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HK40007681B - Lsd1 inhibitor and preparation method and application thereof - Google Patents

Lsd1 inhibitor and preparation method and application thereof Download PDF

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Publication number
HK40007681B
HK40007681B HK19131105.9A HK19131105A HK40007681B HK 40007681 B HK40007681 B HK 40007681B HK 19131105 A HK19131105 A HK 19131105A HK 40007681 B HK40007681 B HK 40007681B
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compound
alkyl
pharmaceutically acceptable
calculated value
tautomer
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HK19131105.9A
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Chinese (zh)
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HK40007681A (en
Inventor
吴凌云
张丽
赵乐乐
孙建军
陈兆国
黎健
陈曙辉
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石药集团中奇制药技术（石家庄）有限公司
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Publication of HK40007681A publication Critical patent/HK40007681A/en
Publication of HK40007681B publication Critical patent/HK40007681B/en

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Description

LSD1 inhibitor and preparation method and application thereof
Cross Reference to Related Applications
The present application claims the priority of chinese patent application CN201710060400.5 filed 24.1/24/2017, chinese patent application CN201710736745.8 filed 24/8/2017 and chinese patent application CN201711460525.3 filed 28/12/2017, the contents of which are incorporated herein by reference.
Technical Field
The invention relates to cyclopropylamine compounds serving as lysine specific demethylase 1 (LSD 1) inhibitors and application of the cyclopropylamine compounds in preparation of medicines for treating LSD 1-related diseases. In particular to a compound shown as a formula (I) and pharmaceutically acceptable salts thereof.
Background
Epigenetics regulates gene expression through different mechanisms, including covalent modifications to histones, such as methylation or demethylation; covalent modification of DNA, such as methylation or hydroxymethylation; and recombination of nuclear chromatin [ Xueshun Wang, boshi Huang, takayoshi Suzuki et al, epigenomics,2015,1379-1396; ]. Although these modifications do not alter the underlying sequence of DNA, such epigenetic changes may persist throughout the cell life cycle or through cell iterative processes through cell division [ Adrian Bird, nature,2007,396-398]. Epigenetic dysfunction can therefore trigger and participate in a variety of disease pathological processes [ James T Lynch, william J Harris & Tim C P someverile, expert opin. The targets,2012,1239-1249], such as various solid tumors, hematological tumors, viral infections, neurological disorders, and the like. Therefore, epigenetics is now a research hotspot in the field of drug development. Lysine-specific demethylase (LSD 1, also known as KDM 1A) is the first demethylase discovered in 2004 and belongs to the family of Flavin Adenine Dinucleotide (FAD) -dependent amino oxidases. [ Yujiang Shi, fei Lan, caitinin Matson et al, cell,2004,941-953] [ Daniel P.Mould, alison E.McGonagle, daniel H.Wiseman et al, medicinal Research Reviews,2015,586-618]. The LSD1 structure includes three main parts: the N-terminal SWIRM domain, the C-terminal aminooxidase domain (AOL), and the central prominent Tower domain. [ Ruchi Anand, ronen Marmorstein, the Journal of Biological Chemistry,2007,35425-35429]. The C-terminal amino oxidase domain contains two active pockets, one is the FDA binding site and the other is the site for recognition and binding to the substrate [ Pete Stavropoulos, hunter Blobel, andre Hoelz, nature Structral & Molecular Biology,2006,626-632]. The function of the SWIRM domain has not been clearly concluded, it is not directly involved in FAD or substrate binding, but mutation or removal of this region reduces LSD1 activity, and therefore it is speculated that this region may affect the action of the active region by modulating conformation. [ Yong Chen, yuting Yang, feng Wang et al, biochemistry,2006,13956-13961]. The Tower domain is the binding domain of LSD1 to other protein factors. After being combined with different protein factors, the LSD1 acts on different substrates, thereby playing different regulation and control roles on histone and gene expression. For example, after LSD1 is combined with CoREST, the binding agent can act on histone H3K4 preferentially, and remove and activate related histone marks through demethylation to inhibit gene transcription; upon binding to androgen receptor proteins, recombinant LSD1 preferentially acts on H3K9, activating androgen receptor-associated gene transcription by demethylation [ Ruchi Anand, ronen Marmorstein, the Journal of Biological Chemistry,2007,35425-35429; tamara Maes, cristina Mascar Rou 1, alberto Ortega et al, epigenomics,2015,609-626; eric Metzger, melanie Wissmann, na Yin et al, nature,2005,436-439. In addition, LSD1 has several non-histone receptors, such as p53, E2F1, DNMT1 and MYPT1, among others [ Yi Chao Zheng, jinlian Ma, zhiru Wang, medicinal Research Reviews,2015,1032-1071].
LSD1 is a FAD-dependent aminooxidase, of which proton transfer is considered to be the most likely oxidation mechanism [ Daniel P.Mould, alison E.McGonagle, daniel H.Wiseman et al, medicinal Research Reviews,2015,586-618]. Firstly, the N-CH of the substrate is transferred by proton 3 The bond is converted to an imine bond, and this imine ion intermediate undergoes a hydrolysis reaction to form on the one hand a demethylated amine and on the other hand formaldehyde. During this catalytic cycle FAD is reduced to FADH2, which is subsequently oxidized back to FAD by a molecule of oxygen, producing a molecule of H2O2[ Yujiang Shi, fei Lan, caitlin Matson, cell,2004,941-953]。
LSD1 is an indispensable regulator in epigenetics that modifies histones by demethylation, and is therefore also referred to as an in vivo "eraser" enzyme. LSD1 can regulate gene expression and thus cell proliferation and differentiation.
In recent years, a large array of structurally diverse compounds have been developed as LSD1 selective inhibitors, as well as LSD1 and MAO-B dual inhibitors. Of these, 2 have entered the clinical trial phase in humans, however, in the face of a huge unmet market, there is still a need in the art for candidate compounds with better activity and better pharmacokinetic parameters to be advanced to clinical trials to meet the therapeutic needs.
