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CN117263917A - Preparation method of compound containing heterocyclic structure and application of compound as antibacterial agent - Google Patents

Preparation method of compound containing heterocyclic structure and application of compound as antibacterial agent Download PDF

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CN117263917A
CN117263917A CN202310730380.3A CN202310730380A CN117263917A CN 117263917 A CN117263917 A CN 117263917A CN 202310730380 A CN202310730380 A CN 202310730380A CN 117263917 A CN117263917 A CN 117263917A
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alkyl
ring
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邓刚
叶艳
彭建彪
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Shanghai Jiyu Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

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Abstract

The invention discloses a preparation method of a compound containing a heterocyclic structure and application of the compound serving as an antibacterial agent, and in particular discloses a compound shown in a formula (I), an optical isomer, a tautomer or pharmaceutically acceptable salt thereof and antifungal application of the compound.

Description

Preparation method of compound containing heterocyclic structure and application of compound as antibacterial agent
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a preparation method of a compound containing a heterocyclic structure and application of the compound serving as an antibacterial 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 novel heterocyclic structures, compared with the existing clinical therapeutic drugs, the invention has better or equivalent candida infection resistance activity, overcomes 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), an optical isomer, a tautomer thereof or a pharmaceutically acceptable salt thereof,
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, said phenyl, 5-6 membered heteroaryl or C 5-6 Cycloalkyl is optionally substituted with 1, 2, 3 or 4R B Substitution of；
Ring C is selected from 4-9 membered heterocyclyl, said 4-9 membered heterocyclyl optionally being substituted with 1, 2 or 3 CN, OH, F, cl, br, I, C groups 1-6 Alkyl, -C (=o) -C 1-6 Alkyl substitution;
R B 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;
R 1 、R 2 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;
R 3 selected from OH, NH 2 Halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -OC (=o) C 1-6 Alkyl, -NHC (=o) C 1-6 Alkyl group,and-OC 1-6 alkyl-OP (=o) 2 (OH) 2 ；
The C is 1-6 Heteroalkyl 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 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 fromThe remaining variables are as defined herein。
In some embodiments of the invention, the ring B is selected from phenyl and pyridyl, optionally substituted with 1, 2, 3 or 4R B Instead, the remaining variables are as defined herein.
In some embodiments of the invention, the ring B is selected fromThe remaining variables are as defined herein.
In some embodiments of the invention, the ring C is selected from 2-azabicyclo [2.2.1 ]]Heptyl, azepanyl, 2, 5-diazabicyclo [2.2.1]Heptyl, piperidinyl, 6-azaspiro [2.5 ]]Octyl, 6-azaspiro [2.6 ]]Nonylalkyl, 8-azabicyclo [3.2.1]Octyl, azepan-2-onyl, pyrrolidinyl, azetidinyl, 2, 6-diazaspiro [3.3 ]]Heptyl and 2-azaspiro [3.3 ]]Heptyl, said 2-azabicyclo [2.2.1]Heptyl, azepanyl, 2, 5-diazabicyclo [2.2.1]Heptyl, piperidinyl, 6-azaspiro [2.5 ] ]Octyl, 6-azaspiro [2.6 ]]Nonylalkyl, 8-azabicyclo [3.2.1]Octyl, azepan-2-onyl, pyrrolidinyl, azetidinyl, 2, 6-diazaspiro [3.3 ]]Heptyl or 2-azaspiro [3.3 ]]Heptyl is optionally substituted with 1, 2 or 3 CN, OH, F, cl, br, I, C groups 1-3 Alkyl, -C (=o) -C 1-3 Alkyl substitution, the remaining variables are as defined herein.
In some embodiments of the invention, the ring C is selected from
The remaining variables are as defined herein.
In some aspects of the invention, R is as defined above B 、R 1 、R 2 Each independently selected from H, CN, OH, F, cl, br, I, methyl, ethyl, n-propyl or isopropyl, the remaining variables being as defined herein.
