WO2015180631A1 - 作为hbv抑制剂的二氢嘧啶并环衍生物 - Google Patents
作为hbv抑制剂的二氢嘧啶并环衍生物 Download PDFInfo
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- WO2015180631A1 WO2015180631A1 PCT/CN2015/079870 CN2015079870W WO2015180631A1 WO 2015180631 A1 WO2015180631 A1 WO 2015180631A1 CN 2015079870 W CN2015079870 W CN 2015079870W WO 2015180631 A1 WO2015180631 A1 WO 2015180631A1
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Classifications
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
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- 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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
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- 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 dihydropyrimidocyclic derivative as an HBV inhibitor, and more particularly to a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
- Hepatitis B virus belongs to the family of hepatic viruses. It can cause acute and/or persistent/progressive chronic diseases. Hepatitis B virus also causes many other clinical characterizations in pathological morphology - especially chronic inflammation of the liver, cirrhosis of the liver and carcinogenesis of hepatocytes. In addition, co-infection with hepatitis D can have an adverse effect in the development of the disease.
- interferon Conventional agents that are approved for the treatment of chronic hepatitis are interferon and amifluudine.
- interferon has only moderate activity and high toxic side effects; although lamivudine has good activity, its drug resistance increases rapidly during treatment and often after stopping treatment. A rebound effect occurs, and the IC50 value of lamivudine (3-TC)> is 300 nM (Science, 299 (2003), 893-896).
- heteroaryl ring-substituted dihydropyrimidine (HAP) compounds represented by Bay41_4109 and Bay39_5493, which are capable of inhibiting HBV replication by preventing the formation of normal nucleocapsids.
- Bay41-4109 showed better drug metabolism parameters in clinical studies (Science, 299 (2003), 893-896).
- Studies on its mechanism of action have revealed that heteroaryl ring-substituted dihydropyrimidines change the angle between the dimers forming the nucleocapsid by acting on the 113-143 amino acid residues of the core protein, resulting in the formation of no Stable expanded nucleocapsid accelerates degradation of core proteins (Biochem. Pharmacol. 66 (2003), 2273-2279).
- R 2 is selected from
- R 3 are independently selected from R 01 is optionally substituted: C 1-10 alkyl or heteroalkyl, 3-6 membered cycloalkyl or heterocycloalkyl, 6 to 10-membered aromatic ring group or Heteroaromatic ring group;
- R 3 ', R 21 , R d1-8 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, -COOH, or selected from those optionally substituted by R 01 : C 1- 4- alkyl, -C 0-4 alkylphenyl, -C 0-4 alkyl-3-6-membered heterocyclic, 3- to 6-membered heterocyclyl-, benzenesulfonylamino or heterophenylsulfonylamino , -D 01 -D 02 -D 03 -H,
- D 01 is selected from a single bond, -C 1-4 alkyl-;
- D 03 is selected from the group consisting of a single bond, -C 1-4 alkyl-, -C 2-4 alkenyl-, -C 3-6 cycloalkyl-, -3 to 6-membered heterocycloalkyl-, 5 to 6 Aryl, 5- to 6-membered heteroaryl; optionally, R 3 and R 3 ' are joined to the same carbon atom or hetero atom to form an optionally substituted 3 to 12 membered ring;
- the numbers of R 01 and R 001 are each independently selected from 0, 1, 2 or 3, and the number of hetero atoms or heteroatoms is independently selected from 1, 2 or 3.
