WO2022057836A1 - Benzourea ring derivative, and preparation method therefor and use thereof - Google Patents
Benzourea ring derivative, and preparation method therefor and use thereof Download PDFInfo
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- WO2022057836A1 WO2022057836A1 PCT/CN2021/118583 CN2021118583W WO2022057836A1 WO 2022057836 A1 WO2022057836 A1 WO 2022057836A1 CN 2021118583 W CN2021118583 W CN 2021118583W WO 2022057836 A1 WO2022057836 A1 WO 2022057836A1
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- WIPO (PCT)
- Prior art keywords
- compound
- pharmaceutically acceptable
- reaction solution
- acceptable salt
- added
- Prior art date
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- 150000003839 salts Chemical class 0.000 claims abstract description 37
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- 125000000217 alkyl group Chemical group 0.000 claims description 30
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- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 5
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- QOWBXWFYRXSBAS-UHFFFAOYSA-N (2,4-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C(OC)=C1 QOWBXWFYRXSBAS-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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
Definitions
- the present invention relates to a class of benzourea ring derivatives and a preparation method and application thereof, in particular to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.
- Soluble guanylate cyclase is widely present in mammalian cytosol and is a heterodimer composed of ⁇ and ⁇ subunits, and ⁇ and ⁇ subunits have two subunits respectively. ⁇ 1, ⁇ 2 and ⁇ 1, ⁇ 2.
- ⁇ 1 ⁇ 1 dimer is mainly distributed in cardiovascular tissues, and its expression level is positively correlated with the degree of tissue vascularization, while ⁇ 2 ⁇ 1 dimer is mainly expressed in the brain and nervous system. Although the two have large differences in tissue distribution and cellular localization, they have similar roles in maintaining sGC enzyme function.
- Soluble guanylate cyclase is a key signal transduction enzyme in the NO-sGC-cGMP signaling pathway. After sGC is activated in vivo, it catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).
- GTP guanosine triphosphate
- cGMP cyclic guanosine monophosphate
- cGMP is an important secondary messenger molecule that activates its downstream effector molecules, such as phosphodiesterase (PDE), cyclic nucleotide-gated ion channel (CNG) and protein kinase G (PKG), etc.
- the NO/cGMP system triggers a series of downstream cascade reactions and plays important physiological functions in the gastrointestinal system, blood circulation system and nervous system, such as promoting vascular and smooth muscle relaxation, inhibiting platelet aggregation, vascular remodeling, apoptosis and inflammation, and participating in neurotransmission, etc.
- the NO/cGMP system can be inhibited, which can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina, heart failure, myocardial infarction, thrombosis, stroke and sexual intercourse dysfunction, etc.
- abnormal sGC-mediated signaling pathways are also closely related to the occurrence of fibrotic diseases such as chronic kidney disease and systemic sclerosis.
- the present invention provides a new class of compounds, which can be used as soluble guanylate cyclase stimulators, and can be used as a stimulator for bird Glycyl cyclase has good in vitro stimulating activity and excellent pharmacokinetic properties.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- R 1 , R 2 and R 3 are each independently H, F or Cl;
- R 4 is C 1-4 alkyl, phenyl-CH 2 - or pyridyl-CH 2 -, wherein said C 1-4 alkyl, phenyl-CH 2 - and pyridyl-CH 2 - are optionally 1, 2, 3, 4 or 5 Ra ;
- R 5 and R 6 are each independently H, F, Cl, Br, I, -OH, -CN or -NH 2 ;
- R is C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH , -CN, -NH and -OCH; or R6 and R7 are linked together with the carbon atoms to which they are attached, making the structural unit for
- R 8 is H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , C 1-3 alkoxy, C 1-3 alkyl or C 3-5 cycloalkyl, wherein said C 1-3 alkoxy, C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R c ;
- R 9 is H, F, Cl, Br, I, C 1-3 alkoxy, C 1-3 alkyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 alkoxy, C 1-3 alkyl, phenyl and 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 R d ;
- Rc and Rd are each independently F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , C1-3alkoxy or optionally independently selected from 1, 2 or 3 C 1-3 alkyl substituted from substituents of F, Cl, Br, I, -OH, -CN and -NH 2 ;
- the 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S- and -N-.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R b are as defined in the present invention.
- R b is -CH 3 , -CH 2 F, -CH 2 CH 3 , -CH 2 CF 3 , -CH(CH 3 ) 2 or -CH 2 CH 2 CH 3 , other
- the variables are as defined in the present invention.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 are defined in the present invention.
- each of the above R a is independently H, F or -CF 3 , and other variables are as defined in the present invention.
- R 4 is Ra and other variables are as defined in the present invention.
- the above-mentioned compound has the structure represented by formula (I-1-a), (I-1-b) or (I-1-c):
- R 1 , R 2 , R 3 , Ra and R b are as defined in the present invention; R 5 and R 6 are each independently H or -NH 2 .
- the above-mentioned compound has the structure represented by formula (I-2-a), (I-2-b) or (I-2-c):
- R 1 , R 2 , R 3 , R 8 , R 9 and Ra are as defined in the present invention; R 5 is H or -NH 2 .
- each of the above Rc and Rd is independently F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , -OCH3 , -CH3 or -CF 3.
- Other variables are as defined in the present invention.
- the above R 8 is H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -OCH 3 , -CH 3 , -CH 2 CH 3 , wherein -OCH 3 , -CH 3 , -CH 2 CH 3 , Optionally substituted with 1, 2 or 3 R c , R c and other variables as defined herein.
- R 8 is H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -OCH 3 , -CH 3 , -CH 2 CH 3 , -C(R c ) 3 , -CH 2 C(R c ) 3 , R c and other variables are as defined in the present invention.
- R 8 is -CH 3 , -CH 2 CH 3 or Other variables are as defined in the present invention.
- R 9 is H, F, Cl, Br, I, -OCH 3 , -CH 3 , -CH 2 CH 3 , phenyl or pyridyl, wherein the -OCH 3 , - CH3 , -CH2CH3, phenyl and pyridyl are optionally substituted with 1, 2 or 3 Rd , Rd and other variables as defined herein.
- R 9 is H, F, Cl, Br, I, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -C(R d ) 3 , -CH 2 C(R d ) 3 , Rd and other variables are as defined herein.
- R 9 is -CH 3 , -CH 2 CH 3 , Other variables are as defined in the present invention.
- the above-mentioned compound has the structure represented by formula (I-2-d), (I-2-e) or (I-2-f):
- the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
- R 1 , R 2 , R 3 , R 5 , Ra and R d are as defined in the present invention.
- the present invention also provides the following compounds:
- the present invention also provides the following compounds:
- the present invention relates to a new class of soluble guanylate cyclase stimulators, and its parent nucleus structure is significantly different from the parent nucleus structure disclosed in the prior art.
- the compounds of the present invention have significant in vitro stimulating activity against guanylate cyclase, and they have excellent pharmacokinetic properties.
- the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
- base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
- acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
- the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
- enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
- cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
- tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
- a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
- proton tautomers also called prototropic tautomers
- prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
- Valence tautomers include interconversions by recombination of some bonding electrons.
- keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
- the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
- the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
- isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
- Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
- a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
- the diastereoisomers were resolved and the pure enantiomers recovered.
- separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
- the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
- deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
- substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
- oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A.
- substituents do not specify through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine rings. The carbon atom is attached to the substituted group.
- the direction of attachment is arbitrary, for example,
- the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
- Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- any one or more sites in the group can be linked to other groups by chemical bonds.
- the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines Express.
- a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
- the straight dashed bonds in the group indicate connections to other groups through the two ends of the nitrogen atoms in the group; the wavy lines in the group indicate connections to other groups through the 1 and 2 carbon atoms in the phenyl group.
- the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” refers to a “ring” of 5-7 atoms arranged around it.
- Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
- C 1-6 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
- the C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl and the like; it can be Is monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine).
- C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
- C 1-4 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
- the C 1-4 alkyl includes C 1-2 , C 1-3 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
- Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl) and so on.
- C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
- Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
- Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
- C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 or C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
- Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
- the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
- a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
- the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
- Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
- leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, affinity substitution reaction).
- representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, 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 groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as 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 preventing hydroxyl side reactions.
- Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl 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 tert-butyl
- acyl groups such as alkanoyl (eg acetyl)
- arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
- 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 enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- SXRD single crystal X-ray diffraction method
- the cultured single crystal is collected by Bruker D8 venture diffractometer
- the light source is CuK ⁇ radiation
- the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
- the solvent used in the present invention is commercially available.
- DMF stands for N,N-dimethylformamide
- K 2 CO 3 stands for potassium carbonate
- MeI stands for methyl iodide
- EtOAc or EA stands for ethyl acetate
- THF stands for tetrahydrofuran
- MeOH stands for methanol
- DCM dichloromethane
- DMSO dimethyl sulfoxide
- PE petroleum ether
- EtOH for ethanol
- ACN for acetonitrile
- TFA trifluoroacetic acid
- FA formic acid
- NH 3 ⁇ H 2 O for ammonia
- TEA for triethyl Amine
- DIPEA or DIEA for N,N-diisopropylethylamine
- NBS for N-bromosuccinimide
- LiHMDS for lithium hexamethyldisilazide
- m-CPBA for m-chloroperoxybenzoic acid
- Boc 2 O represents di-tert-
- Step A Under nitrogen protection, to a solution of 1-1 (2g, 12.57mmol, 1eq) in acetonitrile (30mL) was added DIEA (2.44g, 18.86mmol, 3.28mL, 1.5eq) and 2-fluorobenzylamine (1.73g) , 13.83mmol, 1.57mL, 1.1eq), the reaction solution was stirred at 60°C for 2 hours. The reaction solution was concentrated, water (30 mL) was added, filtered, and the filter cake was vacuum-dried to obtain compound 1-a.
- Step C To a solution of 1-b (2g, 8.54mmol, 1eq) in THF (50mL) was added CDI (4.15g, 25.61mmol, 3eq), the reaction solution was stirred at 65°C for 1 hour and then concentrated, and the residue was added with water ( 30 mL), then dilute hydrochloric acid was added to adjust the pH to about 4, filtered, and the filter cake was dried to obtain compound 1-c.
- Step D Malononitrile (14.93g, 225.98mmol, 14.22mL, 1eq) was dissolved in THF (100mL), then potassium tert-butoxide (27.89g, 248.58mmol, 1.1eq) was added, and the reaction solution was heated at 50°C After stirring for 0.5 hours, compound 1-2 (45 g, 248.58 mmol, 32.14 mL, 1.1 eq) was added, and the reaction solution was stirred at 50 °C for 11.5 hours.
- Step F Compound 1-e (3.8 g, 16.94 mmol, 1 eq) was dissolved in DCM (50 mL), then m-chloroperoxybenzoic acid (6.88 g, 33.89 mmol, 85% purity, 2 eq) was added. The reaction solution was stirred at 20° C. for 12 hours and then filtered, and the filter cake was washed with dichloromethane (100 mL) to obtain compound 1-f.
- Step A To a solution of 2-1 (2 g, 12.80 mmol, 1 eq) in H 2 O (20 mL) and AcOH (7.35 g, 122.40 mmol, 7.00 mL, 9.56 eq) was slowly added NaNO 2 (1.77 g, 25.61 mmol) , 2eq), the reaction solution was stirred at 20° C. for 1 hour, the reaction solution was filtered, and the filter cake was dried under high vacuum to obtain compound 2-a.
- Step B To a suspension of 2-a (2.4g, 12.96mmol, 1eq) in DCM (40mL) was slowly added m-CPBA (3.99g, 19.44mmol, 85% purity, 1.5eq), the reaction solution was heated at 20°C After stirring for 30 minutes, the suspension was filtered, and the filter cake was dried under high vacuum to obtain compound 2-b.
- m-CPBA 3.99g, 19.44mmol, 85% purity, 1.5eq
- Step C Under nitrogen protection, to a solution of 1-c (800mg, 3.07mmol, 1eq) in DMF (5.00mL) was added 2-b (801.26mg, 3.69mmol, 1.2eq), potassium carbonate (849.72mg, 6.15mmol) , 2eq). The reaction solution was stirred at 30° C. for 12 hours. After the reaction solution was cooled, water (20 mL) was added, filtered, and the filter cake was dried to obtain compound 2-c.
- Step D To a solution of 2-c (1.0 g, 2.42 mmol, 1 eq) in DMF (5.00 mL) was added wet Pd/C (100 mg, 10% palladium content) under nitrogen protection. After replacing the reaction solution with hydrogen three times, the reaction solution was stirred at 50° C. for 1 hour under the atmosphere of hydrogen (15 psi). After the reaction solution was filtered, water (50 mL) was added to the filtrate, followed by extraction with ethyl acetate (50 mL ⁇ 2). , the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 2-d.
- Step E Methyl chloroformate (369.75 mg, 3.91 mmol, 303.07 ⁇ L, 5 eq) was added dropwise to a solution of 2-d (300 mg, 782.57 ⁇ mol, 1 eq) in pyridine (3.00 mL) at 0 °C, and the reaction solution was Stir at 0°C for 1 hour. After the reaction was completed, water (20 mL) was added to quench the reaction, and then extracted with ethyl acetate 50 mL (25 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- Step B To a mixed solution of 3-a (900 mg, 3.39 mmol, 1 eq) in MeOH (10.00 mL) and THF (10.00 mL) was added Pd/C (500 mg, 10% purity) under nitrogen protection. The reaction solution was stirred at 30° C. for 0.5 hours under a hydrogen (15 psi) atmosphere, and the reaction solution was filtered and concentrated to obtain compound 3-b.
- Step C To a solution of 3-b (750 mg, 3.19 mmol, 1 eq) in THF (10.00 mL) was added CDI (1.03 g, 6.38 mmol, 2 eq). The reaction solution was stirred at 70°C for 12 hours. The reaction was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 3-c.
- Step D Under nitrogen protection, to a solution of 3-c (200 mg, 765.62 ⁇ mol, 1 eq) in DMF (5.00 mL) was added 1-f (825.79 mg, 4.15 mmol, 1.1 eq) and potassium carbonate (317.45 mg, 2.30 mmol) , 3eq). The reaction solution was stirred at 120 °C for 12 hours. After the reaction was cooled to room temperature, water (20 mL) was added to dilute it, and then extracted with ethyl acetate 50 mL (25 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
- Step B To a solution of 4-a (1.5 g, 5.32 mmol, 1 eq) in MeOH (10.00 mL) and THF (10.00 mL) was added Pd/C (500 mg, 10% purity) under nitrogen. Under an atmosphere of hydrogen (15 psi), the mixture was stirred at 30° C. for 0.5 hours, and the reaction solution was filtered and concentrated to obtain compound 4-b.
- Step C To a solution of 4-b (1.3 g, 5.15 mmol, 1 eq) in THF (10.00 mL) was added CDI (1.67 g, 10.31 mmol, 2 eq). The reaction solution was stirred at 70°C for 1 hour. The reaction was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (50 mL ⁇ 2). The combined organic phases were washed with water (50 mL ⁇ 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound 4-c.
- Step D Under nitrogen protection, to a solution of 4-c (200mg, 718.83 ⁇ mol, 1eq) in DMF (5.00mL) was added 1-f (368.45mg, 1.44mmol, 2eq) and potassium carbonate (298.05mg, 2.16mmol, 3eq). The reaction solution was stirred at 120° C. for 12 hours. After the reaction was cooled to room temperature, water (20 mL) was added to dilute it, and then extracted with ethyl acetate (25 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue Compound 4 was obtained by purification by preparative HPLC [mobile phase: water (0.1% FA)-ACN].
- Step A To a solution of 5-1 (1 g, 6.29 mmol, 689.66 ⁇ L, 1 eq) in MeCN (20 mL) was added 2-fluorobenzylamine (786.62 mg, 6.29 mmol, 715.11 ⁇ L, 1 eq) and diisopropylethylamine (812.39 mg, 6.29 mmol, 1.09 mL, 1 eq). The reaction was stirred at 18°C for 12 hours. The reaction solution was filtered, and the filter cake was concentrated and dried under reduced pressure to obtain compound 5-a.
- Step B To 5-a (804 mg, 3.04 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (80 mg, 10% purity) under nitrogen protection. Stir under a hydrogen atmosphere at 18°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain compound 5-b.
- Step D To a solution of 5-c (150 mg, 576.40 ⁇ mol, 1 eq) in DMF (5 mL) was added 1-f (221.58 mg, 864.59 ⁇ mol, 1.5 eq), potassium carbonate (238.98 mg, 1.73 mmol, 3 eq). The reaction solution was stirred at 120° C. for 12 hours, the reaction solution was concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 5.
- Step A To a solution of compound 3 (150 mg, 342.93 ⁇ mol, 1 eq) in dioxane (2.00 mL) was added isoamyl nitrite (40.17 mg, 342.93 ⁇ mol, 46.18 ⁇ L, 1 eq) and diiodomethane (91.85 mg) , 342.93 ⁇ mol, 27.67 ⁇ L, 1eq), the reaction solution was stirred at 100° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with water (20 mL), and then extracted with ethyl acetate (25 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 6-a.
- Step B To a solution of 6-a (180 mg, 328.30 ⁇ mol, 1 eq) in MeOH (10.00 mL) was added Pd/C (200 mg, 10% purity) under nitrogen protection. The reaction solution was stirred at 20°C for 12 hours under hydrogen (15 psi) atmosphere, the reaction solution was filtered, the filtrate was concentrated and the residue was purified by preparative HPLC [mobile phase: water (0.1% FA)-ACN] to obtain compound 6.
- Step C To a solution of 7-b (270 mg, 1.08 mmol, 1 eq) in tetrahydrofuran (10 mL) was added CDI (350 mg, 2.16 mmol, 2 eq), and the reaction solution was stirred at 70° C. for 12 hours. The reaction solution was concentrated, methanol (10 mL) was added, filtered, and the filter cake was vacuum-dried to obtain compound 7-c.
- Step D To a solution of 7-c (175mg, 632.47 ⁇ mol, 1eq) in DMF (2mL) was added potassium carbonate (262mg, 1.90mmol, 3eq) and compound 1-f (324mg, 1.26mmol, 2eq), the reaction solution was in Stir at 120°C for 12 hours. The reaction solution was filtered, and the filtrate was separated by preparative HPLC [water (0.225% FA)-ACN] to obtain compound 7.
- 3-fluoro-2-pyridyl)methanamine dihydrochloride 918.65 mg, 5.65 mmol, 770.95 ⁇ L, 1 eq
- diisopropylethylamine (2.92 g, 22.60 mmol
- Step B To a mixed solution of 8-a (800 mg, 2.82 mmol, 1 eq) in MeOH (10.00 mL) and THF (10.00 mL) was added Pd/C (200 mg, 10% purity) under nitrogen protection. The reaction solution was stirred at 30° C. for 0.5 hours under a hydrogen atmosphere (15 psi), and the reaction solution was filtered and concentrated to obtain compound 8-b.
- Step C To a solution of 8-b (700 mg, 2.76 mmol, 1 eq) in THF (10.00 mL) was added CDI (896.48 mg, 5.53 mmol, 2 eq). The reaction solution was stirred at 70°C for 12 hours. The reaction was cooled to room temperature, diluted with water (20 mL), and then extracted with ethyl acetate (25 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. MeOH (10 mL) was added to the residue and stirred, filtered, and filtered. Compound 8-c was obtained after the cake was dried.
- Step D Under nitrogen protection, to a solution of 8-c (200 mg, 716.29 ⁇ mol, 1 eq) in DMF (2.00 mL) was added 1-f (367.14 mg, 1.43 mmol, 2 eq) and potassium carbonate (395.98 mg, 2.87 mmol, 4eq). The reaction solution was stirred at 120°C for 1 hour. After the reaction was cooled to room temperature, water (20 mL) was added to dilute it, and then it was extracted with ethyl acetate (25 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue Purification by preparative HPLC [mobile phase: water (0.225% FA)-ACN] afforded compound 8.