In another aspect of the invention, the invention also provides a compound of the formula, an optical isomer, a tautomer, or a pharmaceutically acceptable salt thereof, selected from
In some embodiments of the invention, the above-described compounds, optical isomers, tautomers, or pharmaceutically acceptable salts thereof, are selected from
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.gR) is independent in each case of its definition when it occurs more than once in the composition or structure of the compound. 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,can be selected from->And->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 radicalsWhen, for example, in->The dotted line represents the point of attachment of the group to the rest of the molecule. When a single bond is provided with->When, for example, in->In which the dotted line represents a single bond or is absent, also meaning +.>Represents a single bond->Or double bond->
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.gMiddle L 1 Representing a single bond means that the structure is actually +.>
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,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>The phenyl group and the cyclopentyl group may be linked in the opposite direction to the reading order from left to right to form +.>Combinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
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))。C 1-6 Examples of alkyl groups include, but are not limited to CH 3 、/>
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))。C 1-4 Examples of alkyl groups include, but are not limited to CH 3 、/>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 internal position of the heteroalkyl group, including where the alkyl group is attached to the remainder of the molecule, although the term "alkoxy" is used interchangeably and refers to those alkyl groups 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, and the like. 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 radicals"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, tetrahydrothiophenyl (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, homopiperidinyl, etc.
Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O) m (where m is an integer from 0 to 2), but excluding the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 ring atoms (which may be a specific point or may be an interval of optionally two points, for example 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), of which 1 to 4 are heteroatoms; preferably containing 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, with tetrahydropyranyl, piperidinyl, pyrrolidinyl being preferred. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
Unless otherwise specified, the term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom in common between 5 to 20 membered monocyclic rings (referred to as the spiro atom), wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 11 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:andetc.
Unless otherwise specified, the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 And more preferably 7 to 11 members. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:etc.
Unless otherwise specified, the term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 11 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:etc.
The heterocyclyl ring includes those described above wherein the heterocyclyl (e.g., monocyclic, fused, spiro, and bridged heterocyclyl) is fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include: Etc.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more substituents independently selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, OH, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.
Unless otherwise specifiedThe terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably herein, and the term "5-6 membered heteroaryl" denotes 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 optionally quaternized and the nitrogen and sulfur heteroatoms may 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-to n+m-membered represents a ring having n to n+m atoms, for example, 3-to 12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, etc,10-membered ring, 11-membered ring, and 12-membered ring, also including any one of n to n+m, 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.
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 may 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 usedSoftware naming, commercial compounds are referred to by vendor catalog names.
The disclosed compounds may have 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 raw materials used in the present invention are commercially available unless otherwise specified.
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 Agilent 1260 (ESI) or Shimadzu LC-MS-2020 (ESI) type or Agilent 6215 (ESI) type mass spectrometer; reversed phase preparative HPLC separationIs a full-automatic purification system guided by Agilent 1290 ultraviolet Prep C18OBDTM 21.2×250mm10 μm column) or a fully automated purification system (% guided by Gilson GX281 uv light>Prep C18OBDTM 19X 250mm10 μm column) or Waters QDa-directed fully automated purification System (.about.>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:
DMSO represents dimethylsulfoxide; EA or EtOAc represents ethyl acetate; PE represents petroleum ether; THF represents tetrahydrofuran; meOH represents methanol; acOH represents acetic acid; pd (dppf) Cl 2 Or PdCl 2 (dppf) represents 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride; DIPEA stands for N, N-diisopropylethylamine; MTBE stands for methyl tert-butyl ether; 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 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 Compound 1
Preparation of Compounds 1-3
Compound 1-1 (CAS: 133775-25-4,1.0g,3.72 mmol) was dissolved in a mixed solvent of THF (5 mL) and MTBE (5 mL), and Compound 1-2 (639 mg,5.58 mmol), TEA (1.13 mg,11.16 mmol) was added to react at room temperature for 1 hour. The reaction was cooled to 0deg.C, naOH (0.15 g,3.75 mmol) was added and the reaction was carried out at room temperature for 2 hours. The reaction was extracted with EtOAc (50 ml×3), the organic phases were combined, dried and concentrated to give the crude product, which was purified by separation on a normal phase silica gel column (EtOAc/pe=0-50%) to give the title compound 1-3 (720 mg, 72% yield). LC-MS (ESI) m/z 252.2[ M+H ]] + 。
Preparation of Compound 1
Compound 1-3 (100 mg,0.40 mmol) was dissolved in acetonitrile (1.5 mL) and compound 1-4 (47 mg,0.40 mmol) and LiClO were added 4 (85 mg,0.80 mmol) and the reaction was stirred at 100deg.C for 16 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch) C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 50-80% in12 min; flow rate 30 mL/min) to give the title compound 1 (45 mg, yield: 43%).
