CN116239600A - Preparation method of fused ring compound and application of fused ring compound as antifungal agent - Google Patents

Preparation method of fused ring compound and application of fused ring compound as antifungal agent Download PDF

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CN116239600A
CN116239600A CN202211567806.XA CN202211567806A CN116239600A CN 116239600 A CN116239600 A CN 116239600A CN 202211567806 A CN202211567806 A CN 202211567806A CN 116239600 A CN116239600 A CN 116239600A
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ring
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phenyl
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邓刚
刘小斌
李中尧
黄道臣
汤芮
张琼
彭建彪
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Shanghai Jiyu Pharmaceutical Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

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Abstract

The invention discloses a preparation method of a parallel ring compound and application thereof as an antifungal agent, and in particular discloses a compound shown in a formula (I) and pharmaceutically acceptable salt thereof, and antifungal application of the compound.

Description

Preparation method of fused ring compound and application of fused ring compound as antifungal agent
Technical Field
The invention relates to a preparation method of a parallel ring compound and application of the parallel ring compound as an antifungal agent. The invention also relates to a compound shown in the formula (I) and pharmaceutically acceptable salts thereof, and antifungal application of the compound.
Background
In recent years, with the long-term widespread use of broad-spectrum antibiotics, the increase of chemoradiotherapy, the popularization of bone marrow and organ transplantation operations, the increase of immunosuppressant use, the development of interventional treatments such as heart valve implantation, and the like, the incidence and mortality of clinical invasive fungal infections caused by candida, aspergillus, cryptococcus neoformans, and the like have been remarkably increased. Tens of millions of people with fungal infections worldwide, at least 150 tens of people die from deep invasion of fungi.
The present clinically used antifungal infection medicines comprise azoles, polyenes, echinocandins and the like. The azole antifungal drug is the largest of various antifungal drugs, is also the most common antifungal drug in clinic, has wide antibacterial spectrum and smaller toxicity, and has better tolerance compared with amphotericin B, so the application is the most extensive.
Despite the wide clinical use, these azole antifungal agents still have some drawbacks and limitations, respectively. For example, ketoconazole has great toxic and side effects and is basically used as local medicine at present. Fluconazole has limited activity as a first-line drug for the treatment of localized and deep fungal infections and develops severe resistance due to prolonged use. Itraconazole has poor water solubility and low bioavailability, and cyclodextrin contained in the oral liquid can cause osmotic diarrhea, so that the itraconazole has great harm to patients with renal insufficiency. Posaconazole is a strong CYP3A4 inhibitor, and the clinical application of the posaconazole is limited by the strong drug-drug interaction (DDI), and the physical and chemical properties and the metabolic properties of the posaconazole are also quite unsatisfactory, so that the curative effect stability of the posaconazole is greatly reduced. Ai Shakang oxazole is a moderate-intensity CYP3A4 inhibitor and still presents the problem of drug DDI.
Voriconazole is considered to be the most successful fluconazole derivative, has stronger activity on deep pathogenic fungi including fluconazole-resistant strains such as candida krusei, candida parapsilosis and the like, and is the most optimal medicine for treating fungal infection, especially invasive mycosis caused by aspergillus at present. The disadvantage is that the CYP2C19 is metabolized in the body, and the blood concentration is too high due to individual differences of CYP2C19 metabolism, so that adverse reactions are particularly easy to cause for Chinese people. Side effects such as abnormal visual response, liver dysfunction, etc. after voriconazole administration have also been reported successively.
In view of the defects and limitations of the existing antifungal medicines of the conazole, the novel efficient, broad-spectrum and low-toxicity CYP51 inhibitor antifungal medicines with activity, metabolism, medicine interaction and the like superior to the existing medicines are developed, the limitations and defects of the existing clinical medicines are overcome, the resistance to the fluconazole and the like is overcome, and the novel efficient, broad-spectrum and low-toxicity CYP51 inhibitor antifungal medicines have great clinical value in treating and preventing various fungal infections, especially deep infections caused by candida and aspergillus, and reducing the mortality rate of clinical invasive fungal infections.
Disclosure of Invention
Based on the findings of the problems, the invention provides a series of compounds with brand-new azole structures, compared with the existing clinical therapeutic drugs, the compounds have better or equivalent candida infection resistance activity, overcome the limitations and defects of the existing clinical drugs, and can be used clinically to reduce the death rate of invasive fungal infection.
In a first aspect of the present invention, the present invention provides a compound of formula (I), optical isomers, tautomers and pharmaceutically acceptable salts thereof,
Figure BDA0003986848020000011
wherein,,
ring a is selected from 5-6 membered heteroaryl;
ring B is selected from phenyl, 5-6 membered heteroaryl and C 5-6 Cycloalkyl;
ring C is independently selected from phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, said phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with 1, 2 or 3 Rx;
ring D is independently selected from phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, said phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with 1, 2 or 3R Y Substitution;
and, ring C and ring D are not both aromatic ring systems;
R 3 selected from OH, NH 2 、-OSi(R 9 ) 3 、F、Cl、Br、I、CN、C 1-6 Alkyl, C 1-6 Heteroalkyl group,
Figure BDA0003986848020000021
The C is 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 NH 2 Substitution;
R 2 、R X 、R Y are respectively and independently selected from H, CN, OH, F, cl, br, I, C 1-6 Alkyl, C 1-6 Heteroalkyl, SF 3 、SF 6 、SCN、SO 3 H and SO 2 R 7 The C is 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
or, R 3 Is linked together with Rx to form a 3-9 membered heterocyclic group or C 3-9 A cycloalkyl group;
R 7 、R 9 independently selected from NH 2 、C 1-6 Alkyl, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl optionally being substituted with 1, 2 or 3 CN, OH,F. Cl, br, I or C 1-6 Alkyl substitution;
n is independently selected from 0, 1, 2 or 3;
L 1 selected from single bonds, C 1-6 Alkyl, C 2-6 Alkynyl, phenyl and 5-6 membered heteroaryl groups, said C 1-6 Alkyl, C 2-6 Alkynyl, phenyl or 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
L 2 selected from single bonds, O, S, NH, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclyl, C 3-6 Cycloalkyl and phenyl-O-C 1-6 Alkyl-, said C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclyl, C 3-6 Cycloalkyl or phenyl-O-C 1-6 Alkyl-optionally substituted by 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
L 3 selected from single bond, -C (=O) -, -C (=O) NH-, C 1-6 Alkyl, 3-6 membered heterocyclyl, C 3-6 Cycloalkyl, phenyl and 5-6 membered heteroaryl, said C 1-6 Alkyl, 3-6 membered heterocyclyl, C 3-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
L 4 selected from H, F, cl, br, I, OH, CN, NH 2 、COOH、SF 3 、SF 6 、SCN、SO 2 R 7 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, C 1-6 Alkyl-5-6 membered heterocyclyl, 5-6 membered heteroaryl and benzo 4-6 membered heterocyclyl, said C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, C 1-6 Alkyl-5-6 membered heterocyclyl, 5-6 membered heteroaryl or benzo 5-6 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5R L Substitution;
R L selected from CN, OH, F, cl, br, I, NH 2 、C 1-6 Alkyl and C 1-6 Heteroalkyl group, C 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, NH 2 、F、Cl, br, I or C 1-6 Alkyl substitution;
the C is 1-6 Heteroalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl comprises 1, 2, 3 or 4 groups independently selected from-O-, -NH-, -N=, -S-, -C (=O) O-, -S (=O) 2 -and N.
In another aspect of the present invention, the present invention also provides a compound of formula (II-1) or (II-2), optical isomers, tautomers and pharmaceutically acceptable salts thereof,
Figure BDA0003986848020000031
wherein,,
X 1 、X 2 、X 3 、X 8 are each independently selected from C (R) X ) 2 、NR X S and O;
X 4 、X 5 、X 6 、X 7 are independently selected from CR Y And N;
R 6 selected from H, CN, OH, F, cl, br, I, C 1-6 Alkyl, C 1-6 Heteroalkyl, SF 3 、SF 6 、SCN、SO 3 H and SO 2 R 7 The C is 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
or, R 3 And R is R 6 Are linked together to form a 3-6 membered heterocyclic group or C 3-6 A cycloalkyl group;
ring a, ring B, R 2 、R 3 、R X 、R Y 、L 1 、L 2 、L 3 、L 4 N is as defined above.
In some embodiments of the invention, ring a is selected from tetrazolyl, triazolyl, oxazolyl, pyrimidinyl, thiazolyl, or pyrazolyl, with the remaining variables being as defined herein.
In some embodiments of the invention, the ring A is selected from
Figure BDA0003986848020000032
The remaining variables are as defined herein.
In some embodiments of the invention, ring B is selected from phenyl and pyridyl, and the remaining variables are as defined herein.
In some aspects of the invention, the structural units described above
Figure BDA0003986848020000033
Selected from the group consisting of
Figure BDA0003986848020000034
The remaining variables are as defined herein.
In some aspects of the invention, R is as defined above 3 Selected from OH, NH 2 、C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, -OC (=o) C 1-3 Alkyl and-NHC (=o) C 1-3 Alkyl, the remaining variables are as defined herein.
In some aspects of the invention, L as described above 1 Selected from single bonds, CH 2 、
Figure BDA0003986848020000035
Figure BDA0003986848020000036
The remaining variables are as defined herein.
In some aspects of the invention, L as described above 2 Selected from single bonds, O, S, CH 2 、NH、NCH 3 、
Figure BDA0003986848020000037
Figure BDA0003986848020000038
The remaining variables are as defined herein. />
In some aspects of the invention, L as described above 3 Selected from single bonds, CH 2 、CH 2 CH 2 、-C(＝O)-、-C(＝O)NH-、
Figure BDA0003986848020000039
Figure BDA00039868480200000310
The remaining variables are as defined herein.
In some aspects of the invention, L as described above 4 Selected from H, F, cl, br, I, OH, CN, NH 2 、CHF 2 、CF 3 、OCH 3 、OCF 3 、OCHF 2 、OCH 2 CH 3 、COOH、CONHMe、CONMe 2 、NMe 2 、
Figure BDA0003986848020000041
Figure BDA0003986848020000042
Figure BDA0003986848020000043
The remaining variables are as defined herein.
In some aspects of the invention, the structural units described above
Figure BDA0003986848020000044
Selected from H, I, CN, OH, CF 3 、COOH、CONHMe、CONMe 2 、/>
Figure BDA0003986848020000045
/>
Figure BDA0003986848020000046
/>
Figure BDA0003986848020000051
Figure BDA0003986848020000061
/>
Figure BDA0003986848020000062
The remaining variables are as defined herein.
In some embodiments of the invention, the above-described rings C, D are each independently selected from the group consisting of cyclopentylalkyl, cyclohexenyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, pyridinyl, and pyrimidinyl, the cyclopentylalkyl, cyclohexenyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, pyridinyl, or pyrimidinyl being optionally substituted with 1, 2, or 3 halogens, methyl, ethyl, or cyclopropyl, and rings C and D are not both aromatic ring systems, with the remaining variables being as defined herein.
In some aspects of the invention, the structural units described above
Figure BDA0003986848020000063
Selected from->
Figure BDA0003986848020000064
Figure BDA0003986848020000065
The remaining variables are as defined herein.
In another aspect of the invention, the invention also provides a compound of the formula, optical isomers, tautomers, and pharmaceutically acceptable salts thereof, selected from
Figure BDA0003986848020000066
In another aspect of the invention, the invention also provides a compound of the formula, optical isomers, tautomers, and pharmaceutically acceptable salts thereof, selected from
Figure BDA0003986848020000071
/>
Figure BDA0003986848020000081
In another aspect of the invention, the invention also provides the use of a compound as described above, an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof for the preparation of a medicament for combating fungal infection.
Definition and description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
As used herein, the phrase "at least one" when referring to a list of one or more elements is understood to mean at least one element selected from any one or more of the elements in the list of elements, but does not necessarily include at least one of each element specifically listed within the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements other than the specifically identified elements within the list of elements referred to by the phrase "at least one" may optionally be present, whether related or unrelated to those elements specifically identified.
The term "pharmaceutically acceptable" as used herein is intended to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting neutral forms of such compounds with a sufficient amount of a base in pure 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 the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of an acid in 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, and the like; and organic acid salts including acids such as acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the invention contain basic and acidic functionalities that can be converted to either base or acid addition salts.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
When any variable (e.g., 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 to 2R, the group may optionally be substituted with up to two R's, and R's in each case have independent options. Furthermore, combinations of substituents and/or variants thereof are only permissible if such combinations result in stable compounds. For example, the number of the cells to be processed,
Figure BDA0003986848020000091
can be selected from->
Figure BDA0003986848020000092
And->
Figure BDA0003986848020000093
Etc.
The short dash ("-") that is not between two letters or symbols represents the attachment site for a substituent. For example, C 1-6 Alkylcarbonyl-refers to C attached to the remainder of the molecule through a carbonyl group 1-6 An alkyl group. However, "-" may be omitted when the attachment site for the substituent is apparent to those skilled in the art, for example, a halogen substituent.