HCI-2509 has the following structure:
disclosure of Invention
The invention provides a compound shown as a formula (I), pharmaceutically acceptable salts and tautomers thereof,
wherein the content of the first and second substances,
f is 1 or 2;
r is 0, 1 or 2;
e is 0, 1 or 2;
p is 0 or 1;
m is 0, 1 or 2;
n is 1 or 2;
R 1 、R 2 each independently selected from H, F, cl, br, I, OH, CN, NH 2 -COOH, or selected from C optionally substituted with 1, 2 or 3R 1-3 An alkyl group;
or R 1 And R 2 Joined together to form a 3-to 6-membered ring;
R 3 selected from H, F, cl, br, I, OH, CN, NH 2 、-COOH、-CONH 2 、-L-R 5 Or is selected from C optionally substituted by 1, 2 or 3R 1-6 Alkyl, phenyl, 5-to 12-membered heteroaryl, C 3-7 Cycloalkyl and 4-to 8-membered heterocycloalkyl;
R 4 selected from H, or selected from C optionally substituted with 1, 2 or 3R 1-6 Alkyl radical, C 1-6 A heteroalkyl group;
R 5 selected from phenyl optionally substituted by 1, 2 or 3R, 5-to 10-membered heteroaryl, C 3-10 Cycloalkyl, 4-to 10-membered heterocycloalkyl, 5-to 6-membered heterocycloalkyl-C (= O) -and 5-to 6-membered heterocycloalkyl-C 1-3 Alkyl-;
R 6 selected from H, or selected from C optionally substituted with 1, 2 or 3R 1-6 Alkyl and C 1-6 A heteroalkyl group;
l is selected from-C (= O) -, or from: -C 1-6 Alkyl-, -5-to 9-membered heteroaryl-, -4-to 8-membered heterocycloalkyl-, -phenyl-and-C 3-6 Cycloalkyl-;
r is selected from H, F, cl, br, I, OH and NH 2 、CN、COOH、NH 2 -C (= O) -, or selected from C optionally substituted with 1, 2 or 3R 1-6 Alkyl radical, C 1-6 Heteroalkyl, phenyl-C 1-6 Alkyl-, phenyl, 5-to 6-membered heteroaryl, phenyl-C (= O) -, C 3-6 cycloalkyl-C (= O) -, C 3-6 cycloalkyl-C (= O) -NH, C 3-6 cycloalkyl-NH-C (= O) -and C 3-6 cycloalkyl-C 1-3 Alkyl- -;
r' is selected from: F. cl, br, I, OH, NH 2 、COOH、C 1-3 Alkyl, C substituted by 1 to 3 halogens 1-3 Alkyl radical, C 1-3 alkyl-NH-, N-di (C) 1-3 Alkyl) -amino, C 1-3 alkyl-O-C (= O) -, C 3-6 Cycloalkyl and C 1-3 An alkoxy group;
the 5-to 12-membered heteroaryl group, the 4-to 8-membered heterocycloalkyl group, C 1-6 The "hetero" of heteroalkyl, 5-to 10-membered heteroaryl, 5-to 6-membered heterocycloalkyl, 4-to 10-membered heterocycloalkyl is independently selected from: -NH-, -S-, N, -O-, = O, -C (= O) -, -NH-C (= O) -, -O-C (= O) -, -S (= O) 2 -、-S(＝O)-、-C(＝O)-NH-；
In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1, 2, 3, or 4, respectively.
In some embodiments of the present invention, R' is selected from F, cl, br, I, OH, NH 2 、Me、Et、CF 3 、CHF 2 、CH 2 F、NHCH 3 、N(CH 3 ) 2 、COOH、-C(＝O)-O-CH 3 、-O-CH 3 Andother variables are as defined herein.
In some embodiments of the present invention, R is selected from H, F, cl, br, I, OH, NH 2 、CN、COOH、NH 2 -C (= O) -, or selected from methyl, ethyl, propyl, isobutyl, tert-butyl, C optionally substituted with 1, 2 or 3R 1-6 Alkoxy, phenyl-C 1-3 Alkyl-, phenyl, pyridyl, 1,2, 4-triazolyl, phenyl-C (= O) -, C 1-3 alkyl-C (= O) -, C 1-3 alkyl-NH-, cyclopropanyl-C (= O) -, C 1-3 alkyl-O-C (= O) -C 1-3 Alkyl-, C 1-3 alkyl-O-C (= O) -, C 1-3 alkyl-S (= O) 2 -, cyclopropylalkyl-C (= O) -NH-, cyclopropylalkyl-NH-C (= O) -, C 1-3 alkyl-NH-C (= O) -, cyclobutyloxy-CH 2 -and C 1-3 alkyl-C (= O) -NH-, the other variables are as defined herein.
In some embodiments of the present invention, R is selected from H, F, cl, br, I, OH, NH 2 、CN、COOH、NH 2 -C (= O) -, or selected from Me, et, optionally substituted with 1,2 or 3ROther variables are as defined herein.
In some embodiments of the present invention, R is selected from H, F, cl, br, I, OH, NH 2 、Me、Et、-CF 3 、CN、COOH、The other variables are as defined herein.
In some embodiments of the invention, R is as defined above 1 、R 2 Each independently selected from H, F, cl, br, I, OH, CN, NH 2 COOH, -Me and Et, the other variables being as defined in the invention.
In some embodiments of the invention, L is selected from-C (= O) -, or-C optionally substituted with 1,2, or 3R 1-3 Alkyl-, -phenyl-, -5-to 6-membered heteroaryl-, -5-to 6-membered heterocycloalkyl-and-C 3-6 Cycloalkyl-, the other variables are as defined herein.
In some embodiments of the invention, L as described above is selected from-C (= O) -, or-1, 2, 4-oxadiazolyl-, -methyl-, -ethyl-, -1,3, 4-oxadiazolyl-, -isoxazolyl-, -oxazolyl-, -piperidinyl-, -1,2, 3-triazolyl-, -cyclopropylalkyl-, and-phenyl-optionally substituted with 1,2, or 3R, with the other variables being as defined herein.
In some embodiments of the invention, L is selected from-C (= O) -, or optionally substituted with 1,2 or 3RThe other variables are as defined herein.
In some embodiments of the invention, L is selected from:the other variables are as defined herein.