Compound 1 LC-MS (ESI) m/z 349.2[ M+H ]] + 。 1 H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.76(s,1H),7.68(s,1H),7.46(q,J＝8.9Hz,1H),7.37(d,J＝8.1Hz,1H),4.74(d,J＝4.6Hz,2H),3.26(s,1H),2.94(s,1H),2.80(d,J＝7.2Hz,1H),2.70(d,J＝8.5Hz,1H),2.58(d,J＝8.4Hz,1H),2.38(d,J＝14.7Hz,2H),1.42(d,J＝10.0Hz,2H),1.18(d,J＝9.7Hz,2H),0.98(dd,J＝7.2,2.9Hz,3H).
Example 2: preparation of Compound 2
Preparation of Compound 2
Compound 1-3 (100 mg,0.40 mmol) was dissolved in acetonitrile (1.5 mL) and compound 2-1 (82 mg,0.48 mmol), TEA (1 mL) and LiClO were added 4 (85 mg,0.80 mmol) and the reaction was stirred at 100deg.C for 48 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch)C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 55-85% in12 min; flow rate 30 ml/min) to give the title compound 2 (42 mg, yield: 41%). LC-MS (ESI) m/z 387.2[ M+H ]] + 。 1 H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.78(s,1H),7.49–7.40(m,1H),6.81–6.67(m,2H),4.87(s,2H),3.02(s,3H),2.71(s,1H),2.48(s,1H),2.17(s,4H),1.78(s,2H),0.93(s,3H).
Example 3: preparation of Compound 3
Preparation of Compound 3-2
Compound 1-3 (200 mg,0.80 mmol) was dissolved in acetonitrile (1.5 mL) and compound 3-1 (190 mg,0.96 mmol) and LiClO were added 4 (170 mg,1.60 mmol) was stirred at 100deg.C for 72 hours. After the reaction was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give the crude product, which was purified by separation on a normal phase silica gel column (EtOAc/PE=0-50%) to give the title compound 3-2 (200 mg, 89% yield.) LC-MS (ESI): m/z 450.2[ M+H ] + 。
Preparation of Compound 3
Compound 3-2 (310 mg,0.69 mmol) was dissolved in methanol (1 mL), a hydrochloric acid methanol solution (4N, 4 mL) was added at 0℃and the reaction system was reacted at 0℃for 16 hours. After the reaction is finished, the reaction solution is dried by spinning, and then the reaction solution is directly put into the next step.
Acetonitrile (1.5 mL), methyl iodide (28 mg,0.20 mmol) and triethylamine (81 mg,0.80 mmol) were added to the reaction system, and the mixture was reacted at room temperature for 16 hours. The reaction was extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch)C18 21.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; acetonitrile in the mobile phase in 10-30 wt% for 12 min; the flow rate was 30 ml/min) to give the title compound 3 (5 mg, yield: 2%).
Compound 3 LC-MS (ESI) m/z 364.2[ M+H ]] + 。 1 H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.71(s,1H),7.42–7.31(m,1H),6.78–6.67(m,2H),4.88–4.72(m,2H),3.65(s,1H),3.48(s,2H),3.21(d,J＝10.7Hz,1H),3.07(d,J＝11.6Hz,2H),2.97(s,1H),2.63(d,J＝7.1Hz,3H),1.96(d,J＝10.3Hz,1H),1.79(d,J＝10.6Hz,1H),0.86(dd,J＝6.8,1.2Hz,3H).
Example 4: preparation of Compound 4
Preparation of Compound 4
Compound 1-3 (100 mg,0.40 mmol) was dissolved in acetonitrile (1.5 mL) and compound 4-1 (82 mg,0.48 mmol), TEA (1 mL) and LiClO were added 4 (85 mg,0.80 mmol) and the reaction was stirred at 100deg.C for 48 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch) C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 55-85% in12 min; flow rate 30 mL/min) to give the title compound 4 (75 mg, yield: 71%). LC-MS (ESI) m/z 373.2[ M+H] + 。 1 H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.78(s,1H),7.49–7.37(m,1H),6.84–6.64(m,2H),4.87(s,2H),3.04(s,3H),2.53(s,2H),2.01(s,4H),1.62(s,1H),0.93(s,3H).