With broken lines at the valencies of the radicals
Figure BDA0003986848020000094
When, for example, in->
Figure BDA0003986848020000095
The dotted line represents the point of attachment of the group to the rest of the molecule. When a single bond is provided with->
Figure BDA0003986848020000096
When, for example, in->
Figure BDA0003986848020000097
In which the dotted line represents a single bond or is absent, also meaning +.>
Figure BDA0003986848020000098
Represents a single bond->
Figure BDA0003986848020000099
Or double bond->
Figure BDA00039868480200000910
The term "substituted" or "substituted with …" means that any one or more hydrogen atoms on a particular atom are substituted with substituents, and may include heavy hydrogens and variants of hydrogens, provided that the valence of the particular atom is normal and the substituted compound is stable. The term "optionally substituted" or "optionally substituted …" means that the substituents may or may not be substituted, and the types and numbers of substituents may be arbitrary on the basis of being chemically realizable unless otherwise indicated.
When one of the variables is selected from single bonds, the two groups representing their attachment are directly linked, e.g
Figure BDA00039868480200000911
Middle L 1 Representing a single bond means that the structure is actually +.>
Figure BDA00039868480200000912
When the listed substituents do not indicate which atom is attached to the substituted group, such substituents may be bonded through any atom thereof, for example, a pyridyl group may be attached to the substituted group as a substituent through any carbon atom on the pyridine ring.
When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary, for example,
Figure BDA00039868480200000913
the linking group L is-CH 2 O-, in this case-CH 2 O-may be a group comprising phenyl and cyclopentyl which are linked in the same direction as the reading order from left to right>
Figure BDA00039868480200000914
The phenyl group and the cyclopentyl group may be linked in the opposite direction to the reading order from left to right to form +.>
Figure BDA00039868480200000915
Combinations of such linking groups, substituents and/or variants thereof will only result in stable stabilization of such combinationsThe compound is allowed only in the case of a compound.
Unless otherwise specified, the number of atoms on a ring is generally defined as the number of ring elements, e.g., "3-6 membered ring" refers to a "ring" of 3-6 atoms arranged around a ring.
Unless otherwise specified, the term "C 1-6 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C is 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 groups, etc.; which may be monovalent (e.g. CH 3 ) Divalent (-CH) 2 (-) or multivalent (e.g. inferior)
Figure BDA0003986848020000101
)。C 1-6 Examples of alkyl groups include, but are not limited to CH 3 、/>
Figure BDA0003986848020000102
Figure BDA0003986848020000103
Figure BDA0003986848020000104
Etc.
Unless otherwise specified, the term "C 1-4 Alkyl "is used to denote a straight or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C is 1-4 Alkyl includes C 1-2 、C 1-3 、C 3-4 And C 2-3 Alkyl groups, etc.; which may be monovalent (e.g. CH 3 ) Divalent (-CH) 2 (-) or multivalent (e.g. inferior)
Figure BDA0003986848020000105
)。C 1-4 Examples of alkyl groups include, but are not limited to CH 3 、/>
Figure BDA0003986848020000106
Etc.
Unless otherwise specified, "C 2-6 Alkynyl "is used to denote a straight or branched hydrocarbon group consisting of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or multivalent. The C is 2-6 Alkynyl includes C 2-3 、C 2-4 、C 2-5 、C 3-4 、C 3-5 、C 3-6 、C 4-5 、C 4-6 、C 5-6 、C 6 、C 5 、C 4 、C 3 And C 2 Alkynyl groups. C (C) 2-6 Examples of alkynyl groups include, but are not limited to
Figure BDA0003986848020000107
Etc.
Unless otherwise specified, "C 2-3 Alkynyl "is used to denote a straight or branched hydrocarbon group consisting of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located at any position of the group. It may be monovalent, divalent or multivalent. The C is 2-3 Alkynyl includes C 3 And C 2 Alkynyl groups. C (C) 2-3 Examples of alkynyl groups include, but are not limited to
Figure BDA0003986848020000108
Etc.
The term "heteroalkyl", by itself or in combination with another term, means a stable, straight or branched chain alkyl radical or combination thereof, consisting of a number of carbon atoms and at least one heteroatom or group of heteroatoms. In some embodiments, the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatom is selected from-C (=o) O-, -C (=o) -, -C (=s) -, -S (=o) 2 -、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O) 2 N (H) -and-S (=o) N (H) -. In some embodiments, the heteroalkyl is C 1-6 A heteroalkyl group; in other embodiments, the heteroalkyl is C 1-3 A heteroalkyl group. The heteroatom or heteroatom group may be located in any of the heteroalkyl groupsWhat internal positions, including the attachment of the alkyl group to the remainder of the molecule, but the term "alkoxy" is a conventional expression, refers to those alkyl groups that are attached to the remainder of the molecule through an oxygen atom. Examples of heteroalkyl groups include, but are not limited to, -OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 、-OCH 2 (CH 3 ) 2 、-CH 2 -CH 2 -O-CH 3 、-NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )(CH 2 CH 3 )、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-SCH 3 、-SCH 2 CH 3 、-SCH 2 CH 2 CH 3 、-SCH 2 (CH 3 ) 2 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -CH 2 、-S(＝O)-CH 3 、-CH 2 -CH 2 -S(＝O) 2 -CH 3 And up to two heteroatoms may be contiguous, e.g. -CH 2 -NH-OCH 3 。
Unless otherwise specified, the term "C 1-6 Alkoxy "means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is 1-6 Alkoxy includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 6 、C 5 、C 4 And C 3 Alkoxy groups, and the like. C (C) 1-6 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentoxy (including n-pentoxy, isopentoxy and neopentoxy), hexoxy, and the like.
Unless otherwise specified, the term "C 1-3 Alkoxy "means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through one oxygen atom. The C is 1-3 Alkoxy includes C 1-3 、C 1-2 、C 2-3 、C 1 、C 2 And C 3 Alkoxy groups, and the like. C (C) 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
Unless otherwise specified, the term "C 1-6 Alkylamino "means those alkyl groups containing 1 to 6 carbon atoms that are attached to the remainder of the molecule through an amino group. The C is 1-6 Alkylamino includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 6 、C 5 、C 4 、C 3 And C 2 Alkylamino, and the like. C (C) 1-6 Examples of alkylamino groups include, but are not limited to, -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-N(CH 2 CH 3 )(CH 2 CH 3 )、-NHCH 2 CH 2 CH 3 、-NHCH 2 (CH 3 ) 2 、-NHCH 2 CH 2 CH 2 CH 3 Etc.
Unless otherwise specified, the term "C 1-3 Alkylamino "means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group. The C is 1-3 Alkylamino includes C 1-3 、C 1-2 、C 2-3 、C 1 、C 2 And C 3 Alkylamino, and the like. C (C) 1-3 Examples of alkylamino groups include, but are not limited to, -NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 、-N(CH 3 )CH 2 CH 3 、-NHCH 2 CH 2 CH 3 、-NHCH 2 (CH 3 ) 2 Etc.
Unless otherwise specified, the term "C 1-6 Alkylthio "means those alkyl groups containing 1 to 6 carbon atoms which are attached to the remainder of the molecule through a sulfur atom. The C is 1-6 Alkylthio includes C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 、C 6 、C 5 、C 4 、C 3 And C 2 Alkylthio processA base, etc. C (C) 1-6 Examples of alkylthio groups include, but are not limited to, -SCH 3 、-SCH 2 CH 3 、-SCH 2 CH 2 CH 3 、-SCH 2 (CH 3 ) 2 Etc.
Unless otherwise specified, the term "C 1-3 Alkylthio "means those alkyl groups containing 1 to 3 carbon atoms which are attached to the remainder of the molecule through a sulfur atom. The C is 1-3 Alkylthio includes C 1-3 、C 1-2 、C 2-3 、C 1 、C 2 And C 3 Alkylthio, and the like. C (C) 1-3 Examples of alkylthio groups include, but are not limited to, -SCH 3 、-SCH 2 CH 3 、-SCH 2 CH 2 CH 3 、-SCH 2 (CH 3 ) 2 Etc.
Unless otherwise specified, "C 3-6 Cycloalkyl "means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, said C 3-6 Cycloalkyl includes C 3-5 、C 4-5 And C 5-6 Cycloalkyl groups, and the like; it may be monovalent, divalent or multivalent. C (C) 3-6 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Unless otherwise specified, the term "3-6 membered heterocyclyl" by itself or in combination with other terms, denotes a saturated cyclic group consisting of 3 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p P is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, with respect to the "3-6 membered heterocyclic group", the heteroatom may occupy the position of attachment of the heterocyclic group to the remainder of the molecule. The 3-6 membered heterocyclic group includes 4-6 membered, 5-6 membered, 4 membered, 5 membered, 6 membered heterocyclic groups and the like. Examples of 3-6 membered heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl) Etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl etc.), piperazinyl (including 1-piperazinyl, 2-piperazinyl etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl etc.
Unless otherwise specified, the term "5-6 membered heterocyclyl" alone or in combination with other terms, denotes a saturated cyclic group consisting of 5 to 6 ring atoms, 1,2, 3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms, wherein the nitrogen atoms are optionally quaternized and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p P is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spiro, fused and bridged rings. In addition, with respect to the "5-6 membered heterocyclic group", the heteroatom may occupy the position of attachment of the heterocyclic group to the remainder of the molecule. The 5-6 membered heterocyclic group includes 5-membered and 6-membered heterocyclic groups and the like. Examples of 5-6 membered heterocyclyl groups include, but are not limited to, 1, 3-dioxolane,
Figure BDA0003986848020000111
Pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl, 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl, 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1, 2-oxazinyl, 1, 2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl, and the like.
The terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably herein unless otherwise specified, the term "5-6 membered heteroaryl" meaning a monocyclic group having a conjugated pi-electron system consisting of 5 to 6 ring atoms, 1,2,3 or 4 of which are heteroatoms independently selected from O, S and N, the remainder being carbon atoms. Wherein the nitrogen atom is optionallyQuaternized, the nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., NO and S (O) p P is 1 or 2). The 5-6 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or carbon atom. The 5-6 membered heteroaryl groups include 5-and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (1H-1, 2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 4-pyrimidyl, etc.), pyrimidyl (including 2-pyridyl, 4-pyrimidyl, etc.), pyrimidyl, etc.
Unless otherwise specified, C n-n+m Or C n -C n+m Comprising any one of the specific cases of n to n+m carbons, e.g. C 1-12 Comprises C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 Also included is any one of the ranges n to n+m, e.g. C 1-12 Comprises 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.; similarly, n-membered to n+m-membered means that the number of atoms on the ring is 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, and any one of n to n+m is also included, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 5-10-membered ring, 6-7-membered ring, 6-8-membered ring, 6-9-membered ring, 6-10-membered ring, and the like.
The term "leaving group" refers to a functional group or atom that may be substituted with another functional group or atom by a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromophenylsulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.
The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "mercapto 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: a formyl group; acyl groups such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl groups such as t-butoxycarbonyl (Boc); arylmethoxycarbonyl groups such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups such as benzyl (Bn), trityl (Tr), 1-bis- (4' -methoxyphenyl) methyl; silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing side reactions of a hydroxy group. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and t-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (benzhydryl, DPM); silyl groups such as Trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS), and the like.
It will be appreciated by those skilled in the art that some compounds of formula (I) may contain one or more chiral centers and thus two or more stereoisomers may be present. Thus, the compounds of the invention may exist as individual stereoisomers (e.g. enantiomers, diastereomers) and mixtures thereof in any proportion, e.g. racemates, and, where appropriate, as tautomers and geometric isomers thereof.
The compounds of the 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, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the claimed invention.
The term "stereoisomer" as used herein refers to a compound that has the same chemical constitution but differs in the spatial arrangement of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers and the like.
The term "enantiomer" as used herein refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.
The term "diastereoisomer" as used herein refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high resolution analytical methods such as electrophoresis and chromatography such as HPLC.
Stereochemical definitions and conventions can follow the edition s.p. parker, mcGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, new York; and Eliel, e. And Wilen, s., "Stereochemistry of Organic Compounds", john Wiley & Sons, inc., new York,1994. Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to represent the absolute configuration of the molecule with respect to its chiral center. The prefix d and l or (+) and (-) is used to denote the sign of the compound rotating plane polarized light, where (-) or l indicates that the compound is left-handed. The compound with the prefix (+) or d is dextrorotatory. These stereoisomers are identical for a given chemical structure, except that they are mirror images of each other. Certain stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are generally referred to as enantiomeric mixtures. The 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur in the absence of stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers that are not optically active.
The racemic mixture may be used as such or resolved into individual isomers. The resolution can be carried out to obtain a stereochemically pure compound or a mixture enriched in one or more isomers. Methods for separating isomers are well known (see Allinger n.l. and Eliel e.l. "Topics in Stereochemistry", volume 6, wiley Interscience, 1971), and include physical methods such as chromatography using chiral adsorbents. Individual isomers of chiral form can be prepared from chiral precursors. Alternatively, one or both of the isomers substantially free of the other isomer, i.e., the desired stereoisomer having an optical purity of, for example, at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 99.5% by weight, can be obtained by chemical separation of the individual isomers from the mixture by formation of diastereomeric salts with chiral acids (e.g., individual enantiomers of 10-camphorsulfonic acid, camphoric acid, α -bromocamphoric acid, tartaric acid, diacetyltartaric acid, malic acid, pyrrolidone-5-carboxylic acid, etc.), fractional crystallization of said salts, and then liberating one or both of the resolved bases, optionally repeating this process. Alternatively, the racemate may be covalently linked to a chiral compound (adjunct) to provide the diastereoisomers, as is well known to those skilled in the art.
