CN105085512A - Enteric virus 71 (EV71)-resistant thiadiazolidine derivatives - Google Patents

Enteric virus 71 (EV71)-resistant thiadiazolidine derivatives Download PDF

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Publication number
CN105085512A
CN105085512A CN201410543064.6A CN201410543064A CN105085512A CN 105085512 A CN105085512 A CN 105085512A CN 201410543064 A CN201410543064 A CN 201410543064A CN 105085512 A CN105085512 A CN 105085512A
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mmol
added
radical
400mhz
solution
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Inventor
李鹏
贺海鹰
李宁
黎健
陈曙辉
杨百灵
萧伟
沈旺
王振中
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Jiangsu Kanion Pharmaceutical Co Ltd
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NANJING MINGDE NEW DRUG RESEARCH AND DEVELOPMENT Co Ltd
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Priority to CN201410543064.6A priority Critical patent/CN105085512A/en
Priority to US15/307,710 priority patent/US9988361B2/en
Priority to ES15786304T priority patent/ES2841418T3/en
Priority to JP2016565011A priority patent/JP6389531B2/en
Priority to MYPI2016703942A priority patent/MY176508A/en
Priority to KR1020187016595A priority patent/KR101957178B1/en
Priority to SG11201608710TA priority patent/SG11201608710TA/en
Priority to KR1020167033211A priority patent/KR20160147010A/en
Priority to PCT/CN2015/077043 priority patent/WO2015165340A1/en
Priority to DK15786304.4T priority patent/DK3138840T3/en
Priority to EP15786304.4A priority patent/EP3138840B1/en
Priority to TW104113441A priority patent/TWI658037B/en
Publication of CN105085512A publication Critical patent/CN105085512A/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses novel enteric virus 71 (EV71)-resistant 1,2,5-thiadiazolidin-1,1-dioxide derivatives or pharmaceutically acceptable salts thereof. The invention discloses compounds shown in a formula (II) or pharmaceutically acceptable salts thereof.

Description

Anti-enterovirus 71 thiadiazolidine derivatives
Technical Field
The invention relates to a novel 1,2, 5-thiadiazolidine-1, 1-dioxide derivative resisting enterovirus 71 (EV71) or a pharmaceutically acceptable salt thereof, in particular to a compound shown as a formula (II) or a pharmaceutically acceptable salt thereof.
Background
Enterovirus type 71 belongs to the family of picornaviridae and is one of the most common causes of hand-foot-and-mouth disease. In addition, the medicine also causes various nervous system related diseases such as papulopharyngitis, aseptic meningitis, encephalitis and poliomyelitis-like paralytic diseases, and can be accompanied with serious central nervous system complications or neuroinflammatory pulmonary edema.
The hand-foot-and-mouth disease has the characteristics of high epidemic intensity, strong infectivity, complex transmission path and the like, and no specific enterovirus 71 resistant medicine exists so far.
Although patent documents such as US20030087936, US6706739, US20040116476, US20050267164, US20070049623 and the like in the prior art disclose a series of structures, such as the structure shown in formula (B-i), there is still a need to develop new compounds with better activity and better drug-forming property.
Disclosure of Invention
The invention provides a compound shown as a formula (II) or a pharmaceutically acceptable salt thereof,
wherein,
R3selected from the group consisting of01Substituted 5-membered heterocyclic ring, C6～12Aryl radical, C6～12Aralkyl radical, C5～12Heteroaromatic ring or C5～ 12A heteroaralkyl group;
L2are each independently selected from
m1、m2Each independently selected from 0, 1,2,3, 4,5 or 6;
X1、X2each independently selected from the group consisting of a single bond, -C (R)d1)(Rd2)-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7) -, -O-, -S-, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -, or-S (═ O)2-；
R4Selected from 5-14 membered cycloalkyl or heterocyclic alkyl;
Rd1、Rd2each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH2CHO, COOH, or selected from optionally substituted R01Substituted C1-10Alkyl or heteroalkyl, C3-10Cycloalkyl or heterocycloalkyl radical, or3-10Cycloalkyl-or heterocycloalkyl-substituted C1-10Alkyl or heteroalkyl;
R01selected from F, Cl, Br, I, CN, OH, SH, NH2、CHO、COOH、R02；
R02Is selected from C1-10Alkyl radical, C1-10Alkylamino, N-di (C)1-10Alkyl) amino, C1-10Alkoxy radical, C1-10Alkanoyl radical, C1-10Alkoxycarbonyl radicalsBase, C1-10Alkylsulfonyl radical, C1-10Alkylsulfinyl radical, C3-10Cycloalkyl radical, C3-10Cycloalkylamino radical, C3-10Heterocycloalkylamino, C3-10Cycloalkoxy, C3-10Cycloalkyl acyl, C3-10Cycloalkoxycarbonyl, C3-10Cycloalkylsulfonyl radical, C3-10A cycloalkylsulfinyl group;
"hetero" represents a heteroatom or a heteroatom group selected from-C (═ O) N (R)d3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7) -, -O-, -S-, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -, and/or-S (═ O)2-；
Rd3-d7Each independently selected from H, R03；
R03Is selected from C1-10Alkyl radical, C1-10Alkyl acyl radical, C1-10Alkoxycarbonyl, C1-10Alkylsulfonyl radical, C1-10Alkylsulfinyl radical, C3-10Cycloalkyl radical, C3-10Cycloalkyl acyl, C3-10Cycloalkoxycarbonyl, C3-10Cycloalkylsulfonyl radical, C3-10A cycloalkylsulfinyl group;
R02、R03optionally substituted by R001Substitution;
R001selected from F, Cl, Br, I, CN, OH, N (CH)3)2、NH(CH3)、NH2CHO, COOH, trifluoromethyl, aminomethyl, hydroxymethyl, methyl, methoxy, formyl, methoxycarbonyl, methanesulfonyl, methylsulfinyl;
R01、R001the number of heteroatoms or heteroatom groups is independently selected from 0, 1,2 or 3;
optionally, Rd1And Rd2Are linked to form a 3 or 4 membered carbocyclic or heterocyclic ring.
The inventionIn some embodiments of (1), R3Selected from optionally substituted 5-to 6-membered aryl or heteroaryl.
In some embodiments of the invention, R3Selected from the group consisting of01Substituted pyridyl, phenyl, furyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, thienyl, R01As defined above, R01The number of (a) is selected from 0, 1,2 or 3.
In some embodiments of the invention, R01Selected from F, Cl, Br, I, CN, OH, SH, NH2、CHO、COOH、Me、
In some embodiments of the invention, R3Selected from:
in some embodiments of the invention, L2Is selected fromm3Are 0, 1 or 2 and the other variables are as defined above.
In some embodiments of the invention, X1、X2Are respectively and independently selected from single bond, -O-, -C (═ O) -, -CH (CH)3)-、-C(CH3)2-、-CF2-、-CH(F)-、-CH(OH)、-CH2-、-NH-、-N(CH3)-。
In some embodiments of the invention, L2Selected from:
in some embodiments of the invention, R4Is selected from
T4-7Each independently selected from N or C (R)t)，
D1-3、D5、D6Each independently selected from the group consisting of a single bond, -C (R)d1)(Rd2)-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7) -, -O-, -S-, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -, or-S (═ O)2-，
n2Selected from 0, 1,2 or 3,
n3is selected from the group consisting of 0, 1 or 2,
R5、R6、R7、Rt、Rd1、Rd2each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH2CHO, COOH, or selected from optionally substituted R01Substituted C1-10Alkyl or heteroalkyl, C3-10Cycloalkyl or heterocycloalkyl radical, or3-10Cycloalkyl-or heterocycloalkyl-substituted C1-10An alkyl group or a heteroalkyl group,
the other variables are as defined in claim 1.
In some embodiments of the invention, R4Is selected from
X3Selected from F, Cl, Br, I, CN, OH, SH, NH2CHO, COOH, or selected from optionally substituted R01Substituted C1-10Alkyl or heteroalkyl, C3-10Cycloalkyl or heterocycloalkyl radical, or3-10Cycloalkyl-or heterocycloalkyl-substituted C1-10Alkyl or heteroalkyl.
In some embodiments of the invention, R5-7Are each independently selected from Wherein:
T1-3each independently selected from N or C (R)t)；
D4Is selected from-C (R)d1)(Rd2)-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7) -, -O-, -S-, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -, or-S (═ O)2-；
R8、R9、RtEach independently selected from H, F, Cl, Br, I, CN, OH, SH, NH2CHO, COOH, or selected from optionally substituted R01Substituted C1-10Alkyl or heteroalkyl, C3-10Cycloalkyl or heterocycloalkyl radical, or3-10Cycloalkyl-or heterocycloalkyl-substituted C1-10Alkyl or heteroalkyl;
R10selected from F, Cl, Br、I、CN、OH、SH、NH2CHO, COOH, or selected from optionally substituted R01Substituted C1-10Alkyl or heteroalkyl, C3-10Cycloalkyl or heterocycloalkyl radical, or3-10Cycloalkyl-or heterocycloalkyl-substituted C1-10Alkyl or heteroalkyl.
In some embodiments of the invention, R5-9、R01、RtAre each independently selected from F、Cl、Br、CF3、-C(C2H5)-、-C(OC2H5) -, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, In some embodiments of the invention, R4Selected from:
specifically, the present invention is selected from:
related definitions:
as used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient.
C1-12Is selected from C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11And C12；C3-12Is selected from C3、C4、C5、C6、C7、C8、C9、C10、C11And C12。
C1-12Alkyl or heteroalkyl, C3-12Cyclic or heterocyclic hydrocarbon radicals, by C3-12Cycloalkyl-or heterocycloalkyl-substituted C1-12Alkyl or heteroalkyl groups include, but are not limited to:
C1-12alkyl radical, C1-12Alkylamino, N-di (C)1-12Alkyl) amino, C1-12Alkoxy radical, C1-12Alkanoyl radical, C1-12Alkoxycarbonyl, C1-12Alkylsulfonyl radical, C1-12Alkylsulfinyl radical, C3-12Cycloalkyl radical, C3-12Cycloalkylamino radical, C3-12Heterocycloalkylamino, C3-12Cycloalkoxy, C3-12Cycloalkyl acyl, C3-12Cycloalkanoyloxycarbonyl radical, C3-12Cycloalkylsulfonyl radical, C3-12Cycloalkylsulfinyl, 5-to 12-membered aryl or heteroaryl, 5-to 12-membered aralkyl or heteroaralkyl;
methyl, ethyl, n-propyl, isopropyl, -CH2C(CH3)(CH3) (OH), cyclopropyl, cyclobutyl, propylmethylene, cyclopropanoyl, benzyloxy, trifluoromethyl, aminomethyl, hydroxymethyl, methoxy, formyl, methoxycarbonyl, methylsulfonyl, methylsulfinyl, ethoxy, acetyl, ethylsulfonyl, ethoxycarbonyl, dimethylamino, diethylamino, dimethylaminocarbonyl, diethylaminocarbonyl;
N(CH3)2,NH(CH3),-CH2CF3,-CH2CH2CF3,-CH2CH2F,-CH2CH2S(＝O)2CH3,-CH2CH2CN,-CH2CH(OH)(CH3)2,-CH2CH(F)(CH3)2,-CH2CH2F,-CH2CF3,-CH2CH2CF3,-CH2CH2NH2,-CH2CH2OH,-CH2CH2OCH3,-CH2CH2CH2OCH3,-CH2CH2N(CH3)2,-S(＝O)2CH3,-CH2CH2S(＝O)2CH3,
and
phenyl, thiazolyl, biphenyl, naphthyl, cyclopentyl, furyl, 3-pyrrolinyl, pyrrolidinyl, 1, 3-oxypentacyclyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, imidazolyl, oxazolyl, thiazolyl, 1,2, 3-oxazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,3, 4-thiadiazolyl, 4H-pyranyl, pyridyl, piperidyl, 1, 4-dioxanyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3, 5-trithianyl, 1,3, 5-triazinyl, benzofuryl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolyl, isoquinolyl, cinnolinyl or quinoxalinyl;
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 salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids such as glucuronic acid (see Bergeet al, "pharmaceutical salts," journal of pharmaceutical science66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt.
Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
As used herein, "pharmaceutically acceptable salts" belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base. Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound, for example, salts formed with non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic or organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, glycolic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannin, tartaric acid, and p-toluenesulfonic acid.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains an acid or base, by conventional chemical methods. In general, such salts are prepared by the following method: prepared by reacting 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 the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the present invention in an in vivo environment by chemical or biochemical means.
Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous form.
Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.
The illustrations of enantiomers, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J.chem.Ed.1985,62: 114-120. In 1985,62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomer unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.
The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers by fractional crystallization or chromatography, as is well known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C3H) Iodine-125 (125I) Or C-14(14C) In that respect 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.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of an active agent of the present invention, without interfering with the biological activity of the active agent, and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on the vector, reference may be made to Remington, the science and practice of pharmacy,21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms of the invention, an "effective amount" of one active agent in a composition is the amount required to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.
The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including deuterium and hydrogen variants, so long as the valency of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., ═ O), it means that two hydrogen atoms are substituted. The keto substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
When a substituent's bond can cross-link two atoms on a ring, such substituent can be bonded to any atom on the ring. When no atom is indicated in the listed substituents for connecting to a compound included in the general chemical structure but not specifically mentioned, such substituent may be bonded through any atom thereof. Substituents and/orCombinations of variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unitMeaning that it may be substituted at any position on the cyclohexyl or cyclyldiene.
Substituents for alkyl and heteroalkyl radicals are generally referred to as "alkyl substituents" and may be selected from, but are not limited to, one or more of the following groups: -R ', -OR', -O, ═ NR ', -N-OR', -NR 'R ", -SR', halogen, -SiR 'R" R' ", oc (O) R ', -c (O) R', -CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2And fluoro (C)1-C4) Alkyl, the number of substituents being 0 to (2m '+ 1), where m' is the total number of carbon atoms in such radicals. R ', R ", R'", R "" and R "" each independently preferably is hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy, thioalkoxy, or aralkyl. When a compound of the invention includes more than one R group, for example, each R group is independently selected, as are each of these groups when more than one R ', R ", R'", R "" and R "" groups are present. When R' and R "are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 5-, 6-or 7-membered ring. For example, -NR' R "is intended to include, but not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, those skilled in the art will appreciate that the term "alkyl" is intended to include groups consisting of carbon atoms bonded to non-hydrogen groups, such as haloalkyl (e.g., -CF)3、-CH2CF3) And acyl (examples)Such as-C (O) CH3、-C(O)CF3、-C(O)CH2OCH3Etc.).
Similar to the substituents described for the alkyl radicals, aryl and heteroaryl substituents are generally collectively referred to as "aryl substituents" and are selected, for example, from the group consisting of-R ', -OR', -NR 'R ", -SR', -halogen, -SiR 'R" R' ", OC (O) R ', -C (O) R', -CO2R ', -CONR' R", -OC (O) NR 'R ", -NR" C (O) R', NR 'C (O) NR "R'", -NR "C (O)2R ', -NR" "C (NR' R" R '") -", NR "" C (NR' R "- (NR '") ", -S (O) R', -S (O))2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2Fluorine (C)1-C4) Alkoxy and fluorine (C)1-C4) Alkyl, etc., the number of substituents being between 0 and the total number of open valences on the aromatic ring; wherein R ', R ", R'", R "" and R "" are independently preferably selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. When a compound of the invention includes more than one R group, for example, each R group is independently selected, as are each of these groups when more than one R ', R ", R'", R "" and R "" groups are present.
Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted by a substituent of the formula-T-C (O) - (CRR ') q-U-, wherein T and U are independently selected from-NR-, -O-, CRR' -or a single bond, and q is an integer from 0 to 3. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula-A (CH2) rB-, wherein A and B are independently selected from-CRR' -, -O-, -NR-, -S (O) -, S (O)2-、-S(O)2NR' -or a single bond, and r is an integer of 1 to 4. Optionally, one single bond on the new ring thus formed may be replaced by a double bond. Alternatively, two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced by a substituent of the formula-A (CH2) rB-)Wherein S and d are each independently an integer selected from 0 to 3, X is-O-, -NR', -S-, -S (O)2-or-S (O)2NR' -. The substituents R, R ', R "and R'" are each independently preferably selected from hydrogen and substituted or unsubstituted (C)1-C6) An alkyl group.
Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom. Furthermore, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "halo (C)1-C4) Alkyl "is intended to include, but not be limited to, trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, and the like.
Examples of haloalkyl groups include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "alkoxy" represents the above alkyl group having the specified number of carbon atoms attached through an oxygen bridge. C1-6Alkoxy radicals comprising C1、C2、C3、C4、C5And C6Alkoxy group of (2). Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and S-pentoxy. "cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl, or cyclopentyl. 3-7 cycloalkyl radicals including C3、C4、C5、C6And C7A cycloalkyl group. "alkenyl" includes hydrocarbon chains in either a straight or branched configuration, wherein one or more carbon-carbon double bonds, such as ethenyl and propenyl, are present at any stable site along the chain.
The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
Unless otherwise specified, the term "hetero" denotes a heteroatom or a group of heteroatoms (i.e., a group of atoms containing heteroatoms) including atoms other than carbon (C) and hydrogen (H) and groups of atoms containing such heteroatoms, including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, ═ O (O), and the likeO、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-, and optionally substituted-C (═ O) n (h) -, -C (═ NH) -, -S (═ O)2N (h) -or-S (═ O) n (h) -.
Unless otherwise specified, "cyclic" means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term "ring" includes monocyclic, bicyclic, spiro, fused or bridged rings. The number of atoms in the ring is generally defined as the number of ring members, for example, "5 to 7 membered ring" means 5 to 7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1-3 heteroatoms. Thus, "5 to 7 membered ring" includes, for example, phenylpyridine and piperidinyl; in another aspect, the term "5-to 7-membered heterocycloalkyl ring" includes pyridyl and piperidyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.
Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable heteroatom or heteroatom group containing monocyclic, bicyclic, or tricyclic ring which may be saturated, partially unsaturated, or unsaturated (aromatic), which contains carbon atoms and 1,2,3, or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p). The nitrogen atom may be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituents already defined herein). The heterocyclic ring may be attached to any heteroatom or carbon pendant group to form a stable structure. The heterocyclic rings described herein may be substituted at the carbon or nitrogen position if the resulting compound is stable. The nitrogen atoms in the heterocycle are optionally quaternized. In a preferred embodiment, when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. In another preferred embodiment, the total number of S and O atoms in the heterocycle does not exceed 1. As used herein, the term "aromatic heterocyclic group" or "heteroaryl" means a stable 5,6,7 membered monocyclic or bicyclic or 7,8, 9 or 10 membered bicyclic heterocyclic group aromatic ring comprising carbon atoms and 1,2,3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom may be substituted or unsubstituted (i.e. N or NR, wherein R is H or other substituents already defined herein). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p). It is noted that the total number of S and O atoms on the heteroaromatic ring does not exceed 1. Bridged rings are also included in the definition of heterocyclic. Bridged rings are formed when one or more atoms (i.e., C, O, N or S) connect two non-adjacent carbon or nitrogen atoms. Preferred bridged rings include, but are not limited to: one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In bridged rings, ring substituents may also be present on the bridge.
Examples of heterocyclic compounds include, but are not limited to: acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4 aH-carbazolyl, carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H,6H-1,5, 2-dithiazinyl, dihydrofuro [2,3-b ] tetrahydrofuranyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatino, isobenzofuranyl, pyran, isoindolyl, indolyl, etc, Isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, isoxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthine, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, Pyrazolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, isothiazolylthiothienyl, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 5-triazolyl, 1,3, 4-triazolyl, and xanthenyl. Fused ring and spiro compounds are also included.
Unless otherwise specified, the term "hydrocarbyl" or its derivatives (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent, mean a straight, branched, or cyclic hydrocarbon radical or combination thereof, which may be fully saturated, mono-or poly-unsaturated, mono-, di-, or poly-substituted, may be mono-or di-or poly-valent (such as methine), may include di-or poly-valent radicals, having the specified number of carbon atoms (such as C)1-C10Representing 1 to 10 carbons). "hydrocarbyl" includes, but is not limited to, aliphatic hydrocarbyl including linear and cyclic, specifically including, but not limited to, alkyl, alkenyl, alkynyl, and aromatic hydrocarbyl including, but not limited to, 6-12 membered aromatic hydrocarbyl such as benzene, naphthalene, and the like. In some embodiments, the term "alkyl" denotes a straight or branched chain radical or a combination thereof, which may be fully saturated, mono or polyunsaturated, and may include divalent and polyvalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, and homologs or isomers of radicals such as n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Unsaturated alkyl radicals having one or more double bonds or threeExamples of bonds include, but are not limited to, ethenyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers.
Unless otherwise specified, the term "heterohydrocarbyl" or a subset thereof (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and the like) by itself or in combination with another term means a stable straight-chain, branched, or cyclic hydrocarbon radical, or combination thereof, consisting of a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl," by itself or in combination with another term, means a stable straight-chain, branched-chain hydrocarbon radical, or combination thereof, having a number of carbon atoms and at least one heteroatom constituent. In one exemplary embodiment, the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatoms B, O, N and S can be located at any internal position of the heterohydrocarbyl group (including the position where the hydrocarbyl group is attached to the remainder of the molecule). Examples include, but are not limited to-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3and-CH ═ CH-N (CH)3)-CH3. Up to two heteroatoms may be consecutive, e.g. -CH2-NH-OCH3。
The terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used in the conventional sense to refer to those alkyl groups attached to the rest of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
Unless otherwise specified, the terms "cycloalkyl", "heterocycloalkyl", or a subset thereof (e.g., aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, etc.) by themselves or in combination with other terms, mean cyclized "alkyl", "heteroalkyl", respectively. Furthermore, in the case of a heterohydrocarbyl or heterocycloalkyi (e.g., heteroalkyl, heterocycloalkyl), a heteroatom may occupy the position of the heterocycle attached to the rest of the molecule. Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclyl groups include 1- (1,2,5, 6-tetrahydropyridinyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran indol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl, and 2-piperazinyl.
Unless otherwise specified, the term "aryl" denotes a polyunsaturated aromatic hydrocarbon substituent which may be mono-, di-or poly-substituted, and may be mono-, di-or polyvalent, and which may be monocyclic or polycyclic (preferably 1 to 3 rings) which are fused together or linked covalently. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In one illustrative example, the heteroatom is selected from B, N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroaryl group may be attached to the rest of the molecule through a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 2-oxazolyl, 2-thiazolyl, 2-pyridyl, 4-pyridyl, and the like, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalyl, 5-quinoxalyl, 3-quinolyl, and 6-quinolyl. The substituents for any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
For simplicity, aryl when used in combination with other terms (e.g., aryloxy, arylthio, aralkyl) includes aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like), including those alkyl groups in which a carbon atom (e.g., methylene) has been replaced by, for example, an oxygen atom, such as phenoxymethyl, 2-pyridyloxymethyl 3- (1-naphthyloxy) propyl and the like.
The term "leaving group" refers to a functional group or atom that can be substituted by another functional group or atom through 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-bromobenzenesulfonate, p-toluenesulfonate and the like; acyloxy groups such as acetoxy, trifluoroacetyloxy, and the like.
The term "protecting group" includes, but is not limited to, "amino protecting group," hydroxyl protecting group, "or" thiol protecting group. The term "amino protecting group" refers to a protecting group suitable for use in preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: a formyl group; acyl, for example alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl such as tert-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 hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-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.
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 listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
All solvents used in the present invention are commercially available and can be used without further purification. The invention employs the following abbreviations: aq represents water; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC stands for N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N, N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH stands for ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents tert-butylcarbonyl as an amine protecting group; HOAc represents acetic acid; NaCNBH3Represents sodium cyanoborohydride; r.t. represents room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl2Represents thionyl chloride; CS2Represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N- (phenylsulfonyl) benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-dione; n-Bu4NF represents tetrabutyl ammonium fluoride; iPrOH represents 2-propanol; mp represents melting point; LDA represents lithium diisopropylamide; xantphos represents 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene; pd2(dba)3Represents tris (dibenzylideneacetone) dipalladium; DAST represents diethylaminosulfur trifluoride; pd (dppf) Cl2Represents 1,1' -bis (diphenylphosphino) ferrocene; PCC stands for pyridinium chlorochromate; TsCl represents p-toluenesulfonyl chloride; et (Et)3And N represents triethylamine.
The compound is made by hand orThe software names, and the commercial compounds are under the supplier catalog name.
Compared with the prior art, the compound has high efficiency and low toxicity, makes remarkable and even unexpected progress in the aspects of activity, half-life period, solubility, pharmacokinetics and the like, and is more suitable for pharmacy.
Detailed Description
In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.
Route B
Example 4
2- (5- ((4-fluorophenoxy) pentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 4A
2- ((2-Chloropyridin-4-yl) amino) ethanol
A solution of 2, 4-dichloropyridine (100 g, 675.7 mmol), triethylamine (136.7 g, 1.35 mol) and 2-aminoethanol (41.3 g, 675.7 mmol) in ethanol (500 ml) was dissolved in 1After stirring at 00 ℃ for 72 h, the solvent was removed by rotary evaporation and the residue was purified by column chromatography to give the title compound as a yellow oil (46 g, 40% yield).1H-NMR(CDCl3,400MHz)7.90(d,J＝5.8Hz,1H),6.49(d,J＝2.0Hz,1H),6.41(dd,J＝5.8,2.0Hz,1H),5.17(brs,1H),3.87(t,J＝5.1Hz,2H),3.31(q,J＝5.0Hz,2H)；LCMS(ESI)m/z:173(M+1)。
Example 4B
2-chloro-N- (2-chloroethyl) pyridin-4-amine
Example 4A (5 g, 28.9 mmol) was dissolved in a mixed solvent of dichloromethane and N, N-dimethylformamide (50 ml/5 ml), and thionyl chloride (60 ml) was added dropwise to the mixed solution at 15 ℃ and then raised to 40 ℃ to react for 16 hours. After cooling to room temperature, ice water (200 ml) was poured in,1 mol/l aqueous sodium hydroxide solution was added to adjust the pH to 10, the aqueous layer was extracted with ethyl acetate (100 ml × 6), the combined organic layers were washed with brine (50 ml), dried over sodium sulfate, filtered and evaporated, and the crude product was purified by column chromatography to give the title compound (white solid, 1.7 g, yield 45%) and the starting material was recovered (white solid, 2.0 g). LCMS (ESI) M/z 191(M +1).1H-NMR(CDCl3,400MHz)7.99(d,J＝6.0Hz,1H),6.38-6.55(m,2H),4.75(brs,1H),3.67-3.78(m,2H),3.55(q,J＝5.5Hz,2H)。
Example 4C
N- (2-chloroethyl) -N- (2-chloropyridin-4-yl) sulfamoylcarbamic acid tert-butyl ester
Chlorosulfonic isocyanate (2.7 ml) was added dropwise to a solution of t-butanol (3.4 ml) in dichloromethane (27 ml) at 0 ℃ under nitrogen. After the addition, the temperature gradually increased to room temperature and stirring was continued for 30 minutes until the mixture became clear. The solution was transferred under vacuum to an isopiestic dropping funnel and mixed with triethylamine (11.6 ml) and the above mixed solution was added dropwise to a solution of example 4B (1.7 g, 8.9 mmol) in dichloromethane (20 ml) at 0 ℃ under nitrogen. After stirring at 12 ℃ for 48 hours after the addition was complete, the reaction was quenched with ice water and the aqueous phase was extracted with dichloromethane (50 ml. times.4). The combined organic layers were dried over sodium sulfate, filtered and evaporated to afford the crude title compound (7 g) which was used directly in the next step without further purification.1H-NMR(CDCl3,400MHz)8.45(d,J＝5.5Hz,1H),7.42(d,J＝1.5Hz,1H),7.34(dd,J＝5.3,1.8Hz,1H),4.32(t,J＝6.4Hz,2H),3.67(t,J＝6.3Hz,2H),1.49(s,9H)；LCMS(ESI)m/z:370(M+1)。
Example 4D
5- (2-Chloropyridin-4-yl) -1,2, 5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1, 1-dioxide
To a solution of example 4C (7 g, crude) in dimethylsulfoxide (30 ml) was added potassium carbonate powder (3.4 g) at 15 ℃ and stirred for 3 hours, then poured into 1 l of water and filtered to give a white solid, which was dissolved in dichloromethane and dried over sodium sulfate, filtered and evaporated to give the title compound (2 g, yield 69%).1H-NMR(CDCl3,400MHz)8.32(d,J＝6.0Hz,1H),7.06-7.21(m,2H),3.98-4.12(m,2H),3.79-3.92(m,2H),1.59(s,10H).LCMS(ESI)m/z:334(M+1)。
Example 4E
2- (2-chloropyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To the ethyl acetate/methanol (40 ml/4 ml) mixture of example 4D (1.9 g, 5.69 mmol) was added ethyl acetate hydrochloride (4 mol per liter, 40 ml) and stirred at 60 ℃ for 5 h. After removal of the solution in vacuo, the residue was adjusted to pH 8 with saturated sodium bicarbonate solution, the aqueous layer was extracted with ethyl acetate (250 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (white solid, 1.2 g, 92%).1H-NMR(CDCl3,400MHz)8.29(d,J＝5.8Hz,1H),7.05-7.09(m,1H),7.00(d,J＝2.0Hz,1H),3.95-3.99(m,2H),3.78-3.85(m,2H)；LCMS(ESI)m/z:234(M+1)。
Example 4F
2- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 4E (1.3 g, 5.5 mmol), Pd/C (100 mg), triethylamine (2 ml) were mixed in methanol (30 ml), the mixture was stirred at 25 ℃ for 12 h and filtered, after removal of the solvent in vacuo, to give the title compound (3.8 g, yield 100%) which was used directly in the next step without further purification.1H-NMR(DMSO-d6,400MHz)8.75(s,br,1H),8.68(d,J＝7.0Hz,2H),7.45(d,J＝7.0Hz,2H),4.08(t,J＝6.3Hz,2H),3.64(d,J＝6.3Hz,2H)；LCMS(ESI)m/z:200(M+1)。
Example 4G
1- (5-bromopentyl) oxy-4-fluorobenzene
To a solution of para-fluorophenol (4 g, 35.68 mmol) in acetone (40 ml) were added potassium carbonate (14.79 g, 107 mmol), potassium iodide (0.59 g, 3.6 mmol) and 1, 5-dibromopentane (24.61 g, 107 mmol). The mixed solution was stirred at 80 ℃ for 12 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography after filtration and evaporation (petroleum ether: ethyl acetate ═ 10:1) to obtain the title compound (white solid, 6.6 g, yield 70.8%).1H-NMR(CDCl3,400MHz)6.93-7.01(m,2H)6.79-6.86(m,2H)3.90-3.97(m,2H)3.45(t,J＝6.8Hz,2H)1.94(q,J＝7.2Hz,2H)1.76-1.86(m,2H)1.60-1.68(m,2H)。LCMS(ESI)m/z:262(M+1)。
Example 4H
2- (5- ((4-fluorophenoxy) pentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 4F (30 mg, 0.15 mmol) in N, N-dimethylformamide (2 ml) was added sodium hydride (6 mg, 0.16 mmol, 60% content) at 0 ℃. After 30 minutes at 0 ℃, a solution of example 4G (39.3 mg, 0.15 mmol) in N, N-dimethylformamide (1 ml) was added to the above mixed solution. After stirring and reacting for 6 hours at 15 ℃, water is added for quenching and the water phase is extracted by ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (white solid, 28 mg, yield 49%) which was isolated by HPLC.1H-NMR(400MHz,CDCl3)8.51(d,J＝6.0Hz,2H),7.05(d,J＝5.5Hz,2H),6.91-7.01(m,2H),6.82(dd,J＝9.0,4.0Hz,2H),3.93(t,J＝6.3Hz,2H),3.84(t,J＝6.5Hz,2H),3.54(t,J＝6.3Hz,2H),3.18(t,J＝7.0Hz,2H),1.72-1.87(m,5H),1.56-1.61(m,1H)。LCMS(ESI),m/z:380(M+1).