In some embodiments of the invention, R is as defined above 5 Selected from phenyl, pyridyl, piperidinyl, pyrrolidinyl, azetidinyl, cyclohexyl, cyclobutyl, benzo [ d ] optionally substituted by 1,2 or 3R][1,3]Dioxolyl, piperidinyl-2-keto, 7-azaspiro [3.5 ]]Nonyl, cyclohexyl-CH 2 -, 3a, 7a-dihydro-1H-indolyl, pyrazolyl, pyridinyl, 3a, 7a-dihydrobenzo [ d ] or]Thiazolyl, pyrimidinyl, cyclopentylalkyl, spiro [3.3 ]]Heptylalkyl, bicyclo [2.2.2]Octyl radical, octahydrocyclopenta [ c ]]Pyrrolyl, 2-azaspiro [3.5 ]]Nonanyl, piperidinyl-C (= O) -, 4,5,6, 7-tetrahydro-1H-benzo [ d ] ]Imidazolyl, 5,6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridyl, piperidyl-CH 2 -, bicyclo [1.1.1]Pentyl and piperazinyl, the other variables being as defined herein.
In some embodiments of the present invention, R is 5 Selected from optionally substituted by 1,2 or 3ROther variables are as defined herein.
In some embodiments of the invention, R is as defined above 5 Is selected from
Other variables are as defined herein.
In some embodiments of the present invention, the above-mentioned-L-R 5 Selected from optionally substituted with 1,2 or 3R:other variables are as defined herein.
In some embodiments of the invention, the above-mentioned-L-R 5 Selected from:
the other variables are as defined herein.
In some embodiments of the invention, R is as defined above 3 Selected from H, F, cl, br, I, OH, CN, NH 2 、-COOH、-CONH 2 、-L-R 5 Or is selected from C optionally substituted by 1,2 or 3R 1-3 Alkyl, phenyl, pyrrolidinyl, 1H-imidazolyl, 1H-1,2, 4-triazolyl, pyridyl, thiazolyl, thienyl, pyrrolyl, 2H-tetrazolyl, 6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazolyl, imidazo [1,5-a ]]Pyridyl, oxazolyl, benzo [ d ]]Isoxazolyl, benzo [ d ]]Oxazolyl, 1,2,3,4-4H-2, 7-naphthyridinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2,3,4, 5-tetrahydro-1H-benzo [ d]Azepine group, azetidinyl group, isoindolinyl group, piperidyl group, 2,3,4, 5-tetrahydro-1H-benzo [ b ] ]Azepine radical, 2, 3-dihydro-1H-pyrrolo [3,4-c]Pyridyl, benzisoxazolyl, 5,6,7, 8-tetrahydropyridopyrimidinyl, 3a, 7a-dihydrobenzo [ d]Thiazolyl, 2,4,5, 6-tetrahydropyrrolo [3,4-c ]]Pyrazolyl, 1,4,5, 6-tetrahydropyrrolo [3,4-c ]]Pyrazolyl, piperazinyl, morpholinyl, octahydropyrrolo [3, 4-c)]Pyrrolyl, 1, 4-diazepinyl, cyclohexyl and 1,2, 4-oxadiazolyl, the other variables being as defined herein.
In some embodiments of the invention, R is as defined above 3 Selected from H, F, cl, br, I, OH, CN, NH 2 、-COOH、-CONH 2 、-L-R 5 Or selected from Me, et, optionally substituted by 1,2 or 3R,The other variables are as defined herein.
In some embodiments of the invention, R is as defined above 3 Selected from H, F, cl, br, I, OH, CN, NH 2 、-COOH、Me、Et、
Other variables are as defined herein.
In some embodiments of the invention, R is as defined above 4 Selected from H, or selected from C optionally substituted with 1,2 or 3R 1-3 Alkyl and C 1-4 alkyl-O-C (= O) -, the other variables being as defined herein.
In some embodiments of the present invention, R is 4 Selected from H, me, et andthe other variables are as defined herein.
In some embodiments of the invention, R is as defined above 6 Selected from H, or from optionally substituted by 1,2 or 3RGeneration C 1-3 Alkyl and C 1-4 alkyl-O-C (= O) -, the other variables being as defined herein.
In some embodiments of the present invention, R is 6 Selected from H, me, et andother variables are as defined herein.
In some embodiments of the invention, the structural unitIs selected fromOther variables are as defined herein.
In some embodiments of the invention, the structural unitIs selected fromOther variables are as defined herein.
Still other embodiments of the present invention are derived from any combination of the above variables.
In some embodiments of the invention, the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
wherein the content of the first and second substances,
e、f、m、n、R 5 r is as defined herein;
q 1 、q 2 each independently selected from: 1 or 2.
The invention also provides a compound shown as a formula (I), pharmaceutically acceptable salts and tautomers thereof,
wherein the content of the first and second substances,
f is selected from: 1 or 2;
r is selected from: 0. 1 or 2;
e is selected from: 0. 1 or 2;
p is selected from: 0 or 1;
m is selected from: 0. 1 or 2;
n is selected from: 1 or 2;
R 1 、R 2 each independently selected from H, F, cl, br, I, OH, CN, NH 2 -COOH, or selected from optionally substituted with 1, 2 or 3R: c 1-3 An alkyl group;
or R 1 And R 2 Joined together to form a 3-6 membered ring;
R 3 selected from H, F, cl, br, I, OH, CN, NH 2 、-COOH、-CONH 2 、-L-R 5 Or is selected from optionally substituted with 1, 2 or 3R: c 1-6 Alkyl, phenyl, 5-to 12-membered heteroaryl, C 3-7 Cycloalkyl, 4-to 8-membered heterocycloalkyl;
R 4 selected from the group consisting of: h, or selected from optionally substituted with 1, 2 or 3R: c 1-6 Alkyl radical, C 1-6 A heteroalkyl group;
R 5 selected from optionally substituted with 1, 2 or 3R: phenyl, 5-to 10-membered heteroaryl, C 3-10 Cycloalkyl, 4-to 10-membered heterocycloalkyl, phenyl, 5-to 6-membered heterocycloalkyl-C (= O) -, 5-to 6-membered heterocycloalkyl-C 1-3 Alkyl-;
R 6 selected from the group consisting of: h, or selected from optionally substituted with 1, 2 or 3R: c 1-6 Alkyl radical, C 1-6 A heteroalkyl group;
l is selected from-C (= O) -, or is optionally substituted with 1, 2 or 3RThe following steps: -C 1-6 Alkyl-, -5-to 9-membered heteroaryl-, -4-to 8-membered heterocycloalkyl-, -phenyl-, -3-to 6-membered cycloalkyl-;
r is selected from H, F, cl, br, I, OH and NH 2 CN, COOH, or selected from optionally substituted with 1, 2 or 3R': c 1-6 Alkyl radical, C 1-6 Heteroalkyl, phenyl-C 1-6 Alkyl-, phenyl, 5-to 6-membered heteroaryl, phenyl-C (= O) -, C 3-6 cycloalkyl-C (= O) -, C 3-6 cycloalkyl-C (= O) -NH-;
r' is selected from: F. cl, br, I, OH, NH 2 、COOH、C 1-3 Alkyl, C substituted by 1 to 3 halogens 1-3 Alkyl radical, C 1-3 alkyl-NH-, N-di (C) 1-3 Alkyl) -amino, C 1-3 alkyl-O-C (= O) -or C 3-6 A cycloalkyl group;
The 5-to 12-membered heteroaryl, the 4-to 8-membered heterocycloalkyl, C 1-6 The "hetero" of heteroalkyl, 5-to 10-membered heteroaryl, 5-to 6-membered heterocycloalkyl, 4-to 10-membered heterocycloalkyl is independently selected from: -NH-, -S-, N, -O-, = O, -C (= O) -, -NH-C (= O) -, -O-C (= O) -, -S (= O) 2 -、-S(＝O)-；
In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1,2, 3, or 4, respectively.