The compounds of the invention may be present in particular. Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to the fact that at room temperature, different functional group isomers are in dynamic equilibrium and are capable of rapid interconversion. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also known as proton tautomers) (prototropic tautomer) include interconversions by proton transfer, such as keto-enol isomerisation and imine-enamine isomerisation. Valence isomer (valance tautomer) includes the interconversion by recombination of some of the bond-forming electrons. A specific example of where keto-enol tautomerization is the interconversion between two tautomers of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one.
The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite For example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond between deuterium and carbon is stronger than the bond between normal hydrogen and carbon, so that the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life of the drug and the like compared with the non-deuterated drug. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
"optional" or "optionally" means 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 where it does not.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
The solvent used in the present invention is commercially available.
Compounds are either prepared according to the general nomenclature of the art or are used
Figure BDA0003986848020000131
Software naming, commercial compounds are referred to by vendor catalog names.
The compounds disclosed in the invention can be usedThere can be one or more chiral centers, each having an R configuration or an S configuration independently of the other. The chiral centers of some of the compounds disclosed herein are labeled R, S, R, or S, indicating that the absolute configuration of the chiral center of the compound has not been identified, but that the compound has been chiral resolved and the chiral center is a single configuration chiral center, that the compound is a single configuration enantiomer monomer, or a single configuration diastereomer monomer, or a single diastereomer mixture of the chiral center configurations (e.g., other chiral center configurations have not been resolved). When the chiral center of the compound disclosed by the invention is unidentified in absolute configuration (R configuration or S configuration), the compound can be prepared according to the retention time (R) corresponding to the chiral center under the corresponding chromatographic column conditions (such as chromatographic column model, chromatographic column filling, chromatographic column size, flow equality) T ) Confirm it.
The present invention is more specifically explained in the following examples. It should be understood, however, that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way. The experimental procedures in the following examples, without specifying the specific conditions, are generally carried out according to the conventional conditions for such reactions, or according to the conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated. Unless otherwise specified, the ratio of liquids is the volume ratio.
Technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.
Detailed Description
The present application is described in detail below by way of examples, but is not meant to be limiting in any way. The present application has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present application without departing from the spirit and scope of the application.
The experimental materials and reagents used in the following examples were obtained from commercial sources unless otherwise specified.
In all of the embodiments described herein, the present invention, 1 H-NMR, 13 C-NMR 19 The F-NMR spectra were recorded using a Bruker Assend 400mHz Nuclear magnetic resonance apparatus, the spectra were processed using Topspin software, and deuterated solvents were used as internal deuterium locks. Wherein the method comprises the steps of 13 C-NMR 19 F-NMR pair 1 H decoupling. Partitioning is performed according to a defined chemical shift/coupling pattern, or according to 2D Cosy,HMBC,HSQC or NOESY experiments. The multiplicity of peaks is defined as s singlet, d doublet, t triplet, q quartet, m multiplet, br broad, br.s broad singlet; the coupling constant (J) is accurate to 0.1Hz. Mass spectra were recorded using an Agilent1260 (ESI) or Shimadzu LC-MS-2020 (ESI) type or Agilent 6215 (ESI) type mass spectrometer; reversed phase preparative HPLC separation is a full-automatic purification system guided by Agilent 1290 ultraviolet rays
Figure BDA0003986848020000141
Prep C18OBDTM 21.2×250mm10 μm column) or a fully automated purification system (% guided by Gilson GX281 uv light>
Figure BDA0003986848020000142
Prep C18OBDTM 19X 250mm10 μm column) or Waters QDa-directed fully automated purification System (.about.>
Figure BDA0003986848020000143
Prep C18OBD 29 x 250mm10 μm column). Unless otherwise specified, sepaFlash was used for separation, a normal phase silica gel column (national pharmaceutical systems and chemicals Co., ltd.) was preloaded, and the ratio of eluents was volume ratio in TLC analysis plate (smoke stage Jiang You silica gel development Co., ltd., model: HSGF254, specification: 2.5X15 cm).
Wherein, the Chinese names of the reagents represented by chemical formulas or English letter abbreviations are as follows:
CD 3 OD represents deuterated methanol; DMSO-d6 represents deuterated dimethyl sulfoxide; chloroform-d or CDCl 3 Represents deuterated chloroform; acOH represents acetic acid; alCl 3 Represents aluminum trichloride; aq represents an aqueous solution; n (N) 2 Represents nitrogen; ar represents argon; b (B) 2 Pin 2 Represents a bisboronic acid pinacol ester; BBr (BBr) 3 Represents boron tribromide; BH (BH) 3 Represents borane；(Boc) 2 O represents di-tert-butyl dicarbonate; et (Et) 3 SiH represents triethylsilane; HATU stands for 1- [ bis (dimethylamino) methylene]-1H-1,2, 3-triazolo [4,5-b]Pyridinium 3-oxide hexafluorophosphate; HOBt represents 1-hydroxybenzotriazole; k (K) 2 CO 3 Represents potassium carbonate; KOAc represents potassium acetate; meONa stands for sodium methoxide; LDA represents lithium diisopropylamide; liHMDS represents lithium bis (trimethylsilyl) amide; liOH represents lithium hydroxide; m-CPBA represents m-chloroperoxybenzoic acid; na (Na) 2 CO 3 Represents sodium carbonate; naBH 4 Represents sodium borohydride; naCl represents sodium chloride; naHCO (NaHCO) 3 Represents sodium bicarbonate; naOH represents sodium hydroxide; na (Na) 2 SO 4 Represents sodium sulfate; NBS represents N-bromosuccinimide; n-BuLi represents n-butyllithium; NH (NH) 4 Cl represents ammonium chloride; NMP represents N-methyl-2-pyrrolidone; PBr (PBr) 3 Represents phosphorus tribromide; pd (dppf) Cl 2 Or PdCl 2 (dppf) represents 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride; pd (OAc) 2 Represents palladium acetate; conc represents concentration; (COCl) 2 Represents oxalyl chloride; cs (cells) 2 CO 3 Represents cesium carbonate; cuCl stands for cuprous chloride; cuI stands for cuprous iodide; DCM represents dichloromethane; dioxane or 1,4-Dioxane represents 1, 4-Dioxane; meCN, ACN or CH 3 CN represents acetonitrile; meOH or methanol represents methanol; etOH or ethanol represents ethanol; DEA represents diethylamine; DIPEA or DIEA represents N, N-diisopropylethylamine; DMAP represents 4-dimethylaminopyridine; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EA or EtOAc represents ethyl acetate; PE represents petroleum ether; THF represents tetrahydrofuran; tolene or tol represents Toluene; SOCl 2 Represents thionyl chloride; TFA represents trifluoroacetic acid; FA represents formic acid; TMSCN represents trimethylsilane cyanide; h 2 O represents water; HCl represents hydrogen chloride gas; HCl aq. represents aqueous hydrochloric acid; DEG C represents DEG C; RT or RT represents room temperature; h represents hours; min represents minutes; g represents g; mg represents mg; mL represents mL; mmol represents mmol; m represents a mole; cm represents cm; mm represents millimeters; μm represents micrometers; nm represents nanometers; mL/min represents mL/min; hz stands for hertz; MHz stands for megahertz; bar represents the pressure unit A bar; psi stands for pressure units pounds per square inch; n (N) 2 Represents nitrogen; HPLC means high performance liquid chromatography; I.D. represents the inner diameter; LCMS or LC-MS represents liquid chromatography-mass spectrometry combined; m/z represents mass to charge ratio; ESI stands for electrospray ionization; CO 2 Represents carbon dioxide; TLC stands for thin layer chromatography; UV stands for ultraviolet.
Example 1 preparation of Compounds 1-5,1-6,1-7,1-8,1-9 and 1-10
Figure BDA0003986848020000151
Preparation of Compounds 1-2
Compound 1-1 (2 g,9.05 mmol) was dissolved in acetonitrile (25 mL), the reaction was stirred at room temperature for 0.5 h, 1, 3-dibromopropane (3.65 g,18.10 mmol) was added, potassium carbonate (2.5 g,18.10 mmol) and the mixture was stirred at room temperature overnight. The reaction system was filtered, and the filtrate was dried by spin-drying to give a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 1-2 (2.5 g, yield 50%) as a yellow oil. Compound 1-2: 1 H NMR(400MHz,DMSO-d6)δ7.99-7.98(m,1H),7.43–7.33(m,2H),4.20(t,J＝6.8Hz,2H),3.75(t,J＝6.8Hz,2H),2.32–2.21(m,2H).
preparation of Compounds 1-3
Compound 1-2 (2.5 g,7.31 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to-70 ℃. N-butyllithium (1.6M, 5.5 mL) was added dropwise to the system, and the reaction mixture was stirred at-70℃for 1 hour. The reaction was quenched with saturated aqueous ammonium bicarbonate (15 mL), extracted with ethyl acetate (20 ml×3), concentrated to give crude product, which was purified on a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0-100%) to give the title compound 1-3 (900 mg, yield 91%) as yellow oil. Compounds 1-3: 1 H NMR(400MHz,DMSO-d6)δ8.04(m,1H),7.15–7.07(m,2H),4.20–4.11(m,2H),2.85(t,J＝6.8Hz,2H),2.05–2.00(m,2H).
Preparation of Compounds 1-5 and 1-6
Compounds 1-3 (1 g,7.40 mmol) were dissolved in tetrahydrofuran (28 mL) and cooled to-70 ℃. N-butyllithium (1.6M, 6.9 mL) was added dropwise to the system, and the reaction mixture was stirred at-70℃for 1 hour. Tetrahydrofuran solution (5 mL) containing 1-4 (1.65 g,7.40 mmol) was added dropwise to the reaction system, the reaction was stirred at-70deg.C for 1 hour, quenched with saturated ammonium bicarbonate aqueous solution (15 mL), extracted with ethyl acetate (20 mL. Times.3), and concentrated to give crude product, which was isolated by preparation (preparation method: mobile phase: A:0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: agilent 10 Prep-C18X 21.2mm; column temperature: 25deg.C; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compounds 1-5 (78 mg, yield 3%) and the title compounds 1-6 (150 mg, yield 6%).
Chiral analysis method (chromatographic column model: cellulose-2X 4.6mm I.D.,3 μm; mobile phase: A: CO) 2 Ethanol (0.05% DEA); elution gradient 5 min mobile phase 5% b was raised to 40% b and 40% b was kept eluting for 2.5 min, then 5% b equilibrated for 2.5 min; the flow rate is 2.5mL/min; column temperature is 35 ℃; column pressure 1500psi; the detection wavelength is 220nm; rt=6.026 min). LC-MS (ESI) m/z 359.0[ M+H ] ] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.26(s,1H),8.23-8.21(m,1H),7.64(s,1H),7.38–7.14(m,4H),6.92-6.87(m,1H),6.02(s,1H),5.17(d,J＝14.6Hz,1H),5.03(d,J＝14.6Hz,1H),4.37-4.32(m,1H),4.04-4.01(m,1H),3.59(t,J＝5.6Hz,1H),1.88-1.80(m,1H),1.68–1.50(m,1H).
Chiral analysis method for Compounds 1-6 (column type: cellulose-2X 4.6mm I.D.,3 μm; mobile phase: A: CO) 2 Ethanol (0.05% DEA); elution gradient 5 min mobile phase 5% b was raised to 40% b and 40% b was kept eluting for 2.5 min, then 5% b equilibrated for 2.5 min; the flow rate is 2.5mL/min; column temperature is 35 ℃; column pressure 1500psi; the detection wavelength is 220nm; rt=6.026 min). LC-MS (ESI) m/z 359.0[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.30(s,1H),8.04(t,J＝3.0Hz,1H),7.63(s,1H),7.55-7.49(m,1H),7.19(d,J＝3.0Hz,2H),7.12(s,1H),7.07–7.01(m,1H),6.97–6.92(m,1H),5.23(d,J＝14.6Hz,1H),4.71(d,J＝14.6Hz,1H),3.98-3.93(m,1H),3.65-3.59(m,1H),3.46(t,J＝6.4Hz,1H),2.42–2.31(m,1H),2.02–1.79(m,1H).
Preparation of Compounds 1-7 and 1-8
SFC chiral preparation resolution of Compound 1-5 (78 MG) (preparation and separation method, instrument model: MG II preparation SFC (SFC-1), column model: cellulose-2, 250X 30mm I.D.,10 μm, mobile phase: A for CO) 2 and B for Ethanol; elution gradient: B40%; the flow rate is 70mL/min; column pressure 100bar; column temperature is 38 ℃; the detection wavelength is 220nm; period: -8 min) to give the title compounds 1-7 (25 mg) and 1-8 (25 mg).
Compounds 1-7 LC-MS (ESI) m/z 359.0[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.26(s,1H),8.23-8.21(m,1H),7.64(s,1H),7.41–7.16(m,4H),6.92-6.87(m,1H),6.02(d,J＝1.2Hz,1H),5.17(d,J＝14.8Hz,1H),5.03(d,J＝14.8Hz,1H),4.37-4.31(m,1H),4.04-4.00(m,1H),3.59(t,J＝5.6Hz,1H),1.88-1.80(m,1H),1.64-1.59(m,1H).