Example 5
Example 5A
1- (5-bromopentyl) oxy-4-trifluoromethylbenzene
The procedure for the preparation of this example is as in example 4G.1H-NMR(400MHz,CDCl3)7.54(d,J＝8.53Hz,2H),6.95(d,J＝8.53Hz,2H),4.01(t,J＝6.27Hz,2H),3.42-3.51(m,2H),1.95(quin,J＝7.15Hz,2H),1.76-1.89(m,2H),1.61-1.68(m,2H)。
Example 5B
2- (pyridin-4-yl) -5- (5- (4-trifluoromethylphenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The procedure for the preparation of this example is as in example 4H.1H-NMR(400MHz,CDCl3)8.53(d,J＝6.27Hz,2H),7.50-7.60(m,2H),7.07(d,J＝6.27Hz,2H),6.96(d,J＝8.78Hz,2H),4.04(t,J＝6.27Hz,2H),3.87(t,J＝6.40Hz,2H),3.57(t,J＝6.40Hz,2H),3.21(t,J＝7.15Hz,2H),1.86-1.94(m,2H),1.77-1.85(m,2H),1.60-1.68(m,2H)。
Example 6
2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) oxy) pentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 6A
4 '-chloro- [1,1' -biphenyl ] -4-ol
4-bromophenol (62 g, 360 mmol), 4-chlorobenzeneboronic acid (56 g, 360 mmol), Pd (dppf) Cl2(10 g, 10 mmol) and Na2CO3(76 g, 720 mmol) in THF/H2In O (600 ml/100 ml), the mixture was heated at 70 ℃ for 6 hours under nitrogen. The reaction mixture was poured into water, extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the title compound (60 g, yield 80%). LCMS (ESI) M/z:205(M +1).
Example 6B
4- ((5-bromopentyl) oxy) -4 '-chloro-1, 1' -biphenyl
To a solution of example 6A (20 g, 97.72 mmol) in acetone (200 mL) was added 1, 5-dibromopentane (67 g, 293.2 mmol), K2CO3(27 g, 195.4 mmol) and KI (1.62 g, 9.77 mmol). After the addition was completed, the mixed solution was heated at 80 ℃ for 12 hours. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated, petroleum ether (200 ml) was added to the residue, stirring was continued at 0 ℃ for 2 hours, and filtration gave a solid which was the title compound (white solid, 25 g, yield 75%).1H-NMR(400MHz,CDCl3)7.48(dd,J＝2.01,8.53Hz,4H),7.35-7.41(m,2H),6.91-7.00(m,2H),3.96-4.06(m,2H),3.41-3.50(m,2H),1.96(q,J＝7.15Hz,2H),1.80-1.90(m,2H),1.60-1.71(m,2H)。
Example 6C
2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) oxy) pentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 4F (40 mg, 0.2 mmol) in N, N-dimethylformamide (10 ml) was added sodium hydride (10 mg, 0.4 mmol, 60% content) at 0 ℃, and to the above solution was added a solution of example 6B (71 mg, 0.2 mmol) in N, N-dimethylformamide (2 ml) after stirring for half an hour at 0 ℃. After further stirring the reaction at 15 ℃ for 2 hours, water was added to quench the reaction and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and evaporated, and the residue was purified by preparative HPLC to give the title compound (white solid, 10 mg, yield 11%).1H-NMR(CDCl3,400MHz)8.51(d,J＝6.3Hz,2H),7.50-7.44(m,4H),7.41-7.34(m,2H),7.10-7.04(m,2H),6.95(d,J＝8.8Hz,2H),4.02(t,J＝6.3Hz,2H),3.89-3.81(m,2H),3.55(t,J＝6.4Hz,2H),3.19(t,J＝7.2Hz,2H),1.90-1.84(m,2H),1.82-1.78(m,2H),1.67-1.58(m,2H)，LCMS(ESI)m/z:472(M+1)。
Example 7
(E) -4- ((5- (1, 1-dioxo-5- (pyridin-4-yl) -1,2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyloxime
Example 7A
(E) -4-hydroxybenzaldehyde-oxy-ethyl oxime
To a solution of p-hydroxybenzaldehyde (2.5 g, 20.47 mmol), ethoxyamino hydrochloride (3.91 g, 40.94 mmol) in water (50 ml) was added sodium acetate (3.36 g, 40.94 mmol) and the mixture was stirred at 80 ℃ for 4 hours. Ethyl acetate (50 ml) was added to the reaction system, the aqueous layer was extracted with ethyl acetate (50 ml × 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (brown solid, 3g, 89% yield).1H-NMR(CDCl3,400MHz)8.03(s,1H),7.46(d,J＝8.5Hz,2H),6.78-6.85(m,2H),4.20(q,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H)。
Example 7B
(E) -4- ((5-bromopentyl) oxy) benzaldehyde-oxy-ethyloxime
Example 7A (1.0 g, 6.05 mmol), 1, 5-bisBromopentane (1.39 g, 6.05 mmol), potassium carbonate (1.67 g, 12.11 mmol) and potassium iodide (0.1 g, 0.605 mmol) were mixed in acetone (100 ml) and heated at reflux for 10 hours. Filtration, spin-drying of the filtrate, and purification by column chromatography afforded the title compound (white crystals, 1.2 g, 63%).1H-NMR(CDCl3,400MHz)8.01-8.05(m,1H),7.49-7.55(m,2H),6.86-6.91(m,2H),4.17-4.24(m,2H),3.96-4.01(m,2H),3.41-3.47(m,2H),1.89-1.99(m,2H),1.78-1.86(m,2H),1.60-1.68(m,2H),1.29-1.34(m,3H)。
Example 7C
(E) -4- ((5- (1, 1-dioxo-5- (pyridin-4-yl) -1,2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyloxime
To a solution of example 4F (60 mg, 301.2 mmol) in N, N-dimethylformamide (1 ml) was added sodium hydrogen (10 mg, 250 mmol, 60% content) in portions at 0 ℃, after stirring for 1.5 hours, a solution of example 7B (114 mg, 361.4 mmol) in N, N-dimethylformamide (0.5 ml) was added dropwise to the reaction solution, then warmed to room temperature and stirred for 2 hours, poured into water (10 ml), extracted with ethyl acetate (3 ml × 3), the combined organic phases were dried over anhydrous sodium sulfate, spun dry, and preparative HPLC purified to give the title compound (white solid, 40 mg, yield 30.7%).1H-NMR(CDCl3,400MHz)8.53(d,J＝6.02Hz,1H),8.04(s,1H),7.53(d,J＝8.78Hz,2H),7.07(d,J＝6.27Hz,2H),6.89(d,J＝8.78Hz,2H),4.22(q,J＝7.03Hz,2H),4.02(t,J＝6.27Hz,2H),3.87(t,J＝6.40Hz,2H),3.56(t,J＝6.40Hz,2H),3.20(t,J＝7.15Hz,2H),1.85-1.93(m,2H),1.76-1.84(m,2H),1.67(br.s.,2H),1.34(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:433(M+1)。
Example 8
Example 8A
5-hydroxy-2, 3-dihydro-1H-inden-1-one
Under nitrogen, 5-bromo-1-indanone (1.0 g, 4.7 mmol), N, N, N ', N' -tetramethylethylenediamine (210 mg, 2.37 mmol), K3PO4(1.0 mg, 4.74 mmol) and CuI (90 mg, 0.47 mmol) were mixed in water (5.0 ml). After heating with a microwave at 120 ℃ for 2 hours, the mixed solution was extracted with ethyl acetate (10 ml. times.3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated by filtration and purified by thin layer chromatography to give the title compound as a white solid (120 mg, yield 17%).1H-NMR(CDCl3400MHz)7.71-7.69(m,1H),6.92-6.87(m,2H),3.11-3.09(m,2H),2.72-2.70(m, 2H). Fruit of Chinese wolfberry
Example 8B
(E) -5-hydroxy-2, 3-dihydro-1H-inden-1-one-oxo-ethyl oxime
To a mixed solution of example 8A (50 mg, 0.3 mmol) and water (5 ml) were added ethoxyamino hydrochloride (65 mg, 0.67 mmol) and sodium acetate (55 mg, 0.67 mmol). The mixed solution was heated at 80 ℃ for 1 hour, the aqueous phase was extracted with ethyl acetate (5.0 ml. times.3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was used directly in the next reaction.1H-NMR(CDCl3,400MHz)7.52-7.66(m,1H),6.68-6.87(m,2H),4.12-4.30(m,2H),2.78-3.07(m,4H),1.27-1.41(m,3H)。
Example 8C
(E) -5- ((5-bromopentyl) oxy) -2, 3-dihydro-1H-inden-1-one-oxy-ethyloxime
To a mixed solution of example 8B (80 mg, 0.4 mmol) and acetone (5.0 ml) were added 1, 5-dibromopentane (288 mg, 1.26 mmol, 3.0 equiv.), potassium carbonate (578 mg, 4.18 mmol, 10 equiv.) and potassium iodide (7 mg, 0.04 mmol, 0.1 equiv.), and the mixed solution was heated at 80 ℃ for 5 hours. The reaction was filtered, the filtrate was concentrated, and the concentrated residue was purified by thin layer chromatography to give the title compound (yellow solid, 140 mg, yield 98%). LCMS (ESI) M/z:340(M +1).
Example 8D
(E) -2- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 4F (20 mg, 0.10 mmol) in N, N-dimethylformamide (1.0 ml) was added sodium hydride (8 mg, 0.2 mmol) under nitrogen. After stirring the reaction at 0 ℃ for half an hour, a solution of example 8C (34 mg, 0.1 mmol) in N, N-dimethylformamide (1.0 ml) was slowly added to the above solution. After stirring the reaction overnight at 15 ℃, water (0.5 ml) was added to quench, the aqueous phase was extracted with dichloromethane and the combined organic phases were dried over anhydrousAfter drying over sodium sulfate, filtration and evaporation, the residue was purified by preparative HPLC to give the title compound (17 mg, 37% yield).1H-NMR(CDCl3,400MHz)8.50(d,J＝5.0Hz,2H),7.59(d,J＝9.5Hz,1H),7.05(d,J＝5.5Hz,2H),6.74-6.82(m,2H),4.19(q,J＝7.0Hz,2H),3.96-4.08(m,2H),3.84(t,J＝5.8Hz,2H),3.50-3.58(m,2H),3.17(t,J＝7.0Hz,2H),2.94-3.11(m,2H),2.81-2.92(m,2H),1.72-1.94(m,4H),1.56-1.68(m,2H),1.22-1.40(m,3H)。LCMS(ESI)m/z:459(M+1)。
Example 9
Example 9A
1-bromo-4- ((5-bromopentyl) oxy) benzene
To a solution of 4-bromophenol (5 g, 28.9 mmol) in acetone (50 mL) was added 1, 5-dibromopentane (19.95 g, 86.7 mmol), K2CO3(8 g, 57.8 mmol) and KI (0.4 g, 2.89 mmol). After the addition was completed, the mixed solution was stirred at 80 ℃ for 12 hours. After filtration, the filtrate was concentrated, petroleum ether (100 ml) was added to the concentrated residue, and after stirring at 0 ℃ for 1 hour, filtration was carried out to obtain the title compound (yellow solid, 4g, yield 43%).1H-NMR(CDCl3,400MHz)7.37-7.39(m,1H),7.34-7.36(m,1H),6.77-6.79(m,1H),6.75-6.77(m,1H),3.93(t,J＝6.27Hz,2H),3.44(t,J＝6.78Hz,2H),1.90-1.99(m,2H),1.75-1.84(m,2H),1.58-1.67(m,2H)。LCMS(ESI)m/z:323(M+1)。
Example 9B
4- (4- ((5-bromopentyl) oxy) phenyl) -1-ethyl-1H-pyrazole
To a mixed solution of 1, 4-dioxane (3 mL) and water (0.5 mL) of example 9A (80 mg, 0.25 mmol), 1-ethylpyrazole-4-boronic acid pinacol ester (55 mg, 0.25 mmol) and sodium carbonate (53 mg, 0.5 mmol) at 25 ℃ under nitrogen atmosphere was added the catalyst Pd (dppf) Cl2(9 mg, 12.4 micromoles), after stirring for 16 hours at 80 ℃, water (10 ml) was added, the aqueous layer was extracted with dichloromethane (10 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by preparation of thin layer plates to give the title compound (white solid, 26 mg, yield 31%).1H-NMR(CDCl3,400MHz)7.70(s,1H),7.52-7.60(m,1H),7.38(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),4.20(q,J＝7.3Hz,2H),3.98(t,J＝6.4Hz,2H),3.45(t,J＝6.8Hz,2H),1.95(q,J＝7.2Hz,2H),1.77-1.86(m,2H),1.60-1.71(m,2H),1.49-1.54(m,3H)。
Example 9C
2- (5- (4- (1-ethyl-1H-pyrazol-4-yl) phenoxy) pentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The procedure for the preparation of this example is as in example 8D.1H-NMR(CDCl3,400MHz)8.51(d,J＝6.5Hz,2H),7.70(s,1H),7.56(s,1H),7.38(d,J＝8.5Hz,2H),7.05(d,J＝6.3Hz,2H),6.89(d,J＝8.8Hz,2H),4.17-4.23(m,2H),3.99(t,J＝6.1Hz,2H),3.83-3.86(m,2H),3.53-3.56(m,2H),3.18(t,J＝7.2Hz,2H),1.70-1.99(m,4H),1.64(s,br.,2H),1.57-1.58(m,3H).LCMS(ESI)m/z:456(M+1)。
Example 10
Example 10A
N', 4-dihydroxybenzamidines
To a solution of 4-hydroxybenzonitrile (5 g, 42 mmol) in isopropanol (90 ml) were added DIPEA (42 g, 419 mmol) and NH2OH HCl (29.1 mg, 1.15 mmol). The mixed solution was heated at 80 ℃ for 4 hours, cooled to room temperature, and then the solution was filtered to obtain the title compound as a solid (4 g, yield 62.6%).1H-NMR(CDCl3,400MHz)7.50(d,J＝8.5Hz,2H),6.82(d,J＝8.5Hz,2H)。LCMS(ESI)m/z:153(M+1)。
Example 10B
4- (5-ethyl-1, 2, 4-oxadiazol-3-yl) phenol
To a solution of example 10A (3 g, 19.57 mmol) in pyridine (10 mL) was added propionic anhydride (2.57 g, 19.57 mmol) at 0 ℃. After the addition was completed, the mixed solution was heated at 60 ℃ for 1 hour. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate: 10:1) to obtain the title compound (3 g, yield 80%).1H-NMR(CDCl3,400MHz)7.97(d,J＝8.5Hz,2H),6.94(d,J＝8.5Hz,2H),2.99(q,J＝7.6Hz,2H),1.46(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:191(M+1)。
Example 10C
3- (4- ((5-bromopentyl) oxy) phenyl) -5-ethyl-1, 2, 4-oxadiazole
To a solution of example 10B (10 g, 52.58 mmol) in N, N-dimethylformamide (100 ml) were added cesium carbonate (34.26 g, 105.15 mmol) and 1, 5-dibromopentane (36.27 g, 157.73 mmol). The mixed solution was stirred at 10 ℃ for 12 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography after filtration and evaporation (petroleum ether: ethyl acetate ═ 10:1) to obtain the title compound (white solid, 10 g, yield 56%).1H-NMR(CDCl3,400MHz)8.02(d,J＝8.5Hz,2H),6.95-7.03(m,2H),4.00-4.08(m,2H),3.41-3.51(m,2H),2.97(q,J＝7.6Hz,2H),1.92-2.01(m,2H),1.82-1.91(m,2H),1.64-1.71(m,2H),1.46(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:339(M+1)。
Example 10D
2- (5- (4- (5-ethyl-1, 2, 4-oxadiazol-3-yl) phenoxy) pentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 4F (20 mg, 0.1 mmol) in N, N-dimethylformamide (5 ml) was added sodium hydride (3.6 mg, 0.15 mmol) at 0 ℃. Maintaining at 0 deg.C for 30 min, adding into the above mixed solutionExample 10C (34 mg, 0.1 mmol) in N, N-dimethylformamide (1 ml). After stirring and reacting for 4 hours at 15 ℃, water is added to quench the reaction, and the aqueous phase is extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (white solid, 3 mg, yield 7%).1H-NMR(400MHz,CDCl3)8.51(d,J＝5.0Hz,2H),8.00(d,J＝9.0Hz,2H),7.05(d,J＝6.3Hz,2H),6.96(d,J＝8.8Hz,2H),4.04(t,J＝6.1Hz,2H),3.85(t,J＝6.4Hz,2H),3.54(t,J＝6.4Hz,2H),3.19(t,J＝7.3Hz,2H),2.96(q,J＝7.5Hz,2H),1.91-1.76(m,4H),1.68-1.62(m,2H),1.44(t,J＝7.7Hz,3H)。LCMS(ESI)m/z:458(M+1)。
Example 11
Example 11A
5- (4-methoxyphenyl) -1H-tetrazole
To a solution of 4-methoxybenzonitrile (6 g, 450 mmol) in N, N-dimethylformamide (60 ml) were added sodium azide (3.2 g, 496 mmol) and NH4Cl (600 mg, 11.2 mmol). The mixed solution was heated at 110 ℃ for 24 hours, cooled to room temperature, added with water, extracted with dichloromethane, the aqueous phase was adjusted to pH-8 by addition of 1 mol per liter hydrochloric acid, and the aqueous phase was filtered to give the title compound as a solid (white solid, 7 g, 88% yield).1H-NMR(CDCl3,400MHz)7.96(d,J＝8.8Hz,2H)7.13(d,J＝8.8Hz,2H)3.90(s,3H)。LCMS(ESI)m/z:177(M+1)。
Example 11B
2-ethyl-5- (4-methoxyphenyl) -2H-tetrazole
To a solution of example 11A (3 g, 17.07 mmol) in acetonitrile (30 ml) was added potassium carbonate (4.71 g, 34.06 mmol) and iodoethane (2.92 g, 18.73 mmol) at 0 ℃. After the addition was completed, the mixed solution was heated at 100 ℃ for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate: 10:1) to give the title compound (white solid, 2.1 g, yield 60%).1H-NMR(CDCl3,400MHz)8.08(d,J＝8.5Hz,2H)7.00(d,J＝8.5Hz,2H)4.68(q,J＝7.2Hz,2H)3.87(s,3H)1.68(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:205(M+1)。
Example 11C
4- (2-ethyl-2H-tetrazol-5-yl) phenol
To example 11B (1 g, 450 mmol) was added 10 ml of a solution of hydrobromic acid in acetic acid. The mixed solution was heated at 110 ℃ for 24 hours, cooled, and the reaction mixture was added to ice water, and the aqueous phase was filtered to give the title compound as a solid (white solid, 0.7 g, yield 75.2%).1H-NMR(CDCl3,400MHz)8.08(d,J＝8.5Hz,2H),7.00(d,J＝8.5Hz,2H),4.68(q,J＝7.2Hz,2H),3.87(s,2H),1.68(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:191(M+1)。
Example 11D
5- (4- ((5-bromopentyl) oxy) phenyl) -2-ethyl-2H-tetrazole
To a solution of example 11C (0.3 g, 1.58 mmol) in acetone (5 ml) was added potassium carbonate (0.653 g, 4.73 mmol) and 1, 5-dibromopentane (1.09 g, 4.73 mmol). The mixed solution was stirred at 80 ℃ for 12 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography after filtration and evaporation (petroleum ether: ethyl acetate ═ 10:1) to obtain the title compound (white solid, 0.3 g, yield 56%).1H-NMR(CDCl3,400MHz)8.08(d,J＝8.8Hz,2H),7.01(d,J＝8.8Hz,2H),4.70(q,J＝7.4Hz,2H),4.05(t,J＝6.4Hz,2H),3.44-3.52(m,2H),1.93-2.03(m,2H),1.83-1.91(m,2H),1.64-1.73(m,5H),LCMS(ESI)m/z:340(M+1)。
Example 11E
2- (5- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) pentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 4F (30 mg, 0.15 mmol) in N, N-dimethylformamide (2 ml) was added sodium hydride (7 mg, 0.17 mmol, 60% content) at 0 ℃. After 30 minutes of reaction at 0 ℃, a solution of example 11D (51 mg, 0.15 mmol) in N, N-dimethylformamide (1 ml) was added to the above mixed solution. After stirring and reacting for 6 hours at 15 ℃, water is added for quenching and the water phase is extracted by ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (white solid, 5 mg, yield 7.26%).1H-NMR(400MHz,CDCl3):8.51(d,J＝6.5Hz,2H),8.06(d,J＝8.5Hz,2H),7.05(d,J＝6.0Hz,2H),6.99(d,J＝9.0Hz,2H),4.68(q,J＝7.5Hz,2H),4.04(t,J＝6.0Hz,2H),3.85(t,J＝6.3Hz,2H),3.55(t,J＝6.3Hz,2H),3.19(t,J＝7.3Hz,2H),1.85-1.93(m,2H),1.75-1.82(m,2H),1.68(t,J＝7.5Hz,5H)。LCMS(ESI)m/z:458(M+1)。
Example 12
Example 12A
N, 2-dihydroxy-4-methoxybenzamide
To an aqueous solution (500 ml) of hydroxylamine hydrochloride (53 g, 766 mmol) was slowly added an aqueous solution (250 ml) of sodium hydroxide (71 g, 1.78 mol) dropwise with magnetic stirring. A solution of methyl 4-methoxysalicylate (93 g, 510 mmol) in dioxane (250 ml) was added slowly dropwise to the above solution under nitrogen and reacted for 12 hours. After completion of the reaction, the reaction mixture was slowly added to ice water and then concentrated hydrochloric acid was added dropwise to a pH of 2, followed by filtration to obtain the title compound (84 g, yield 90%).1H-NMR(400MHz,MeOD)7.57(d,J＝9.04Hz,1H),6.41-6.54(m,2H),3.75-3.87(m,3H)。LCMS(ESI)m/z:184(M+1)。
Example 12B
6-methoxybenzo [ d ] isoxazol-3 (2H) -ones
Example 12A (40 g, 0.22 mol) was added dropwise to a solution of carbonyldiimidazole (50 g, 031 mol) in anhydrous tetrahydrofuran (600 ml), and after completion of the addition, the mixture was refluxed for 8 hours. After completion of the reaction, the reaction solution was spin-dried, 400 ml of water was added, pH was adjusted to 6 with citric acid, and the title compound was obtained by filtration (23 g, yield 63%).1H-NMR(400MHz,MeOD)7.57(d,J＝8.53Hz,1H),6.97(d,J＝1.51Hz,1H),6.91(dd,J＝1.76,8.78Hz,1H),3.84-3.93(m,3H)。LCMS(ESI)m/z:166(M+1)。
Example 12C
3-ethoxy-6-methoxybenzo [ d ] isoxazoles
To a solution of example 12B (10 g, 60 mmol) in anhydrous tetrahydrofuran (200 ml) was added anhydrous ethanol (3.5 g, 76 mmol) and triphenylphosphine (24 g, 90 mmol) sequentially while cooling on ice. DIAD (18 ml, 90 mmol) was then added slowly to the above solution, after stirring the reaction for 15 minutes at 0 ℃, slowly warmed to room temperature and stirred overnight, quenched after the reaction was complete by the addition of water (200 ml), the aqueous layer was extracted with ethyl acetate (200 ml × 2), the combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by silica gel column chromatography to give the title compound (5.6 g, 48% yield). LCMS (ESI) M/z:194(M +1).
Example 12D
3-ethoxybenzo [ d ] isoxazol-6-ols
Boron tribromide (4.2 g, 16.8 mmol) was slowly added dropwise to a solution of example 12C (810 mg, 4.2 mmol) in dichloromethane (10 ml) under nitrogen at-78 ℃. After the addition was complete, the reaction was slowly warmed to room temperature and stirred overnight. After completion of the reaction, the reaction solution was slowly added dropwise to ice water (100 ml) to quench, the aqueous layer was extracted with ethyl acetate (100 ml × 2), the combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (650 mg, yield 86.7%).1H-NMR(CDCl3,400MHz)7.48(d,J＝8.53Hz,1H),6.90-7.08(m,2H),6.85(d,J＝8.03Hz,1H),4.47(q,J＝7.03Hz,2H),1.51(t,J＝7.03Hz,3H)。
Example 12E
6- ((5-bromopentyl) oxy) -3-ethoxy [ d ] isoxazole
To a solution of example 12D (0.2 g, 1.12 mmol) in N, N-dimethylformamide (20 ml) was added sodium hydride (54 mg, 1.34 mmol, 60% content) in portions at 0 ℃ under nitrogen protection, and after the addition was completed, the mixed solution was stirred at room temperature for 1 hour, then a solution of 1, 5-dibromopentane (770 mg, 2.33 mmol) in N, N-dimethylformamide (10 ml) was added to the above solution, and the reaction was continued stirring at room temperature for 10 hours. The reaction was poured into water (100 ml), the aqueous phase was extracted with ethyl acetate (50 ml × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (yellow liquid, 0.2 g, yield 54.6%). LCMS (ESI) M/z:328(M +1).