- Step D Under nitrogen protection, to a solution of 9-c (1.76g, 5.53mmol, 1eq) in DMF (50mL) was added 1-f (4.25g, 16.59mmol, 3eq), potassium carbonate (2.29g, 16.59mmol) , 3eq). The reaction solution was stirred at 120°C for 12 hours. The reaction solution was poured into water (200 mL), extracted with EtOAc (50 mL ⁇ 3), the organic phase was washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 9-d.
- Step E Under nitrogen protection, to a solution of 9-d (2.99g, 6.25mmol, 1eq) in DMF (30mL) was added p-methoxybenzyl chloride (1.37g, 8.75mmol, 1.19mL, 1.4eq), carbonic acid Potassium (1.73 g, 12.50 mmol, 2 eq). The reaction solution was stirred at 50°C for 12 hours.
- Step C To a solution of 10-b (1.9 g, 6.46 mmol, 1 eq) in tetrahydrofuran (30 mL) was added CDI (2.09 g, 12.91 mmol, 2 eq) under nitrogen protection. The reaction solution was stirred at 70°C for 12 hours, the reaction solution was concentrated, and water (50 mL) was added to the residue. It was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, and the residue was washed with methanol (10 mL) after filtration, and dried to obtain compound 10-c.
- Step F 10-e (700mg, 1.14mmol, 1eq) was added to a mixture of TFA (6.16g, 54.03mmol, 4.00mL, 47.59eq) and triethylsilane (1.46g, 12.52mmol, 2.00mL, 11.03eq)
- TFA 6.16g, 54.03mmol, 4.00mL, 47.59eq
- triethylsilane (1.46g, 12.52mmol, 2.00mL, 11.03eq)
- Step G Under nitrogen protection, to a solution of 10-f (400.00 mg, 857.56 ⁇ mol, 1 eq) in DMF (2 mL) was added 9-1 (939.78 mg, 3.43 mmol, 4 eq) and potassium carbonate (177.79 mg, 1.29 mmol, 1.5eq). The reaction solution was stirred at 90°C for 0.5 hour. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL). The organic phase was dried over sodium sulfate and concentrated to obtain compound 10-g.
- Step H To a solution of 10-g (400 mg, 653.06 ⁇ mol, 1 eq) in TFA (2 mL) was added trifluoromethanesulfonic acid (3.40 g, 22.65 mmol, 2 mL, 34.69 eq) under nitrogen. The reaction solution was stirred at 100°C for 2 hours. The reaction solution was poured into an aqueous solution of sodium hydroxide (30 mL, 1 mol/L) for neutralization, extracted with ethyl acetate (50 mL), and the organic phase was concentrated and purified by preparative HPLC [water (0.225% TFA)-ACN] to obtain Compound 10.
- Step C To a solution of 11-b (2.0 g, 6.80 mmol, 1 eq) in THF (20.00 mL) was added CDI (1.65 g, 10.19 mmol, 1.5 eq). The reaction solution was stirred at 70°C for 12 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was washed with methanol (20 mL) to obtain compound 11-c .
- Step E To a solution of 11-d (300 mg, 643.30 ⁇ mol, 1 eq) in TFA (4 mL) was added trifluoromethanesulfonic acid (850.00 mg, 5.66 mmol, 0.5 mL, 8.80 eq) under nitrogen protection. The reaction solution was stirred at 80°C for 1 hour. The reaction solution was cooled to room temperature, poured into an aqueous solution of saturated sodium bicarbonate (50 mL), extracted with ethyl acetate (100 mL), the organic phase was concentrated, and the residue was slurried with petroleum ether (20 mL) at room temperature to obtain compound 11 -e.
- Step F Add 1-f (243.17mg, 948.84 ⁇ mol, 2eq) and potassium carbonate (196.70mg, 1.42mmol, 3eq) to a solution of 11-e (150mg, 474.42 ⁇ mol, 1eq) in DMF (2.00mL), and react The solution was stirred at 120 °C for 12 hours. After the reaction was cooled to room temperature, water (20 mL) was added to dilute it, and then it was extracted with ethyl acetate (25 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue passed through Purification by preparative HPLC [water (0.025% FA)-ACN] afforded compound 11.
- Step A To a solution of 12-1 (7g, 39.78mmol, 1eq) and cesium carbonate (38.88g, 119.33mmol, 3eq) in 1,4-dioxane (150mL) was added picolinic acid (3.92g, 31.82mmol) , 0.8eq), cuprous iodide (3.03g, 15.91mmol, 0.4eq) and diethyl malonate (25.48g, 159.10mmol, 24.04mL, 4eq), the reaction solution was stirred at 100 ° C for 18 hours.
- Step B To a solution of compound 12-a (12g, 35.97mmol, 1eq) in DMSO (120mL) was added water (647.94mg, 35.97mmol, 647.94 ⁇ L, 1eq) and lithium chloride (6.10g, 143.86mmol, 4eq) , the reaction solution was stirred at 120 °C for 12 hours.
- Step C THF (15 mL) and LiHMDS (1 M, 15.54 mL, 0.8 eq) were added to a round-bottomed flask, and a solution of compound 12-b (3.73 g, 19.43 mmol, 1 eq) in THF (10 mL) was added at -40°C And stirred for 1 hour, and then dropwise added methyl iodide (2.21 g, 15.54 mmol, 967.47 ⁇ L, 0.8 eq) in THF (10 mL) solution, the reaction solution was stirred at -40 ° C for 1 hour, and heated to 20 ° C and stirred for 1 hour.
- Step D LiHMDS (1 M, 10.14 mL, 1 eq) was added dropwise to a solution of compound 12-c (2 g, 10.14 mmol, 1 eq) in THF (15 mL) at -78°C under nitrogen protection and stirred for 30 minutes, then added A solution of NBS (2.17 g, 12.17 mmol, 1.2 eq) in THF (5 mL) was warmed to 20°C and stirred for 1 hour.
- Step E To a round bottom flask at 0°C was added DMF (10 mL), sodium hydride (589.00 mg, 14.73 mmol, 60% pure, 1.9 eq) and malononitrile (1.02 g, 15.50 mmol, 975.29 ⁇ L, 2 eq) ), and after stirring for 15 minutes, a solution of compound 12-d (2.14 g, 7.75 mmol, 1 eq) in DMF (15 mL) was added dropwise, and the reaction solution was stirred at 20° C. for 1 hour.
- S-methylthiourea (1.76g, 12.63mmol, 1.5 eq, 0.5H 2 SO 4
- potassium bicarbonate 1.69g, 16.84mmol, 2eq
- Step H To a solution of compound 9-c (0.4g, 1.32mmol, 1eq) in DMF (4mL) under nitrogen protection was added 12-g (892.70mg, 2.65mmol, 2eq) and potassium carbonate (548.62mg, 3.97mmol) , 3eq), the reaction solution was stirred at 120 ° C for 18 hours. 20 mL of water was added to the reaction solution, and after filtration, the filter cake was dried to obtain compound 12-h.
- Step I Under nitrogen protection, to a solution of compound 12-h (0.8g, 1.43mmol, 1eq) in DMF (8mL) was added potassium carbonate (395.21mg, 2.86mmol, 2eq) and p-methoxybenzyl chloride (335.88mg) , 2.14mmol, 292.07 ⁇ L, 1.5eq), the reaction solution was stirred at 50°C for 12 hours.
- Step L under nitrogen protection, to a solution of compound 12-k (0.22g, 288.22 ⁇ mol, 1eq) in TFA (1.54g, 13.51mmol, 1mL, 46.86eq) was added trifluoromethanesulfonic acid (1.70g, 11.33mmol, 1 mL, 39.30 eq), the reaction solution was stirred at 60 °C for 6 hours and then concentrated, the residue was dissolved in EtOAc, the pH was adjusted to 7-8 with aqueous sodium bicarbonate solution, and then the aqueous phase was extracted with EtOAc (5 mL ⁇ 2), and the combined The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [water (0.225% FA)-ACN] to give compound 12, which was then separated by SFC (chromatographic column: DAICEL CHIRALPAK IC (250mm ⁇ 30 mm, 10 ⁇ m); mobile phase: A: CO 2 , B: [
- Step A Under nitrogen protection, to a solution of 10-c (500mg, 1.56mmol, 1eq) in DMF (3mL) was added 12-g (789.90mg, 2.34mmol, 1.5eq) and potassium carbonate (1.08g, 7.81mmol, 5eq), the reaction solution was stirred at 120° C. for 12 hours, water (20 mL) was added to the reaction solution to dilute, filtered, and the filter cake was dried to obtain compound 14-a.
- Step C Triethylsilane (1.46g, 12.52mmol, 2mL, 24.96eq) was added to a solution of 14-b (350mg, 501.68 ⁇ mol, 1eq) in TFA (9.24g, 81.04mmol, 6mL, 161.54eq), and the reaction was carried out The solution was stirred at 100 °C for 12 hours, the reaction solution was concentrated, the residue was diluted with saturated aqueous NaHCO 3 (10 mL), extracted with ethyl acetate (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the compound 14-c.
- Step D Under nitrogen protection, to a solution of 14-c (200mg, 365.31 ⁇ mol, 1eq) in DMF (2mL) was added 9-1 (400.33mg, 1.46mmol, 4eq) and potassium carbonate (151.46mg, 1.10mmol, 3eq) ). The reaction solution was stirred at 90°C for 0.5 hour. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL), drying over sodium sulfate, and concentration to obtain compound 14-d.
- Step E To a solution of 14-d (250 mg, 360.47 ⁇ mol, 1 eq) in TFA (1 mL) was added trifluoromethanesulfonic acid (0.5 mL) under nitrogen protection. The reaction solution was stirred at 100°C for 2 hours.
- cGMP-D2 D2-labeled cyclic guanosine monophosphate
- LNCap medium RPMI1640+10% fetal bovine serum+1% double antibody
- cGMP standard curve According to the ratio of cGMP concentration to 665/615, use Graphpad prism to make the standard curve.
- the compounds of the present invention can effectively stimulate sGC and increase the level of cGMP.
- Drug preparation Weigh an appropriate amount of drug, dissolve it in a mixed solvent of 10% DMSO + 50% PEG400 + 40% H 2 O, and prepare 0.5 mg/mL; weigh an appropriate amount of drug, dissolve in 10% EtOH + 40% In the mixed solvent of PEG400+50% H 2 O, it was prepared at 0.6 mg/mL;
- mice in Group 1 were given a single dose of the drug at 1.0 mg/kg at a concentration of 0.5 mg/mL via tail vein, and animals in Group 2 were given the compound at a dose of 3 mg/kg at a concentration of 0.6 mg/mL by gavage.
- Plasma samples were collected from animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose.
- the drug concentration in the plasma samples was determined by LC-MS/MS method, and the kinetic parameters of the tested drugs are shown in Table 2.
- the compounds of the present invention have good pharmacokinetic properties in rats.
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Abstract
Disclosed are a class of benzourea ring derivatives, and a preparation method therefor and the use thereof. Specifically disclosed are a compound as represented by formula (I) and a pharmaceutically acceptable salt thereof. <img file="623409dest_path_image001.jpg" he="97.37" img-content="drawing" img-format="jpg" inline="yes" orientation="portrait" wi="99.48"/>
Description
本申请主张如下优先权：This application claims the following priority:
CN202010975022.5，2020年09月16日；CN202010975022.5, September 16, 2020;
CN202110796623.4，2021年07月14日。CN202110796623.4, July 14, 2021.
本发明涉及一类苯并脲环衍生物及其制备方法和应用，具体涉及式(I)所示化合物及其药学上可接受的盐。The present invention relates to a class of benzourea ring derivatives and a preparation method and application thereof, in particular to a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.
可溶性鸟苷酸环化酶(sGC)广泛存在于哺乳动物的细胞溶质内，是由α和β两种亚基组成的异源二聚体，α和β亚基又分别有两种亚构体α1、α2和β1、β2。α1β1二聚体主要分布于心血管组织中，表达水平与组织血管化的程度呈正相关，而α2β1二聚体主要表达在大脑和神经系统中。虽然两者在组织分布和细胞定位上有较大的差异，但它们在维持sGC酶功能方面有着相似作用。Soluble guanylate cyclase (sGC) is widely present in mammalian cytosol and is a heterodimer composed of α and β subunits, and α and β subunits have two subunits respectively. α1, α2 and β1, β2. α1β1 dimer is mainly distributed in cardiovascular tissues, and its expression level is positively correlated with the degree of tissue vascularization, while α2β1 dimer is mainly expressed in the brain and nervous system. Although the two have large differences in tissue distribution and cellular localization, they have similar roles in maintaining sGC enzyme function.
可溶性鸟苷酸环化酶是NO-sGC-cGMP信号通路中关键的信号转导酶，sGC在体内被激活后会催化三磷酸鸟苷(GTP)转化为环磷酸鸟苷(cGMP)。cGMP是一种重要的二级信使分子，通过激活其下游的多种效应分子，如磷酸二酯酶(PDE)、环核苷酸门控离子通道(CNG)和蛋白激酶G(PKG)等，进而引发下游一系列级联反应，在胃肠系统、血液循环系统和神经系统中发挥重要的生理功能，如促进血管和平滑肌舒张，抑制血小板凝聚、血管重塑、细胞凋亡和炎症发生以及参与神经传递等。在病理生理学条件下，NO/cGMP系统可被抑制，这可导致例如高血压、血小板激活、增加的细胞增生、内皮机能障碍、动脉硬化、心绞痛、心力衰竭、心肌梗死、血栓形成、中风和性功能障碍等。近两年又有研究显示，sGC介导的信号通路异常还与慢性肾脏疾病、系统性硬化病等纤维化疾病的发生有着密切的关系。Soluble guanylate cyclase is a key signal transduction enzyme in the NO-sGC-cGMP signaling pathway. After sGC is activated in vivo, it catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is an important secondary messenger molecule that activates its downstream effector molecules, such as phosphodiesterase (PDE), cyclic nucleotide-gated ion channel (CNG) and protein kinase G (PKG), etc. In turn, it triggers a series of downstream cascade reactions and plays important physiological functions in the gastrointestinal system, blood circulation system and nervous system, such as promoting vascular and smooth muscle relaxation, inhibiting platelet aggregation, vascular remodeling, apoptosis and inflammation, and participating in neurotransmission, etc. Under pathophysiological conditions, the NO/cGMP system can be inhibited, which can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina, heart failure, myocardial infarction, thrombosis, stroke and sexual intercourse dysfunction, etc. In the past two years, other studies have shown that abnormal sGC-mediated signaling pathways are also closely related to the occurrence of fibrotic diseases such as chronic kidney disease and systemic sclerosis.
传统的对于可溶性鸟苷酸环化酶进行刺激性治疗，仅使用其效果以NO为基础的化合物如有机硝酸盐类。这是通过生物转化形成的并且通过进攻血红素的中心铁原子激活可溶性鸟苷酸环化酶。除了副作用，耐受性的发展也是此类治疗方法决定性的缺点之一。Traditional stimulatory treatments for soluble guanylate cyclase use only compounds whose effects are based on NO, such as organic nitrates. This is formed by biotransformation and activates soluble guanylate cyclase by attacking the central iron atom of heme. In addition to side effects, the development of tolerance is one of the decisive drawbacks of this type of treatment.
2013年10月FDA批准了一种新的鸟苷酸环化酶刺激剂，名叫利奥西呱(Riociguat)(WO2003095451A1)，是一种吡唑并吡啶类化合物，用于治疗肺动脉高血压，但其在人体内半衰期较短，清除率较高，一天需要服用3次。In October 2013, the FDA approved a new guanylate cyclase stimulator, named Riociguat (WO2003095451A1), which is a pyrazolopyridine compound for the treatment of pulmonary arterial hypertension. It has a short half-life in the human body and a high clearance rate, and needs to be taken 3 times a day.
针对目前市场和临床未满足的对此类可溶性鸟苷酸环化酶刺激剂的需求，本发明提供了一类新化合物，此类化合物可作为可溶性鸟苷酸环化酶的刺激剂，对鸟苷酸环化酶具有很好的体外刺激活性，并具有优良的药代动力学性质。In view of the current unmet market and clinical needs for such soluble guanylate cyclase stimulators, the present invention provides a new class of compounds, which can be used as soluble guanylate cyclase stimulators, and can be used as a stimulator for bird Glycyl cyclase has good in vitro stimulating activity and excellent pharmacokinetic properties.
发明内容SUMMARY OF THE INVENTION
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
其中，R
1、R
2和R
3各自独立地为H、F或Cl；
wherein R 1 , R 2 and R 3 are each independently H, F or Cl;
R
4为C
1-4烷基、苯基-CH
2-或吡啶基-CH
2-，其中所述C
1-4烷基、苯基-CH
2-和吡啶基-CH
2-任选被1、2、3、4或5个R
a所取代；
R 4 is C 1-4 alkyl, phenyl-CH 2 - or pyridyl-CH 2 -, wherein said C 1-4 alkyl, phenyl-CH 2 - and pyridyl-CH 2 - are optionally 1, 2, 3, 4 or 5 Ra ;
各R
a独立地为H、F、Cl、Br、I、-OH、-CN、-NH
2、-NO
2、-C(＝O)OH、C
1-3烷氧基或任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN、-NH
2和-OCH
3的取代基所取代的C
1-3烷基；
Each Ra is independently H, F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , -C(=O)OH, C1-3alkoxy or optionally , 2 or 3 C 1-3 alkyl substituted with substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH 2 and -OCH 3 ;
R
5和R
6各自独立地为H、F、Cl、Br、I、-OH、-CN或-NH
2；
R 5 and R 6 are each independently H, F, Cl, Br, I, -OH, -CN or -NH 2 ;
R
7为-NH-C(＝O)O-R
b；
R 7 is -NH-C(=O)OR b ;
R
b为任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN、-NH
2和-OCH
3的取代基所取代的C
1-6烷基；或R
6和R
7与它们相连的碳原子连接在一起，使结构单元
为
R is C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH , -CN, -NH and -OCH; or R6 and R7 are linked together with the carbon atoms to which they are attached, making the structural unit for
R
8为H、F、Cl、Br、I、-OH、-CN、-NH
2、-NO
2、C
1-3烷氧基、C
1-3烷基或C
3-5环烷基，其中所述C
1-3烷氧基、C
1-3烷基和C
3-5环烷基任选被1、2或3个R
c所取代；
R 8 is H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , C 1-3 alkoxy, C 1-3 alkyl or C 3-5 cycloalkyl, wherein said C 1-3 alkoxy, C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R c ;
R
9为H、F、Cl、Br、I、C
1-3烷氧基、C
1-3烷基、苯基或5-6元杂芳基，其中所述C
1-3烷氧基、C
1-3烷基、苯基和5-6元杂芳基任选被1、2或3个R
d所取代；
R 9 is H, F, Cl, Br, I, C 1-3 alkoxy, C 1-3 alkyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 alkoxy, C 1-3 alkyl, phenyl and 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 R d ;
R
c和R
d各自独立地为F、Cl、Br、I、-OH、-CN、-NH
2、-NO
2、C
1-3烷氧基或任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN和-NH
2的取代基所取代的C
1-3烷基；
Rc and Rd are each independently F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , C1-3alkoxy or optionally independently selected from 1, 2 or 3 C 1-3 alkyl substituted from substituents of F, Cl, Br, I, -OH, -CN and -NH 2 ;
所述5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。The 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S- and -N-.
在本发明的一些方案中，上述化合物具有式(I-1)所示结构：In some schemes of the present invention, the above-mentioned compound has the structure represented by formula (I-1):
其中，R
1、R
2、R
3、R
4、R
5、R
6和R
b如本发明所定义。
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R b are as defined in the present invention.
在本发明的一些方案中，上述R
b为-CH
3、-CH
2F、-CH
2CH
3、-CH
2CF
3、-CH(CH
3)
2或-CH
2CH
2CH
3，其他变量如本发明所定义。
In some solutions of the present invention, the above R b is -CH 3 , -CH 2 F, -CH 2 CH 3 , -CH 2 CF 3 , -CH(CH 3 ) 2 or -CH 2 CH 2 CH 3 , other The variables are as defined in the present invention.