- the above compound, or a pharmaceutically acceptable salt thereof has the structure of formula (II):
- R 31-32 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, -COOH, or selected from the group consisting of 1, 2 or 3 R 01 : C 1 -4 alkyl, -C 0-4 alkylphenyl, -C 0-4 alkyl-3-6-membered heterocyclic, 3- to 6-membered heterocyclyl-, benzenesulfonylamino or heterobenzenesulfonyl Amino group, -D 01 -D 02 -D 03 -H,
- D 01 is selected from a single bond, -C 1-4 alkyl-;
- D 03 is selected from the group consisting of a single bond, -C 1-4 alkyl-, -C 2-4 alkenyl-, -C 3-6 cycloalkyl-, -3 to 6-membered heterocycloalkyl-, 5 to 6
- An aryl group, a 5- to 6-membered heteroaryl group; m and n are each independently selected from 1 or 2;
- the above -D 03 -H is selected from the group consisting of: H, Me, Et,
- R 3 ', R 21 , R d1 - d8 , R 31-32 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, -COOH, or Selected from CH 3 optionally substituted by 1, 2 or 3 R 01 ,
- R 3 ', R 21 , R d1 - d8 , and R 31-32 are each independently selected from the group consisting of: H, F, Cl, Br, I, OH, NH 2 , CN, -COOH, CH 3 ,
- the structural unit From:
- the structural unit From:
- the above L, D 21 is selected from the group consisting of a single bond, -O-, -NH-; or R 21 is selected from the group consisting of C 1-4 alkyl, C 1-4 alkylamino, N, N-di ( C 1-4 alkyl)amino, C 1-4 alkylamino-C 1-4 alkyl-, N,N-di(C 1-4 alkyl)amino-C 1-4 alkyl-, C 1- 4 -alkoxy, C 1-4 alkoxy-C 1-4 alkyl-, halo C 1-4 alkyl-, dihalo C 1-4 alkyl-, aminooxy C 1-4 alkane Base-, hydroxy-C 1-4 alkyloxy-, hydroxy C 1-3 alkylamino-.
- the above R 21 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, A Aminoethyl, ethylaminoethyl, propylaminoethyl, dimethylaminoethyl, diethylaminomethyl, dimethylaminomethyl, diethylaminoethyl, methoxymethyl, methoxy Base, methoxypropyl, ethoxymethyl, propoxymethyl, ethoxyethyl, propoxypropyl, fluoromethyl, fluoroethyl, fluoropropyl, difluoromethyl, difluoro Ethyl, difluoropropyl, aminooxymethyl, aminooxyethyl, aminooxypropyl, hydroxymethyloxy
- R 3 or R 4 are each independently selected from the group consisting of 1, 2 or 3 R 001 substituted: phenyl, pyridyl, quinolyl, isoquinolinyl, thiazolyl, Thienyl, oxazolyl, isoxazolyl, pyrazolyl, isothiazole, furyl, pyrrolyl, pyrrolidinyl, 1,3-oxapentacyclyl, 2-pyrazolyl, pyrazolidinyl, Imidazolyl, 1,2,3-oxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, piperidinyl, 1,4 -dioxolyl, morpholinyl, piperazinyl, piperidinyl, pyrimidinyl, pyrazinyl, 1,3,5-trithiaalkyl, 1,3,5-triazinyl
- R 001 is as defined above.
- R 3 is selected from
- R 4 is selected from
- the structural unit From:
- the compounds of the invention are selected from the group consisting of
- 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 alkyl or heteroalkyl, C 3-12 cyclo or heterocycloalkyl, C 1-12 alkyl or heteroalkyl substituted by C 3-12 cycloalkyl or heterocycloalkyl includes, but is not limited to:
- pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- 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. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention. Certain compounds of the invention may exist in polycrystalline or amorphous form.
- 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 salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art.
- the diastereomeric resolution is carried out by crystallization or chromatography, and then 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.
- pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
- excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
- an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
- an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
- active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
- substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
- it means that two hydrogen atoms are substituted.
- 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.
- substituents 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.
- 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.
- R', R", R"', R"" and R""' are each independently preferred Hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (eg substituted by 1 to 3 halogen aryl), substituted or unsubstituted alkyl, alkoxy, sulphur Alkoxy group or aralkyl group.
- each R group is independently selected as if present Each of these groups of more than one R', R", R"', R"" and R""' groups.
- R' and R" When R' and R" are attached to the same nitrogen atom, they may be bonded to the nitrogen The atoms combine to form a 5-, 6- or 7-membered ring.
- -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
- alkyl is intended to include carbon.
- a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
- a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.).
- Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
- two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 The integer.
- a single bond on the new ring thus formed can be replaced with a double bond.
- two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
- the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.
- halo or halogen
- 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.
- haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
- Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
- the C 1-6 alkoxy group includes a 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.
- Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
- the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
- Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
- halo or halogen refers to fluoro, chloro, bromo and iodo.
- 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).
- N nitrogen
- S sulfur
- Si silicon
- Ge germanium
- Al aluminum
- 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).