Compounds 1-8 LC-MS (ESI) m/z 359.0[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.26(s,1H),8.23-8.21(m,1H),7.64(s,1H),7.41–7.16(m,4H),6.92-6.87(m,1H),6.02(d,J＝1.2Hz,1H),5.17(d,J＝14.8Hz,1H),5.03(d,J＝14.8Hz,1H),4.37-4.31(m,1H),4.04-4.00(m,1H),3.59(t,J＝5.6Hz,1H),1.88-1.80(m,1H),1.64-1.59(m,1H).
Preparation of Compounds 1-9 and 1-10
SFC chiral preparation resolution of Compounds 1-6 (150 MG) (preparation separation method, apparatus model: MG II preparation SFC (SFC-1), column model: cellulose-2, 250X 30mm I.D.,10 μm, mobile phase: A for CO) 2 and B for Ethanol; elution gradient: B40%; the flow rate is 70mL/min; column pressure 100bar; column temperature is 38 ℃; the detection wavelength is 220nm; period: -8 min) to give the title compounds 1-9 (60 mg) and the title compounds 1-10 (60 mg).
Compounds 1-9 LC-MS (ESI) m/z 359.0[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.05-8.33(m,1H),7.63(s,1H),7.55-7.49(m,1H),7.19(d,J＝2.8Hz,2H),7.11(s,1H),7.07-7.01(m,1H),6.97-6.92(m,1H),5.23(d,J＝14.8Hz,1H),4.71(d,J＝14.8Hz,1H),3.98-3.93(m,1H),3.65-3.60(m,1H),3.46(t,J＝6.4Hz,1H),2.40-2.31(m,1H),1.96-1.89(m,1H).
Compounds 1-10 LC-MS (ESI) m/z 359.0[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.05-8.33(m,1H),7.63(s,1H),7.55-7.49(m,1H),7.19(d,J＝2.8Hz,2H),7.11(s,1H),7.07-7.01(m,1H),6.97-6.92(m,1H),5.23(d,J＝14.8Hz,1H),4.71(d,J＝14.8Hz,1H),3.98-3.93(m,1H),3.65-3.60(m,1H),3.46(t,J＝6.4Hz,1H),2.40-2.31(m,1H),1.96-1.89(m,1H).
Example 2 preparation of Compounds 2-8 and 2-9
Figure BDA0003986848020000171
Preparation of Compound 2-2
Compound 2-1 (22 g,122.1 mmol) was dissolved in dichloroethane (250 mL) and boron tribromide (52.7 mL,555.0 mmol) was slowly added and the reaction stirred at 80℃for 16 h. The reaction solution was poured into a saturated sodium hydrogencarbonate solution (150 mL), the pH was then adjusted to about 4 with acetic acid, ethyl acetate (50 mL. Times.3) was added for extraction, and the resultant was concentrated to give the objective product 2-2 (15 g, yield 59%). LC-MS (ESI) m/z 165.0[ M+H ]] + .
Preparation of Compounds 2-3
Compound 2-2 (15.0 g,73.19 mmol) was dissolved in tetrahydrofuran (150 mL), then 3-buten-1-ol (8.0 mL,87.2 mmol), triphenylphosphine (38.1 g,145.4 mmol) was added, the solution was cooled to 0deg.C, diisopropyl azodicarboxylate (28.8 mL,145.4 mmol) was then slowly added dropwise, the reaction stirred at room temperature for 12 hours, TLC plate and the starting material was complete. The reaction solution was then poured into water (200 mL), ethyl acetate (100 ml×3) was added to extract, and the organic phase was washed with saturated brine (30 ml×3), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified on a normal phase silica gel column (biotage, silica gel column, 330g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 2-3 (7.5 g, yield 47%) as a colorless oil. 1 H NMR(400MHz,CDCl 3 )δ8.18(s,1H),5.98-5.79(m,1H),5.35-5.08(m,2H).4.20(m,2H),2.64(m,2H).
Preparation of Compounds 2-4
Compound 2-3 (12 g,55.04 mmol) was dissolved in 1, 4-dioxane (200 mL), followed by the addition of potassium acetate (16.08 g,164.34 mmol), triphenylphosphine (5.7 g,21.91 mmol), palladium acetate (1.80 g,8.20 mmol), respectively,the reaction system was stirred at 100℃for 12h. The reaction solution was filtered, and the filtrate was concentrated to give a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 120g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 2-4 (6.5 g, yield 64%) as a white solid. LC-MS (ESI) m/z 183.0[ M+H ]] + .
Preparation of Compounds 2-5
Compound 2-4 (7.7 g,42.17 mmol) was dissolved in dichloromethane (100 mL) at room temperature, the reaction solution was cooled to-60℃and then ozone was introduced into the reaction system for reaction for 40 minutes, TLC was used to detect complete reaction of the starting materials, dimethyl sulfide (5 mL) was then added for quenching reaction, and vacuum concentration was performed to obtain crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 120g, UVA 254, ethyl acetate/petroleum ether=0 to 100%) to obtain compound 2-5 (1.93 g, yield 27%) as yellow solid. 1 H NMR(400MHz,CDCl 3 )δ8.66(s,1H),4.71(t,J＝8.0Hz,2H),3.04(t,J＝8.0Hz,2H).
Preparation of Compounds 2-6
Compound 2-5 (0.9 g,2.89 mmol) was dissolved in dichloromethane (10 mL) and ethanol (2 mL), and sodium borohydride (92 mg,2.44 mmol) was added and the reaction stirred at 25℃for 1 hour. The reaction solution was poured into water (50 mL), then dichloromethane (50 mL. Times.3) was added for extraction, and the organic phase was dried by spinning to give crude compound 2-6 (305 mg, yield 100%), the crude product was a yellow oil, and the crude product was directly fed for the next reaction. LC-MS (ESI) m/z 187.0[ M+H ] ] + .
Preparation of Compounds 2-7
Compound 2-6 (500 mg,2.68 mmol) was dissolved in dichloromethane (10 mL), triethylamine (814 mg,8.06 mmol) and methanesulfonyl chloride (365 mg,3.21 mmol) were then added, the reaction mixture was stirred at 25℃for 1 hour, the reaction mixture was poured into water (50 mL), dichloromethane (50 mL. Times.3) was then added for extraction, and the organic phase was dried by spinning to give crude 2-7 (580 mg, 100% yield) which was directly added for the next reaction. LC-MS (ESI) m/z 264.9[ M+H ]] + 。
Preparation of Compounds 2-8
Compound 1-4 (803 mg,1.63 mmol) was dissolved in tetrahydrofuran (10 mL), zinc powder (349 mg,5.45 mmol), lead powder (225 mg,1.09 mmol) and the reaction system was replaced with argon three times,the reaction solution was warmed to 70℃and then a tetrahydrofuran solution (2 mL) of Compound 2-7 (290 mg,1.09 mmol) was slowly added dropwise, and the reaction was carried out overnight at 70 ℃. After the reaction was completed, the reaction solution was filtered, and the filtrate was spin-dried to give crude 2-8 (360 mg), which was isolated by preparative separation (preparation method: mobile phase: A:0.1% aqueous formic acid; B: acetonitrile; chromatographic column: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 2-8 (78 mg, yield 3%). LC-MS (ESI) m/z 394.2[ M+H] + .
Preparation of Compounds 2-9
The crude compound 2-8 (950 mg,2.41 mmol) was dissolved in methanol (10 mL), then Pd/C (50 mg,10% wt), triethylamine (950 mg,2.41 mmol) was added, and after three hydrogen substitutions, the reaction solution was warmed to 60℃and reacted for 2 hours. The reaction solution was filtered and the filtrate was spin-dried to give a crude product which was isolated by preparative separation (preparation method: mobile phase: A:0.1% aqueous formic acid; B: acetonitrile; column chromatography: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 2-9 (17.0 mg, yield 0.98%). LC-MS (ESI) m/z 360.2[ M+H] + 。 1 H NMR (400 MHz, DMSO-d 6) delta 8.82 (s, 1H), 8.42 (s, 1H), 8.19 (m, 1H), 7.62 (s, 1H), 7.36-7.12 (m, 2H), 6.94-6.89 (m, 1H), 5.81 (s, 1H), 5.24-5.20 (m, 1H), 5.06-5.02 (m, 1H) 4.41-4.35 (m, 1H), 4.15-4.10 (m, 1H), 3.64-3.61 (m, 1H), 1.91-1.711 (m, 1H), 1.62-1.57 (m, 1H) example 3 preparation of Compounds 3-4 and 3-5
Figure BDA0003986848020000181
Preparation of Compound 3-3
Compound 3-1 (4 g,17.02 mmol), tetrazole 3-2 (1.19 g,17.02 mmol) was dissolved in acetonitrile (25 mL), the reaction was stirred at room temperature for 0.5 h, potassium carbonate (3.53 g,25.53 mmol) was added and the mixture was stirred at room temperature overnight. The reaction system was filtered, and the filtrate was dried by spin-drying to give a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 3-3 (1.5 g, yield 39%) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.81(s,1H),8.09(td,J＝8.6,6.4Hz,1H),7.13-7.08(m,1H),7.06-7.01(m,1H),5.88(d,J＝3.6Hz,2H).
Preparation of Compounds 3-4 and 3-5
Compound 1-3 (600 mg,4.44 mmol) was dissolved in tetrahydrofuran (28 mL), cooled to-70 ℃, n-butyllithium (1.6M, 2.77 mL) was added dropwise, the reaction was stirred at-70℃for 1 hour, tetrahydrofuran solution (5 mL) in which compound 3-3 (0.995 g,4.44 mmol) was dissolved was added dropwise to the reaction, the reaction was stirred at-70℃for 1 hour, saturated ammonium bicarbonate aqueous solution (50 mL) was added to quench the reaction, ethyl acetate (50 mL. Times.3) was extracted, and the crude product was obtained by concentration (preparation method: mobile phase: A:0.1% aqueous formic acid solution; B: acetonitrile; column: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to obtain the title compound 3-4 (70 mg), the title compound 3-5 (50 mg).
Compounds 3-4 LC-MS (ESI) m/z 360.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.25-8.24(m,1H),7.41–7.16(m,4H),6.91(td,J＝8.4,2.4Hz,1H),6.16(s,1H),5.49(d,J＝14.6Hz,1H),5.33(d,J＝14.6Hz,1H),4.36-4.30(m,1H),4.06-4.01(m,1H),3.68-3.65(m,1H),1.86-1.78(m,1H),1.66-1.59(m,1H).
Compounds 3-5 LC-MS (ESI) m/z 360.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.12-8.10(m,1H),7.53-7.47(m,1H),7.31(s,1H),7.27–7.17(m,2H),7.12-7.10(m,1H),6.99-6.94(m,1H),5.59(d,J＝14.6Hz,1H),4.92(dd,J＝14.6,1.2Hz,1H),3.97-3.93(m,1H),3.55–3.49(m,2H),2.38–2.31(m,1H),1.97-1.90(m,1H).
Example 4 preparation of Compounds 4-4 and 4-5
Figure BDA0003986848020000191
Preparation of Compounds 4-2 and 4-3
Compound 4-1 (500 mg,4.20 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to-65 ℃. N-butyllithium (1.6M, 3.93 mL) was added at-65℃and stirred at-65℃for 20 minutes. To the reaction system was added dropwise a tetrahydrofuran solution (2 mL) containing compounds 1 to 4 (4638 mg,2.1 mmol) dissolved therein, and stirring was continued for 10 minutes. The reaction was quenched by addition of saturated aqueous ammonium chloride (15 mL). Extraction with ethyl acetate (50 mL. Times.3) combined organic phases and spin-drying afforded crude product. The crude product was prepared (preparation method: mobile phase: A:0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 4-2 (30 mg, yield 2%) and compound 4-3 (50 mg, yield 3%).
Compounds 4-2 LC-MS (ESI) m/z 343.0[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.44–8.01(m,2H),7.63(s,1H),7.39(dd,J＝21.0,8.1Hz,2H),7.03(t,J＝6.2Hz,1H),6.80(q,J＝8.9,8.3Hz,2H),5.94(s,1H),5.13(d,J＝14.5Hz,1H),4.71(d,J＝14.4Hz,1H),3.59(d,J＝8.4Hz,1H),2.57–2.48(m,1H),2.07(ddd,J＝47.8,21.5,8.9Hz,3H).
Compounds 4-3 LC-MS (ESI) m/z 343.0[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.39(dd,J＝5.0,1.5Hz,1H),8.21(s,1H),7.63–7.50(m,2H),7.24–7.01(m,3H),6.82(td,J＝8.5,2.6Hz,1H),5.65–5.25(m,2H),4.94(d,J＝14.6Hz,1H),3.84(dd,J＝9.0,6.6Hz,1H),2.84(td,J＝9.6,9.1,4.5Hz,1H),2.66(ddd,J＝15.9,8.9,6.3Hz,1H),1.79–1.52(m,2H).
Preparation of Compounds 4-4 and 4-5
SFC chiral preparation resolution of Compound 4-3 (34 MG) (preparation separation method, instrument model: MG II preparation SFC (SFC-14), column model: chiralPak AD, 250X 30mm I.D.,10 μm, mobile phase: A for CO2 and B for Ethanol (0.1% NH3H 2O), elution gradient: B35%, flow rate: 70mL/min, column pressure: 100bar, column temperature: 38 ℃ C., detection wavelength: 220nm, period: 7 min) to give the title compound 4-4 (17 MG) and the title compound 4-5 (15 MG).