在本发明的一些方案中，上述R
7为-NH-C(＝O)O-CH
3，其他变量如本发明所定义。
In some aspects of the present invention, the above R 7 is -NH-C(=O)O-CH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述化合物具有式(I-2)所示结构：In some schemes of the present invention, the above-mentioned compound has the structure represented by formula (I-2):
其中，R
1、R
2、R
3、R
4、R
5、R
8和R
9本发明所定义。
Wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 are defined in the present invention.
在本发明的一些方案中，上述各R
a独立地为H、F、Cl、Br、I、-OH、-CN、-NH
2、-NO
2、-C(＝O)OH、-CH
3、-CH
2CH
3、-CH
2CH
2CH
3、-CH
2(CH
3)
2、-OCH
3、-OCH
2CH
3、-CF
3、-CH
2CF
3、-CF
2CF
3、-CH
2CH
2CF
3、-CH
2OH或-CH
2CH
2OH，其他变量如本发明所定义。
In some aspects of the present invention, each of the above Ra is independently H, F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , -C(=O)OH, -CH3 , -CH2CH3 , -CH2CH2CH3 , -CH2 ( CH3 )2 , -OCH3 , -OCH2CH3 , -CF3 , -CH2CF3 , -CF2CF3 , -CH2CH2CF3 , -CH2OH or -CH2CH2OH , other variables are as defined in the present invention.
在本发明的一些方案中，上述各R
a独立地为H、F或-CF
3，其他变量如本发明所定义。
In some aspects of the present invention, each of the above R a is independently H, F or -CF 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R
4为
R
a及其他变量如本发明所定义。
In some aspects of the present invention, the above R 4 is Ra and other variables are as defined in the present invention.
在本发明的一些方案中，上述R
4为
其他变量如本发明所定义。
In some aspects of the present invention, the above R 4 is Other variables are as defined in the present invention.
在本发明的一些方案中，上述化合物具有式(I-1-a)、(I-1-b)或(I-1-c)所示结构：In some embodiments of the present invention, the above-mentioned compound has the structure represented by formula (I-1-a), (I-1-b) or (I-1-c):
其中，R
1、R
2、R
3、R
a和R
b如本发明所定义；R
5和R
6各自独立地为H或-NH
2。
wherein, R 1 , R 2 , R 3 , Ra and R b are as defined in the present invention; R 5 and R 6 are each independently H or -NH 2 .
在本发明的一些方案中，上述化合物具有式(I-2-a)、(I-2-b)或(I-2-c)所示结构：In some schemes of the present invention, the above-mentioned compound has the structure represented by formula (I-2-a), (I-2-b) or (I-2-c):
其中，R
1、R
2、R
3、R
8、R
9和R
a如本发明所定义；R
5为H或-NH
2。
Wherein, R 1 , R 2 , R 3 , R 8 , R 9 and Ra are as defined in the present invention; R 5 is H or -NH 2 .
在本发明的一些方案中，上述R
c和R
d各自独立地为F、Cl、Br、I、-OH、-CN、-NH
2、-NO
2、-OCH
3、-CH
3或-CF
3，其他变量如本发明所定义。
In some aspects of the invention, each of the above Rc and Rd is independently F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , -OCH3 , -CH3 or -CF 3. Other variables are as defined in the present invention.
在本发明的一些方案中，上述R
8为H、F、Cl、Br、I、-OH、-CN、-NH
2、-NO
2、-OCH
3、-CH
3、-CH
2CH
3、
其中所述-OCH
3、-CH
3、-CH
2CH
3、
任选被1、2或3个R
c所取代，R
c和其他变量如本发明所定义。
In some embodiments of the present invention, the above R 8 is H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -OCH 3 , -CH 3 , -CH 2 CH 3 , wherein -OCH 3 , -CH 3 , -CH 2 CH 3 , Optionally substituted with 1, 2 or 3 R c , R c and other variables as defined herein.
在本发明的一些方案中，上述R
8为H、F、Cl、Br、I、-OH、-CN、-NH
2、-NO
2、-OCH
3、-CH
3、-CH
2CH
3、-C(R
c)
3、-CH
2C(R
c)
3、
R
c和其他变量如本发明所定义。
In some embodiments of the present invention, the above R 8 is H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -OCH 3 , -CH 3 , -CH 2 CH 3 , -C(R c ) 3 , -CH 2 C(R c ) 3 , R c and other variables are as defined in the present invention.
在本发明的一些方案中，上述R
8为-CH
3、-CH
2CH
3或
其他变量如本发明所定义。
In some aspects of the present invention, the above R 8 is -CH 3 , -CH 2 CH 3 or Other variables are as defined in the present invention.
在本发明的一些方案中，上述R
9为H、F、Cl、Br、I、-OCH
3、-CH
3、-CH
2CH
3、苯基或吡啶基，其中所述-OCH
3、-CH
3、-CH
2CH
3、苯基和吡啶基任选被1、2或3个R
d所取代，R
d和其他变量如本发明所定义。
In some embodiments of the present invention, the above R 9 is H, F, Cl, Br, I, -OCH 3 , -CH 3 , -CH 2 CH 3 , phenyl or pyridyl, wherein the -OCH 3 , - CH3 , -CH2CH3, phenyl and pyridyl are optionally substituted with 1, 2 or 3 Rd , Rd and other variables as defined herein.
在本发明的一些方案中，上述R
9为H、F、Cl、Br、I、-CH
3、-CH
2CH
3、-OCH
3、-OCH
2CH
3、-C(R
d)
3、-CH
2C(R
d)
3、
R
d和其他变量如本发明所定义。
In some embodiments of the present invention, the above R 9 is H, F, Cl, Br, I, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -C(R d ) 3 , -CH 2 C(R d ) 3 , Rd and other variables are as defined herein.
在本发明的一些方案中，上述R
9为-CH
3、-CH
2CH
3、
其他变量如本发明所定义。
In some aspects of the present invention, the above R 9 is -CH 3 , -CH 2 CH 3 , Other variables are as defined in the present invention.
在本发明的一些方案中，上述化合物具有式(I-2-d)、(I-2-e)或(I-2-f)所示结构：In some schemes of the present invention, the above-mentioned compound has the structure represented by formula (I-2-d), (I-2-e) or (I-2-f):
其中，带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；Wherein, the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
R
9为
R9 is
R
1、R
2、R
3、R
5、R
a和R
d如本发明所定义。
R 1 , R 2 , R 3 , R 5 , Ra and R d are as defined in the present invention.
本发明还有一些方案是由上述变量任意组合而来。There are also some solutions of the present invention that are formed by any combination of the above variables.
本发明还提供了下述化合物：The present invention also provides the following compounds:
本发明还提供了下述化合物：The present invention also provides the following compounds:
技术效果technical effect
本发明涉及的一类新的可溶性鸟苷酸环化酶刺激剂，其母核结构显著区别于现有技术中已公开的母核结构。本发明化合物对鸟苷酸环化酶具有显著的体外刺激活性，且其具有优良的药代动力学性质。The present invention relates to a new class of soluble guanylate cyclase stimulators, and its parent nucleus structure is significantly different from the parent nucleus structure disclosed in the prior art. The compounds of the present invention have significant in vitro stimulating activity against guanylate cyclase, and they have excellent pharmacokinetic properties.
定义和说明Definition and Explanation
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。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
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。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
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、有机胺或镁盐或类似的盐。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。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。The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
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。The pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
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。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.
除非另有说明，用楔形实线键
和楔形虚线键
表示一个立体中心的绝对构型，用直形实线键
和直形虚线键
表示立体中心的相对构型，用波浪线
表示楔形实线键
或楔形虚线键
或用波浪线
表示直形实线键
和直形虚线键
Use solid wedge keys unless otherwise specified and wedge-dotted keys Indicate the absolute configuration of a stereocenter, using a straight solid key and straight dashed keys Indicate the relative configuration of the stereocenter, with a wavy line Represents a solid wedge key or wedge-dotted key or with wavy lines Represents a straight solid key and straight dashed keys
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The compounds of the present invention may exist in particular. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％， 或者大于等于99.8％，或者大于等于99.9％。Unless otherwise indicated, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in one enantiomer" refer to one of the isomers or pairs The enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise indicated, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
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)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。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。
Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate). The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语“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。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. .
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，取代基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。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
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。The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
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。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
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。
When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
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。When one of the variables is selected from a single bond, it means that the two groups connected to it are directly connected, for example, when L in A-L-Z represents a single bond, it means that the structure is actually 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。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not specify through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine rings. The carbon atom is attached to the substituted group.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
所述连接基团、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。
When the listed linking group does not indicate its direction of attachment, the direction of attachment is arbitrary, for example, The linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。所述位点与其他基团连接的化学键可以用直形实线键
直形虚线键
或波浪线
表示。例如-OCH
3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连。
Unless otherwise specified, when a group has one or more attachable sites, any one or more sites in the group can be linked to other groups by chemical bonds. The chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines Express. For example, a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group; The straight dashed bonds in the group indicate connections to other groups through the two ends of the nitrogen atoms in the group; the wavy lines in the group indicate connections to other groups through the 1 and 2 carbon atoms in the phenyl group.
除非另有规定，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个原子的“环”。Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring" refers to a "ring" of 5-7 atoms arranged around it.
除非另有规定，C
n-n+m或C
n-C
n+m包括n至n+m个碳的任何一种具体情况，例如C
1-12包括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，也包括n至n+m中的任何一个范围，例如C
1-12包括C
1-
3、C
1-6、C
1-9、C
3-6、C
3-9、C
3-12、C
6-9、C
6-12、和C
9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, also including any one range from n to n+m, for example, 3-12-membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
除非另有规定，术语“C
1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C
1-6烷基包括C
1-5、C
1-4、C
1-3、C
1-2、C
2-6、C
2-4、C
6和C
5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
Unless otherwise specified, the term "C 1-6 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl and the like; it can be Is monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine). Examples of C 1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
除非另有规定，术语“C
1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C
1-4烷基包括C
1-2、C
1-3和C
2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)等。
Unless otherwise specified, the term "C 1-4 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 alkyl includes C 1-2 , C 1-3 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent ( such as methine). Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl) and so on.
除非另有规定，术语“C
1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C
1-3烷基包括C
1-2和C
2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C
1-
3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) . Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
除非另有规定，术语“C
1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C
1-3烷氧基包括C
1-2、C
2-3、C
3和C
2烷氧基等。C
1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
Unless otherwise specified, the term " C1-3alkoxy " refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like. Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，“C
3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C
3-5环烷基包括C
3-4或C
4-5环烷基等；其可以是一价、二价或者多价。C
3-5环烷基的实例包括，但不限于， 环丙基、环丁基、环戊基等。
Unless otherwise specified, "C 3-5 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 5 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl including C 3 -4 or C 4-5 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent. Examples of C3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)
p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention, and the term "5-6 membered heteroaryl" means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2- -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
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三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。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、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "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 groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as 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-butyldimethylsilyl (TBS) and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
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。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 enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：DMF代表N,N-二甲基甲酰胺；K
2CO
3代表碳酸钾；MeI代表碘甲烷；EtOAc或EA代表乙酸乙酯；THF代表四氢呋喃；MeOH代表甲醇；DCM代表二氯甲烷；DMSO代表二甲基亚砜；PE代表石油醚；EtOH代表乙醇；ACN代表乙腈；TFA代表三氟乙酸；FA代表甲酸；NH
3·H
2O代表氨水；TEA代表三乙胺；DIPEA或DIEA代表N,N-二异丙基乙胺；NBS代表N-溴代丁二酰亚胺；LiHMDS 代表六甲基二硅基氨基锂；m-CPBA代表间氯过氧苯甲酸；Boc
2O代表二碳酸二叔丁酯；代表Boc代表叔丁氧羰基，是氨基的一种保护基；CDI代表N,N'-羰基二咪唑；PEG400代表聚乙二醇400；LCMS代表液质联用色谱；HPLC代表液相色谱；TLC代表薄层层析；MEC代表最小有效浓度；LnCap代表前列腺癌细胞；sGC代表可溶性鸟苷酸环化酶；cGMP代表环磷酸鸟苷；SFC代表超临界流体色谱。
The present invention adopts the following abbreviations: DMF stands for N,N-dimethylformamide; K 2 CO 3 stands for potassium carbonate; MeI stands for methyl iodide; EtOAc or EA stands for ethyl acetate; THF stands for tetrahydrofuran; MeOH stands for methanol; DCM for dichloromethane; DMSO for dimethyl sulfoxide; PE for petroleum ether; EtOH for ethanol; ACN for acetonitrile; TFA for trifluoroacetic acid; FA for formic acid; NH 3 ·H 2 O for ammonia; TEA for triethyl Amine; DIPEA or DIEA for N,N-diisopropylethylamine; NBS for N-bromosuccinimide; LiHMDS for lithium hexamethyldisilazide; m-CPBA for m-chloroperoxybenzoic acid ; Boc 2 O represents di-tert-butyl dicarbonate; represents Boc represents tert-butoxycarbonyl, which is a protective group of amino; CDI represents N,N'-carbonyldiimidazole; PEG400 represents polyethylene glycol 400; LCMS represents liquid Mass spectrometry chromatography; HPLC for liquid chromatography; TLC for thin layer chromatography; MEC for minimum effective concentration; LnCap for prostate cancer cells; sGC for soluble guanylate cyclase; cGMP for cyclic guanosine monophosphate; Critical Fluid Chromatography.
化合物依据本领域常规命名原则或者使用
软件命名，市售化合物采用供应商目录名称。
Compounds are named according to conventional nomenclature in the art or are used Software naming, commercially available compounds use supplier catalog names.
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。The present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. For those skilled in the art, various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention. will be obvious.
实施例1Example 1
步骤A：氮气保护下，向1-1(2g,12.57mmol,1eq)的乙腈(30mL)溶液中加入DIEA(2.44g,18.86mmol,3.28mL,1.5eq)和2-氟苄胺(1.73g,13.83mmol,1.57mL,1.1eq)，反应液在60℃下搅拌2小时。反应液浓缩后加入水(30mL)，过滤，滤饼真空干燥后得到化合物1-a。Step A: Under nitrogen protection, to a solution of 1-1 (2g, 12.57mmol, 1eq) in acetonitrile (30mL) was added DIEA (2.44g, 18.86mmol, 3.28mL, 1.5eq) and 2-fluorobenzylamine (1.73g) , 13.83mmol, 1.57mL, 1.1eq), the reaction solution was stirred at 60°C for 2 hours. The reaction solution was concentrated, water (30 mL) was added, filtered, and the filter cake was vacuum-dried to obtain compound 1-a.
步骤B：向1-a(2.5g,9.46mmol,1eq)的THF(30mL)和水(10mL)的溶液中加入还原铁粉(2.64g,47.31mmol,5eq)和NH
4Cl(2.53g,47.31mmol,5eq)。反应液在70℃下搅拌12小时。将反应液过滤，滤液浓缩后柱层析分离(PE/EtOAc＝1/0,5/1)得到化合物1-b。
Step B: To a solution of 1-a (2.5 g, 9.46 mmol, 1 eq) in THF (30 mL) and water (10 mL) was added reduced iron powder (2.64 g, 47.31 mmol, 5 eq) and NH 4 Cl (2.53 g, 47.31 mmol, 5eq). The reaction solution was stirred at 70°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography (PE/EtOAc=1/0, 5/1) to obtain compound 1-b.
步骤C：向1-b(2g,8.54mmol,1eq)的THF(50mL)溶液中加入CDI(4.15g,25.61mmol,3eq)，反应液在65℃搅拌1小时后浓缩，残留物加入水(30mL)，然后加入稀盐酸调节pH到4左右，过滤，滤饼干燥，得到化合物1-c。Step C: To a solution of 1-b (2g, 8.54mmol, 1eq) in THF (50mL) was added CDI (4.15g, 25.61mmol, 3eq), the reaction solution was stirred at 65°C for 1 hour and then concentrated, and the residue was added with water ( 30 mL), then dilute hydrochloric acid was added to adjust the pH to about 4, filtered, and the filter cake was dried to obtain compound 1-c.
步骤D：将丙二腈(14.93g,225.98mmol,14.22mL,1eq)溶于THF(100mL)中，然后加入叔丁醇钾(27.89g,248.58mmol,1.1eq)，反应液在50℃下搅拌0.5小时，然后加入化合物1-2(45g,248.58mmol,32.14mL,1.1eq)，反应液在50℃下继续搅拌11.5小时，反应完成后加入100mL水淬灭，然后用EtOAc(100mL×2)萃取，有机相通过无水硫酸钠干燥，过滤后浓缩滤液，残留物通过柱层析(PE/EtOAc＝10/1-5/1)纯化得到化合物1-d。Step D: Malononitrile (14.93g, 225.98mmol, 14.22mL, 1eq) was dissolved in THF (100mL), then potassium tert-butoxide (27.89g, 248.58mmol, 1.1eq) was added, and the reaction solution was heated at 50°C After stirring for 0.5 hours, compound 1-2 (45 g, 248.58 mmol, 32.14 mL, 1.1 eq) was added, and the reaction solution was stirred at 50 °C for 11.5 hours. After the reaction was completed, 100 mL of water was added to quench, and then EtOAc (100 mL×2 ) extraction, the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated after filtration, and the residue was purified by column chromatography (PE/EtOAc=10/1-5/1) to obtain compound 1-d.
步骤E：将化合物1-d(20g,120.35mmol,1eq)、S-甲基硫脲(27.04g,144.42mmol,1.2eq,0.5HSO
4)和三乙胺(24.36g,240.71mmol,33.50mL,2eq)溶于DMF(60mL)中，氮气置换3次后，在100℃下搅拌12小时后过滤，浓缩滤液，残留物通过柱层析(PE/EtOAc＝10/1-1/1)纯化得到化合物1-e。
Step E: Compound 1-d (20g, 120.35mmol, 1eq), S-methylthiourea (27.04g, 144.42mmol, 1.2eq, 0.5HSO4 ) and triethylamine (24.36g, 240.71mmol, 33.50mL) were combined , 2eq) was dissolved in DMF (60 mL), after nitrogen replacement 3 times, stirred at 100 °C for 12 hours, filtered, the filtrate was concentrated, and the residue was purified by column chromatography (PE/EtOAc=10/1-1/1) Compound 1-e is obtained.
步骤F：将化合物1-e(3.8g,16.94mmol,1eq)溶于DCM(50mL)中，然后加入间氯过氧苯甲酸(6.88g,33.89mmol,85％纯度,2eq)。反应液在20℃下搅拌12小时后过滤，滤饼用二氯甲烷(100mL)洗涤得到化合物1-f。LCMS(ESI)m/z:257.2(M+1)。Step F: Compound 1-e (3.8 g, 16.94 mmol, 1 eq) was dissolved in DCM (50 mL), then m-chloroperoxybenzoic acid (6.88 g, 33.89 mmol, 85% purity, 2 eq) was added. The reaction solution was stirred at 20° C. for 12 hours and then filtered, and the filter cake was washed with dichloromethane (100 mL) to obtain compound 1-f. LCMS (ESI) m/z: 257.2 (M+1).
步骤G：在氮气保护下，向化合物1-c(0.2g,768.53μmol,1eq)和1-f(244.37mg,768.53μmol,1eq)的DMF(3mL)溶液中加入K
2CO
3(318.64mg,2.31mmol,3eq)。反应液在140℃下搅拌2小时，加入水(15mL)，过滤，滤饼用制备HPLC纯化[水(0.1％TFA)-ACN]，然后用柱层析分离(PE/EtOAc＝3/1～1/1)得到化合物1。
1H NMR(400MHz,DMSO-d
6):δppm 11.15(s,1H),7.50(d,J＝7.7Hz,1H),7.41-7.31(m,1H),7.29-7.21(m,1H),7.20-7.11(m,2H),7.11-7.04(m,1H),7.03-6.93(m,3H),5.23(s,2H),1.54-1.29(s,6H)；LCMS(ESI)m/z:437.1(M+1)。
Step G: To a solution of compound 1-c (0.2 g, 768.53 μmol, 1 eq) and 1-f (244.37 mg, 768.53 μmol, 1 eq) in DMF (3 mL) was added K 2 CO 3 (318.64 mg) under nitrogen protection , 2.31 mmol, 3eq). The reaction solution was stirred at 140° C. for 2 hours, water (15 mL) was added, filtered, and the filter cake was purified by preparative HPLC [water (0.1% TFA)-ACN], and then separated by column chromatography (PE/EtOAc=3/1～ 1/1) to obtain compound 1. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.15 (s, 1H), 7.50 (d, J=7.7 Hz, 1H), 7.41-7.31 (m, 1H), 7.29-7.21 (m, 1H), 7.20-7.11(m, 2H), 7.11-7.04(m, 1H), 7.03-6.93(m, 3H), 5.23(s, 2H), 1.54-1.29(s, 6H); LCMS(ESI) m/z : 437.1(M+1).