In some embodiments of the invention, R' is selected from: F. cl, br, I, OH, me, et, CF 3 、CHF 2 、CH 2 F、NHCH 3 、N(CH 3 ) 2 、COOH、-C(＝O)-O-CH 3 、The other variables are as defined herein.
In some embodiments of the present invention, R is selected from H, F, cl, br, I, OH, NH 2 CN, COOH, or selected from optionally substituted with 1,2 or 3R': methyl, ethyl, propyl, isobutyl, tert-butyl, C 1-6 Alkoxy, phenyl-C 1-3 Alkyl-, phenyl, pyridyl, 1,2, 4-triazolyl, phenyl-C (= O) -, C 1-3 alkyl-C (= O) -, C 1-3 alkyl-NH-, cyclopropanyl-C (= O) -, C 1-3 alkyl-O-C (= O) -C 1-3 Alkyl-, C 1-3 alkyl-O-C (= O) -, C 1-3 alkyl-S (= O) 2 -, cyclopropane-C (= O) -NH-, the other variables are as defined herein.
In some embodiments of the present invention, R is selected from H, F, cl, br, I, OH, NH 2 CN, COOH, or selected from optionally substituted with 1,2 or 3R': me, et,
Other variables are as defined herein.
In some embodiments of the invention, R is selected from: H. f, cl, br, I, OH, NH 2 、Me、Et、-CF 3 、CN、COOH、The other variables are as defined herein.
In some embodiments of the present invention, R is 1 、R 2 Each independently selected from: H. f, cl, br, I, OH, CN, NH 2 -COOH, me, et, other variables as defined herein.
In some embodiments of the invention, L is selected from-C (= O) -, or optionally substituted with 1,2 or 3R: c 1-3 Alkyl, phenyl, 5-to 6-membered heteroaryl, 5-to 6-membered heterocycloalkyl, 3-to 6-membered cycloalkyl, the other variables being as defined herein.
In some embodiments of the invention, L is selected from-C (= O) -, or optionally substituted with 1,2 or 3R: 1,2, 4-oxadiazolyl, methyl, ethyl, 1,3, 4-oxadiazolyl, isoxazolyl, oxazolyl, piperidinyl, 1,2, 3-triazolyl, cyclopropylalkyl, phenyl, the other variables being as defined herein.
In some embodiments of the invention, L is selected from-C (= O) -, or optionally substituted with 1,2 or 3R:
in some embodiments of the present invention, L is selected from:other variables are as defined herein.
In some embodiments of the invention, R is as defined above 5 Selected from optionally substituted with 1,2 or 3R: phenyl, pyridyl, piperidyl, pyrrolidinyl, azetidinyl, cyclohexyl, cyclobutyl, benzo [ d ] or a salt thereof][1,3]Dioxolyl, piperidinyl-2-keto, 7-azaspiro [3.5 ]]Nonyl, cyclohexyl-CH 2 -, 3a, 7a-dihydro-1H-indolyl, pyrazolyl, pyridinyl, 3a, 7a-dihydrobenzo [ d ] or]Thiazolyl, pyrimidinyl, cyclopentylalkyl, spiro [3.3 ]]Heptylalkyl, bicyclo [2.2.2]Octyl radical, octahydrocyclopenta [ c ]]Pyrrolyl, 2-azaspiro [3.5 ]]Nonanyl, piperidinyl-C (= O) -, 4,5,6, 7-tetrahydro-1H-benzo [ d ]]Imidazolyl, 5,6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridyl, piperidyl-CH 2 -, bicyclo [1.1.1]Pentyl, other variables are as defined herein.
In some embodiments of the present invention, R is 5 Selected from the group consisting of optionally substituted with 1,2 or 3R:other variables are as defined herein.
In some embodiments of the present invention, R is 5 Selected from:other variables are as defined herein.
In some embodiments of the invention, the above-mentioned-L-R 5 Selected from optionally substituted with 1,2 or 3R:other variables are as defined herein.
In some embodiments of the present invention, the above-mentioned-L-R 5 Selected from:
other variables are as defined herein.
In some embodiments of the present invention, R is 3 Selected from H, F, cl, br, I, OH, CN, NH 2 、-COOH、-CONH 2 、-L-R 5 Or selected from optionally substituted with 1,2 or 3R: c 1-3 Alkyl, phenyl, pyrrolidinyl, 1H-imidazolyl, 1H-1,2, 4-triazolyl, pyridyl, thiazolyl, thienyl, pyrrolyl, 2H-tetrazolyl, 6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazolyl, imidazo [1,5-a ]]Pyridyl, oxazolyl, benzo [ d ]]Isoxazolyl, benzo [ d ]]Oxazolyl, 1,2,3,4-4H-2, 7-naphthyridinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2,3,4, 5-tetrahydro-1H-benzo [ d]Azepinyl, azetidinyl, isoindolinyl, piperidinyl, 2,3,4,5-tetrahydro-1H-benzo [ b]Azepine radical, 2, 3-dihydro-1H-pyrrolo [3,4-c]Pyridyl, benzisoxazolyl, 5,6,7, 8-tetrahydropyridopyrimidinyl, 3a, 7a-dihydrobenzo [ d]Thiazolyl, 2,4,5, 6-tetrahydropyrrolo [3,4-c ]]Pyrazolyl, 1,4,5, 6-tetrahydropyrrolo [3,4-c ]]Pyrazolyl, piperazinyl, morpholinyl, octahydropyrrolo [3,4-c ] o]Pyrrolyl, 1, 4-diazepinyl, cyclohexyl, 1,2, 4-oxadiazolyl, the other variables being as defined herein.