Compounds 4-4 LC-MS (ESI): 343.1[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.39(dd,J＝5.0,1.5Hz,1H),8.21(s,1H),7.63–7.50(m,2H),7.24–7.01(m,3H),6.82(td,J＝8.5,2.6Hz,1H),5.65–5.25(m,2H),4.94(d,J＝14.6Hz,1H),3.84(dd,J＝9.0,6.6Hz,1H),2.84(td,J＝9.6,9.1,4.5Hz,1H),2.66(ddd,J＝15.9,8.9,6.3Hz,1H),1.79–1.52(m,2H).
Compounds 4-5 LC-MS (ESI): 343.1[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.39(dd,J＝5.0,1.5Hz,1H),8.21(s,1H),7.63–7.50(m,2H),7.24–7.01(m,3H),6.82(td,J＝8.5,2.6Hz,1H),5.65–5.25(m,2H),4.94(d,J＝14.6Hz,1H),3.84(dd,J＝9.0,6.6Hz,1H),2.84(td,J＝9.6,9.1,4.5Hz,1H),2.66(ddd,J＝15.9,8.9,6.3Hz,1H),1.79–1.52(m,2H).
Example 5 preparation of Compounds 5A,5B1,5B2 and 5C
Figure BDA0003986848020000201
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Preparation of Compound 5-2
To a solution of 5-fluoropyridin-3-ol (3.80 g,33.60 mmol) in water (92 mL) was added sodium carbonate (7.138 g,67.22 mmol) and potassium iodide (11.158 g,67.19 mmol) at room temperature. A solution of iodine (1.94 g,47.05 mmol) in water (13 mL) was added dropwise with stirring over 1.5 hours. The reaction mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the pH of the reaction mixture was adjusted to 5-6 with hydrochloric acid solution (4M) until a precipitate was obtained, which was collected by filtration and dried in a vacuum oven to give the title compound 5-2 (2.97 g, 37%). 1 H NMR(400MHz,DMSO-d6)δ11.46(s,1H),7.96(d,J＝2.8Hz,1H),7.03(dd,J＝10.2,2.8Hz,1H).
Preparation of Compound 5-3
Compound 5-2 (1 g,4.18 mmol), potassium carbonate (1.16 g,8.37 mmol) was dissolved in acetonitrile (25 mL), the reaction was stirred at room temperature for 0.5 h, then 1, 3-dibromopropane (1.01 g,5.03 mmol) was added and the mixture was stirred at room temperature overnight. The reaction system was filtered, and the filtrate was dried by spin-drying to give a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 10g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 5-3 (1.3 g, yield 86%). 1 H NMR(400MHz,DMSO-d6)δ7.99(d,J＝2.4Hz,1H),6.83(dd,J＝9.7,2.4Hz,1H),4.19(t,J＝5.6Hz,2H),3.71(t,J＝6.0Hz,2H),2.41(p,J＝6.0Hz,2H).
Preparation of Compounds 5-4 and 5-4a
Compound 5-3 (1.3 g,3.61 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to-70 ℃. N-butyllithium (1.6M, 3.4 mL) was added dropwise, and the reaction was stirred at-70℃for 1 hour. The reaction system was quenched with saturated aqueous ammonium bicarbonate (60 mL), extracted with ethyl acetate (20 ml×3), concentrated to give crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0-100%) to give the title compound 5-4 (100 mg) and the title compound 5-4a (400 mg).
Compound 5-4: 1 H NMR(400MHz,DMSO-d6)δ8.19(dd,J＝2.4,0.8Hz,1H),7.20(dd,J＝9.0,2.4Hz,1H),4.35–4.27(m,2H),3.12(td,J＝6.8,1.2Hz,2H),2.23–2.10(m,2H).
compounds 5-4a: 1 H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.99(s,1H),4.24–4.19(m,2H),2.73(t,J＝6.4Hz,2H),1.98–1.92(m,2H).
preparation of Compound 5A
Compound 5-4 (100 mg,0.652 mmol) was dissolved in tetrahydrofuran (1 mL) and cooled to-70 ℃. N-butyllithium (1.6M, 0.4 mL) was added dropwise, and the reaction was stirred at-70℃for 1 hour. To the reaction system was added dropwise a tetrahydrofuran solution (2 mL) containing Compound 1-4 (145 mg,0.652 mmol) dissolved therein, and the reaction mixture was stirred at-70℃for 1 hour. The reaction system was quenched with aqueous ammonium bicarbonate (60 mL), extracted with ethyl acetate (20 mL. Times.3), and concentrated to give crude product, which was prepared (preparation method: mobile phase: A:0.1% aqueous formic acid; B: acetonitrile; column chromatography: agilent 10Prep-C18 250X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 5A (2.5 mg).
Compound 5A LC-MS (ESI) m/z 377.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.22(s,1H),8.00(d,J＝2.8Hz,1H),7.62(s,1H),7.27-7.22(m,1H),7.09-7.05(m,1H),6.89-6.85(m,1H),6.66(s,1H),5.21–5.06(m,2H),4.13-4.09(m,1H),4.02-3.98(m,1H),2.84(t,J＝6.4Hz,2H),1.97-1.92(m,2H).
Preparation of Compounds 5B1,5B2 and 5C
Compound 5-4a (400 mg,2.61 mmol) was dissolved in tetrahydrofuran (3 mL) and cooled to-70 ℃. N-butyllithium (1.6N/L, 2.61 mL) was added dropwise, and the reaction mixture was stirred at-70℃for 1 hour. A tetrahydrofuran solution containing compounds 1 to 4 (583 mg,0.652 mmol) was added dropwise to the reaction system, followed by stirring at-70℃for 1 hour. The reaction system was quenched with aqueous ammonium bicarbonate (60 mL), extracted with ethyl acetate (20 mL. Times.3), and concentrated to give crude product, which was prepared (preparation method: mobile phase: A:0.1% aqueous formic acid; B: acetonitrile; column chromatography: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the target product 5C (26 mg), 5B1 (17 mg), 5B2 (40 mg).
Compound 5C LC-MS (ESI) m/z 377.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.25(s,1H),8.01(s,1H),7.64(s,1H),7.38-7.32(m,1H),7.08-7.02(m,1H),6.92-6.87(m,1H),6.62(s,1H),5.20–5.08(m,2H),4.20(t,J＝5.2Hz,2H),2.64–2.61(m,2H),1.93-1.88(m,2H).
LC-MS (ESI) m/z 377.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.98(s,1H),7.76(s,1H),7.68(s,1H),7.15-7.09(m,1H),7.03-6.97(m,1H),6.81-6.76(m,1H),5.73(s,1H),5.05(d,J＝14.2,1H),4.84(d,J＝14.2Hz,1H),4.60-4.53(m,1H),4.35-4.31(m,1H),3.73(d,J＝4.8Hz,1H),2.59-2.54(m,1H),2.00-1.90(m,1H).
Compound 5B2 LC-MS (ESI) m/z 377.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.19(s,1H),8.14(s,1H),7.60(s,1H),7.33–7.20(m,2H),6.94-6.89(m,1H),5.86(s,1H),4.97(dd,J＝14.2,2.4Hz,1H),4.57-4.40(m,1H),4.42(dd,J＝14.2,3.6Hz,1H),4.23–4.10(m,1H),3.76(d,J＝4.8Hz,1H),1.80-1.70(m,1H),1.44-1.39(m,1H).
Example 6 preparation of Compounds 6-8 and 6-9
Figure BDA0003986848020000221
Preparation of Compound 6-3
Compound 5-2 (crude, 33.60 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to 0deg.C. 3-buten-1-ol (2.54 g,35.28 mmol), DEAD (6.14 g,35.28 mmol), triphenylphosphine (9.69 g,36.96 mmol) were added and the reaction stirred at 0deg.C for 1 hour. Ethyl acetate (20 mL x 3) and concentrating to obtain crude product, and purifying the crude product with normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0-100%) to obtain target product 6-3 (12 g, crude product).
Preparation of Compounds 6-4
In a round bottom flask was charged compound 6-3 (trude, 34.12 mmol), triphenylphosphine (2.68 g,10.24 mmol), palladium acetate (0.766 g,3.41mmo 1) and potassium acetate (16.74 g,170.10 mmol). Anhydrous DMF (200 mL) was added under nitrogen and dissolved, followed by stirring in an oil bath at 105 ℃. After 10 hours the plate was spotted and TLC checked complete reaction of starting material. After the reaction mixture was cooled to room temperature, the reaction mixture was quenched by addition of water (100 mL), extracted with ethyl acetate (20 mL. Times.3), washed with saturated brine (20 mL. Times.3), and dried over anhydrous sodium sulfate. Filtration, addition of silica gel to the filtrate followed by spin-drying and purification with a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0-100%) gave the title compound 6-4 (1.2 g) as a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ8.09(d,J＝2.4Hz,1H),6.90(dd,J＝9.2,2.4Hz,1H),6.11(d,J＝1.6Hz,1H),5.05(dd,J＝1.6,0.8Hz,1H),4.38–4.20(m,2H),2.91–2.72(m,2H).
Preparation of Compounds 6-5
To a round bottom flask was added compound 6-4 (1 g,6.05 mmol) and dichloromethane (60 mL) and cooled to-78℃in a dry ice-acetone bath and ozone gas was vented. After the reaction mixture turned dark blue, aeration was stopped. Dimethyl sulfide (5 mL) was added to the reaction mixture, and the mixture was naturally warmed to room temperature. After stirring for 2 hours, the reaction was added with water (50 mL), extracted with dichloromethane (50 ml×3), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 6-5 (636 mg, yield 63%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ8.33(d,J＝2.3Hz,1H),7.10(dd,J＝8.8,2.4Hz,1H),4.64(t,J＝6.5Hz,2H),3.05–2.83(m,2H).
Preparation of Compounds 6-6
Compound 6-5 (636 mg,3.81 mmol) was dissolved in THF (28 mL) and cooled to 0deg.C. DIBAL-H (1M, 5.70 mL) was added thereto, and the reaction mixture was stirred at 0℃for 1 hour. Spin-drying gives crude product which is purified by normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0-100%) to give the title compound 6-6 (500 mg, yield 78%). LC-MS (ESI) m/z 170.0[ M+H ]] + .
Preparation of Compounds 6-7
Compound 6-6 (300 mg,1.17 mmol) was dissolved in dichloromethane (28 mL) and cooled to 0deg.C. Methanesulfonyl chloride (304 mg,2.66 mmol) was added, and the reaction solution was stirred at 0℃for 1 hour. The reaction system was added with water (50 mL), extracted with methylene chloride (50 ml×3), dried over anhydrous sodium sulfate, and concentrated to give a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 6-7 (438 mg, yield 100%).
Preparation of Compounds 6-8 and 6-9
Compound 1-4 (271mg, 1.21 mmol) was dissolved in tetrahydrofuran (10 mL), zinc powder (390 mg,6.07 mmol) was added, lead powder (25 mg,0.121 mmol) was substituted three times with argon, DIBAL-H (1M, 0.5 mL) was added to activate for 40min, the reaction solution was warmed to 70℃and then 7-7 (300 mg,1.21 mmol) in tetrahydrofuran was slowly added dropwise, the reaction was completed at 60℃overnight, and after completion of the reaction, filtration and spin-drying of the filtrate gave a crude product which was isolated (preparation method: mobile phase: 0.1% aqueous formic acid; B: acetonitrile; column: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 6-8 (20 mg) and the title compound 6-9 (20 mg).
Compounds 6-8 LC-MS (ESI) m/z 377.0[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.26(d,J＝2.4Hz,1H),8.20(s,1H),7.62(s,1H),7.36–7.19(m,3H),6.93-6.90(m,1H),5.70(s,1H),5.18–4.90(m,2H),4.43–4.29(m,1H),4.07(dd,J＝9.6,4.8Hz,1H),3.62(d,J＝4.8Hz,1H),1.88–1.72(m,1H),1.65–1.48(m,1H).
Compounds 6-9 LC-MS (ESI) m/z 377.0[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.04(d,J＝2.4Hz,1H),7.65(s,1H),7.40-7.34(m,1H),7.22-7.18(m,1H),7.04-7.00(m,1H),6.92-6.88(m,1H),6.39(s,1H),5.22(d,J＝14.6Hz,1H),4.79(d,J＝14.6Hz,1H),4.06-3.99(mz,1H),3.54-3.52(m,2H),2.43-2.39(m,1H),2.05–1.85(m,1H).
EXAMPLE 7 preparation of Compounds 7-11 and 7-11a
Figure BDA0003986848020000231
Preparation of Compound 7-2
Compound 7-1 (12 g,54.30 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to 0deg.C. 3-buten-1-ol (4.11 g,57.01 mmol), DEAD (15.67 g,59.73 mmol), triphenylphosphine (9.93 g,57.01 mmol) were added and the reaction solution was stirred at 0℃for 1 hour. Ethyl acetate (50 mL x 3) was extracted and the ethyl acetate was concentrated to give a crude product, which was subjected to a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 7-2 (14.5 g, yield 97%). 1 H NMR(400MHz,Chloroform-d)δ8.00(dd,J＝4.4,1.6Hz,1H),7.18(dd,J＝8.0,4.4Hz,1H),6.98(dd,J＝8.0,1.6Hz,1H),5.99-5.94(m,1H),5.28–5.10(m,2H),4.07(t,J＝6.4Hz,2H),2.70–2.55(m,2H).