- 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). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one.
- 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, anthracycline, benzimidazolyl, benzofuranyl, benzinyl furanyl, Benzononylphenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzene And imidazolinyl, oxazolyl, 4aH-carbazolyl, porphyrinyl, chromanthyl, chromene, porphyrinyldecahydroquinolinyl, 2H,6H-1,5,2-di Thiazinyl, dihydrofuro[2,3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazo
- hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
- the hydrocarbon radical or a combination thereof may be fully saturated, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (methine), may include a divalent or polyvalent radical having the specified number of carbon atoms (e.g., C 1 -C 10 represents 1 to 10 carbons).
- 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.
- alkyl refers to a straight or branched chain of atoms 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 alkyl 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 Structure.
- 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 heteroatom or heteroatom group can be located at any internal position of the heterohydrocarbyl group (including where the hydrocarbyl group is attached to the rest of the molecule).
- Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
- alkoxy alkylamino and “alkylthio” (or thioalkoxy) are used conventionally to mean passing through an oxygen atom, respectively. Amino or a sulfur atom is attached to those alkyl groups of the remainder of the molecule.
- 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.
- aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 1 to 3 rings; at least one of which is aromatic), which 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, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
- aryl groups when used in conjunction with other terms (eg, 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).
- substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
- protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
- amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
- Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
- 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, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
- alkyl groups such as methyl, ethyl and t-butyl groups
- acyl groups such as alkanoyl groups (e.g., acetyl)
- arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
- 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 replacement, Preferred embodiments include, but are not limited to, embodiments of the invention.
- the solvent used in the present invention is commercially available.
- the present invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for carbonyl Diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl and is an amine protecting group; BOC
- A EC 50 ⁇ 100nM
- B 100nM ⁇ EC 50 ⁇ 500nM
- C 500nM ⁇ EC 50 ⁇ 1000nM
- D 1000nM ⁇ EC 50 ⁇ 5000nM
- Example 4 was prepared as described in Example 1.
- Example 5 was prepared as described in Example 1 and isolated by SFC preparation.
- Examples 8, 9 were prepared as described in Examples 6, 7 by high performance liquid phase separation.
- Example 15 and 16 were dissolved in 1 mL of ethyl acetate, and then 4 mL of ethyl hydrogen chloride solution was added thereto, and the mixture was stirred at 20 ° C for 30 minutes, concentrated under reduced pressure, and lyophilized to give Example 15 and Example 16 respectively. .
- Examples 17, 18 were prepared as described in Examples 15, 16 by high performance liquid phase separation.
- Examples 19, 20 were prepared as described in Examples 15, 16 by SFC separation.
- Examples 21, 22 were prepared as described in Examples 15, 16 by SFC separation.
- Examples 26, 27 were obtained by high performance liquid phase separation from 23-5.
- Examples 30, 31 were prepared as described in Examples 28, 29 by SFC separation.
- Example 33 was prepared as described in Example 32.
- the compound 34-2 (30 g, 158 mmol) was dissolved in anhydrous tetrahydrofuran (400 mL), and hexanes hexanes (16.5 mL, 165 mmol) was slowly added dropwise at room temperature, and the mixture was stirred at room temperature for 1 hour. The temperature was then lowered to 0 ° C, sodium borohydride (300 mg, 8 mmol) was added and the mixture was stirred vigorously for 30 min then warmed to room temperature and stirred overnight. Then, absolute ethanol (80 mL), p-TsOH (450 mg, 4 mmol) was added, and the mixture was stirred at room temperature for half an hour. The reaction mixture was concentrated under reduced pressure and purified to silicagel eluting eluting eluting eluting eluting
- the compound 36-3 (10 g, 16.0 mmol) was dissolved in anhydrous tetrahydrofuran (1000 mL), and sodium borohydride (600 mg, 16.0 mmol) was added portionwise at room temperature, and methanol (1 mL) was added, and the mixture was stirred at room temperature for 10 min under nitrogen atmosphere. Thereafter, the temperature was raised to a reflux state, and stirred under reflux for 6 hours.
- the reaction solution was cooled to room temperature, concentrated under reduced Celite, and then evaporated and evaporated. Extract with ethyl acetate (400 mL x 3), combine the organic phases, sequentially with water (200 mL x 2), saturated sodium chloride solution (100 The residue was washed with aq. EtOAc (EtOAc) (EtOAc) 75%.