In some embodiments of the invention, R is as defined above 3 Selected from H, F, cl, br, I, OH, CN, NH 2 、-COOH、-CONH 2 、-L-R 5 Or selected from optionally substituted with 1, 2 or 3R: me, et,Other variables are as defined herein.
The inventionIn some embodiments of the above, R 3 Selected from the group consisting of: H. f, cl, br, I, OH, CN, NH 2 、-COOH、Me、Et、
Other variables are as defined herein.
In some embodiments of the invention, R is as defined above 4 Selected from H, or selected from optionally substituted with 1, 2 or 3R: c 1-3 Alkyl radical, C 1-4 alkyl-O-C (= O) -, the other variables being as defined herein.
In some embodiments of the invention, R is as defined above 4 Selected from: H. me, et,Other variables are as defined herein.
In some embodiments of the invention, R is as defined above 6 Selected from H, or selected from optionally substituted with 1, 2 or 3R: c 1-3 Alkyl radical, C 1-4 alkyl-O-C (= O) -, the other variables being as defined herein.
In some embodiments of the present invention, R is 6 Selected from: H. me, et,The other variables are as defined herein.
In some embodiments of the present invention, the structural unitSelected from the group consisting of:other variables are as defined herein.
In some embodiments of the invention, the structural unitSelected from the group consisting of:the other variables are as defined herein.
In some embodiments of the invention, the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
Wherein the content of the first and second substances,
e、f、m、n、R 5 r is as defined herein;
q 1 、q 2 each independently selected from: 1 or 2.
The invention also provides a compound shown as a formula (I), pharmaceutically acceptable salts and tautomers thereof,
wherein the content of the first and second substances,
f is selected from: 1 or 2;
r is selected from: 0. 1 or 2;
e is selected from: 0. 1 or 2;
p is selected from: 0 or 1;
m is selected from: 0. 1 or 2;
n is selected from: 1 or 2;
R 1 、R 2 each independently selected from H, F, cl, br, I, OH, CN, NH 2 -COOH, or selected from optionally substituted with 1, 2 or 3R: c 1-3 An alkyl group;
or R 1 And R 2 Joined together to form a 3-to 6-membered ring;
R 3 selected from H, F, cl, br, I, OH, CN, NH 2 、-COOH、-CONH 2 、-L-R 5 Or is selected from optionally substituted with 1, 2 or 3R: c 1-6 Alkyl, phenyl, 5-to 12-membered heteroaryl, C 3-7 Cycloalkyl, 4-to 8-membered heterocycloalkyl;
R 4 selected from: h, or selected from optionally substituted with 1, 2 or 3R: c 1-6 Alkyl radical, C 1-6 A heteroalkyl group;
R 5 selected from optionally substituted with 1, 2 or 3R: phenyl, 5-to 9-membered heteroaryl, C 3-7 Cycloalkyl, 4-to 8-membered heterocycloalkyl;
R 6 selected from the group consisting of: h, or selected from optionally substituted with 1, 2 or 3R: c 1-6 Alkyl radical, C 1-6 A heteroalkyl group;
l is selected from optionally substituted with 1, 2 or 3R: c 1-6 Alkyl, 5-to 9-membered heteroaryl, 4-to 8-membered heterocycloalkyl;
r is selected from H, F, cl, br, I, OH and NH 2 CN, COOH, or selected from optionally substituted with 1, 2 or 3R': c 1-6 Alkyl radical, C 1-6 Heteroalkyl, phenyl-C 1-6 Alkyl-;
r' is selected from: F. cl, br, I, OH, NH 2 、Me、Et、CF 3 、CHF 2 、CH 2 F、NHCH 3 、N(CH 3 ) 2 、COOH；
The 5-to 12-membered heteroaryl, the 4-to 8-membered heterocycloalkyl, C 1-6 The "hetero" of heteroalkyl, 5-to 9-membered heteroaryl are each independently selected from: -NH-, -S-, N, -O-, = O;
in any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1, 2, 3 or 4, respectively.
In some embodiments of the present invention, R is selected from H, F, cl, br, I, OH, NH 2 CN, COOH, or selected from optionally substituted with 1, 2 or 3R': methyl, ethyl, propyl, isobutyl, C 1-6 Alkoxy, phenyl-C 1-3 Alkyl-, the other variables are as defined herein.
In some embodiments of the invention, R is selected from: H. f, cl, br, I, OH, NH 2 、Me、Et、-CF 3 、CN、COOH、The other variables are as defined herein.
In some embodiments of the invention, R is as defined above 1 、R 2 Each independently selected from: H. f, cl, br, I, OH, CN, NH 2 -COOH, me, et, other variables as defined herein.
In some embodiments of the invention, L is selected from optionally substituted with 1, 2 or 3R: c 1-3 Alkyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, the other variables are as defined herein.
In some embodiments of the invention, L is selected from optionally substituted with 1,2 or 3R: 1,2, 4-oxadiazolyl, methyl, ethyl, 1,3, 4-oxadiazolyl, isoxazolyl, oxazolyl, piperidinyl, and other variables are as defined herein.
In some embodiments of the invention, L is selected from optionally substituted with 1,2 or 3R:the other variables are as defined herein.
In some embodiments of the invention, L is selected from:other variables are as defined herein.
In some embodiments of the invention, R is as defined above 5 Selected from optionally substituted with 1,2 or 3R: phenyl, pyridyl, piperidinyl, pyrrolidinyl, azetidinyl, cyclohexyl, cyclobutyl, and other variables are as defined herein.
In some embodiments of the invention, R is as defined above 5 Selected from optionally substituted with 1,2 or 3R:other variables are as defined herein.