Example 12F
2- (5- ((3-ethoxybenzo [ d ] isoxazol-6-yl) oxy) pentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 4F (60 mg, 0.3 mmol) in N, N-dimethylformamide (3 ml) was added sodium hydrogen (24 mg, 0.6 mmol, 60% content) at 0 ℃ under nitrogen. After stirring at 0 ℃ for 0.5 h, a solution of example 12E (100 mg, 0.3 mmol) in N, N-dimethylformamide (1 ml) was added dropwise. The reaction mixture was stirred at 0 ℃ for 1.5 hours. Saturated NH for reaction mixture4Aqueous Cl (5 ml) was quenched, diluted with water (50 ml) and extracted with ethyl acetate (15 ml × 4). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered and dried by spinning, and the residue was purified by preparative chromatography to give the title compound (white solid, 60 mg, yield 45%).1H-NMR(400MHz,CDCl3)8.53(br.s.,1H),7.47(d,J＝8.5Hz,1H),7.27(s,1H),7.07(br.s.,2H),6.78-6.89(m,2H),4.46(q,J＝7.0Hz,2H),4.03(t,J＝6.2Hz,2H),3.85(t,J＝6.2Hz,2H),3.55(t,J＝6.27Hz,2H),3.19(t,J＝7.28Hz,2H),1.85-1.94(m,2H),1.80(q,J＝7.4Hz,2H),1.64-1.68(m,2H),1.50(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:447(M+1)。
Route C
Example 13
2- (2- (2- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) oxy) ethoxy) ethyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine
-1, 1-dioxide
Example 13A
4- (2- (2-bromoethoxy) ethoxy) -4 '-chloro-1, 1' -biphenyl
To a mixture of example 6A (1 g, 4.89 mmol), potassium carbonate (1.35 g, 9.77 mmol) and potassium iodide (810 mg, 4.89 mmol) in acetone (15 ml) was added 1-bromo-2- (2-bromoethoxy) ethane (3.4 g, 14.66 mmol). The mixture was stirred at 70 ℃ for 3 hours and then spin-dried, and 20 ml of petroleum ether was added to the system, followed by filtration to obtain the title compound (1.5 g, yield 86%).1H-NMR(CDCl3,400MHz)7.47(dd,J＝8.5,4.0Hz,4H),7.34-7.41(m,2H),6.99(d,J＝8.5Hz,2H),4.16-4.22(m,2H),3.85-3.96(m,4H),3.51(t,J＝6.3Hz,2H)。
Example 13B
2- (2- (2- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) oxy) ethoxy) ethyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
This example was prepared according to example 12F.1H-NMR(CDCl3,400MHz)8.48(d,J＝6.0Hz,2H),7.45-7.51(m,4H),7.36-7.41(m,2H),7.02(d,J＝6.3Hz,2H),6.98(d,J＝8.8Hz,2H),4.16-4.20(m,2H),3.88(q,J＝4.9Hz,4H),3.76(dd,J＝11.9,5.1Hz,4H),3.40(t,J＝4.9Hz,2H)。LCMS(ESI)m/z:474(M+1)。
Route D
Example 14
(E) -4- ((5- (1, 1-dioxo-5- (pyridin-4-yl) -1,2, 5-thiadiazolidin-2-yl) -3-methylpentyl) oxy) benzaldehyde-oxy-ethyloxime
Example 14A
3-methylpentane-1, 5-diylbis (4-methylphenylsulfonyl)
To a solution of 3-methyl-1, 5 pentanediol (40 g, 338.5 mmol) in dichloromethane (400 ml) was added triethylamine (160 ml) and p-toluenesulfonyl chloride (258.1 g, 1.35 mol). The mixed solution was stirred at 20 ℃ for 12 hours, then extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the title compound (colorless liquid, 80 g, yield 55%).1H-NMR(CDCl3,400MHz)7.78(d,J＝8.0Hz,4H),7.37(d,J＝8.0Hz,4H),4.01(q,J＝6.0Hz,4H),2.46(s,6H)1.57-1.69(m,3H)1.43(dq,J＝13.4,6.7Hz,2H),0.78(d,J＝6.3Hz,3H)。LCMS(ESI)m/z:299(M+1)。
Example 14B
(E) -5- (4- ((ethoxyimino) methyl) phenoxy) -3-methylpentyl-4-methylbenzenesulfonyl
A mixture of example 7A (4.98 g, 30.17 mmol), example 14A (11.7 g, 27.43 mmol), potassium carbonate (7.58 g, 54.86 mmol) and acetonitrile (110 ml) was reacted at 80 ℃ for 16 h. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction system, the aqueous layer was extracted with ethyl acetate (100 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography to give the title compound (colorless solid, 3.7 g, 32% yield).1H-NMR(CDCl3,400MHz)8.03(s,1H),7.46(d,J＝8.5Hz,2H),6.78-6.85(m,2H),4.20(q,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H)。
Example 14C
(E) -4- ((5- (1, 1-dioxo-5- (pyridin-4-yl) -1,2, 5-thiadiazolidin-2-yl) -3-methylpentyl) oxy) benzaldehyde-oxy-ethyloxime
The preparation of this example is as in example 12F.1H-NMR(CDCl3,400MHz)8.51(d,J＝5.5Hz,2H),8.02(s,1H),7.50(d,J＝8.5Hz,2H),7.04(d,J＝6.0Hz,2H),6.87(d,J＝8.5Hz,2H),4.17-4.24(m,2H),3.98-4.07(m,2H),3.82(t,J＝6.5Hz,2H),3.48-3.55(m,2H),3.20(t,J＝7.5Hz,2H),1.79-1.93(m,3H),1.66-1.73(m,1H),1.56-1.61(m,1H),1.31(t,J＝7.0Hz,3H),1.03(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:447(M+1)。
Example 15
2- (5- ((3-ethoxybenzo [ d ] isoxazol-6-yl) oxy) -3-methylpentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 15A
5- ((3-ethoxybenzo [ d ] isoxazol-6-yl) oxy) -3-methylpentyl 4-methylbenzenesulfonate
To a solution of example 12D (0.3 g, 1.67 mmol) in N, N-dimethylformamide (5 ml) were added potassium carbonate (0.69 g, 5.0 mmol) and example 14A (2.14 g, 5.0 mmol). The mixed solution was stirred at 80 ℃ for 12 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography after filtration and evaporation (petroleum ether: ethyl acetate 10:1) to obtain the title compound (white solid, 0.3 g, yield 41.3%).1H-NMR(CDCl3,400MHz)7.79(d,J＝8.0Hz,2H)7.46(d,J＝8.5Hz,1H)7.33(d,J＝8.0Hz,2H)6.78-6.84(m,2H)4.47(q,J＝7.0Hz,2H)4.07-4.15(m,2H)3.93-4.01(m,2H)2.43(s,3H)1.74-1.89(m,3H)1.60-1.66(m,1H)1.54-1.58(m,1H)1.51(t,J＝7.0Hz,3H)0.92(d,J＝6.5Hz,3H).LCMS(ESI)m/z:434(M+1)。
Example 15B
2- (5- ((3-ethoxybenzo [ d ] isoxazol-6-yl) oxy) -3-methylpentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 4F (30 mg, 0.15 mmol) in N, N-dimethylformamide (2 ml) was added sodium hydride (6.62 mg, 0.165 mmol) at 0 ℃. After stirring at 0 ℃ for 30 minutes, a solution of example 15A (65 mg, 0.15 mmol) in N, N-dimethylformamide (1 ml) was added to the above mixed solution. After stirring and reacting for 6 hours at 15 ℃, water is added for quenching and the water phase is extracted by ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (white solid, 18 mg, yield 25.8%).1H-NMR(400MHz,CDCl3)8.53(d,J＝6.0Hz,2H)7.46-7.51(m,1H)7.06(d,J＝6.3Hz,2H)6.86(dd,J＝4.3,2.5Hz,2H)4.48(q,J＝7.0Hz,2H)4.08(q,J＝5.7Hz,2H)3.86(t,J＝6.4Hz,2H)3.50-3.60(m,2H)3.24(t,J＝7.4Hz,2H)1.88-1.99(m,2H)1.77-1.87(m,1H)1.61-1.75(m,3H)1.52(t,J＝7.2Hz,3H)1.07(d,J＝6.3Hz,3H)。LCMS(ESI)m/z:461(M+1)。
Route E
Example 16
2- (2-aminopyridin-4-yl) -5- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) oxy) pentyl) -1,2, 5-thiadiazolidine 1 alkane-1, 1-dioxide
Example 16A
2- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) oxy) pentyl) -5- (2-chloropyridin-4-yl) -1,2, 5-thiadiazolidine 1 alkane-1, 1-dioxide
To a solution of example 4E (200 mg, 0.86 mmol) in N, N-dimethylformamide (3 ml) was added NaH (68 mg, 1.72 mmol, 60% content) in portions at 0 ℃ under nitrogen. After the reaction mixture was stirred at room temperature for 0.5 hour, a solution of example 6B (303 mg, 0.86 mmol) in N, N-dimethylformamide (5 ml) was added and the mixture was stirred at room temperature for 8 hours. After quenching the reaction with water, extraction with ethyl acetate (50 ml × 3), combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was isolated and purified by thin layer chromatography to give the title compound (80 mg, yield 22%).1H-NMR(CDCl3,400MHz)8.29(d,J＝5.8Hz,1H),7.48-7.52(m,4H),7.38-7.42(m,2H),7.09(dd,J＝5.8,2.3Hz,1H),7.01(d,J＝2.0Hz,1H),6.98(d,J＝8.8Hz,2H),4.05(t,J＝6.3Hz,2H),3.86(t,J＝6.4Hz,2H),3.58(t,J＝6.4Hz,2H),3.21(t,J＝7.2Hz,2H),1.76-1.95(m,4H),1.63-1.70(m,2H)。LCMS(ESI)m/z:506(M+1)。
Example 16B
2- (2-aminopyridin-4-yl) -5- (5- ((4 '-chloro- [1,1' -biphenyl ] -4-yl) oxy) pentyl) -1,2, 5-thiadiazolidine 1 alkane-1, 1-dioxide
To a mixed solution of dioxane/N, N-dimethylformamide (1.5 ml/0.5 ml) of example 16A (80 mg, 0.16 mmol), tert-butyl carbamate (74 mg, 0.63 mmol) and cesium carbonate (103 mg, 0.32 mmol) was added Pd under a nitrogen blanket2(dba)3(20 mg, 0.03 mmol) and Xant-Phos (10 mg, 0.03 mmol), and after the addition was complete the mixed solution was stirred at 110 ℃ for 16 h. After removal of the solvent in vacuo, the residue was extracted with ethyl acetate (250 ml. times.3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residueThe title compound was obtained after purification by preparative HPLC (30 mg, yield 31%).1H-NMR(CDCl3,400MHz):7.80(sbr,1H),7.48(dd,J＝8.8,3.3Hz,4H),7.35-7.41(m,2H),6.96(d,J＝8.5Hz,2H),6.58(s,br,1H),6.33(s,br,1H),4.02(t,J＝6.0Hz,2H),3.87(s,br,2H),3.55(t,J＝6.3Hz,2H),3.19(t,J＝7.3Hz,2H),1.85-1.90(m,2H),1.76-1.82(m,2H),1.63(d,J＝6.5Hz,2H)。LCMS(ESI)m/z:487(M+1)。
Route F
Example 17
(E) -4- ((5- (5- (2-aminopyridin-4-yl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) -3-methylpentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
Example 17A
(E) -4- ((5- (5- (2-chloropyridin-4-yl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) -3-methylpentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
This example was prepared using the method described in example 16A.1H-NMR(CDCl3,400MHz):8.29(d,J＝5.5Hz,1H),8.04(s,1H),7.53(d,J＝8.8Hz,2H),7.08(dd,J＝5.8,2.0Hz,1H),7.01(s,1H),6.90(d,J＝8.5Hz,2H),4.22(q,J＝7.0Hz,2H),4.01-4.12(m,2H),3.80-3.88(m,2H),3.50-3.61(m,2H),3.23(t,J＝7.5Hz,2H),1.60-1.98(m,5H),1.34(t,J＝7.0Hz,3H),1.06(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:481(M+1)。
Example 17B
(E) -4- ((5- (5- (2-aminopyridin-4-yl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) -3-methylpentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 16.1H-NMR(CDCl3,400MHz)8.03(s,1H),7.98(d,J＝5.5Hz,1H),7.51(d,J＝8.5Hz,2H),6.88(d,J＝8.5Hz,2H),6.41(d,J＝6.0Hz,1H),6.29(s,1H),4.20(q,J＝7.2Hz,2H),4.01-4.09(m,2H),3.77(t,J＝6.3Hz,2H),3.43-3.55(m,2H),3.19(t,J＝7.5Hz,2H),1.63-1.95(m,5H),1.32(t,J＝7.0Hz,3H),1.03(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:462(M+1)。
Route G
Example 18
2- (5- ((3-ethoxybenzo [ d ] isoxazol-6-) oxo) pentyl) -5- (2- (methylamino) pyridine-4-) -1,2, 5-thiadiazoline-1, 1-dioxide
Example 18A
2- (2-chloropyridine-4-) -5- (5- ((3-ethoxybenzo [ d ] isoxazole-6-) oxo) pentyl) -1,2, 5-thiadiazoline-1, 1-dioxide
To a solution of example 4E (271 mg, 1.16 mmol) in N, N-dimethylformamide was added sodium hydride (93 mg, 2.32 mmol) at 0 ℃ under nitrogen. After stirring at 0 ℃ for 0.5 h, a solution of example 12E (400 mg, 1.22 mmol) in N, N-dimethylformamide (5 ml) was added dropwise. The reaction mixture was stirred at 0 ℃ for 1 hour and at room temperature for 12 hours. Saturated NH for reaction mixture4Aqueous Cl (5 ml) was quenched, diluted with copious amounts of water (120 ml) and extracted with ethyl acetate (30 ml × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spun dry, and the residue was purified by column chromatography (dichloromethane: methanol ═ 20:1) to give the title compound (white solid, 210 mg, yield 38%).1H-NMR(400MHz,CDCl3)8.27(d,J＝6.0Hz,1H),7.47(d,J＝9.0Hz,1H),7.06(dd,J＝6.0,2.0Hz,1H),6.99(d,J＝2.0Hz,1H),6.81-6.87(m,2H),4.46(q,J＝7.0Hz,2H),4.02(t,J＝6.2Hz,2H),3.84(t,J＝6.2Hz,2H),3.56(t,J＝6.2Hz,2H),3.19(t,J＝7.0Hz,2H),1.85-1.93(m,2H),1.80(q,J＝7.4Hz,2H),1.50(t,J＝7.0Hz,3H),0.80-0.92(m,2H)。LCMS(ESI)m/z:481(M+1)。
Example 18B
2- (5- ((3-ethoxybenzo [ d ] isoxazol-6-) oxo) pentane) -5- (2- (methylamino) pyridine-4-) -1,2, 5-thiadiazoline-1, 1-dioxide
To a solution of example 18A (100 mg, 0.2 mmol) in N-methylpyrrolidone (8 ml) was added a solution of methylamine in tetrahydrofuran (5 ml, 2 mol per liter, 12.5 mmol).The mixture was stirred in a closed pot at 110 ℃ for 72 hours, the solvent was removed from the reaction mixture under vacuum, and the residue was purified by preparative chromatography to give the title compound as a yellow powder (10 mg, 10% yield).1H-NMR(400MHz,CDCl3)8.02(brs,1H),7.48(brs,1H),6.85(brs,2H),6.38(brs,1H),6.16(brs,1H),4.49(brs,2H),4.04(brs,2H),3.84(brs,2H),3.52(brs,2H),3.19(brs,2H),2.94(brs,3H),1.91(brs,2H),1.81(brs,2H),1.69-1.75(m,2H),1.52(brs,3H)。LCMS(ESI)m/z:476(M+1)。
Route H
Example 19
2- (4- (6- (4-chlorophenyl) chroman-2-yl) butyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 19A
5- ((tetrahydro-2H-pyran-2-yl) oxy) pentan-1-ol
1, 5-pentanediol (60 g, 0.57 mol), 3, 4-dihydropyran (48.5 g, 0.57 mol) and p-toluenesulfonic acid (50 mg) were stirred at 40 ℃ for 3 hours. After the reaction was stopped, potassium carbonate solution (200 ml) was added, and the aqueous phase was extracted with ethyl acetate (150 ml. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered to dryness and the residue was used directly in the next reaction.1H-NMR(CDCl3,400MHz)4.54(d,J＝3.5Hz,1H),3.78-3.89(m,1H),3.68-3.77(m,1H),3.60(br.s.,2H),3.43-3.52(m,1H),3.32-3.41(m,1H),2.02(br.s.,1H),1.80(m,1H),1.65-1.68(m,1H),1.39-1.70(m,10H)。
Example 19B
5- ((tetrahydro-2H-pyran-2-yl) oxy) pentanal
To a solution of example 19A (60 g, 0.30 mol) in dichloromethane (400 ml) was added PCC (90 g) in portions and the reaction mixture was stirred at room temperature for 5 hours. After filtration, the filtrate was concentrated and purified by column chromatography to give the title compound.1H-NMR(400MHz,CDCl3)9.62-9.79(m,1H),4.50(br.s.,1H),3.58-3.91(m,2H),3.25-3.53(m,2H),2.50-2.68(m,2H),2.42(dd,J＝1.25,3.51Hz,2H),1.48-1.79(m,8H)。
Example 19C
6- (4-chlorophenyl) -2- (4- ((tetrahydro-2H-pyran-2-yl) oxy) butyl) chroman-4-one
A mixture of example 19B (7.5 g, 40.27 mmol), example 1F (9.93 g, 40.27 mmol) and piperidine (3.43 g, 40.27 mmol) in ethanol (100 ml) was stirred at 85 ℃ for 3 h. Dichloromethane (50 ml) and water (50 ml) were added to the reaction, the pH of the reaction was adjusted to 6 with dilute aqueous hydrochloric acid, the aqueous layer was extracted with dichloromethane (100 ml. times.3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by passing throughPurification by column chromatography gave the title compound (yellow liquid, 7 g, 42% yield).1H-NMR(400MHz,CDCl3)8.05(d,J＝2.3Hz,1H),7.67(dd,J＝8.7,2.4Hz,1H),7.48(d,J＝8.5Hz,2H),7.38(d,J＝8.5Hz,2H),7.04(d,J＝8.5Hz,1H),4.58(d,J＝4.3Hz,1H),4.43-4.52(m,1H),3.86(td,J＝7.3,3.9Hz,1H),3.74-3.82(m,1H),3.47-3.54(m,1H),3.39-3.45(m,1H),2.67-2.76(m,2H),1.89-1.99(m,1H),1.76-1.86(m,2H),1.63-1.71(m,4H),1.49-1.59(m,5H)。
Example 19D
4- (6- (4-chlorophenyl) chroman-2-yl) butyl-2, 2, 2-trifluoroacetate
To a solution of example 19C (2.5 g, 6.03 mmol) in trifluoroacetic acid (20 mL) was added triethylhydrosilane (10 mL) and the mixture was reacted at 50 ℃ for 3 hours. The solvent was evaporated, ethyl acetate (20 ml) and water (20 ml) were added to the reaction system, the aqueous layer was extracted with ethyl acetate (20 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated to provide the title compound (yellow liquid, 2g, yield 80%).
Example 19E
4- (6- (4-chlorophenyl) chroman-2-yl) butan-1-ol
To a mixture of 1, 4-dioxane (5 ml) and water (2 ml) of example 19D (500 mg, 1.21 mmol) was added lithium hydroxide (29 mg, 1.21 mmol) and the mixture was reacted at 25 ℃ for 3 hours. Ethyl acetate (10 ml) and water (10 ml) were added to the reactionThe aqueous layer was extracted with ethyl acetate (10 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography to give the title compound (colorless solid, 300 mg, 78% yield).1H-NMR(400MHz,CDCl3)7.43-7.47(m,2H),7.33-7.38(m,2H),7.26-7.30(m,2H),6.86(d,J＝8.3Hz,1H),4.03(br.s.,1H),3.70(t,J＝5.9Hz,2H),2.76-2.95(m,2H),1.98-2.08(m,1H),1.71-1.85(m,2H),1.58-1.70(m,5H)。
Example 19F
2- (4-bromobutyl) -6- (4-chlorophenyl) chroman
Triphenylphosphine (420 mg, 1.6 mmol) was slowly added to a mixture of example 19E (500 mg, 1.6 mmol), carbon tetrabromide (3.4 g, 10.3 mmol) in tetrahydrofuran (5 ml) at 0 deg.C, and the mixture was reacted at 60 deg.C for 1 hour. After the reaction solution was concentrated under reduced pressure, the residue was purified by column chromatography to give the title compound (yellow solid, 658 mg, yield 83%).1H-NMR(400MHz,CDCl3)7.43-7.48(m,2H),7.34-7.38(m,2H),7.24-7.29(m,2H),6.86(d,J＝8.5Hz,1H),4.00-4.07(m,1H),3.45-3.49(m,2H),2.77-2.96(m,2H),1.90-2.02(m,3H),1.62-1.80(m,5H)。
Example 19G
2- (4- (6- (4-chlorophenyl) chroman-2-yl) butyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Prepared as described in example 18A in this example。1H-NMR(400MHz,CDCl3)8.51(d,J＝6.0Hz,2H),7.42-7.48(m,2H),7.33-7.40(m,2H),7.29(s,3H),7.05(d,J＝6.0Hz,2H),6.85(d,J＝8.5Hz,1H),4.03(br.s.,1H),3.86(t,J＝6.5Hz,2H),3.52-3.59(m,2H),3.20(t,J＝7.0Hz,2H),2.77-2.95(m,2H),2.03(d,J＝13.1Hz,1H),1.64-1.85(m,7H)。LCMS(ESI)m/z:498(M+1)。
Route I
Example 20
2- (4- (6-bromobenzodihydropyran-2-yl) butyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 20A
6-bromo-2- (4- ((tetrahydro-2H-pyran-2-yl) oxy) butyl) chroman-4-one
Example 19B (5.0 g, 29 mmol), 5 '-bromo-2' -hydroxyacetophenone (6.37 g, 29 mmol) and piperidine (2.0 ml) were mixed in ethanol (150 ml), and after addition of reflux for 4 hours, evaporated to dryness under reduced pressure, the resulting residue was purified by column chromatography to give the title compound (yellow solid, 6.5 g, yield 57%).1H-NMR(CDCl3,400MHz)8.00(d,J＝2.3Hz,1H),7.56(dd,J＝8.8,2.3Hz,1H),6.90(d,J＝8.8Hz,1H),4.60(br.s.,1H),4.40-4.52(m,1H),3.72-3.95(m2H),3.37-3.59(m,2H),2.66-2.80(m,2H),1.48-2.01(m,12H)。
Example 20B
4- (6-bromo-chroman-2-yl) butyl-2, 2, 2-trifluoroacetate
Example 20A (1.0 g, 2.57 mmol) and triethylhydrosilane (7.3 g, 62.8 mmol) were mixed in trifluoroacetic acid (20 ml) and heated at 60 ℃ for 5 hours. After concentration under reduced pressure, the crude product was used directly in the next reaction (5.8 g, 97% crude yield).1H-NMR(CDCl3,400MHz)7.17(d,J＝2.0Hz,2H),6.60-6.70(m,1H),4.30-4.47(m,2H),3.96(td,J＝7.8,2.0Hz,1H),2.67-2.90(m,2H),1.97(ddt,J＝13.5,5.6,2.8Hz,1H),1.48-1.89(m,8H)。
Example 20C
4- (6-bromobenzodihydropyran-2-yl) butan-1-ol
The preparation of this example is as in example 19E.1H-NMR(CDCl3,400MHz)7.11-7.24(m,1H),6.64-6.75(m,1H),3.99(d,J＝5.0Hz,1H),3.61-3.80(m,2H),2.66-2.91(m，2H),1.93-2.06(m,1H),1.47-1.84(m,10H)。
Example 20D
4- (6-bromo-chroman-2-yl) butyl-4-methylbenzenesulfonic acid
To a solution of example 20C (71 mg, 0.25 mmol) in dichloromethane (5.0 ml) was added triethylamine (76 mg, 0.75 mmol) and p-toluenesulfonyl chloride (95 mg, 0.5 mmol) in that order. The reaction mixture was stirred at 12 ℃ for 4 hours, concentrated under reduced pressure, and the crude product was purified by thin layer chromatography to give the title compound (colorless liquid, 60 mg, yield 55%).1H-NMR(CDCl3，400MHz)7.73-7.85(m，2H)，7.36(d，J＝8.0Hz，2H)，7.17(d，J＝4.8Hz，2H)，6.61-6.69(m，1H)，4.03-4.11(m，2H)，3.84-3.97(m，1H)，2.66-2.89(m，2H)，2.45(s，3H)，1.88-2.01(m，1H)，1.42-1.83(m,7H)。
Example 20E
2- (4- (6-bromobenzodihydropyran-2-yl) butyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation of this example is as in example 18A.1H-NMR(CDCl3,400MHz)8.52(d,J＝6.0Hz,2H),7.14-7.19(m,2H),7.06(d,J＝6.0Hz,2H),6.65-6.69(m,1H),3.97(s.,1H),3.86(t,J＝6.3Hz,2H),3.56(t,J＝6.5Hz,2H),3.19(t,J＝7.0Hz,2H),2.67-2.89(m,2H),1.94-2.04(m,1H),1.53-1.84(m,7H)。LCMS(ESI)m/z:466(M+1)。
Route J
Example 21
(E) -2- (4- (1, 1-dioxo-5- (pyridin-4-yl) -1,2, 5-thiadiazolidin-2-yl) butyl) chroman-6-carbaldehyde-oxy-ethyloxime
Example 21A
2- (4-hydroxybutyl) chroman-6-carbaldehyde
To a solution of example 20C (600 mg, 2.1 mmol) in dry tetrahydrofuran (10.0 mL) was slowly added n-butyllithium (2.5 mol per liter, 1.8 mL, 4.6 mmol) dropwise under nitrogen at-78 deg.C, and stirring was continued for 2 hours after addition was complete. The reaction was then again lowered to-78 ℃ and N, N-dimethylformamide (380 mg, 5.2 mmol) was added slowly dropwise. After the addition was complete, the reaction was allowed to warm to room temperature slowly and stirred overnight. After quenching by addition of water (5.0 ml), the aqueous phase was extracted with ethyl acetate (10.0 ml × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by thin layer chromatography to give the title compound (colorless liquid, 70.0 mg, yield 15%).1H-NMR(CDCl3,400MHz)9.83(s,1H),7.55-7.68(m,2H),6.83-6.92(m,1H),4.03-4.20(m,1H),3.71(t,J＝6.0Hz,2H),2.72-2.92(m,2H),2.00-2.13(m,1H),1.46-1.87(m,7H)。
Example 21B
(E) -2- (4-hydroxybutyl) chroman-6-carbaldehyde-oxy-ethyloxime
To a solution of example 21A (70 mg, 0.32 mmol) in water (2.0 ml) were added ethoxyamino hydrochloride (97 mg, 1.6 mmol) and sodium acetate (130 mg, 1.59 mmol), and the reaction was stopped after heating at 60 ℃ for 3 hours. The aqueous phase was extracted with ethyl acetate (5.0 ml. times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was used directly in the next reaction (70 mg, yield 79%).
Example 21C
(E) -4- (6- ((ethoxyimino) methyl) chroman-2-yl) butyl-4-methylbenzenesulfonate
To a solution of example 21B (70 mg, 0.25 mmol) in dichloromethane (5.0 ml) was added triethylamine (76 mg, 0.75 mmol) and p-toluenesulfonyl chloride (95 mg, 0.5 mmol) in that order. The reaction mixture was stirred at 12 ℃ for 4 hours, concentrated under reduced pressure, and the crude product was purified by thin layer chromatography to give the title compound (colorless liquid, 60 mg, yield 55%).1H-NMR(CDCl3,400MHz)7.98(s,1H),7.79(d,J＝8.0Hz,2H),7.24-7.39(m,2H),6.69-6.77(m,1H),4.12-4.23(m,2H),4.06(t,J＝6.3Hz,2H),3.92(brs,1H),2.68-2.87(m,2H),2.43(s,3H),1.89-1.99(m,1H),1.43-1.78(m,7H),1.26-1.37(m,3H)。
Example 21D
(E) -2- (4- (1, 1-dioxo-5- (pyridin-4-yl) -1,2, 5-thiadiazolidin-2-yl) butyl) chroman-6-carbaldehyde-oxy-ethyloxime
Preparation method of this exampleReference is made to example 18A.1H-NMR(CDCl3,400MHz)8.52(brs,2H),7.98(s,1H),7.21-7.35(m,2H),7.07(d,J＝5.0Hz,2H),6.77(d,J＝9.0Hz,1H),4.15-4.28(m,2H),4.02(brs,1H),3.86(t,J＝6.5Hz,2H),3.52-3.61(m,2H),3.19(t,J＝7.0Hz,2H),2.72-2.90(m,2H),1.95-2.04(m,1H),1.57-1.84(m,8H),1.31(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:459(M+1)。
Example 22
(R) -1- (4- (6- (4-chlorophenyl) chroman-2-yl) butyl) -3- (pyridin-4-yl) imidazolidinone
(S) -1- (4- (6- (4-chlorophenyl) chroman-2-yl) butyl) -3- (pyridin-4-yl) imidazolidinone
The product of example 2 was resolved using SFC to obtain 2 chiral isomers. The conditions used for the splitting were as follows:
the method comprises the following steps: AS-H _ S _5_40_3ML _8MIN _15CM
Chromatographic column of ChiralpakAS-H150 x 4.6mmI.D.,5um
Mobile phase 40% ethanol (0.05% DEA) -CO2
Flow rate of 3mL/min
The wavelength is 220 nm;
example 22a is the first isomer with a retention time of 2.80 minutes; example 22b is the second isomer with a retention time of 4.04 minutes.