Preparation of Compound 7-3
In a round bottom flask was charged compound 7-2 (14.50 g,52.71 mmol), triphenylphosphine (4.15 g,15.81 mmol), palladium acetate (1.18 g,5.27mmo 1) and potassium acetate (25.87 g,263.55 mmol). Anhydrous DMF (200 mL) was added under nitrogen and dissolved, followed by stirring in an oil bath at 105 ℃. After 10 hours the plate was spotted and TLC checked complete reaction of starting material. After the reaction mixture was cooled to room temperature, the reaction mixture was quenched by addition of water (100 mL), extracted with ethyl acetate (50 mL. Times.3), washed with saturated brine (50 mL. Times.3), and dried over anhydrous sodium sulfate. Filtration, addition of silica gel to the filtrate followed by spin-drying to give sand, the title compound 7-3 (5.5 g, 71% yield) as a yellow oil, was obtained as a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%). 1 H NMR(400MHz,DMSO-d6)δ8.17(dd,J＝4.2,1.6Hz,1H),7.32–7.16(m,2H),6.09(d,J＝2.0Hz,1H),5.07(d,J＝2.0Hz,1H),4.20(dd,J＝6.0,5.2Hz,2H),2.80-2.75(m,2H).
Preparation of Compound 7-4
To a round bottom flask was added compound 7-3 (6 g,40.77 mmol) and dichloromethane (150 mL) and cooled to-78℃in a dry ice-acetone bath and ozone gas was vented. After the reaction mixture turned dark blue, aeration was stopped. Dimethyl sulfide (30 mL) was added to the reaction mixture, and the mixture was naturally warmed to room temperature. After stirring for 2 hours, the reaction was added with water (100 mL), extracted with dichloromethane (100 ml×3), dried over anhydrous sodium sulfate, concentrated, and purified by a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 7-4 (5.9 g, yield 97%) as a white solid. 1 H NMR(400MHz,CDCl 3 )δ8.48(ddd,J＝18.0,3.9,1.6Hz,1H),7.43–7.36(m,2H),4.66–4.56(m,2H),2.98(dd,J＝8.4,4.6Hz,2H).
Preparation of Compounds 7-5
Compound 7-4 (200 mg,1.34 mmol) was dissolved in dichloromethane (28 mL) and cooled to 0deg.C. Copper triflate (480 mg,1.34 mmol) was added and the reaction stirred at 0deg.C for 1 hour. The reaction system was washed with water (20 ml×3), dried, and spin-dried to give a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 7-5 (100 mg, yield 30%). LC-MS (ESI) m/z 249.2[ M+H ]] + .
Preparation of Compounds 7-6
Compound 7-5 (1.10 g,4.43 mmol) was dissolved in dichloromethane (10 mL), BAST (1.47 g,6.64 mmol) was added, and after three times of argon substitution, the reaction mixture was warmed to 70℃and reacted overnight. After the reaction was completed, filtration and spin-drying of the filtrate gave a crude product, which was subjected to a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 7-6 (750 mg, yield 95%). 1 H NMR(400MHz,Chloroform-d)δ8.40(dd,J＝4.2,1.2Hz,1H),7.39-7.35(m,1H),7.31-7.28(m,1H),4.50-4.40(m,1H),4.30-4.23(m,1H),2.85–2.56(m,2H).
Preparation of Compounds 7-7
Compound 7-6 (700 mg,3.93 mmol) was dissolved in concentrated hydrochloric acid (10 mL), and the reaction mixture was warmed to 70℃and reacted overnight. After the reaction was completed, the filtrate was dried by spin to give the crude title compound 7-7 (750 mg, crop).
Preparation of Compounds 7-8
Compound 7-7 (1g crude,5.07mmol) was dissolved in dichloromethane (28 mL) and cooled to 0deg.C. DIEA (1.31 g,10.04 mmol), HATU (2.31 g,6.09 mmol), morphine (0.530 g,6.09 mmol) were added and the reaction stirred at 0deg.C for 1 hour. The reaction system was washed with water (20 ml×3), dried, and spin-dried to give a crude product, which was purified by a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 7-8 (500 mg, yield 37%). LC-MS (ESI): m/z 267.2[ M+H ]] + .
Preparation of Compounds 7-9
2, 4-difluorobromobenzene(284 mg,1.46 mmol) was dissolved in diethyl ether (4 mL) and cooled to-70 ℃. Butyl lithium (2.5M, 0.58 mL) was added dropwise and the reaction stirred at-70℃for 1 hour. To the reaction system was added dropwise an ether solution (5 mL) containing 7-8 (300 mg,1.13 mmol) of the compound dissolved therein, and the reaction mixture was stirred at-70℃for 1 hour. Silica gel powder was added and spin-dried to give the title compounds 7-9 (100 mg, crude) as white solids as normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0-100%). LC-MS (ESI) m/z 294.1[ M+H ] ] + .
Preparation of Compounds 7-10
Compound 7-9 (50 mg,0.170 mmol), trimethylsulfoxide iodide (56 mg,0.255 mmol), naOH (14 mg,0.314 mmol) were dissolved in dichloromethane (5 mL) and water (1 mL), and the reaction solution was stirred at 60℃for 12 hours. The dichloromethane phase was separated and concentrated to give crude product, which was purified by normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0-100%) to afford title compound 7-10 (50 mg, impure). LC-MS (ESI) m/z 308.2[ M+H ]] + .
Preparation of Compounds 7-11 and 7-11a
Compound 7-10 (50 mg,0.162 mmol), triazole (23 mg,0.325 mmol), naH (10 mg,0.244mm, dissolved in DMF (1 mL), the reaction mixture stirred at 60 ℃ C. For 12 hours, saturated aqueous ammonium bicarbonate (10 mL), ethyl acetate (30 mL. Times.3) were added to the reaction system and extracted, and concentrated to give crude product, which was prepared (preparation: mobile phase: A:0.1% aqueous formic acid; B: acetonitrile; column: agilent 10 Prep-C18250X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 7-11 (3 mg, yield 1.9%).
Compounds 7-11 LC-MS (ESI) m/z 377.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.35(dd,J＝4.2,1.6Hz,1H),8.32(s,1H),7.67(s,1H),7.48–7.34(m,3H),7.18-7.11(m,1H),6.92–6.86(m,2H),5.50(q,J＝14.7Hz,2H),4.40-4.35(m,1H),4.06-3.99(m,1H),2.26-2.12(m,1H),1.98-1.87(m,1H)。
Example 8 preparation of Compounds 8-4 and 8-5
Figure BDA0003986848020000251
Preparation of Compound 8-2
Compound 8-1 (1 g,8.84 mmol), potassium carbonate (3.67 g,26.53 mmol) was dissolved in acetonitrile (25 mL), the reaction was stirred at room temperature for 0.5 h, 1, 3-dibromopropane was added (2.68 g,13.26 mmol), and the mixture was stirred at room temperature overnight. Filtration and spin-drying of the filtrate gave a crude product which was subjected to a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 8-2 (1.3 g, yield 63%). LC-MS (ESI) m/z 233.8[ M+H ] ] + .
Preparation of Compound 8-3
Compound 8-2 (1.3 g,5.55 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to-70 ℃. N-butyllithium (2.5M, 4.89 mL) was added dropwise, and the reaction mixture was stirred at-70℃for 1 hour. The reaction was quenched with aqueous ammonium bicarbonate (10 mL), extracted with ethyl acetate (20 ml×3), and concentrated to give a crude product, which was subjected to a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0 to 100%) to give the title compound 8-3 (600 mg, yield 70%). 1 H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.98(s,1H),4.27–4.19(m,2H),2.77(t,J＝6.4Hz,2H),2.07–2.00(m,2H).
Preparation of Compounds 8-4 and 8-5
Compound 8-3 (300 mg,1.96 mmol) was dissolved in tetrahydrofuran (28 mL) and cooled to-70 ℃. N-butyllithium (1.6M, 1.2 mL) was added dropwise, and the reaction mixture was stirred at-70℃for 1 hour. A solution of Compound 3-3 (263 mg,1.18 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction system, and the reaction mixture was stirred at-70℃for 1 hour. The reaction was quenched with aqueous ammonium bicarbonate (10 mL), extracted with ethyl acetate (20 mL. Times.3), and concentrated to give crude product, which was prepared (preparation method: mobile phase: A:0.1% aqueous formic acid; B: acetonitrile; column chromatography: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 8-4 (4 mg) and the title compound 8-5 (13 mg).
Compound 8-4 LC-MS (ESI) m/z 378.4[ M+H ] ] + .1H NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.00(s,1H),7.79(s,1H),7.21-7.17(m,1H),7.00-6.94(m,1H),6.83-6.78(m,1H),6.01(s,1H),5.34(d,J＝14.2Hz,1H),5.08(d,J＝14.2Hz,1H),4.53-4.47(m,1H),4.36-4.32(m,1H),3.80(d,J＝4.8Hz,1H),2.64–2.54(m,1H),2.06–1.88(m,1H).
Compounds 8-5 LC-MS (ESI) m/z 378.4[ M+H ]] + .1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.21(s,1H),8.16(s,1H),7.39-7.33(m,1H),7.25-7.19(m,1H),6.95-6.90(m,1H),6.05(s,1H),5.31-5.27(m,1H),4.66-4.62(m,1H),4.56–4.46(m,1H),4.20-4.16(m,1H),3.82(d,J＝4.8Hz,1H),1.83-1.73(m,1H),1.44-1.40(m,1H).
EXAMPLE 9 preparation of Compounds 9-6 and 9-7
Figure BDA0003986848020000261
Preparation of Compound 9-2
Compound 9-1 (10 g,38.15 mmol) was dissolved in an aqueous solution (200 mL) of sodium carbonate (8.3 g,78.3 mmol), and iodine beads (9.94 g,38.15 mmol) were added in portions at room temperature and stirred at room temperature for 6 hours. LC-MS detection reaction was complete. The pH of the reaction system was adjusted to 6 to 7 with an aqueous hydrochloric acid solution (2M). Extraction with ethyl acetate (20 mL. Times.3) and concentration gives crude product. Spin-drying afforded the title compound 9-2 (13 g, 66% yield). LC-MS (ESI) m/z 255.9[ M+H ]] + .
Preparation of Compound 9-3
Compound 9-2 (5 g,19.57 mmol), 3-bromopropanol (3.26 g,23.49 mmol), triphenylphosphine (6.16 g,23.49 mmol) was dissolved in tetrahydrofuran (50 mL), and DEAD (4.09 g,23.49 mmol) was added. The reaction was carried out at room temperature for 2 hours. LCMS detected complete reaction. Water (50 mL) was added and extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined and spin-dried to give the crude product, which was used in a normal phase silica gel column (biotage, silica gel column, 20g, UV254, ethyl acetate/petroleum ether=0-100%) to give the title compound 9-3 (6.0 g, yield 81%). LC-MS (ESI) m/z 375.9[ M+H ]] + .
Preparation of Compound 9-4
Compound 9-3 (5 g,13.28 mmol) was dissolved in tetrahydrofuran (30 mL). N-butyllithium (1.6M, 9.3 mL) was added dropwise at-65 ℃. After 1 hour of reaction, samples were taken and sent to LC-MS for monitoring the completion of the reaction. The reaction system was quenched with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases combined and dried by spin to give crude product which was purified by a normal phase silica gel column (biotage, silica gel column, 20g, UV254, acetic acid) Ethyl ester/petroleum ether=0 to 100%) to afford the title compound 9-4 (1.5 g, yield 66%). LC-MS (ESI) m/z 170.0[ M+H ]] + .
Preparation of Compound 9-5
Compound 9-4 (1.4 g,8.25 mmol), tricyclohexylphosphorus (231 mg,0.83 mmol), palladium acetate (185 mg,0.83 mmol), potassium phosphate (5.26 g,24.76 mmol), cyclopropylboronic acid (0.78 g,9.08 mmol) were dissolved in 1, 4-dioxane (10 mL) and water (2 mL) and reacted at 110℃for 16h. Water (50 mL) was added and extracted with ethyl acetate (50 ml×3), the organic phases were combined and spin-dried to give crude product, which was used in normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0-100%) to give the title compound 9-5 (300 mg, yield 20%). LC-MS (ESI) m/z 176.0[ M+H ]] + . 1 H NMR(400MHz,Chloroform-d)δ7.96(d,J＝2.0Hz,1H),6.71(d,J＝1.9Hz,1H),4.23–4.08(m,2H),2.93(t,J＝6.6Hz,2H),2.17–2.02(m,2H),1.89–1.79(m,1H),1.04–0.91(m,2H),0.67(dt,J＝6.6,4.8Hz,2H).
Preparation of Compounds 9-6 and 9-7
Compound 9-5 (300 mg,3.23 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to-65 ℃. N-butyllithium (1.6M, 3.03 mL) was added at-65℃and the mixture was stirred at-65℃for 20 minutes. A solution of compounds 1-4 (382 mg,1.71 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction system, and stirring was continued for 10 minutes. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined and dried by spin to give the crude product. The crude product was prepared (preparation method: mobile phase: A:0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 9-6 (40 mg, yield 6%) and the title compound 9-7 (50 mg, yield 7%).
