stirred at 120 ° C for 16 hours.
  • the reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)
  • EtOAc EtOAc
  • the obtained solid was purified by high performance liquid chromatography (column: Boston Green ODS 150*30 5 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 35%-65%, 12 minutes) Example 2 was obtained.
  • Examples 3 to 9 can be obtained by referring to the production method of Example 2.
  • Step A Dissolve 2-3 (50.00 mg, 130.28 micromoles) in DMF (2 mL), add potassium carbonate (36.01 mg, 260.56 micromoles), (2,2-difluoro-3-hydroxy-propyl) 4-P-toluenesulfonic acid (34.69 mg, 130.28 ⁇ mol), and the system was stirred at 100 ° C for 12 hours.
  • Step B Dissolve 10-2 (40.00 mg, 26.79 ⁇ mol) in tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) with lithium hydroxide monohydrate (1.12 mg, 26.79 ⁇ mol), system Stir at 25 degrees Celsius for 1 hour.
  • the reaction solution was adjusted to pH 3-4 and purified by high performance liquid chromatography (column: Boston Green ODS 150*30 5 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; elution gradient: 30%- 54%, 10 minutes) purification gave Example 10.
  • Examples 11 to 12 can be obtained by referring to the preparation method of Example 10.
  • Step C To a solution of 13-3 (3.64 g, 13.25 mmol), benzyl chloride (2.18 g, 17.23 mmol, 1.98 ml) in dimethylformamide (10.00 mL) 34.45 mmol. The mixed solution was stirred at 25 ° C for 20 hours. Ethyl acetate (150 ml) and water (30 ml) were added to the solution, and the solution was further stirred at 20 ° C for 10 minutes. Then the organic phase was separated and passed through water ( After washing with saturated brine (30 ml * 2), it was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 13-4.
  • Step D 13-4 (2.00 g, 5.48 mmol) and a solution of lithium hydroxide monohydrate (1.38 g, 32.89 mmol) in tetrahydrofuran (20 ml) and water (10 ml) were stirred at 10-20 ° C for 10 hours. . The solution was then washed with ethyl acetate / petroleum ether 1 / 1 (5 mL * 3). The aqueous phase is acidified to a pH of 1 to 2. The solution was extracted with methylene chloride (50 mL *3). Methoxypropanol) benzoic acid (1.30 g, 3.71 mmol, 67.63%).
  • Step E To a solution of lithium hexamethyldisilazide (1 mol/L, 23.88 ml) in tetrahydrofuran (20 mL) dropwise at 70 ° C (5 min) 13-5 (2.94 g, 7.96 m) A solution of ethyl 2-(dimethylaminomethylene)-3-oxobutanoate (1.62 g, 8.76 mmol, 1.10 eq) in THF (20 mL). The cooling bath was then removed and the mixture allowed to stir for 5 minutes.
  • Step F To a solution of 13-6 (3.00 g, 6.36 mmol) in THF (20 mL The solution was stirred at 25 ° C in a hydrogen (15 psi) atmosphere for 2 hours. The brown suspension was then filtered to give a yellow liquid which was concentrated under reduced vacuo. The yellow residue was further triturated with EtOAc (EtOAc/EtOAc (EtOAc)
  • Step G Stir a solution of 13-7 (800.00 mg, 2.10 mmol), potassium carbonate (580.48 mg, 4.20 mmol) and dibromotoluene (551.10 mg, 2.21 mmol) in DMF (20.00 mL) at 100 °C 10 hours. Ethyl acetate (60 ml) and water (10 ml) were added to the reaction mixture, the organic phase was separated, and the aqueous phase was extracted with ethyl acetate (20 ml*3), and all organic phases were combined and water (10) ML *3) Washed and saturated brine (10 mL * 3), and concentrated under reduced pressure to give a yellow liquid.
  • Step H To a solution of 13-7A (240.00 mg, 510.74 mmol), MeOH (EtOAc) (EtOAc) The solution was then stirred at 25 degrees Celsius for 19 hours. The solution was again washed with ethyl acetate/petroleum ether (1/4) (5 mL) and the pH was adjusted to 2-3 by dilute aqueous hydrochloric acid (1 mol/L). The solution was extracted by dichloromethane (40 mL * 3). The organic phases were combined and concentrated under reduced pressure to give a yellow liquid.
  • the yellow liquid was purified by high performance chromatography column (separation column: Agela ASB 150*25 mm*5 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile], elution gradient: 42%-72%, 10 min). 13_A.
  • Step I To a solution of 13-7B (290.00 mg, 617.14 mmol) MeOH (EtOAc) The solution was then stirred at 25 degrees Celsius for 19 hours. The solution was again washed with ethyl acetate/petroleum ether (1/4) (5 mL) and the pH was adjusted to 2-3 by dilute aqueous hydrochloric acid (1 mol/L). The solution was extracted by dichloromethane (40 mL * 3). The organic phases were combined and concentrated under reduced pressure to give a liquid.
  • the liquid was purified by high performance chromatography column (separation column: Agela ASB 150*25mm*5 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile], elution gradient: 42%-72% CO 2 , 11 min)
  • Example 13_B The liquid was purified by high performance chromatography column (separation column: Agela ASB 150*25mm*5 ⁇ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile], elution gradient: 42%-72% CO 2 , 11 min) Example 13_B.
  • Step A To a solution of 14-1 (1.00 g, 10.09 mmol) and bromosuccinimide (3.77 g, 21.19 mmol) in carbon tetrachloride (10.00 mL) was added benzoyl peroxide (122.21) Mg, 504.50 mmol), the resulting mixed solution was lighted at 80 ° C and stirred for 16 hours. After the reaction was completed, the solvent in the mixed solution was removed, and the mixture was dissolved in 60 ml of water and extracted with ethyl acetate (50 ml * 3), and the organic phase was combined, washed with 60 ml of brine, Dry over sodium sulfate, filter and concentrate to give a residue. The residue was purified by silica gel column chromatography (eluent:EtOAc:EtOAc
  • Example 14 was prepared by following the procedure of Example B, Step B, C.
  • Examples 15 to 24 can be obtained by referring to the preparation method of Example 14.
  • Examples 25 to 34 can be obtained by referring to the preparation method of Example 35.
  • EtOAc methylene chloride
  • Step B 35-2 (1.70 g, 9.13 mmol) was dissolved in dichloromethane (20.00 mL) cooled to -78.
  • Diisobutylaluminum hydride (1 mole, 27.39 ml) was added drop by drop at minus 78 degrees Celsius. The mixture was stirred for 2 hours.
  • Step C A solution of triphenyl phosphite (2.93 g, 9.44 mmol, 2.48 ml) was dissolved in dichloromethane (20.00 mL), and liquid bromine (1.51 g) and triethylamine were added to the system at minus 60 degrees Celsius. (1.00 g, 9.91 mmol, 1.37 ml) at minus 60 degrees Celsius. Then 35-3 (600.00 mg, 4.72 mmol) was added at minus 60 degrees Celsius. The mixture was stirred and stirred at 25 ° C for 3 hours.
  • Example 35 was prepared by following the procedure of Example 13, Step D, E.
  • Examples 36 to 40 can be obtained by referring to the preparation method of Example 35.
  • Step A 41-1 (2.00 g, 11.23 mmol) was dissolved in tetrahydrofuran (120 mL) and cooled to minus 60 °C.
  • N-butyllithium 2.5 moles per liter, 4.72 ml was slowly added dropwise at minus 60 ° C, then N,N-dimethylformamide (1.30 ml, 16.85 mmoles) was added, and the reaction was carried out under zero. Stir at 60 degrees Celsius for one hour, then raise to 25 degrees Celsius for 3 hours. The reaction was quenched with EtOAc (EtOAc m. Compound 41-2 was obtained.
  • Step D 41-4 (300.00 mg, 611.05 ⁇ mol) was dissolved in methanol (6.00 mL), aqueous sodium hydroxide (4.00 moles per liter, 611.05 liters) was added, and the mixture was stirred at 25 ° C for 0.5 hour. The reaction mixture was concentrated in vacuo, EtOAc EtOAc (EtOAc)
  • Examples 42 and 43 can be obtained by referring to the preparation method of Example 41.
  • Step A 44-1 (25.00 g, 220.97 mmol) was dissolved in toluene (250.00 ml), and p-toluenesulfonic acid monohydrate (12.61 g, 66.29 mmol) and ethylene glycol (41.15 g, 662.91 m) were added thereto. Moore). Stir for 16 hours at 130 ° C using a water trap. 50 ml of a saturated aqueous solution of sodium hydrogencarbonate and 450 ml of methyl tert-butyl ether (150 ml * 3) were used. The organic phase was washed with brine (3 ml, dryness
  • Step C 44-3 (13.30 g, 69.40 mmol) was dissolved in tetrahydrofuran (37.00 ml), and hydrochloric acid (1 mol, 36.78 ml) was added. Stir at 75 degrees Celsius for 3 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and extracted with 50 ml of ethyl acetate and ethyl acetate (200 ml). The organic layer was combined, dried over anhydrous sodium sulfate, filtered, evaporated, evaporated .
  • Example 44 was prepared by referring to the procedure of Preparation D, E, F of Example 13.
  • Step A 45-1 (18.12 ml, 170.53 mmol) was dissolved in dichloromethane (425.00 ml), pyridine (2.76 mL, 34.11 mmol) was added at minus 10 ° C, then phosphorus pentachloride was added in one portion. (35.51 g, 170.53 mmol). The reaction solution was stirred at minus 10 ° C for 1 hour, then sodium hydrogencarbonate (42.98 g, 511.59 mmol) was added. Stir at 0.25 ° C for 0.25 hours. The reaction solution was filtered, and the filtrate was dried over anhydrous magnesium sulfate.
  • Step B 45-3 (50.00 g, 297.35 mmol), potassium carbonate (41.10 g, 297.35 mmol) dissolved in N,N-dimethylformamide (250.00 mL) Oxypropane (45.50 g, 297.35 mmol) was dissolved in N,N-dimethylformamide (150.00 ml), and added dropwise to the above system at 90 ° C, and dripped in one hour. The reaction solution was stirred at 90 ° C for 0.5 hours. After adding water (500 ml), EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc:
  • Step C Dissolve liquid bromine (9.44 ml, 183.14 mmol) in chloroform (150 ml) and add to a solution of 45-4 (40.00 g, 166.49 mmol) in chloroform (570 ml) at 0 ° C. Stir at 25 degrees Celsius for 0.5 hours. The organic layer was evaporated to dryness crystals crystals crystals
  • Step D The sheared sodium metal (10.50 g, 456.84 mmol) was added portionwise to dry methanol (250.00 mL) under nitrogen atmosphere and the mixture was stirred at 50 ° C for 3 hours.
  • the system was poured into a system of 45-5 (45.00 g, 114.21 mmol) and copper chloride (7.68 g, 57.10 mmol) in N,N-dimethylformamide (225.00 ml) at 25 ° C.
  • the reaction solution was stirred at 110 ° C for 16 hours under a nitrogen atmosphere.
  • the reaction mixture was quenched with EtOAc (EtOAc) (EtOAc (EtOAc) Dry, filter and concentrate under reduced pressure.
  • the residue was purified with EtOAc EtOAc (EtOAc:EtOAc:
  • Step E 45-6 (17.00 g, 62.90 mmol) was dissolved in N,N-dimethylformamide (100.00 ml), and potassium carbonate (13.04 g, 94.35 mmol) and benzyl bromide (11.83 g). , 69.19 mmol, 8.22 ml). The system was stirred at 25 degrees Celsius for 16 hours. After adding water (200 ml *3), EtOAc (EtOAc (EtOAc) Compound 45-7 was obtained.
  • Step F 45-7 (22.79 g, 63.24 mmol) was dissolved in methanol (60.00 ml) and tetrahydrofuran (60.00 ml), then aqueous potassium hydroxide (6 mol/L, 61.55 ml) was added and stirred at 45 ° C for 2 hours. .
  • the reaction solution was adjusted to pH 3-4 with 1 mol/L hydrochloric acid, and the suspension was filtered to give a cake. The residue was purified with EtOAc (EtOAc)EtOAc.
  • Step G 45-8 (20.00 g, 57.74 mmol) was dissolved in dichloromethane (200.00 mL), oxalyl chloride (7.58 ml, 86.61 mmol) and N,N-dimethylformamide (4.44 l, 57.74 micromolar). The system was stirred at 25 degrees Celsius for 2 hours. The mixture was concentrated to dryness under reduced pressure to give Compound 45-9.
  • Step H 45-9 (21.06 g, 57.73 mmol) and ethyl 2-acetyl-3-dimethylaminoacetate (13.90 g, 75.05 mmol) were dissolved in tetrahydrofuran (200.00 mL) at -70 to - It was added dropwise to lithium hexamethyldisilazide (1 mol/liter, 150.09 ml) at 60 °C. After the dropwise addition, acetic acid (115.55 ml, 2.02 mol/liter) and ammonium acetate (5.78 g, 75.05 mmol) were added. The system was stirred at 65 degrees Celsius for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate (m.sub.2) (EtOAc) (EtOAc) The residue was washed with methyl tert-butyl ether (EtOAc) (EtOAc)
  • Step I 45-10 (20.00 g, 42.78 mmol) was dissolved in tetrahydrofuran (250.00 ml). Palladium carbon (10%, 1 g) was added under nitrogen atmosphere. The system was replaced with 3 hydrogens in vacuo at 25 ° C. Under a hydrogen atmosphere (15 Psi), the mixture was stirred for 16 hours. Filtration and concentration of the filtrate under reduced pressure gave Compound 45-11.
  • Step L Example 45-12A (71.00 mg, 140.32 ⁇ mol) was dissolved in tetrahydrofuran (2.00 ml) and methanol (2.00 ml), and aqueous sodium hydroxide (4 mol / liter, 1.00 ml) was added. Stir at 0.5 degrees Celsius. The reaction mixture was adjusted to pH 3 with 1 mol/L hydrochloric acid, methylene chloride (20 ml.sup.2), and the organic phase was dried over anhydrous sodium sulfate.
  • Eee value (enantiomeric excess) method OD-3S_3_40_3ML separation column: Chiralcel OD-3 100 ⁇ 4.6 mm ID, 3 ⁇ m mobile phase: 40% methanol (0.05% diethylamine) CO 2 flow rate: 3 mL/min Wavelength: 220nm.
  • Examples 46 to 48 can be prepared by referring to the preparation method of Example 45.
  • Ee value (enantiomeric excess) method OD-3S_3_40_3ML separation column: Chiralcel OD-3 100 ⁇ 4.6mm ID, 3 ⁇ m mobile phase: 40% methanol (0.05% diethylamine) in CO 2 flow rate: 3mL/min wavelength : 220 nm.
  • Example 47 Prehydrolysis of the compound by chiral HPLC (Separation column: AS (250 mm * 30 mm, 10 ⁇ m); mobile phase: [0.1% aqueous ammonia-methanol]; elution gradient: 45% - 45%, 2.3 min; 90 min) column separation
  • Eee value (enantiomeric excess) method OD-3S_3_40_3ML separation column: Chiralcel OD-3 100 ⁇ 4.6 mm ID, 3 ⁇ m mobile phase: 40% methanol (0.05% diethylamine) CO 2 flow rate: 3 mL/min Wavelength: 220nm.