In some embodiments of the invention, R is as defined above 5 Selected from:other variables are as defined herein.
In some embodiments of the present invention, the above-mentioned-L-R 5 Selected from optionally substituted with 1,2 or 3R:other variables are as defined herein.
In some embodiments of the present invention, the above-mentioned-L-R 5 Selected from:other variables are as defined herein.
In some embodiments of the invention, R is as defined above 3 Selected from H, F, cl, br, I, OH, CN, NH 2 、-COOH、-CONH 2 、-L-R 5 Or selected from optionally substituted with 1,2 or 3R: c 1-3 Alkyl, phenyl, pyrrolidinyl, 1H-imidazolyl, 1H-1,2, 4-triazolyl, pyridyl, thiazolyl, thienyl, pyrrolyl, 2H-tetrazolyl, 6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazolyl, imidazo [1,5-a ]]Pyridyl, oxazolyl, benzo [ d ]]Isoxazolyl, benzo [ d ]]Oxazolyl, 1,2,3,4-4H-2, 7-naphthyridinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2,3,4, 5-tetrahydro-1H-benzo [ d]Azepine group, azetidinyl group, isoindolinyl group, piperidyl group, 2,3,4, 5-tetrahydro-1H-benzo [ b ]]Azepine radical, 2, 3-dihydro-1H-pyrrolo [3,4-c]Pyridyl, benzisoxazolyl, 5,6,7, 8-tetrahydropyridopyrimidinyl, and other variables are as defined herein.
In some embodiments of the invention, R is as defined above 3 Selected from H, F, cl, br, I, OH, CN, NH 2 、-COOH、-CONH 2 、-L-R 5 Or selected from optionally substituted with 1,2 or 3R: me, et,Other variables are as defined herein.
In some embodiments of the invention, R is as defined above 3 Selected from: H. f, cl, br, I, OH, CN, NH 2 、-COOH、Me、Et、
The other variables are as defined herein.
In some embodiments of the present invention, R is 4 Selected from H, or selected from optionally substituted with 1, 2 or 3R: c 1-3 Alkyl radical, C 1-4 alkyl-O-C (= O) -, the other variables being as defined herein.
In some embodiments of the invention, R is as defined above 4 Are respectively selected from: H. me, et,Other variables are as defined herein.
In some embodiments of the present invention, R is 6 Selected from H, or selected from optionally substituted with 1, 2 or 3R: c 1-3 Alkyl radical, C 1-4 alkyl-O-C (= O) -, the other variables are as defined herein.
In some embodiments of the present invention, R is 6 Are respectively selected from: H. me, et,Other variables are as defined herein.
In some embodiments of the invention, the structural unitSelected from:the other variables are as defined herein.
In some embodiments of the invention, the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
wherein e, f, m, n, R 5 R is as defined in the claims; q1, q 2 Each independently selected from: 1 or 2.
The present invention also provides compounds of the formula, pharmaceutically acceptable salts thereof, and tautomers thereof, selected from the group consisting of:
the invention also provides a composition which comprises the compound or the pharmaceutically acceptable salt thereof used as an active ingredient with a therapeutically effective amount and a pharmaceutically acceptable carrier.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or a composition containing the compound or the pharmaceutically acceptable salt thereof in preparing a medicament for treating LSD1 related diseases.
Definitions and explanations
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless otherwise 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. 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 amines 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 an 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 such as arginine and the like, and salts of organic acids such as glucuronic acid and the like. Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to either base or acid addition salts.
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.
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.
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.
Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
Unless otherwise indicated, the term "cis-trans isomer" or "geometric isomer" results from the inability of a double bond or a single bond to rotate freely within a ring-forming carbon atom.
Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecules have two or more chiral centers and a non-mirror image relationship between the molecules.
Unless otherwise indicated, "(D)" or "(+)" means dextrorotation, "(L)" or "(-) -means levorotation," (DL) "or" (±) "means racemization.
Using solid wedge keys, unless otherwise indicatedAnd wedge dotted bondShowing the absolute configuration of a solid centre, by means of straight solid keysAnd straight dotted line bondShowing the relative configuration of the centres of solids, by wavy linesIndicating solid-line wedge-shaped keysOr wedge dotted bondOr by wavy linesIndicating straight solid-line keysAnd straight dotted line bond
The compounds of the present invention may be present specifically. Unless otherwise indicated, the term "tautomer" or "tautomeric form" means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be rapidly interconverted. If tautomers are possible (e.g., in solution), then the chemical equilibrium of the tautomers can be reached. For example, proton tautomers (proto tautomers), also known as proton transfer tautomers (prototropic tautomers), include interconversions by proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence isomers (valencetatomer) include interconversion by recombination of some of the bonding electrons. A specific example of where keto-enol tautomerization is the interconversion between the two tautomers pentane-2, 4-dione and 4-hydroxypent-3-en-2-one.
Unless otherwise indicated, the terms "enriched in one isomer", "isomer enriched", "enantiomer enriched" or "enantiomeric enrichment" refer to a content of one isomer or enantiomer of less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
Unless otherwise indicated, the term "isomeric excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or enantiomers. For example, where one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the isomer or enantiomer excess (ee value) is 80%.
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, where 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 diastereomeric resolution by conventional methods 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, it can be put in use A compound is labeled with a radioactive isotope, such as tritium (A) 3 H) Iodine-125 (I) 125 I) Or C-14 ( 14 C) In that respect For example, deuterium can be used to replace hydrogen to form a deuterated drug, the bond formed by deuterium and carbon is firmer than the bond formed by common hydrogen and carbon, and compared with an un-deuterated drug, the deuterated drug has the advantages of reducing toxic and side effects, increasing the stability of the drug, enhancing the curative effect, prolonging the biological half-life period of the drug and the like. 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 and minerals, cream bases, lotion bases, ointment bases, and the like. Such bases include suspending agents, viscosity increasing agents, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "substituted" means that any one or more hydrogen atoms on the specified atom is replaced with a substituent, and may include variations of deuterium and hydrogen, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e = O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted and, unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical feasibility.
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 the number of one linking group is 0, e.g. - (CRR) 0 -, represents that the linking group is a single bond.
When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, for example, where L represents a single bond in A-L-Z means that the structure is actually A-Z.