- Example 42 was isolated via SFC preparation to give the chiral pure Example 43 and Example 44.
- This embodiment was prepared as described in Examples 42, 43 and 44.
- This embodiment was prepared as described in Examples 42, 43 and 44.
- This embodiment was prepared as described in Examples 42, 43, 44.
- This embodiment was prepared as described in Examples 42, 43, 44.
- This embodiment was prepared as described in Examples 42, 43, 44.
- Example 36-6 (200 mg, 0.398 mmol) was dissolved in anhydrous pyridine (5 mL). After the completion of the addition, the mixture was stirred under nitrogen for 2 hours, and then cyclopropylsulfonyl chloride (56 mg, 0.477 mmol) was added, and stirring was continued for 2 hours under nitrogen atmosphere.
- TLC (petroleum ether: ethyl acetate; 1:1) showed the disappearance of the starting material, the reaction mixture was poured into a saturated sodium hydrogen carbonate solution (15 mL), and extracted with dichloromethane (20 mL x 3).
- Example 61 The diastereomer was isolated via SFC to give the chiral pure Example 61, and Example 62.
- This embodiment was prepared as described in Examples 61, 62.
- Example 69 was prepared as described in Example 1.
- Example 70 was prepared as described in Example 1.
- Example 71 was prepared as described in Example 1.
- Example 72 was prepared as described in Example 1.
- Example 73 was prepared as described in Example 1.
- Example 74 was prepared as described in Example 1.
- Example 76 was prepared as described in Example 1.
- Example 77 was prepared as described in Example 1.
- Example 78 was prepared as described in Example 1.
- Example 79 was prepared as described in Example 1.
- Example 81 was prepared as described in Example 80.
- Example 83 was obtained as in Example 82-8.
- Example 84 was obtained as in Example 82.
- Example 85 was obtained as in Example 82.
- Example 86 was obtained as in Example 82.
- Example 87 was obtained as in Example 82.
- Example 88 was obtained as in Example 82.
- Example 89 was obtained as in Example 82.
- Example 90 was obtained as in Example 82.
- Example 91 was obtained as in Example 82.
- Example 92 was obtained as in Example 82.
- Example 93 was obtained as in Example 82.
- Example 96 was obtained as in Example 95.
- Example 97 was obtained as in Example 95.
- Example 98 was obtained as in Example 95.
- Example 99 was obtained as in Example 95.
- Example 100 was obtained as in Example 94.
- Example 101 was obtained as in Example 95.
- Example 102 was obtained as in Example 94.
- Example 103 was obtained as in Example 95.
- Example 105 The second, third steps of Example 105 were prepared in the same manner as in Example 104.
- This example was prepared in the same manner as in Example 104.
- This example was prepared as described in Example 107.
- the first step (synthesis of 113-3)
- the compound 113-3 (1.76 g, 3.02 mmol, 1.0 eq) was dissolved in anhydrous THF (50 mL), and sodium borohydride (571 mg, 15.1 mmol, 5.0 eq) was added portionwise at 0 ° C. Stir at 60 ° C for 18 hours. The reaction solution was cooled to room temperature and quenched with water (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated. 39%.
- the first step (synthesis of 115-3)
- the first step (synthesis of 119-2)
- Examples 121, 122 The synthesis of Examples 121, 122 is the same as in Examples 119, 120.
- the first step (synthesis of 123)
- Example 127 The synthesis of Example 127 was the same as that of Example 123.