  • Step B 49-2 (47.00 g, 211.48 mmol) was dissolved in acetonitrile (200.00 mL) and cooled to 0 <0>C, then N-chlorosuccinimide (28.52 g, 213.59 mmol) was added. The mixture was heated to 90 degrees Celsius and stirred for two hours. The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals The organic phase was separated, washed with brine (100 mL ⁇
  • Step C To a solution of 49-3 (53.00 g, 206.48 mmol), benzyl bromide (38.85 g, 227.13 mmol) in dimethylformamide (400.00 ml) . The mixed solution was then stirred at 25 ° C for 1 hour. Ethyl acetate (800 ml) and water (150 ml) were added to the solution, and the solution was stirred at 20 ° C for 10 minutes, and the organic phase was separated, washed with water (130 ml * 2), and washed with saturated brine (130 ml * 2) And dried over anhydrous sodium sulfate and dried under reduced pressure to give compound 49-4.
  • Ethyl acetate 800 ml
  • water 150 ml
  • Step D To a mixed solution of 49-4 (60.00 g, 173.01 mmol) of methanol (300.00 ml) and water (100.00 ml) was added potassium hydroxide (74.07 g, 1.32 mol). The solution was allowed to stir at 50 ° C for two hours. The solution was concentrated under reduced pressure to 100 mL and washed ethyl acetate / pet ether (4 / 1 100 mL). The aqueous phase was separated, and the pH was adjusted to 3 to 4 by 1 mol/liter of dilute hydrochloric acid to obtain a suspension. The suspension was filtered to give a solid. The obtained solid was filtered with water (100 ml), and then recrystallized from n-heptane/ethyl acetate to give compound 49-5.
  • potassium hydroxide 74.07 g, 1.32 mol
  • Step F To a solution of lithium hexamethyldisilazide (1 mol/L, 195.75 ml) in tetrahydrofuran (20 mL) dropwise (over 5 min) at 49 ° C, compound 49-6 (27.0 0 g) A solution of ethyl (6Z)-2-(dimethylaminomethylene)-3-oxobutanoate (14.50 g, 78.30 mmol) in tetrahydrofuran (300 mL). After the addition was completed, the cooling bath was removed, and the mixed solution was further stirred for 5 minutes.
  • Step G To a solution of 49-7 (26.00 g, 57.28 mmol) of tetrahydrofuran (500.00 ml) was added palladium carbon (1.00 g, 10%) (reaction system N 2 substitution). The solution was then stirred at 25 ° C under a hydrogen atmosphere (30 psi) for 2 hours. The brown suspension was filtered to give a yellow liquid. The solution was concentrated under reduced pressure to dryness crystals crystals crystals crystals crystals.
  • Step H, I can be prepared by referring to the preparation method of Example 13.
  • Ee value (enantiomeric excess) method AD-3S_3_40_3ML_8MIN separation column: Chiralpak AD-3 100 ⁇ 4.6 mm ID, 3 ⁇ m mobile phase: 40% methanol (0.05% diethylamine) CO 2 flow rate: 3 mL / min wavelength: 220nm.
  • Example 50 The preparation method of Example 50 was prepared by referring to the preparation method of Example 13.
  • Example 50 Prehydrolysis of the compound by chiral HPLC (separation column: OJ (250 mm * 30 mm, 10 ⁇ m); mobile phase: [0.1% ammonia-methanol]; elution gradient: 40% - 40%, 3 min; 700 min) column separation
  • Eee value (enantiomeric excess) method OD-3S_3_5_40_3ML separation column: Chiralcel OD-3 100 ⁇ 4.6 mm ID, 3 ⁇ m mobile phase: methanol (0.05% diethylamine) 5%-40%, CO 2 , flow rate: 3 mL/min wavelength: 220 nm.
  • Example 50_A 1 H NMR (400 MHz, DMSO-d6) ⁇ 9.11 (s, 1H), 8.88 (br s, 1H), 8.38 (s, 1H), 7.96 (s, 1H), 7.54 (br s, 1H), 7.01 (s, 1H), 4.06-3.94 (m, 2H), 1.28-1.20 (m, 1H), 0.62-0.56 (m, 2H), 0.38-0.32 (m, 2H).
  • Step A To a solution of 51-1 (20.00 g, 178.33 mmol) in dichloromethane (150.00 mL), pyridine (2.82 g, 35.67 mmol) was added at -10 ° C, then palladium was added thereto. Phosphorus (37.14 g, 178.33 mmol) was obtained, and the resulting mixture was reacted at -10 ° C for 0.5 hour. After the reaction was completed, sodium hydrogencarbonate (44.94 g, 534.99 mmol) was added to the reaction mixture. The reaction was stirred for 0.5 h then filtered through EtOAc (EtOAc)EtOAcEtOAcEtOAcEtOAcEtOAc
  • Step B A solution of 51-3 (10.00 g, 26.19 mmol), cesium carbonate (38.40 g, 117.86 mmol) and 51-2 (21.88 g, 130.95 mmol) of dimethyl sulfoxide (100.00 ml) Stir for 16 hours at Celsius. After completion of the reaction, the reaction was quenched with 50 ml of water, and then the mixture was diluted with 150 ml of water, extracted with dichloromethane (100 ml * 3), and the organic phase was combined with saturated brine (100 ml * 3) After washing, it was dried over anhydrous sodium sulfate and evaporated.
  • the step C hydrolysis method can be obtained by referring to the preparation method of Example 13.
  • the HBV DNA content of HepG2.2.15 cell culture supernatant was detected by real-time quantitative qPCR assay (real time-qPCR), and the HBV surface antigen content was detected by enzyme-linked immunosorbent assay (ELISA), and the EC 50 value of the compound was evaluated.
  • the inhibitory effect of the compound on HBV was evaluated.
  • HepG2.2.15 cell culture medium (DMEM/F12, Invitrogen-11330032; 10% serum, Invitrogen-10099141; 100 units/ml penicillin and 100 ⁇ g/ml streptomycin, fetal bovine serum-SV30010; 1% non-essential amino acids, Invitrogen-11140050 2 mM L-Glutamine, Invitrogen-25030081; 300 ⁇ g/ml Geneticin, Invitrogen-10131027
  • Hepatitis B surface antigen quantitative detection kit (Antu Bio, CL 0310)
  • HepG2.2.15 cells 4 x 10 4 cells/well were plated into 96-well plates and incubated overnight at 37 ° C, 5% CO 2 .
  • the culture medium in the culture well was collected, and some samples were taken for ELISA to determine the content of hepatitis B virus S antigen; some samples were extracted using high-throughput DNA purification kit (Qiagen-51162).
  • the qPCR plate was sealed with an optical sealing plate, centrifuged at 1500 rpm for 2 minutes, and then the HBV copy number of each sample was quantitatively detected by a fluorescence quantitative qPCR instrument.
  • the qPCR running program is as follows:
  • Inhibition rate (%) (1 - value in sample / DMSO control value) x 100%.
  • Test compound EC 50 (nM) Test compound EC 50 (nM) 1 11.82 30 18.52 2 34.5 31 90.54 3 27.61 32 35.22 4 14.98 33 12.64 5 15.05 34 21.27 6 6.04 35 25.15 7 211.2 37 10.59 8 20.84 38 20.35 9 74.06 39_A 3.51 10 50.96 39_B 764.9 11 40.8 40_A 15.18 12 78.06 40_B >1000 13_A 300 41 17.76 13_B 7.33 42 2.19 14 6.88 43 19.36 15 8.2 44 128.9 16 45.29 45_A 77.10 17 254.1 45_B 0.22 18 40.82 46_A 79.66 19 3.88 46_B 43.01 20 11.02 47_A 0.44 twenty one 7.12 47_B 26.88 twenty two 20.65 48 >1000 twenty three 85.88 49_A 2.54 twenty four 59.32 49_B 333.9 25 18.71 50_A 0.69 26 152.2 50_B 2.82 27 23.57 51_A 1.13 28 277
  • the representative compounds of the present invention can effectively reduce the HBV-DNA content and have a significant inhibitory effect on HBV.
  • Test compound EC 50 (nM) Test compound EC 50 (nM) 1 27.65 30 28.2 2 55.78 31 202.7 3 47.62 32 71.05
  • the compound of the present invention can effectively reduce the surface antigen content of HBV (HBsAg) and has a significant inhibitory effect on HBV.

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Abstract

作为乙肝表面抗原抑制剂的式(I)的10-氧代-6,1-二氢苯并[e]吡啶并[1,2-c][1,3]恶嗪-9-羧酸衍生物，或其药学上可接受的盐，以及式(I)化合物或其药学上可接受的盐和其药用组合物在制备治疗乙型病毒性肝炎的药物中的应用。

Description

乙型肝炎病毒表面抗原抑制剂
相关申请的交叉引用
本申请主张2017年3月9日提交的中国专利申请CN201710138275.5的优先权，其内容在此并入本申请。
技术领域
本发明涉及新的作为乙肝表面抗原抑制剂的10-氧代-6,10-二氢苯并[e]吡啶并[1,2-c][1,3]恶嗪-9-羧酸衍生物，具体涉及式(I)所示化合物或其药学上可接受的盐，以及式(I)所示化合物或其药学上可接受的盐和药用组合物在治疗乙型病毒性肝炎中的应用。
背景技术
乙型病毒性肝炎，简称乙肝，是一种由乙型肝炎病毒(Hepatitis B Virus，简称HBV)感染机体后所引起的疾病。乙型肝炎病毒是一种嗜肝病毒，主要存在于肝细胞内并损害肝细胞，引起肝细胞炎症、坏死、纤维化。乙型病毒性肝炎分急性和慢性两种。急性乙型肝炎在成年人中大多数可通过其自身的免疫机制而自愈。但是慢性乙型肝炎(CHB)已成为全球健康保健所面临的极大挑战，同时也是引起慢性肝病，肝硬化(cirrhosis)和肝癌(HCC)的主要原因(Edward J.G.,et al.,The oral toll-like receptor-7agonist GS-9620in patients with chronic hepatitis B virus infection.Journal of Hepatology(2015)；63:320-328)。据估计，全球有20亿人感染了慢性乙型肝炎病毒，超过3亿5千万人口已发展成为了乙型肝炎，每年近60万人死于慢性乙型肝炎的并发症(Edward J.G.,et al.,The oral toll-like receptor 7agonist GS-9620in patients with chronic hepatitis B virus infection.Journal of Hepatology(2015))。我国是乙肝高发区，乙型肝炎累积病人多，危害严重。据资料显示，我国现有乙型肝炎病毒感染者约9300万，而其中约2000万患者确诊为慢性乙型肝炎，当中10％-20％可演变成肝硬化，1％-5％可发展成肝癌。(张春红,干扰素在乙型肝炎治疗中的应用.中国医药指南(2013)；11:475-476.)