Compounds 9-6 LC-MS (ESI) m/z 399.1[ M+H ]] + .1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),8.01(d,J＝1.9Hz,1H),7.56(s,1H),7.30–7.07(m,2H),6.90–6.72(m,2H),5.90(s,1H),5.08(d,J＝14.7Hz,1H),4.93(d,J＝14.7Hz,1H),4.31–4.18(m,1H),3.91(dd,J＝10.2,4.9Hz,1H),3.47(t,J＝5.4Hz,1H),1.96–1.82(m,1H),1.80–1.67(m,1H),1.52(d,J＝4.0Hz,1H),0.92(dd,J＝8.3,3.0Hz,2H),0.67(dd,J＝7.3,5.1Hz,2H).
Compounds 9-7 LC-MS (ESI) m/z 399.1[ M+H ]] + .1H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.83(d,J＝2.0Hz,1H),7.56(s,1H),7.46(td,J＝8.9,6.8Hz,1H),7.12(s,1H),6.98(ddd,J＝12.1,9.2,2.7Hz,1H),6.88(td,J＝8.5,2.7Hz,1H),6.74(d,J＝2.0Hz,1H),5.14(d,J＝14.5Hz,1H),4.59(d,J＝14.5Hz,1H),3.83(td,J＝7.3,3.6Hz,1H),3.55(ddd,J＝11.2,8.0,3.2Hz,1H),2.28–2.14(m,1H),1.82(td,J＝8.5,4.2Hz,2H),0.97–0.83(m,2H),0.70–0.58(m,2H).
Example 10 preparation of Compounds 10-10,10-11,10-2 and 10-13
Figure BDA0003986848020000271
Preparation of Compound 10-2
To compound 10-1 (10 g,57.47 mmol), sodium carbonate (12.18 g,114.94 mmol) was added water (50 mL). Iodine granules (16.05 g,63.22 mmol) were added in portions at room temperature and stirred for 6h at room temperature. LCMS detected complete reaction. The pH was adjusted to 6-7 with aqueous hydrochloric acid (2M). A yellow solid precipitated and was stirred for 1 hour. Filtration and washing of the filter cake with water (50 mL. Times.3) and drying of the filter cake gave the title compound 10-2 (14.2 g, 82% yield). LC-MS (ESI) m/z 299.8[ M+H ]] + .
Preparation of Compound 10-3
Compound 10-2 (5 g,16.67 mmol), 3-bromopropanol (2.78 g,20.01 mmol), triphenylphosphine (5.52 g,20.01 mmol) was dissolved in tetrahydrofuran (50 mL), and DEAD (3.48 g,20.01 mmol) was added dropwise at 0deg.C. The reaction was carried out at room temperature for 2 hours. LCMS detected complete reaction. Water (50 mL) was added and extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined and spin-dried to give the crude product, which was used in a normal phase silica gel column (biotage, silica gel column, 20g, UV254, ethyl acetate/petroleum ether=0-100%) to give the title compound 10-3 (6.2 g, yield 88%). LC-MS (ESI) m/z 421.8[ M+H ]] + .
Preparation of Compound 10-4
Compound 10-3 (3 g,7.13 mmol) was dissolved in tetrahydrofuran (30 mL). N-butyllithium (1.6M, 4.9 mL) was added dropwise at-65 ℃. After 1 hour of reaction, the reaction system was quenched with saturated aqueous ammonium chloride (50 mL)The organic phases were combined and dried to give crude product, which was purified by extraction with ethyl acetate (50 ml×3) to give title compound 10-4 (600 mg, 39% yield) over a normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0-100%). LC-MS (ESI) m/z 214.0[ M+H ]] + .
Preparation of Compound 10-6
Compound 10-4 (1.24 g,5.79 mmol), compound 10-5 (1.53 g,6.95 mmol), pd (dppf) Cl 2 (423 mg,0.58 mmol) potassium carbonate (1.6 g,11.59 mmol) was dissolved in 1, 4-dioxane (10 mL) and water (2 mL) and reacted at 110℃for 16h. Water (50 mL) was added and extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined and spin-dried to give the crude product, which was used in a normal phase silica gel column (biotage, silica gel column, 20g, UV254, ethyl acetate/petroleum ether=0-100%) to give the title compound 10-6 (700 mg, yield 39%). LC-MS (ESI) m/z 310.2[ M+H ]] + . 1 H NMR(400MHz,Chloroform-d)δ8.31(d,J＝2.0Hz,1H),7.55–7.49(m,2H),7.25(d,J＝2.0Hz,1H),7.06–6.99(m,2H),4.40(q,J＝8.1Hz,2H),4.27–4.18(m,2H),3.01(t,J＝6.5Hz,2H),2.21–2.12(m,2H).
Preparation of Compounds 10-8 and 10-9
Compound 10-6 (1.0 g,3.23 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to-65 ℃. N-butyllithium (1.6M, 3.03mL,4.85 mmol) was added at-65℃and stirred for 20 minutes at-65℃and then compound 10-5 (0.616 g,3.23 mmol) was added and stirred for 10 minutes at room temperature. Saturated aqueous ammonium chloride (50 mL) was added, quenched and extracted with ethyl acetate (50 mL. Times.3) and the organic phases were combined and dried to give the crude product. The crude product was prepared (preparation method: mobile phase: A:0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 10-8 (100 mg, yield 6%) and the title compound 10-9 (100 mg, yield 6%).
Compounds 10-8 LC-MS (ESI) m/z 464.4[ M+H ]] + . 1 H NMR(400MHz,Chloroform-d)δ8.42(d,J＝2.0Hz,1H),7.58–7.50(m,2H),7.46(d,J＝6.3Hz,1H),7.33(d,J＝2.0Hz,1H),7.07–7.01(m,2H),6.93–6.81(m,2H),4.48(d,J＝3.7Hz,1H),4.41(q,J＝8.1Hz,2H),4.30(s,1H),3.90–3.77(m,1H),3.01(d,J＝5.0Hz,1H),2.61(d,J＝5.0Hz,1H),2.07(d,J＝3.9Hz,2H).
Compounds 10-9 LC-MS (ESI) m/z 464.4[ M+H ]] + . 1 H NMR(400MHz,Chloroform-d)δ8.48(d,J＝2.0Hz,1H),7.59–7.52(m,2H),7.52–7.45(m,1H),7.33(d,J＝2.0Hz,1H),7.08–7.00(m,2H),6.89–6.69(m,2H),4.41(q,J＝8.1Hz,2H),4.21(dtd,J＝17.6,11.2,6.5Hz,2H),3.46(t,J＝5.5Hz,1H),3.15(d,J＝4.8Hz,1H),3.03(d,J＝4.7Hz,1H),2.38–2.24(m,1H),2.21–2.09(m,1H).
Preparation of Compounds 10-10 and 10-11
Compound 10-8 (100 mg,0.22 mmol) was dissolved in DMF (2 mL), 1H-tetrazole (30.23 mg,0.43 mmol) was added, potassium carbonate (59.65 mg,0.43 mmol), the reaction was heated to 80℃and stirred for 4 days, water (10 mL) was added, and extracted with ethyl acetate (10 mL. Times.3), and the combined organic phases were dried by spinning to give crude product. The crude preparation (preparation: mobile phase: A:0.1% formic acid in water; B: acetonitrile; column chromatography: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) gave the title compound 10-10 (30 mg, yield 26%) and the title compound 10-11 (33 mg, 29%).
Compounds 10-10 LC-MS (ESI) m/z 534.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.44(s,1H),7.74(d,J＝8.3Hz,2H),7.50(d,J＝8.1Hz,2H),7.18(d,J＝8.3Hz,2H),7.12(m,1H),7.02–6.94(m,1H),5.62(d,J＝14.5Hz,1H),4.98(d,J＝14.5Hz,1H),4.84(q,J＝8.8Hz,3H),4.04–3.97(m,1H),3.56(m,2H),2.37(m,1H),2.07–1.92(m,1H).
Compounds 10-11 LC-MS (ESI) m/z 534.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.69(s,1H),8.44(d,J＝2.0Hz,1H),7.80–7.71(m,2H),7.51(dd,J＝6.2,2.2Hz,2H),7.20–7.14(m,2H),7.15–7.07(m,1H),7.01–6.92(m,1H),5.84(d,J＝14.3Hz,1H),5.21(d,J＝14.3Hz,1H),4.84(q,J＝8.8Hz,2H),4.05–3.96(m,1H),3.60(m,2H),2.39(m,1H),1.99(m,1H).
Preparation of Compounds 10-12 and 10-13
Compound 10-9 (100 mg,0.22 mmol) was dissolved in DMF (2 mL), 1H-tetrazole (30.23 mg,0.43 mmol) was added, potassium carbonate (59.65 mg,0.43 mmol), the reaction was heated to 80℃and stirred for 4 days, water (10 mL) was added, and extracted with ethyl acetate (10 mL. Times.3), and the combined organic phases were dried by spinning to give crude product. The crude preparation (preparation: mobile phase: A:0.1% formic acid in water; B: acetonitrile; column chromatography: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) gave the title compound 10-12 (50 mg, 43%) and the title compound 10-13 (10 mg, 9%).
Compounds 10-12 LC-MS (ESI) m/z 534.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.57(d,J＝2.1Hz,1H),7.87–7.72(m,2H),7.56(d,J＝2.1Hz,1H),7.37–7.13(m,4H),6.92(td,J＝8.5,2.6Hz,1H),6.10(s,1H),5.52(d,J＝14.7Hz,1H),5.37(d,J＝14.7Hz,1H),4.84(q,J＝8.8Hz,2H),4.38(td,J＝10.4,3.0Hz,1H),4.08(dt,J＝10.0,4.5Hz,1H),3.71(t,J＝5.5Hz,1H),1.94–1.78(m,1H),1.72–1.60(m,1H).
Compounds 10-13 LC-MS (ESI) m/z 534.2[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.56(d,J＝2.1Hz,1H),7.83–7.76(m,2H),7.51(d,J＝2.1Hz,1H),7.36–7.24(m,2H),7.21–7.15(m,2H),6.94(d,J＝2.3Hz,1H),6.09(s,1H),5.85(d,J＝14.3Hz,1H),5.58(d,J＝14.4Hz,1H),4.84(q,J＝8.9Hz,2H),4.36(d,J＝3.1Hz,1H),4.15–3.97(m,1H),3.73(t,J＝5.5Hz,1H),1.80(m,1H),1.68–1.58(m,1H).
EXAMPLE 11 preparation of Compound 11
Figure BDA0003986848020000291
Compound 10-6 (500 mg,1.62 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to-65 ℃. N-butyllithium (1.6M, 1.52 mL) was added at-65℃and the mixture was stirred at-65℃for 20 minutes, then a solution of tetrahydrofuran (2 mL) containing 1-4 (180 mg,0.8 mmol) was added dropwise thereto, and the mixture was stirred slowly to room temperature for 10 minutes. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined and dried by spin to give the crude product. The crude product was prepared (preparation method: mobile phase: 0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 11 (70 mg, 8%).
Compound 11 LC-MS (ESI) m/z 533.2[ M+H ]] + .
EXAMPLE 12 preparation of Compound 12-3
Figure BDA0003986848020000292
Preparation of Compound 12-2
Into a three-necked flask, compound 12-1 (0.90 g,5.83 mmol) and THF (5 mL) were added, N 2 Replacing, and cooling to-78 ℃. LDA (2M, 2.9mL,5.83 mmol) was added dropwise to the flask and stirred for 30 minutes. A solution of compounds 1 to 4 (1.0 g,4.48 mmol) in tetrahydrofuran (2 mL) was added dropwise to the reaction system, and the mixture was reacted at room temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined and dried by spin to give the crude title compound 12-2 (1.1 g, 65% yield) as a pale yellow solid. LC-MS (ESI) m/z 378.2[ M+H ] ] + .
Preparation of Compound 12-3
Compound 12-2 (200 mg,0.53 mmol), TEA (1 mL) and methanol (2 mL) were added to a three-necked flask, H 2 Palladium on carbon (117 mg,0.11 mmol) was added to the flask for displacement, and reacted at 60℃for 16 hours. After the reaction system was cooled, the reaction solution was filtered, and a crude filtrate was prepared (preparation method: mobile phase: A:0.1% formic acid aqueous solution; B: acetonitrile; chromatographic column: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) to give the title compound 12-3.LC-MS (ESI) m/z 344.0[ M+H ]] + .1H NMR(400MHz,Chloroform-d)δ8.91(s,1H),8.48(s,1H),8.18(s,1H),7.71(d,J＝20.0Hz,2H),6.83(s,1H),6.57(s,1H),5.86(s,1H),5.17(d,J＝14.3Hz,1H),4.92(d,J＝14.2Hz,1H),3.71–3.35(m,1H),2.69(s,1H),2.41(s,2H),2.26(s,1H).
EXAMPLE 13 preparation of Compounds 13-3 and 13-4
Figure BDA0003986848020000301
Preparation of Compound 13-2
To a single vial (50 mL) was added compound 13-1 (1.0 g,6.70 mmol) and chloroform (15 mL) at room temperature. Reduce to 0 ℃. Phosphorus tribromide (3.58 g,13.40 mmol) was then slowly added dropwise. After the completion of the dropwise addition, the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched by slow dropwise addition of saturated sodium bicarbonate solution (50 mL) at 0deg.C. Extraction with ethyl acetate (50 ml×3), washing with saturated brine (20 ml×3), drying the organic phase, filtering, concentrating the ethyl acetate to give crude product, which was purified on normal phase silica gel column (biotage, silica gel column, 20g, uv254, ethyl acetate/petroleum ether=0-100%) to give the title compound 13-2 (1.1 g, yield 77%). LC-MS (ESI) m/z 212.0[ M+H ] ] + .