Example 5: preparation of Compound 5
Preparation of Compound 5
Compound 1-3 (100 mg,0.40 mmol) was dissolved in acetonitrile (1.5 mL) and compound 5-1 (71 mg,0.48 mmol), TEA (1 mL) and LiClO were added 4 (85 mg,0.80 mmol) and the reaction was stirred at 100deg.C for 48 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch)C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 50-80% in12 min; the flow rate was 30 ml/min) to give the title compound 5 (72 mg, yield: 70%). LC-MS (ESI) m/z 363.2[ M+H ]] + 。 1 H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.72(s,1H),7.54–7.39(m,1H),6.77–6.63(m,2H),5.71(s,1H),4.84–4.62(m,2H),2.77(q,J＝7.1Hz,1H),2.58–2.44(m,2H),2.25(s,2H),1.42–1.15(m,4H),0.96(dd,J＝7.2,3.3Hz,3H),0.16(d,J＝4.6Hz,4H).
Example 6: preparation of Compound 6
Preparation of Compound 6
Compound 1-3 (100 mg,0.40 mmol) was dissolved in acetonitrile (1.5 mL) and compound 6-1 (71 mg,0.48 mmol), TEA (1 mL) and LiClO were added 4 (85 mg,0.80 mmol) and the reaction was stirred at 100deg.C for 48 hours. After the reaction was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined and dried Concentrating to obtain crude product, and separating and purifying (preparation method comprises chromatographic column: welch)C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 50-80% in12 min; flow rate 30 mL/min) to give the title compound 6 (54 mg, yield: 51%). LC-MS (ESI) m/z 387.2[ M+H ]] + 。 1 H NMR(400MHz,Chloroform-d)δ7.91(s,1H),7.78(s,1H),7.51–7.37(m,1H),6.83–6.62(m,2H),4.86(s,2H),3.21–2.95(m,2H),2.72–2.33(m,2H),2.26–1.77(m,4H),1.02(dd,J＝9.1,6.7Hz,3H),0.91(d,J＝7.0Hz,3H).
Example 7: preparation of Compound 7
Preparation of Compound 7
Compound 1-3 (100 mg,0.40 mmol) was dissolved in acetonitrile (1.5 mL) and compound 7-1 (71 mg,0.48 mmol), TEA (1 mL) and LiClO were added 4 (85 mg,0.80 mmol) and the reaction was stirred at 100deg.C for 48 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch)C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 45-65% in12 min; flow rate 30 mL/min) to give the title compound 7 (39 mg, yield: 37%).
Compound 7 LC-MS (ESI) m/z 377.2[ M+H ]] + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.27(s,1H),7.69(s,1H),7.32(td,J＝9.0,6.8Hz,1H),7.12(ddd,J＝12.0,9.1,2.6Hz,1H),6.92(td,J＝8.5,2.6Hz,1H),5.52(s,1H),4.91–4.73(m,2H),3.17(q,J＝6.8Hz,1H),2.92(ddd,J＝19.6,10.4,4.2Hz,2H),2.71–2.58(m,1H),1.75–1.48(m,4H),1.43–1.17(m,3H),0.86–0.72(m,3H),0.37–0.20(m,4H).
Example 8: preparation of Compound 8
Preparation of Compound 8
Compound 1-3 (100 mg,0.40 mmol) was dissolved in acetonitrile (1.5 mL) and compound 8-1 (71 mg,0.48 mmol), TEA (1 mL) and LiClO were added 4 (85 mg,0.80 mmol) and the reaction was stirred at 100deg.C for 48 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch) C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 55-75% in12 min; flow rate 30 mL/min) to give the title compound 8 (43 mg, yield: 40%). LC-MS (ESI) m/z 399.2[ M+H ]] + 。 1 H NMR(400MHz,Chloroform-d)δ7.89(s,1H),7.69(s,1H),7.39–7.28(m,1H),6.73–6.64(m,2H),4.91(s,1H),4.73(s,2H),3.43(s,1H),3.25(s,1H),3.01(d,J＝7.0Hz,1H),2.26–1.98(m,4H),1.96–1.74(m,3H),1.65(d,J＝8.2Hz,1H),0.84(d,J＝7.2Hz,3H).