乙肝功能性治愈的关键是清除HBsAg(乙型肝炎病毒表面抗原)，产生表面抗体。HBsAg量化是一个非常重要的生物指标。在慢性感染病人中，很少能观察到HBsAg的减少和血清转化，这是目前治疗的终点。
乙型肝炎病毒(HBV)的表面抗原蛋白在HBV侵入肝细胞的过程中起非常重要的作用，对于防治HBV的感染有重要意义。表面抗原蛋白包括大(L)、中(M)和小(S)的表面抗原蛋白，共享共同的C端S区。它们从一个开放读码框中表达，其不同的长度是由读码框三个AUG起始密码子决定的。这三个表面抗原蛋白包括前S1/前S2/S，前S2/S和S域。HBV表面抗原蛋白被整合到内质网(ER)膜，由N端信号序列启动(Eble et al.，1987，1990；Schmitt et al.,2004)。它们不仅构成了病毒体的基本结构，而且还形成球状和丝状亚病毒颗粒(SVPs，HBsAg)，聚集在ER，宿主ER和前高尔基体器(Huovila et al.,1992)，SVP包含大多S表面抗原蛋白(Chisari et al.,1986)。L蛋白(Bruss，1997，2004)，在病毒的形态发生与核衣壳相互作用方面是至关重要的，但对于SVP的形成是没有必要的。(Lunsdorf et al.,2011年)。由于它们缺乏核衣壳，所述的SVPs是非感染性的。SVPs大大参与了疾病进展，尤其是对乙肝病毒的免疫应答，在感染者的血液里，SVPs的量至少是病毒数量的10，000倍(Bruns et al.，1998；Ganem and Prince,2004)，诱捕了免疫系统，削弱人体对乙肝病毒的免疫反应。HBsAg也可抑制人 的天然免疫，能够抑制多糖(LPS)和IL-2诱导的细胞因子产生(Vanlandschoot et al.,2002)，抑制树状细胞DC功能以及LPS对ERK-1/2和c-Jun N端的干扰激酶-1/2在单核细胞的诱导活性(Op den Brouw et al.,2009)。值得注意的是，肝硬化和肝细胞癌的疾病进展很大程度也与持续分泌的HBsAg相关(Chisari et al.,1989；Wang et al.，2004；Yang et al.,2009；Wu et al.,2014)。这些研究结果表明HBsAg在慢性肝炎的发展中起重要作用。
目前被批准上市的抗HBV药物主要是免疫调节剂(干扰素-α和聚乙二醇干扰素-α-2α)和抗病毒治疗药物(拉米夫定、阿德福韦酯、恩替卡韦、替比夫定、替诺福韦、克拉夫定等)。其中，抗病毒治疗药物属于核苷酸类药物，其作用机制是抑制HBV DNA的合成，并不能直接减少HBsAg水平。与延长治疗一样，核苷酸类药物显示HBsAg清除速度类似于自然观察结果(Janssen et al.Lancet(2005)，365，123-129；Marcellin et al.N.Engl.J.Med.(2004)，351，1206-1217；Buster et al.Hepatology(2007)，46，388-394)。
临床已有疗法降低HBsAg疗效不佳，因此，开发能够有效降低HBsAg的小分子口服抑制剂是目前临床用药所亟需的。
虽然WO2016128335A1公开了一系列用于治疗或者预防乙型肝炎病毒感染的2-氧代-6，7二氢苯并[a]喹嗪3-羧酸衍生物(通式结构如下所示)，但是该系列稠环化合物仍然有分子刚性较强、溶解性不够理想以及易于芳构化的问题。因此，就临床应用而言，对成药性更佳的药物的需求依然存在。
Figure PCTCN2018078581-appb-000001
发明内容
本发明提供式(I)化合物或其药学上可接受的盐，
Figure PCTCN2018078581-appb-000002
其中，
R 1选自H、OH、CN、NH 2，或者选自任选被1、2或3个R取代的：C 1-5烷基、C 1-5杂烷基、C 2-5炔基、C 3-6烷基和3～6元杂环烷基；
R 2选自H、卤素，或者选自任选被1、2或3个R取代的：C 1-3烷基和C 1-3杂烷基；
m选自0、1、2、3、4和5；
A选自任选被1、2或3个R取代的：苯基或5～6元杂芳基；
R选自H、卤素、OH、CN、NH 2、＝O、CH 3、CH 3CH 2、CH 3O、CF 3、CHF 2、CH 2F；
所述C 1-5杂烷基、3～6元杂环烷基、C 1-3杂烷基、5～6元杂芳基之“杂”，分别独立地选自：N、-O-、＝O、-S-、-NH-、-(C＝O)-、-(S＝O)-、-(S＝O) 2-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，上述R选自H、F、Cl、Br、OH、CH 3、CH 3O、CF 3、CHF 2、CH 2F。
本发明的一些方案中，上述R 1选自H、OH、CN、NH 2，或者选自任选被1、2或3个R取代的：CH 3、CH 3CH 2、CH 3CH 2CH 2、CH 3CH 2CH 2CH 2、CH 3O、CH 3CH 2O、CH 3S、CH 3S(＝O)、CH 3S(＝O) 2、CH 3SCH 2、CH 3CH 2S、CH 3NH、
Figure PCTCN2018078581-appb-000003
吡咯烷基、哌啶基、四氢吡喃基、吗啉基、2-吡咯烷酮基、3-吡咯烷酮基。
本发明的一些方案中，上述R 1选自H、OH、CN、NH 2，或者选自任选被1、2或3个R取代的：CH 3、CH 3CH 2、CH 3CH 2CH 2、CH 3CH 2CH 2CH 2、CH 3O、CH 3CH 2O、CH 3S、CH 3S(＝O)、CH 3S(＝O) 2、CH 3SCH 2、CH 3CH 2S、CH 3NH、
Figure PCTCN2018078581-appb-000004
Figure PCTCN2018078581-appb-000005
本发明的一些方案中，上述R 1选自：H、OH、CH 3、CHF 2、CH 3O、
Figure PCTCN2018078581-appb-000006
Figure PCTCN2018078581-appb-000007
本发明的一些方案中，上述R 2选自H、F、Cl、Br，或者选自任选被1、2或3个R取代的：CH 3、CH 3CH 2、CH 3O、CH 3CH 2O、
Figure PCTCN2018078581-appb-000008
本发明的一些方案中，上述R 2选自Cl和CH 3O。
本发明的一些方案中，上述A选自任选被1、2或3个R取代的：苯基、噻吩基、噻唑基、异噻唑基、恶唑基、异恶唑基。
本发明的一些方案中，上述A选自任选被1、2或3个R取代的：
Figure PCTCN2018078581-appb-000009
Figure PCTCN2018078581-appb-000010
本发明的一些方案中，上述A选自：
Figure PCTCN2018078581-appb-000011
Figure PCTCN2018078581-appb-000012
本发明的一些方案中，上述A选自：
Figure PCTCN2018078581-appb-000013
Figure PCTCN2018078581-appb-000014
本发明的一些方案中，上述m为3。
本发明的一些方案中，上述R 2选自Cl和CH 3O。
本发明的一些方案中，上述R 1为CH 3O。
本发明的一些方案中，上述m为1。
本发明的一些方案中，上述R 2为Cl。
本发明的一些方案中，上述R 1为
Figure PCTCN2018078581-appb-000015
本发明的一些方案中，上述A选自任选被1、2或3个R取代的：
Figure PCTCN2018078581-appb-000016
Figure PCTCN2018078581-appb-000017
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2018078581-appb-000018
Figure PCTCN2018078581-appb-000019
其中，
R 1、R 2、A、R、m如上述所定义。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自
Figure PCTCN2018078581-appb-000020
Figure PCTCN2018078581-appb-000021
Figure PCTCN2018078581-appb-000022
Figure PCTCN2018078581-appb-000023
Figure PCTCN2018078581-appb-000024
本发明还提供化合物或其药学上可接受的盐，其选自
Figure PCTCN2018078581-appb-000025
Figure PCTCN2018078581-appb-000026
Figure PCTCN2018078581-appb-000027
Figure PCTCN2018078581-appb-000028
Figure PCTCN2018078581-appb-000029
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自
Figure PCTCN2018078581-appb-000030
Figure PCTCN2018078581-appb-000031
本发明还提供一种药物组合物，其含有治疗有效量的根据权利要求上述的化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供上述化合物或其药学上可接受的盐或上述的药物组合物在制备治疗乙型肝炎药物中的应用。
本发明还有一些方案是由上述各变量任意组合而来。
技术效果
本发明创造性地设计并合成出了全新的以六元氮氧缩醛为母核结构的系列化合物。本发明化合物通过巧妙的设计，克服了六元环氮氧缩醛母核结构在体内酸性环境可能不稳定、易于水解的缺陷。经过相关实验的验证，证实了本发明化合物在一定温度范围和酸性范围内具被良好的稳定性。另外，创造性的用氧原子取代碳原子后，本发明的系列化合物相对于现有技术，其活性能够很好地保持。这一点在乙肝表面抗原活性方面体外抑制实验中得到了验证。同时，氧原子取代碳原子的设计使母核避免了因碳原子的存在而被脱氢芳构化的可能，本发明化合物水溶性会得到提高，从而能够获得更加优良的成药性质。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使 用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明，用楔形键和虚线键
Figure PCTCN2018078581-appb-000032
表示一个立体中心的绝对构型，用
Figure PCTCN2018078581-appb-000033
表示一 个立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基的键可以交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种取代基可以通过其任何原子相键合。取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。例如，结构单元
Figure PCTCN2018078581-appb-000034
表示其可在 环己基或者环己二烯上的任意一个位置发生取代。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O) 2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。
如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、 吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C 1-C 12表示1至12个碳，C 1-12选自C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12；C 3-12选自C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11和C 12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。实例包括但不限于-CH 2-CH 2-O-CH 3、-CH 2-CH 2-NH-CH 3、-CH 2-CH 2-N(CH 3)-CH 3、-CH 2-S-CH 2-CH 3、-CH 2-CH 2、-S(O)-CH 3、-CH 2-CH 2-S(O) 2-CH 3、-CH＝CH-O-CH 3、-CH 2-CH＝N-OCH 3和–CH＝CH-N(CH 3)-CH 3。至多两个杂原子可以是连续的，例如-CH 2-NH-OCH 3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH 2F)或多取代的(如-CF 3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C 1-C 4)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括氯、溴；磺酸酯基，如甲苯磺酸酯、对甲苯磺酸酯等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”。
术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基；芳基甲基，如苄基(Bn)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐。
化合物经手工或者
Figure PCTCN2018078581-appb-000035
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2018078581-appb-000036
步骤A：将1-1(50.00克，274.47毫摩尔)溶解在二氯甲烷(250毫升)中，搅拌下加入磺酰氯(44.45克，329.36毫摩尔)，控制温度在25至30摄氏度。体系在25至30摄氏度下搅拌48小时。反应完后，体系倒入300毫升饱和碳酸氢钠水溶液，乙酸乙酯(150毫升*3)萃取，合并有机相，用饱和食盐水(40毫升*3)洗涤，无水硫酸钠干燥，过滤并减压浓缩。残余物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝10/1至2/1)，得到1-2。
步骤B：将1-2(20.00克，92.33毫摩尔)溶解在N,N-二甲基甲酰胺(60毫升)，搅拌下加入苄溴(14.26毫升，120.03毫摩尔)和碳酸钾(33.18克，240.06毫摩尔)，控制温度在25至30摄氏度。体系在25至30摄氏度搅拌48小时。反应结束后，向体系中加入乙酸乙酯(200毫升)和水(500毫升)，分液得到有机相。有机相用水(50毫升*2)和食盐水(60毫升*2)洗涤，无水硫酸钠干燥，过滤并减压浓缩，得到1-3。
步骤C：将1-3(36克，117.36毫摩尔)溶解在四氢呋喃(40毫升)和水(40毫升)中，加入一水合氢氧化锂(29.55克，704.18毫摩尔)。体系在30摄氏度搅拌48小时。反应结束后，向体系中加入水(200毫升)，用乙酸乙酯(50毫升*3)萃取。将水相调节pH＝1-2，乙酸乙酯(50毫升*3)萃取水相，合并有机相，无水硫酸钠干燥，过滤并减压浓缩，得到1-4。
步骤D：将1-4(15克，51.25毫摩尔)溶解在二氯甲烷中(150毫升)，在氮气保护下加入草酰氯(9.76克，76.88毫摩尔)和N，N-二甲基甲酰胺(394.26微升，5.13毫摩尔)。该体系在25摄氏度下搅拌2小时。减压浓缩除去溶剂，得到1-5。
步骤E：在零下70摄氏度下，将六甲基二硅基胺基锂(1摩尔/升，101.06毫升)滴加到1-5(15.72克，50.53毫摩尔)和2-乙酰基-3-二甲氨基丙烯酸乙酯(7.8克，42.11毫摩尔)的四氢呋喃(93毫升)溶液中。撤去干冰丙酮浴，向体系中加入乙酸(84.22毫升，1.47摩尔)和乙酸铵(4.22克，54.74毫摩尔)，减压浓缩除去四氢呋喃，在60-65摄氏度下搅拌1.5小时。减压浓缩旋干，将残渣用甲基叔丁基醚(150毫升)和石油醚(200毫升)洗涤，过滤得滤饼，减压干燥，得到1-6。
步骤F：将1-6(5克，12.08毫摩尔)溶解在四氢呋喃(1.25升)中，在氮气保护下加入钯碳(10％，500毫克)，体系在真空置换几次氢气后，于25摄氏度下，氢气气氛(15Psi)保护下搅拌15分钟。过滤，将滤渣溶解在二氯甲烷/甲醇＝10/1(1500毫升)的混合液中，过滤除去钯碳，将滤液减压浓缩，得到1-7。
1H NMR(400MHz，DMSO-d6)δ8.54(s，1H)，7.72(s，1H)，6.78(s，1H)，6.51(s，1H)，4.23(q，J＝7.1Hz，2H)，3.83(s，3H)，1.30(t，J＝7.1Hz，3H)。
步骤G：将1-7(3克，9.27毫摩尔)溶解在N,N-二甲基甲酰胺(60毫升)中，加入碳酸钾(10.25克，74.16毫摩尔)和二溴甲苯(6.59克，27.81毫摩尔)，体系在100摄氏度下搅拌32小时。反应液加水(300毫升)淬灭，乙酸乙酯(300毫升*2)萃取。合并有机相，用水(300毫升*2)洗涤，无水硫酸钠干燥，过滤减压浓缩，用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝10：1至1：0)，得到1-8。