实施例2Example 2
步骤A：向2-1(2g,12.80mmol,1eq)的H
2O(20mL)和AcOH(7.35g,122.40mmol,7.00mL,9.56eq)的溶液中缓慢加入NaNO
2(1.77g,25.61mmol,2eq)，反应液在20℃下搅拌1小时，将反应液过滤，滤饼在高真空下干燥得到化合物2-a。
Step A: To a solution of 2-1 (2 g, 12.80 mmol, 1 eq) in H 2 O (20 mL) and AcOH (7.35 g, 122.40 mmol, 7.00 mL, 9.56 eq) was slowly added NaNO 2 (1.77 g, 25.61 mmol) , 2eq), the reaction solution was stirred at 20° C. for 1 hour, the reaction solution was filtered, and the filter cake was dried under high vacuum to obtain compound 2-a.
步骤B：向2-a(2.4g,12.96mmol,1eq)的DCM(40mL)悬浮液中慢慢加入m-CPBA(3.99g,19.44mmol,85％纯度,1.5eq)，反应液在20℃下搅拌30分钟，将悬浮液过滤，滤饼在高真空下干燥得到化合物2-b。Step B: To a suspension of 2-a (2.4g, 12.96mmol, 1eq) in DCM (40mL) was slowly added m-CPBA (3.99g, 19.44mmol, 85% purity, 1.5eq), the reaction solution was heated at 20°C After stirring for 30 minutes, the suspension was filtered, and the filter cake was dried under high vacuum to obtain compound 2-b.
步骤C：氮气保护下，在1-c(800mg,3.07mmol,1eq)的DMF(5.00mL)溶液中加入2-b(801.26mg,3.69mmol,1.2eq)，碳酸钾(849.72mg,6.15mmol,2eq)。反应液在30℃下搅拌12小时，反应液冷却后加入水(20mL)，过滤，滤饼干燥后得到化合物2-c。Step C: Under nitrogen protection, to a solution of 1-c (800mg, 3.07mmol, 1eq) in DMF (5.00mL) was added 2-b (801.26mg, 3.69mmol, 1.2eq), potassium carbonate (849.72mg, 6.15mmol) , 2eq). The reaction solution was stirred at 30° C. for 12 hours. After the reaction solution was cooled, water (20 mL) was added, filtered, and the filter cake was dried to obtain compound 2-c.
步骤D：在氮气保护下，向2-c(1.0g,2.42mmol,1eq)的DMF(5.00mL)溶液中加入湿Pd/C(100mg,10％钯含量)。将反应液用氢气置换3次后，在氢气(15psi)氛围下，于50℃搅拌1小时，反应液过滤后，向滤液中加入水(50mL)，然后用乙酸乙酯(50mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩得到化合物2-d。Step D: To a solution of 2-c (1.0 g, 2.42 mmol, 1 eq) in DMF (5.00 mL) was added wet Pd/C (100 mg, 10% palladium content) under nitrogen protection. After replacing the reaction solution with hydrogen three times, the reaction solution was stirred at 50° C. for 1 hour under the atmosphere of hydrogen (15 psi). After the reaction solution was filtered, water (50 mL) was added to the filtrate, followed by extraction with ethyl acetate (50 mL×2). , the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 2-d.
步骤E：在0℃下，向2-d(300mg,782.57μmol,1eq)的吡啶(3.00mL)溶液中滴加氯甲酸甲酯(369.75mg,3.91mmol,303.07μL,5eq)，反应液在0℃下搅拌1小时。反应完成后，加入水(20mL)淬灭反应，然后用乙酸乙酯50mL(25mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩，残留物通过制备HPLC[流动相：水(0.075％FA)-ACN]纯化得到化合物2。
1H NMR(400MHz,DMSO-d
6)：δppm 8.17(br s,1H),8.07(br d,J＝6.8Hz,1H),7.42-7.34(m,3H),7.26(br t,J＝9.0Hz,3H),7.20-7.13(m,3H),7.11-7.07(m,1H),5.27(s,2H),3.65(br s,3H)；LCMS(ESI)m/z:442.3(M+1)。
Step E: Methyl chloroformate (369.75 mg, 3.91 mmol, 303.07 μL, 5 eq) was added dropwise to a solution of 2-d (300 mg, 782.57 μmol, 1 eq) in pyridine (3.00 mL) at 0 °C, and the reaction solution was Stir at 0°C for 1 hour. After the reaction was completed, water (20 mL) was added to quench the reaction, and then extracted with ethyl acetate 50 mL (25 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to preparative HPLC [mobile phase: water ( 0.075% FA)-ACN] was purified to give compound 2. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.17 (br s, 1H), 8.07 (br d, J=6.8 Hz, 1H), 7.42-7.34 (m, 3H), 7.26 (br t, J= 9.0Hz, 3H), 7.20-7.13(m, 3H), 7.11-7.07(m, 1H), 5.27(s, 2H), 3.65(br s, 3H); LCMS(ESI) m/z: 442.3(M +1).
实施例3Example 3
步骤A：氮气保护下，向1-1(600mg,3.77mmol,1eq)的乙腈(4.00mL)溶液中加入(3-氟-2-吡啶基)甲胺二盐酸(825.79mg,4.15mmol,1.1eq)，二异丙基乙胺(1.95g,15.09mmol,2.63mL,4eq)。反应液在60℃下搅拌0.5小时，反应完成后减压浓缩，残留物通过柱层析分离纯化(PE:EtOAc＝20:1-7:1)，得到化合物3-a。Step A: Under nitrogen protection, to a solution of 1-1 (600 mg, 3.77 mmol, 1 eq) in acetonitrile (4.00 mL) was added (3-fluoro-2-pyridyl)methanamine dihydrochloride (825.79 mg, 4.15 mmol, 1.1 eq), diisopropylethylamine (1.95 g, 15.09 mmol, 2.63 mL, 4 eq). The reaction solution was stirred at 60° C. for 0.5 hours. After the reaction was completed, it was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE:EtOAc=20:1-7:1) to obtain compound 3-a.
步骤B：在氮气保护下，向3-a(900mg,3.39mmol,1eq)的MeOH(10.00mL)和THF(10.00mL)混合溶液中加入Pd/C(500mg,10％纯度)。反应液在氢气(15psi)氛围下，于30℃搅拌0.5小时，反应液过滤浓缩得到化合物3-b。Step B: To a mixed solution of 3-a (900 mg, 3.39 mmol, 1 eq) in MeOH (10.00 mL) and THF (10.00 mL) was added Pd/C (500 mg, 10% purity) under nitrogen protection. The reaction solution was stirred at 30° C. for 0.5 hours under a hydrogen (15 psi) atmosphere, and the reaction solution was filtered and concentrated to obtain compound 3-b.
步骤C：在3-b(750mg,3.19mmol,1eq)的THF(10.00mL)溶液中加入CDI(1.03g,6.38mmol,2eq)。反应液在70℃搅拌12小时。反应冷却到室温后，加入水(50mL)稀释，然后用乙酸乙酯(50mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩得到化合物3-c。Step C: To a solution of 3-b (750 mg, 3.19 mmol, 1 eq) in THF (10.00 mL) was added CDI (1.03 g, 6.38 mmol, 2 eq). The reaction solution was stirred at 70°C for 12 hours. The reaction was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 3-c.
步骤D：氮气保护下，在3-c(200mg,765.62μmol,1eq)的DMF(5.00mL)溶液中加入1-f(825.79mg,4.15mmol,1.1eq)和碳酸钾(317.45mg,2.30mmol,3eq)。反应液在120℃下搅拌12小时，反应冷却到室温后，加入水(20mL)稀释，然后用乙酸乙酯50mL(25mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩，残留物通过制备HPLC[流动相：水(0.075％FA)-ACN]纯化得到化合物3。
1H NMR(400MHz,DMSO-d
6)δppm 11.14(s,1H),8.29(d,J＝4.6Hz,1H),7.78(t,J＝9.8Hz,1H),7.49(d,J＝7.9Hz,1H),7.43-7.36(m,1H),7.04(br d,J＝5.0Hz,1H),6.99-6.85(m,3H),5.37(s,2H),1.37(s,6H).LCMS(ESI)m/z:438.4(M+1)。
Step D: Under nitrogen protection, to a solution of 3-c (200 mg, 765.62 μmol, 1 eq) in DMF (5.00 mL) was added 1-f (825.79 mg, 4.15 mmol, 1.1 eq) and potassium carbonate (317.45 mg, 2.30 mmol) , 3eq). The reaction solution was stirred at 120 °C for 12 hours. After the reaction was cooled to room temperature, water (20 mL) was added to dilute it, and then extracted with ethyl acetate 50 mL (25 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The compound was purified by preparative HPLC [mobile phase: water (0.075% FA)-ACN] to give compound 3. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 11.14 (s, 1H), 8.29 (d, J=4.6 Hz, 1H), 7.78 (t, J=9.8 Hz, 1H), 7.49 (d, J=7.9 Hz, 1H), 7.43-7.36(m, 1H), 7.04(br d, J=5.0Hz, 1H), 6.99-6.85(m, 3H), 5.37(s, 2H), 1.37(s, 6H). LCMS (ESI) m/z: 438.4 (M+1).
实施例4Example 4
步骤A：氮气保护下，在4-1(1.0g,5.65mmol,649.35μL,1eq)的乙腈(5.00mL)溶液中加入2-氟苄胺(848.04mg,6.78mmol,770.95μL,1.2eq)，二异丙基乙胺(2.19g,16.94mmol,2.95mL,3eq)。反应液在40℃下搅拌1小时，反应液减压浓缩，粗品通过柱层析分离纯化(PE:EtOAc＝20:1-7:1)，得到化合物4-a。Step A: Under nitrogen protection, 2-fluorobenzylamine (848.04 mg, 6.78 mmol, 770.95 μL, 1.2 eq) was added to a solution of 4-1 (1.0 g, 5.65 mmol, 649.35 μL, 1 eq) in acetonitrile (5.00 mL) , diisopropylethylamine (2.19g, 16.94mmol, 2.95mL, 3eq). The reaction solution was stirred at 40° C. for 1 hour, the reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (PE:EtOAc=20:1-7:1) to obtain compound 4-a.
步骤B：在氮气保护下，向4-a(1.5g,5.32mmol,1eq)的MeOH(10.00mL)和THF(10.00mL)的溶液中加入Pd/C(500mg,10％纯度)。在氢气(15psi)氛围下，于30℃搅拌0.5小时，反应液过滤浓缩得到化合物4-b。Step B: To a solution of 4-a (1.5 g, 5.32 mmol, 1 eq) in MeOH (10.00 mL) and THF (10.00 mL) was added Pd/C (500 mg, 10% purity) under nitrogen. Under an atmosphere of hydrogen (15 psi), the mixture was stirred at 30° C. for 0.5 hours, and the reaction solution was filtered and concentrated to obtain compound 4-b.
步骤C：在4-b(1.3g,5.15mmol,1eq)的THF(10.00mL)溶液中加入CDI(1.67g,10.31mmol,2eq)。反应液在70℃搅拌1小时。反应冷却到室温后，加入水(50mL)稀释，然后用乙酸乙酯(50mL×2)萃取，合并的有机相用水(50mL×2)洗涤，经过无水硫酸钠干燥后，减压浓缩得到化合物4-c。Step C: To a solution of 4-b (1.3 g, 5.15 mmol, 1 eq) in THF (10.00 mL) was added CDI (1.67 g, 10.31 mmol, 2 eq). The reaction solution was stirred at 70°C for 1 hour. The reaction was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (50 mL×2). The combined organic phases were washed with water (50 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the compound 4-c.
步骤D：氮气保护下，在4-c(200mg,718.83μmol,1eq)的DMF(5.00mL)溶液中加入1-f(368.45mg,1.44mmol,2eq)和碳酸钾(298.05mg,2.16mmol,3eq)。反应液在120℃下搅拌12小时，反应冷却到室温后，加入水(20mL)稀释，然后用乙酸乙酯(25mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩，残留物通过制备HPLC[流动相：水(0.1％FA)-ACN]纯化得到化合物4。
1H NMR(400MHz,DMSO-d
6):δppm 11.16(s,1H),7.54(dd,J＝2.9,8.8Hz,1H),7.42-7.34(m,1H),7.25(dd,J＝8.5,10.5Hz,1H),7.21-7.17(m,2H),7.17-7.08(m,1H),7.05-6.91(m,2H),5.24(s,2H),1.36(s,6H)；LCMS(ESI)m/z:455.4(M+1)。
Step D: Under nitrogen protection, to a solution of 4-c (200mg, 718.83μmol, 1eq) in DMF (5.00mL) was added 1-f (368.45mg, 1.44mmol, 2eq) and potassium carbonate (298.05mg, 2.16mmol, 3eq). The reaction solution was stirred at 120° C. for 12 hours. After the reaction was cooled to room temperature, water (20 mL) was added to dilute it, and then extracted with ethyl acetate (25 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue Compound 4 was obtained by purification by preparative HPLC [mobile phase: water (0.1% FA)-ACN]. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.16 (s, 1H), 7.54 (dd, J=2.9, 8.8 Hz, 1H), 7.42-7.34 (m, 1H), 7.25 (dd, J=8.5 ,10.5Hz,1H),7.21-7.17(m,2H),7.17-7.08(m,1H),7.05-6.91(m,2H),5.24(s,2H),1.36(s,6H); LCMS( ESI) m/z: 455.4 (M+1).
实施例5Example 5
步骤A：向5-1(1g,6.29mmol,689.66μL,1eq)的MeCN(20mL)溶液中加入2-氟苄胺(786.62mg,6.29mmol,715.11μL,1eq)和二异丙基乙胺(812.39mg,6.29mmol,1.09mL,1eq)。反应于18℃下搅拌12小时。反应液过滤，滤饼通过减压浓缩干燥后得化合物5-a。Step A: To a solution of 5-1 (1 g, 6.29 mmol, 689.66 μL, 1 eq) in MeCN (20 mL) was added 2-fluorobenzylamine (786.62 mg, 6.29 mmol, 715.11 μL, 1 eq) and diisopropylethylamine (812.39 mg, 6.29 mmol, 1.09 mL, 1 eq). The reaction was stirred at 18°C for 12 hours. The reaction solution was filtered, and the filter cake was concentrated and dried under reduced pressure to obtain compound 5-a.
步骤B：在氮气保护下向5-a(804mg,3.04mmol,1eq)的MeOH(10mL)中加入Pd/C(80mg,纯度10％)。在18℃氢气氛围下搅拌12小时。将反应液过滤，滤液浓缩后得到化合物5-b。Step B: To 5-a (804 mg, 3.04 mmol, 1 eq) in MeOH (10 mL) was added Pd/C (80 mg, 10% purity) under nitrogen protection. Stir under a hydrogen atmosphere at 18°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain compound 5-b.
步骤C：在氮气保护下向5-b(596mg,2.54mmol,1eq)的THF(10mL)溶液中缓慢加入CDI(825.12mg,5.09mmol,2eq)。反应液在70℃下搅拌2小时，将反应液浓缩，残留物通过柱层析(PE:EtOAc＝5:1-1:1)纯化得到化合物5-c。Step C: To a solution of 5-b (596 mg, 2.54 mmol, 1 eq) in THF (10 mL) was slowly added CDI (825.12 mg, 5.09 mmol, 2 eq) under nitrogen protection. The reaction solution was stirred at 70° C. for 2 hours, the reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc=5:1-1:1) to obtain compound 5-c.
步骤D：向5-c(150mg,576.40μmol,1eq)的DMF(5mL)溶液中加入1-f(221.58mg,864.59μmol,1.5eq)，碳酸钾(238.98mg,1.73mmol,3eq)。反应液在120℃下搅拌12小时，将反应液浓缩，残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得化合物5。
1H NMR(400MHz,DMSO-d
6):δppm 11.13(br s,1H),7.73(dd,J＝4.9,8.8Hz,1H),7.43-7.09(m,5H),7.01-6.83(m,3H),5.16(s,2H),1.36(s,6H)；LCMS(ESI)m/z:437.2(M+1)。
Step D: To a solution of 5-c (150 mg, 576.40 μmol, 1 eq) in DMF (5 mL) was added 1-f (221.58 mg, 864.59 μmol, 1.5 eq), potassium carbonate (238.98 mg, 1.73 mmol, 3 eq). The reaction solution was stirred at 120° C. for 12 hours, the reaction solution was concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 5. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.13 (br s, 1H), 7.73 (dd, J=4.9, 8.8 Hz, 1H), 7.43-7.09 (m, 5H), 7.01-6.83 (m, 3H), 5.16 (s, 2H), 1.36 (s, 6H); LCMS (ESI) m/z: 437.2 (M+1).
实施例6Example 6
步骤A：在化合物3(150mg,342.93μmol,1eq)的二氧六环(2.00mL)溶液中加入亚硝酸异戊酯(40.17mg,342.93μmol,46.18μL,1eq)和二碘甲烷(91.85mg,342.93μmol,27.67μL,1eq)，反应液在100℃下搅拌1小时。反应液冷却到室温，加入水(20mL)稀释，然后用乙酸乙酯(25mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩得到化合物6-a。Step A: To a solution of compound 3 (150 mg, 342.93 μmol, 1 eq) in dioxane (2.00 mL) was added isoamyl nitrite (40.17 mg, 342.93 μmol, 46.18 μL, 1 eq) and diiodomethane (91.85 mg) , 342.93 μmol, 27.67 μL, 1eq), the reaction solution was stirred at 100° C. for 1 hour. The reaction solution was cooled to room temperature, diluted with water (20 mL), and then extracted with ethyl acetate (25 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 6-a.
步骤B：在氮气保护下，向6-a(180mg,328.30μmol,1eq)的MeOH(10.00mL)溶液中加入Pd/C(200mg,10％纯度)。反应液在氢气(15psi)氛围下，于20℃搅拌12小时，将反应液过滤，滤液浓缩后残留物通过制备HPLC[流动相：水(0.1％FA)-ACN]纯化得到化合物6。
1H NMR(400MHz,DMSO-d
6):δppm 11.78(s,1H),8.63(s,1H),8.34-8.22(m,1H),7.87-7.73(m,1H),7.54(dd,J＝0.9,8.1Hz,1H),7.45-7.39(m,1H),7.16-7.04(m,1H),6.99(dd,J＝0.8,2.8Hz,1H),5.39(s,2H),1.41(s,6H)；LCMS(ESI)m/z:423.3(M+1)。
Step B: To a solution of 6-a (180 mg, 328.30 μmol, 1 eq) in MeOH (10.00 mL) was added Pd/C (200 mg, 10% purity) under nitrogen protection. The reaction solution was stirred at 20°C for 12 hours under hydrogen (15 psi) atmosphere, the reaction solution was filtered, the filtrate was concentrated and the residue was purified by preparative HPLC [mobile phase: water (0.1% FA)-ACN] to obtain compound 6. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.78 (s, 1H), 8.63 (s, 1H), 8.34-8.22 (m, 1H), 7.87-7.73 (m, 1H), 7.54 (dd, J =0.9,8.1Hz,1H),7.45-7.39(m,1H),7.16-7.04(m,1H),6.99(dd,J=0.8,2.8Hz,1H),5.39(s,2H),1.41( s, 6H); LCMS (ESI) m/z: 423.3 (M+1).