- the first step (synthesis of 134-3)
Abstract
Description
Claims (13)
- 式(I)所示化合物或其药学上可接受的盐,其中,D11-14中的0~2个分别独立地选自单键、-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)-或-S(=O)2-,其余选自-C(Rd1)(Rd2)-;L选自单键、-O-、-S-、-NH-、-C(=O)-、-C(=S)-、-S(=O)-、-S(=O)2-、-C(=O)N(Rd3)-、-N(Rd4)-、-[C(Rd1)(Rd2)]0~ 6;D21选自单键、-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、-[C(Rd1)(Rd2)]0~6;R3、R4分别独立地选自任选被R01取代的:C1-10烷基或杂烷基、3~6元环烷基或杂环烷基、6~10元芳环基或杂芳环基;R3’、R21、Rd1-d8分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-COOH,或选自任选被R01取代的:C1-4烷基、-C0-4烷基苯基、-C0-4烷基-3~6元杂环基、3~6元杂环基酰基-、苯磺酰氨基或杂苯磺酰氨基、-D01-D02-D03-H、D01选自单键、-C1-4烷基-;D02选自O、S、NH、-C(=O)-、-S(=O)2-、-C(=O)O-、-C(=O)NH-、-C(=S)NH-、-S(=O)2NH-、-S(=O)NH-、-NHC(=O)O-、-NHC(=O)NH-、-NHS(=O)2NH-、-C(=O)NHS(=O)2-、-NHS(=O)NH-、-C(=O)NHS(=O)-、-NHS(=O)2O-、-NHS(=O)O-、-C(=N)-、-NH-C(=N)-;D03选自单键、-C1-4烷基-、-C2-4烯基-、-C3-6环烷基-、-3~6元杂环烷基-、5~6元芳基、5~6元杂芳基;任选地,R3与R3’共同连接到同一个碳原子或杂原子上形成一个任选被取代的3~12元环;“杂”表示杂原子或杂原子团,选自-C(=O)N(Rd3)-、-N(Rd4)-、-C(=NRd5)-、-S(=O)2N(Rd6)-、-S(=O)N(Rd7)-、-O-、-S-、=O、=S、-C(=O)O-、-C(=O)-、-C(=S)-、-S(=O)、-S(=O)2-或/和-P(=O)(ORd8)2;R01选自F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH、=NH、=O、=S、或任选被R001取代的:C1-10烷基、C1-10烷氨基、N,N-二(C1-10烷基)氨基、C1-10烷氧基、C1-10烷酰基、C1-10烷氧羰基、-C1-5烷基-C(=O)O-C1-5烷基、C1-10烷基磺酰基、C1-10烷基亚磺酰基、3~10元环烷基、3~10元环烷氨基、3~10 元杂环烷氨基、3~10元环烷氧基、3~10元环烷基酰基、3~10元环烷氧羰基、3~10元环烷基磺酰基、3~10元环烷基亚磺酰基;R001选自F、Cl、Br、I、CN、OH、N(CH3)2、NH(CH3)、NH2、CHO、COOH、=NH、=O、=S、三卤代甲基、二卤代甲基、一卤代甲基、氨甲基、羟甲基、甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基;在上述任意一种情况下,R01、R001的数目分别独立地选自0、1、2或3,杂原子或杂原子团的数目分别独立地选自1、2或3。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其具有式(Ⅱ)所示结构:其中,R31-32分别独立地选自H、F、Cl、Br、I、OH、NH2、CN、-COOH,或选自任选被1、2或3个R01取代的:C1-4烷基、-C0-4烷基苯基、-C0-4烷基-3~6元杂环基、3~6元杂环基酰基-、苯磺酰氨基或杂苯磺酰氨基、-D01-D02-D03-H、D01选自单键、-C1-4烷基-;D02选自O、S、NH、-C(=O)-、-S(=O)2-、-C(=O)O-、-C(=O)NH-、-C(=S)NH-、-S(=O)2NH-、-S(=O)NH-、-NHC(=O)O-、-NHC(=O)NH-、-NHS(=O)2NH-、-C(=O)NHS(=O)2-、-NHS(=O)NH-、-C(=O)NHS(=O)-、-NHS(=O)2O-、-NHS(=O)O-、-C(=N)-、-NH-C(=N)-;D03选自单键、-C1-4烷基-、-C2-4烯基-、-C3-6环烷基-、-3~6元杂环烷基-、5~6元芳基、5~6元杂芳基;m、n分别独立地选自1或2;其他变量如权利要求1所定义。
- 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,其中所述L、D21选自单键、-O-、-NH-;或R21选自C1-4烷基、C1-4烷氨基、N,N-二(C1-4烷基)氨基、C1-4烷氨基-C1-4烷基-、N,N-二(C1-4烷基)氨基-C1-4烷基-、C1-4烷氧基、C1-4烷氧基-C1-4烷基-、卤代C1-4烷基-、二卤代C1-4烷基-、氨氧基C1-4烷基-、羟代C1-4烷基氧基-、羟代C1-3烷基氨基-。