1H NMR(400MHz，CDCl 3)δ7.96(s，1H)，7.63(s，1H)，7.51-7.44(m，3H)，7.34(dd，J＝1.9，7.5Hz，2H)，6.83(s，1H)，6.63(s，1H)，6.59(s，1H)，4.31(q，J＝7.1Hz，2H)，3.92(s，3H)，1.33(t，J＝7.1Hz，3H)。
步骤H：将1-8(100.00毫克，242.81微摩尔)溶解在甲醇(2毫升)和水(1毫升)中，加入氢氧化钠(19.42毫克，485.62微摩尔)，25摄氏度下搅拌16小时。反应液用1摩尔/升的盐酸调节pH＝3，用二氯甲烷(15毫升*2)萃取。合并有机相，用食盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩。残渣用石油醚/乙酸乙酯＝5/1洗涤，过滤得滤饼，减压干燥得到实施例1。
1H NMR(400MHz，DMSO-d6)δ16.12(s，1H)，8.72(s，1H)，8.26(s，1H)，7.54(s，1H)，7.51 (s，1H)，7.47-7.43(m，3H)，7.27(dd，J＝2.6，6.4Hz，2H)，7.11(s，1H)，3.92(s，3H)。
实施例2
Figure PCTCN2018078581-appb-000037
步骤A：将1-8(1.60克，3.89毫摩尔)溶解在二氯甲烷(160毫升)中，零下70摄氏度逐滴加入三溴化硼(2.25毫升，23.34毫摩尔)，25摄氏度下搅拌16小时。反应液在零摄氏度下用甲醇(60毫升)淬灭，减压浓缩旋干，加入水(50毫升)和二氯甲烷(30毫升)，过滤得到固体，减压干燥得到2-2。
1H NMR(400MHz，DMSO-d6)δ11.53(br s，1H)，8.73(s，1H)，8.18(s，1H)，7.51(s，1H)，7.46-7.41(m，5H)，7.21(dt，J＝2.4，3.5Hz，2H)，6.75(s，1H)。
步骤B：将2-2(1.20克，3.25毫摩尔)溶解在甲醇(30毫升)中，零摄氏度下加入氯化亚砜(2.36毫升，32.50毫摩尔)，反应液在50摄氏度下搅拌16小时。体系减压浓缩旋干，固体用石油醚/乙酸乙酯＝3/1(12毫升)，过滤得到滤饼，减压干燥得到2-3。
步骤C：将2-3(100.00毫克,，260.57微摩尔)，3-溴-2,2-二甲基-1-丙醇(65.29毫克，390.86微摩尔)，碘化钠(7.81毫克，52.11微摩尔)，碳酸钾混合在N，N-二甲基甲酰胺(2毫升)中，于120摄氏度下搅拌16小时。反应液用1摩尔/升盐酸调节pH＝3-4，二氯甲烷(15毫升*2)萃取，合并有机相用水(20毫升*2)洗涤，无水硫酸钠干燥，过滤减压浓缩。所得固体经高效液相制备色谱法纯化(柱子：Boston Green ODS 150*30 5微米；流动相：[水(0.225％甲酸)-乙腈]；洗脱梯度：35％-65％,12分钟)纯化得到实施例2。
1H NMR(400MHz，DMSO-d6)δ8.74(br s，1H)，8.35(s，1H)，8.21(br d，J＝0.7Hz，1H)，7.55(s，1H)，7.45-7.41(m，3H)，7.21(br s，2H)，7.05(s，1H)，3.83(s，2H)，3.28(s，2H)，0.93(s，6H)。
实施例3至9均可参照实施例2的制备方法制得。
实施例3
Figure PCTCN2018078581-appb-000038
1H NMR(400MHz,CDCl 3)δ8.24(s,1H),7.72(s,1H),7.60-7.45(m,3H),7.33(dd,J＝1.3,7.9Hz,2H),7.02(s,1H),6.72(s,1H),6.64(s,1H),4.22(d,J＝4.6Hz,2H),3.91-3.73(m,2H),3.49(s,3H)。
实施例4
Figure PCTCN2018078581-appb-000039
1H NMR(400MHz,CDCl 3)δ8.25(s,1H),7.76(s,1H),7.57-7.51(m,3H),7.33(br d,J＝6.5Hz,2H),7.05(s,1H),6.70(s,1H),6.65(s,1H),6.32(s,0.25H),6.19(s,0.45H),6.05(s,0.3H),4.29(dt,J＝3.8,12.6Hz,2H)。
实施例5
Figure PCTCN2018078581-appb-000040
1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.54(s,2H),7.46-7.43(m,4H),7.24(br s,1H),7.14(s,1H),7.13-7.13(m,1H),4.25(br t,J＝5.3Hz,3H),3.61-3.53(m,6H),2.73(t,J＝5.6Hz,3H)。
实施例6
Figure PCTCN2018078581-appb-000041
1H NMR(400MHz,MeOH-d4)δ8.51(br s,1H),8.35(s,1H),7.99(br s,1H),7.49(br s,3H),7.37(br s,2H),7.19(br s,2H),6.96(s,1H),4.23(br t,J＝6.0Hz,2H),3.79(t,J＝6.1Hz,2H),2.05(br t,J＝6.1Hz,3H)。
实施例7
Figure PCTCN2018078581-appb-000042
1H NMR(400MHz,MeOH-d4)δ8.55-8.41(m,2H),7.98(br s,1H),7.48(br s,3H),7.37(br s,2H),7.19(br s,2H),6.97(br s,1H),4.20(br s,2H),3.94(br s,2H)。
实施例8
Figure PCTCN2018078581-appb-000043
1H NMR(400MHz,MeOH-d4)δ8.50(br s,1H),7.99(br s,1H),7.54-7.32(m,6H),7.22(br s,1H),6.93(br s,1H),5.13-5.06(m,1H),4.19-4.07(m,1H),4.13(br s,1H),3.60(br t,J＝5.8Hz,2H),1.88(br s,2H),1.61(br s,5H)。
实施例9
Figure PCTCN2018078581-appb-000044
1H NMR(400MHz,CDCl 3)δ8.22(s,1H),7.75(s,1H),7.61-7.48(m,3H),7.37(d,J＝6.5Hz,2H),7.04(s,1H),6.88(s,1H),6.63(s,1H),4.85(t,J＝2.4Hz,2H),2.63(t,J＝2.4Hz,1H)。
实施例10
Figure PCTCN2018078581-appb-000045
步骤A：将2-3(50.00毫克，130.28微摩尔)溶解在DMF(2毫升)中，加入碳酸钾(36.01毫克，260.56微摩尔)，(2,2-二氟-3-羟基-丙基)4-对甲基苯磺酸(34.69毫克，130.28微摩尔)，体系在100 摄氏度下搅拌12小时。反应液用1摩尔/升盐酸调节pH＝3-4，二氯甲烷(15毫升*2)萃取，合并有机相用水(20毫升*2)洗涤，无水硫酸钠干燥，过滤减压浓缩。经硅胶板纯化(二氧化硅，二氯甲烷：甲醇＝15:1)得到10-2。
步骤B：将10-2(40.00毫克，26.79微摩尔)溶解在四氢呋喃(1毫升)，甲醇(1毫升)和水(1毫升)加入一水合氢氧化锂(1.12毫克，26.79微摩尔)，体系在25摄氏度下搅拌1小时。反应液调节pH＝3-4，经高效液相制备色谱法纯化(柱子：Boston Green ODS 150*30 5微米；流动相：[水(0.225％甲酸)-乙腈]；洗脱梯度：30％-54％,10分钟)纯化得到实施例10。
1H NMR(400MHz，METHANOL-d4)δ8.51(s，1H)，8.08(s，1H)，7.50(br d，J＝3.3Hz，3H)，7.38(br d，J＝4.4Hz，2H)，7.24(br d，J＝18.3Hz，2H)，7.07(s，1H)，4.45(br t，J＝11.4Hz，2H)，3.91(t，J＝13.1Hz，2H)。
实施例11至12均可参照实施例10的制备方法制得
实施例11
Figure PCTCN2018078581-appb-000046
1H NMR(400MHz，DMSO-d6)δ8.73(s，1H)，8.27(s，1H)，7.54(s，1H)，7.52(s，1H)，7.47-7.43(m，3H)，7.26(dd，J＝2.6，6.5Hz，2H)，7.13(s，1H)，4.26(t，J＝6.1Hz，2H)，3.28-3.24(m，2H)，3.03(s，3H)，2.23-2.13(m，2H)。
实施例12
Figure PCTCN2018078581-appb-000047
1H NMR(400MHz，MeOH-d4)δ8.35(br s，1H)，7.91(s，1H)，7.38(br s，3H)，7.27(br s，2H)，7.09(br d，J＝17.0Hz，2H)，6.86-6.81(m，1H)，4.04(br s，2H)，3.45-3.37(m，5H)，2.29-2.21(m，2H)，2.02-1.97(m，2H)，1.96-1.92(m，2H)。
实施例13(13_A和13_B)
Figure PCTCN2018078581-appb-000048
Figure PCTCN2018078581-appb-000049
步骤A：将13-1(10.00克，59.5毫摩尔)在0摄氏度下溶解于二氯甲烷(500毫升)，然后向其中加入磺酰氯(10.77克，79.77毫摩尔，7.98毫升)。混合溶液在35摄氏度下搅拌38小时。然后将溶液倒入300毫升饱和碳酸氢钠水溶液中并搅拌。水相经乙酸乙酯萃取(150毫升*3次)，然后将合并的有机相经饱和食盐水洗涤(40毫升*3次)，并通过无水硫酸钠干燥，并经过减压蒸馏得到白色残留物。然后将白色残留物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝30/1至20/1)得到化合物13-2。
1H NMR(400MHz,MeOH-d 4)δ10.75(s,1H),7.74(s,1H),6.54(s,1H),5.98(s,1H),3.85(s,3H)。
步骤B：将13-2(8.00克，39.49毫摩尔)，1-溴-3-甲氧基-丙烷(7.25克，47.39毫摩尔)溶于二甲基甲酰胺(100.00毫升)，并在冷却至0摄氏度后向其中加入碳酸钾(10.92克，78.98毫摩尔)。再将混合溶液升温至25摄氏度并搅拌10小时。然后将乙酸乙酯(300毫升)和水(50毫升)加入溶液中，并在25摄氏度下搅拌10分钟。将有机相分离出来并饱和食盐水洗涤(40毫升*3)，然后通过无水硫酸钠干燥，并减压浓缩得到黄色液体。再将黄色液体经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝30/1至20/1)得到化合物13-3。
1H NMR(400MHz,CDCl 3)δ10.90(s,1H),7.82(s,1H),6.52(s,1H),4.16(t,J＝6.0Hz,2H),3.94(s,3H),3.60(t,J＝6.0Hz,2H),3.38(s,3H),2.13(t,J＝6.0Hz,2H)。
步骤C：向13-3(3.64克，13.25毫摩尔)，(氯化苄(2.18克，17.23毫摩尔，1.98毫升)的二甲基甲酰胺(10.00毫升)溶液中加入碳酸钾(4.76克，34.45毫摩尔)。混合溶液在25摄氏度下搅拌20小时。乙酸乙酯(150毫升)和水(30毫升)加入溶液中，溶液再在20摄氏度下搅拌10分钟。然后分离有机相并经过水(30毫升*2)洗饱和食盐水(30毫升*2)洗涤，然后通过无水硫酸钠干燥，并经减压浓缩得到化合物13-4。
步骤D：13-4(2.00克，5.48毫摩尔)和一水合氢氧化锂(1.38克，32.89毫摩尔)的四氢呋喃 (20毫升)和水(10毫升)溶液在10～20摄氏度下搅拌10小时。然后将溶液经乙酸乙酯/石油醚1/1洗涤(5毫升*3)。将水相调酸性至酸碱度值1～2。再将溶液经二氯甲烷(50毫升*3)萃取，将有机相合并后经无水硫酸钠干燥，并减压浓缩得到白色固体化合物2-苄氧基-5-氯-4-(3-甲氧基丙烷)苯甲酸(1.30克，3.71毫摩尔，67.63％)。向2-苄氧基-5-氯-4-(3-甲氧基丙烷)苯甲酸甲酸(1.00克，2.85毫摩尔)的二氯甲烷(10.00毫升)溶液中加入氯化亚砜(508.60毫克，4.28毫摩尔，310.12微升)。混合液在25摄氏度下搅拌1小时。然后将溶液减压浓缩得到残留物。再将残留物溶于甲苯，并继续减压浓缩得到残留物。将残留物13-5在氮气环境下保存。
1H NMR(400MHz,DMSO-d 6)δ12.87-12.22(m,1H),7.74(s,1H),7.53(br d,J＝7.2Hz,2H),7.40(t,J＝7.6Hz,2H),7.36-7.30(m,1H),6.94(s,1H),5.27(s,2H),4.20(s,2H),3.50(s,2H),3.26(s,3H),1.98(t,J＝6.4Hz,2H)。
步骤E：零下70摄氏度下向六甲基二硅基胺基锂(1摩尔/升，23.88毫升)的四氢呋喃(20毫升)溶液中逐滴加入(5分钟)13-5(2.94克，7.96毫摩尔)和2-(二甲基氨基亚甲基)-3-氧代丁酸乙酯(1.62g,8.76毫摩尔,1.10eq)的四氢呋喃(20毫升)溶液。然后移走冷却槽并让混合物持续搅拌5分钟。再将醋酸铵(3.23克，41.95毫摩尔)和醋酸(67.85克，1.13毫摩尔)加入混合物中，并将绝大部分四氢呋喃通过旋转蒸发仪在60摄氏度下除去。并将残留物在60～65摄氏度下加热1.5小时。将反应混合物冷却，然后向其中加入水(40毫升)和二氯甲烷(200毫升)。混合物搅拌10分钟后分离，有机相经水洗(10毫升*3)和碳酸氢钠水溶液洗，干燥，然后浓缩得到黄色残余物。残余物再经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到化合物13-6.
步骤F：向13-6(3.00g,6.36毫摩尔)的四氢呋喃(20毫升)溶液中加入活化湿钯炭(500毫克)。溶液在25摄氏度下于氢气(15psi)气氛中搅拌2小时。然后将棕色悬浊液过滤得到黄色液体，并将其减压浓缩得到黄色残留物。再将黄色残留物经石油醚/乙酸乙酯(4/1)打浆(两次)并过滤得到淡黄色固体化合物13-7。
步骤G：将13-7(800.00毫克,2.10毫摩尔)，碳酸钾(580.48毫克，4.20毫摩尔)和二溴甲苯(551.10毫克，2.21毫摩尔)的DMF(20.00毫升)溶液在100摄氏度下搅拌10小时。再将乙酸乙酯(60毫升)和水(10毫升)加入反应溶液，再将有机相分离，并将水相通过乙酸乙酯(20毫升*3)萃取，合并所有有机相并经水(10毫升*3)洗和饱和食盐水(10毫升*3)，并减压浓缩得到黄色液体。黄色液体经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1至5/1)得到白色固体。再将固体经手性色谱柱制备分离(分离柱:AD(250mm*30mm,10μm)；流动相:[0.1％氨水-甲醇]，洗脱梯度:50％-50％,5.9min；800min)纯化得到实施例13-7A(保留时间＝3.831min)和实施例13-7B(保留时间＝4.552min)。
步骤H：向13-7A(240.00毫克,510.74毫摩尔,)的甲醇(9毫升)和水(3毫升)溶液中加入一水合氢氧化锂(107.15毫克，2.55毫摩尔)。然后溶液在25摄氏度下搅拌19小时。再将溶液经过乙酸乙酯/石油醚(1/4)(5毫升)洗涤，并通过稀盐酸水溶液(1摩尔/升)调节酸碱度至2～3。再通过二氯甲烷(40毫升*3)对溶液进行萃取。合并有机相并减压浓缩得到黄色液体。黄色液体经高效色谱柱(分离柱:Agela ASB 150*25mm*5μm；流动相:[水(0.1％三氟乙酸)-乙腈]，洗脱梯度:42％-72％,10min)纯化得到实施例13_A。
1H NMR(400MHz,CDCl 3)δ15.46(br s,1H),8.15(s,1H),7.62(s,1H),7.49-7.37(m,3H),7.24(br d,J＝7.0 Hz,2H),6.93(s,1H),6.61(s,1H),6.55(s,1H),4.67(br s,3H),4.08(t,J＝6.2Hz,2H),3.51(t,J＝5.9Hz,2H),3.28(s,3H),2.08-1.93(m,2H)。
步骤I：向13-7B(290.00毫克,617.14毫摩尔)的甲醇(9毫升)和水(3毫升)溶液中加入一水合氢氧化锂(129.48毫克,3.09毫摩尔)。然后溶液在25摄氏度下搅拌19小时。再将溶液经过乙酸乙酯/石油醚(1/4)(5毫升)洗涤，并通过稀盐酸水溶液(1摩尔/升)调节酸碱度至2～3。再通过二氯甲烷(40毫升*3)对溶液进行萃取。合并有机相并减压浓缩得到液体。液体经高效色谱柱(分离柱:Agela ASB 150*25mm*5μm；流动相:[水(0.1％三氟乙酸)-乙腈]，洗脱梯度:42％-72％CO 2,11min)纯化得到实施例13_B。
1H NMR(400MHz,CDCl 3)δ8.14(s,1H),7.62(s,1H),7.50-7.36(m,3H),7.24(br d,J＝7.0Hz,1H),7.26-7.22(m,1H),6.93(s,1H),6.61(s,1H),6.54(s,1H),4.08(t,J＝6.2Hz,2H),3.51(t,J＝5.9Hz,2H),3.28(s,3H),2.04(t,J＝6.1Hz,2H)。
实施例14
Figure PCTCN2018078581-appb-000050