实施例7Example 7
步骤A：向7-1(1g,5.70mmol,1eq)的甲苯(10mL)溶液中加入2-氟苄胺(784mg,6.26mmol,712.73μL,1.1eq)和N,N-二异丙基乙胺(2.21g,17.09mmol,2.98mL,3eq)，反应液在80℃搅拌2小时。反应液浓缩后经柱层析(石油醚：乙酸乙酯＝20:1)分离得到化合物7-a。Step A: To a solution of 7-1 (1 g, 5.70 mmol, 1 eq) in toluene (10 mL) was added 2-fluorobenzylamine (784 mg, 6.26 mmol, 712.73 μL, 1.1 eq) and N,N-diisopropylethyl acetate Amine (2.21 g, 17.09 mmol, 2.98 mL, 3 eq), the reaction solution was stirred at 80 °C for 2 hours. The reaction solution was concentrated and separated by column chromatography (petroleum ether:ethyl acetate=20:1) to obtain compound 7-a.
步骤B：向7-a(1.3g,4.63mmol,1eq)的四氢呋喃(13mL)和水(4mL)溶液中加入锌粉(1.51g,23.16mmol,5eq)和氯化铵(1.24g,23.16mmol,5eq)，反应液在50℃搅拌12小时。反应液过滤后浓缩，残留物经柱层析(石油醚：乙酸乙酯＝3:1)分离得到化合物7-b。Step B: To a solution of 7-a (1.3g, 4.63mmol, 1eq) in tetrahydrofuran (13mL) and water (4mL) was added zinc powder (1.51g, 23.16mmol, 5eq) and ammonium chloride (1.24g, 23.16mmol) , 5eq), the reaction solution was stirred at 50 ° C for 12 hours. The reaction solution was filtered, concentrated, and the residue was separated by column chromatography (petroleum ether:ethyl acetate=3:1) to obtain compound 7-b.
步骤C：向7-b(270mg,1.08mmol,1eq)的四氢呋喃(10mL)溶液中加入CDI(350mg,2.16mmol,2eq)，反应液在70℃搅拌12小时。反应液浓缩后加入甲醇(10mL)，过滤，滤饼真空干燥得到化合物7-c。Step C: To a solution of 7-b (270 mg, 1.08 mmol, 1 eq) in tetrahydrofuran (10 mL) was added CDI (350 mg, 2.16 mmol, 2 eq), and the reaction solution was stirred at 70° C. for 12 hours. The reaction solution was concentrated, methanol (10 mL) was added, filtered, and the filter cake was vacuum-dried to obtain compound 7-c.
步骤D：向7-c(175mg,632.47μmol,1eq)的DMF(2mL)溶液中加入碳酸钾(262mg,1.90mmol,3eq)和化合物1-f(324mg,1.26mmol,2eq)，反应液在120℃下搅拌12小时。反应液过滤，滤液经制备HPLC分离[水(0.225％FA)-ACN]得到化合物7。
1H NMR(400MHz,DMSO-d
6):δppm 11.12(br s,1H),7.71(d,J＝8.56Hz,1H),7.32-7.42(m,1H),7.31-7.32(m,1H),7.17-7.32(m,3H),7.11(dd,J＝8.56,2.08Hz,1H),6.94(br s,2H),5.16(s,2H),1.20-1.46(s,6H)；LCMS(ESI)m/z:453.1(M+1)。
Step D: To a solution of 7-c (175mg, 632.47μmol, 1eq) in DMF (2mL) was added potassium carbonate (262mg, 1.90mmol, 3eq) and compound 1-f (324mg, 1.26mmol, 2eq), the reaction solution was in Stir at 120°C for 12 hours. The reaction solution was filtered, and the filtrate was separated by preparative HPLC [water (0.225% FA)-ACN] to obtain compound 7. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.12 (br s, 1H), 7.71 (d, J=8.56 Hz, 1H), 7.32-7.42 (m, 1H), 7.31-7.32 (m, 1H) ,7.17-7.32(m,3H),7.11(dd,J=8.56,2.08Hz,1H),6.94(br s,2H),5.16(s,2H),1.20-1.46(s,6H); LCMS( ESI) m/z: 453.1 (M+1).
实施例8Example 8
步骤A：氮气保护下，向4-1(1.0g,5.65mmol,649.35μL,1eq)的乙腈(5.00mL)溶液中加入(3-氟-2-吡啶基)甲胺二盐酸(918.65mg,5.65mmol,770.95μL,1eq)，二异丙基乙胺(2.92g,22.60mmol,3.94mL,4eq)。反应液在40℃下搅拌1小时，反应液浓缩后通过柱层析分离纯化(PE:EtOAc＝20:1-7:1)，得到化合物8-a。Step A: Under nitrogen protection, to a solution of 4-1 (1.0 g, 5.65 mmol, 649.35 μL, 1 eq) in acetonitrile (5.00 mL) was added (3-fluoro-2-pyridyl)methanamine dihydrochloride (918.65 mg, 5.65 mmol, 770.95 μL, 1 eq), diisopropylethylamine (2.92 g, 22.60 mmol, 3.94 mL, 4 eq). The reaction solution was stirred at 40° C. for 1 hour, and the reaction solution was concentrated and separated and purified by column chromatography (PE:EtOAc=20:1-7:1) to obtain compound 8-a.
步骤B：在氮气保护下，向8-a(800mg,2.82mmol,1eq)的MeOH(10.00mL)和THF(10.00mL)混合溶液中加入Pd/C(200mg,10％纯度)。反应液在氢气(15psi)氛围下，于30℃搅拌0.5小时，反应液过滤浓缩后得到化合物8-b。Step B: To a mixed solution of 8-a (800 mg, 2.82 mmol, 1 eq) in MeOH (10.00 mL) and THF (10.00 mL) was added Pd/C (200 mg, 10% purity) under nitrogen protection. The reaction solution was stirred at 30° C. for 0.5 hours under a hydrogen atmosphere (15 psi), and the reaction solution was filtered and concentrated to obtain compound 8-b.
步骤C：向8-b(700mg,2.76mmol,1eq)的THF(10.00mL)溶液中加入CDI(896.48mg,5.53mmol,2eq)。反应液在70℃搅拌12小时。反应冷却到室温后，加入水(20mL)稀释，然后用乙酸乙酯(25mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩，残留物加入MeOH(10mL)搅拌，过滤，滤饼干燥后得到化合物8-c。Step C: To a solution of 8-b (700 mg, 2.76 mmol, 1 eq) in THF (10.00 mL) was added CDI (896.48 mg, 5.53 mmol, 2 eq). The reaction solution was stirred at 70°C for 12 hours. The reaction was cooled to room temperature, diluted with water (20 mL), and then extracted with ethyl acetate (25 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. MeOH (10 mL) was added to the residue and stirred, filtered, and filtered. Compound 8-c was obtained after the cake was dried.
步骤D：氮气保护下，向8-c(200mg,716.29μmol,1eq)的DMF(2.00mL)溶液中加入1-f(367.14mg,1.43mmol,2eq)和碳酸钾(395.98mg,2.87mmol,4eq)。反应液在120℃下搅拌1小时，反应冷却到室温后，加入水(20mL)稀释，然后用乙酸乙酯(25mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩，残留物通过制备HPLC[流动相：水(0.225％FA)-ACN]纯化得到化合物8。
1H NMR(400MHz,DMSO-d
6):δppm 11.15(s,1H),8.30(td,J＝1.3,4.7Hz,1H),7.80(ddd,J＝1.2,8.6,10.1Hz,1H),7.58-7.47(m,1H),7.43(td,J＝4.4,8.5Hz,1H),7.23-7.05(m,1H),6.99(br s,2H),5.38(s,2H),1.36(s,6H)；LCMS(ESI)m/z:456.4(M+1)。
Step D: Under nitrogen protection, to a solution of 8-c (200 mg, 716.29 μmol, 1 eq) in DMF (2.00 mL) was added 1-f (367.14 mg, 1.43 mmol, 2 eq) and potassium carbonate (395.98 mg, 2.87 mmol, 4eq). The reaction solution was stirred at 120°C for 1 hour. After the reaction was cooled to room temperature, water (20 mL) was added to dilute it, and then it was extracted with ethyl acetate (25 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue Purification by preparative HPLC [mobile phase: water (0.225% FA)-ACN] afforded compound 8. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.15 (s, 1H), 8.30 (td, J=1.3, 4.7 Hz, 1H), 7.80 (ddd, J=1.2, 8.6, 10.1 Hz, 1H), 7.58-7.47(m, 1H), 7.43(td, J=4.4, 8.5Hz, 1H), 7.23-7.05(m, 1H), 6.99(br s, 2H), 5.38(s, 2H), 1.36(s , 6H); LCMS (ESI) m/z: 456.4 (M+1).
实施例9Example 9
步骤A：向1-1(3g,18.86mmol,1eq)的MeCN(60mL)溶液中加入2,4-二甲氧基苄胺(3.78g,22.63mmol,3.41mL,1.2eq)和TEA(3.82g,37.71mmol,5.25mL,2eq)。反应液于70℃下搅拌1小时。将反应液浓缩，残留物通过柱层析(PE:EtOAc＝1:0-10:1)纯化得到化合物9-a。Step A: To a solution of 1-1 (3g, 18.86mmol, 1eq) in MeCN (60mL) was added 2,4-dimethoxybenzylamine (3.78g, 22.63mmol, 3.41mL, 1.2eq) and TEA (3.82 g, 37.71 mmol, 5.25 mL, 2 eq). The reaction solution was stirred at 70°C for 1 hour. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc=1:0-10:1) to obtain compound 9-a.
步骤B：氮气保护下，向9-a(3.92g,12.80mmol,1e)的THF(60mL)和水(20mL)溶液中加入锌粉(4.18g,63.99mmol,5eq)和NH
4Cl(3.42g,63.99mmol,5eq)。反应液在60℃下搅拌1小时，将反应液过滤后浓缩，残留物通过柱层析(PE:EtOAc＝10:1-5:1)纯化得到化合物9-b。
Step B: To a solution of 9-a (3.92 g, 12.80 mmol, 1e) in THF (60 mL) and water (20 mL) under nitrogen protection was added zinc powder (4.18 g, 63.99 mmol, 5 eq) and NH 4 Cl (3.42 g, 63.99 mmol, 5 eq). The reaction solution was stirred at 60° C. for 1 hour, the reaction solution was filtered and concentrated, and the residue was purified by column chromatography (PE:EtOAc=10:1-5:1) to obtain compound 9-b.
步骤C：在氮气保护下，向9-b(2.63g,9.51mmol,1eq)的THF(40mL)溶液中缓慢加入CDI(3.08g,19.01mmol,2eq)。反应液在60℃下搅拌12小时。将反应液浓缩，残留物通过柱层析(PE:EtOAc＝5:1-0:1) 纯化得到化合物9-c。Step C: To a solution of 9-b (2.63 g, 9.51 mmol, 1 eq) in THF (40 mL) was slowly added CDI (3.08 g, 19.01 mmol, 2 eq) under nitrogen protection. The reaction solution was stirred at 60°C for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc=5:1-0:1) to obtain compound 9-c.
步骤D：在氮气保护下，向9-c(1.76g,5.53mmol,1eq)的DMF(50mL)溶液中加入1-f(4.25g,16.59mmol,3eq)，碳酸钾(2.29g,16.59mmol,3eq)。反应液在120℃下搅拌12小时。将反应液倒入到水(200mL)中，用EtOAc(50mL×3)萃取，有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩得化合物9-d。Step D: Under nitrogen protection, to a solution of 9-c (1.76g, 5.53mmol, 1eq) in DMF (50mL) was added 1-f (4.25g, 16.59mmol, 3eq), potassium carbonate (2.29g, 16.59mmol) , 3eq). The reaction solution was stirred at 120°C for 12 hours. The reaction solution was poured into water (200 mL), extracted with EtOAc (50 mL×3), the organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 9-d.
步骤E：在氮气保护下，向9-d(2.99g,6.25mmol,1eq)的DMF(30mL)溶液中加入对甲氧基苄氯(1.37g,8.75mmol,1.19mL,1.4eq)，碳酸钾(1.73g,12.50mmol,2eq)。反应液在50℃下搅拌12小时。将反应液倒入到水(100mL)中，用EtOAc(50mL×4)萃取，有机相用饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析(PE:EtOAc＝5:1-0:1)纯化得化合物9-e。Step E: Under nitrogen protection, to a solution of 9-d (2.99g, 6.25mmol, 1eq) in DMF (30mL) was added p-methoxybenzyl chloride (1.37g, 8.75mmol, 1.19mL, 1.4eq), carbonic acid Potassium (1.73 g, 12.50 mmol, 2 eq). The reaction solution was stirred at 50°C for 12 hours. The reaction solution was poured into water (100 mL), extracted with EtOAc (50 mL×4), the organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (PE:EtOAc=5:1-0:1) to obtain compound 9-e.
步骤F：向9-e(1.24g,1.35mmol,1eq)的三氟乙酸(7.70g,67.53mmol,5mL,50.16eq)溶液中加入三乙基硅烷(728.00mg,6.26mmol,1mL,4.65eq)。反应液在120℃下搅拌12小时。将反应液浓缩，残留物通过柱层析(PE:EtOAc＝5:1-0:1)纯化得到化合物9-f。Step F: To a solution of 9-e (1.24g, 1.35mmol, 1eq) in trifluoroacetic acid (7.70g, 67.53mmol, 5mL, 50.16eq) was added triethylsilane (728.00mg, 6.26mmol, 1mL, 4.65eq) ). The reaction solution was stirred at 120°C for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc=5:1-0:1) to obtain compound 9-f.
步骤G：在氮气保护下，向9-f(572mg,1.28mmol,1eq)的DMF(15mL)溶液中加入9-1(1.40g,5.10mmol,4eq)，碳酸钾(528.86mg,3.83mmol,3eq)。反应液在100℃下搅拌1小时。将反应液倒入到水(50mL)中，用EtOAc(20mL×4)萃取，有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析(PE:EtOAc＝5:1-1:1)纯化得化合物9-g。Step G: Under nitrogen protection, to a solution of 9-f (572mg, 1.28mmol, 1eq) in DMF (15mL) was added 9-1 (1.40g, 5.10mmol, 4eq), potassium carbonate (528.86mg, 3.83mmol, 3eq). The reaction solution was stirred at 100°C for 1 hour. The reaction solution was poured into water (50 mL), extracted with EtOAc (20 mL×4), the organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (PE:EtOAc=5:1-1:1) to obtain compound 9-g.
步骤H：向9-g(455mg,765.34μmol,1eq)的三氟甲磺酸(3.40g,22.66mmol,2mL,29.60eq)溶液中加入三氟乙酸(6.16g,54.02mmol,4mL,70.59eq)。反应液在120℃下搅拌2小时。将反应液浓缩，残留物溶解在EtOAc(5mL)中，用NaOH(4M)水溶液调pH＝7-8，EtOAc(20mL×3)萃取，合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得到化合物9。
1H NMR(400MHz,DMSO-d
6):δppm 11.13(br s,1H),7.55-7.45(m,1H),7.13-7.03(m,2H),6.96(br s,2H),4.28(t,J＝6.9Hz,2H),2.72(tt,J＝7.0,19.1Hz,2H),1.44-1.29(m,6H)；LCMS(ESI)m/z:475.4(M+1)。
Step H: To a solution of 9-g (455mg, 765.34μmol, 1eq) in trifluoromethanesulfonic acid (3.40g, 22.66mmol, 2mL, 29.60eq) was added trifluoroacetic acid (6.16g, 54.02mmol, 4mL, 70.59eq) ). The reaction solution was stirred at 120°C for 2 hours. The reaction solution was concentrated, the residue was dissolved in EtOAc (5 mL), adjusted to pH=7-8 with aqueous NaOH (4M), extracted with EtOAc (20 mL×3), and the combined organic phases were washed with saturated brine (20 mL×2). , dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 9. 1 H NMR (400MHz, DMSO-d 6 ): δppm 11.13 (br s, 1H), 7.55-7.45 (m, 1H), 7.13-7.03 (m, 2H), 6.96 (br s, 2H), 4.28 (t , J=6.9 Hz, 2H), 2.72 (tt, J=7.0, 19.1 Hz, 2H), 1.44-1.29 (m, 6H); LCMS (ESI) m/z: 475.4 (M+1).
实施例10Example 10
步骤A：氮气保护下，向4-1(1.8g,10.16mmol,1.17mL,1eq)的乙腈(10mL)溶液中加入2,4-二甲氧基苄胺(1.87g,11.18mmol,1.68mL,1.1eq)和二异丙基乙胺(5.25g,40.66mmol,7.08mL,4eq)，反应液在40℃下搅拌1小时。反应液浓缩后，残留物通过柱层析纯化分离(石油醚：乙酸乙酯＝20：1-7：1)得到化合物10-a。Step A: Under nitrogen protection, to a solution of 4-1 (1.8g, 10.16mmol, 1.17mL, 1eq) in acetonitrile (10mL) was added 2,4-dimethoxybenzylamine (1.87g, 11.18mmol, 1.68mL) , 1.1eq) and diisopropylethylamine (5.25g, 40.66mmol, 7.08mL, 4eq), the reaction solution was stirred at 40°C for 1 hour. After the reaction solution was concentrated, the residue was purified and separated by column chromatography (petroleum ether:ethyl acetate=20:1-7:1) to obtain compound 10-a.
步骤B：向10-a(2.3g,7.09mmol,1eq)的四氢呋喃(30mL)和水(3mL)的溶液中加入锌粉(2.32g,35.46mmol,5eq)和氯化铵(1.90g,35.46mmol,5eq)，反应液在60℃下搅拌0.5小时。反应液过滤后浓缩，残留物通过柱层析分离(石油醚：乙酸乙酯＝10：1-5：1)得到化合物10-b。Step B: To a solution of 10-a (2.3g, 7.09mmol, 1eq) in tetrahydrofuran (30mL) and water (3mL) was added zinc powder (2.32g, 35.46mmol, 5eq) and ammonium chloride (1.90g, 35.46g) mmol, 5eq), the reaction solution was stirred at 60 °C for 0.5 hours. The reaction solution was filtered and concentrated, and the residue was separated by column chromatography (petroleum ether:ethyl acetate=10:1-5:1) to obtain compound 10-b.
步骤C：氮气保护下，向10-b(1.9g,6.46mmol,1eq)的四氢呋喃(30mL)溶液中加入CDI(2.09g,12.91mmol,2eq)。反应液在70℃下搅拌12小时后反应液浓缩，残留物加入水(50mL)。用乙酸乙酯(100mL)萃取，无水硫酸钠干燥，过滤后残留物用甲醇(10mL)洗涤，干燥得到化合物10-c。Step C: To a solution of 10-b (1.9 g, 6.46 mmol, 1 eq) in tetrahydrofuran (30 mL) was added CDI (2.09 g, 12.91 mmol, 2 eq) under nitrogen protection. The reaction solution was stirred at 70°C for 12 hours, the reaction solution was concentrated, and water (50 mL) was added to the residue. It was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, and the residue was washed with methanol (10 mL) after filtration, and dried to obtain compound 10-c.
步骤D：氮气保护下，向10-c(900mg,2.81mmol,1eq)的DMF(2mL)溶液中加入1-f(1.80g,7.02mmol,2.5eq)和碳酸钾(1.17g,8.43mmol,3eq)，反应液在120℃下搅拌12小时，向反应液中加入水(30mL)稀释，过滤，滤饼用石油醚和乙酸乙酯的混合溶剂(PE:EtOAc＝5:1，10mL)洗涤，干燥得到化合物10-d。Step D: Under nitrogen protection, to a solution of 10-c (900mg, 2.81mmol, 1eq) in DMF (2mL) was added 1-f (1.80g, 7.02mmol, 2.5eq) and potassium carbonate (1.17g, 8.43mmol, 3eq), the reaction solution was stirred at 120 °C for 12 hours, water (30 mL) was added to the reaction solution to dilute, filtered, and the filter cake was washed with a mixed solvent of petroleum ether and ethyl acetate (PE:EtOAc=5:1, 10 mL) , and dried to obtain compound 10-d.