Example 9: preparation of Compound 9
Preparation of Compound 9
Compound 2 (100 mg,0.26 mmol) was dissolved in THF (1.5 mL) and H 2 O (0.5 mL) in the mixed solvent, add I 2 (198 mg,0.78 mmol) and NaHCO 3 (65 mg,0.78 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch)C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; acetonitrile in mobile phase in 20-40% in12 min; flow rate 30 mL/min) to give the title compound 9 (35 mg, yield: 29%). LC-MS (ESI) m/z 401.2[ M+H] + 。 1 H NMR(400MHz,Chloroform-d)δ7.86–7.71(m,2H),7.40–7.29(m,1H),6.81–6.66(m,2H),5.44–5.31(m,1H),5.23–5.08(m,2H),4.20(d,J＝14.3Hz,1H),3.89(dd,J＝16.2,7.8Hz,1H),3.65(dd,J＝16.2,9.7Hz,1H),2.78–2.58(m,2H),2.44–2.01(m,4H),0.97(d,J＝7.1Hz,3H).
Example 10: preparation of Compound 10
Preparation of Compound 10
Compound 1-3 (100 mg,0.40 mmol) was dissolved in acetonitrile (1.5 mL) and compound 10-1 (86 mg,0.60 mmol), TEA (1 mL) and LiClO were added 4 (85 mg,0.80 mmol) and the reaction was stirred at 100deg.C for 48 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch) C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 50-70% in12 min; flow rate 30 ml/min) to give the title compound 10 (46 mg, yield: 43%). LC-MS (ESI) m/z 359.2[ M+H ]] + 。 1 H NMR(400MHz,Chloroform-d)δ7.79(s,1H),7.71(s,1H),7.39–7.28(m,1H),6.73–6.54(m,2H),4.83(s,2H),3.22(d,J＝10.5Hz,2H),2.96(s,2H),2.87(s,1H),2.17(d,J＝11.6Hz,2H),0.78(d,J＝6.8Hz,3H).
Example 11: preparation of Compound 11
Preparation of Compound 11
Compound 1-3 (100 mg,0.40 mmol) was dissolved in acetonitrile (1.5 mL) and compound 11-1 (84 mg,0.60 mmol), TEA (1 mL) and LiClO were added 4 (85 mg,0.80 mmol) and the reaction was stirred at 100deg.C for 48 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch)C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 45-65% in12 min; flow rate 30 ml/min) to give the title compound 11 (41 mg, yield: 38%). LC-MS (ESI) m/z 355.2[ M+H ]] + 。 1 H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.78(s,1H),7.54–7.39(m,1H),6.84–6.68(m,2H),5.25(s,1H),4.83(d,J＝8.4Hz,2H),2.94(dd,J＝16.3,9.1Hz,2H),2.70–2.46(m,2H),2.26(d,J＝8.7Hz,1H),1.96–1.74(m,4H),0.96(dd,J＝7.1,2.3Hz,3H).
Example 12: preparation of Compound 12
Preparation of Compound 12
Compound 1-3 (200 mg,0.80 mmol) was dissolved in acetonitrile (2.0 mL) and compound 12-1 (155 mg,1.20 mmol), TEA (2 mL) and LiClO were added 4 (340 mg,3.20 mmol) and the reaction was stirred at 85℃for 48 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch) C1821.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 40% -60% in12 min; flow rate30 ml/min) to give the title compound 12 (124 mg, yield: 62%). LC-MS (ESI) m/z 345.2[ M+H ]] + 。 1 H NMR(400MHz,Chloroform-d)δ7.78(s,1H),7.69(s,1H),7.39–7.23(m,1H),6.79–6.54(m,2H),4.86–4.70(m,2H),3.91–3.69(m,2H),3.67–3.53(m,2H),3.21–3.04(m,1H),0.79(d,J＝6.7Hz,3H).