步骤A:向14-1(1.00克，10.09毫摩尔)和溴代丁二酰亚胺(3.77克，21.19毫摩尔)的四氯化碳(10.00毫升)溶液中加入过氧苯甲酰(122.21毫克，504.50毫摩尔)，得到的混合溶液在80摄氏度下光照并搅拌16小时。反应完成后，移走混合溶液中的溶剂，并将混合物溶于60毫升水，再通过乙酸乙酯萃取(50毫升*3)，合并有机相，经60毫升饱和食盐水洗涤，再通过无水硫酸钠干燥，过滤并浓缩得到残余物。将残余物经过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/0至10/1)得到化合物14-2。
1H NMR(400MHz,CDCl 3)δ7.82(d,J＝8.0Hz 1H),7.50(d,J＝7.6Hz 1H),6.66(s,1H)。
参照实施例13步骤B，C的制备方法制得实施例14。
实施例14： 1H NMR(400MHz,CDCl 3)δ15.44(br s,1H),8.60(br s,1H),7.76(br d,J＝2.7Hz,1H),7.64(s,1H),7.47(br d,J＝2.4Hz,1H),7.11(br s,1H),6.97(s,1H),6.76(s,1H),4.19(br t,J＝6.0Hz,2H), 3.60(br t,J＝5.2Hz,2H),3.37(s,3H),2.17-2.10(m,2H)。
实施例15至24均可参照实施例14的制备方法制得
实施例15
Figure PCTCN2018078581-appb-000051
1H NMR(400MHz,CDCl 3)δ15.47(s,1H),8.00(s,1H),7.78(s,1H),7.63-7.52(m,2H),7.50-7.39(m,2H),7.02(s,1H),6.84(s,1H),6.70(s,1H),4.16(t,J＝6.2Hz,2H),3.59(t,J＝5.9Hz,2H),3.39-3.31(m,3H),2.12(quin,J＝6.1Hz,2H)。
实施例16
Figure PCTCN2018078581-appb-000052
1H NMR(400MHz,CDCl 3)δ15.46(br s,1H),8.28(s,1H),7.69(s,1H),7.52-7.46(m,1H),7.44-7.37(m,1H),7.32(s,1H),7.12(br d,J＝7.2Hz,1H),7.01(s,1H),6.73-6.62(m,2H),4.16(t,J＝6.0Hz,2H),3.59(t,J＝6.0Hz,2H),3.36(s,3H),2.13(t,J＝6.4Hz,2H)。
实施例17
Figure PCTCN2018078581-appb-000053
1H NMR(400MHz,CDCl 3)δ15.49(br s,1H),8.26(s,1H),7.68(s,1H),7.46(br d,J＝8.0Hz,2H),7.23(br d,J＝8.0Hz,2H),7.00(s,1H),6.75-6.58(m,2H),4.15(t,J＝6.0Hz,2H),3.59(t,J＝6.0Hz,2H),3.36(s,3H),2.12(br t,J＝6.0Hz,2H)。
实施例18
Figure PCTCN2018078581-appb-000054
1H NMR(400MHz,CDCl 3)δ8.21(s,1H),7.70(s,1H),7.37-7.29(m,2H),7.23-7.15(m,2H),7.00(s,1H),6.68(s,1H),6.62(s,1H),4.16(br t,J＝6.0Hz,2H),3.59(t,J＝6.0Hz,2H),3.36(s,3H),2.17-2.09(m,2H)。
实施例19
Figure PCTCN2018078581-appb-000055
1H NMR(400MHz,CDCl 3)δ15.46(br s,1H),8.14(s,1H),7.76(s,1H),7.63-7.56(m,1H),7.32-7.29(m,2H),7.28(br s,1H),7.02(s,1H),6.81(s,1H),6.69(s,1H),4.15(t,J＝6.0Hz,2H),3.58(t,J＝6.0Hz,2H),3.35(s,3H),2.12(t,J＝6.0Hz,2H)。
实施例20
Figure PCTCN2018078581-appb-000056
1H NMR(400MHz,CDCl 3)δ15.46(br s,1H),8.29(s,1H),7.68(s,1H),7.49-7.42(m,1H),7.24-7.18(m,1H),7.05(br d,J＝9.2Hz,1H),7.03-6.99(m,2H),6.71-6.64(m,2H),4.16(t,J＝6.0Hz,2H),3.59(t,J＝6.0Hz,2H),3.36(s,3H),2.13(quin,J＝6.0Hz,2H)。
实施例21
Figure PCTCN2018078581-appb-000057
1H NMR(400MHz,MeOH-d4)δ15.55(br s,1H),8.05(s,1H),7.76(s,1H),7.47(t,J＝7.0Hz,1H),7.37(d,J＝7.5Hz,1H),7.33(t,J＝7.6Hz,1H),7.21(d,J＝7.7Hz,1H),7.02(s,1H),6.68-6.61(m,2H),4.15(t,J＝6.2Hz,2H),3.58(t,J＝5.9Hz,2H),3.35(s,3H),2.44(s,3H),2.12(t,J＝6.0Hz,2H)。
实施例22
Figure PCTCN2018078581-appb-000058
1H NMR(400MHz,MeOH-d4)δ15.58(br s,1H),8.19(s,1H),7.71(s,1H),7.43-7.30(m,2H),7.16-7.10(m,2H),7.00(s,1H),6.69(s,1H),6.54(s,1H),4.15(t,J＝6.0Hz,2H),3.59(t,J＝6.0Hz,2H),3.36(s,3H),2.40(s,3H),2.12(t,J＝6.0Hz,2H)。
实施例23
Figure PCTCN2018078581-appb-000059
1H NMR(400MHz,CDCl 3)δ15.59(br s,1H),8.19(s,1H),7.70(s,1H),7.33-7.28(m,2H),7.25-7.19(m,2H),6.99(s,1H),6.68(s,1H),6.55(s,1H),4.15(br t,J＝6.1Hz,2H),3.58(t,J＝5.8Hz,2H),3.35(s,3H),2.41(s,3H),2.14-2.09(m,2H)。
实施例24
Figure PCTCN2018078581-appb-000060
1H NMR(400MHz,CDCl 3)δ15.49(br s,1H),8.29(s,1H),7.70(s,1H),7.01(s,1H),6.77-6.67(m,2H),6.65-6.56(m,3H),4.18(t,J＝6.2Hz,2H),3.82(s,3H),3.60(t,J＝5.9Hz,2H),3.38(s,3H),2.14(quin,J＝6.1Hz,2H)。
实施例25至34均可参照实施例35的制备方法制得
实施例25
Figure PCTCN2018078581-appb-000061
1H NMR(400MHz,CDCl 3)δ15.59(br s,1H),8.01(s,1H),7.79(s,1H),7.34-7.29(m,1H),7.27(s,1H),7.07(dd,J＝4.0,9.0Hz,1H),7.00(s,1H),6.75(s,1H),6.70(s,1H),4.19(t,J＝6.2Hz,2H),3.90(s,3H),3.61(t,J＝5.9Hz,2H),3.38(s,3H),2.15(quin,J＝6.1Hz,2H)。
实施例26
Figure PCTCN2018078581-appb-000062
1H NMR(400MHz,CDCl 3)δ15.59(br s,1H),8.01(s,1H),7.79(s,1H),7.34-7.29(m,1H),7.27(s,1H),7.07(dd,J＝4.0,9.0Hz,1H),7.00(s,1H),6.75(s,1H),6.70(s,1H),4.19(t,J＝6.2Hz,2H),3.90(s,3H),3.61(t,J＝5.9Hz,2H),3.38(s,3H),2.15(quin,J＝6.1Hz,2H)。
实施例27
Figure PCTCN2018078581-appb-000063
1H NMR(400MHz,CDCl 3)δ7.99(s,1H),7.70(s,1H),7.54(dt,J＝5.9,8.3Hz,1H),7.38(d,J＝8.2Hz,1H),7.19-7.13(m,1H),6.95(s,1H),6.87(s,1H),6.63(s,1H),4.14-4.04(m,2H),3.51(t,J＝5.8Hz,2H),3.28(s,3H),2.05(quin,J＝6.0Hz,2H)。
实施例28
Figure PCTCN2018078581-appb-000064
1H NMR(400MHz,CDCl 3)δ＝15.51(br s,1H),8.53(s,1H),7.68(s,1H),6.98-6.89(m,2H),6.75(s,1H),4.24-4.15(m,2H),3.66-3.57(m,2H),3.39(s,3H),2.33(s,3H),2.25(s,3H),2.15(quin,J＝6.1Hz,2H).
实施例29
Figure PCTCN2018078581-appb-000065
1H NMR(400MHz,CDCl 3)δ8.18(s,1H),7.79(s,1H),7.71-7.63(m,1H),7.16(t,J＝8.6Hz,2H),7.03(s, 1H),6.83(s,1H),6.71(s,1H),4.22-4.12(m,2H),3.63-3.62(m,1H),3.60(t,J＝5.9Hz,1H),3.37(s,3H),2.14(quin,J＝6.1Hz,2H)。
实施例30
Figure PCTCN2018078581-appb-000066
1H NMR(400MHz,CDCl 3)δ15.38(br s,1H),8.35(s,1H),7.69(s,1H),7.02(s,1H),6.95(br t,J＝8.3Hz,1H),6.79(br d,J＝5.0Hz,2H),6.71(s,2H),4.19(t,J＝6.0Hz,2H),3.61(t,J＝6.0Hz,2H),3.38(s,3H),2.15(t,J＝6.0Hz,2H)。
实施例31
Figure PCTCN2018078581-appb-000067
1H NMR(400MHz,CDCl 3)δ15.37(br s,1H),8.19(s,1H),7.74(s,1H),7.45-7.35(m,1H),7.25-7.19(m,1H),7.03(s,1H),6.94(br t,J＝6.9Hz,1H),6.87(s,1H),6.68(s,1H),4.16(t,J＝6.2Hz,2H),3.58(t,J＝5.9Hz,2H),3.35(s,3H),2.12(t,J＝6.1Hz,2H)。
实施例32
Figure PCTCN2018078581-appb-000068
1H NMR(400MHz,CDCl 3)δ15.38(br s,1H),8.14(s,1H),7.76(s,1H),7.29(br s,1H),7.09-6.93(m,3H),6.78(s,1H),6.70(s,1H),4.17(t,J＝6.0Hz,2H),3.59(t,J＝6.0Hz,2H),3.36(s,3H),2.13(t,J＝6.0Hz,2H)。
实施例33
Figure PCTCN2018078581-appb-000069
1H NMR(400MHz,CDCl 3)δ15.41(br s,1H),8.13(s,1H),7.75(s,1H),7.30(br d,J＝6.1Hz,1H),7.07-7.00 (m,3H),6.77(s,1H),6.69(s,1H),4.16(t,J＝6.2Hz,2H),3.59(t,J＝5.9Hz,2H),3.35(s,3H),2.13(quin,J＝6.1Hz,2H)。
实施例34
Figure PCTCN2018078581-appb-000070
1H NMR(400MHz,CDCl 3)δ15.51(br s,1H),8.13(s,1H),7.78(s,1H),7.25-7.19(m,1H),7.10(td,J＝3.8,8.8Hz,1H),7.02(s,1H),6.84(dd,J＝3.1,5.3Hz,1H),6.75-6.71(m,1H),6.73(d,J＝2.5Hz,1H),4.18(t,J＝6.2Hz,2H),3.82(s,3H),3.60(t,J＝5.9Hz,2H),3.37(s,3H),2.14(quin,J＝6.1Hz,2H)。
实施例35
Figure PCTCN2018078581-appb-000071
步骤A:35-1(20.00克,139.7毫摩尔)和HATU(79.68克,209.55毫摩尔)的混合物溶解在二氯甲烷(250.00毫升)中，然后添加三乙胺(49.48克,488.95毫摩尔，67.78毫升)。混合物在25摄氏度搅拌10分钟，然后加入N-甲氧基甲胺的盐酸盐(27.25g,279.40毫摩尔)。加料完成后，反应体系氮气置换3次，然后在氮气保护下25摄氏度搅拌3小时。反应液用二氯甲烷萃取((150毫升*3)。有机相用水(250毫升*3)，饱和食盐水(200毫升*2)，无水硫酸钠干燥，过滤，减压浓缩。粗品用残留物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/0至1/1)获得化合物35-2。
1H NMR(400MHz,CDCl 3)δ8.88(s,1H),3.47(s,3H),3.30(s,3H),2.55(s,3H)。
步骤B:将35-2(1.70g，9.13毫摩尔)溶解在二氯甲烷中(20.00毫升)冷却到-78摄氏度。二异丁基氢化铝(1摩尔,27.39毫升)在零下78摄氏度一滴一滴地加入。混合物搅拌2小时。反应混合物在零下78摄氏度一滴一滴地加甲醇(2.2毫升)淬灭,搅拌10分钟,然后撤掉干冰丙酮浴。混合物加水(1.2毫升),氢 氧化钠(4摩尔，1.2毫升),水(3毫升)。添加后,混合物25摄氏度搅拌15分钟,用MgSO 4干燥，过滤，减压浓缩得产物。得到化合物35-3。
1H NMR(400MHz,CDCl 3)δ10.05(s,1H),9.18-9.28(m,1H),2.67(s,3H)。
步骤C:亚磷酸三苯酯的溶液(2.93克,9.44毫摩尔,2.48毫升)溶解在二氯甲烷(20.00毫升)中，在零下60摄氏度向体系中添加液溴(1.51克)和三乙胺(1.00克，9.91毫摩尔，1.37毫升)在零下60摄氏度。然后在零下60摄氏度加入35-3(600.00毫克,4.72毫摩尔,)。混合物搅拌在25摄氏度搅拌3小时。反应混合物在25摄氏度用5毫升饱和硫代硫酸钠溶液淬灭，,然后乙酸乙酯60毫升(20毫升*3)萃取。合并后的有机层用饱和氯化钠水溶液洗90毫升(30毫升*3),用无水硫酸钠干燥，过滤和在减压下浓缩。残留物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/0)。得到化合物35-4。
1H NMR(400MHz,CDCl 3)δ8.86(s，1H),6.73(s，1H)，2.58-2.68(m，3H)。
参照实施例13步骤D,E的制备方法制得实施例35。
实施例35： 1H NMR(400MHz,CDCl 3)δ15.45(br s,1H),8.20-8.54(m,2H),7.74(s,1H),7.05(s,1H),6.91(br s,1H),6.63(s,1H),4.16(t,J＝6.15Hz,2H),3.59(t,J＝5.90Hz,2H),3.37(s,3H),2.67(br s,3H),2.13(quin,J＝5.99Hz,2H)。
实施例36至40可参照实施例35的制备方法制得
实施例36
Figure PCTCN2018078581-appb-000072
1H NMR(400MHz,CDCl 3)δ8.60(s,1H),8.20(s,1H),8.02(s,1H),6.68(s,1H),6.53(s,1H),4.03-4.11(m,2H),3.44-3.57(m,2H),3.24(s,3H),2.32-2.35(m,3H),2.11(s,3H),1.94(t,J＝6.24Hz,2H)。
实施例37
Figure PCTCN2018078581-appb-000073
1H NMR(400MHz，CDCl 3)δ15.36(br s，1H)，8.60-8.41(m，3H)，7.70(s，1H)，7.02(s，1H)，6.70(s，1H)，4.18(br t，J＝6.1Hz，2H)，3.60(br t，J＝5.6Hz，2H)，3.51(s，3H)，2.17-2.13(m，2H)。
实施例38
Figure PCTCN2018078581-appb-000074
1H NMR(400MHz,CDCl 3)δ15.34(br s,1H),8.89(br s,1H),8.50(br s,1H),7.81(br s,1H),7.70(s,1H),7.14(br s,1H),7.00(s,1H),6.67(br s,1H),4.16(br t,J＝5.77Hz,2H),3.58(br t,J＝5.83Hz,2H),3.35(s,3H),2.09-2.14(m,2H)
实施例39(39_A和39_B)
Figure PCTCN2018078581-appb-000075