Preparation of Compounds 13-3 and 13-4
Zinc powder (1.7 g,25.93 mmol), THF (20 mL), lead powder (107.43 mg,0.152 mmol) and iodine simple substance (1.32 g,5.19 mmol) were added to a three-necked flask at room temperature, stirred for 10 minutes at room temperature and then cooled to 0 ℃. After the disappearance of yellow color, compound 13-2 (1.1 g,5.19 mmol) was added dropwise to the reaction system as a solution of Compound 1-4 (1.39 g,6.22 mmol) in tetrahydrofuran (2 mL). Stir at room temperature overnight. The reaction system was quenched with water (50 mL. Times.3), and extracted with ethyl acetate (50 mL. Times.3). The organic phase is dried and concentrated to obtain crude product. The crude preparation (preparation: mobile phase: A:0.1% formic acid in water; B: acetonitrile; chromatographic column: agilent 10 Prep-C18X 21.2mm; column temperature: 25 ℃ C.; gradient: 55% -75% acetonitrile in 12min; flow rate: 30 mL/min) gave title compound 13-3 (75.85 mg, yield 4.1%) and title compound 13-4 (15.44 mg, yield 0.84%).
Compound 13-3 LC-MS (ESI): m/z 357.1[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.43(d,J＝4.4Hz,1H),8.28(s,1H),7.68(s,1H),7.54(d,J＝7.7Hz,1H),7.30–7.08(m,3H),6.85(t,J＝7.9Hz,1H),6.74(s,1H),5.17(d,J＝14.6Hz,1H),4.92(d,J＝14.6Hz,1H),3.50(t,J＝6.9Hz,1H),2.64(t,J＝6.0Hz,2H),1.99–1.73(m,2H),1.53(s,1H),1.40(s,1H).
Compound 13-4 LC-MS (ESI): m/z 357.1[ M+H ]] + . 1 H NMR(400MHz,DMSO-d6)δ8.27(d,J＝6.9Hz,3H),7.68(dd,J＝15.8,8.9Hz,1H),7.61–7.47(m,2H),7.21(dd,J＝7.5,4.7Hz,1H),7.03(dt,J＝16.8,9.2Hz,2H),5.06(d,J＝14.6Hz,1H),4.54(d,J＝14.7Hz,1H),3.35(m,1H),2.64(s,2H),2.00(d,J＝9.4Hz,1H),1.72(d,J＝10.0Hz,2H),1.43(d,J＝8.9Hz,1H).
Test example 1 minimum inhibitory concentration (Minimal Inhibitory Concentration, MIC) test of Compounds against fungal growth
(1) The main reagent comprises:
RPMI1640 medium, gibco, cat# 31800-014
Saccharum dextrose agar (Sabouraud dextrose agar, SDA) brand of Haibo, cat# HB0253-81
Amphotericin B brand Abcam, cat# ab141199
(2) The fungal strains are shown in Table 1 below:
TABLE 1
Strain class Strain coding Strain destination
Aspergillus fumigatus Aspergillus fumigatus ATCC MYA-4609 CBS 101355[AF 293]
Candida albicans ATCC MYA-2876 SC5314
(3) The testing method comprises the following steps:
MIC testing was performed according to guidelines and requirements of CLSI M27 (for yeast) and M38 (for aspergillus).
Strain preparation the strain was streaked onto SDA plates 1 day in advance with glycerol strain stored at-80 ℃. Culturing at 35 deg.C under 40-60% humidity for 18-24 hr. Aspergillus fumigatus requires streaking inoculation 3 days and 2 days in advance.
Culture medium and compound preparation liquid culture medium RPMI was prepared with pure water, and 0.165mol/L MOPS was added and pH was adjusted to 7.0, and after filtration sterilization with a filter of 0.22 μm filter membrane, it was stored at 4℃for not more than 3 months. 0.85% physiological saline is sterilized at 121 ℃ for 30 minutes and then stored at room temperature (not more than 1 week). The compound was dissolved in DMSO at 12.8mg/mL and stored at-20 ℃.
For yeast, 3-5 colonies were picked from the SDA plate on the day of the test, and fully suspended in 5mL of sterilized 0.85% physiological saline. The turbidity of the bacterial liquid is measured by a turbidity meter, and the turbidity is adjusted to about 0.2. The bacterial solutions were diluted 50-fold and 20-fold (1000-fold total) in sequence with RPMI1640 medium as inoculum. The final inoculum concentration was 500-2500CFU/mL.
For Aspergillus, 5mL of physiological saline was used to cover the mycelium, spores were gently scraped off with a spreader, and the spore suspension was transferred to a sterile tube. Appropriate amounts of spore suspension were aspirated and counted under a microscope using a hemocytometer. Spore concentration was adjusted to about 0.4-5x10 with RPMI1640 medium 4 spores/mL。
The compound was diluted with DMSO up to 800 μg/mL (or 400 μg/mL) and 10 2-fold gradient dilutions were performed for a total of 11 concentrations. Transfer 2. Mu.L of the gradient diluted compound to the corresponding well of the 96-well plate and transfer 198. Mu.L of the inoculum to the test plate, incubate at 35℃for 24 hours (Aspergillus fumigatus and Cryptococcus neoformans for 48 and 72 hours, respectively).
(4) MIC assessment:
after the incubation, the fungal growth was visually observed, and the point of minimum compound concentration at which the inhibition of yeast growth was not less than 50% (100% inhibition of aspergillus) was defined as the minimum inhibitory concentration MIC (μg/mL). MIC determination can be aided with a magnifying glass or reading OD530 nm. The test board photographs the record file. The results are shown in Table 2 below.
TABLE 2 results of in vitro antifungal Activity of partially preferred Compounds MIC (μg/mL)
Figure BDA0003986848020000311
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Figure BDA0003986848020000321
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Claims (17)

1. A compound shown in a formula (I), optical isomer, tautomer and pharmaceutically acceptable salt thereof,
Figure FDA0003986848010000011
wherein,,
ring a is selected from 5-6 membered heteroaryl;
ring B is selected from phenyl, 5-6 membered heteroaryl and C 5-6 Cycloalkyl;
ring C is independently selected from phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, said phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with 1, 2 or 3 Rx;
ring D is independently selected from phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, said phenyl, 5-6 membered heteroaryl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with 1, 2 or 3R Y Substitution;
and, ring C and ring D are not aromatic at the same time;
R 3 selected from OH, NH 2 、-OSi(R 9 ) 3 、F、Cl、Br、I、CN、C 1-6 Alkyl, C 1-6 Heteroalkyl group,
Figure FDA0003986848010000012
The C is 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 NH 2 Substitution;
R 2 、R X 、R Y are respectively and independently selected from H, CN, OH, F, cl, br, I, C 1-6 Alkyl, C 1-6 Heteroalkyl, SF 3 、SF 6 、SCN、SO 3 H and SO 2 R 7 The C is 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
or, R 3 Is linked together with Rx to form a 3-9 membered heterocyclic group or C 3-9 A cycloalkyl group;
R 7 、R 9 independently selected from NH 2 、C 1-6 Alkyl, phenyl and 5-6 membered heteroaryl, said phenyl or 5-6 membered heteroaryl optionally being substituted with 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
n is independently selected from 0, 1, 2 or 3;
L 1 selected from single bonds, C 1-6 Alkyl, C 2-6 Alkynyl, phenyl and 5-6 membered heteroaryl groups, said C 1-6 Alkyl, C 2-6 Alkynyl, phenyl or 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
L 2 selected from single bonds, O, S, NH, C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclyl, C 3-6 Cycloalkyl and phenyl-O-C 1-6 Alkyl-, said C 1-6 Alkyl, C 1-6 Heteroalkyl, 3-6 membered heterocyclyl, C 3-6 Cycloalkyl or phenyl-O-C 1-6 Alkyl-optionally substituted by 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
L 3 selected from single bond, -C (=O) -, -C (=O) NH-, C 1-6 Alkyl, 3-6 membered heterocyclyl, C 3-6 Cycloalkyl, phenyl and 5-6 membered heteroaryl, said C 1-6 Alkyl, 3-6 membered heterocyclyl, C 3-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl groups are optionally substituted by 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
L 4 selected from H, F, cl, br, I, OH, CN, NH 2 、COOH、SF 3 、SF 6 、SCN、SO 2 R 7 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, C 1-6 Alkyl-5-6 membered heterocyclyl, 5-6 membered heterocyciylAryl and benzo 4-6 membered heterocyclyl, said C 1-6 Alkyl, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, C 1-6 Alkyl-5-6 membered heterocyclyl, 5-6 membered heteroaryl or benzo 5-6 membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5R L Substitution;
R L selected from CN, OH, F, cl, br, I, NH 2 、C 1-6 Alkyl and C 1-6 Heteroalkyl group, C 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, NH 2 F, cl, br, I or C 1-6 Alkyl substitution;
the C is 1-6 Heteroalkyl, 5-6 membered heterocyclyl or 5-6 membered heteroaryl groups comprise 1, 2 3 or 4 are independently selected from the group consisting of-O-; -NH-, -N=, -S-, -
C(＝O)-、-C(＝O)O-、-S(＝O)-、-S(＝O) 2 -and N.
2. A compound represented by the formula (II-1) or (II-2), an optical isomer, a tautomer thereof and a pharmaceutically acceptable salt thereof,
Figure FDA0003986848010000021
wherein,,
X 1 、X 2 、X 3 、X 8 are each independently selected from C (R) X ) 2 、NR X S and O;
X 4 、X 5 、X 6 、X 7 are independently selected from CR Y And N;
R 6 selected from H, CN, OH, F, cl, br, I, C 1-6 Alkyl, C 1-6 Heteroalkyl, SF 3 、SF 6 、SCN、SO 3 H and SO 2 R 7 The C is 1-6 Alkyl or C 1-6 Heteroalkyl is optionally substituted with 1, 2 or 3 CN, OH, F, cl, br, I or C 1-6 Alkyl substitution;
or, R 3 And R is R 6 Is connected to aStarting with the formation of 3-to 6-membered heterocyclic groups or C 3-6 A cycloalkyl group;
ring a, ring B, R 2 、R 3 、R X 、R Y 、L 1 、L 2 、L 3 、L 4 N is as defined in claim 1.
3. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein ring a is selected from tetrazolyl, triazolyl, oxazolyl, pyrimidinyl, thiazolyl or pyrazolyl.
4. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein ring a is selected from the group consisting of
Figure FDA0003986848010000022
5. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein ring B is selected from phenyl and pyridyl.
6. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein the structural unit
Figure FDA0003986848010000023
Selected from->
Figure FDA0003986848010000024
7. The compound of claim 1 or 2, optical isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein R 3 Selected from OH, NH 2 、C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino, C 1-3 Alkylthio, -OC (=o) C 1-3 Alkyl and-NHC (=o) C 1-3 An alkyl group.
8. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein L 1 Selected from single bonds, CH 2 、
Figure FDA0003986848010000025
9. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein L 2 Selected from single bonds, O, S, CH 2 、NH、NCH 3 、
Figure FDA0003986848010000026
10. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein L 3 Selected from single bonds, CH 2 、CH 2 CH 2 、-C(＝O)-、-C(＝O)NH-、
Figure FDA0003986848010000031
Figure FDA0003986848010000032
11. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein L 4 Selected from H, F, cl, br, I, OH, CN, NH 2 、CHF 2 、CF 3 、OCH 3 、OCF 3 、OCHF 2 、OCH 2 CH 3 、COOH、
CONHMe、CONMe 2 、NMe 2 、
Figure FDA0003986848010000033
Figure FDA0003986848010000034
12. The compound according to claim 1 or 2, optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein the structural unit
Figure FDA0003986848010000035
Selected from H, I, CN, OH, CF 3 、COOH、CONHMe、CONMe 2 、/>
Figure FDA0003986848010000036
Figure FDA0003986848010000037
/>
Figure FDA0003986848010000041
/>
Figure FDA0003986848010000051
13. The compound of claim 1, optical isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein ring C, ring D are each independently selected from the group consisting of cyclopentyl, cyclohexyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, pyridinyl, and pyrimidinyl, the cyclopentyl, cyclohexenyl, tetrahydropyranyl, tetrahydrofuranyl, phenyl, pyridinyl, or pyrimidinyl being optionally substituted with 1, 2, or 3 halogens, methyl, ethyl, or cyclopropyl, and ring C and ring D are not both aromatic ring systems.
14. The compound according to claim 1,Optical isomers, tautomers and pharmaceutically acceptable salts thereof, wherein the structural unit
Figure FDA0003986848010000052
Selected from->
Figure FDA0003986848010000053
Figure FDA0003986848010000054
15. A compound of the formula, optical isomers, tautomers and pharmaceutically acceptable salts thereof, selected from
Figure FDA0003986848010000061
16. A compound of the formula, optical isomers, tautomers and pharmaceutically acceptable salts thereof, selected from
Figure FDA0003986848010000062
/>
Figure FDA0003986848010000071
Figure FDA0003986848010000081
17. Use of a compound according to any one of claims 1 to 16, an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for combating fungal infections.
CN202211567806.XA 2021-12-08 2022-12-07 Preparation method of fused ring compound and application of fused ring compound as antifungal agent Pending CN116239600A (en)

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