Procedure K
Example 23
(E) -4- ((5(5 (2-aminopyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
Example 23A
(E) -4-hydroxybenzaldehyde-oxy-ethyl oxime
To a solution of p-hydroxybenzaldehyde (2.5 g, 20.5 mmol), ethoxyamino hydrochloride (3.9 g, 40.9 mmol) in water (50 ml) was added sodium acetate (3.4 g, 40.9 mmol) and the mixture was stirred at 80 ℃ for 4 hours. Ethyl acetate (50 ml) was added to the reaction system, the aqueous layer was extracted with ethyl acetate (50 ml × 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (brown solid, 3g, 89% yield).1HNMR(CDCl3,400MHz)8.03(s,1H),7.46(d,J＝8.5Hz,2H),6.78-6.85(m,2H),4.20(q,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H)。
Example 23B
(E) -4- ((6-bromohexyl) oxy) benzaldehyde-oxy-ethyl ketoxime
A solution of example 23A (1.0 g, 6.1 mmol), 1, 5-dibromopentane (1.4 g, 6.1 mmol), potassium carbonate (1.67 g, 12.1 mmol) and potassium iodide (0.1 g, 0.61 mmol) in acetone (100 mL) was heated to reflux for 10 h. After the reaction was cooled to room temperature, it was filtered, and the filtrate was spin-dried and purified by column chromatography to give the title compound (white crystals, 1.2 g, 63%).1HNMR(CDCl3,400MHz)8.01-8.05(m,1H),7.49-7.55(m,2H),6.86-6.91(m,2H),4.17-4.24(m,2H),3.96-4.01(m,2H),3.41-3.47(m,2H),1.89-1.99(m,2H),1.78-1.86(m,2H),1.60-1.68(m,2H),1.29-1.34(m,3H)。
Example 23C
(E) -4- ((5- (5- (2-chloropyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
To a solution of example 4E (100 mg, 428 micromoles) in N, N-dimethylformamide (3 ml) was added sodium hydride (51.4 mg, 1.3 mmol) under nitrogen at 10 ℃, and after the reaction solution was stirred for 2 hours, a solution of example 23B (134.5 mg, 428 micromoles) in N, N-dimethylformamide (1 ml) was added, followed by stirring at 40 ℃ for 8 hours. After the completion of the TLC detection reaction, water (10 ml) was added to quench the reaction, the aqueous layer was extracted with ethyl acetate (20 ml × 3), the organic layers were combined and dried over anhydrous sodium sulfate, filtered and evaporated, and the crude product was separated with a thin layer chromatography plate (petroleum ether/ethyl acetate ═ 1:1) to give the title compound (white solid, 140 mg, yield: 70%).1HNMR(400MHz,CHLOROFORM-d)8.29(d,J＝5.77Hz,1H),8.05(s,1H),7.53(d,J＝9.03Hz,2H),7.09(dd,J＝2.01,5.77Hz,1H),7.01(d,J＝2.01Hz,1H),6.89(d,J＝8.78Hz,2H),4.22(q,J＝7.03Hz,2H),4.02(t,J＝6.15Hz,2H),3.86(t,J＝6.40Hz,2H),3.54-3.60(m,2H),3.20(t,J＝7.28Hz,2H),1.60-1.91(m,6H),1.34(t,J＝7.15Hz,3H)。LCMS(M+1):467。
Example 23D
(E) -4- ((5- (5- (2-aminopyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
Example 23C (80 mg, 171.3 micromoles), tert-butyl carbamate (120 mg, 1.0 mmol) and Cs were added under nitrogen blanket2CO3Pd was added to a (112 mg, 343. mu. mol) mixed solution of dioxane and N, N-dimethylformamide (3 ml)/(1 ml)2(dba)3(30 mg, 33. mu. mol) and Xant-Phos (15 mg, 38. mu. mol), stirred well and then heated to 110 ℃ for 10 hours. TLC (petroleum ether: ethyl acetate: 2: 1-dichloromethane: methanol: 20:1) detection reaction was completed and quenched by addition of water (10 ml), extracted with ethyl acetate (30 ml x3), and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was isolated by preparative HPLC (trifluoroacetic acid) to give the title compound as a white solid (20 mg, 26% yield).1HNMR(400MHz,CHLOROFORM-d)7.95-8.07(m,2H),7.51(d,J＝8.53Hz,2H),6.88(d,J＝8.53Hz,2H),6.42(dd,J＝2.01,5.52Hz,1H),6.29(d,J＝2.01Hz,1H),4.52(br.s.,1H),4.20(q,J＝7.19Hz,2H),4.00(t,J＝6.27Hz,2H),3.80(t,J＝6.53Hz,2H),3.50(t,J＝6.27Hz,2H),3.16(t,J＝7.28Hz,2H),1.73-1.90(m,4H),1.62-1.65(m,2H),1.32(t,J＝7.03Hz,3H)。LCMS(M+1):448。
Example 24
4- ((5- (5- (2-aminopyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde
The reaction mixture of example 23(30 mg, 67 micromoles) and trifluoroacetic acid (0.5 ml) in water (0.5 ml) and methanol (0.5 ml) was stirred at 40 ℃ for 16 hours. The residue was separated by preparative HPLC to give the title compound (2 mg, yield: 7%).1HNMR(CDCl3,400MHz):7.75(d,J＝8.5Hz,2H),7.68(s,1H),6.96(d,J＝8.8Hz,2H),4.45(q,J＝7.4Hz,2H),3.84(s,3H),1.59(d,J＝3.8Hz,3H)。LCMS(ESI)m/z:405(M+1)。
Example 25
(E) -4- ((6- (5- (2-aminopyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) hexyl) oxy) benzaldehyde-oxy-ethyl ketoxime
Example 25A
(E) -4- ((6-bromohexyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation of this example is as in example 23B.1HNMR(400MHz,CHLOROFORM-d)8.04(d,J＝4.52Hz,1H),7.51(d,J＝4.52Hz,2H),6.88(d,J＝5.77Hz,2H),4.15-4.29(m,2H),3.99(d,J＝5.77Hz,2H),3.37-3.50(m,2H),1.74-2.00(m,4H),1.52(br.s.,4H),1.23-1.37(m,3H)。
Example 25B
4- ((6- (5- (2-chloropyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) hexyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation of this example is as in example 23C.1HNMR(400MHz,CHLOROFORM-d)8.28(d,J＝6.02Hz,1H),8.04(s,1H),7.52(d,J＝8.78Hz,2H),7.07(dd,J＝2.13,5.90Hz,1H),7.01(d,J＝2.01Hz,1H),6.89(d,J＝8.78Hz,2H),4.21(q,J＝7.03Hz,2H),4.00(t,J＝6.27Hz,2H),3.84(t,J＝6.40Hz,2H),3.55(t,J＝6.27Hz,2H),3.17(t,J＝7.28Hz,2H),1.79-1.87(m,2H),1.70-1.78(m,2H),1.49-1.58(m,4H),1.33(t,J＝7.03Hz,4H)。LCMS(ESI)m/z:480(M+1)。
Example 25C
(E) -4- ((6- (5- (2-aminopyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) hexyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 23.1HNMR(400MHz,CHLOROFORM-d)8.00-8.06(m,1H),7.93(d,J＝6.02Hz,1H),7.51(d,J＝9.03Hz,3H),6.87(d,J＝8.53Hz,3H),6.46(d,J＝4.52Hz,1H),6.28(s,1H),4.12-4.24(m,3H),3.98(t,J＝6.27Hz,3H),3.79(t,J＝6.27Hz,2H),3.49(t,J＝6.27Hz,2H),3.13(t,J＝7.03Hz,3H),1.77-1.85(m,2H),1.67-1.76(m,3H),1.51(t,J＝10.54Hz,5H),1.32(t,J＝7.03Hz,4H)。LCMS(ESI)m/z:462(M+1)。
Example 26
(E) -4- (4- (5- (2-aminopyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) butyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 25.1HNMR(400MHz,CHLOROFORM-d)8.05(s,1H),7.99(d,J＝5.77Hz,1H),7.53(d,J＝8.78Hz,2H),6.90(d,J＝8.78Hz,2H),6.43(d,J＝4.52Hz,1H),6.30(s,1H),4.56(br.s.,1H),4.22(q,J＝7.03Hz,2H),4.06(t,J＝5.14Hz,2H),3.77(t,J＝6.27Hz,2H),3.51(t,J＝6.27Hz,2H),3.22(t,J＝6.40Hz,2H),1.93(br.s.,5H),1.34(t,J＝7.15Hz,4H)。LCMS(ESI)m/z:434(M+1)。
Example 27
4- (5- (5- (4- (2-ethyltetrazol-5-yl) phenoxy) pentyl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
Example 27A
2- (5- (4- (2-ethyltetrazol-5-yl) phenoxy) pentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 4E (100 mg, 0.43 mmol) in N, N-dimethylformamide (3 ml) was added sodium hydride (20 mg, 0.85 mmol) at 0 ℃. After 30 minutes at 0 ℃, a solution of example 11D (51 mg, 0.15 mmol) in N, N-dimethylformamide (1 ml) was added to the above mixed solution. Stirring and reacting at 15 ℃ for 6After an hour, the reaction was quenched with water and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, evaporated and column separated (petroleum ether: ethyl acetate ═ 1:1) to give the title compound (white solid, 120 mg, yield 57%).1HNMR(CDCl3400MHz,)8.27(d,J＝6.0Hz,1H),8.07(d,J＝8.5Hz,2H),7.07(dd,J＝5.8,2.3Hz,1H),6.99-7.00(m,2H),4.69(q,J＝7.2Hz,2H),4.05(t,J＝6.3Hz,2H),3.84(t,J＝6.3Hz,2H),3.56(t,J＝6.3Hz,2H),3.19(t,J＝7.0Hz,2H),1.86-1.93(m,2H),1.76-1.83(m,2H),1.64-1.71(m,5H)。LCMS(ESI)m/z:492(M+1)。
Example 27B
4- (5- (5- (4- (2-yltetrazol-5-yl) phenoxy) pentyl) -1, 1-oxo-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
To a solution of example 27A (120 mg, 0.24 mmol) in N, N-dimethylformamide (1 ml) was added cesium carbonate (159 mg, 0.49 mmol), tert-butyl carbamate (171 mg, 1.5 mmol) at 0 ℃. Adding Pd under the protection of nitrogen2(dba)3(8.6 mg, 20 mmol), Xantphos (11.7 mg, 20 mmol). After stirring the mixture at 110 ℃ for 15 hours, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (white solid, 15 mg, yield 12%).1HNMR(CDCl3400MHz,)8.51(d,J＝6.5Hz,2H)8.06(d,J＝8.5Hz,2H)7.05(d,J＝6.0Hz,2H)6.99(d,J＝9.0Hz,2H)4.68(q,J＝7.5Hz,2H)4.04(t,J＝6.0Hz,2H)3.85(t,J＝6.3Hz,2H)3.55(t,J＝6.3Hz,2H)3.19(t,J＝7.3Hz,2H)1.85-1.93(m,2H)1.76-1.83(m,2H)1.68(t,J＝7.5Hz,5H)。LCMS(ESI)m/z:473(M+1)。
Example 28
4- (5- (5- ((3-ethoxy-1, 2-benzoxazol-6-yl) oxy) pentyl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
Example 28A
2- (2-chloro-4-pyridinyl) -5- (5- ((3-ethoxy-1, 2-benzoxazol-6-yl) oxy) pentyl) -1,2, 5-thiadiazolidine 1, 1-dioxide
Sodium hydrogen (53.3 mg, 2.2 mmol) was added portionwise to a solution of example 4E (500 mg, 1.8 mmol) in N, N-dimethylformamide (1 ml) at 0 ℃ under nitrogen, after 1 hour reaction at 0 ℃, a solution of example 12E (911 mg, 2.8 mmol) in N, N-dimethylformamide (1 ml) was added dropwise to the above system, warmed to room temperature for 2 hours, the reaction was poured into water (10 ml), extracted with ethyl acetate (10 ml × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed on a rotary evaporator to give the title compound (white solid, 50.00 mg, 5.6% yield). LCMS (ESI) M/z:481(M +1).
Example 28B
4- (5- (5- ((3-ethoxy-1, 2-benzoxazol-6-yl) oxy) pentyl) -1, 1-dioxido 1,2, 5-thiadiazolidin-2-yl) pyridin-2-amine
Under nitrogenCesium carbonate (339 mg, 1.0 mmol), Pd, was added under protection2(dba)3(47.6 mg, 52. mu. mol), Xantphos (60.2 mg, 0.1 mmol) were added to a solution of example 28A (250 mg, 0.5 mmol) and tert-butyl carbamate (61 mg, 0.5 mmol) in dioxane (2 mL) and N, N-dimethylformamide (1 mL), and the reaction was allowed to warm to 110 ℃ for 10 hours. The reaction solution was then poured into water (150 ml) and extracted with ethyl acetate (100 ml. times.3). The organic phases were combined, washed with saturated brine (100 ml × 2), dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by preparative HPLC to give the title compound (white solid, 25 mg, yield 10.4%).1HNMR(CDCl3,400MHz)7.98(d,J＝6.02Hz,1H),7.47(d,J＝9.54Hz,1H),6.81-6.87(m,2H),6.42(dd,J＝1.76,5.77Hz,1H),6.30(d,J＝1.51Hz,1H),4.53(br.s.,1H),4.47(q,J＝7.03Hz,2H),4.03(t,J＝6.02Hz,2H),3.81(t,J＝6.53Hz,2H),3.51(t,J＝6.53Hz,2H),3.17(t,J＝7.28Hz,2H),1.85-1.95(m,2H),1.79(quin,J＝7.40Hz,2H),1.65-1.68(m,2H),1.51(t,J＝7.28Hz,3H)。LCMS(ESI)m/z:462(M+1)。
Procedure L
Example 29
(S, E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3-methylpentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
And (R, E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3-methylpentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 29A
(E) -5-hydroxy-2, 3-dihydro-1H-indene-1-oxo-ethyl ketoxime
A mixed solution of example 8B (2.5 g, 13.1 mmol), 14A (6.1 g, 14.4 mmol) and potassium carbonate (3.6 g, 26.1 mmol) in acetonitrile (50 ml) was reacted at 80 ℃ for 16 hours. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction system, the aqueous layer was extracted with ethyl acetate (50 ml × 3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 20:1 to 5:1) to give the title compound (colorless liquid, 2.5 g, 39% yield).1H-NMR(CDCl3,400MHz)7.79(d,J＝8.0Hz,2H),7.60(d,J＝9.0Hz,1H),7.34(d,J＝8.0Hz,2H),6.74-6.80(m,2H),4.20(q,J＝7.0Hz,2H),4.08-4.13(m,2H),3.91-4.01(m,2H),2.95-3.03(m,2H),2.85-2.93(m,2H),2.44(s,3H),1.72-1.87(m,3H),1.50-1.61(m,2H),1.33(t,J＝7.0Hz,3H),0.91(d,J＝6.5Hz,3H)。
Example 29B
(E) -2- (2-chloropyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3-methylpentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To the mixture of N, N-dimethylformamide (40 ml) of example 4E (1.3 g, 4.8 mmol) was slowly added sodium hydrogen (673 mg, 16.8 mmol) at 0 ℃ for 30 minutes, and then the mixture of N, N-dimethylformamide (40 ml) of example 29A (2.5 g, 5.6 mmol) was added dropwise and mixedThe mixture was reacted at 25 ℃ for 12 hours. Water (30 ml) was added to the reaction system, the aqueous layer was extracted with dichloromethane (40 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 5:1 to 1:1) to give the title compound (yellow liquid, 2.1 g, 66% yield).1H-NMR(CDCl3,400MHz)8.25(d,J＝6.0Hz,1H),7.55-7.61(m,1H),7.04(dd,J＝5.5,2.0Hz,1H),6.98(d,J＝2.0Hz,1H),6.75-6.80(m,2H),4.18(q,J＝7.0Hz,2H),4.11(q,J＝7.4Hz,1H),3.97-4.05(m,2H),3.80(t,J＝6.5Hz,2H),3.47-3.55(m,2H),3.19(t,J＝7.3Hz,2H),2.94-2.98(m,2H),2.86-2.90(m,2H),1.78-1.87(m,2H),1.53-1.71(m,2H),1.31(t,J＝7.0Hz,3H),1.02(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:507(M+1)。
Example 29C
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3-methylpentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation process of this example refers to example 28.1H-NMR(CDCl3,400MHz)7.97(d,J＝5.8Hz,1H),7.53-7.68(m,1H),6.76-6.80(m,2H),6.41(dd,J＝5.8,2.0Hz,1H),6.27(d,J＝2.0Hz,1H),4.49(br.s.,2H),4.19(q,J＝7.0Hz,2H),4.03(q,J＝6.0Hz,2H),3.76(t,J＝6.4Hz,2H),3.44-3.50(m,2H),3.18(t,J＝7.5Hz,2H),2.95-3.00(m,2H),2.86-2.91(m,2H),1.68-1.92(m,5H),1.32(t,J＝7.0Hz,3H),1.03(d,J＝6.3Hz,3H)。LCMS(ESI)m/z:488(M+1)。
Example 29D
(S, E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3-methylpentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
(R, E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3-methylpentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 29C by chiral separation (AD-H _3UM _3_60 _3ml _5MIN, Column: ChiralpakAD-350 x 4.6mm I.D.,3UM mobile phase: 60% methanol (0.05% DEA) -CO)2The flow rate is 3 ml/min; wavelength: 220 nm; the peak time: 1.334min,1.823min) to yield the title compound.1H-NMR(CDCl3,400MHz)7.97(d,J＝6.0Hz,1H),7.56-7.63(m,1H),6.79(br.s.,2H),6.41(dd,J＝6.0,2.0Hz,1H),6.27(d,J＝1.8Hz,1H),4.51(br.s.,2H),4.17-4.23(m,2H),3.99-4.08(m,2H),3.76(t,J＝6.4Hz,2H),3.45-3.51(m,2H),3.18(t,J＝7.5Hz,2H),2.95-3.00(m,2H),2.86-2.91(m,2H),1.69-1.93(m,5H),1.32(t,J＝7.0Hz,3H),1.03(d,J＝6.5Hz,3H)。LCMS(ESI)m/z:488(M+1)。
1H-NMR(CDCl3,400MHz)7.97(d,J＝5.8Hz,1H),7.53-7.68(m,1H),6.76-6.80(m,2H),6.41(dd,J＝5.8,2.0Hz,1H),6.27(d,J＝2.0Hz,1H),4.49(br.s.,2H),4.19(q,J＝7.0Hz,2H),4.03(q,J＝6.0Hz,2H),3.76(t,J＝6.4Hz,2H),3.44-3.50(m,2H),3.18(t,J＝7.5Hz,2H),2.95-3.00(m,2H),2.86-2.91(m,2H),1.68-1.92(m,5H),1.32(t,J＝7.0Hz,3H),1.03(d,J＝6.3Hz,3H)。LCMS(ESI)m/z:488(M+1)。
Example 30
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3, 3-dimethylpentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 30A
3, 3-dimethylpentane-1, 5-diol
To a solution of 4, 4-dimethylglutaric anhydride (500 mg, 3.5 mmol) in tetrahydrofuran (20 ml) was added lithium aluminum hydride (534 mg, 14.1 mmol) at 0 ℃ under nitrogen. After the addition was complete, the mixture was stirred at 80 ℃ for 12 hours. The reaction solution was cooled to room temperature and poured into ice water (50 ml) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (30 ml x3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (yellow liquid, 300 mg, 64% yield). 1HNMR (400MHz, CHLOROFORM-d)3.69(t, J ═ 7.15Hz,4H),3.25(br.s.,2H),1.49-1.63(m,4H),0.89-0.95(m, 6H).
Example 30B
3, 3-dimethylpentane-1, 5-diylbis (4-methylbenzenesulfonic acid)
To a solution of example 30A (10 g, 75.6 mmol) in dichloromethane (200 ml) was added p-toluenesulfonyl chloride (43 g, 227 mmol) and triethylamine (23 g, 227 mmol) at 0 ℃. After the addition was completed, the above mixed solution was stirred at 25 ℃ for 12 hours, and after the raw materials disappeared, the reaction solution was poured into ice water (300 ml) 15 and stirred for 20 minutes. The aqueous phase was extracted with dichloromethane (50 ml x 4). The combined organic phases were washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (yellow liquid, 20 g, 60% yield). 1HNMR (400MHz, CHLOROFORM-d)7.77(d, J ═ 8.53Hz,2H),7.35(d, J ═ 8.03Hz,2H),4.02(t, J ═ 7.03Hz,2H),2.45(s,3H),1.55(t, J ═ 7.03Hz,2H),0.84(s, 3H).
Example 30C
(E) -5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3, 3-dimethylpentyl-4-methylbenzenesulfonic acid
To a solution of example 30C (1.0 g, 2.3 mmol) and example 8B (173.6 mg, 908 micromole) in acetone (20 ml) was added potassium carbonate (627 mg, 4.54 mmol). The reaction mixture was stirred at 70 ℃ for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Water (50 ml) was added to the residue and extracted with ethyl acetate (30 ml × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated by filtration and purified by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (yellow solid, 300 mg, 72% yield). 1HNMR (400MHz, CHLOROFORM-d)7.77-7.82(m,2H),7.59(d, J ═ 8.53Hz,1H),7.33(d, J ═ 8.53Hz,2H),6.75(br.s.,2H),4.11-4.24(m,4H),3.97(t, J ═ 6.78Hz,2H),2.81-3.02(m,4H),2.38-2.46(m,4H),1.70(dt, J ═ 2.51,7.03Hz,4H),1.32(t, J ═ 7.03Hz,3H),0.96(s, 6H).
Example 30D
(E) -2- (2-chloropyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3, 3-dimethylpentyl) -1, 2-thiadiazolidine-1, 1-dioxide
To a solution of example 4E (153 mg, 653 micromoles) in N, N-dimethylformamide (5 ml) was added sodium hydrogen (52 mg, 1.3 mmol) at 0 ℃ under nitrogen. After the addition was completed, the reaction was stirred at room temperature for 30 minutes. Example 30C (300 mg, 653 micromolar) was added to the above solution and stirring was continued at room temperature for 11 hours. The reaction was poured into ice water (30 ml) and the aqueous phase was extracted with ethyl acetate (20 ml × 3). The combined organic phases were dried over anhydrous sodium sulfate, concentrated by filtration and the crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (yellow solid, 150 mg, 44% yield). 1HNMR (400MHz, chloproform-d) 8.27(d, J ═ 6.02Hz,1H),8.02(s,2H),7.60(d, J ═ 9.03Hz,1H),7.06(dd, J ═ 2.26,5.77Hz,1H),6.99(d, J ═ 2.01Hz,1H),6.77-6.82(m,2H),4.20(q, J ═ 7.03Hz,2H),4.05(t, J ═ 6.78Hz,2H),3.82(t, J ═ 6.27Hz,2H),3.54(t, J ═ 6.27Hz,2H),3.18-3.26(m,2H),2.97-3.03(m,2H),1.79(t, J ═ 6.27Hz,2H), 1.53 (t, J ═ 6.79, 1H), 1.06 (t, 1.06H), 1.06 (t, J ═ 6.06H). LCMS (ESI) M/z:521(M +1).
Example 30E
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3, 3-dimethylpentyl) -1, 2-thiadiazolidine-1, 1-dioxide
The preparation method of the embodiment refers to the embodiment 29.1HNMR(400MHz,CHLOROFORM-d)7.82(br.s.,1H),7.61(d,J＝8.53Hz,1H),6.81(br.s.,2H),6.58(d,J＝4.02Hz,1H),6.36(br.s.,1H),4.21(d,J＝6.78Hz,2H),4.06(br.s.,2H),3.84(br.s.,2H),3.53(br.s.,2H),3.21(br.s.,2H),2.74-3.07(m,4H),1.58-1.85(m,4H),1.33(t,J＝6.53Hz,4H),1.06(br.s.,6H)。LCMS(ESI)m/z:502(M+1)。
Example 31
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3, 3-difluoropentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 31A
Diethyl-3, 3-difluoropentane diacid ester
To a solution of dibromohydantoin (2.16 g, 7.56 mmol), pyridine hydrofluoric acid solution (2.2 ml, 1.8 mmol) in dichloromethane (15 ml) was slowly added a dichloromethane solution of diethyl-2, 2' - (1, 3-dithiolane-2, 2-diyl) diacetic acid (501 mg, 1.8 mmol) at-65 ℃, the mixed solution was further stirred at-65 ℃ for 5 hours, raised to 25 ℃ for 3 hours, water (10 ml) was added to the reaction system, the system was adjusted to pH 3-4 with an aqueous solution of sodium carbonate, the aqueous layer was extracted with dichloromethane (20 ml × 3), filtered to dry, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (white solid, 210 mg, yield 38%) as a yellow liquid (300 mg, yield 74%).1HNMR(CDCl3,400MHz)4.18(q,J＝7.0Hz,4H),3.24(t,J＝15.1Hz,4H),1.26-1.30(m,6H)。
Example 31B
3, 3-difluoropentane-1, 5-diol
Example 31A (300 mg, 1.34 mmol) was added dropwise to a solution of lithium aluminum hydride (102 mg, 2.68 mmol) in tetrahydrofuran (3 ml) at 0 ℃ and after the addition was complete, the mixed solution was stirred at 25 ℃ for 3 hours. Water (0.5 ml) and 10% sodium hydroxide solution (0.5 ml) were added to the reaction and the system was dried over sodium sulfate, filtered and evaporated to give the title compound (160 mg, yield 72%).1HNMR(CDCl3,400MHz):3.77-3.90(m,4H),2.21(tt,J＝16.8,5.8Hz,4H)。
Example 31C
1, 5-dibromo-3, 3-difluoropentane
To a solution of example 31B (160 mg, 1.1 mmol), triphenylphosphine (1.79 g, 6.8 mmol) in tetrahydrofuran (5 ml) was added carbon tetrabromide (1.5 g, 4.6 mmol) dropwise at 0 ℃ and after the addition, the mixture was stirred at 60 ℃ for 3 hours. Filtration, the filter cake washed with ethyl acetate (300 ml × 3), the filtrate was dried by spinning, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (200 mg, yield 53%).1HNMR(CDCl3,400MHz):3.45-3.51(m,4H),2.48(tt,J＝16.2,7.9Hz,4H)。
Example 31D
(E) -5- ((5-bromo-3, 3-difluoropentyl) oxy) -2, 3-dihydro-1H-inden-1-one-oxo-ethyl ketoxime
The preparation of this example is as in example 30C.1HNMR(CDCl3,400MHz):7.56-7.62(m,1H),6.76-6.83(m,2H),4.19(q,J＝6.9Hz,2H),4.01(t,J＝6.0Hz,2H),3.43-3.52(m,2H),2.95-3.02(m,2H),2.84-2.92(m,2H),2.03-2.12(m,2H),1.91-2.00(m,2H),1.32(t,J＝7.0Hz,3H)。
Example 31E
(E) -2- (2-chloropyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3, 3-difluoropentyl) -1, 2-thiadiazolidine-1, 1-dioxide
The preparation of this example is as in example 30D.1HNMR(CDCl3,400MHz):8.26(d,J＝5.8Hz,1H),7.60(d,J＝9.3Hz,1H),7.04(dd,J＝5.8,2.3Hz,1H),6.98(d,J＝2.0Hz,1H),6.73-6.86(m,3H),4.19(d,J＝7.0Hz,2H),4.00-4.05(m,2H),3.76-3.84(m,2H),3.55(t,J＝6.4Hz,2H),3.23(t,J＝6.1Hz,2H),2.96(d,J＝7.3Hz,2H),2.86-2.90(m,2H),1.86-1.96(m,4H),1.32(s,3H)。LCMS(ESI)m/z:529(M+1)。
Example 31F
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) -3, 3-difluoropentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation process of this example refers to example 29.1HNMR(CDCl3,400MHz):7.96(d,J＝5.8Hz,1H),7.51-7.64(m,1H),6.71-6.84(m,2H),6.40(dd,J＝5.8,1.8Hz,1H),6.24(d,J＝1.5Hz,1H),4.55(br.s.,2H),4.19(q,J＝7.0Hz,2H),4.04(t,J＝5.4Hz,2H),3.72(t,J＝6.4Hz,2H),3.42-3.55(m,2H),3.20(t,J＝6.5Hz,2H),2.92-3.00(m,2H),2.83-2.92(m,2H),1.86-1.95(m,4H),1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:510(M+1)。
Procedure M
Example 32
(E) -4- ((5- (5- (2-methylpyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
Example 32A
N-tert-butyl-N- (2-chloroethyl) sulfonylureas
A solution of N- (oxymethylene) sulfamoyl chloride (244 g, 1.73 mol) in dichloromethane (1.0 l) was added dropwise to tert-butanol (453 g, 2.1 mol) at 0 ℃ over one hour under nitrogen. After the addition was completed, the mixed solution was stirred at 25 ℃ for 1 hour. A mixture of the mixed solution and triethylamine (872 g, 8.6 mol) was added dropwise to a solution of 2-chloroethylamine (200 g, 1.73 mol) in dichloromethane (2 l) over 2 hours. The mixed solution was stirred at 25 ℃ for 10 hours and filtered, and the filtrate was concentrated and dissolved in 2 liters of water, and the pH was adjusted to 5 to 6 with 4N hydrochloric acid. A large amount of solid precipitated, the solid was filtered and washed with petroleum ether (1 l) to give the title compound (white solid, 350 g, 78.5% yield) which was used in the next step without further purification.
Example 32B
Tert-butyl-1, 2, 5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1, 1-dioxide
To a solution of example 32A (350 g, 1.35 mol) in dimethyl sulfoxide (3 l) was added a mixed solution of potassium carbonate (280 g, 2.03 mol) at room temperature, and the mixture was stirred at room temperature for 10 hours and then filtered. The filtrate was poured into 5 l of water, the pH was adjusted to 5-6 with 4N hydrochloric acid, the solid was filtered and washed with petroleum ether (1 l), and the solid was recrystallized from (petroleum ether/ethyl acetate 1/1) (1 l) to give the title compound (white solid, 250 g, 84% yield).
Example 32C
4- ((5-bromophenyl) pentyl) benzaldehyde
The preparation of this example is as in example 4G.1HNMR(400MHz,CHLOROFORM-d)9.81-9.89(m,1H),7.81(d,J＝8.80Hz,2H),6.97-7.02(m,2H),4.04(t,J＝6.40Hz,2H),3.39-3.46(m,2H),1.94(t,J＝7.60Hz,2H),1.84(t,J＝7.20Hz,2H),1.61-1.65(m,2H)。
Example 32D
Tert-butyl ester 5(5 (4-formylphenoxy) pentyl) -1,2, 5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1, 1-dioxide
To a solution of example 32C (550 mg, 2.5 mmol) in N, N-dimethylformamide (8 ml) was added sodium hydride (81 mg, 2.0 mmol) under nitrogen at 0 ℃ and after stirring for 0.5 h at 0 ℃, a solution of 4- ((5-bromophenyl) pentyl) benzaldehyde (671 mg, 2.5 mmol) in N, N-dimethylformamide (19 ml) was added dropwise thereto. After stirring at 0 ℃ for 0.5 h the reaction was checked by TLC for completion. The reaction was quenched by the addition of water (10 ml), the aqueous layer was extracted with ethyl acetate (10 ml x3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the crude product was separated on a thin layer chromatography plate (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (white solid, 400 mg, 60%).1HNMR(400MHz,CHLOROFORM-d)9.88(s,1H),7.82(d,J＝8.53Hz,2H),6.98(d,J＝8.53Hz,2H),4.05(t,J＝6.27Hz,2H),3.79(t,J＝6.53Hz,2H),3.32(t,J＝6.27Hz,2H),3.08(t,J＝7.28Hz,2H),1.82-1.91(m,2H),1.72-1.79(m,2H),1.57-1.64(m,2H),1.54(s,10H)。
Example 32E
4- ((5- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde
To a solution of example 32D (4 g, 9.7 mmol) in dichloromethane (40 ml) was added trifluoroacetic acid (5 ml) at 0 ℃ and stirred at 15 ℃ for 4 h. After the end of the reaction, the pH was adjusted to 7 with saturated sodium bicarbonate solution at 0 ℃ and extracted with dichloromethane (30 ml x2), the combined organic layers were dried over sodium sulfate, filtered and evaporated to give the crude title compound (colorless oil, 2.66 g, 88% yield) which was used directly in the next step.
Example 32F
(E) -4- ((5- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
To a solution of example 32E (1.0 g, 3.2 mmol) in ethanol (50 ml) was added ethoxyamino hydrochloride (1.56 g, 16 mmol) and sodium acetate (1.31 g, 16 mmol) under nitrogen and heated to 60 ℃ for one hour. After completion of the reaction, the solvent was concentrated and evaporated, water (20 ml) was added, extracted with ethyl acetate (20 ml × 3), and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (colorless oil, 1.1 g, 97% yield) which was used directly in the next reaction.