实施例39水解前化合物经手性HPLC柱(分离柱:AD(250mm*30mm,10μm)；流动相:[0.1％氨水-乙醇]，洗脱梯度:60％-60％,4.12min；220min)分离得到两个构型的异构体，分别水解得到实施例39_A(保留时间＝1.594min)，ee值(对映体过量)：100％和实施例39_B(保留时间＝2.593min)，ee值(对映体过量)：98％。SFC(超临界流体色谱)方法：AD-3S_4_40_3ML分离柱:Chiralpak AD-3 100×4.6mm I.D.,3μm流动相:40％异丙醇(0.05％二乙胺)CO 2流速:3mL/min波长:220nm。
实施例39_A  1H NMR(400MHz,CDCl 3)δ15.48(s,1H),8.82(d,J＝1.88Hz,1H),8.48(s,1H),7.66(s,1H),7.39(d,J＝1.63Hz,1H),6.95(s,1H),6.92(s,1H),6.73(s,1H),4.17(t,J＝6.21Hz,2H),3.59(dt,J＝2.20,5.87Hz,2H),3.36(s,3H),2.13(quin,J＝6.05Hz,2H)。
实施例39_B  1H NMR(400MHz,CDCl 3)δ15.50(br s,1H),8.81(d,J＝1.51Hz,1H),8.49(s,1H),7.66(s,1H),7.39(s,1H),6.88-7.00(m,2H),6.73(s,1H),4.17(br t,J＝6.21Hz,2H),3.53-3.66(m,2H),3.36(s,3H),2.13(quin,J＝5.99Hz,2H)。
实施例40(40_A和40_B)
Figure PCTCN2018078581-appb-000076
实施例40经手性HPLC(分离柱:AD(250mm*30mm,10μm)；流动相:[0.1％氨水-异丙醇]:45％-45％in CO 2,2min；1000min)柱分离得到两个构型的异构体，实施例40_A(保留时间＝1.540min)，ee值(对映体过量)：96.4％和实施例40_B(保留时间＝2.067min)，ee值(对映体过量)：93.5％。
实施例40_A： 1H NMR(400MHz,MeOH-d4)δ9.02(s,1H),8.65(br s,1H),8.41(s,1H),8.08(br s,1H), 7.67(s,1H),7.17(br s,1H),6.95(s,1H),4.58(br s,3H),4.21(br t,J＝5.9Hz,2H),3.61(t,J＝6.1Hz,2H),2.12-2.07(m,2H)。
实施例40_B： 1H NMR(400MHz,MeOH-d4)δ9.02(s,1H),8.66(s,1H),8.42(s,1H),8.09(br s,1H),7.67(s,1H),7.20(br s,1H),6.97-6.93(m,1H),6.95(s,1H),4.58(br s,3H),4.21(br t,J＝6.2Hz,2H),3.61(t,J＝6.0Hz,2H),2.10(br t,J＝6.1Hz,2H)。
实施例41
Figure PCTCN2018078581-appb-000077
步骤A:将41-1(2.00克，11.23毫摩尔)溶于四氢呋喃(120毫升)，冷却到零下60摄氏度。在零下60摄氏度下将正丁基锂(2.5摩尔每升，4.72毫升)慢慢滴加进去，然后在加入N,N-二甲基甲酰胺(1.30毫升，16.85豪摩尔，)，反应在零下60摄氏度下搅拌一小时，然后升到25摄氏度搅拌3小时。反应用水淬灭，然后用二氯甲烷(50毫升*3)萃取，有机相用饱和食盐水(35毫升*2)洗涤，无水硫酸钠干燥，过滤，真空浓缩。得到化合物41-2。
1H NMR(400MHz,CDCl 3)：δ9.78(s,1H),7.68(s,1H),2.49(d,J＝1.0Hz,3H)。
步骤B:将亚磷酸三苯酯(52.22克，168.3毫摩尔)溶于二氯甲烷(300毫升)然后冷却到零下60摄氏度。在0摄氏度下将溴素(8.67毫升，168.3毫摩尔)慢慢滴入反应，然后将三乙胺(18.73克，185.13毫摩尔，25.66毫升)和41-2(10.7克，84.15毫摩尔)按顺序加入反应，反应液在零下60摄氏度下搅拌1小时，然后移除冷却槽，反应在25摄氏度下继续搅拌3小时。反应用水淬灭，然后用二氯甲烷(500毫升*3)萃取，有机相用饱和食盐水(350毫升*2)洗涤，无水硫酸钠干燥，过滤，真空浓缩。产物经过柱层析法纯化(二氧化硅，石油醚：乙酸乙酯＝100:0)得到化合物41-3。
1H NMR(400MHz,CDCl 3)δ7.25(s,1H),6.85(s,1H),2.49(s,3H)。
步骤C:将41-3(3.52克，9.23毫摩尔)和41-3(5.00克，18.45毫摩尔)溶于N,N-二甲基甲酰胺(15毫升)，加入碳酸钾(7.01克，50.74毫摩尔)，混合溶液在100摄氏度下搅拌16小时。反应用水淬灭，然后用二氯甲烷(50.00毫升*3)萃取，有机相用食盐水(35.00毫升*2)洗涤，无水硫酸钠干燥，过滤，真空浓缩。产物经过柱层析法纯化(二氧化硅，石油醚：乙酸乙酯＝0:100)得到化合物41-4。
步骤D:将41-4(300.00毫克，611.05微摩尔)溶于甲醇(6.00毫升)加入氢氧化钠水溶液(4.00摩尔每升，611.05微升)，混合液在25摄氏度下搅拌0.5小时。将反应液真空浓缩，加入N，N-二甲基甲酰胺(2.00毫升)，然后用甲酸将pH调至3-4，剩余反应物经过制备型高效液相色谱法纯化得到实施例41。
1HNMR(400MHz,CDCl 3)δ15.45(br s,1H),8.55(s,1H),7.67(s,1H),7.39(s,1H),6.98(s,2H),6.75(s,1H),4.25–4.16(m,2H),3.66–3.57(m,2H),3.39(s,3H),2.47(s,3H),2.16(quin,J＝6.1Hz,2H)。
实施例42和43可参照实施例41的制备方法制得
实施例42
Figure PCTCN2018078581-appb-000078
1H NMR(400MHz,CDCl 3)δ15.46(br s,1H),8.55(s,1H),7.68(s,1H),7.01-6.96(m,3H),6.71(s,1H),3.97(d,J＝6.8Hz,2H),2.38(s,3H),1.41-1.30(m,1H),0.77-0.71(m,2H),0.47-0.42(m,2H)。
实施例43
Figure PCTCN2018078581-appb-000079
1H NMR(400MHz,CDCl 3):δ15.62(br s,1H),8.83(br s,1H),8.45(br s,1H),7.40(br s,1H),7.01(br s,1H),6.95(br s,1H),6.87(br s,1H),6.70(br s,1H),4.16(br s,2H),3.88(br s,3H),3.56(br s,2H),3.35(br s,3H),2.13(br s,2H).
实施例44
Figure PCTCN2018078581-appb-000080
Figure PCTCN2018078581-appb-000081
步骤A:将44-1(25.00克，220.97毫摩尔)溶于甲苯(250.00毫升)，向其中加入一水合对甲苯磺酸(12.61克，66.29毫摩尔)和乙二醇(41.15克，662.91毫摩尔)。利用分水器在130摄氏度下，搅拌16小时。用饱和碳酸氢钠水溶液50毫升和甲基叔丁基醚450毫升(150毫升*3)。有机相用饱和食盐水300毫升(100毫升*3)洗，硫酸钠干燥，过滤并减压浓缩得到44-2。
1HNMR(400MHz,CDCl 3)δ7.76(d,J＝3.2Hz,1H),7.31(d,J＝3.2Hz,1H),6.10(s,1H),4.11-4.00(m,4H)。
步骤B：将44-2(24.60克，156.50毫摩尔)溶于四氢呋喃(615.00毫升)，冷却到零下78摄氏度，向其中缓慢滴加正丁基锂(2.5摩尔，75.12毫升)，滴加完成后，搅拌30分钟，加入四氯化碳(75.40毫升)，反应液在0摄氏度下搅拌1小时。用饱和氯化铵溶液100毫升淬灭反应，用水100毫升和乙酸乙酯600毫升(200毫升*3)萃取，硫酸钠干燥，过滤并减压浓缩，残留物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/0至10/1)，得到44-3。
1HNMR(400MHz,CDCl 3)δ＝7.62(s,1H),6.03(s,1H),4.16-4.07(m,4H)。
步骤C:将44-3(13.30克，69.40毫摩尔)溶于四氢呋喃(37.00毫升)，向其中加入盐酸(1摩尔，36.78毫升)。在75摄氏度下搅拌3小时。反应液用饱和的碳酸氢钠溶液中和，用水50毫升和乙酸乙酯600毫升(200毫升*3)萃取。合并有机相，采用无水硫酸钠干燥，过滤并减压浓缩，残留物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝30/1至20/1)，得到44-4。
参照实施例13的步骤D,E,F制备方法制得实施例44。
实施例44： 1H NMR(400MHz,DMSO-d6)δ8.97(br s,1H),8.32(s,1H),8.30-8.24(m,1H),8.27(br s,1H),7.94(s,1H),7.82(s,1H),7.48(br s,1H),7.12(s,1H),4.04(br dd,J＝7.2,11.6Hz,2H),1.25(br d,J＝8.4Hz,1H),0.61(br d,J＝7.9Hz,2H),0.38(br s,2H),。
实施例45(45_A和45_B)
Figure PCTCN2018078581-appb-000082
Figure PCTCN2018078581-appb-000083
步骤A：将45-1(18.12毫升，170.53毫摩尔)溶解在二氯甲烷(425.00毫升)中，在零下10摄氏度下加入吡啶(2.76毫升，34.11毫摩尔)，随后一次性加入五氯化磷(35.51克，170.53毫摩尔)。反应液在零下10摄氏度下搅拌1小时，然后加入碳酸氢钠(42.98克，511.59毫摩尔)。在零下10摄氏度下搅拌0.25小时。过滤反应液，滤液用无水硫酸镁干燥，过滤得滤液，减压浓缩旋干，得到化合物45-2。
1H NMR(400MHz，CDCl 3)δ7.02(d，J＝3.9Hz，1H)，6.87(s，1H)，6.80(d，J＝4.0Hz，1H)。
步骤B：45-3(50.00克，297.35毫摩尔)，碳酸钾(41.10克，297.35毫摩尔)溶于N,N-二甲基甲酰胺(250.00毫升)中，将1-溴-3-甲氧基丙烷(45.50克，297.35毫摩尔)溶于N,N-二甲基甲酰胺(150.00毫升)中，于90摄氏度下滴加到上述体系中，一小时内滴完。反应液在90摄氏度下搅拌0.5小时。加入水(500毫升)，乙酸乙酯(500毫升*2)萃取，合并有机相，用水(1000毫升*3)和食盐水(500毫升)洗涤，无水硫酸钠干燥，过滤并减压浓缩。残余物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝1/0)，得到45-4。
步骤C：将液溴(9.44毫升，183.14毫摩尔)溶于氯仿(150毫升)与零摄氏度下滴加到45-4(40.00克，166.49毫摩尔)的氯仿(570毫升)溶液中，体系在25摄氏度下搅拌0.5小时。减压浓缩旋干，残余物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝1/0-50/1)，得到化合物45-5。
步骤D：剪切的金属钠(10.50克，456.84毫摩尔)在氮气气氛下分批加入到无水甲醇(250.00毫升)中，体系在50摄氏度下搅拌3小时。该体系一次性于25摄氏度下倒入45-5(45.00克，114.21毫 摩尔)和氯化铜(7.68克，57.10毫摩尔)的N,N-二甲基甲酰胺(225.00毫升)的体系中，氮气保护下，该反应液在110摄氏度下搅拌16小时。反应液用6摩尔/升的盐酸(180毫升)淬灭，乙酸乙酯(500毫升*2)萃取，合并有机相用水(500毫升*2)，食盐水(400毫升)洗涤，无水硫酸钠干燥，过滤并减压浓缩。残余物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝50/1-10/1)，得到化合物45-6。
步骤E：将45-6(17.00克，62.90毫摩尔)溶解在N,N-二甲基甲酰胺(100.00毫升)中，加入碳酸钾(13.04克，94.35毫摩尔)和溴化苄(11.83克，69.19毫摩尔，8.22毫升)。体系在25摄氏度搅拌16小时。加水(200毫升*3)，乙酸乙酯(200毫升*2)萃取，合并有机相用水(200毫升*2)，食盐水(200毫升)洗涤，无水硫酸钠干燥，过滤并减压浓缩，得到化合物45-7。
步骤F：将45-7(22.79克，63.24毫摩尔)溶解在甲醇(60.00毫升)和四氢呋喃(60.00毫升)中，加入氢氧化钾水溶液(6摩尔/升，61.55毫升)，45摄氏度搅拌2小时。反应液用1摩尔/升盐酸调节pH＝3-4，悬浮液过滤得到滤饼。残渣用石油醚/乙酸乙酯＝10/1(50毫升)，过滤并减压浓缩干燥，得到化合物45-8。
1H NMR(400MHz，CDCl 3)δ10.85(br s，1H)，7.64(s，1H)，7.48-7.39(m，5H)，6.71(s，1H)，5.27(s，2H)，4.17(t，J＝6.5Hz，2H)，3.89(s，3H)，3.58(t，J＝5.9Hz，2H)，3.38(s，3H)，2.13(quin，J＝6.2Hz，2H)。
步骤G：将45-8(20.00克，57.74毫摩尔)溶解在二氯甲烷(200.00毫升)中，加入草酰氯(7.58毫升，86.61毫摩尔)和N,N-二甲基甲酰胺(4.44微升，57.74微摩尔)。体系在25摄氏度搅拌2小时。减压浓缩旋干，得到化合物45-9。
步骤H：将45-9(21.06克，57.73毫摩尔)和2-乙酰基-3-二甲氨基丙烯酸乙酯(13.90克，75.05毫摩尔)溶解在四氢呋喃(200.00毫升)，于-70至-60摄氏度下滴加到六甲基二硅基胺基锂(1摩尔/升，150.09毫升)中。滴加完后，加入乙酸(115.55毫升，2.02摩尔/升)和乙酸铵(5.78克，75.05毫摩尔)。体系在65摄氏度下搅拌1小时。加入饱和碳酸氢钠水溶液(1000毫升)，乙酸乙酯(200毫升)萃取，有机相用水(200毫升)和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤减压浓缩旋干。残渣用甲基叔丁基醚MTBE(50毫升)洗涤，过滤得到化合物45-10。
1H NMR(300MHz，CDCl 3)δ11.03(s，1H)，9.02(s，1H)，7.71(s，1H)，7.64(s，1H)，7.46-7.31(m，5H)，6.69(s，1H)，5.11(s，2H)，4.48(q，J＝7.2Hz，2H)，4.14(t，J＝6.6Hz，2H)，3.93(s，3H)，3.58(t，J＝5.9Hz，2H)，3.38(s，3H)，2.11(quin，J＝6.3Hz，2H)，1.46(t，J＝7.1Hz，3H)。
步骤I：将45-10(20.00克，42.78毫摩尔)溶解在四氢呋喃(250.00毫升)中在氮气保护下加入钯碳(10％，1克)，体系在真空置换3次氢气后，于25摄氏度下，氢气气氛(15Psi)保护搅拌16小时。过滤，将滤液减压浓缩，得到化合物45-11。
1H NMR(400MHz，CDCl 3)δ14.24(br s，1H)，11.27(s，1H)，8.86(s，1H)，7.23(s，1H)，7.16(s，1H)，6.56(s，1H)，4.49(q，J＝7.1Hz，2H)，4.17(t，J＝6.5Hz，2H)，3.90(s，3H)，3.59(t，J＝6.1Hz，2H)，3.38(s，3H)，2.15(quin，J＝6.3Hz，2H)，1.47(t，J＝7.2Hz，3H)。
步骤J：将45-11(5.00克，13.25毫摩尔)溶解在二甲基亚砜(50.00毫升)中加入碳酸铯(17.27 克，53.00毫摩尔)和2-氯-5-(二氯甲基)噻吩(13.35克，66.25毫摩尔)。体系在100摄氏度下搅拌16小时。反应液用水(100毫升)稀释，二氯甲烷(100毫升)萃取，有机相用水(100毫升*2)和饱和食盐水(100毫升)，无水硫酸钠干燥，过滤并减压旋干。残余物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-1/1至二氯甲烷/乙醇＝100/1-30/1)，得到化合物45-12。
步骤K：将45-12(200.00毫克，395.28微摩尔)通过手性HPLC(分离柱:OJ(250mm*30mm,10μm)；流动相:[0.1％氨水-甲醇]；洗脱梯度:30％-30％,2.3min；90min)纯化得到实施例45-12A(保留时间＝2.194min)和45-12B(保留时间＝2.544min)。
步骤L：将实施例45-12A(71.00毫克，140.32微摩尔)溶解在四氢呋喃(2.00毫升)和甲醇(2.00毫升)中，加入氢氧化钠水溶液(4摩尔/升，1.00毫升)，体系在25摄氏度下搅拌0.5小时。反应液用1摩尔/升盐酸调节pH＝3，二氯甲烷(20毫升*2)萃取，合并有机相用无水硫酸钠干燥，过滤减压浓缩，得到实施例45_13A。