步骤E：氮气保护下，向10-d(1.0g,2.01mmol,1eq)的DMF(10mL)溶液中加入碳酸钾(556.78mg, 4.03mmol,2eq)和对甲氧基苄氯(441.63mg,2.82mmol,384.02μL,1.4eq)，反应液于50℃搅拌1小时，反应液加入水(10mL)，过滤，滤饼通过柱层析分离(石油醚：乙酸乙酯＝3：1-0：1)得到化合物10-e。Step E: Under nitrogen protection, to a solution of 10-d (1.0 g, 2.01 mmol, 1 eq) in DMF (10 mL) was added potassium carbonate (556.78 mg, 4.03 mmol, 2 eq) and p-methoxybenzyl chloride (441.63 mg, 2.82mmol, 384.02μL, 1.4eq), the reaction solution was stirred at 50°C for 1 hour, water (10mL) was added to the reaction solution, filtered, and the filter cake was separated by column chromatography (petroleum ether:ethyl acetate=3:1-0: 1) Compound 10-e is obtained.
步骤F：将10-e(700mg,1.14mmol,1eq)加入到TFA(6.16g,54.03mmol,4.00mL,47.59eq)和三乙基硅烷(1.46g,12.52mmol,2.00mL,11.03eq)的混合溶液中，反应液在100℃下搅拌12小时，将反应液浓缩，残留物用饱和NaHCO
3水溶液(20mL)稀释后，用乙酸乙酯(40mL)萃取，有机相通过无水硫酸钠干燥后浓缩，残留物通过柱层析分离(石油醚/乙酸乙酯＝3/1-1/2)得到化合物10-f。
Step F: 10-e (700mg, 1.14mmol, 1eq) was added to a mixture of TFA (6.16g, 54.03mmol, 4.00mL, 47.59eq) and triethylsilane (1.46g, 12.52mmol, 2.00mL, 11.03eq) In the mixed solution, the reaction solution was stirred at 100 °C for 12 hours, the reaction solution was concentrated, the residue was diluted with saturated aqueous NaHCO 3 (20 mL), extracted with ethyl acetate (40 mL), and the organic phase was dried over anhydrous sodium sulfate. After concentration, the residue was separated by column chromatography (petroleum ether/ethyl acetate=3/1-1/2) to obtain compound 10-f.
步骤G：氮气保护下，向10-f(400.00mg,857.56μmol,1eq)的DMF(2mL)溶液中加入9-1(939.78mg,3.43mmol,4eq)和碳酸钾(177.79mg,1.29mmol,1.5eq)。反应液在90℃搅拌0.5小时。反应液加入水(10mL)，然后用乙酸乙酯(20mL)萃取，有机相经硫酸钠干燥后浓缩得到化合物10-g。Step G: Under nitrogen protection, to a solution of 10-f (400.00 mg, 857.56 μmol, 1 eq) in DMF (2 mL) was added 9-1 (939.78 mg, 3.43 mmol, 4 eq) and potassium carbonate (177.79 mg, 1.29 mmol, 1.5eq). The reaction solution was stirred at 90°C for 0.5 hour. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL). The organic phase was dried over sodium sulfate and concentrated to obtain compound 10-g.
步骤H：氮气保护下，向10-g(400mg,653.06μmol,1eq)的TFA(2mL)溶液中加入三氟甲烷磺酸(3.40g,22.65mmol,2mL,34.69eq)。反应液在100℃下搅拌2小时。将反应液倒入到氢氧化钠(30mL,1mol/L)的水溶液中中和，用乙酸乙酯(50mL)萃取，有机相浓缩后通过制备HPLC纯化[水(0.225％TFA)-ACN]得到化合物10。
1H NMR(400MHz,DMSO-d
6):δppm 11.14(br s,1H),7.53(dd,J＝3.1,8.9Hz,1H),7.22-7.05(m,1H),6.97-6.77(m,2H),4.29(t,J＝6.9Hz,2H),2.90-2.63(m,2H),1.36(s,6H)；LCMS(ESI)m/z:493.3(M+1)。
Step H: To a solution of 10-g (400 mg, 653.06 μmol, 1 eq) in TFA (2 mL) was added trifluoromethanesulfonic acid (3.40 g, 22.65 mmol, 2 mL, 34.69 eq) under nitrogen. The reaction solution was stirred at 100°C for 2 hours. The reaction solution was poured into an aqueous solution of sodium hydroxide (30 mL, 1 mol/L) for neutralization, extracted with ethyl acetate (50 mL), and the organic phase was concentrated and purified by preparative HPLC [water (0.225% TFA)-ACN] to obtain Compound 10. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.14 (br s, 1H), 7.53 (dd, J=3.1, 8.9 Hz, 1H), 7.22-7.05 (m, 1H), 6.97-6.77 (m, 2H), 4.29 (t, J=6.9 Hz, 2H), 2.90-2.63 (m, 2H), 1.36 (s, 6H); LCMS (ESI) m/z: 493.3 (M+1).
实施例11Example 11
步骤A：氮气保护下，向11-1(2.0g,11.29mmol,1.32mL,1eq)的四氢呋喃(10.00mL)溶液中加入2,4-二甲氧基苄胺(1.89g,11.29mmol,1.70mL,1eq)和二异丙基乙胺(4.38g,33.88mmol,5.90mL,3eq)。反应液在20℃下搅拌12小时，反应液浓缩后残留物通过柱层析分离纯化(PE:EtOAc＝30:1-5:1)，得到化合物11-a。Step A: Under nitrogen protection, to a solution of 11-1 (2.0 g, 11.29 mmol, 1.32 mL, 1 eq) in tetrahydrofuran (10.00 mL) was added 2,4-dimethoxybenzylamine (1.89 g, 11.29 mmol, 1.70 g) mL, 1 eq) and diisopropylethylamine (4.38 g, 33.88 mmol, 5.90 mL, 3 eq). The reaction solution was stirred at 20° C. for 12 hours. After the reaction solution was concentrated, the residue was separated and purified by column chromatography (PE:EtOAc=30:1-5:1) to obtain compound 11-a.
步骤B：向11-a(3.0g,9.25mmol,1eq)的H
2O(2.00mL)和THF(20.00mL)混合溶液中加入铁粉(5.17g,92.51mmol,10eq)和氯化铵(4.95g,92.51mmol,10eq)。反应液在80℃搅拌1小时，反应液过滤后滤液浓缩，得到的残留物通过石油醚和乙酸乙酯的混合溶剂(PE:EtOAc＝1:1，30mL)室温打浆得到化合物11-b。
Step B: Add iron powder (5.17g, 92.51mmol , 10eq) and ammonium chloride ( 4.95g, 92.51mmol, 10eq). The reaction solution was stirred at 80° C. for 1 hour. The reaction solution was filtered, and the filtrate was concentrated. The obtained residue was slurried at room temperature with a mixed solvent of petroleum ether and ethyl acetate (PE:EtOAc=1:1, 30 mL) to obtain compound 11-b.
步骤C：在11-b(2.0g,6.80mmol,1eq)的THF(20.00mL)溶液中加入CDI(1.65g,10.19mmol,1.5eq)。反应液在70℃搅拌12小时。反应冷却到室温后，加入乙酸乙酯(100mL)稀释，然后用水(100mL×2)洗涤，有机相经过无水硫酸钠干燥后减压浓缩，残留物通过甲醇(20mL)洗涤得到化合物11-c。Step C: To a solution of 11-b (2.0 g, 6.80 mmol, 1 eq) in THF (20.00 mL) was added CDI (1.65 g, 10.19 mmol, 1.5 eq). The reaction solution was stirred at 70°C for 12 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL×2), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was washed with methanol (20 mL) to obtain compound 11-c .
步骤D：氮气保护下，向11-c(1.0g,3.12mmol,1eq)的DMF(4mL)溶液中加入9-1(3.42g,12.49mmol,4eq)和碳酸钾(1.29g,9.37mmol,3eq)。反应液在90℃搅拌1小时。反应液加入水(30mL)，然后用乙酸乙酯(100mL)萃取，硫酸钠干燥后浓缩，残留物通过柱层析(PE:EtOAc＝30:1-3:1)纯化得到化合物11-d。Step D: Under nitrogen protection, to a solution of 11-c (1.0g, 3.12mmol, 1eq) in DMF (4mL) was added 9-1 (3.42g, 12.49mmol, 4eq) and potassium carbonate (1.29g, 9.37mmol, 3eq). The reaction solution was stirred at 90°C for 1 hour. The reaction solution was added with water (30 mL), then extracted with ethyl acetate (100 mL), dried over sodium sulfate and concentrated, and the residue was purified by column chromatography (PE:EtOAc=30:1-3:1) to obtain compound 11-d.
步骤E：氮气保护下，向11-d(300mg,643.30μmol,1eq)的TFA(4mL)溶液中加入三氟甲烷磺酸(850.00mg,5.66mmol,0.5mL,8.80eq)。反应液在80℃下搅拌1小时。反应液冷却到室温，将反应液倒入到饱和碳酸氢钠(50mL)的水溶液中，用乙酸乙酯(100mL)萃取，有机相浓缩后，残留物通过石油醚(20mL)室温打浆得到化合物11-e。Step E: To a solution of 11-d (300 mg, 643.30 μmol, 1 eq) in TFA (4 mL) was added trifluoromethanesulfonic acid (850.00 mg, 5.66 mmol, 0.5 mL, 8.80 eq) under nitrogen protection. The reaction solution was stirred at 80°C for 1 hour. The reaction solution was cooled to room temperature, poured into an aqueous solution of saturated sodium bicarbonate (50 mL), extracted with ethyl acetate (100 mL), the organic phase was concentrated, and the residue was slurried with petroleum ether (20 mL) at room temperature to obtain compound 11 -e.
步骤F：在11-e(150mg,474.42μmol,1eq)的DMF(2.00mL)溶液中加入1-f(243.17mg,948.84μmol,2eq)和碳酸钾(196.70mg,1.42mmol,3eq)，反应液在120℃下搅拌12小时，反应冷却到室温后，加入水(20mL)稀释，然后用乙酸乙酯(25mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩，残留物通过制备HPLC[水(0.025％FA)-ACN]纯化得到化合物11。
1H NMR(400MHz,DMSO-d
6):δppm 11.13(br s,1H),7.52(dd,J＝2.1,9.2Hz,1H),7.17(ddd,J＝2.4,10.0,11.9Hz,1H),7.00(br s,2H),4.26(t,J＝6.8Hz,2H),2.81-2.59(m,2H),1.36(s,6H).LCMS(ESI)m/z:493.3(M+1)。
Step F: Add 1-f (243.17mg, 948.84μmol, 2eq) and potassium carbonate (196.70mg, 1.42mmol, 3eq) to a solution of 11-e (150mg, 474.42μmol, 1eq) in DMF (2.00mL), and react The solution was stirred at 120 °C for 12 hours. After the reaction was cooled to room temperature, water (20 mL) was added to dilute it, and then it was extracted with ethyl acetate (25 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue passed through Purification by preparative HPLC [water (0.025% FA)-ACN] afforded compound 11. 1 H NMR (400MHz, DMSO-d 6 ): δppm 11.13 (br s, 1H), 7.52 (dd, J=2.1, 9.2Hz, 1H), 7.17 (ddd, J=2.4, 10.0, 11.9Hz, 1H) ,7.00(br s,2H),4.26(t,J=6.8Hz,2H),2.81-2.59(m,2H),1.36(s,6H).LCMS(ESI)m/z:493.3(M+1 ).
实施例12Example 12
步骤A：向12-1(7g,39.78mmol,1eq)和碳酸铯(38.88g,119.33mmol,3eq)的1,4-二氧六环(150mL)溶液中加入吡啶甲酸(3.92g,31.82mmol,0.8eq)，碘化亚铜(3.03g,15.91mmol,0.4eq)和丙二酸二乙酯(25.48g,159.10mmol,24.04mL,4eq)，反应液在100℃下搅拌18小时。将反应液冷却至室温后过滤，向滤液中加入100mL水，EtOAc(100mL×3)萃取，合并的有机相用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤浓缩得到残留物，残留物用柱层析纯化(PE:EA＝100:1-10:1)得到化合物12-a。LCMS(ESI)m/z:256.1(M+1)。Step A: To a solution of 12-1 (7g, 39.78mmol, 1eq) and cesium carbonate (38.88g, 119.33mmol, 3eq) in 1,4-dioxane (150mL) was added picolinic acid (3.92g, 31.82mmol) , 0.8eq), cuprous iodide (3.03g, 15.91mmol, 0.4eq) and diethyl malonate (25.48g, 159.10mmol, 24.04mL, 4eq), the reaction solution was stirred at 100 ° C for 18 hours. The reaction solution was cooled to room temperature and filtered, 100 mL of water was added to the filtrate, extracted with EtOAc (100 mL×3), the combined organic phases were washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue , the residue was purified by column chromatography (PE:EA=100:1-10:1) to obtain compound 12-a. LCMS (ESI) m/z: 256.1 (M+1).
步骤B：向化合物12-a(12g,35.97mmol,1eq)的DMSO(120mL)溶液中加入水(647.94mg,35.97mmol,647.94μL,1eq)和氯化锂(6.10g,143.86mmol,4eq)，反应液在120℃下搅拌12小时。向反应液中加入100mL水，用EtOAc 600mL(200mL×3)萃取，合并的有机相用饱和食盐水400mL(200mL×2)洗涤，无水硫酸钠干燥，过滤浓缩得到残留物，残留物用柱层析纯化(PE:EA＝50:1-5:1)得到化合物12-b。LCMS(ESI)m/z:184.1(M+1)。Step B: To a solution of compound 12-a (12g, 35.97mmol, 1eq) in DMSO (120mL) was added water (647.94mg, 35.97mmol, 647.94μL, 1eq) and lithium chloride (6.10g, 143.86mmol, 4eq) , the reaction solution was stirred at 120 °C for 12 hours. 100 mL of water was added to the reaction solution, extracted with EtOAc 600 mL (200 mL×3), the combined organic phases were washed with saturated brine 400 mL (200 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, the residue was washed with a column Chromatographic purification (PE:EA=50:1-5:1) gave compound 12-b. LCMS (ESI) m/z: 184.1 (M+1).
步骤C：向圆底烧瓶中加入THF(15mL)和LiHMDS(1M,15.54mL,0.8eq),在-40℃下加入化合物12-b(3.73g,19.43mmol,1eq)的THF(10mL)溶液并搅拌1小时，然后滴加入碘甲烷(2.21g,15.54mmol,967.47μL,0.8eq)的THF(10mL)溶液，反应液在-40℃下搅拌1小时，升温至20℃下搅拌1小时。向反应液中加入30mL水，用EtOAc 90mL(30mL×3)萃取，合并的有机相用饱和食盐水40mL(20mL×2)洗涤，无水硫酸钠干燥，过滤浓缩得到残留物，残留物用柱层析纯化(PE:EA＝50:1-10:1)得到化合物12-c。Step C: THF (15 mL) and LiHMDS (1 M, 15.54 mL, 0.8 eq) were added to a round-bottomed flask, and a solution of compound 12-b (3.73 g, 19.43 mmol, 1 eq) in THF (10 mL) was added at -40°C And stirred for 1 hour, and then dropwise added methyl iodide (2.21 g, 15.54 mmol, 967.47 μL, 0.8 eq) in THF (10 mL) solution, the reaction solution was stirred at -40 ° C for 1 hour, and heated to 20 ° C and stirred for 1 hour. 30 mL of water was added to the reaction solution, extracted with 90 mL of EtOAc (30 mL×3), the combined organic phases were washed with saturated brine 40 mL (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, the residue was washed with a column Chromatographic purification (PE:EA=50:1-10:1) gave compound 12-c.
步骤D：在-78℃，氮气保护下，向化合物12-c(2g,10.14mmol,1eq)的THF(15mL)溶液中滴加LiHMDS(1M,10.14mL,1eq)并搅拌30分钟，然后加入NBS(2.17g,12.17mmol,1.2eq)的THF(5mL)溶液，升温至20℃搅拌1小时。向反应液中加入20mL水，用EtOAc(20mL×3)萃取，合并的有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤浓缩得到残留物，残留物用柱层析纯化(PE:EA＝50:1-10:1)得到化合物12-d。LCMS(ESI)m/z:278.1(M+1)。Step D: LiHMDS (1 M, 10.14 mL, 1 eq) was added dropwise to a solution of compound 12-c (2 g, 10.14 mmol, 1 eq) in THF (15 mL) at -78°C under nitrogen protection and stirred for 30 minutes, then added A solution of NBS (2.17 g, 12.17 mmol, 1.2 eq) in THF (5 mL) was warmed to 20°C and stirred for 1 hour. 20 mL of water was added to the reaction solution, extracted with EtOAc (20 mL×3), the combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was subjected to column chromatography Purification (PE:EA=50:1-10:1) gave compound 12-d. LCMS (ESI) m/z: 278.1 (M+1).
步骤E：在0℃下，向圆底烧瓶中加入DMF(10mL)，氢化钠(589.00mg,14.73mmol,60％纯度,1.9eq)和丙二腈(1.02g,15.50mmol,975.29μL,2eq)，搅拌15分钟后滴加化合物12-d(2.14g,7.75mmol,1eq)的DMF(15mL)溶液，反应液在20℃下搅拌1小时。向反应液中加入20mL水，用EtOAc(30mL×3)萃取，合并的有机相用饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤浓缩得到残留物，残留物用柱层析纯化(PE:EA＝10:1-5:1)得到化合物12-e。Step E: To a round bottom flask at 0°C was added DMF (10 mL), sodium hydride (589.00 mg, 14.73 mmol, 60% pure, 1.9 eq) and malononitrile (1.02 g, 15.50 mmol, 975.29 μL, 2 eq) ), and after stirring for 15 minutes, a solution of compound 12-d (2.14 g, 7.75 mmol, 1 eq) in DMF (15 mL) was added dropwise, and the reaction solution was stirred at 20° C. for 1 hour. 20 mL of water was added to the reaction solution, extracted with EtOAc (30 mL×3), the combined organic phases were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, which was subjected to column chromatography Purification (PE:EA=10:1-5:1) gave compound 12-e.
步骤F：氮气保护下，向化合物12-e(2.2g,8.42mmol,1eq)的1,4-二氧六环(20mL)溶液中加入S-甲基硫脲(1.76g,12.63mmol,1.5eq,0.5H
2SO
4)和碳酸氢钾(1.69g,16.84mmol,2eq)，反应液在100℃下搅拌12小时。向反应液中加入20mL水，用EtOAc(20mL×3)萃取，合并的有机相用无水硫酸钠干燥，过滤浓缩得到残留物，残留物用柱层析纯化(PE:EA＝10:1-1:1)得到化合物12-f。
Step F: Under nitrogen protection, to a solution of compound 12-e (2.2g, 8.42mmol, 1eq) in 1,4-dioxane (20mL) was added S-methylthiourea (1.76g, 12.63mmol, 1.5 eq, 0.5H 2 SO 4 ) and potassium bicarbonate (1.69g, 16.84mmol, 2eq), the reaction solution was stirred at 100°C for 12 hours. 20 mL of water was added to the reaction solution, extracted with EtOAc (20 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain a residue, and the residue was purified by column chromatography (PE:EA=10:1- 1:1) to obtain compound 12-f.
步骤G：氮气保护下，向化合物12-f(1.2g,3.93mmol,1eq)的二氯甲烷(15mL)溶液中加入间氯过氧苯甲酸(1.36g,7.86mmol,2eq)，反应液在20℃下搅拌2小时。将反应液浓缩，残留物用柱层析分离(PE:EA＝10:1-1:1)得到化合物12-g。Step G: Under nitrogen protection, to a solution of compound 12-f (1.2g, 3.93mmol, 1eq) in dichloromethane (15mL) was added m-chloroperoxybenzoic acid (1.36g, 7.86mmol, 2eq), the reaction solution was at Stir at 20°C for 2 hours. The reaction solution was concentrated, and the residue was separated by column chromatography (PE:EA=10:1-1:1) to obtain compound 12-g.