Example 32G
(E) -4- ((5- (5- (2-methylpyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
Example 32F (130 mg, 366. mu. mol), 4-bromo-2-methylpyridine (189 mg, 1.1 mmol), Cs was reacted under nitrogen2CO3(179 mg, 549 micromole), Pd2(dba)3A solution of (34 mg, 37. mu.M) and Xant-phos (21 mg, 37. mu.M) in dioxane (2 ml) was heated to 100 ℃ for 6 hours. TLC showed complete consumption of starting material. Cooling the reaction solution to room temperature, and adding BEthyl acetate (20 ml) and the organic phase was washed with saturated brine (30 ml), dried over sodium sulfate, filtered, concentrated and purified by preparative thin layer chromatography (dichloromethane: methanol ═ 30:1) to afford the title compound (white solid, 100 mg, 61% yield).1HNMR(400MHz,CHLOROFORM-d)8.39(d,J＝5.52Hz,1H),8.02(s,1H),7.51(d,J＝8.53Hz,2H),6.95(s,1H),6.87(d,J＝8.53Hz,3H),4.20(q,J＝7.36Hz,2H),4.00(t,J＝6.27Hz,2H),3.84(t,J＝6.27Hz,2H),3.53(t,J＝6.27Hz,2H),3.18(t,J＝7.28Hz,2H),2.56(s,3H),1.82-1.90(m,2H),1.74-1.81(m,2H),1.62(br.s.,2H),1.25-1.36(m,3H)。LCMS(ESI)m/z:447(M+1)。
Example 33
(E) -4- ((5- (5- (6-methylpyridazin-3-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 32.1HNMR(400MHz,CHLOROFORM-d)8.02(s,1H),7.61(d,J＝9.03Hz,1H),7.51(d,J＝8.53Hz,2H),7.32(d,J＝9.54Hz,1H),6.87(d,J＝8.53Hz,2H),4.16-4.30(m,4H),4.00(t,J＝6.27Hz,2H),3.56(t,J＝6.27Hz,2H),3.19(t,J＝7.28Hz,2H),2.66(s,3H),1.75-1.91(m,4H),1.60-1.66(m,2H),1.32(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:447(M+1)。
Example 34
(E) -4- ((5- (5- (6-chloropyridazin-3-yl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 32. 1HNMR (400MHz, CHLOROFORM-d) d8.02(s,1H),7.68(d, J ═ 9.03Hz,1H),7.45-7.54(m,1H),6.87(d, J ═ 8.53Hz,1H),4.15-4.29(m,5H),4.00(t, J ═ 6.02Hz,2H),3.57(t, J ═ 6.53Hz,2H),3.20(t, J ═ 7.28Hz,2H),1.75-1.91(m,4H),1.60-1.67(m,2H),1.32(t, J ═ 7.03Hz, 3H). LCMS (ESI) M/z 468(M +1).
Example 35
(E) -4- ((5- (1, 1-dioxido-5 (thiazol-2-yl) -1,2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 32. 1HNMR (400MHz, CHLOROFORM-d) d8.02(s,1H),7.51(d, J ═ 8.53Hz,2H),7.43(d, J ═ 3.51Hz,1H),6.98(d, J ═ 3.51Hz,1H),6.87(d, J ═ 9.03Hz,2H),4.20(q, J ═ 7.03Hz,2H),4.12(t, J ═ 6.53Hz,2H),4.00(t, J ═ 6.27Hz,2H),3.56(t, J ═ 6.53Hz,2H),3.19(t, J ═ 7.28Hz,2H),1.82-1.89(m,2H),1.74-1.80(m,2H),1.58-1.65(m,2H), 1.58-2 (t, J ═ 7.28Hz, 2H). LCMS (ESI) M/z 439(M +1).
Example 36
(E) -N- (4- (5- (5- (4- ((ethoxyimino) methyl) phenoxy) pentyl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-yl) acetamide
Example 36A
N- (4-bromopyridin-2-yl) acetamide
Acetyl chloride (454 mg, 5.8 mmol) was added to a solution of 4-bromo-2-aminopyridine (1.0 g, 5.8 mmol) and triethylamine (1.75 g, 17 mmol) in dichloromethane (50 ml) at 0 ℃ under nitrogen. The reaction was allowed to react at room temperature for 1 hour, quenched by pouring into ice water (50 ml), and extracted with dichloromethane (20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (white solid, 400 mg, 33%).1HNMR(400MHz,CHLOROFORM-d)8.38-8.53(m,1H),8.08(d,J＝5.02Hz,1H),7.93(br.s.,1H),7.21(d,J＝4.52Hz,1H),2.22(s,3H)。
Example 36B
(E) -N- (4- (5- (5- (4- ((ethoxyimino) methyl) phenoxy) pentyl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-yl) acetamide
The preparation process of this example refers to example 32.1HNMR(400MHz,CHLOROFORM-d)8.13(d,J＝5.52Hz,1H),8.02(s,1H),7.92(br.s.,1H),7.79(s,1H),7.51(d,J＝8.53Hz,2H),7.17(dd,J＝2.01,6.02Hz,1H),6.87(d,J＝8.53Hz,2H),4.13-4.28(m,2H),4.00(t,J＝6.27Hz,2H),3.90(t,J＝6.53Hz,2H),3.53(t,J＝6.53Hz,2H),3.18(t,J＝7.28Hz,2H),2.21(s,3H),1.73-1.92(m,4H),1.60-1.65(m,2H),1.28-1.40(m,3H)。LCMS(ESI)m/z:490(M+1)。
Example 37
(E) -ethyl 4- (5- (5- (4- ((ethoxyimino) methyl) phenoxy) pentyl) -dioxido-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-ylcarboxylic acid methyl ester
The preparation process of this example refers to example 32.1HNMR(400MHz,CHLOROFORM-d)8.63(d,J＝5.77Hz,1H),8.04(s,1H),7.75(d,J＝2.26Hz,1H),7.53(d,J＝8.78Hz,2H),7.40(dd,J＝2.38,5.65Hz,1H),6.89(d,J＝8.78Hz,2H),4.22(q,J＝7.03Hz,2H),4.00-4.06(m,5H),3.93(t,J＝6.40Hz,2H),3.59(t,J＝6.40Hz,2H),3.21(t,J＝7.28Hz,2H),1.77-1.93(m,4H),1.61-1.70(m,5H),1.33(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:491(M+1)。
Example 38
(E) -4- ((5- (5- (6-aminopyrimidin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
Example 38A
(E) -4- (5- (5- (6-chloropyrimidin-4-yl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 32. LCMS (ESI) M/z 468(M +1).
Example 38B
(E) -4- ((5- (5- (6-aminopyrimidin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 28.1HNMR(CHLOROFORM-d,400MHz):8.33(s,1H),8.02(s,1H),7.51(d,J＝8.5Hz,2H),6.87(d,J＝8.5Hz,2H),6.34(s,1H),4.93(br.s.,2H),4.16-4.25(m,2H),4.05(t,J＝6.5Hz,2H),4.00(t,J＝6.3Hz,2H),3.44-3.50(m,2H),3.16(t,J＝7.3Hz,2H),1.82-1.90(m,2H),1.74-1.79(m,2H),1.55-1.60(m,2H),1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:449(M+1)。
Procedure N
Example 39
(E) -4- ((5- (5- (2-fluoropyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
To a dioxane solution (2 ml) of example 32F (60 mg, 169 micromole), 4-bromo-2-fluoro-pyridine (30 mg, 169 micromole) and cesium carbonate (83 mg, 253 micromole) was added Pd under nitrogen blanket2(dba)3(15 mg, 17. mu. mol) and Xant-Phos (10 mg, 17. mu. mol), stirred well and then warmed to 100 ℃ for 4 hours. After the TLC detection reaction is finished, the solvent is concentrated and evaporated. Water (20 ml) was added and extracted with ethyl acetate (20 ml x3), the combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated, and the crude product was purified by thin layer chromatography (petroleumEther ethyl acetate 2:1) to give the title compound (white solid, 70 mg, 92%).1HNMR(400MHz,CHLOROFORM-d)8.12(d,J＝6.02Hz,1H),8.03(s,1H),7.51(d,J＝8.53Hz,2H),7.02(d,J＝5.52Hz,1H),6.82-6.93(m,2H),6.58(d,J＝2.01Hz,1H),4.20(q,J＝7.03Hz,2H),4.00(t,J＝6.02Hz,2H),3.85(t,J＝6.53Hz,2H),3.52-3.59(m,2H),3.19(t,J＝7.28Hz,2H),1.74-1.91(m,4H),1.59-1.67(m,2H),1.29-1.39(m,3H)。LCMS(M+1):451。
Example 40
(E) -4- ((5- (5- (2- ((2-hydroxyethyl) amino) pyridin-4-yl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
To a solution of example 39(20 mg, 44. mu. mol) and 2-aminoethanol (27 mg, 444. mu. mol) in dimethylsulfoxide (0.5 ml) was added triethylamine (27 mg, 266. mu. mol) under nitrogen. The mixed solution was reacted at 100 ℃ for 2 hours. After completion of the reaction, the reaction was quenched with water (5 ml) and extracted with ethyl acetate (10 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by thin layer chromatography (dichloromethane: methanol ═ 20:1) to give the title compound (colorless oily liquid, 12 mg, 55%).1HNMR(400MHz,CHLOROFORM-d)8.02(s,1H),7.84-7.95(m,1H),7.51(d,J＝8.53Hz,2H),6.85-6.93(m,2H),6.41(dd,J＝1.76,6.27Hz,1H),6.25(d,J＝1.51Hz,1H),5.47(br.s.,1H),4.15-4.29(m,2H),4.00(t,J＝6.27Hz,2H),3.81(t,J＝4.77Hz,4H),3.45-3.56(m,4H),3.16(t,J＝7.03Hz,2H),1.81-1.90(m,2H),1.72-1.81(m,2H),1.56-1.67(m,2H),1.27-1.40(m,3H).LCMS(ESI)m/z:492(M+1)。
EXAMPLE 41
(E) -4- ((5- (5- (2- (methylamino) pyridin-4-yl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 40.1HNMR(400MHz,CHLOROFORM-d)7.97-8.05(m,2H),7.51(d,J＝8.53Hz,2H),6.87(d,J＝8.53Hz,2H),6.36(dd,J＝2.01,6.02Hz,1H),6.14(d,J＝2.01Hz,1H),4.64(br.s.,1H),4.20(q,J＝7.03Hz,2H),4.00(t,J＝6.27Hz,2H),3.82(t,J＝6.27Hz,2H),3.49(t,J＝6.27Hz,2H),3.16(t,J＝7.28Hz,2H),2.92(d,J＝5.02Hz,3H),1.73-1.91(m,4H),1.62-1.66(m,2H),1.28-1.39(m,3H)。LCMS(ESI)m/z:462(M+1)。
Example 42
(E) -4- ((5- (5- (2- (azetidin-1-yl) pyridin-4-yl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 40.1HNMR(400MHz,CHLOROFORM-d)8.00-8.06(m,1H),7.50(d,J＝8.78Hz,1H),6.87(d,J＝8.78Hz,1H),6.40(dd,J＝2.01,5.77Hz,1H),5.92(d,J＝1.76Hz,1H),4.19(q,J＝7.03Hz,2H),4.05(t,J＝7.40Hz,4H),3.99(t,J＝6.27Hz,2H),3.80(t,J＝6.40Hz,2H),3.43-3.51(m,3H),3.15(t,J＝7.15Hz,2H),2.38(quin,J＝7.34Hz,2H),1.81-1.89(m,2H),1.72-1.79(m,2H),1.57-1.65(m,2H),1.31(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:488(M+1)。
Example 43
(E) -4- ((5- (5- (2- (dimethylamino) pyridin-4-yl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-ethyl ketoxime
The preparation process of this example refers to example 40. 1HNMR (400MHz, chloproform-d) 8.09(d, J ═ 5.77Hz,1H),8.03(s,1H),7.52(d, J ═ 8.53Hz,2H),6.88(d, J ═ 8.78Hz,2H),6.38(dd, J ═ 1.88,5.90Hz,1H),6.26(d, J ═ 1.76Hz,1H),4.21(q, J ═ 7.03Hz,2H),3.97-4.04(m,2H),3.85(t, J ═ 6.27Hz,2H),3.51(t, J ═ 6.27Hz,2H),3.17(t, J ═ 7.15Hz,2H),3.12(s,5H), 1.92-1.73, 1.58 (t, 1.7.7, 7H), 3.67 (t, 3.7H). LCMS (ESI) M/z:476(M +1).
Example 44
(E) -4- (5- (5- (4- ((ethoxyimino) methyl) phenoxy) pentyl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) benzonitrile
To a solution of example 32F (50 mg, 141. mu. mol) and 4-fluorobenzonitrile (17 mg, 141. mu. mol) in N, N-dicarboximide (1 ml) was added potassium carbonate (39 mg, 281. mu. mol) under a nitrogen atmosphere at 0 ℃ and the mixture was reacted at 80 ℃ for 3 hours. After the reaction was completed, water (40 ml) was poured and extracted with ethyl acetate (20 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by thin layer chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (white solid, 30 mg, 66%).1HNMR(400MHz,CHLOROFORM-d)8.02(s,1H),7.66(d,J＝8.53Hz,2H),7.51(d,J＝8.53Hz,2H),7.25(s,2H),6.82-6.93(m,2H),4.16-4.29(m,2H),4.00(t,J＝6.27Hz,2H),3.86(t,J＝6.53Hz,2H),3.54(t,J＝6.27Hz,2H),3.18(t,J＝7.28Hz,2H),1.74-1.90(m,4H),1.60-1.67(m,2H),1.29-1.40(m,3H)。LCMS(ESI)m/z:457(M+1)。
Procedure O
Example 45
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 45A
Tert-butyl 5 (5-bromopentyl) -1,2, 5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1, 1-dioxide
To a solution of example 32B (100 mg, 428 micromoles) in DMF (8 ml) was added sodium hydrogen (17 mg, 428 micromoles) at 10 ℃ under nitrogen. After 1 hour, the mixed solution was added to a DMF (4 ml) solution of 1, 5-dibromopentane (98 mg, 428 μmol), the reaction was stirred at 10 ℃ for 10 hours, then quenched by addition of water, the aqueous phase was extracted with ethyl acetate (20 ml x3), the combined organic phases were washed with saturated brine (10 ml x2), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 20:1) to give the title compound (yellow liquid, 50 mg, 38% yield).1HNMR(400MHz,CHLOROFORM-d)3.82(t,J＝6.53Hz,2H),3.44(t,J＝6.65Hz,2H),3.34(t,J＝6.53Hz,2H),3.08(t,J＝7.15Hz,2H),1.92(quin,J＝7.09Hz,2H),1.66-1.79(m,2H),1.56-1.62(m,12H)。
Example 45B
(E) -tert-butyl-5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1, 1-dioxide
To a solution of example 45A (100 mg, 269 micromole) and example 8B (52 mg, 269 micromole) in N, N-dimethylformamide (1 ml) was added potassium carbonate (112 mg, 808 micromole) under nitrogen. The reaction mixture was reacted at 80 ℃ for 10 hours, and after completion of the reaction, it was quenched by adding water (50 ml), and the aqueous phase was extracted with ethyl acetate (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (white solid, 70 mg, 54%).1HNMR(400MHz,CHLOROFORM-d)7.54-7.64(m,1H),6.74-6.83(m,2H),4.20(q,J＝7.03Hz,2H),3.98(t,J＝6.27Hz,2H),3.80(t,J＝6.53Hz,2H),3.32(t,J＝6.53Hz,2H),3.08(t,J＝7.28Hz,2H),2.95-3.02(m,2H),2.85-2.93(m,2H),1.67-1.87(m,4H),1.51-1.59(m,11H),1.32(t,J＝7.03Hz,3H)。
Example 45C
(E) -2- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 45B (100 mg, 208 micromoles) in methanol (1 mL) was added potassium carbonate (57 mg) under nitrogen415 micromoles). The reaction mixture was reacted at 50 ℃ for 72 hours, and after completion of the reaction by thin layer chromatography, the solvent was concentrated to dryness, water (10 ml) was added, and extraction was performed with ethyl acetate (20 ml). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (white solid, 50 mg, 63%).1HNMR(400MHz,CHLOROFORM-d)8.09(d,J＝8.78Hz,2H),7.03(d,J＝8.78Hz,2H),4.40(s,3H),3.89(s,3H)。
Example 45D
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
A solution of example 45C (550 mg, 1.4 mmol), 4-bromo 2-aminopyridine (499 mg, 2.9 mmol), potassium carbonate (498 mg, 3.6 mmol), 8-hydroxyquinoline (209 mg, 1.4 mmol), (1R,2R) -cyclohexanediamine (165 mg, 1.4 mmol) and cuprous iodide (275 mg, 1.4 mmol) in DMF (10 mL) was heated at 120 ℃ for 10 h under nitrogen. After the reaction was complete, water was added to quench and the aqueous phase was extracted with ethyl acetate (10 ml × 3). The organic phase was washed with saturated brine (5 ml), dried over anhydrous sodium sulfate, concentrated and the crude product was purified by preparative thin layer chromatography (dichloromethane: methanol ═ 30:1) to afford the title compound (white solid, 350 mg, 51% yield).1HNMR(400MHz,DMSO-d6)8.09(d,J＝8.78Hz,1H),7.44(d,J＝8.53Hz,1H),6.92(s,1H),6.82(d,J＝8.53Hz,1H),6.34(br.s.,1H),6.15(br.s.,1H),4.09(q,J＝7.03Hz,2H),3.99(t,J＝6.40Hz,2H),3.79(t,J＝6.40Hz,2H),3.49(t,J＝6.40Hz,2H),3.04(t,J＝7.03Hz,2H),2.89-2.98(m,2H),2.69-2.82(m,2H),1.59-1.81(m,5H),1.40-1.54(m,2H),1.22(t,J＝7.03Hz,3H)。LCMS(ESI)m/z:474(M+1)。
Example 46
(E) -2- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -5- (thien-3-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The procedure for the preparation of this example is as in example 44.1HNMR(CDCl3400MHz,)7.60(d,J＝9.5Hz,1H)7.35(dd,J＝5.0,3.0Hz,1H)7.18(dd,J＝5.5,1.0Hz,1H)6.76-6.85(m,3H)4.20(q,J＝7.0Hz,2H)3.99(t,J＝6.3Hz,2H)3.79(t,J＝6.3Hz,2H)3.49(t,J＝6.5Hz,2H)3.16(t,J＝7.3Hz,2H)2.95-3.02(m,2H)2.86-2.92(m,2H)1.81-1.89(m,2H)1.70-1.79(m,2H)1.64(br.s.,2H)1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:464(M+1)。
Example 47
(E) -2- (6-aminopyridin-3-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The procedure for the preparation of this example is as in example 44.1HNMR(400MHz,CHLOROFORM-d)8.01(br.s.,1H),7.59(dt,J＝3.26,6.02Hz,2H),6.76-6.85(m,2H),6.56(d,J＝9.03Hz,1H),4.20(q,J＝7.19Hz,2H),3.99(t,J＝6.27Hz,2H),3.74(t,J＝6.27Hz,2H),3.46(t,J＝6.40Hz,2H),3.15(t,J＝7.28Hz,2H),2.95-3.01(m,2H),2.86-2.92(m,2H),1.72-1.89(m,4H),1.56-1.60(m,2H),1.28-1.38(m,3H)。
Example 48
(E) -2- (2-amino-3-fluoropyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 48A
(E) -2- (2-chloro-3-fluoropyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 45C (100 mg, 262 micromolar) in N, N-dimethylformamide (3 ml) was added under nitrogen 2-chloro-5-fluoro-4-iodopyridine (101 mg, 393 micromolar), potassium carbonate (54 mg, 393 micromolar), 8-hydroxyquinoline (38 mg, 262 micromolar) and cuprous iodide (25 mg, 131 micromolar). The mixture was reacted at 120 ℃ for 10 hours. Thin layer chromatography showed the reaction was complete, quenched with water (10 ml) and extracted with ethyl acetate (10 ml × 2). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was isolated and purified by tlc (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (white solid, 50 mg, 37%).1HNMR(400MHz,CHLOROFORM-d)8.21(d,J＝3.51Hz,1H),7.60(d,J＝9.03Hz,1H),7.46(d,J＝6.02Hz,1H),6.74-6.84(m,2H),4.20(q,J＝7.03Hz,2H),4.07(dt,J＝3.01,6.27Hz,2H),4.00(t,J＝6.27Hz,2H),3.54(t,J＝6.27Hz,2H),3.18(t,J＝7.28Hz,2H),2.95-3.02(m,2H),2.86-2.93(m,2H),1.73-1.91(m,4H),1.61-1.66(m,2H),1.32(t,J＝7.03Hz,3H)。
Example 48B
(E) -2- (2-amino-3-fluoropyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 48A (50 mg, 98. mu. mol) in dioxane (1 mL) was added under nitrogen tert-butyl carbamate (69 mg, 587. mu. mol), cesium carbonate (64 mg, 196. mu. mol), Pd2(dba)3(9 mg, 9.8. mu. mol) and Xant-phos (6 mg, 10. mu. mol). The mixture was reacted at 110 ℃ for 10 hours. Thin layer chromatography showed the reaction was complete, quenched with water (10 ml) and extracted with ethyl acetate (10 ml × 3). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by tlc plate separation (dichloromethane: methanol ═ 20:1) to give the title compound as a white solid (5 mg, 10%).1HNMR(400MHz,METHANOL-d4)7.97(d,J＝6.53Hz,1H),7.56(d,J＝8.53Hz,1H),6.91(s,1H),6.79-6.88(m,2H),4.05(t,J＝6.27Hz,2H),3.65(t,J＝6.27Hz,2H),3.22(t,J＝7.03Hz,2H),2.99-3.05(m,2H),2.86-2.92(m,2H),1.73-1.93(m,5H),1.58-1.70(m,2H),1.31(t,J＝7.03Hz,4H)。LCMS(ESI)m/z:492(M+1)。
Example 49
(E) -2- (2-amino-5-fluoropyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 49A
(E) -2- (2-chloro-5-fluoropyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 45C (100 mg, 262 micromolar) in N, N-dimethylformamide (3 ml) was added under nitrogen 2-chloro-5-fluoro-4 iodopyridine (101 mg, 393 micromolar), potassium carbonate (54 mg, 393 micromolar), 8-hydroxyquinoline (38 mg, 262 micromolar) and cuprous iodide (25 mg, 131 micromolar). The mixture was reacted at 120 ℃ for 10 hours. Thin layer chromatography showed the reaction was complete, quenched with water (10 ml) and extracted with ethyl acetate (10 ml × 2). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was isolated and purified by tlc (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (white solid, 50 mg, 37%).1HNMR(400MHz,CHLOROFORM-d)8.21(d,J＝3.51Hz,1H),7.60(d,J＝9.03Hz,1H),7.46(d,J＝6.02Hz,1H),6.74-6.84(m,2H),4.20(q,J＝7.03Hz,2H),4.07(dt,J＝3.01,6.27Hz,2H),4.00(t,J＝6.27Hz,2H),3.54(t,J＝6.27Hz,2H),3.18(t,J＝7.28Hz,2H),2.95-3.02(m,2H),2.86-2.93(m,2H),1.73-1.91(m,4H),1.61-1.66(m,2H),1.32(t,J＝7.03Hz,3H)。
Example 49B
(E) -2- (2-amino-5-fluoropyridin-4-yl) -5- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 49A (50 mg, 98. mu. mol) in dioxane (1 mL) was added under nitrogen tert-butyl carbamate (69 mg, 587. mu. mol), cesium carbonate (64 mg, 196. mu. mol), Pd2(dba)3(9 mg, 9.8. mu. mol) and Xant-phos (5.6 mg, 9.8 micromole). The mixture was reacted at 110 ℃ for 10 hours. Thin layer chromatography showed the reaction was complete, quenched with water (10 ml) and extracted with ethyl acetate (10 ml × 3). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude product was purified by thin layer chromatography (dichloromethane: methanol ═ 20:1) to give the title compound as a white solid (5 mg, 10%).1HNMR(400MHz,METHANOL-d4)7.97(d,J＝6.53Hz,1H),7.56(d,J＝8.53Hz,1H),6.91(s,1H),6.79-6.88(m,2H),4.05(t,J＝6.27Hz,2H),3.65(t,J＝6.27Hz,2H),3.22(t,J＝7.03Hz,2H),2.99-3.05(m,2H),2.86-2.92(m,2H),1.73-1.93(m,5H),1.58-1.70(m,2H),1.31(t,J＝7.03Hz,4H)。LCMS(ESI)m/z:492(M+1)。
Procedure P
Example 50
(E) -2- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -5- (2- (methylamino) pyridin-4-yl) -1, 2-thiadiazolidine-1, 1-dioxide
Example 50A
(E) -2- (5- ((1- (ethoxyimino) -2, 3-hydro-1H-inden-5-yl) oxy) pentyl) -5- (2-fluoropyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
In this example the method as described in example 50AAnd (4) preparing.1HNMR(400MHz,CHLOROFORM-d)7.80(d,J＝5.5Hz,1H)7.62(d,J＝9.3Hz,1H)6.77-6.85(m,3H)4.65(br.s.,2H)4.22(q,J＝7.0Hz,2H)3.99-4.05(m,4H)3.52(t,J＝6.4Hz,2H)3.18(t,J＝7.2Hz,2H)2.97-3.04(m,2H)2.87-2.94(m,2H)1.75-1.91(m,4H)1.63-1.68(m,2H)1.34(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:474(M+1)。
Example 50B
(E) -2- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -5- (2- (methylamino) pyridin-4-yl) -1, 2-thiadiazolidine-1, 1-dioxide
The preparation process of this example refers to example 40.1HNMR(400MHz,METHANOL-d4)7.80(d,J＝7.53Hz,1H),7.56(d,J＝8.53Hz,1H),6.81-6.93(m,3H),6.39(d,J＝2.01Hz,1H),4.17(q,J＝7.03Hz,2H),4.05(t,J＝6.15Hz,2H),3.99(t,J＝6.53Hz,2H),3.66(t,J＝6.53Hz,2H),3.22(t,J＝7.03Hz,2H),2.96-3.05(m,5H),2.84-2.92(m,2H),1.76-1.91(m,4H),1.58-1.71(m,2H),1.31(t,J＝7.03Hz,3H。LCMS(ESI)m/z:488(M+1)。
Example 51
(E) -2- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -5- (2- ((2-hydroxyethyl) amino) pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation process of this example refers to example 40.1HNMR(400MHz,CHLOROFORM-d)7.84(d,J＝6.3Hz,1H),7.61(d,J＝9.0Hz,1H),6.74-6.85(m,2H),6.52(d,J＝5.3Hz,1H),6.27(s,1H),4.22(q,J＝7.0Hz,2H),4.01(t,J＝6.1Hz,2H),3.87(d,J＝4.8Hz,4H),2.86-3.62(m,10H),1.85-1.89(m,2H),1.76-1.82(m,2H),1.63(d,J＝7.0Hz,2H),1.34(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:518(M+1)。
Procedure Q
Example 52
4- (5- (2- (2- (4- ((E) -ethoxyiminomethyl) phenoxy) ethoxy) ethyl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
Example 52A
2- (5-bromopentyl) -5- (2-chloropyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 4E (4.0 g, 17 mmol) in N, N-dimethylformamide (140 mL) was added sodium hydride (1.0 g, 27 mmol) at 10 ℃ and the reaction was stirred at 10 ℃ for 1 hour. To the reaction solution was added dropwise a solution of 1, 5-dibromopentane (3.9 g, 17 mmol) in N, N-dimethylformamide (40 ml) while maintaining the temperature, and the reaction was continued for 1 hour. After completion of the reaction was checked by thin layer chromatography, the reaction solution was poured into ice water (100 ml) and extracted with ethyl acetate (100 ml × 2). The supernatant was dried, concentrated and purified by column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (white solid, 2.7 g, 41% yield)Rate).1HNMR(400MHz,CHLOROFORM-d)8.27(d,J＝5.5Hz,1H),7.07(dd,J＝6.0,2.0Hz,1H),7.00(d,J＝1.5Hz,1H),3.85(t,J＝6.5Hz,2H),3.56(t,J＝6.3Hz,2H),3.44(t,J＝6.5Hz,2H),3.17(t,J＝7.0Hz,2H),1.88-1.98(m,2H),1.74(q,J＝7.4Hz,2H),1.58-1.64(m,2H)。
Example 52B
(E) -1- (4- (2- (2- (5- (2-chloro-4-pyridyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) phenyl) N-ethoxyazomethine
To a solution of example 52A (0.1 g, 0.26 mmol) in N, N-dimethylformamide (5 ml) were added potassium carbonate (36 mg, 0.26 mmol), potassium iodide (43 mg, 0.26 mmol) and p-aminohydroxyphenol (43 mg, 0.26 mmol). The mixed solution was stirred at 80 ℃ for 15 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography after filtration and evaporation (petroleum ether: ethyl acetate ═ 2:1) to obtain the title compound (white solid, 60 mg, yield 49%). LCMS (ESI) M/z 439(M +1).