步骤M：将实施例45_13A(65.00毫克，136.01微摩尔)溶解在四氢呋喃(15.00毫升)中，于氮气气氛下加入钯碳(10％，30毫克)，悬浮液真空置换几次氢气，体系在氢气气氛(15Psi)下于25摄氏度下搅拌16小时。反应液过滤，滤液减压浓缩旋干，残渣用硅胶板(二氧化硅，二氯甲烷/甲醇＝15:1)纯化，得到实施例45_A。(保留时间＝1.941min)，ee值(对映体过量)：100％。
测ee值(对映体过量)方法：OD-3S_3_40_3ML分离柱:Chiralcel OD-3 100×4.6mm I.D.,3μm流动相:40％甲醇(0.05％二乙胺)CO 2流速:3mL/min波长:220nm。
实施例45_B，(保留时间＝3.040min)，ee值(对映体过量)：100％。
实施例45_A： 1H NMR(400MHz，CDCl 3)δ15.66(br s，1H)，8.41(br s，1H)，7.48(d，J＝4.9Hz，1H)，7.09-7.03(m，3H)，7.01(s，1H)，6.97-6.93(m，1H)，6.67(s，1H)，4.16(t，J＝6.5Hz，2H)，3.92(s，3H)，3.57(t，J＝5.9Hz，2H)，3.37(s，3H)，2.14(quin，J＝6.2Hz，1H)，2.18-2.11(m，1H)。
实施例45_B： 1H NMR(400MHz，CDCl 3)δ15.63(br s，1H)，8.37(br s，1H)，7.49(br d，J＝4.4Hz，1H)，7.06(br s，3H)，7.00(s，1H)，6.91(br s，1H)，6.68(s，1H)，4.16(t，J＝6.5Hz，2H)，3.93(s，3H)，3.57(t，J＝5.9Hz，2H)，3.37(s，3H)，2.15(quin，J＝6.2Hz，2H)。
实施例46至实施例48均可参照实施例45的制备方法制得
实施例46(46_A和46_B)
Figure PCTCN2018078581-appb-000084
实施例46水解前化合物经手性HPLC(分离柱:OJ(250mm*30mm,10μm)；流动相:[0.1％氨水-甲醇]；洗脱梯度:30％-30％,3min；40min)柱分离得到两个构型的异构，时间＝2.592min和时间＝2.829min。分别水解，得到实施例46_A(保留时间＝2.396min)，ee值(对映体过量)：95.7％和实施例46_B(保留时间＝2.887min)，ee值(对映体过量)：100％。测ee值(对映体过量)方法：OD-3S_3_40_3ML分离柱: Chiralcel OD-3 100×4.6mm I.D.,3μm流动相:40％甲醇(0.05％二乙胺)in CO 2流速:3mL/min波长:220nm。
实施例46_A: 1H NMR(400MHz，CDCl 3)δ15.42(br s，1H)，8.50-8.44(m，1H)，7.62(s，1H)，6.91(s，2H)，6.74(d，J＝3.8Hz，1H)，6.69(d，J＝3.5Hz，1H)，6.61(s，1H)，4.10(br t，J＝6.0Hz，2H)，3.52(t，J＝5.8Hz，2H)，3.29(s，3H)，2.06(quin，J＝6.0Hz，2H)。
实施例46_B: 1H NMR(400MHz，CDCl 3)δ15.44(br s，1H)，8.49(s，1H)，7.62(s，1H)，6.93(s，1H)，6.91(s，1H)，6.75-6.72(m，1H)，6.70(d，J＝3.8Hz，1H)，6.61(s，1H)，4.14-4.07(m，2H)，3.52(t，J＝5.9Hz，2H)，3.29(s，3H)，2.06(quin，J＝6.1Hz，2H)。
实施例47(47_A和47_B)
Figure PCTCN2018078581-appb-000085
实施例47水解前化合物经手性HPLC(分离柱:AS(250mm*30mm,10μm)；流动相:[0.1％氨水-甲醇]；洗脱梯度:45％-45％,2.3min；90min)柱分离得到两个构型的异构体，(保留时间＝2.110min)和(保留时间＝2.574min)，分别水解，得到实施例47_A(保留时间＝2.705min)，ee值(对映体过量)：99％和实施例47_B(保留时间＝1.818min)，ee值(对映体过量)：100％。测ee值(对映体过量)方法：OD-3S_3_40_3ML分离柱:Chiralcel OD-3 100×4.6mm I.D.,3μm流动相:40％甲醇(0.05％二乙胺)CO 2流速:3mL/min波长:220nm。
实施例48
Figure PCTCN2018078581-appb-000086
1H NMR(400MHz,DMSO-d6)δ8.88(br s，1H)，8.29(br d，J＝7.8Hz，1H)，7.62-7.44(m，2H)，7.25(s，1H)，6.91(s，1H)，4.15(br t，J＝6.1Hz，2H)，3.48(br s，2H)，3.23(s,3H)，1.96(quin，J＝6.2Hz，2H)。
实施例49(49_A和49_B)
Figure PCTCN2018078581-appb-000087
Figure PCTCN2018078581-appb-000088
步骤A:将49-1(50.01克，297.41毫摩尔)溶于二甲基甲酰胺(300毫升)并冷却至0摄氏度，然后向其中加入碳酸钾(41.10克，297.41毫摩尔)。混合物加热至90摄氏度后在一小时左右缓慢向其中滴入溴甲基环丙烷(40.15克，297.41毫摩尔)，之后让混合物在90摄氏度下搅拌1小时。再将溶液倒入200毫升水中，并通过乙酸乙酯(400毫升*3)萃取，收集有机相并通过水洗(150毫升)和饱和食盐水洗(100毫升*3)，减压浓缩得到白色固体。再将白色固体经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝30/1至20/1)纯化得到化合物49-2。
1H NMR(400MHz,CDCl 3)δ10.87(s,1H),7.65(d,J＝8.8Hz,1H),6.40-6.34(m,2H),3.83(s,3H),3.74(d,J＝6.9Hz,2H),1.23-1.15(m,1H),0.62-0.55(m,2H),0.28(q,J＝5.0Hz,2H)。
步骤B:将49-2(47.00克，211.48毫摩尔)溶于乙腈(200.00毫升)并冷却至0摄氏度，然后向其中加入N-氯代丁二酰亚胺(28.52克，213.59毫摩尔)。将混合物加热至90摄氏度并搅拌两小时。将反应液减压浓缩得到黄色残余物，再将得到的黄色残余物溶于乙酸乙酯(400毫升)，并向其中加入水(300毫升)，让溶液在25摄氏度下搅拌2分钟。分离有机相，并饱和食盐水洗(100毫升*3)，再经无水硫酸钠干燥，减压浓缩，再通过石油醚/二氯甲烷(30/1)打浆得到化合物49-3。
步骤C:向49-3(53.00克，206.48毫摩尔)，溴化苄(38.85克，227.13毫摩尔)的二甲基甲酰胺 (400.00毫升)溶液中加入碳酸钾(62.78克，454.26毫摩尔)。然后混合溶液在25摄氏度下搅拌1小时。再将乙酸乙酯(800毫升)和水(150毫升)加入溶液中，让溶液在20摄氏度下搅拌10分钟，分离有机相，水洗(130毫升*2)，饱和食盐水水洗(130毫升*2)，并通过无水硫酸钠干燥，再减压干燥得到化合物49-4。
步骤D:向49-4(60.00克，173.01毫摩尔)的甲醇(300.00毫升)和水(100.00毫升)的混合溶液中加入氢氧化钾(74.07克，1.32摩尔)。让溶液在50摄氏度下搅拌两小时。再将溶液减压浓缩至100毫升，并乙酸乙酯/石油醚(4/1 100毫升)洗涤。将水相分离，并通过1摩尔/升稀盐酸调节酸碱度至3～4后得到悬浊液。将悬浊液过滤后得到固体。得到的固体经水(100毫升)打浆过滤后，再通过正庚烷/乙酸乙酯的混合溶剂重结晶得到化合物49-5。
1H NMR(400MHz,CDCl 3)δ8.18-8.16(m,1H),7.48-7.43(m,5H),6.58(s,1H),5.29(s,2H),3.92(d,J＝6.8Hz,2H),1.29(br s,1H),0.72-0.68(m,2H),0.44-0.39(m,2H)。
步骤E:向49-5(26.00克，78.13毫摩尔)的二氯甲烷(30毫升)溶液中，逐滴加入草酰氯(19.83克，156.26毫摩尔)。完毕后混合溶液在28摄氏度下搅拌两小时。然后将溶液减压浓缩得到化合物49-6。
步骤F:在零下70摄氏度下向六甲基二硅基氨基锂(1摩尔/升，195.75毫升)的四氢呋喃(20毫升)溶液中逐滴加入(超过5分钟)化合物49-6(27.0 0克，76.87毫摩尔)和(2Z)-2-(二甲基氨基亚甲基)-3-氧代丁酸乙酯(14.50g,78.30mmol)的四氢呋喃(300毫升)溶液。滴加完毕移走冷却槽，并让混合溶液继续搅拌5分钟。再将醋酸铵(9.05克，117.45毫摩尔)和醋酸(164.09克，2.73摩尔)加入混合溶液，之后通过旋转蒸发仪在60摄氏度下除去绝大部分四氢呋喃。残余物在60到65摄氏度之间加热1.5小时。在反应混合液冷却后，向其中加入水(100毫升)和乙酸乙酯(300毫升)。然后混合物继续搅拌10分钟并分离。其中有机相经过水洗(100毫升*3)和饱和碳酸氢钠(100毫升)水溶液洗后，干燥，并浓缩得到黄色残余物。黄色残余物再经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到化合物49-7。
1H NMR(400MHz,CDCl 3)δ11.06(br s,1H),9.00(s,1H),8.06(s,1H),7.62(s,1H),7.41-7.32(m,5H),6.58(s,1H),5.19-5.15(m,2H),4.47(q,J＝7.1Hz,2H),3.87(d,J＝6.7Hz,2H),1.46(t,J＝7.2Hz,3H),1.32-1.22(m,1H),0.69-0.62(m,2H),0.41-0.35(m,2H)。
步骤G:.向49-7(26.00克,57.28毫摩尔)的四氢呋喃(500.00毫升)溶液中加入钯碳(1.00克，10％)(反应体系先N 2置换)。再将溶液在25摄氏度下氢气气氛下(30psi)搅拌2小时。将棕色悬浊液过滤得到黄色液体。再将溶液减压浓缩得到黄色残余物，并经过石油醚/乙酸乙酯(4/1 60毫升)混合溶剂打浆两次，过滤得到化合物49-8。
1H NMR(400MHz,CDCl 3)δ14.48(s,1H),11.18(s,1H),8.78(s,1H),7.64(s,1H),7.19(s,1H),6.43(s,1H),4.40(q,J＝7.1Hz,2H),3.84(d,J＝6.7Hz,2H),1.38(t,J＝7.2Hz,3H),1.35-1.20(m,1H),0.64-0.54(m,2H),0.37-0.31(m,2H)。
步骤H,I可参照实施例13的制备方法制得
实施例49水解前化合物经手性HPLC柱(分离柱:AS(250mm*30mm,10μm)；流动相:[0.1％氨水-甲醇]；洗脱梯度:30％-30％,4.4min；600min)分离得到两个构型的异构体(49-9A和49-9B)，分别水解得到实施 例49_A(保留时间＝3.885min)，ee值(对映体过量)：100％和实施例49_B(保留时间＝4.831min)，ee值(对映体过量)：100％。测ee值(对映体过量)方法：AD-3S_3_40_3ML_8MIN分离柱:Chiralpak AD-3 100×4.6mm I.D.,3μm流动相:40％甲醇(0.05％二乙胺)CO 2流速:3mL/min波长:220nm。
实施例49_A： 1H NMR(400MHz,CDCl 3)δ16.16(s,1H),9.08(d,J＝1.96Hz,1H),8.97(s,1H),8.24(s,1H),7.82(d,J＝0.86Hz,1H),7.79(s,1H),7.47(s,1H),7.07(s,1H),3.95-4.08(m,2H),1.22-1.31(m,1H),0.58-0.65(m,2H),0.32-0.40(m,2H)。
实施例49_B： 1H NMR(400MHz,CDCl 3)δ16.14(br s,1H),9.07(d,J＝1.83Hz,1H),8.96(s,1H),8.23(s,1H),7.80(br d,J＝15.89Hz,2H),7.45(s,1H),7.06(s,1H),3.98-4.07(m,2H),1.23-1.32(m,1H),0.58-0.68(m,2H),0.32-0.44(m,2H)。
实施例50(50_A和50_B)
Figure PCTCN2018078581-appb-000089
实施例50的制备方法参照实施例13的制备方法制得
实施例50水解前化合物经手性HPLC(分离柱:OJ(250mm*30mm,10μm)；流动相:[0.1％氨水-甲醇]；洗脱梯度:40％-40％,3min；700min)柱分离得到两个构型的异构体，(保留时间＝3.277min和保留时间＝3.598min)，分别水解得到实施例50_A(保留时间＝4.408min)，ee值(对映体过量)：95.5％和实施例50_B(保留时间＝4.145min)，ee值(对映体过量)：84.9％。测ee值(对映体过量)方法：OD-3S_3_5_40_3ML分离柱:Chiralcel OD-3 100×4.6mm I.D.,3μm流动相:甲醇(0.05％二乙胺)5％-40％，CO 2，流速:3mL/min波长:220nm。
实施例50_A： 1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.88(br s,1H),8.38(s,1H),7.96(s,1H),7.54(br s,1H),7.01(s,1H),4.06-3.94(m,2H),1.28-1.20(m,1H),0.62-0.56(m,2H),0.38-0.32(m,2H)。
实施例50_B： 1H NMR(400MHz,DMSO-d6)δ15.86(br s,1H),9.11(s,1H),8.89(s,1H),8.39(s,1H),7.96(s,1H),7.55(s,1H),7.01(s,1H),4.06-3.94(m,2H),1.24(br t,J＝7.0Hz,1H),0.63-0.56(m,2H),0.63-0.56(m,1H),0.38-0.33(m,2H)。
实施例51(51_A和51_B)
Figure PCTCN2018078581-appb-000090
Figure PCTCN2018078581-appb-000091
步骤A:在-10摄氏度下，向51-1(20.00克，178.33毫摩尔)的二氯甲烷溶液(150.00毫升)中，加入吡啶(2.82克，35.67毫摩尔)，然后再向其中加入五氯化磷(37.14克，178.33毫摩尔)，得到的混合物在-10摄氏度下反应0.5小时。反应完成后，向反应体系中加入碳酸氢钠(44.94克，534.99毫摩尔)。反应继续搅拌0.5小时，然后通过硅藻土过滤，并用二氯甲烷洗涤(20毫升*3)，将滤液浓缩得到残余物51-2。
1H NMR(400MHz,CDCl 3)δ7.68(d,J＝3.91Hz,1H),7.35-7.44(m,5H),7.22(d,J＝3.67Hz,1H),6.91(s,1H),5.34(s,2H)。
步骤B:将51-3(10.00克,26.19毫摩尔)，碳酸铯(38.40克，117.86毫摩尔)和51-2(21.88克，130.95毫摩尔)的二甲亚砜(100.00毫升)溶液在100摄氏度下搅拌16小时。反应完成后，用50毫升水淬灭反应，再用150毫升水稀释反应液，用二氯甲烷(100毫升*3)进行萃取，再将有机相合并，用饱和食盐水(100毫升*3)洗涤，采用无水硫酸钠干燥后，减压浓缩得到残余物。残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/乙醇＝100/1至8/1)得到化合物51-4。再将固体经手性色谱柱制备分离(分离柱:AS(250mm*30mm,10μm)；流动相:[0.1％氨水-乙醇]；洗脱梯度:40％-40％,4.3min；120minmin)纯化得51-4_A(保留时间＝2.516min)和51-4_B(保留时间＝5.098min)。
步骤C水解方法可参照实施例13的制备方法制得
51-4_A水解得到化合物51_A(保留时间＝3.842min)，ee值(对映体过量)：100％和51-4_B水解得到化合物51_B(保留时间＝2.682min)，ee值(对映体过量)：100％。测ee值(对映体过量)方法：OD-3S_3_40_3ML分离柱:Chiralcel OD-3 100×4.6mm I.D.,3μm流动相:40％甲醇(0.05％二乙胺)CO 2流速:3mL/min波长:220nm。
化合物51_A： 1H NMR(400MHz,CHLOROFORM-d)δ15.40(s,1H),8.32(s,1H),7.62(s,1H),7.41(dd,J＝1.28,4.83Hz,1H),6.93-6.98(m,2H),6.91(s,1H),6.88(s,1H),6.62(s,1H),4.09(t,J＝6.24Hz,2H),3.51(t,J＝5.87Hz,2H),3.28(s,3H),2.05(quin,J＝6.08Hz,2H)
化合物51_B： 1H NMR(400MHz,CHLOROFORM-d)δ15.46(s,1H),8.38(s,1H),7.69(s,1H),7.48(dd,J＝1.47,4.89Hz,1H),7.00-7.04(m,2H),6.98(s,1H),6.93(s,1H),6.69(s,1H),4.16(t,J＝6.24Hz,2H),3.58(t,J＝5.93Hz,2H),3.35(s,3H),2.12(quin,J＝6.05Hz,2H).