Example 13: preparation of Compound 13
Preparation of Compound 13-2
Compound 13-1 (0.5 g,2.06 mmol) and triethylamine (0.73 g,7.20 mmol) were dissolved in 5mL of dichloromethane, acetyl chloride (0.19 g,2.47 mmol) was added dropwise at 0deg.C, and the reaction was continued at room temperature for 18 hours. The reaction was extracted with DCM (50 ml×3), the organic phases were combined, dried and concentrated to give the crude product, which was purified by separation on a normal phase silica gel column (EtOAc/pe=0-50%) to give the title compound 13-2 (0.16 g, yield: 32%). LC-MS (ESI) m/z 241.2[ M+H ]] + 。
Preparation of Compound 13-3
Compound 13-2 (160 mg,0.67 mmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added dropwise at 0deg.C, and the reaction system was stirred at room temperature for 0.5 h. Saturated NaHCO is added into the reaction system 3 The solution (100 mL) was quenched. The reaction was extracted with EtOAc (50 ml×3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by separation on a normal phase silica gel column (EtOAc/pe=0-50%) to give the title compound 13-3 (100 mg, yield: 71%). LC-MS (ESI) m/z 141.2[ M+H ] ] + 。
Preparation of Compound 13
Compound 1-3 (200 mg,0.80 mmol) was dissolved in acetonitrile (2.0 mL) and compound 13-3 (169 mg,1.20 mmol), TEA (2 mL) and LiClO were added 4 (340 mg,3.20 mmol) and the reaction was stirred at 85℃for 48 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch)C18 21.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 30-50% in12min; flow rate 30 mL/min) to give the title compound 13 (160 mg, yield: 80%). LC-MS (ESI) m/z 392.2[ M+H ]] + 。 1 HNMR(400MHz,Methanol-d 4 )δ8.27(s,1H),8.21(s,1H),7.71(s,1H),7.37–7.31(m,1H),6.95–6.89(m,1H),6.84–6.79(m,1H),4.82–4.72(m,1H),4.32(s,2H),4.08(s,2H),3.85(d,J＝8.24Hz,2H),3.71(d,J＝8.24Hz,2H),1.86(s,3H),0.86(d,J＝6.64Hz,3H).
Example 14: preparation of Compound 14
Preparation of Compound 14-2
Compound 14-1 (894 mg,4.27 mmol) was dissolved in DCM (15 mL) and the reaction was cooled to 0deg.C and diethylaminosulfur trifluoride (2.05 g,12.71 mmol) was added and the reaction was reacted at room temperature for 5 hours. The reaction was extracted with DCM (50 ml×3), the organic phases were combined, dried and concentrated to give the crude product, which was purified by separation on a normal phase silica gel column (EtOAc/pe=0-20%) to give the title compound 14-2 (800 mg, yield: 80%). LC-MS (ESI) m/z 178.0[ M+H-55 ]] + 。
Preparation of Compound 14-3
Compound 14-2 (400 mg,1.7 mmol) was dissolved in DCM (5 mL) and TFA (1 mL) was added dropwise and the reaction was allowed to react at room temperature for 8 hours. Concentration by drying gave crude 14-3 (230 mg, 100% yield). LC-MS (ESI) m/z 135.0[ M+H ] ] + 。
Preparation of Compound 14
Compound 14-3 (230 mg,0.93 mmol), compound 1-3 (155 mg,0.62 mmol), lithium perchlorate (262 mg,2.48 mmol) and DIPEA (387 mg,3.0 mmol) were dissolved in acetonitrile (5 mL), and the reaction system was tube-sealed at 90℃for 16 hours. After the reaction system was cooled, extracted with EtOAc (50 mL. Times.3), the organic phases were combined, dried and concentrated to give a crude product, which was purified by preparative separation (preparative method: chromatographic column: welch)C18 21.2x250mm; column temperature: 25 ℃; mobile phase: water (10 mM/L NH) 4 HCO 3 ) -acetonitrile; the acetonitrile proportion of the mobile phase is 40% -60% in12 min; flow rate 30 mL/min) to give the title compound 14 (63 mg, yield: 27%) LC-MS (ESI) m/z 385.2[ M+H ]] + 。 1 HNMR(400MHz,DMSO-d 6 )δ8.28(s,1H),7.61(s,1H),7.22(td,J＝8.9,6.8Hz,1H),7.10(ddd,J＝11.9,9.2,2.6Hz,1H),6.86(td,J＝8.6,2.6Hz,1H),5.31(s,1H),4.66(s,2H),3.49(d,J＝6.9Hz,2H),2.96(qd,J＝6.6,2.5Hz,1H),2.72(t,J＝12.6Hz,4H),0.65(d,J＝6.5Hz,3H).