步骤H：氮气保护下，向化合物9-c(0.4g,1.32mmol,1eq)的DMF(4mL)溶液中加入12-g(892.70 mg,2.65mmol,2eq)和碳酸钾(548.62mg,3.97mmol,3eq)，反应液在120℃搅拌18小时。向反应液中加入20mL水，过滤后，滤饼干燥得到化合物12-h。Step H: To a solution of compound 9-c (0.4g, 1.32mmol, 1eq) in DMF (4mL) under nitrogen protection was added 12-g (892.70mg, 2.65mmol, 2eq) and potassium carbonate (548.62mg, 3.97mmol) , 3eq), the reaction solution was stirred at 120 ° C for 18 hours. 20 mL of water was added to the reaction solution, and after filtration, the filter cake was dried to obtain compound 12-h.
步骤I：氮气保护下，向化合物12-h(0.8g,1.43mmol,1eq)的DMF(8mL)溶液中加入碳酸钾(395.21mg,2.86mmol,2eq)和对甲氧基苄氯(335.88mg,2.14mmol,292.07μL,1.5eq)，反应液在50℃下搅拌12小时。向反应液中加入10mL水，然后用EtOAc(10mL×3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物用柱层析分离(PE:EtOAc＝10:1-3:1)得到化合物12-i。Step I: Under nitrogen protection, to a solution of compound 12-h (0.8g, 1.43mmol, 1eq) in DMF (8mL) was added potassium carbonate (395.21mg, 2.86mmol, 2eq) and p-methoxybenzyl chloride (335.88mg) , 2.14mmol, 292.07μL, 1.5eq), the reaction solution was stirred at 50°C for 12 hours. 10 mL of water was added to the reaction solution, followed by extraction with EtOAc (10 mL×3), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE : EtOAc=10:1-3:1) to obtain compound 12-i.
步骤J：向化合物12-i(458mg,622.33μmol,1eq)的TFA(7.70g,67.53mmol,5mL,108.51eq)溶液中加入三乙基硅烷(336.48mg,2.89mmol,462.20μL,4.65eq)，反应液在120℃下搅拌18小时后浓缩，残留物通过柱层析(PE:EtOAc＝5:1-1:1)纯化得到化合物12-j。Step J: To a solution of compound 12-i (458 mg, 622.33 μmol, 1 eq) in TFA (7.70 g, 67.53 mmol, 5 mL, 108.51 eq) was added triethylsilane (336.48 mg, 2.89 mmol, 462.20 μL, 4.65 eq) , the reaction solution was stirred at 120° C. for 18 hours and then concentrated, and the residue was purified by column chromatography (PE:EtOAc=5:1-1:1) to obtain compound 12-j.
步骤K：向化合物12-j(0.33g,569.80μmol,1eq)的DMF(3mL)溶液中加入碳酸钾(315.00mg,2.28mmol,4eq)和9-1(624.44mg,2.28mmol,4eq)，反应液在100℃下搅拌12小时后加入9-1(312.22mg,1.14mmol,2eq)和碳酸钾(157.50mg,1.14mmol,2eq)继续搅拌5小时，向反应液加入水(3mL)，过滤，滤饼通过柱层析分离(PE:EtOAc＝5:1-3:1)得到化合物12-k。Step K: To a solution of compound 12-j (0.33g, 569.80μmol, 1eq) in DMF (3mL) was added potassium carbonate (315.00mg, 2.28mmol, 4eq) and 9-1 (624.44mg, 2.28mmol, 4eq), The reaction solution was stirred at 100 °C for 12 hours, and then 9-1 (312.22 mg, 1.14 mmol, 2 eq) and potassium carbonate (157.50 mg, 1.14 mmol, 2 eq) were added, and the stirring was continued for 5 hours. Water (3 mL) was added to the reaction solution and filtered. , the filter cake was separated by column chromatography (PE:EtOAc=5:1-3:1) to obtain compound 12-k.
步骤L：氮气保护下，向化合物12-k(0.22g,288.22μmol,1eq)的TFA(1.54g,13.51mmol,1mL,46.86eq)溶液中加入三氟甲烷磺酸(1.70g,11.33mmol,1mL,39.30eq)，反应液在60℃下搅拌6小时后浓缩，残留物溶于EtOAc中，用碳酸氢钠水溶液调节pH至7-8，然后用EtOAc(5mL×2)萃取水相，合并的有机相用无水硫酸钠干燥，过滤后浓缩，残留物通过制备HPLC纯化[水(0.225％FA)-ACN]得到化合物12，然后化合物12用SFC分离(色谱柱：DAICEL CHIRALPAK IC(250mm×30mm,10μm)；流动相：A：CO
2，B：[0.1％氨水的异丙醇溶液]；B％：50％-50％；流速：70mL/min)得到化合物12A和12B。
Step L: under nitrogen protection, to a solution of compound 12-k (0.22g, 288.22μmol, 1eq) in TFA (1.54g, 13.51mmol, 1mL, 46.86eq) was added trifluoromethanesulfonic acid (1.70g, 11.33mmol, 1 mL, 39.30 eq), the reaction solution was stirred at 60 °C for 6 hours and then concentrated, the residue was dissolved in EtOAc, the pH was adjusted to 7-8 with aqueous sodium bicarbonate solution, and then the aqueous phase was extracted with EtOAc (5 mL×2), and the combined The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [water (0.225% FA)-ACN] to give compound 12, which was then separated by SFC (chromatographic column: DAICEL CHIRALPAK IC (250mm× 30 mm, 10 μm); mobile phase: A: CO 2 , B: [0.1% ammonia in isopropanol]; B%: 50%-50%; flow rate: 70 mL/min) to obtain compounds 12A and 12B.
化合物12A(SFC保留时间：1.439分钟)：
1H NMR(400MHz,DMSO-d
6):δppm 11.39(br s,1H),8.55(d,J＝2.9Hz,1H),7.78(dt,J＝3.0,8.8Hz,1H),7.68-7.47(m,2H),7.15-6.98(m,2H),6.78(br s,2H),4.30(br t,J＝6.9Hz,2H),2.86-2.60(m,2H),1.82(s,3H)；LCMS(ESI)m/z:556.1(M+1)。
Compound 12A (SFC retention time: 1.439 min): 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.39 (br s, 1H), 8.55 (d, J=2.9 Hz, 1H), 7.78 (dt, J= 3.0,8.8Hz,1H),7.68-7.47(m,2H),7.15-6.98(m,2H),6.78(br s,2H),4.30(br t,J＝6.9Hz,2H),2.86-2.60 (m, 2H), 1.82 (s, 3H); LCMS (ESI) m/z: 556.1 (M+1).
化合物12B(SFC保留时间:1.903分钟)：
1H NMR(400MHz,DMSO-d
6):δppm 11.39(br s,1H),8.55(d,J＝3.1Hz,1H),7.78(dt,J＝3.1,8.7Hz,1H),7.70-7.49(m,2H),7.15-7.01(m,2H),6.78(br s,2H),4.30(t,J＝6.8Hz,2H),2.83-2.62(m,2H),1.82(s,3H)；LCMS(ESI)m/z:556.1(M+1)。
Compound 12B (SFC retention time: 1.903 min): 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.39 (br s, 1H), 8.55 (d, J=3.1 Hz, 1H), 7.78 (dt, J= 3.1,8.7Hz,1H),7.70-7.49(m,2H),7.15-7.01(m,2H),6.78(br s,2H),4.30(t,J=6.8Hz,2H),2.83-2.62( m, 2H), 1.82 (s, 3H); LCMS (ESI) m/z: 556.1 (M+1).
实施例13Example 13
向11-e(200mg,632.56μmol,1eq)的DMF(2mL)溶液中加入12-g(320.07mg,948.84μmol,1.5eq)和碳酸钾(262.28mg,1.90mmol,3eq)，反应液在120℃下搅拌12小时，向反应液中加入水(20mL)稀释，用乙酸乙酯(50mL)萃取，有机相浓缩后通过制备HPLC纯化[水(0.05％氨水)-乙腈]得到化合物13，化合物13通过SFC(色谱柱：DAICEL CHIRALPAK IC(250mm×30mm,10μm)；流动相：A：CO
2，B：[0.1％氨水的甲醇溶液]；B％：30％-30％；流速：60mL/min)分离得到化合物13A和13B。
To 11-e (200mg, 632.56μmol, 1eq) in DMF (2mL) solution was added 12-g (320.07mg, 948.84μmol, 1.5eq) and potassium carbonate (262.28mg, 1.90mmol, 3eq), the reaction solution was at 120 Stir at ℃ for 12 hours, add water (20 mL) to the reaction solution to dilute, extract with ethyl acetate (50 mL), concentrate the organic phase and purify by preparative HPLC [water (0.05% ammonia water)-acetonitrile] to obtain compound 13, compound 13 Passed through SFC (column: DAICEL CHIRALPAK IC (250mm×30mm, 10μm); mobile phase: A: CO 2 , B: [0.1% ammonia in methanol]; B%: 30%-30%; flow rate: 60 mL/min ) isolated to give compounds 13A and 13B.
化合物13A(SFC保留时间：1.326min)：
1H NMR(400MHz,DMSO-d
6)δppm 11.37(br s,1H),8.55(d,J＝2.9Hz,1H),7.78(dt,J＝3.0,8.8Hz,1H),7.65-7.46(m,2H),7.18(ddd,J＝2.4,9.9,11.9Hz,1H),6.81(br s,2H),4.27(t,J＝6.8Hz,2H),2.86-2.65(m,2H),1.82(s,3H)；LCMS(ESI)m/z:574.4(M+1)。
Compound 13A (SFC retention time: 1.326 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.37 (br s, 1H), 8.55 (d, J=2.9 Hz, 1H), 7.78 (dt, J=3.0 ,8.8Hz,1H),7.65-7.46(m,2H),7.18(ddd,J=2.4,9.9,11.9Hz,1H),6.81(br s,2H),4.27(t,J=6.8Hz,2H ), 2.86-2.65 (m, 2H), 1.82 (s, 3H); LCMS (ESI) m/z: 574.4 (M+1).
化合物13B(SFC保留时间：1.651min)：
1H NMR(400MHz,DMSO-d
6)δppm 11.39(s,1H),8.55(d,J＝3.1Hz,1H),7.78(d,J＝2.9Hz,1H),7.67-7.53(m,2H),7.18(ddd,J＝2.3,9.9,12.0Hz,1H),6.81(br s,2H),4.27(t,J＝6.8Hz,2H),2.86-2.59(m,2H),1.82(s,3H)；LCMS(ESI)m/z:574.4(M+1)。
Compound 13B (SFC retention time: 1.651 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.39 (s, 1H), 8.55 (d, J=3.1 Hz, 1H), 7.78 (d, J=2.9 Hz) ,1H),7.67-7.53(m,2H),7.18(ddd,J＝2.3,9.9,12.0Hz,1H),6.81(br s,2H),4.27(t,J＝6.8Hz,2H),2.86 -2.59 (m, 2H), 1.82 (s, 3H); LCMS (ESI) m/z: 574.4 (M+1).
实施例14Example 14
步骤A：氮气保护下，向10-c(500mg,1.56mmol,1eq)的DMF(3mL)溶液中加入12-g(789.90mg,2.34mmol,1.5eq)和碳酸钾(1.08g,7.81mmol,5eq)，反应液在120℃下搅拌12小时，向反应液中加入水(20mL)稀释，过滤，滤饼干燥得到化合物14-a。Step A: Under nitrogen protection, to a solution of 10-c (500mg, 1.56mmol, 1eq) in DMF (3mL) was added 12-g (789.90mg, 2.34mmol, 1.5eq) and potassium carbonate (1.08g, 7.81mmol, 5eq), the reaction solution was stirred at 120° C. for 12 hours, water (20 mL) was added to the reaction solution to dilute, filtered, and the filter cake was dried to obtain compound 14-a.
步骤B：氮气保护下，向14-a(500mg,865.78μmol,1eq)的DMF(5mL)溶液中加入碳酸钾(239.31mg,1.73mmol,2eq)和对甲氧基苄氯(203.38mg,1.30mmol,176.86μL,1.5eq)，反应液在70℃搅拌1小时后加入水(20mL)，过滤，残留物通过柱层析分离(石油醚：乙酸乙酯＝10：1-1：1)得到化合物14-b。Step B: To a solution of 14-a (500 mg, 865.78 μmol, 1 eq) in DMF (5 mL) under nitrogen protection was added potassium carbonate (239.31 mg, 1.73 mmol, 2 eq) and p-methoxybenzyl chloride (203.38 mg, 1.30 mmol, 176.86μL, 1.5eq), the reaction solution was stirred at 70°C for 1 hour, water (20mL) was added, filtered, and the residue was separated by column chromatography (petroleum ether:ethyl acetate=10:1-1:1) to obtain Compound 14-b.
步骤C：向14-b(350mg,501.68μmol,1eq)的TFA(9.24g,81.04mmol,6mL,161.54eq)溶液中加入三乙基硅烷(1.46g,12.52mmol,2mL,24.96eq)，反应液在100℃下搅拌12小时，将反应液浓缩，残留物用饱和NaHCO
3水溶液(10mL)稀释后，用乙酸乙酯(20mL)萃取，有机相通过无水硫酸钠干燥，过滤后浓缩得到化合物14-c。
Step C: Triethylsilane (1.46g, 12.52mmol, 2mL, 24.96eq) was added to a solution of 14-b (350mg, 501.68μmol, 1eq) in TFA (9.24g, 81.04mmol, 6mL, 161.54eq), and the reaction was carried out The solution was stirred at 100 °C for 12 hours, the reaction solution was concentrated, the residue was diluted with saturated aqueous NaHCO 3 (10 mL), extracted with ethyl acetate (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain the compound 14-c.
步骤D：氮气保护下，向14-c(200mg,365.31μmol,1eq)的DMF(2mL)溶液中加入9-1(400.33mg,1.46mmol,4eq)和碳酸钾(151.46mg,1.10mmol,3eq)。反应液在90℃搅拌0.5小时。向反应液中加入水 (10mL)，然后用乙酸乙酯(20mL)萃取，硫酸钠干燥后浓缩得到化合物14-d。Step D: Under nitrogen protection, to a solution of 14-c (200mg, 365.31μmol, 1eq) in DMF (2mL) was added 9-1 (400.33mg, 1.46mmol, 4eq) and potassium carbonate (151.46mg, 1.10mmol, 3eq) ). The reaction solution was stirred at 90°C for 0.5 hour. Water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (20 mL), drying over sodium sulfate, and concentration to obtain compound 14-d.
步骤E：氮气保护下，向14-d(250mg,360.47μmol,1eq)的TFA(1mL)溶液中加入三氟甲烷磺酸(0.5mL)。反应液在100℃下搅拌2小时。反应液冷却到20℃后倒入到氢氧化钠(20mL,2mol/L)的水溶液中，用乙酸乙酯(50mL)萃取，有机相浓缩后通过制备HPLC纯化[水(0.225％TFA)-ACN]得到化合物14，化合物14再通过SFC(色谱柱：DAICEL CHIRALPAK IC(250mm×30mm,10μm)；流动相：A：CO
2，B：[0.1％氨水的甲醇溶液]；B％：30％-30％；流速：60mL/min)分离得到化合物14A和14B。
Step E: To a solution of 14-d (250 mg, 360.47 μmol, 1 eq) in TFA (1 mL) was added trifluoromethanesulfonic acid (0.5 mL) under nitrogen protection. The reaction solution was stirred at 100°C for 2 hours. The reaction solution was cooled to 20 °C, poured into an aqueous solution of sodium hydroxide (20 mL, 2 mol/L), extracted with ethyl acetate (50 mL), and the organic phase was concentrated and purified by preparative HPLC [water (0.225% TFA)-ACN] ] Compound 14 was obtained, which was then passed through SFC (chromatographic column: DAICEL CHIRALPAK IC (250mm×30mm, 10μm); mobile phase: A: CO 2 , B: [0.1% ammonia in methanol]; B%: 30%- 30%; flow rate: 60 mL/min) isolated compounds 14A and 14B.
化合物14A(SFC保留时间：1.259min)：
1H NMR(400MHz,DMSO-d
6)δppm 11.38(br s,1H),8.54(d,J＝3.0Hz,1H),7.78(dt,J＝3.1,8.8Hz,1H),7.70-7.49(m,2H),7.15(td,J＝8.5,11.3Hz,1H),6.78(br s,2H),4.30(t,J＝6.9Hz,2H),2.87-2.68(m,2H),1.82(s,3H)；LCMS(ESI)m/z:474.4(M+1)。
Compound 14A (SFC retention time: 1.259 min): 1 H NMR (400 MHz, DMSO-d 6 ) δppm 11.38 (br s, 1H), 8.54 (d, J=3.0 Hz, 1H), 7.78 (dt, J=3.1 ,8.8Hz,1H),7.70-7.49(m,2H),7.15(td,J=8.5,11.3Hz,1H),6.78(br s,2H),4.30(t,J=6.9Hz,2H), 2.87-2.68 (m, 2H), 1.82 (s, 3H); LCMS (ESI) m/z: 474.4 (M+1).
化合物14B(SFC保留时间：1.559min)：
1H NMR(400MHz,DMSO-d
6)δppm 11.39(br s,1H),8.54(d,J＝3.0Hz,1H),7.78(dt,J＝3.0,8.8Hz,1H),7.66-7.51(m,2H),7.15(td,J＝8.3,11.5Hz,1H),6.79(br s,2H),4.30(t,J＝6.9Hz,2H),2.84-2.70(m,2H),1.82(s,3H)；LCMS(ESI)m/z:474.4(M+1)。
Compound 14B (SFC retention time: 1.559 min): 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.39 (br s, 1H), 8.54 (d, J=3.0 Hz, 1H), 7.78 (dt, J=3.0 ,8.8Hz,1H),7.66-7.51(m,2H),7.15(td,J=8.3,11.5Hz,1H),6.79(br s,2H),4.30(t,J=6.9Hz,2H), 2.84-2.70 (m, 2H), 1.82 (s, 3H); LCMS (ESI) m/z: 474.4 (M+1).
实验例1：体外活性测试Experimental Example 1: In Vitro Activity Test
一、基于lnCap细胞的cGMP表达测试1. cGMP expression test based on lnCap cells
1.实验步骤1. Experimental steps
1)溶液配制1) Solution preparation
●
10％BSA(牛血清蛋白)
● 10% BSA (bovine serum albumin)
将10g BSA溶解于100mL双蒸水(ddH
2O)得到10％BSA。
10 g of BSA was dissolved in 100 mL of double distilled water (ddH2O) to give 10% BSA.
●
5mM DETA(二乙烯三胺)-NO
● 5mM DETA (diethylenetriamine)-NO
称取10mg DETA-NO溶解于12.2mL双蒸水(ddH
2O)得到5mM DETA-NO，分装并冻存于-20℃冰箱。
10 mg of DETA-NO was weighed and dissolved in 12.2 mL of double-distilled water (ddH 2 O) to obtain 5 mM DETA-NO, which was aliquoted and stored in a -20°C refrigerator.
●
洗涤缓冲液(Washing Buffer,50mL)
● Washing Buffer (Washing Buffer, 50mL)
●
分析缓冲液(Assay Buffer,50mL)
● Assay Buffer (Assay Buffer, 50mL)
●
检测缓冲液(Detection Buffer)
● Detection Buffer
a)将50μL cGMP-D2(D2标记的环单磷鸟苷)加入到1mL裂解液(lysis buffer)混合均匀。a) Add 50 μL of cGMP-D2 (D2-labeled cyclic guanosine monophosphate) to 1 mL of lysis buffer and mix well.
b)将50μL anti-cGMP cryptate(Eu
3+穴状化合物标记的抗环单磷鸟苷抗体)加入到1mL裂解液(lysis buffer)
b) 50 μL of anti-cGMP cryptate (Eu 3+ cryptate-labeled anti-cyclic monophosphate antibody) was added to 1 mL of lysis buffer
混合均匀。well mixed.
2)化合物稀释2) Compound dilution
(1)用DMSO将化合物稀释至5mM。转移10μL化合物到Echo用浅孔板中。(1) Compounds were diluted to 5 mM with DMSO. Transfer 10 μL of compound to a shallow-well plate for Echo.
(25)用Echo对化合物进行梯度稀释，将每个化合物稀释10个浓度梯度并分别加50nL到384微孔板中。(25) The compounds were serially diluted with Echo, 10 concentration gradients were diluted for each compound and 50 nL were added to a 384 microwell plate.