Example 52C
(E) -1- (4- (5- (5- (2-chloro-4-pyridinyl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyloxy) phenyl) -N- (cyclopropyl) methylamine
To a solution of example 52B (110 mg, 0.25 mmol) in N, N-dimethylformamide (2 ml) was added cyclopropylbromide (34 mg, 0.25 mmol) and potassium carbonate (35 mg, 0.15 mmol) at 0 ℃. At 50 deg.CAfter stirring for 15 hours, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered to evaporate the solvent and separated by column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the title compound (yellow solid, 50 mg, yield 40%). LCMS (ESI) M/z 450(M +1).1HNMR(400MHz,CDCl3)8.04(s,1H),7.63(d,J＝7.0Hz,1H),7.53(d,J＝8.5Hz,2H),6.90(d,J＝8.5Hz,2H),6.62(d,J＝7.5Hz,1H),6.10(s,1H),4.16-4.25(m,4H),3.82-3.88(m,4H),3.72(dd,J＝11.5,5.0Hz,4H),3.40(t,J＝4.8Hz,2H),1.32(t,J＝7.0Hz,3H)。
Example 52D
4- (5- (2- (2- (4- ((E) -ethoxyiminomethyl) phenoxy) ethoxy) ethyl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
To a solution of example 52C (50 mg, 0.1 mmol) in N, N-dimethylformamide (1.5 ml) was added cesium carbonate (66 mg, 0.2 mmol), tert-butyl carbamate (23 mg, 0.2 mmol) at 0 ℃. After the nitrogen is replaced, Pd is added under the protection of nitrogen2(dba)3(19 mg, 20. mu. mol), Xantphos (12 mg, 20. mu. mol). After stirring the mixture at 110 ℃ for 15 hours, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (white solid, 5 mg, yield 10%) which was purified by preparative HPLC.1HNMR(400MHz,CDCl3)8.08(s,1H),7.65(d,J＝7.0Hz,1H),7.53(d,J＝8.8Hz,2H),6.89(d,J＝8.5Hz,2H),6.70(d,J＝6.8Hz,1H),6.21(br.s.,1H),3.95-4.06(m,4H),3.83-3.90(m,2H),3.59(t,J＝6.1Hz,2H),3.21(t,J＝7.2Hz,2H),1.75-1.92(m,3H),1.57-1.69(m,3H),1.16-1.28(m,1H),0.57-0.64(m,2H),0.34(q,J＝4.9Hz,2H)。LCMS(ESI)m/z:474(M+1)。
Example 53
(E) -4- ((5(5 (2-aminopyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) benzaldehyde-oxy-isopropyl ketoxime
The preparation of this example is as in example 52.1HNMR(400MHz,CHLOROFORM-d)8.00(s,1H),7.95(d,J＝6.0Hz,1H),7.50(d,J＝8.5Hz,2H),6.86(d,J＝9.0Hz,2H),6.43(d,J＝5.0Hz,1H),6.28(br.s.,1H),4.42(dt,J＝12.3,6.4Hz,1H),3.99(t,J＝6.3Hz,2H),3.80(t,J＝6.3Hz,2H),3.47-3.53(m,2H),3.15(t,J＝7.3Hz,2H),1.82-1.89(m,2H),1.73-1.80(m,4H),1.29(d,J＝6.0Hz,6H)。LCMS(ESI)m/z:462(M+1)。
Example 54
(E) -2- (2-aminopyridin-4-yl) -5- (5- (4- (1- (ethoxyimino) propyl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 54A
(E) -1- (4-hydroxyphenyl) propan-1-one-oxo-ethyl ketoxime
A mixed solution of 4-hydroxypropiophenone (1 g, 6.7 mmol), sodium acetate (1.1 g, 3.3 mmol), and ethoxyamine hydrochloride (814 mg, 13.3 mmol) in ethanol (10 ml) was added to the mixtureAfter stirring at 80 ℃ for 2 hours, water (10 ml) and ethyl acetate (20 ml) were added to the reaction system, and the aqueous layer was extracted with ethyl acetate (20 ml. times.3), filtered and evaporated to give the title compound (brown solid, 1.28 g, yield 99%).1HNMR(400MHz,CDCl3)7.48(d,J＝8.5Hz,2H),6.74-6.79(m,2H),4.20(q,J＝7.0Hz,2H),2.72(q,J＝7.7Hz,2H),1.30(t,J＝7.0Hz,3H),1.11(t,J＝7.5Hz,3H)。
Example 54B
(E) -2- (2-chloropyridin-4-yl-5- (5- (4- (1- (ethoxyimino) propyl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation of this example is as in example 52C.1HNMR(400MHz,CDCl3)8.26(d,J＝5.8Hz,1H),7.57(d,J＝8.5Hz,2H),7.06(dd,J＝5.8,2.0Hz,1H),6.99(d,J＝1.8Hz,1H),6.86(d,J＝8.8Hz,2H),4.20(q,J＝7.0Hz,2H),3.99(t,J＝6.1Hz,2H),3.83(t,J＝6.4Hz,2H),3.54(t,J＝6.4Hz,2H),3.17(t,J＝7.3Hz,2H),2.72(q,J＝7.5Hz,2H),1.74-1.88(m,4H),1.61(d,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H),1.12(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:495(M+1)。
Example 54C
(E) -2- (2-aminopyridin-4-yl) -5- (5- (4- (1- (ethoxyimino) propyl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation of this example is as in example 52.1HNMR(400MHz,CDCl3)7.85(d,J＝6.0Hz,1H),7.57(d,J＝8.5Hz,2H),6.86(d,J＝9.0Hz,2H),6.52(d,J＝6.5Hz,1H),6.29(s,1H),5.58(br.s.,2H),4.20(q,J＝7.0Hz,2H),3.99(t,J＝6.0Hz,2H),3.80-3.85(m,2H),3.52(t,J＝6.3Hz,2H),3.17(t,J＝7.3Hz,2H),2.69-2.75(m,2H),1.85(d,J＝7.0Hz,2H),1.75(br.s.,2H),1.61(d,J＝7.0Hz,2H),1.31(t,J＝7.0Hz,3H),1.12(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:477(M+1)。
Example 55
(E) -4- (2-2- (5- (2-aminopyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) ethoxy) benzaldehyde-oxy-ethyl ketoxime
Example 55A
2-2-2 (-bromoethoxy) ethyl) -5-2-chloropyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The production method of this example refers to example 52A.1HNMR(400MHz,CDCl3)8.29(d,J＝5.77Hz,1H),7.08(dd,J＝2.26,5.77Hz,1H),7.02(d,J＝2.26Hz,1H),3.78-3.92(m,8H),3.53(t,J＝5.52Hz,2H),3.42(t,J＝4.89Hz,2H)。
Example 55B
(E) -1- (4- (2- (2- (5- (2-chloro-4-pyridyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) ethoxy) phenyl) -N-ethoxyazomethine
To a solution of example 55A (0.1 g, 0.26 mmol) in N, N-dimethylformamide (2 ml) were added potassium carbonate (72 mg, 0.52 mmol), potassium iodide (8.6 mg, 0.05 mmol) and example 7A (47 mg, 0.29 mmol). The mixed solution was stirred at 80 ℃ for 12 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography after filtration and evaporation (petroleum ether: ethyl acetate ═ 1:1) to obtain the title compound (white solid, 60 mg, yield 49%). LCMS (ESI) M/z 469(M +1).
Example 55C
4- (5- (2- (2- (4- ((E) -ethoxyiminomethyl) phenoxy) ethoxy) ethyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
To a solution of example 55B (60 mg, 0.13 mmol) in N, N-dimethylformamide (1 ml) was added cesium carbonate (84 mg, 0.26 mmol), tert-butyl carbamate (18 mg, 0.15 mmol) at 0 ℃. After the nitrogen is replaced, Pd is added under the protection of nitrogen2(dba)3(22 mg, 24. mu. mol), Xantphos (14 mg, 24. mu. mol). After stirring the mixture at 110 ℃ for 15 hours, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (white solid, 5 mg, yield 8.7%).1HNMR(400MHz,CDCl3)8.04(s,1H),7.63(d,J＝7.0Hz,1H),7.53(d,J＝8.5Hz,2H),6.90(d,J＝8.5Hz,2H),6.62(d,J＝7.5Hz,1H),6.10(s,1H),4.16-4.25(m,4H),3.82-3.88(m,4H),3.72(dd,J＝11.5,5.0Hz,4H),3.40(t,J＝4.8Hz,2H),1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:450(M+1)。
Example 56
(E) -5- ((5- (5- (2-aminopyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) methylpyridinecarboxaldehyde-oxy-ethylketoxime
Example 56A
(E) -5-hydroxypyridinal-oxo-ethyl ketoxime
An aqueous solution (5 ml) of ethoxyamino hydrochloride (244 mg, 2.5 mmol), 5-hydroxypyridine-2-aldehyde (308 mg, 2.5 mmol), sodium acetate (410 mg, 5.0 mmol) was heated to 80 ℃ and stirred for 2 hours. Thin layer chromatography showed disappearance of starting material and the reaction mixture was extracted with ethyl acetate (10 ml x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (white solid, 410 mg, 99% yield) which was used in the next step without purification.
Example 56B
(E) -5- ((5- (5- (2-chloropyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) methylpyridinecarboxaldehyde-oxy-ethylketoxime
Example 52A (346 mg, 998 micromoles), exampleExample 56A (163 mg, 978. mu.M) and potassium carbonate (276 mg, 2.0 mmol), potassium iodide (17 mg, 100. mu.M) in acetone (5 mL) were heated to 70 ℃ and reacted for 3 hours. The reaction solution was cooled to room temperature, filtered and concentrated to obtain a crude product. The crude product was purified using preparative thin layer chromatography plate (petroleum ether: ethyl acetate ═ 3:1) to afford the title compound (white solid, 150 mg, yield: 35%).1HNMR(400MHz,CHLOROFORM-d)8.30-8.24(m,2H),8.12(s,1H),7.71(d,J＝9.0Hz,1H),7.18(dd,J＝2.8,8.8Hz,1H),7.05(dd,J＝2.0,5.5Hz,1H),6.99(d,J＝2.0Hz,1H),4.25(q,J＝7.0Hz,2H),4.04(t,J＝6.3Hz,2H),3.84(t,J＝6.5Hz,2H),3.55(t,J＝6.5Hz,2H),3.22-3.14(m,2H),1.92-1.83(m,2H),1.79(quin,J＝7.4Hz,2H),1.70-1.56(m,2H),1.33(t,J＝7.3Hz,3H)。
Example 56C
(E) -5- ((5- (5- (2-aminopyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) methylpyridinecarboxaldehyde-oxy-ethylketoxime
Tert-butyl carbamate (163 mg, 1.4 mmol) and example 56B (120 mg, 278. mu. mol), Pd were combined under nitrogen2(dba)3(25 mg, 28. mu. mol), Xantphos (32 mg, 56. mu. mol), cesium carbonate (181 mg, 556. mu. mol) in dioxane (3 ml) was heated to 100 ℃ for 6 hours. After the reaction heat was reduced to room temperature, concentrated by filtration, and the resulting crude product was purified by prep-HPLC (neutral separation method) to give the title compound (white solid, 30 mg, 26% yield).1HNMR(400MHz,CHLOROFORM-d)8.27(d,J＝2.0Hz,1H),8.11(s,1H),7.97(d,J＝5.5Hz,1H),7.70(d,J＝8.8Hz,1H),7.18(dd,J＝2.3,8.5Hz,1H),6.41(d,J＝4.5Hz,1H),6.28(s,1H),4.49(br.s.,2H),4.25(q,J＝6.9Hz,2H),4.04(t,J＝6.0Hz,2H),3.79(t,J＝6.1Hz,2H),3.49(t,J＝6.3Hz,2H),3.15(t,J＝7.2Hz,2H),1.93-1.82(m,2H),1.82-1.67(m,2H),1.67-1.55(m,2H),1.33(t,J＝6.9Hz,3H)。LCMS(ESI)m/z:449(M+1)。
Example 57
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (methoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 57A
5- ((5- (5- (2-chloropyridin-4-yl) -1, 1-dioxido-1, 2, 5-thiadiazolidin-2-yl) pentyl) oxy) -2, 3-dihydro-1H-inden-1-one
To a solution of example 52A (2.0 g, 5.2 mmol) and 5-hydroxy-1-indanone (774 mg, 5.2 mmol) in acetone (30 mL) was added potassium carbonate (1.45 g, 10.5 mmol) at room temperature, and the reaction was heated to 70 ℃ for 2 hours to complete the reaction. After the reaction solution was cooled to room temperature and concentrated, the residue was poured into water (50 ml), the aqueous phase was extracted with ethyl acetate (30 ml × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (yellow solid, 1.3 g, 55% yield).1HNMR(400MHz,CDCl3)8.28(d,J＝5.77Hz,1H),7.67-7.73(m,1H),7.08(dd,J＝2.01,5.77Hz,1H),7.01(d,J＝1.76Hz,1H),6.88-6.93(m,2H),4.07(t,J＝6.15Hz,2H),3.80-3.91(m,2H),3.58(t,J＝6.27Hz,2H),3.21(t,J＝7.28Hz,2H),3.04-3.13(m,3H),2.65-2.73(m,3H),1.87-1.96(m,2H),1.76-1.85(m,2H),1.57-1.68(m,2H)。
Example 57B
(E) -2- (2-chloropyridin-4-yl) -5- (5- ((1- (hydroxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 57A (1.3 g, 2.9 mmol) and hydroxylamine hydrochloride (603 mg, 8.7 mmol) in ethanol (30 ml) was added sodium acetate (711 mg, 8.7 mmol) at room temperature under nitrogen, and the reaction was allowed to react at 70 ℃ for 2 hours to complete the reaction. The reaction was concentrated and poured into water (50 ml), extracted with ethyl acetate (30 ml × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (yellow solid, 1.30 g, 97% yield).1HNMR(400MHz,CDCl3)8.29(d,J＝5.77Hz,1H),7.53-7.58(m,1H),7.08(dd,J＝2.26,5.77Hz,1H),7.01(d,J＝2.01Hz,1H),6.82(d,J＝5.02Hz,2H),3.98-4.07(m,2H),3.86(t,J＝6.40Hz,2H),3.57(t,J＝6.40Hz,2H),3.20(t,J＝7.15Hz,2H),2.94-3.10(m,5H),1.75-1.94(m,4H),1.56-1.71(m,2H)。
Example 57C
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (methoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation of this example is as in example 56.1H-NMR(400MHz,CDCl3)7.97(d,J＝5.8Hz,1H),7.59(d,J＝9.3Hz,1H),6.77-6.81(m,2H),6.42(dd,J＝5.9,1.9Hz,1H),6.29(d,J＝1.8Hz,1H),4.52(br.s.,2H),3.99(t,J＝6.3Hz,2H),3.96(s,3H),3.79(t,J＝6.4Hz,2H),3.47-3.52(m,2H),3.16(t,J＝7.2Hz,2H),2.96-3.01(m,2H),2.85-2.90(m,2H),1.65-1.93(m,4H),1.61-1.64(m,2H)。LCMS(ESI)m/z:460(M+1)。
Example 58
(E) -2- (2-aminopyridin-4-yl) -5- (5- (1- (isopropoxy) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -
1,2, 5-thiadiazolidine 1, 1-dioxide
The preparation of this example is as in example 56.1H-NMR(400MHz,CDCl3)7.80(br.s.,1H),7.58(d,J＝9.0Hz,1H),6.77(br.s.,2H),6.57(br.s.,1H),6.36(br.s.,1H),4.36-4.41(m,1H),3.96-4.00(m,2H),3.84(br.s.,2H),3.51(br.s.,2H),3.14(t,J＝6.9Hz,2H),2.93-2.98(m,2H),2.83-2.88(m,2H),1.80-1.85(m,2H),1.71-1.77(m,2H),1.59(d,J＝6.8Hz,2H),1.32(d,J＝6.0Hz,2H),1.24-1.28(m,6H)。LCMS(ESI)m/z:488(M+1)。
Example 59
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1-ethoxyimino) -7-fluoro-2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 59A
5-bromo-7-fluoro-indan-1-one-oxo-ethyl ketoxime
A solution of 5-bromo-7-fluoro-indedin-1-one (1.8 g, 7.9 mmol) and ethoxyamino hydrochloride (1.53 g, 15.7 mmol), sodium acetate (1.29 g, 15.7 mmol) in ethanol (10 mL) was heated at 70 deg.C for 3 hours. The starting material disappeared, water (20 ml) was added, the aqueous phase was extracted with ethyl acetate (30 ml x3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (yellow solid, 2.0 g, 94% yield) which was used directly in the next reaction.
Example 59B
(E) -7-fluoro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 3-dihydro-1H-inden-1-one-oxo-ethylketoxime
Example 59A (2.00 g, 7.35 mmol), the bis-pinacol borate (2.24 g, 8.82 mmol), potassium acetate (2.16 g, 22.05 mmol), Pd (dppf) Cl were added under nitrogen2(537.80 mg, 735.00 micromoles) of dioxane (5 ml) was heated to 50 ℃ for 10 hours. The reaction solution was cooled to room temperature and filtered, and the crude product was used directly in the next step.
Example 59C
(E) -7-fluoro-5-hydroxy-2, 3-dihydro-1H-inden-1-one-oxo-ethyl ketoxime
To a mixed solution of example 59B (2.0 g, 6.6 mmol) in sodium hydroxide solution (2 ml, 2N) and tetrahydrofuran (8 ml) was added hydrogen peroxide (2.3 g, 65.5 mmol). The mixed solution was stirred at 25 ℃ for 10 minutes, and then water (5.0 ml) was added. The mixed solution was extracted with ethyl acetate (10 ml × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product, which was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate ═ 2:1) to afford the title compound (yellow solid, 1.20 g, 88% yield).
1HNMR(400MHz,CDCl3)6.56(m,1H),6.48-6.46(m,1H),4.24-4.18(m,2H),4.14-4.09(m,2H),2.96-2.89(m,2H),1.31-1.23(m,3H)。
Example 59D
(E) -2- (2-chloropyridin-4-yl) -5- (5- ((1- (ethoxyimino) -7-fluoro-2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To an acetone solution (5 ml) of example 52A (192 mg, 502 micromole), example 59C (105 mg, 502 micromole) was added potassium iodide (8 mg, 50 micromole) and potassium carbonate (139 mg, 1.0 mmol). The mixed solution was stirred at 70 ℃ for 15 hours until the reaction of the raw materials was completed. Water (5.0 ml) was added and extracted with ethyl acetate (10 ml × 3). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (yellow solid, 220 mg, 86% yield). LCMS (ESI) M/z 511(M +1).
Example 59E
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((1- (ethoxyimino) -7-fluoro-2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To example 59D (102 mg, 199 μmol), tert-butyl carbamate (222 mg, 1.9 mmol), Pd2(dba)3To a solution of (18 mg, 20 micromoles) in dioxane (5.0 ml) was added xanthphos (23 mg, 40 micromoles) and potassium carbonate (83 mg, 599 micromoles). The reaction was stirred at 100 ℃ for 16 h, filtered, concentrated and purified by preparative HPLC (neutral) to give the title compound (white solid, 52 mg, 53% yield).1HNMR(400MHz,CHLOROFORM-d)7.97(d,J＝6.0Hz,1H),6.60(s,1H),6.51(d,J＝11.5Hz,1H),6.42(d,J＝4.0Hz,1H),6.29(s,1H),4.56(br.s.,2H),4.23(q,J＝7.0Hz,2H),3.50(t,J＝6.5Hz,2H),3.16(t,J＝7.3Hz,2H),2.99(d,J＝8.0Hz,2H),2.93(d,J＝8.5Hz,2H),1.88-1.80(m,2H),1.80-1.72(m,2H),1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:492(M+1)。
Example 60
2- (2-chloro-4-pyridyl) -5- (5- (4- (2-isopropyltetrazol-5-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 60A
2-isopropyl-5- (4-methoxyphenyl) tetrazole
To a solution of example 11A (3 g, 17 mmol) in acetonitrile (30 mL) at 0 deg.C was added potassium carbonate (4.7 g, 34 mmol) and isopropyl iodide (2.92 g, 17 mmol)Millimole). After the addition was completed, the mixed solution was heated at 100 ℃ for 5 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate: 10:1) to give the title compound (white solid, 2.1 g, yield 60%).1HNMR(400MHz,CDCl3)8.08(d,J＝8.5Hz,2H),7.00(d,J＝8.5Hz,2H),4.68(q,J＝7.2Hz,2H),3.87(s,3H),1.68(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:205(M+1)。
Example 60B
4- (2-isopropyl-2H-tetrazol-5-yl) phenol
To 60A (1 g, 4.6 mmol) was added a solution of hydrogen bromide in acetic acid (20 ml). The mixed solution was heated at 110 ℃ for 24 hours, cooled to a temperature at which the reaction solution was added to ice water, and the aqueous phase was filtered to give a solid which was the title compound (white solid, 0.7 g, yield 75%).1HNMR(400MHz,CDCl3)8.08(d,J＝8.5Hz,2H),7.00(d,J＝8.5Hz,2H),4.68(q,J＝7.2Hz,2H),3.87(s,2H),1.68(t,J＝7.5Hz,3H)。LCMS(ESI)m/z:191(M+1)。
Example 60C
2- (2-chloro-4-pyridyl) -5- (5- (4- (2-isopropyltetrazol-5-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 52A (200 mg, 0.52 mmol) in acetone (3 ml) was added potassium carbonate (270 mg, 2 mmol), potassium iodide (81 mg, 0.49 mmol) at 0 ℃, and to the above mixed solution was added example 60B (449 mg, 2.2 mmol)). After stirring the mixture at 80 ℃ for reaction for 15 hours, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound as a white solid (200 mg, 74% yield).1HNMR(400MHz,CDCl3)8.28(d,J＝6.0Hz,1H),8.09(d,J＝8.8Hz,2H),7.08(dd,J＝5.8,2.0Hz,1H),6.96-7.02(m,3H),5.10(dt,J＝13.5,6.7Hz,1H),4.06(t,J＝6.1Hz,2H),3.86(t,J＝6.3Hz,2H),3.57(t,J＝6.3Hz,2H),3.51(s,2H),3.21(t,J＝7.2Hz,2H),1.86-1.93(m,2H),1.78-1.84(m,2H),1.72(s,3H),1.70(s,3H)。LCMS(ESI)m/z:506(M+1)。
Example 60D
2- (2-chloro-4-pyridyl) -5- (5- (4- (2-isopropyltetrazol-5-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 60C (200 mg, 0.40 mmol) in N, N-dimethylformamide (1 ml) was added cesium carbonate (386 mg, 1.2 mmol), tert-butyl carbamate (93 mg, 0.79 mmol) at 0 ℃. Adding Pd under the protection of nitrogen2(dba)3(19 mg, 20. mu. mol), Xantphos (12 mg, 20. mu. mol). After stirring the mixture at 110 ℃ for 15 hours, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to preparative HPLC purification to give the title compound (white solid, 40 mg, yield 20%).1HNMR(400MHz,CDCl3)8.08(d,J＝8.5Hz,2H),7.99(d,J＝5.3Hz,1H),7.00(d,J＝8.8Hz,2H),6.44(d,J＝4.0Hz,1H),6.30(s,1H),5.10(dt,J＝13.4,6.7Hz,1H),4.54(br.s.,2H),4.05(t,J＝6.1Hz,2H),3.80(t,J＝6.3Hz,2H),3.47-3.54(m,2H),3.18(t,J＝7.2Hz,2H),1.88(d,J＝7.5Hz,2H),1.76-1.82(m,2H),1.71(d,J＝6.8Hz,6H),1.61-1.68(m,2H)。LCMS(ESI)m/z:487(M+1)。
Example 61
2- (2-aminopyridin-4-yl) -5- (5- (4- (2-methyl-2H-tetrazol-5-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation process of this example refers to example 60.1HNMR(400MHz,DMSO-d6)7.95(d,J＝8.78Hz,2H),7.80-7.89(m,1H),7.09(d,J＝8.78Hz,2H),6.59(br.s.,2H),6.41(d,J＝4.27Hz,1H),6.25(s,1H),4.38(s,3H),4.04(t,J＝6.27Hz,2H),3.84(t,J＝6.40Hz,2H),3.52(t,J＝6.27Hz,2H),3.07(t,J＝7.03Hz,2H),1.62-1.83(m,4H),1.44-1.56(m,2H)。LCMS(ESI)m/z:459(M+1)。
Example 62
2- (2-aminopyridin-4-yl) -5- (5- ((3-ethylbenzo [ d ] isoxazol-6-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 62A
3-ethylbenzo [ d ] isoxazol-6-ols
The preparation method of the embodiment refers to tetrahedron, Lett, 2006, 8247-8250.1HNMR(400MHz,CDCl3)7.50-7.48(m,1H),7.00(m,1H),6.85-6.82(m,1H),2.94(m,2H),1.45(t,J＝8.0Hz,3H)。
Example 62B
2- (2-Chloropyridin-4-yl) -5- (5- ((3-ethylbenzo [ d ] isoxazol-6-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Potassium carbonate (36 mg, 0.26 mmol) and potassium iodide (4.3 mg, 0.026 mmol) were added to a mixed solution of example 52A (100 mg, 0.26 mmol) and example 62A (42.6 mg, 0.26 mmol) in acetone (10 ml). Then after 10 hours at 50 ℃. The reaction was filtered and evaporated and the residue was purified by HPLC to give the title compound (white solid, 100 mg, yield 82%).1HNMR(400MHz,CDCl3)8.28(d,J＝5.77Hz,1H),7.54(d,J＝8.53Hz,1H),7.08(dd,J＝2.26,5.77Hz,1H),7.01(d,J＝2.01Hz,2H),6.89(dd,J＝2.38,8.66Hz,1H),4.02(t,J＝6.15Hz,2H),3.86(t,J＝6.40Hz,2H),3.57(t,J＝6.40Hz,2H),3.15-3.24(m,2H),2.91-2.97(m,2H),1.85-1.98(m,2H),1.74-1.84(m,2H),1.58-1.69(m,2H),1.45(t,J＝7.65Hz,3H)。
Example 62C
2- (2-aminopyridin-4-yl) -5- (5- ((3-ethylbenzo [ d ] isoxazol-6-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Cesium carbonate (189 mg, 0.58 mmol), Xantphos (22 mg, 0.038 mmol) and Pd were added under nitrogen blanket2(dba)3(18 mg, 0.019 mmol) dioxane (2 mmol) from example 62B (90 mg, 0.193 mmol) and tert-butyl carbamate (136 mg, 0.116 mmol) was addedL) solution, then reacted at 110 ℃ for 10 hours, the reaction was poured into water, extracted with ethyl acetate (100 ml × 3), the organic phases were combined, dried over sodium sulfate, filtered and evaporated, and the residue was purified by preparative HPLC to give the title compound (white solid, 20 mg, yield 23%).1HNMR(400MHz,CDCl3)7.98(d,J＝5.52Hz,1H),7.50-7.56(m,1H),7.00(d,J＝2.01Hz,1H),6.85-6.90(m,1H),6.42(d,J＝6.02Hz,1H),6.30(s,1H),4.01(t,J＝6.27Hz,2H),3.76-3.84(m,2H),3.51(t,J＝6.27Hz,2H),3.17(t,J＝7.28Hz,2H),2.93(d,J＝7.53Hz,2H),1.84-1.97(m,2H),1.79(t,J＝7.53Hz,2H),1.64(d,J＝7.03Hz,2H),1.43(t,J＝7.78Hz,3H)。LCMS(ESI)m/z:446(M+1)。
Example 63
4- (5- (5- (4- (5-ethyl-1, 3, 4-oxadiazol-2-yl) phenoxy) pentyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
Example 63A
4- (5-Ethyl-1, 3, 4-oxadiazol-2-yl) phenol
Methanesulfonic acid (63 mg 658 μmol) was added to a mixed solution of 4-hydroxybenzoyl hydrazine (500 mg, 3.3 mmol) and triethyl orthoformate (579 mg, 3.3 mmol) in dioxane (10 ml) and then reacted at 110 ℃ for 1 hour. The reaction was filtered and the filtrate evaporated to give the title compound (150.00 mg of yellow solid, 24% yield).1HNMR(400MHz,CDCl3)7.79(d,J＝9.03Hz,2H),6.87(d,J＝8.53Hz,2H),2.87(q,J＝7.53Hz,2H),1.36(t,J＝7.53Hz,3H)。
Example 63B
2- (2-chloro-4-pyridinyl) -5- (5- (4- (5-ethyl-1, 3, 4-oxadiazol-2-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Potassium carbonate (29 mg, 0.02 mmol), potassium iodide (3.5 mg, 2 micromoles) was added to a mixture of example 52A (80 mg, 0.02 mmol) and example 63A (47.71 mg, 0.25 mmol) in N, N-dimethylformamide (2 ml). Then, the reaction mixture was reacted at 80 ℃ for 10 hours, and then poured into water (100 ml) and extracted with ethyl acetate (100 ml. times.3). The combined organic phases were dried over sodium sulfate, filtered and evaporated, and the residue was passed through a column to give the title compound (yellow solid, 100 mg, yield 97%).1HNMR(400MHz,CDCl3)8.22(d,J＝5.77Hz,1H),7.91(d,J＝8.78Hz,2H),7.02(dd,J＝2.26,5.77Hz,1H),6.98(d,J＝1.76Hz,1H),6.94(d,J＝9.03Hz,2H),3.95-4.04(m,2H),3.83(t,J＝6.40Hz,3H),3.54(t,J＝6.40Hz,3H),3.11-3.22(m,3H),2.87-2.90(m,2H),1.79-1.90(m,2H),1.69-1.79(m,2H),1.52-1.64(m,2H),1.39(t,J＝7.65Hz,3H)。
Example 63C
4- (5- (5- (4- (5-ethyl-1, 3, 4-oxadiazol-2-yl) phenoxy) pentyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
Pd is added under the protection of nitrogen2(dba)3(15 mg, 0.016 mmol), cesium carbonate (106 mg, 0.032 mol) and xanthphos (19 mg, 3. mu. mol)) A solution of example 63B (80 mg, 0.16 mmol) and tert-butyl carbamate (114 mg, 0.40 mmol) in dioxane (1 ml) was added, followed by reaction at 110 ℃ for 10 hours. After the reaction was completed, the reaction solution was poured into water (20 ml), extracted with ethyl acetate (10 ml × 3), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by preparative HPLC to give the title compound (white solid, 25 mg, yield 33%).1HNMR(400MHz,CDCl3)7.92-8.02(m,3H),6.98(d,J＝9.03Hz,2H),6.43(dd,J＝1.76,5.77Hz,1H),6.30(d,J＝1.51Hz,1H),4.57(br.s.,1H),4.05(t,J＝6.02Hz,2H),3.73-3.87(m,2H),3.51(t,J＝6.53Hz,2H),3.18(t,J＝7.28Hz,2H),2.95(q,J＝7.53Hz,2H),1.84-1.94(m,2H),1.75-1.83(m,2H),1.65-1.69(m,2H),1.44(t,J＝7.53Hz,3H)。LCMS(ESI)m/z:473(M+1)。
Example 64
2- (2-aminopyridin-4-yl) -5- (5- (4- (2-ethyl-2H-1, 2, 3-triazol-4-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 64A
4- (4-methoxyphenyl) 1,2, 3-triazole
To a solution of cuprous iodide (144 g, 757 mmol), 4-methoxyphenylacetylene (2 g, 15.1 mmol) in N, N-dimethylformamide (5.4 ml) and methanol (0.6 ml) was added trimethylsilyl azide (2.62 g, 22.7 mmol) under nitrogen. After the mixed solution was stirred at 100 ℃ for 16 hours, the residue after filtration and evaporation was purified by column chromatography (stone)Ethyl acetate 10:1, petroleum ether 2:1) to give the title compound (yellow solid, 2g, 75% yield).1HNMR(400MHz,CDCl3)7.88(s,1H),7.75(d,J＝8.5Hz,2H),6.98(d,J＝8.5Hz,2H),3.85(s,3H)。
Example 64B
2-Ethyl-4 (4-methoxyphenyl) -1,2, 3-triazole
A mixture of example 64A (1 g, 5.71 mmol), iodoethane (2.67 g, 17.13 mmol) and potassium carbonate (1.58 g, 11.42 mmol) in acetonitrile (10 ml) was reacted at 70 ℃ for 16 h. Water (10 ml) was added to the reaction system, the aqueous layer was extracted with ethyl acetate (10 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (yellow liquid, 1 g, yield 86%).1HNMR(400MHz,CDCl3)7.62-7.73(m,3H),6.92(d,J＝8.5Hz,2H),4.45(q,J＝7.5Hz,2H),3.81(s,3H),1.56(t,J＝7.3Hz,3H)。
Example 64C
4- (2-Ethyl-2H-1, 2, 3-triazol-4-yl) -phenol
To a solution of example 64B (200 mg, 984 micromoles) in dichloromethane (5 ml) was added boron tribromide (986 mg, 3.94 mmol) at-78 ℃. After the mixture was reacted at 25 ℃ for 1 hour, water (5 ml) was added to the reaction system, and the aqueous layer was substituted with dichloromethaneExtraction with alkane (10 ml × 3) filtered and evaporated gave the title compound (yellow solid, 160 mg, 86% yield).1HNMR(400MHz,CDCl3)7.74(s,1H),7.66(d,J＝8.5Hz,2H),6.89(d,J＝8.5Hz,2H),4.46-4.52(m,2H),1.59(t,J＝7.3Hz,3H)。
Example 64D
2- (2-chloropyridin-4-yl) -5- (5- (4- (2-ethyl-2H-1, 2, 3-triazol-4-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation of this example is as in example 63.1HNMR(400MHz,CDCl3)8.26(d,J＝6.0Hz,1H),7.74(s,1H),7.69(d,J＝9.0Hz,2H),7.06(dd,J＝5.5,2.0Hz,1H),6.99(d,J＝2.0Hz,1H),6.93(d,J＝8.5Hz,2H),4.49(q,J＝7.4Hz,2H),4.01(t,J＝6.3Hz,2H),3.83(t,J＝6.5Hz,2H),3.55(t,J＝6.5Hz,2H),3.18(t,J＝7.0Hz,2H),1.83-1.90(m,2H),1.75-1.82(m,2H),1.62-1.67(m,2H),1.61(d,J＝4.0Hz,3H)。LCMS(ESI)m/z:492(M+1)。
Example 64E
2- (2-aminopyridin-4-yl) -5- (5- (4- (2-ethyl-2H- [1,2,3] triazol-4-yl) -phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 64D (80 mg, 163. mu. mol), tert-butyl carbamate (115 mg, 978. mu. mol), cesium carbonate (106 mg, 326. mu. mol) in dioxane (3 mL) and N, N dimethylformamide (0.5 mL) under nitrogen was added Xantphos (8 mg, 13.8. mu. mol) and Pd2(dba)3(9 mg, 9.8. mu. mol). After the mixture was reacted at 110 ℃ for 16 hours, water (10 ml) was added to the reaction system, the aqueous layer was extracted with dichloromethane (10 ml. times.3), filtered and evaporated, and the residue was isolated by preparative separation to give the title compound (brown solid, 30 mg, yield 39%).1HNMR(400MHz,CDCl3)7.98(d,J＝6.0Hz,1H),7.74(s,1H),7.69(d,J＝8.5Hz,2H),6.94(d,J＝9.0Hz,2H),6.38-6.44(m,1H),6.29(s,1H),4.49(q,J＝7.5Hz,4H),4.01(t,J＝6.0Hz,2H),3.80(t,J＝6.5Hz,2H),3.47-3.53(m,2H),3.16(t,J＝7.3Hz,2H),1.84-1.91(m,2H),1.74-1.80(m,2H),1.64(br.s.,3H)。LCMS(ESI)m/z:472(M+1)。
Example 65
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((5 (ethoxyimino) -5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 65A
(E) -6-hydroxy-3, 4-dihydronaphthalen-1 (2H) -one-oxo-ethyl ketoxime
To a solution of 6-hydroxy-1-tetralone (1 g, 6.2 mmol) in water (10 ml) was added ethoxyamino hydrochloride (1.88 g, 30.9 mmol) and sodium acetate (2.5 g, 30.9 mmol). The mixed solution was stirred at 80 ℃ for 2 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the title compound was obtained after filtration and evaporation (yellow solid, 0.8 g, yield 63%). LCMS (ESI) M/z:206(M +1).