When a substituent is absent, it indicates that the substituent is absent, e.g., when X is absent in A-X, it indicates that the structure is actually A. When a substituent may be attached to more than one atom of a ring, such substituent may be bonded to any atom of the ring, e.g. a building blockIndicates that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene. When no atom through which a substituent is attached to a substituted group is indicated in the listed substituents, such substituents may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be attached to a substituted group through any one of carbon atoms on the pyridine ring. When the listed linking groups do not indicate their direction of attachment, the direction of attachment is arbitrary, for example,wherein the linking group L is-M-W-, in which case-M-W-can be formed by connecting the ring A and the ring B in the same direction as the reading sequence from left to rightThe ring A and the ring B may be connected in the reverse direction of the reading sequence from left to rightThe only combinations of said linking groups, substituents and/or variants thereof areCombinations are permissible in cases where they result in stable compounds.
Unless otherwise specified, the term "hetero" denotes a heteroatom or a heteroatom group (i.e., a heteroatom-containing atomic group) including atoms other than carbon (C) and hydrogen (H) and atomic groups containing such heteroatoms, including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, = O, = S, -C (= O) O-, -C (= O) -, -C (= S) -, -S (= O) 2 -, and optionally substituted-C (= O) N (H) -, -C (= NH) -, -S (= O) 2 N (H) -or-S (= O) N (H) -.
Unless otherwise specified, "ring" means a substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl group. 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, e.g., "5 to 7 membered ring" means 5 to 7 atoms arranged around the ring. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms. Thus, "5-to 7-membered ring" includes, for example, phenyl, pyridine 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 comprises carbon atoms and 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S, wherein any of the above heterocycles may be fused to a benzene ring to form a bicyclic ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (O) p, p being 1 or 2). 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 pendant carbon atom 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. Another preferred embodiment is that 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, where 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, p being 1 or 2). 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 rings. A bridged ring is formed when one or more atoms (i.e., C, O, N, or S) connects two non-adjacent carbon or nitrogen atoms. Preferred bridge 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, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazine, phenothiazine, benzoxanthinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, piperidyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, 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, isothiazolylthienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, and xanthenyl. Fused ring and spiro compounds are also included.
Unless otherwise specified, the term "hydrocarbyl" or its derivatives (e.g., alkyl, alkenyl, alkynyl, aryl, etc.) by itself or as part of another substituent, means a straight, branched, or cyclic hydrocarbon radical, or combinations thereof, which may be fully saturated (e.g., alkyl), mono-or poly-unsaturated (e.g., alkenyl, alkynyl, aryl), which may be mono-or poly-substituted, which may be mono (e.g., methyl), di (e.g., methylene), or multi (e.g., methine), which may contain a designated number of carbon atoms (e.g., C) 1 -C 12 Represents 1 to 12 carbons, C 1-12 Is selected from C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 ；C 3-12 Is selected from C 3 、C 4 、C 5 、C 6 、C 7 、C 8 、C 9 、C 10 、C 11 And C 12 . ). "hydrocarbyl" includes, but is not limited to, aliphatic and aromatic hydrocarbyl groups, including chain and cyclic, particularlyIncluding but not limited to alkyl, alkenyl, alkynyl including but not limited to 6-12 membered aromatic hydrocarbon groups such as benzene, naphthalene, and the like. In some embodiments, the term "hydrocarbyl" 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 hydrocarbon radicals have one or more double or triple bonds, examples of which 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 "heterocarbyl" or subset thereof (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and the like) by itself or in combination with another term, means a stable linear, 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, consisting of a number of carbon atoms and at least one heteroatom. In a typical 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 heteroatom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including the position at which the hydrocarbyl group is attached to the remainder of the molecule, but the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are used by convention to refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Examples include, but are not limited to-CH 2 -CH 2 -O-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -CH 2 、-S(O)-CH 3 、-CH 2 -CH 2 -S(O) 2 -CH 3 、-CH＝CH-O-CH 3 、-CH 2 -CH＝N-OCH 3 and-CH = CH-N (CH) 3 )-CH 3 . Up to two heteroatoms may be consecutive, e.g. -CH 2 -NH-OCH 3 。
Unless otherwise specified, the terms "cycloalkyl," "heterocycloalkyl," or subset thereof (e.g., aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, etc.) by themselves or in combination with other terms, mean a cyclized "hydrocarbyl," "heterocarbyl," respectively. In addition, in the case of heterohydrocarbyl or heterocycloalkcarbyl (e.g., heteroalkyl, heterocycloalkyl), a heteroatom may occupy the position in which the heterocycle is 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 "alkyl" is used to indicate a straight or branched chain saturated hydrocarbon radical, which may be monosubstituted (e.g., -CH) 2 F) Or polysubstituted (e.g. -CF) 3 ) And may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Examples of alkyl groups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.
Unless otherwise specified, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds at any position in the chain, which may be mono-or poly-substituted, and which may be mono-, di-or polyvalent. Examples of alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, hexadienyl, and the like.
Unless otherwise specified, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds at any position in the chain, which may be mono-or poly-substituted, and which may be mono-, di-or polyvalent. Examples of alkynyl include ethynyl, propynyl, butynyl, pentynyl and the like.
Unless otherwise specified, cycloalkyl includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom is saturated, may be mono-or poly-substituted, and may be mono-, di-or polyvalent. Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2] bicyclooctane, [4.4.0] bicyclodecane, and the like.
Unless otherwise specified, cycloalkenyl includes any stable cyclic or polycyclic hydrocarbon radical containing one or more unsaturated carbon-carbon double bonds at any position on the ring, which may be mono-or polysubstituted, and which may be mono-, di-or polyvalent. Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
Unless otherwise specified, cycloalkynyl includes any stable cyclic or polycyclic hydrocarbon radical containing one or more carbon-carbon triple bonds at any position in the ring, which may be mono-or poly-substituted, and which may be mono-, di-or polyvalent.
Unless otherwise specified, "cycloalkenylalkyl" or "cycloalkenylalkyl" refers to a cycloalkenylsubstituted alkyl group.
Unless otherwise specified, "cycloalkynylalkyl" or "cycloalkynylalkyl" refers to a cycloalkynyl substituted alkyl group.