- 根据权利要求8所述的化合物或其药学上可接受的盐,其中所述R21选自甲基、乙基、正丙基、异丙基、甲氨基、乙氨基、丙氨基、二甲氨基、二乙基氨基、二丙基氨基、甲氨基乙基、乙氨基乙基、丙氨基乙基、二甲基氨基乙基、二乙基氨基甲基、二甲基氨基甲基、二乙基氨基乙基、甲氧甲基、甲氧乙基、甲氧丙基、乙氧基甲基、丙氧基甲基、乙氧基乙基、丙氧基丙基、氟甲基、氟乙基、氟丙基、二氟甲基、二氟乙基、二氟丙基、氨氧基甲基、氨氧基乙基、氨氧基丙基、羟甲基氧基、羟乙基氧基、羟丙基氧基。
- 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R3或R4分别独立地选自任选被1、2或3个R001取代的:苯基、吡啶基、喹啉基、异喹啉基、噻唑基、噻吩基、恶唑基、异恶唑基、吡唑基、异噻唑、呋喃基、吡咯基、吡咯烷基、1,3-氧五环基、2-吡唑啉基、吡唑烷基、咪唑基、1,2,3-唑基、1,2,3-三唑基、1,2,4-三唑基、1,3,4-噻二唑基、哌啶基、1,4-二氧六环基、吗啉基、哌嗪基、哌啶基、嘧啶基、吡嗪基、1,3,5-三噻烷基、1,3,5-三嗪基、茚基、萘基、苯并呋喃基、苯并噻吩基、吲哚基、苯并咪唑基、苯并噻唑基、苯并戊烷基、环丙基;R001如权利要求1所定义。
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RU2016151893A RU2693897C2 (ru) | 2014-05-30 | 2015-05-27 | Производное на основе дигидропиримидо-кольца в качестве ингибитора hbv |
KR1020167037087A KR102428878B1 (ko) | 2014-05-30 | 2015-05-27 | Hbv억제제인 디히드로피리미도 축합환 유도체 |
US15/314,599 US9938301B2 (en) | 2014-05-30 | 2015-05-27 | Dihydropyrimido fused ring derivative as HBV inhibitor |
BR112016028000-8A BR112016028000B1 (pt) | 2014-05-30 | 2015-05-27 | Derivado de alça de di-hidropirimido como um inibidor de hbv |
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EP15799888.1A EP3150600B1 (en) | 2014-05-30 | 2015-05-27 | Dihydropyrimido loop derivative as hbv inhibitor |
AU2015266481A AU2015266481B2 (en) | 2014-05-30 | 2015-05-27 | Dihydropyrimido fused ring derivative as HBV inhibitor |
CN201580026816.4A CN106459061B (zh) | 2014-05-30 | 2015-05-27 | 作为hbv抑制剂的二氢嘧啶并环衍生物 |
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JP2017516816A (ja) | 2017-06-22 |
CN106459061A (zh) | 2017-02-22 |
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BR112016028000A8 (pt) | 2021-07-20 |
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KR102428878B1 (ko) | 2022-08-04 |
IL249261B (en) | 2019-03-31 |
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EP3150600A1 (en) | 2017-04-05 |
RU2016151893A (ru) | 2018-07-03 |
BR112016028000B1 (pt) | 2022-05-17 |
EP3150600A4 (en) | 2017-04-05 |
TW201546073A (zh) | 2015-12-16 |
CN106459061B (zh) | 2020-01-21 |
US20170197986A1 (en) | 2017-07-13 |
US9938301B2 (en) | 2018-04-10 |
JP6710642B2 (ja) | 2020-06-17 |
CA2950807A1 (en) | 2015-12-03 |
CA2950807C (en) | 2022-05-31 |
AU2015266481B2 (en) | 2018-06-07 |
KR20170006299A (ko) | 2017-01-17 |
ES2687606T3 (es) | 2018-10-26 |
BR112016028000A2 (pt) | 2017-08-22 |
EP3150600B1 (en) | 2018-06-27 |
RU2693897C2 (ru) | 2019-07-05 |
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