Example 65B
(E) -2- (2-chloropyridin-4-yl) -5- (5- ((5- (ethoxyimino) -5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 52A (0.1 g, 0.26 mmol) in N, N dimethylformamide (2 ml) was added potassium carbonate (72 mg, 0.52 mmol), potassium iodide (9 mg, 0.05 mmol) and example 64A (53.6 mg, 0.26 mmol). The mixed solution was stirred at 80 ℃ for 15 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography after filtration and evaporation (petroleum ether: ethyl acetate ═ 1:1) to obtain the title compound (white solid, 60 mg, yield 45%).1HNMR(400MHz,CDCl3)8.28(d,J＝5.8Hz,1H),7.92(d,J＝8.8Hz,1H),7.07(dd,J＝5.8,2.0Hz,1H),7.01(d,J＝2.0Hz,1H),6.74(dd,J＝8.8,2.5Hz,1H),6.63(d,J＝2.3Hz,1H),4.21(q,J＝7.0Hz,2H),3.99(t,J＝6.3Hz,2H),3.85(t,J＝6.3Hz,2H),3.56(t,J＝6.4Hz,2H),3.15-3.22(m,2H),2.67-2.77(m,4H),1.84(dt,J＝12.1,6.4Hz,6H),1.58-1.66(m,2H),1.33(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:507(M+1)。
Example 65C
(E) -2- (2-aminopyridin-4-yl) -5- (5- ((5- (ethoxyimino) -5,6,7, 8-tetrahydronaphthalen-2-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 65B (60 mg, 0.12 mmol) in N, N-dimethylformamide (1 mL) was added cesium carbonate (77 mg, 0.24 mmol), tert-butyl carbamate at 0 deg.C(15 mg, 0.13 mmol), after replacement of the nitrogen, Pd was added under nitrogen protection2(dba)3(22 mg, 23.7 mmol) and xanthphos (14 mg, 23.7 mmol). After stirring the reaction at 110 ℃ for 15 hours, water was added to quench the reaction and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (white solid, 15 mg, yield 26%) which was purified by preparative HPLC.1HNMR(400MHz,CDCl3)7.91(d,J＝8.5Hz,1H),7.62(d,J＝7.0Hz,1H),6.68-6.75(m,2H),6.62(d,J＝2.0Hz,1H),6.18(s,1H),4.20(q,J＝7.0Hz,2H),3.98(t,J＝6.3Hz,2H),3.84(t,J＝6.3Hz,2H),3.57(t,J＝6.3Hz,2H),3.19(t,J＝7.0Hz,2H),2.65-2.76(m,4H),1.81-1.87(m,4H),1.76(d,J＝7.0Hz,2H),1.57-1.63(m,2H),1.32(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:488(M+1)。
Example 66
2- (2-aminopyridin-4-yl) -5- (5- ((2-propylbenzo [ d ] oxazol-6-yl) oxy) pentyl) -1,2, 5-thiadiazolidine 1, 1-dioxide
Example 66A
2-propylbenzo [ d ] oxazol-6-ol
This example is described in the patent (WO2005037814) LCMS (ESI) M/z:178(M +1).
Example 66B
2- (2-Chloropyridin-4-yl) -5- (5- ((2-propylbenzo [ d ] oxazol-6-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 52A (0.1 g, 0.26 mmol) in N, N-dimethylformamide (2 mL) were added potassium carbonate (72 mg, 0.52 mmol), potassium iodide (9 mg, 0.05 mmol) and 2-propyl 6-hydroxybenzoxazole (56 mg, 0.3 mmol). The mixed solution was stirred at 80 ℃ for 15 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography after filtration and evaporation (petroleum ether: ethyl acetate ═ 1:1) to obtain the title compound (white solid, 50 mg, yield 40%). LCMS (ESI) M/z 479(M +1).
Example 66C
2- (2-aminopyridin-4-yl) -5- (5- ((2-propylbenzo [ d ] oxazol-6-yl) oxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 66B (50 mg, 0.10 mmol) in N, N-dimethylformamide (1 ml) at 0 ℃, cesium carbonate (68 mg, 0.21 mmol), tert-butyl carbamate (15 mg, 0.13 mmol) were added, and after the nitrogen gas had been replaced, Pd was added under nitrogen protection2(dba)3(19 mg, 21. mu. mol) and Xantphos (12 mg, 20. mu. mol). After stirring the reaction at 110 ℃ for 15 hours, water was added to quench the reaction and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to afford the title compound (white solid, 8 mg, yield 17%) which was purified by preparative HPLC.1HNMR(400MHz,CDCl3)7.92(d,J＝6.3Hz,1H),7.54(d,J＝8.5Hz,1H),7.02(d,J＝2.3Hz,1H),6.90(dd,J＝8.8,2.3Hz,1H),6.50(d,J＝5.8Hz,1H),6.33(s,1H),4.03(t,J＝6.3Hz,2H),3.85(t,J＝6.4Hz,2H),3.54(t,J＝6.3Hz,2H),3.19(t,J＝7.2Hz,2H),2.89(t,J＝7.5Hz,2H),1.87-1.94(m,4H),1.80(q,J＝7.3Hz,2H),1.61-1.70(m,2H),1.06(t,J＝7.4Hz,3H)。LCMS(ESI)m/z:460(M+1)。
Example 67
2- (2-aminopyridin-4-yl) -5- (5- (4- (5-ethylisoxazol-3-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 67A
(E) -4-hydroxybenzaldehyde oximes
To a solution of 4-hydroxybenzaldehyde (10 g, 82 mmol) in ethanol (100 ml) was added sodium acetate (20 g, 246 mmol) and hydroxylamine hydrochloride (17 mg, 246 mmol). The mixed solution was heated at 70 ℃ for 15 hours, cooled to room temperature, added with water, extracted with ethyl acetate, and the organic phase was spin-dried and then separated by column (petroleum ether: EA ═ 3:1) to obtain the title compound as a solid (white solid, 7 g, yield 62%). LCMS (ESI) M/z 138(M +1).
Example 67B
4- (5-Ethylisoxazol-3-yl) phenol
Chlorosuccinimide (2.9 g, 22 mmol) was added to a solution of example 67A (3 g, 22 mmol) in 1, 2-dichloroethane (30 ml) at 0 ℃. After one hour reaction at room temperature, 1-butyne (1.2 g, 22 mmol) was added under ice bath and after addition the mixed solution was heated at 20 ℃ for 2 hours. After the addition of triethylamine (2.2 g, 22 mmol) was completed in an ice bath, the mixed solution was heated at 20 ℃ for 15 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate: 10:1) to give the title compound (white solid, 1 g, yield 24%). LCMS (ESI) M/z:190(M +1).
Example 67C
2- (2-Chloropyridin-4-yl) -5- (5- (4- (5-ethylisoxazol-3-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 52A (0.1 g, 0.26 mmol) in N, N-dimethylformamide (2 ml) were added potassium carbonate (72 mg, 0.5 mmol), potassium iodide (9 mg, 0.05 mmol) and 67B (59 mg, 0.3 mmol). The mixed solution was stirred at 80 ℃ for 15 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography after filtration and evaporation (petroleum ether: ethyl acetate ═ 2:1) to obtain the title compound (white solid, 60 mg, yield 49%). LCMS (ESI) M/z:492(M +1).
Example 67D
2- (2-aminopyridin-4-yl) -5- (5- (4- (5-ethylisoxazol-3-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
To a solution of example 67C (50 mg, 0.101 mmol) in N, N-dimethylformamide (1.5 ml) was added cesium carbonate (66.36 mg, 0.202 mmol), tert-butyl carbamate (23.26 mg, 0.202 mmol) at 0 ℃. After the nitrogen is replaced, Pd is added under the protection of nitrogen2(dba)3(18.57 mg, 20.28 mmol)/Xantphos (11.74 mg, 20.28 mmol). After stirring the mixture at 110 ℃ for 15 hours, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (white solid, 3 mg, yield 6.25%).1HNMR(400MHz,CDCl3)7.98(d,J＝5.5Hz,1H),7.72(d,J＝8.5Hz,2H),6.95(d,J＝8.5Hz,2H),6.39-6.44(m,1H),6.29(s,1H),6.23(s,1H),4.48(br.s.,2H),4.03(t,J＝6.0Hz,2H),3.79(t,J＝6.5Hz,2H),3.50(t,J＝6.3Hz,2H),3.17(t,J＝7.3Hz,2H),2.81(q,J＝7.5Hz,2H),1.82-1.94(m,2H),1.70-1.82(m,2H),1.64(br.s.,2H),1.34(t,J＝7.8Hz,3H)。LCMS(ESI)m/z:472(M+1)。
Example 68
2- (2-aminopyridin-4-yl) -5- (5- (4- (5 (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 68A
4- (5- (5- (2-chloro-4-pyridinyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) -pentoxy) benzonitrile
To a solution of example 52A (500 mg, 1.31 mmol) in N, N-dimethylformamide (5 ml) was added p-cyanophenol (187 mg, 1.57 mmol) at 0 ℃. To the above mixed solution was added potassium carbonate (362 mg, 2.62 mmol), and after stirring at 80 ℃ for 15 hours, the reaction was quenched with water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, evaporated and column separated (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (white solid, 350 mg, yield 63%). LCMS (ESI) M/z 421(M +1).
Example 68B
4- (5- (5- (2-amino-4-pyridyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) -pentoxy) benzonitrile
To a solution of example 68A (100 mg, 0.24 mmol) in N, N-dimethylformamide (1.5 ml) was added cesium carbonate (154 mg, 0.48 mmol), tert-butyl carbamate (42 mg, 0.36 mmol) at 0 ℃. Adding Pd under the protection of nitrogen2(dba)3(18.57 mg, 20.28. mu. mol) and Xantphos (11.7 mg, 20. mu. mol). After stirring the mixture at 110 ℃ for 15 hours, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and separated by filtration on an evaporation column (dichloromethane: methanol ═ 10:1) to give the title compound (white solid, 30 mg, yield 31%). LCMS (ESI) M/z:402(M +1).
Example 68C
N- (4- (5- (5- (4-cyanophenoxy) pentyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) -2-pyridinyl) carbamic acid tert-butyl ester
To a solution of 68B (0.3 g, 0.75 mmol) in acetonitrile was added N, N-dimethylaminopyridine (45 mg, 0.37 mmol) and BOC anhydride (489 mg, 2.2 mmol). The mixed solution was heated at 20 ℃ for 15 hours, cooled to a temperature at which the reaction solution was added to ice water, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and separated by filtration on an evaporation column (dichloromethane: methanol ═ 10:1) to give the title compound (red oil, 0.2 g, yield 53%). LCMS (ESI) M/z 502(M +1).
Example 68D
N- (4- (5- (5- (4- ((Z) -N' -hydroxycarbamimidoyl) phenoxy) pentyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) -2-pyridinyl) carbamic acid tert-butyl ester
To a solution of example 68C (0.1 g, 0.2 mmol) in isopropanol (2 ml) was added triethylamine (40 mg, 0.4 mmol) and hydroxylamine hydrochloride (27.8 mg, 0.4 mmol). After the mixed solution was stirred at 80 ℃ for 5 hours, it was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and filtered to evaporate to give the title compound (white solid, 70 mg, yield 66%). LCMS (ESI) M/z 535(M +1).
Example 68E
2- (2-aminopyridin-4-yl) -5- (5- (4- (5 (trifluoromethyl) -1,2, 4-oxadiazol-3-yl) phenoxy) pentyl) -1,2, 5-thiadiazolidine 1, 1-dioxide
To a solution of example 68D (60 mg, 0.11 mmol) in pyridine (1 ml) was added TFAA (35 mg, 0.17 mmol) at 0 ℃. After stirring the mixture at 80 ℃ for 2 hours, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound as a white solid (5 mg, 7% yield).1HNMR(400MHz,CDCl3)8.06(d,J＝8.8Hz,2H),8.00(d,J＝6.0Hz,1H),7.02(d,J＝8.8Hz,2H),6.44(dd,J＝5.8,2.0Hz,1H),6.31(d,J＝2.0Hz,1H),4.50(br.s.,2H),4.08(t,J＝6.3Hz,2H),3.83(t,J＝6.3Hz,2H),3.53(t,J＝6.4Hz,2H),3.19(t,J＝7.2Hz,2H),1.87-1.96(m,2H),1.81(quin,J＝7.4Hz,2H),1.65-1.70(m,2H)。LCMS(ESI)m/z:513(M+1)。
Example 69
2- (2-aminopyridin-4-yl) -5- (5- (4- (5-methyl-1, 2, 4-oxadiazol-3-yl) phenoxy) pentyl-1, 2, 5-thiadiazolidine-1, 1-dioxide
The preparation of this example is as in example 68.1HNMR(400MHz,CDCl3)7.96(d,J＝8.78Hz,1H),7.79(d,J＝7.28Hz,1H),7.06(d,J＝8.78Hz,2H),6.80(dd,J＝2.51,7.28Hz,1H),6.47(d,J＝2.26Hz,1H),4.10(t,J＝6.15Hz,2H),3.97(t,J＝6.40Hz,2H),3.60-3.71(m,2H),3.22(t,J＝7.03Hz,2H),2.65(s,3H),1.85-1.94(m,2H),1.76-1.84(m,2H),1.60-1.70(m,2H)。LCMS(ESI)m/z:459(M+1)。
Scheme R
Example 70
(E) -2- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -5- (pyridazin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 70A
5- (3, 6-Dichloropyridazin-4-yl) -1,2, 5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1, 1-dioxide
The preparation of this example is as in example 32G.1HNMR(400MHz,CDCl3)7.87(s,1H),4.02-4.12(m,4H),1.58(s,10H)。LCMS(ESI)m/z:369(M+1)。
Example 70B
5- (pyridazin-4-yl) -1,2, 5-thiadiazolidine-2-carboxylic acid tert-butyl ester-1, 1-dioxide
To a solution of example 70A (890 mg, 2.4 mmol) in methanol (40 ml) was added sodium acetate (396 mg, 4.8 mmol) and Pd/C (1 g) under nitrogen. The mixture was allowed to react for 5 hours at 15Psi after replacement of hydrogen at 15 ℃. After the reaction was complete, the mixture was filtered and the filtrate was concentrated to give the title compound as a yellow solid (520 mg, 72%).1HNMR(400MHz,CDCl3)9.13(d,J＝3.01Hz,1H),9.08(d,J＝6.02Hz,1H),7.35(dd,J＝3.01,6.02Hz,1H),4.06-4.12(m,2H),3.93-3.98(m,2H),1.59(s,9H)。LCMS(ESI)m/z:301(M+1)。
Example 70C
2- (pyridazin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxides
The preparation of this example is as in example 32E.1HNMR(400MHz,DMSO-d6)9.07(d,J＝2.51Hz,1H),9.01(d,J＝6.02Hz,1H),8.26(br.s.,1H),7.26(dd,J＝3.01,6.02Hz,1H),3.96-4.00(m,2H),3.62(br.s.,2H)。
Example 70D
(E) -2- (5- ((1- (ethoxyimino) -2, 3-dihydro-1H-inden-5-yl) oxy) pentyl) -5- (pyridazin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation of this example is as in example 32D.1HNMR(400MHz,CDCl3)8.01(br.s.,1H),7.59(dt,J＝3.26,6.02Hz,2H),6.76-6.85(m,2H),6.56(d,J＝9.03Hz,1H),4.20(q,J＝7.19Hz,2H),3.99(t,J＝6.27Hz,2H),3.74(t,J＝6.27Hz,2H),3.46(t,J＝6.40Hz,2H),3.15(t,J＝7.28Hz,2H),2.95-3.01(m,2H),2.86-2.92(m,2H),1.72-1.89(m,4H),1.56-1.60(m,2H),1.28-1.38(m,3H)。LCMS(ESI)m/z:474(M+1)。
Procedure S
Example 71
2- (5- ((3-ethoxybenzo [ d ] isoxazol-6-yl) oxy) -3-fluoropentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 71A
1- (2-bromoethyl) cyclopropanol
To a mixture of ethyl 3-bromopropionate (10 g, 55 mmol) in tetrahydrofuran (250 ml) at 0 ℃ was added titanium tetraisopropoxide (7.9 g, 28 mmol), then ethyl grignard reagent (14.7 g, 110 mmol) was slowly added to the reaction system at 0 ℃, stirred for 1 hour and then raised to 25 ℃ and stirred for 2 hours, to the system was added saturated aqueous ammonium chloride solution at 0 ℃, extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, and the residue after filtration and evaporation was purified by column chromatography (petroleum ether: ethyl acetate ═ 10:1 to petroleum ether: ethyl acetate ═ 5:1) to obtain the title compound (colorless liquid, 4.9 g, yield 54%).1HNMR(400MHz,CDCl3)3.61(t,J＝7.3Hz,2H),2.26(br.s.,1H),2.11(t,J＝7.3Hz,2H),0.78-0.82(m,2H),0.50-0.56(m,2H)。
Example 71B
1, 5-dibromopentane-3-one
0℃To a solution of example 71A (500 mg, 3.0 mmol) in carbon tetrachloride (8 mL) was added N-bromosuccinimide (539 mg, 3.0 mmol) and the mixture was reacted at 25 ℃ for 16 hours. Filtered and evaporated, and the residue purified by column chromatography (petroleum ether: ethyl acetate: 20:1 to petroleum ether: ethyl acetate: 10:1) to give the title compound (yellow liquid, 500 mg, 68% yield).1HNMR(400MHz,CDCl3)3.56(t,J＝6.8Hz,2H),3.04(t,J＝6.8Hz,2H)。
Example 71C
1, 5-dibromopentane-3-ol
To a solution of example 71B (500 mg, 2.1 mmol) in methanol (5 mL) was added sodium borohydride (155 mg, 4.1 mmol) at 0 deg.C, and the mixture was reacted at 25 deg.C for 3 hours. Water (5 ml) was added to the reaction, the aqueous layer was extracted with dichloromethane (10 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (340 mg, 67% yield).1HNMR(400MHz,CDCl3)4.07(d,J＝4.6Hz,1H),3.51-3.57(m,4H),1.96-2.04(m,4H)。
Example 71D
1-bromo-5- ((3-ethoxybenzo [ d ] isoxazol-6-yl) oxy) pentan-3-ol
Example 71C (329 mg, 1.34 mmol), example 12D (150 mg, 837 micromoles), potassium iodide (14 mg, 84 micromoles) in acetone (5 ml)) The mixture was reacted at 60 ℃ for 16 hours. Water (5 ml) and dichloromethane (10 ml) were added to the reaction system, the aqueous layer was extracted with dichloromethane (10 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (colorless solid, 190 mg, 66% yield).1HNMR(400MHz,CDCl3)7.45-7.50(m,1H),6.83-6.88(m,2H),4.43-4.48(m,2H),4.11-4.32(m,3H),3.55-3.65(m,2H),1.94-2.09(m,4H),1.50(t,J＝7.2Hz,3H)。
Example 71E
2- (5- ((3-ethoxybenzo [ d ] isoxazol-6-yl) oxy) -3-hydroxypentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 71D (20 mg, 58 micromole), example 4F (12 mg, 58 micromole), potassium iodide (1 mg, 5.8 micromole) in a mixture of N, N-dimethylformamide (3 ml) was reacted at 60 ℃ for 3 hours. Water (5 ml) and dichloromethane (10 ml) were added to the reaction system, the aqueous layer was extracted with dichloromethane (10 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by preparative isolation to give the title compound (colorless solid, 8 mg, 30% yield).1HNMR(400MHz,CDCl3)8.64(d,J＝6.5Hz,2H),7.48(d,J＝8.5Hz,1H),7.31(d,J＝6.5Hz,2H),6.86(d,J＝4.5Hz,2H),4.45-4.50(m,2H),4.11-4.27(m,2H),3.95-4.01(m,2H),3.71-3.75(m,4H),3.44(dt,J＝15.6,7.8Hz,2H),2.03(br.s.,4H),1.49-1.53(m,3H)。LCMS(ESI)m/z:463(M+1)。
Example 72
2- (5- ((3-ethoxybenzo [ d ] isoxazol-6-yl) oxy) -3-fluoropentyl) -5- (pyridin-4-yl) -1,2, 5-thiadiazolidine 1, 1-dioxide
DAST (37 mg, 227 mmol) was added dropwise to a solution of example 71E (35 mg, 76 micromoles) in dichloromethane (2 mL) under nitrogen at-78 ℃. After the mixed solution was stirred at 20 ℃ for 1 hour, water (5 ml) was added to the reaction system, the aqueous layer was extracted with dichloromethane (10 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was isolated and purified by preparative separation to give the title compound (colorless solid, 35 mg, yield 95%).1HNMR(400MHz,CDCl3)8.53(d,J＝6.3Hz,2H),7.47(d,J＝9.3Hz,1H),7.07(d,J＝6.3Hz,2H),6.84-6.87(m,2H),4.83-5.12(m,1H),4.42-4.49(m,2H),4.06-4.19(m,2H),3.83-3.89(m,2H),3.57-3.62(m,2H),3.31-3.42(m,2H),1.98-2.29(m,4H),1.48-1.50(m,3H)。LCMS(ESI)m/z:465(M+1)。
Procedure T
Example 73
2- (2-aminopyridin-4-yl) -5- (2- (1- (2- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) ethyl) cyclopropyl) ethyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 73A
Dimethyl 2,2' - (cyclopropane-1, 1-diyl) diacetic acid
Reference is made to the preparation of example 8A (journal of medicinal chemistry,57 (2); 364; 377; 2014)
Example 73B
2,2' - (cyclopropane-1, 1-diyl) diethanol
Example 72A (249 mg, 1.34 mmol) was added dropwise to a solution of lithium aluminum hydride (102 mg, 2.68 mmol) in tetrahydrofuran (3 ml) at 0 ℃ and after the addition was complete, the mixed solution was stirred at 25 ℃ for 3 hours. Water (0.5 ml) and 10% sodium hydroxide solution (0.5 ml) were added to the reaction and the system was dried over sodium sulfate, filtered and evaporated to give the title compound (122 mg, yield 72%).
Example 73C
2,2' - (cyclopropane-1, 1-diyl) diethyl-4-methylbenzenesulfonic acid
A mixed solution of example 73B (1 g, 7.9 mmol), p-toluenesulfonyl chloride (5.9 g, 30.7 mmol), and triethylamine (3.1 g, 30.7 mmol) in dichloromethane (80 ml) was stirred at 25 ℃ for 16 hours and at room temperature for 12 hours. Water (40 ml) was added to the reaction system, and the aqueous layer was extracted with methylene chloride (40 ml. times.3),the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate: 10:1 to petroleum ether: ethyl acetate: 5:1) to give the title compound (yellow liquid, 730 mg, 20% yield).1HNMR(400MHz,CDCl3)7.78(s,4H),7.34(br.s.,4H),4.03-4.07(m,4H),2.45(s,6H),1.48-1.52(m,3H),0.25-0.34(m,4H)。
Example 73D
2- (1- (2- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) ethyl) cyclopropyl) ethyl-4-methylbenzenesulfonic acid
Prepared as described in example 29A in this example.1HNMR(400MHz,CDCl3)8.04-8.07(m,4H),7.72-7.77(m,4H),7.36(br.s.,4H),6.91-7.00(m,4H),2.42(s,3H),1.49-1.55(m,3H),0.37(d,J＝9.5Hz,2H),0.28(s,2H)。LCMS(ESI)m/z:457(M+1)。
Example 73E
5- (2- (1- (2- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) ethyl) cyclopropylamino) ethyl) -1, 2-thiadiazolidine-2-carboxylic acid tert-butyl ester-1, 1-dioxide
The preparation of this example is as in example 32D. LCMS (ESI) M/z 507(M +1).
Example 73F
2- (2- (1- (2- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) ethyl) cyclopropyl) ethyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 73E (60 mg, 0.18 mmol), potassium carbonate (82 mg, 0.6 mmol) in methanol (2 ml) was stirred at 60 ℃ for 4 h. Spin-dry, water (5 ml) and dichloromethane (10 ml) were added to the reaction, the aqueous layer was extracted with dichloromethane (10 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (colorless solid, 40 mg, 75% yield). LCMS (ESI) M/z:407(M +1).