实验例1：HBV体外测试
1.实验目的：
通过实时定量qPCR试验(real time-qPCR)检测HepG2.2.15细胞培养上清的HBV DNA含量，及酶联免疫吸附测定(ELISA)检测HBV表面抗原含量，以化合物的EC 50值为指标，来评价化合物对HBV的抑制作用。
2.实验材料:
2.1.细胞系：HepG2.2.15细胞
HepG2.2.15细胞培养基(DMEM/F12，Invitrogen-11330032；10％血清，Invitrogen-10099141；100units/ml青霉素和100μg/ml链霉素，胎牛血清-SV30010；1％非必需氨基酸，Invitrogen-11140050；2mM L-谷氨酰胺，Invitrogen-25030081；300μg/ml遗传霉素，Invitrogen-10131027
2.2.试剂：
胰酶(Invitrogen-25300062)
DPBS(Corning-21031CVR)
DMSO(Sigma-D2650-100ML)
高通量DNA纯化试剂盒(QIAamp 96DNA Blood Kit，Qiagen-51162)
定量快速启动通用探针试剂(FastStart Universal Probe Master，Roche-04914058001)
乙型肝炎表面抗原定量检测试剂盒(安图生物，CL 0310)
2.3.耗材与仪器：
96孔细胞培养板(Corning-3599)
CO 2培养箱(HERA-CELL-240)
光学封板膜(ABI-4311971)
定量PCR 96孔板(Applied Biosystems-4306737)
荧光定量PCR仪(Applied Biosystems-7500real time PCR system)
3.实验步骤和方法：
3.1种HepG2.2.15细胞(4x10 4细胞/孔)到96孔板，在37℃，5％CO 2培养过夜。
3.2第二天，稀释化合物，共8个浓度，3倍梯度稀释。加不同浓度化合物到培养孔中，双复孔。培养液中DMSO的终浓度为0.5％。10μM恩替卡韦作为100％抑制对照；0.5％的DMSO作为0％抑制对照。
3.3第五天，更换含有化合物的新鲜培养液。
3.4第八天收取培养孔中的培养液，取部分样品ELISA测定乙肝病毒S抗原的含量；取部分样品使用 高通量DNA纯化试剂盒(Qiagen-51162)提取DNA。
3.5PCR反应液的配制如表1所示：
表1 PCR反应液的配制
Figure PCTCN2018078581-appb-000092
前引物序列：GTGTCTGCGGCGTTTTATCA
后引物序列：GACAAACGGGCAACATACCTT
探针序列：5'+FAM+CCTCTKCATCCTGCTGCTATGCCTCATC+TAMRA-3'
3.6在96孔PCR板中每孔加入15μl的反应混合液，然后每孔加入10μl的样品DNA或HBV DNA的标准品。
3.7用光学封板膜将qPCR板封住，1500rpm离心2分钟，然后用荧光定量qPCR仪定量检测各样本HBV拷贝数。qPCR运行程序如下：
Figure PCTCN2018078581-appb-000093
3.8数据分析：
计算抑制百分比：
抑制率(％)＝(1-样品中的值/DMSO对照值)x100％。
将各化合物对HBV抑制百分比用GraphPad Prism软件拟合剂量效应曲线，并计算化合物对HBV的50％抑制浓度(EC 50)值。
3.9 ELISA测定乙肝病毒S抗原的含量
具体步骤参照该产品说明书，步骤简述如下：
取50μl样品和标准品分别加入到反应板中，再每孔分别加入50μl酶结合物，震荡混匀，37℃温浴60分钟，然后用洗液洗板5次，再每孔加入50μl发光底物，混匀，室温避光反应10分钟，最后用酶标仪检测化学发光强度。用以下公式计算各化合物的抑制百分比：抑制率(％.)＝(1-样品中的值/DMSO对照值)x100％。将各化合物对HBV抑制百分比用GraphPad Prism软件拟合剂量效应曲线，并计算化合物对HBV的50％抑制浓度(EC 50)值。
4.实验结果：见表2、表3。
表2 HBV-DNA实验结果
受试化合物 EC 50(nM) 受试化合物 EC 50(nM)
1 11.82 30 18.52
2 34.5 31 90.54
3 27.61 32 35.22
4 14.98 33 12.64
5 15.05 34 21.27
6 6.04 35 25.15
7 211.2 37 10.59
8 20.84 38 20.35
9 74.06 39_A 3.51
10 50.96 39_B 764.9
11 40.8 40_A 15.18
12 78.06 40_B >1000
13_A 300 41 17.76
13_B 7.33 42 2.19
14 6.88 43 19.36
15 8.2 44 128.9
16 45.29 45_A 77.10
17 254.1 45_B 0.22
18 40.82 46_A 79.66
19 3.88 46_B 43.01
20 11.02 47_A 0.44
21 7.12 47_B 26.88
22 20.65 48 >1000
23 85.88 49_A 2.54
24 59.32 49_B 333.9
25 18.71 50_A 0.69
26 152.2 50_B 2.82
27 23.57 51_A 1.13
28 277.7 51_B 147.2
29 4.113    
结论：本发明代表性化合物能有效减少HBV-DNA含量，对HBV的抑制作用显著。
表3 HBsAg实验结果
受试化合物 EC 50(nM) 受试化合物 EC 50(nM)
1 27.65 30 28.2
2 55.78 31 202.7
3 47.62 32 71.05
4 31.88 33 10.25
5 49.95 34 29.63
6 20.33 35 11.03
7 299.3 37 26.58
8 66.22 38 12.32
9 137.5 39_A 6.75
10 102.4 39_B >1000
11 73.89 40_A 1.45
12 212.7 40_B 10.08
13_A 300 41 57.97
13_B 7.33 42 7.88
14 6.88 43 15.42
15 8.2 44 212.2
16 45.29 45_A 104.6
17 254.1 45_B 1.09
18 73.7 46_A 122.9
19 20.9 46_B 73.96
20 22.47 47_A 0.84
21 16.27 47_B 46.01
22 38.23 48 103.3
23 127 49_A 4.62
24 35.5 49_B 965.9
25 35.92 50_A 1.31
26 101.3 50_B 3.62
27 39.15 51_A 1.54
28 152.5 51_B 349.7
29 12.19    
结论：本发明化合物能有效减少HBV表面抗原含量(HBsAg)，对HBV的抑制作用显著。

Claims (23)

  1. 式(I)化合物或其药学上可接受的盐，
    Figure PCTCN2018078581-appb-100001
    其中，
    R 1选自H、OH、CN、NH 2，或者选自任选被1、2或3个R取代的：C 1-5烷基、C 1-5杂烷基、C 2-5炔基、C 3-6环烷基和3～6元杂环烷基；
    R 2选自H、卤素，或者选自任选被1、2或3个R取代的：C 1-3烷基和C 1-3杂烷基；
    m选自0、1、2、3、4和5；
    A选自任选被1、2或3个R取代的：苯基或5～6元杂芳基；
    R选自H、卤素、OH、CN、NH 2、＝O、CH 3、CH 3CH 2、CH 3O、CF 3、CHF 2、CH 2F；
    所述C 1-5杂烷基、3～6元杂环烷基、C 1-3杂烷基、5～6元杂芳基之“杂”，分别独立地选自：N、-O-、＝O、-S-、-NH-、-(C＝O)-、-(S＝O)-、-(S＝O) 2-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R选自H、F、Cl、Br、OH、CH 3、CH 3O、CF 3、CHF 2、CH 2F。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 1选自H、OH、CN、NH 2，或者选自任选被1、2或3个R取代的：CH 3、CH 3CH 2、CH 3CH 2CH 2、CH 3CH 2CH 2CH 2、CH 3O、CH 3CH 2O、CH 3S、CH 3S(＝O)、CH 3S(＝O) 2、CH 3SCH 2、CH 3CH 2S、CH 3NH、
    Figure PCTCN2018078581-appb-100002
    Figure PCTCN2018078581-appb-100003
    吡咯烷基、哌啶基、四氢吡喃基、吗啉基、2-吡咯烷酮基、3-吡咯烷酮基。
  4. 根据权利要求3所述化合物或其药学上可接受的盐，其中，R 1选自H、OH、CN、NH 2，或者选自任选被1、2或3个R取代的：CH 3、CH 3CH 2、CH 3CH 2CH 2、CH 3CH 2CH 2CH 2、CH 3O、CH 3CH 2O、CH 3S、CH 3S(＝O)、CH 3S(＝O) 2、CH 3SCH 2、CH 3CH 2S、CH 3NH、
    Figure PCTCN2018078581-appb-100004
    Figure PCTCN2018078581-appb-100005
  5. 根据权利要求4所述的化合物或其药学上可接受的盐，其中，R 1选自：H、OH、CH 3、CHF 2、CH 3O、
    Figure PCTCN2018078581-appb-100006
  6. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 2选自H、F、Cl、Br，或者选自任选被1、2或3个R取代的：CH 3、CH 3CH 2、CH 3O、CH 3CH 2O、
    Figure PCTCN2018078581-appb-100007
  7. 根据权利要求6所述的化合物或其药学上可接受的盐，其中，R 2选自Cl和CH 3O。
  8. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，A选自任选被1、2或3个R取代的：苯基、噻吩基、噻唑基、异噻唑基、恶唑基、异恶唑基。
  9. 根据权利要求8所述的化合物或其药学上可接受的盐，其中，A选自任选被1、2或3个R取代的：
    Figure PCTCN2018078581-appb-100008
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，其中，A选自：
    Figure PCTCN2018078581-appb-100009
    Figure PCTCN2018078581-appb-100010
  11. 根据权利要求10所述的化合物或其药学上可接受的盐，其中，A选自：
    Figure PCTCN2018078581-appb-100011
    Figure PCTCN2018078581-appb-100012
  12. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，m为3。
  13. 根据权利要求12所述的化合物或其药学上可接受的盐，其中，R 2选自Cl和CH 3O。
  14. 根据权利要求13所述的化合物或其药学上可接受的盐，其中，R 1为CH 3O。
  15. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，m为1。
  16. 根据权利要求15所述的化合物或其药学上可接受的盐，其中，R 2为Cl。
  17. 根据权利要求16所述的化合物或其药学上可接受的盐，其中，R 1为
    Figure PCTCN2018078581-appb-100013
  18. 根据权利要求14或17所述的化合物或其药学上可接受的盐，其中，A选自任选被1、2或3个R取代的：
    Figure PCTCN2018078581-appb-100014
  19. 根据权利要求1～18任意一项所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2018078581-appb-100015
    其中，
    R 1、R 2、A、R、m如权利要求1～18所定义。
  20. 化合物或其药学上可接受的盐，其选自
    Figure PCTCN2018078581-appb-100016
    Figure PCTCN2018078581-appb-100017
    Figure PCTCN2018078581-appb-100018
    Figure PCTCN2018078581-appb-100019
    Figure PCTCN2018078581-appb-100020
  21. 根据权利要求20所述的化合物或其药学上可接受的盐，其选自
    Figure PCTCN2018078581-appb-100021
    Figure PCTCN2018078581-appb-100022
    Figure PCTCN2018078581-appb-100023
  22. 一种药物组合物，其含有治疗有效量的根据权利要求1～21任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  23. 根据权利要求1～21任意一项所述的化合物或其药学上可接受的盐或根据权利要求22所述的药物组合物在制备治疗乙型肝炎药物中的应用。
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US11472808B2 (en) 2019-06-04 2022-10-18 Enanta Pharmaceuticals, Inc. Substituted pyrrolo[1,2-c]pyrimidines as hepatitis B antiviral agents
US11760755B2 (en) 2019-06-04 2023-09-19 Enanta Pharmaceuticals, Inc. Hepatitis B antiviral agents
US11738019B2 (en) 2019-07-11 2023-08-29 Enanta Pharmaceuticals, Inc. Substituted heterocycles as antiviral agents
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RU2823673C1 (ru) * 2019-09-19 2024-07-29 Фуцзянь Акейлинк Биотекнолоджи Ко., Лтд. Способ получения кристаллической формы ингибитора поверхностного антигена вируса гепатита в
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