3)准备LNCap细胞3) Prepare LNCap cells
(1)LNCap培养基：RPMI1640+10％胎牛血清+1％双抗(1) LNCap medium: RPMI1640+10% fetal bovine serum+1% double antibody
(2)将细胞传代过程中用到的磷酸盐缓冲液、胰酶、培养基放到37℃水浴锅中预热。(2) The phosphate buffer, trypsin, and medium used in the cell passaging process were placed in a 37° C. water bath to preheat.
(3)从37℃5％CO
2培养箱中取出细胞(第14代)，用移液器吸去培养瓶中的旧培养液。
(3) Remove the cells (passage 14) from the 37°C 5% CO 2 incubator, and remove the old culture medium in the culture flask with a pipette.
(4)吸取5mL磷酸盐缓冲液加入到培养瓶中漂洗细胞，然后弃去液体。(4) Pipet 5 mL of phosphate buffer into the culture flask to rinse the cells, and then discard the liquid.
(5)吸取3mL胰酶加入培养瓶，摇晃后弃去液体，将培养瓶放入培养箱中。(5) Pipet 3 mL of trypsin into the culture flask, shake and discard the liquid, and put the culture flask into the incubator.
(6)约2分钟后取出培养瓶，观察细胞都已分离后，吸取9mL培养基加入培养瓶并反复吹打几次，将细胞悬液转移至50mL离心管中。(6) After about 2 minutes, take out the culture flask and observe that the cells have been separated. Add 9 mL of medium to the culture flask and pipet repeatedly for several times. Transfer the cell suspension to a 50 mL centrifuge tube.
(7)吸取0.7mL细胞悬液加入计数杯，在ViCell XR上计数。剩余细胞，1000rpm离心5min，并去上清。(7) Pipette 0.7 mL of cell suspension into the counting cup and count on ViCell XR. The remaining cells were centrifuged at 1000 rpm for 5 min, and the supernatant was removed.
(8)加入10mL洗涤缓冲液(washing buffer)清洗细胞，1000rpm离心5min，并去上清。(8) Add 10 mL of washing buffer to wash the cells, centrifuge at 1000 rpm for 5 min, and remove the supernatant.
(9)加入分析缓冲液(assay buffer)并调整细胞浓度至1.25×10
6/mL。8μL/孔加入微孔板中。
(9) Add assay buffer and adjust the cell concentration to 1.25×10 6 /mL. 8 μL/well was added to the microplate.
4)DETA-NO配制和添加4) DETA-NO preparation and addition
(1)取10μL 5mM的DETA-NO分别加入到1240μL和1657μL分析缓冲液(assay buffer)中，得40μM和30μM的DETA-NO。(1) Add 10 μL of 5mM DETA-NO to 1240 μL and 1657 μL of assay buffer, respectively, to obtain 40 μM and 30 μM of DETA-NO.
(2)用Bravo转移2μL/孔的DETA-NO到384微孔板中。(2) Use Bravo to transfer 2 μL/well of DETA-NO into a 384 microwell plate.
(3)1500rpm离心5min。将微孔板于37℃孵育30min。(3) Centrifuge at 1500 rpm for 5 min. The microplate was incubated at 37°C for 30 min.
5)准备cGMP标准曲线5) Prepare the cGMP standard curve
(1)将1mM的cGMP存储液用试验缓冲液(assay buffer)稀释至10μM。然后4倍梯度稀释11个浓度梯度。(1) Dilute 1 mM cGMP stock solution to 10 μM with assay buffer. Eleven concentration gradients were then diluted 4-fold.
(2)将稀释好的cGMP加10μL/孔至微孔板中。(2) Add 10 μL/well of diluted cGMP to the microplate.
6)加检测试剂并读板6) Add detection reagent and read plate
(1)用Bravo转移5μL/孔的cGMP-D2到384微孔板中。1500rpm离心1min。(1) Transfer 5 μL/well of cGMP-D2 into a 384 microwell plate with Bravo. Centrifuge at 1500 rpm for 1 min.
(2)用Bravo转移5μL/孔的anti-cGMP cryptate到384微孔板中。1500rpm离心1min。(2) Transfer 5 μL/well of anti-cGMP cryptate to a 384 microwell plate with Bravo. Centrifuge at 1500 rpm for 1 min.
(3)常温孵育1h。(3) Incubate at room temperature for 1 h.
(4)用envision读取665/615。(4) Read 665/615 with envision.
7)数据分析7) Data analysis
(1)cGMP标准曲线：根据cGMP的浓度与665/615的比值用Graphpad prism做标准曲线。(1) cGMP standard curve: According to the ratio of cGMP concentration to 665/615, use Graphpad prism to make the standard curve.
(2)HTRF(均相时间分辨荧光技术)比值(665/615)转换成cGMP浓度：在Graphpad prism中，将HTRF比值(665/615)复制到cGMP标准曲线的比值列中，运行分析“Log inhibitor vs response-variable slope”，选择“interpolate”，将HTRF比值(665/615)转换成cGMP浓度。(2) Convert the HTRF (Homogeneous Time-Resolved Fluorescence) ratio (665/615) to cGMP concentration: In Graphpad prism, copy the HTRF ratio (665/615) into the ratio column of the cGMP standard curve, run the analysis "Log inhibitor vs response-variable slope", select "interpolate" to convert the HTRF ratio (665/615) to cGMP concentration.
(3)化合物激活曲线：根据转换的cGMP浓度与化合物的浓度用Graphpad prism中“Log agonist vs response- variable slope”分析方法做曲线。(3) Compound activation curve: According to the converted cGMP concentration and the compound concentration, use the "Log agonist vs response-variable slope" analysis method in Graphpad prism to make a curve.
表1 本发明化合物对sGC刺激活性的MEC值Table 1 MEC value of compounds of the present invention on sGC stimulating activity
| 实施例Example | MEC(nM)MEC(nM) |
| 11 | 7.27.2 |
| 22 | 167.5167.5 |
| 33 | 2020 |
| 55 | 10.310.3 |
| 66 | 4141 |
| 88 | 22.122.1 |
| 99 | 15.915.9 |
| 1010 | 13.813.8 |
| 1111 | 6.36.3 |
| 12B12B | 1.91.9 |
| 13B13B | 1.61.6 |
| 14B14B | 44 |
结论：本发明化合物能够有效刺激sGC，提高cGMP水平。Conclusion: The compounds of the present invention can effectively stimulate sGC and increase the level of cGMP.
实验例2：大鼠体内药代动力学评价Experimental Example 2: Pharmacokinetic Evaluation in Rats
实验目的：Purpose:
检测本发明化合物在大鼠体内的药代动力学参数Detection of pharmacokinetic parameters of the compounds of the present invention in rats
实验方案：Experimental program:
1)实验动物：6只7-9周龄的雄性SD大鼠，随机分为2组，每组3只；1) Experimental animals: 6 male SD rats aged 7-9 weeks were randomly divided into 2 groups with 3 rats in each group;
2)药物配制：称取适量药物，溶于10％DMSO+50％PEG400+40％H
2O的混合溶剂中，配置成0.5mg/mL；称取适量药物，溶于10％EtOH+40％PEG400+50％H
2O的混合溶剂中，配置成0.6mg/mL；
2) Drug preparation: Weigh an appropriate amount of drug, dissolve it in a mixed solvent of 10% DMSO + 50% PEG400 + 40% H 2 O, and prepare 0.5 mg/mL; weigh an appropriate amount of drug, dissolve in 10% EtOH + 40% In the mixed solvent of PEG400+50% H 2 O, it was prepared at 0.6 mg/mL;
实验操作：Experimental operation:
第1组动物通过尾静脉单次注射给予剂量为1.0mg/kg、浓度为0.5mg/mL的药物，第2组动物通过灌胃给予剂量为3mg/kg、浓度为0.6mg/mL的化合物。动物于给药后0.0833(仅尾静脉注射组)、0.25、0.5、1、2、4、6、8和24小时采集血浆样品。Animals in Group 1 were given a single dose of the drug at 1.0 mg/kg at a concentration of 0.5 mg/mL via tail vein, and animals in Group 2 were given the compound at a dose of 3 mg/kg at a concentration of 0.6 mg/mL by gavage. Plasma samples were collected from animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose.
数据分析：data analysis:
使用LC-MS/MS方法测定血浆样品中的药物浓度，得出测试药物的动力学参数见表2。The drug concentration in the plasma samples was determined by LC-MS/MS method, and the kinetic parameters of the tested drugs are shown in Table 2.
表2 本发明化合物的药代动力学测试结果Table 2 Pharmacokinetic test results of the compounds of the present invention
--表示不存在-- means does not exist
结论：本发明化合物具有良好的大鼠体内药代动力学性质。Conclusion: The compounds of the present invention have good pharmacokinetic properties in rats.
Claims (21)
- 式(I)所示化合物或其药学上可接受的盐，A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,其中，R 1、R 2和R 3各自独立地为H、F或Cl； wherein R 1 , R 2 and R 3 are each independently H, F or Cl;R 4为C 1-4烷基、苯基-CH 2-或吡啶基-CH 2-，其中所述C 1-4烷基、苯基-CH 2-和吡啶基-CH 2-任选被1、2、3、4或5个R a所取代； R 4 is C 1-4 alkyl, phenyl-CH 2 - or pyridyl-CH 2 -, wherein said C 1-4 alkyl, phenyl-CH 2 - and pyridyl-CH 2 - are optionally 1, 2, 3, 4 or 5 Ra ;各R a独立地为H、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-C(＝O)OH、C 1-3烷氧基或任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN、-NH 2和-OCH 3的取代基所取代的C 1-3烷基； Each Ra is independently H, F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , -C(=O)OH, C1-3alkoxy or optionally , 2 or 3 C 1-3 alkyl substituted with substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH 2 and -OCH 3 ;R 5和R 6各自独立地为H、F、Cl、Br、I、-OH、-CN或-NH 2； R 5 and R 6 are each independently H, F, Cl, Br, I, -OH, -CN or -NH 2 ;R 7为-NH-C(＝O)O-R b； R 7 is -NH-C(=O)OR b ;R b为任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN、-NH 2和-OCH 3的取代基所取代的C 1-6烷基；或R 6和R 7与它们相连的碳原子连接在一起，使结构单元为R is C 1-6 alkyl optionally substituted with 1, 2 or 3 substituents independently selected from F, Cl, Br, I, -OH , -CN, -NH and -OCH; or R6 and R7 are linked together with the carbon atoms to which they are attached, making the structural unitforR 8为H、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、C 1-3烷氧基、C 1-3烷基或C 3-5环烷基，其中所述C 1-3烷氧基、C 1-3烷基和C 3-5环烷基任选被1、2或3个R c所取代； R 8 is H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , C 1-3 alkoxy, C 1-3 alkyl or C 3-5 cycloalkyl, wherein said C 1-3 alkoxy, C 1-3 alkyl and C 3-5 cycloalkyl are optionally substituted with 1, 2 or 3 R c ;R 9为H、F、Cl、Br、I、C 1-3烷氧基、C 1-3烷基、苯基或5-6元杂芳基，其中所述C 1-3烷氧基、C 1-3烷基、苯基和5-6元杂芳基任选被1、2或3个R d所取代； R 9 is H, F, Cl, Br, I, C 1-3 alkoxy, C 1-3 alkyl, phenyl or 5-6 membered heteroaryl, wherein the C 1-3 alkoxy, C 1-3 alkyl, phenyl and 5-6 membered heteroaryl are optionally substituted with 1, 2 or 3 R d ;R c和R d各自独立地为F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、C 1-3烷氧基或任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN和-NH 2的取代基所取代的C 1-3烷基； Rc and Rd are each independently F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , C1-3alkoxy or optionally independently selected from 1, 2 or 3 C 1-3 alkyl substituted from substituents of F, Cl, Br, I, -OH, -CN and -NH 2 ;所述5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。The 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S- and -N-.
- 根据权利要求1所述的化合物或其药学上可接受的盐，其化合物具有式(I-1)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, the compound has a structure represented by formula (I-1):其中，R 1、R 2、R 3、R 4、R 5、R 6和R b如权利要求1所定义。 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R b are as defined in claim 1 .
- 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 b为-CH 3、-CH 2F、-CH 2CH 3、-CH 2CF 3、-CH(CH 3) 2或-CH 2CH 2CH 3。 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R b is -CH 3 , -CH 2 F, -CH 2 CH 3 , -CH 2 CF 3 , -CH(CH 3 ) 2 or -CH 2 CH 2 CH 3 .
- 根据权利要求1所述的化合物或其药学上可接受的盐，其中R 7为-NH-C(＝O)O-CH 3。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is -NH-C(=O)O-CH 3 .
- 根据权利要求1所述的化合物或其药学上可接受的盐，其化合物具有式(I-2)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, the compound has a structure represented by formula (I-2):其中，R 1、R 2、R 3、R 4、R 5、R 8和R 9如权利要求1所定义。 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and R 9 are as defined in claim 1 .
- 根据权利要求1所述的化合物或其药学上可接受的盐，其中各R a独立地为H、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-C(＝O)OH、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH 2(CH 3) 2、-OCH 3、-OCH 2CH 3、-CF 3、-CH 2CF 3、-CF 2CF 3、-CH 2CH 2CF 3、-CH 2OH或-CH 2CH 2OH。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each Ra is independently H, F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , -C ( = O ) OH, -CH3 , -CH2CH3 , -CH2CH2CH3 , -CH2 ( CH3 )2 , -OCH3 , -OCH2CH3 , -CF3 , -CH2 CF3 , -CF2CF3 , -CH2CH2CF3 , -CH2OH or -CH2CH2OH .
- 根据权利要求6所述的化合物或其药学上可接受的盐，其中各R a独立地为H、F或-CF 3。 The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein each Ra is independently H, F, or -CF3 .
- 根据权利要求1、2或5～7任一项所述的化合物或其药学上可接受的盐，其中R 4为The compound according to any one of claims 1, 2 or 5 to 7 or a pharmaceutically acceptable salt thereof, wherein R 4 is
- 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R 4为The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R is
- 根据权利要求1所述的化合物或其药学上可接受的盐，其化合物具有式(I-1-a)、(I-1-b)或(I-1-c)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-1-a), (I-1-b) or (I-1-c):其中，R 1、R 2、R 3、R a和R b如权利要求1所定义；R 5和R 6各自独立地为H或-NH 2。 wherein R 1 , R 2 , R 3 , Ra and R b are as defined in claim 1; R 5 and R 6 are each independently H or -NH 2 .
- 根据权利要求1所述的化合物或其药学上可接受的盐，其化合物具有式(I-2-a)、(I-2-b)或(I-2-c)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure represented by formula (I-2-a), (I-2-b) or (I-2-c):其中，R 1、R 2、R 3、R 8、R 9和R a如权利要求1所定义；R 5为H或-NH 2。 wherein R 1 , R 2 , R 3 , R 8 , R 9 and Ra are as defined in claim 1; R 5 is H or -NH 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 c和R d各自独立地为F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-OCH 3、-CH 3或-CF 3。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R c and R d are each independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , - OCH 3 , -CH 3 or -CF 3 .
- 根据权利要求1、5～7或10～12任一项所述的化合物或其药学上可接受的盐，其中R 8为H、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-OCH 3、-CH 3、-CH 2CH 3、其中所述-OCH 3、-CH 3、-CH 2CH 3、任选被1、2或3个R c所取代。 The compound according to any one of claims 1, 5-7 or 10-12 or a pharmaceutically acceptable salt thereof, wherein R 8 is H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -OCH 3 , -CH 3 , -CH 2 CH 3 ,wherein -OCH 3 , -CH 3 , -CH 2 CH 3 ,Optionally substituted with 1, 2 or 3 Rcs.
- 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 8为H、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-OCH 3、-CH 3、-CH 2CH 3、-C(R c) 3、-CH 2C(R c) 3、The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R 8 is H, F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -OCH 3 , - CH 3 , -CH 2 CH 3 , -C(R c ) 3 , -CH 2 C(R c ) 3 ,
- 根据权利要求14所述的化合物或其药学上可接受的盐，其中R 8为-CH 3、-CH 2CH 3或The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R 8 is -CH 3 , -CH 2 CH 3 or
- 根据权利要求1、5～7或10～12任一项所述的化合物或其药学上可接受的盐，其中R 9为H、F、Cl、Br、I、-OCH 3、-CH 3、-CH 2CH 3、苯基或吡啶基，其中所述-OCH 3、-CH 3、-CH 2CH 3、苯基和吡啶基任选被1、2或3个R d所取代。 The compound according to any one of claims 1, 5-7 or 10-12 or a pharmaceutically acceptable salt thereof, wherein R 9 is H, F, Cl, Br, I, -OCH 3 , -CH 3 , -CH2CH3, phenyl or pyridyl, wherein said -OCH3 , -CH3 , -CH2CH3 , phenyl and pyridyl are optionally substituted with 1 , 2 or 3 Rd .
- 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 9为H、F、Cl、Br、I、-CH 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-C(R d) 3、-CH 2C(R d) 3、The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R 9 is H, F, Cl, Br, I, -CH 3 , -CH 2 CH 3 , -OCH 3 , -OCH 2 CH 3 , -C(R d ) 3 , -CH 2 C(R d ) 3 ,
- 根据权利要求17所述的化合物或其药学上可接受的盐，其中R 9为-CH 3、-CH 2CH 3、The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein R 9 is -CH 3 , -CH 2 CH 3 ,
- 根据权利要求11所述的化合物或其药学上可接受的盐，其化合物具有式(I-2-d)、(I-2-e)或(I-2-f)所示结构：The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure represented by formula (I-2-d), (I-2-e) or (I-2-f):其中，带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在；Wherein, the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer;R 9为R9 isR 1、R 2、R 3、R 5、R a和R d如权利要求11所定义。 R 1 , R 2 , R 3 , R 5 , Ra and R d are as defined in claim 11 .
- 下式化合物或其药学上可接受的盐，A compound of the formula or a pharmaceutically acceptable salt thereof,
- 下式化合物或其药学上可接受的盐，A compound of the formula or a pharmaceutically acceptable salt thereof,
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| CN202010975022.5 | 2020-09-16 | ||
| CN202010975022 | 2020-09-16 | ||
| CN202110796623.4 | 2021-07-14 | ||
| CN202110796623 | 2021-07-14 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022228365A1 (en) * | 2021-04-27 | 2022-11-03 | 南京明德新药研发有限公司 | Derivative of six-membered heteroaromatic urea ring and application thereof |
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|---|---|---|---|---|
| WO2003004503A1 (en) * | 2001-07-04 | 2003-01-16 | Bayer Healthcare Ag | Morpholine-bridged pyrazolopyridine derivatives |
| US6903089B1 (en) * | 2000-11-22 | 2005-06-07 | Bayer Aktiengesellschaft | Lactam-substituted pyrazolopyridine derivatives |
| CN1665811A (en) * | 2002-05-08 | 2005-09-07 | 拜耳医药保健股份公司 | Carbamate-substituted pyrazolopyridines |
| US20110039893A1 (en) * | 2006-10-11 | 2011-02-17 | Takeda Pharmaceutical Company Limited | Gsk-3beta inhibitor |
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| US6903089B1 (en) * | 2000-11-22 | 2005-06-07 | Bayer Aktiengesellschaft | Lactam-substituted pyrazolopyridine derivatives |
| WO2003004503A1 (en) * | 2001-07-04 | 2003-01-16 | Bayer Healthcare Ag | Morpholine-bridged pyrazolopyridine derivatives |
| CN1665811A (en) * | 2002-05-08 | 2005-09-07 | 拜耳医药保健股份公司 | Carbamate-substituted pyrazolopyridines |
| US20110039893A1 (en) * | 2006-10-11 | 2011-02-17 | Takeda Pharmaceutical Company Limited | Gsk-3beta inhibitor |
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| WO2022228365A1 (en) * | 2021-04-27 | 2022-11-03 | 南京明德新药研发有限公司 | Derivative of six-membered heteroaromatic urea ring and application thereof |
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