Example 73G
2- (2-aminopyridin-4-yl) -5- (2- (1- (2- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) ethyl) cyclopropyl) ethyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Under nitrogen atmosphere example 73F (40 mg, 988 micromoles), potassium carbonate (27 mg, 0.2 mmol), 2-amino-4-bromopyridine (26 mg, 148 micromoles) in N, N-dimethylformamide (2 ml) was added 8-hydroxyquinoline (14 mg, 98 micromoles) and cuprous iodide (2 mg, 9.8 micromoles). The mixture was stirred at 120 ℃ for 12 hours. Spin-dry, water (5 ml) was added to the reaction system, the aqueous layer was extracted with dichloromethane (10 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by preparative chromatography (dichloromethane: methanol ═ 20:1, dichloromethane: ethyl acetate ═ 1: 2) to give the title compound (colorless solid, 20 mg, 39% yield).1HNMR(400MHz,CDCl3)8.05-8.08(m,2H),7.91(d,J＝6.0Hz,1H),6.99-7.02(m,2H),6.45-6.47(m,1H),6.28(br.s.,1H),5.00(br.s.,2H),4.66-4.69(m,2H),4.11-4.17(m,2H),3.76-3.80(m,2H),3.50(t,J＝6.5Hz,2H),3.26-3.34(m,2H),1.80(t,J＝6.3Hz,2H),1.71-1.76(m,2H),1.68(s,3H),0.25-0.62(m,4H)。LCMS(ESI)m/z:499(M+1)。
Flow U
Example 74
4- (5- (5- ((5- (2-ethyltetrazol-5-yl) -2-pyridyl) oxy) pentyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
Example 74A
5- (2-amino-4-pyridinyl) -1, 1-dioxo-1, 2, 5-thiadiazolidine-2-carboxylic acid tert-butyl ester
4-bromo-2-aminopyridine (10 g, 57.8 mmol), example 32B (25.7 g, 115.6 mmol), (1S,2S) -N1,N2Dimethylcyclohexanediamine (1.64 g, 11.6 mmol), potassium carbonate (24 g, 173 mmol) and cuprous iodide (16.5 g, 86.7 mmol) were dissolved in N, N-dimethylformamide (150 ml). The mixture was stirred at 100 ℃ for 12 hours under nitrogen. The reaction solution was poured into a continuously stirred mixture of ice water (300 ml), aqueous ammonia (100 ml) and ethyl acetate (200 ml). Extracting with ethyl acetate, drying the combined organic phases with anhydrous sodium sulfate, and filteringAfter evaporation the residue was recrystallized from methanol and filtered to give the title compound (7.5 g, yield 70%).1HNMR(400MHz,DMSO-d6)7.87(d,J＝5.0Hz,1H),6.40(d,J＝4.0Hz,1H),6.30(s,1H),6.09(br.s.,2H),3.99-3.89(m,2H),3.87-3.75(m,2H),1.50(s,9H)。
Example 74B
4- (1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
To a solution of example 74A (5.0 g, 15.9 mmol) in ethyl acetate (20 mL) was added a solution of ethyl acetate hydrochloride (4 mol/L) (50 mL) at 0 ℃. The mixture was reacted at 25 ℃ for 2 hours and spin dried to give the hydrochloride salt of the title compound (3.95 g, 97% yield).1HNMR(400MHz,DMSO-d6)8.44(t,J＝7.8Hz,1H),7.91(d,J＝7.3Hz,1H),7.82(br.s.,2H),6.63(dd,J＝2.3,7.3Hz,1H),6.41(d,J＝2.3Hz,1H),3.94(t,J＝6.3Hz,2H),3.59(q,J＝6.5Hz,2H)。
Example 74C
6- (5-hydroxypentyloxy) pyridine-3-carbonitrile
To a solution of example 1, 5-pentanediol (11.3 g, 108.3 mmol) in N, N-dimethylformamide (50 ml) was added sodium hydrogen (8.7 g, 216.5 mmol, 60%) in portions at 0 ℃ under nitrogen. After the reaction mixture was stirred at 0 ℃ for 0.5 hour, a solution of 2-chloro-5-cyanopyridine (5 g, 36.1 mmol) in N, N-dimethylformamide (20 ml) was added and the mixture was stirred at 0 ℃ for 2 hours. After quenching the reaction with water, extraction was performed with ethyl acetate (100 ml. times.3),the combined organic layers were dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography to give the title compound (4.7 g, yield 63%).1HNMR(400MHz,CDCl3)8.49(d,J＝2.0Hz,1H),7.78(dd,J＝2.3,8.5Hz,1H),6.81(d,J＝8.5Hz,1H),4.46-4.33(m,2H),3.79-3.61(m,2H),1.84(quin,J＝7.2Hz,2H),1.71-1.45(m,4H)。LCMS(ESI)m/z:207(M+1)。
Example 74D
5- ((5 (2H-tetrazol-5-yl) -2-pyridinyl) oxy) pent-1-ol
To N, N-dimethylformamide (20.00 ml) of example 74C (2.00 g, 9.70 mmol) was added sodium azide (1.89 g, 29.09 mmol) and ammonium chloride (1.56 g, 29.09 mmol). After stirring the mixture at 110 ℃ for 12 h, quench it with water, adjust the pH to 3 with dilute hydrochloric acid, extract it with ethyl acetate, dry the organic phase over anhydrous sodium sulfate, filter and evaporate to give the title compound (white solid, 2.3 g, yield 90%).1HNMR(400MHz,CDCl3)8.81(d,J＝2.3Hz,1H),8.27(dd,J＝2.4,8.7Hz,1H),6.99(d,J＝8.8Hz,1H),4.52-4.29(m,2H),3.68-3.50(m,2H),1.86(quin,J＝7.0Hz,2H),1.75-1.47(m,4H)。LCMS(ESI)m/z:250(M+1)。
Example 74E
5- ((5- (2-ethyltetrazol-5-yl) -2-pyridinyl) oxy) pent-1-ol
To a solution of example 74D (1 g, 4.01 mmol) and potassium carbonate (2.77 g, 20.05 mmol) in acetonitrile (15 ml) under nitrogenIodoethane (93 mg, 2.32 mmol) was added. Stirring was carried out at 25 ℃ for 4 hours. The reaction mixture was quenched with water (50 ml), extracted with ethyl acetate (30 ml × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spun dry, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (white solid, 700 mg, yield 60%).1HNMR(400MHz,CDCl3)8.93(d,J＝2.0Hz,1H),8.29(dd,J＝2.3,8.8Hz,1H),6.85(d,J＝8.5Hz,1H),4.72(q,J＝7.3Hz,2H),4.39(t,J＝6.7Hz,2H),3.81-3.62(m,2H),1.86(quin,J＝7.1Hz,2H),1.75-1.50(m,7H)。LCMS(ESI)m/z:278(M+1)。
Example 74F
5- ((5 (2-ethyltetrazol-5-yl) -2-pyridinyl) oxy) pentyl methanesulfonate
To a solution of example 74E (0.1 g, 0.36 mmol) and triethylamine (146 mg, 1.44 mmol) in tetrahydrofuran (8 ml) was added dropwise a solution of methanesulfonyl chloride (83 mg, 0.72 mmol) in tetrahydrofuran (1 ml) at 0 ℃ under nitrogen. Stirring was carried out at 0 ℃ for 2 hours. The reaction mixture was quenched with water (20 ml), extracted with ethyl acetate (20 ml × 3), the organic phases combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and dried by roto-drying to give the title compound (white solid, 120 mg, yield 92.7%).1HNMR(400MHz,CDCl3)8.93(d,J＝2.3Hz,1H),8.30(dd,J＝2.4,8.7Hz,1H),6.85(d,J＝8.8Hz,1H),4.72(q,J＝7.3Hz,2H),4.40(t,J＝6.5Hz,2H),4.33-4.23(m,2H),3.03(s,3H),1.98-1.67(m,9H)。LCMS(ESI)m/z:356(M+1)。
Example 74G
4- (5- (5- ((5- (2-ethyltetrazol-5-yl) -2-pyridyl) oxy) pentyl) -1, 1-dioxo-1, 2, 5-thiadiazolidin-2-yl) pyridin-2-amine
Example 73F (422 mg, 1.97 mmol) was added to a solution of example 74B (0.7 g, 1.97 mmol) and potassium carbonate (0.54 g, 3.94 mmol) in N, N-dimethylformamide (12 ml) under nitrogen. Stirring was carried out at 60 ℃ for 12 hours. The reaction mixture was quenched with water (50 ml), extracted with ethyl acetate (30 ml × 3), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spun dry, and the residue was purified by column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the title compound (white solid, 350 mg, yield 36%).1HNMR(400MHz,CDCl3)8.86(d,J＝2.0Hz,1H),8.32(dd,J＝2.3,8.8Hz,1H),7.80(d,J＝6.3Hz,1H),6.95(d,J＝8.8Hz,1H),6.52(dd,J＝2.0,6.0Hz,1H),6.31(d,J＝1.8Hz,1H),4.76(q,J＝7.3Hz,2H),4.41(t,J＝6.4Hz,2H),3.84(t,J＝6.4Hz,2H),3.56(t,J＝6.3Hz,2H),3.22-3.10(m,2H),1.97-1.76(m,4H),1.75-1.58(m,5H).。LCMS(ESI)m/z:474(M+1)。
Example 75
2- (2-aminopyridin-4-yl) -5- (5- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) -3, 3-dimethylpentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
Example 75A
3, 3-dimethylpentanediol
To a solution of lithium aluminum hydride (50 g, 1.32 mol) in tetrahydrofuran (1.3 l) was added dropwise 3, 3-dimethylglutaric acid (50 g, 312 mmol) in tetrahydrofuran (200 ml) at 80 ℃ and after completion of the addition, the mixed solution was stirred at 80 ℃ for 2 hours. Water (200 ml) was added to the reaction, the aqueous layer was extracted with ethyl acetate (300 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated to give the title compound (38 g, yield 92%).1HNMR(400MHz,CDCl3)3.67(t,J＝7.03Hz,4H)，3.50(br.s.,1H),1.50-1.61(m,4H),0.92(s,6H)。
Example 75B
6- ((5-hydroxy-3, 3-dimethylpentyl) oxy) nicotinonitrile
The preparation of this example is as in example 74C.1HNMR(400MHz,CDCl3)8.47(d,J＝2.0Hz,1H),7.76(dd,J＝8.5,2.3Hz,1H),6.78(d,J＝8.8Hz,1H),4.44(t,J＝7.4Hz,2H),3.75(t,J＝7.4Hz,2H),1.75(t,J＝7.4Hz,2H),1.61(t,J＝7.4Hz,2H),1.01(s,6H)。
Example 75C
5- ((5- (2H-tetrazol-5-yl) pyridin-2-yl) oxy) -3, 3-dimethylpentan-1-ol
The preparation of this example is as in example 74D.1HNMR(400MHz,CDCl3)8.81(d,J＝2.3Hz,1H),8.26(dd,J＝8.8,2.3Hz,1H),7.00(d,J＝8.8Hz,1H),4.39(t,J＝7.4Hz,2H),3.49(t,J＝7.4Hz,2H),1.68(t,J＝7.4Hz,2H),1.45(t,J＝7.4Hz,2H),0.92-0.97(m,6H)。
Example 75D
5- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) -3, 3-dimethylpentan-1-ol
The preparation of this example is as in example 74E.1HNMR(400MHz,CDCl3)8.92(d,J＝2.0Hz,1H),8.27(dd,J＝8.5,2.3Hz,1H),6.82(d,J＝8.8Hz,1H),4.70(q,J＝7.4Hz,2H),4.44(t,J＝7.4Hz,2H),3.77(t,J＝7.4Hz,2H),1.78(s,3H),1.64-1.71(m,4H),1.02(s,6H)。
Example 75E
5- (4- (2-Ethyl-2H-tetrazol-5-yl) phenoxy) -3, 3-dimethylpentyl methanesulfonate
The preparation of this example is as in example 74F.1HNMR(400MHz,CDCl3)8.92(d,J＝2.0Hz,1H),8.27(dd,J＝8.5,2.0Hz,1H),6.83(d,J＝9.0Hz,1H),4.66-4.73(m,2H),4.44(t,J＝7.0Hz,2H),4.37(t,J＝7.3Hz,2H),3.02(s,3H),1.80(dt,J＝14.2,7.2Hz,4H),1.69(t,J＝7.5Hz,3H),1.06(s,6H)。
Example 75F
2- (2-aminopyridin-4-yl) -5- (5- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) -3, 3-dimethylpentyl) -1,2, 5-thiadiazolidine-1, 1-dioxide
The preparation of this example is as in example 74G.1HNMR(400MHz,CDCl3)8.93(d,J＝2.0Hz,1H),8.28(dd,J＝8.8,2.3Hz,1H),7.97(d,J＝6.0Hz,1H),6.85(d,J＝8.5Hz,1H),6.43(dd,J＝5.8,2.3Hz,1H),6.30(d,J＝2.0Hz,1H),4.71(q,J＝7.4Hz,2H),4.58(br.s.,2H),4.45(t,J＝7.0Hz,2H),3.81(t,J＝6.5Hz,2H),3.50-3.56(m,2H),3.24(d,J＝8.5Hz,2H),1.81(t,J＝7.0Hz,2H),1.74(d,J＝8.5Hz,2H),1.67-1.71(m,3H),1.08(s,6H)。LCMS(ESI)m/z:501(M+1)。
Procedure V
Example 76
4- (5- (5- (4- (2-ethyltetrazol-5-yl) phenoxy) -3, 3-dimethyl-pentyl) -1, 1-dioxo-1, 2, 5-thiadiazol-2-yl) pyridin-2-amine
Example 76A
3, 3-dimethylpentyl-1, 5-di (4-methylbenzenesulfonic acid) ester
The preparation of this example is as in example 14A.1HNMR(400MHz,CDCl3)7.77(d,J＝8.53Hz,2H),7.35(d,J＝8.03Hz,2H),4.02(t,J＝7.03Hz,2H),2.45(s,3H),1.55(t,J＝7.03Hz,2H),0.84(s,3H)。
Example 76B
5- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) -3, 3-dimethylpentyl-4-methylbenzenesulfonate
To a solution of example 76A (6 g, 31.55 mmol), example 11A (2.6 g, 31.55 mmol) in acetone (100 ml) was added potassium carbonate (8.72 g, 63.29 mmol) and potassium iodide (5.24 g, 31.55 mmol). The mixed solution was stirred at 80 ℃ for 12 hours, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography after filtration and evaporation (petroleum ether: ethyl acetate ═ 10:1) to obtain the title compound (white solid, 8.0 g, yield 56%).1HNMR(400MHz,CDCl3)8.09(d,J＝8.5Hz,2H),7.00(d,J＝8.8Hz,2H),4.70(q,J＝7.3Hz,2H),4.38(t,J＝7.4Hz,2H),4.11(t,J＝6.8Hz,2H),3.0-3.04(m,3H),1.80-1.87(m,4H),1.70(t,J＝7.4Hz,3H),1.08(s,6H)。LCMS(ESI)m/z:459(M+1)。
Example 76C
5- (4- (2-ethyl-2H-tetrazol-5-yl) phenoxy) -3, 3-dimethylpentyl-1, 2, 5-thiadiazole-1, 1-dioxide
To a solution of example 76B (969 mg, 4.4 mmol) in N, N-dimethylformamide (5 ml) was added sodium hydride (41.9 mg, 1.7 mmol) at 0 ℃. After 30 minutes at 0 ℃, the N, N-dimethylformamide (1 mmol) of example 32B (400 mg, 0.87 mmol) was added to the above mixed solutionL) solution was stirred at 20 ℃ for 2 hours, potassium carbonate (0.24 mg, 1.7 mmol) was added to the reaction solution, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, evaporated and column separated (petroleum ether: ethyl acetate ═ 1:1) to give the title compound (yellow oil, 100 mg, yield 28%).1HNMR(400MHz,CDCl3)7.56(d,J＝8.5Hz,2H),6.92(d,J＝9.0Hz,2H),4.00(t,J＝6.5Hz,2H),3.66-3.72(m,2H),3.47-3.52(m,2H),3.46(s,6H),3.35-3.41(m,2H),3.04(t,J＝7.3Hz,2H),1.79-1.88(m,2H),1.66-1.74(m,2H),1.52-1.60(m,2H),1.23(t,J＝7.0Hz,3H)。LCMS(ESI)m/z:409(M+1)。
Example 76D
4- (5- (5- (4- (2-ethyltetrazol-5-yl) phenoxy) -3, 3-dimethyl-pentyl) -1, 1-dioxo-1, 2, 5-thiadiazol-2-yl) pyridin-2-amine
To a solution of example 76C (100 mg, 0.24 mmol) in N, N-dimethylformamide (2 ml) was added potassium carbonate (67 mg, 0.49 mmol), 2-amino 4-bromopyridine (85 mg, 0.489 mmol), 8-hydroxyquinoline (35 mg, 0.25 mmol), cuprous iodide (23 mg, 0.12 mmol) at 0 ℃. After nitrogen displacement, cyclohexane diamine (14 mg, 0.12 mmol) was added. After stirring the mixture at 110 ℃ for 15 hours, water was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound (white solid, 35 mg, yield 29%).1HNMR(400MHz,CDCl3)8.07(d,J＝8.5Hz,1H),7.98(d,J＝5.5Hz,1H),6.99(d,J＝8.5Hz,2H),6.42(d,J＝4.5Hz,1H),6.29(s,1H),4.69(q,J＝7.5Hz,2H),4.48(br.s.,2H),4.11(t,J＝6.5Hz,2H),3.79(t,J＝6.0Hz,2H),3.46-3.53(m,2H),3.16-3.25(m,2H),1.83(t,J＝6.5Hz,2H),1.68-1.76(m,5H),1.07(s,6H)。LCMS(ESI)m/z:501(M+1)。
Experimental example 1: EV71 in vitro cytopathic effect (CPE) assay
Purpose of the experiment:
the in vitro antiviral activity and cytotoxicity of the compound against hand-foot-mouth disease virus EV71 were examined by cytopathic effect (CPE) assay.
Experimental materials:
1. the virus strain Shenzhen/120F1/09
2. Cell line: human rhabdomyoma RD cells
3. Cell culture medium: DMEM Medium supplemented with 10% serum, Penicilin/Streptomyces and L-Glutamine (1 ×)
4. Detection reagent: cell activity detection reagent CCK8
The experimental method comprises the following steps:
1. cell inoculation: RD cells were digested from adherent state, diluted with medium at a density of 80000/ml, and seeded into 100ul to 96 well plate microwells.
2. Compound dilution:
the first step is as follows: dry powders of the test compounds were prepared as 10mM DMSO solutions. Compounds were then diluted 3-fold, 8 concentration points. The reference compound will be diluted in the same way.
The second step is that: DMSO dilutions of compounds were further diluted with cell culture medium. 10ul DMSO solution per well was added to 240ul medium.
3. Compound dilutions were added to cell-seeded 96-well plates in 50ul volumes per well, duplicate wells, with a final DMSO concentration of 1%.
4. Virus dilution: diluting EV71 virus solution by 10000 times, wherein the concentration is 100TCID5050 ul. Virus dilutions were added to 96-well plates at 50ul volumes per well. Another 96-well plate was prepared by replacing virus with medium, inoculated with cells, and added with compound for detectionThe compounds were tested for their toxic effects on cells.
5. The 96-well plates were incubated at 37 ℃ under 5% CO2 for 3 days.
EC50 and CC50 tests: the cell activity assay reagent CCK8 was added to the microwells at 20 ul/well. And reading the absorbance at the wavelength of 450nm and the wavelength of 630nm by using a microplate reader.
7. Analysis data were analyzed using prism5.0 and the antiviral activity EC50 value and cytotoxicity CC50 value of the compound were calculated.
The results are shown in Table 1:
TABLE 1EV71CPE detection EC50Test results
Note: a is less than or equal to 50 nM; b is more than 50nM and less than or equal to 100 nM; c is more than 100nM and less than or equal to 500 nM; d is more than 500nM and less than or equal to 1000 nM.
And (4) conclusion: the compound has obvious inhibition effect on EV71 virus at cellular level.

Claims (10)

1. A compound represented by the formula (II) or a pharmaceutically acceptable salt thereof,
wherein,
R3selected from the group consisting of01Substituted 5-membered heterocyclic ring, C6～12Aryl radical, C6～12Aralkyl radical, C5～12Heteroaromatic ring or C5～12A heteroaralkyl group;
L2are each independently selected from
m1、m2Each independently selected from 0, 1,2,3, 4,5 or 6;
X1、X2each independently selected from the group consisting of a single bond, -C (R)d1)(Rd2)-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7) -, -O-, -S-, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -, or-S (═ O)2-；
R4Selected from 5-14 membered cycloalkyl or heterocyclic alkyl;
Rd1、Rd2each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH2CHO, COOH, or selected from optionally substituted R01Substituted C1-10Alkyl or heteroalkyl, C3-10Cycloalkyl or heterocycloalkyl radical, or3-10Cycloalkyl-or heterocycloalkyl-substituted C1-10Alkyl or heteroalkyl;
R01selected from F, Cl, Br, I, CN, OH, SH, NH2、CHO、COOH、R02；
R02Is selected from C1-10Alkyl radical, C1-10Alkylamino, N-di (C)1-10Alkyl) amino, C1-10Alkoxy radical, C1-10Alkanoyl radical, C1-10Alkoxycarbonyl, C1-10Alkylsulfonyl radical, C1-10Alkylsulfinyl radical, C3-10Cycloalkyl radical, C3-10Cycloalkylamino radical, C3-10Heterocycloalkylamino, C3-10Cycloalkoxy, C3-10Cycloalkyl acyl, C3-10Cycloalkoxycarbonyl, C3-10Cycloalkylsulfonyl radical, C3-10A cycloalkylsulfinyl group;
"hetero" represents a heteroatom or a heteroatom group selected from-C (═ O) N (R)d3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7)-、-O-、-S-、＝O、＝S、-C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -, and/or-S (═ O)2-；
Rd3-d7Each independently selected from H, R03；
R03Is selected from C1-10Alkyl radical, C1-10Alkyl acyl radical, C1-10Alkoxycarbonyl, C1-10Alkylsulfonyl radical, C1-10Alkylsulfinyl radical, C3-10Cycloalkyl radical, C3-10Cycloalkyl acyl, C3-10Cycloalkoxycarbonyl, C3-10Cycloalkylsulfonyl radical, C3-10A cycloalkylsulfinyl group;
R02、R03optionally substituted by R001Substitution;
R001selected from F, Cl, Br, I, CN, OH, N (CH)3)2、NH(CH3)、NH2CHO, COOH, trifluoromethyl, aminomethyl, hydroxymethyl, methyl, methoxy, formyl, methoxycarbonyl, methanesulfonyl, methylsulfinyl;
R01、R001the number of heteroatoms or heteroatom groups is independently selected from 0, 1,2 or 3;
optionally, Rd1And Rd2Are linked to form a 3 or 4 membered carbocyclic or heterocyclic ring.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R3Selected from optionally substituted 5-to 6-membered aryl or heteroaryl;
preferably, R3Selected from the group consisting of01Substituted pyridyl, phenyl, furyl, pyrazolyl, pyrrolyl, thiazolyl, pyridazinyl, pyrimidinyl, thienyl, R01As defined in claim 1, R is01The number of (a) is selected from 0, 1,2 or 3;
preferably, R01Selected from F, Cl, Br, I, CN, OH, SH, NH2、CHO、COOH、Me、
3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R3Selected from:
4. a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein L2Is selected fromm3Is 0, 1 or 2, the other variables are as defined in claim 1; preferably, X1、X2Are respectively and independently selected from single bond, -O-, -C (═ O) -, -CH (CH)3)-、-C(CH3)2-、-CF2-、-CH(F)--CH(OH)、-CH2-、-NH-、-N(CH3)-；
More preferably, L2Selected from:
5. a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R4Is selected fromT4-7Each independently selected from N or C (R)t)，D1-3、D5、D6Each independently selected from the group consisting of a single bond, -C (R)d1)(Rd2)-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7) -, -O-, -S-, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -, or-S (═ O)2-，
n2Selected from 0, 1,2 or 3,
n3is selected from the group consisting of 0, 1 or 2,
R5、R6、R7、Rt、Rd1、Rd2each independently selected from H, F, Cl, Br, I, CN, OH, SH, NH2CHO, COOH, or selected from optionally substituted R01Substituted C1-10Alkyl or heteroalkyl, C3-10Cycloalkyl or heterocycloalkyl radical, or3-10Cycloalkyl-or heterocycloalkyl-substituted C1-10An alkyl group or a heteroalkyl group,
the other variables are as defined in claim 1.
6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein said R4Is selected fromX3Selected from F, Cl, Br, I, CN, OH, SH, NH2CHO, COOH, or selected from optionally substituted R01Substituted C1-10Alkyl or heteroalkyl, C3-10Cycloalkyl or heterocycloalkyl radical, or3-10Cycloalkyl-or heterocycloalkyl-substituted C1-10Alkyl or heteroalkyl.
7. A compound according to claim 5 or 6, or a pharmaceutically acceptable salt thereof, wherein said R5-7Are each independently selected fromR01、 Wherein:
T1-3each independently selected from N or C (R)t)；
D4Is selected from-C (R)d1)(Rd2)-、-C(＝O)N(Rd3)-、-N(Rd4)-、-C(＝NRd5)-、-S(＝O)2N(Rd6)-、-S(＝O)N(Rd7) -, -O-, -S-, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -, or-S (═ O)2-；R8、R9、RtEach independently selected from H, F, Cl, Br, I, CN, OH, SH, NH2CHO, COOH, or selected from optionally substituted R01Substituted C1-10Alkyl or heteroalkyl, C3-10Cycloalkyl or heterocycloalkyl radical, or3-10Cycloalkyl-or heterocycloalkyl-substituted C1-10Alkyl or heteroalkyl;
R10selected from F, Cl, Br, I, CN, OH, SH, NH2CHO, COOH, or selected from optionally substituted R01Substituted C1-10Alkyl or heteroalkyl, C3-10Cycloalkyl or heterocycloalkyl radical, or3-10Cycloalkyl-or heterocycloalkyl-substituted C1-10Alkyl or heteroalkyl.
8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, wherein:
R5-9、R01、Rtare each independently selected from F、Cl、Br、CF3、-C(C2H5)-、-C(OC2H5) -, methyl, ethyl, propyl, methoxyA group, an ethoxy group, a propoxy group,
9. A compound or pharmaceutically acceptable salt thereof according to claim 8, wherein R is4Selected from:
10. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from:
CN201410543064.6A 2014-04-28 2014-10-14 Enteric virus 71 (EV71)-resistant thiadiazolidine derivatives Pending CN105085512A (en)

Priority Applications (12)

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CN201410543064.6A CN105085512A (en) 2014-04-28 2014-10-14 Enteric virus 71 (EV71)-resistant thiadiazolidine derivatives
US15/307,710 US9988361B2 (en) 2014-04-28 2015-04-21 Anti-enterovirus 71 thiadiazolidine derivative
ES15786304T ES2841418T3 (en) 2014-04-28 2015-04-21 Thiadiazolidine derivative as anti-enterovirus 71
JP2016565011A JP6389531B2 (en) 2014-04-28 2015-04-21 Anti-enterovirus 71 thiadiazolidine derivative
MYPI2016703942A MY176508A (en) 2014-04-28 2015-04-21 Anti-enterovirus 71 thiadiazolidine derivative
KR1020187016595A KR101957178B1 (en) 2014-04-28 2015-04-21 Anti-enterovirus 71 thiadiazolidine derivative
SG11201608710TA SG11201608710TA (en) 2014-04-28 2015-04-21 Anti-enterovirus 71 thiadiazolidine derivative
KR1020167033211A KR20160147010A (en) 2014-04-28 2015-04-21 Anti-enterovirus 71 thiadiazolidine derivative
PCT/CN2015/077043 WO2015165340A1 (en) 2014-04-28 2015-04-21 Anti-enterovirus 71 thiadiazolidine derivative
DK15786304.4T DK3138840T3 (en) 2014-04-28 2015-04-21 THIADIAZOLIDINE DERIVATIVES AS AN ANTI-ENTEROVIRUS 71
EP15786304.4A EP3138840B1 (en) 2014-04-28 2015-04-21 Thiadiazolidine derivative as anti-enterovirus 71
TW104113441A TWI658037B (en) 2014-04-28 2015-04-27 Anti-enterovirus 71 thiadiazolidine derivatives

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Cited By (3)

* Cited by examiner, † Cited by third party
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WO2017071569A1 (en) * 2015-10-26 2017-05-04 江苏康缘药业股份有限公司 Salt form and crystal form of 1,2,5—thiadiazolidin-1,1-dioxide, preparation method thereof and intermediate
CN111883828A (en) * 2020-07-24 2020-11-03 香河昆仑化学制品有限公司 Non-aqueous electrolyte of lithium ion battery and lithium ion battery
CN114539020A (en) * 2022-01-17 2022-05-27 南京迈诺威医药科技有限公司 Preparation method of 1, 5-dibromo-3, 3-difluoropentane

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017071569A1 (en) * 2015-10-26 2017-05-04 江苏康缘药业股份有限公司 Salt form and crystal form of 1,2,5—thiadiazolidin-1,1-dioxide, preparation method thereof and intermediate
CN107406439A (en) * 2015-10-26 2017-11-28 江苏康缘药业股份有限公司 The salt form of the dioxide of 1,2,5 thiadiazolidine 1,1, crystal formation and preparation method thereof and intermediate
US10227339B2 (en) 2015-10-26 2019-03-12 Jiangsu Kanion pharmaceutical CO. LTD Salt form and crystal form of 1,2,5-thiadiazolidin-1,1-dioxide, preparation method thereof and intermediate
CN107406439B (en) * 2015-10-26 2020-06-16 江苏康缘药业股份有限公司 Salt form and crystal form of 1,2, 5-thiadiazolidine-1, 1-dioxide, preparation method and intermediate thereof
CN111883828A (en) * 2020-07-24 2020-11-03 香河昆仑化学制品有限公司 Non-aqueous electrolyte of lithium ion battery and lithium ion battery
CN111883828B (en) * 2020-07-24 2022-12-30 香河昆仑新能源材料股份有限公司 Non-aqueous electrolyte of lithium ion battery and lithium ion battery
CN114539020A (en) * 2022-01-17 2022-05-27 南京迈诺威医药科技有限公司 Preparation method of 1, 5-dibromo-3, 3-difluoropentane
CN114539020B (en) * 2022-01-17 2023-12-08 南京迈诺威医药科技有限公司 Preparation method of 1, 5-dibromo-3, 3-difluoropentane

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