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
Voriconazole brand name Adamas, cat No. 22105A
Amphotericin B brand Abcam, cat# ab141199
(2) The fungal strains are shown in Table 1 below:
TABLE 1
(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, cryptococcus neoformans, respectively, require 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 0.4-5x 10 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 partial Compounds MIC (μg/mL)
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.

Claims (8)

1. A compound of formula (I), an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof,
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, said phenyl, 5-6 membered heteroaryl or C 5-6 Cycloalkyl is optionally substituted with 1, 2, 3 or 4R B Substitution;
ring C is selected from 4-9 membered heterocyclyl, said 4-9 membered heterocyclyl optionally being substituted with 1, 2 or 3 CN, OH, F, cl, br, I, C groups 1-6 Alkyl, -C (=o) -C 1-6 Alkyl substitution;
R B 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;
R 1 、R 2 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;
R 3 selected from OH, NH 2 Halogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, -OC (=o) C 1-6 Alkyl, -NHC (=o) C 1-6 Alkyl group,and-OC 1-6 alkyl-OP (=o) 2 (OH) 2 ；
The C is 1-6 Heteroalkyl or 5-6 membered heteroaryl groups comprise 1, 2, 3 or 4 groups independently selected from-O- -NH-, -n=, -S-, -C (=o) -, -and-
C(＝O)O-、-S(＝O)-、-S(＝O) 2 -and N.
2. The compound of claim 1, an optical isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the ring a is selected from tetrazolyl, triazolyl, oxazolyl, pyrimidinyl, thiazolyl, or pyrazolyl;
optionally, the ring A is selected from
3. The compound of claim 1, an optical isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl and pyridinyl, optionally substituted with 1, 2, 3, or 4R B Substitution;
optionally, the ring B is selected from
4. The compound of claim 1, an optical isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said ring C is selected from 2-azabicyclo [2.2.1 ]]Heptyl, azepanyl, 2, 5-diazabicyclo [2.2.1]Heptyl, piperidinyl, 6-azaspiro [2.5 ]]Octyl, 6-azaspiro [2.6 ] ]Nonylalkyl, 8-azabicyclo [3.2.1]Octyl, azepan-2-onyl, pyrrolidinyl, azetidinyl, 2, 6-diazaspiro [3.3 ]]Heptyl and 2-azaspiro [3.3 ]]Heptyl, said 2-azabicyclo [2.2.1]Heptyl, azepanyl, 2, 5-diazabicyclo [2.2.1]Heptyl, piperidinyl, 6-azaspiro [2.5 ]]Octyl, 6-azaspiro [2.6 ]]Nonylalkyl, 8-azabicyclo [3.2.1]Octyl, azepan-2-onyl, pyrrolidinyl, azetidinyl, 2, 6-diazaspiro [3.3 ]]Heptyl or 2-azaspiro [3.3 ]]Heptyl is optionally substituted with 1, 2 or 3 CN, OH, F, cl, br, I, C groups 1-3 Alkyl, -C (=o) -C 1-3 Alkyl substitution.
5. The compound of claim 1, an optical isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein said ring C is selected from the group consisting of
6. The compound of claim 1, an optical isomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R B 、R 1 、R 2 Each independently selected from H, CN, OH, F, cl, br, I, methyl, ethyl, n-propyl or isopropyl.
7. A compound of the formula, an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof, selected from
8. The compound of claim 7, an optical isomer, tautomer or pharmaceutically acceptable salt thereof, selected from the group consisting of
CN202310730380.3A 2022-06-20 2023-06-19 Preparation method of compound containing heterocyclic structure and application of compound as antibacterial agent Pending CN117263917A (en)

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