Unless otherwise specified, the term "halo" 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 -C 4 ) Alkyl "is intended to include, but not be limited to, trifluoromethyl, 2-trifluoroethyl, 4-chlorobutyl, and 3-bromopropyl, and the like. Unless otherwise specified, examples of haloalkyl include, but are not limited to: trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroAnd (4) ethyl.
"alkoxy" represents the above alkyl group having the specified number of carbon atoms attached through an oxygen bridge, unless otherwise specified, C 1-6 Alkoxy includes C 1 、C 2 、C 3 、C 4 、C 5 And C 6 An alkoxy 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.
Unless otherwise specified, the term "aryl" means a polyunsaturated aromatic hydrocarbon substituent, which may be mono-or polysubstituted, and which may be mono-, di-or polyvalent, and which may be mono-or polycyclic (e.g., 1 to 3 rings; wherein at least one ring is aromatic), fused together or linked covalently. The term "heteroaryl" refers to an aryl (or ring) containing one to four heteroatoms. In one illustrative example, the heteroatoms are selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are 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, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolyl, 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-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-quinoxalyl, 5-isoquinolyl, 5-quinoxalinyl, and 6-isoquinolyl. The substituents for any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
Unless otherwise specified, 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.
The solvent used in the present invention can be commercially available. 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; naCNBH 3 Represents sodium cyanoborohydride; r.t. represents room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc 2 O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl 2 Represents thionyl chloride; CS 2 Represents carbon disulfide; tsOH represents p-toluenesulfonic acid; NFSI stands for N-fluoro-N- (phenylsulfonyl) benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-dione; n-Bu 4 NF represents tetrabutyl ammonium fluoride; iPrOH represents 2-propanol; mp represents melting point; LDA represents lithium diisopropylamide; FAD represents flavin adenine dinucleotide; TMSOTf stands for trimethylsilyl trifluoromethanesulfonate; alloc represents an allyl formate group; DIBAL-H stands for diisobutylaluminum hydride.
The compound is made by hand orThe software names, and the commercial compounds are under the supplier catalog name.
As a novel LSD1 inhibitor, the compound has remarkable in vitro activity, has further research value and can be used for searching and verifying in vivo activity of various disease models.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limited in any way. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof. Reference example 1 and reference example 2 used the starting material as the trans racemate.
Reference example 1
The synthesis route is as follows:
compound A (26.0 g, 160mmol), diphenylphosphorylazide (44.1g, 154mmol) and triethylamine (24.3 g, 231mmol) were dissolved in t-butanol (250 mL) under nitrogen, and the reaction mixture was stirred at 90 ℃ for 12 hours. Water (500 mL) was added to the reaction mixture, which was extracted with ethyl acetate (300mL. Times.2). The organic phases were combined, washed with saturated brine (300mLx 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by silica gel column chromatography (8. 1 H NMR(400MHz,CDCl 3 )δ7.30-7.26(m,1H),7.20-7.19(m,1H),7.16-7.14(m,1H),7.15-7.10(m,2H),2.80-2.70(m,1H),2.08-2.04(m,1H),1.48(s,9H),1.22-1.16(m,2H).
Reference example 2
The synthesis route is as follows:
compound A-1 (27.0 g, 115mmol) was dissolved in ethyl acetate (100 mL), hydrochloric acid/ethyl acetate (4M, 260mL, 1.04mol) was added at 0 ℃, the reaction solution was stirred at 25 ℃ for 2 hours, the reaction solution was concentrated under reduced pressure to remove the solvent, the residue was adjusted to pH =8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (100mL. Times.2), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Compound A-2 (11.1 g). 1 H NMR(400MHz,CDCl 3 )δ7.19-7.16(m,2H),7.09-7.07(m,1H),6.96-6.94(m,2H),2.50-2.46(m,1H),1.81-1.77(m,1H),0.99-0.95(m,1H),0.93-0.90(m,1H).
Example 1
The synthesis route is as follows:
first step of
Compound 1-1 (10.60g, 93.7 mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL), cesium carbonate (61.1g, 187mmol) and compound 1-2 (21.1g, 112mmol) were added portionwise at 0 deg.C, the reaction was stirred at 0 deg.C for 30 minutes, warmed to room temperature and stirred for 2 hours. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ4.26(q,J＝6.8Hz,2H),1.68(t,J＝3.2Hz,2H),1.62(t,J＝3.2Hz,2H),1.33(t,J＝6.8Hz,3H).
Second step of
Compound 1-3 (2.10g, 15.9mmol) was dissolved in methanol (20 mL), and lithium borohydride (0.492g, 22) was added in portions at 0 deg.C6 mmol), the reaction was warmed to room temperature and stirred for 1 hour. Water (10 mL) was added to the reaction mixture, hydrochloric acid (1 mol/L) was added dropwise to adjust the pH to 7, extraction was performed with ethyl acetate (50mL. Times.5), and the organic phases were combined. The organic phase was washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 1-4 (2.20 g). 1 H NMR(400MHz,CDCl 3 )δ3.63(s,2H),2.20(s,1H),1.29(dd,J 1 ＝5.2Hz,J 2 ＝2.0Hz,2H),0.99(dd,J 1 ＝5.2Hz,J 2 ＝2.0Hz,2H).
The third step
Compound 1-4 (1.90g, 19.5 mmol) was dissolved in methylene chloride (20 mL), methanesulfonyl chloride (4.70g, 41.0 mmol) and triethylamine (4.16g, 41.1mmol) were added dropwise at 0 ℃ and the reaction solution was stirred at room temperature for 1 hour. The reaction was quenched with water (10 mL) and sodium hydroxide solution (5mL, 1mol/L), adjusted to pH 6 by the addition of 1N hydrochloric acid solution, extracted with ethyl acetate (30mL. Times.2), and the organic phases combined. The organic phase was washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by silica gel column chromatography (1. 1 H NMR(400MHz,CDCl 3 )δ4.14(s,2H),3.09(s,3H),1.43-1.40(m,2H),1.16-1.13(m,2H).
The fourth step
Compound A-1 (221mg, 0.954mmol) was dissolved in anhydrous N, N-dimethylformamide (5 mL), sodium hydride (76.1mg, 1.90mmol, 60%) was added thereto at 0 ℃ and stirred for 0.5 hour, then compound 1-5 (200mg, 1.14mmol) was added thereto, and the reaction mixture was stirred at room temperature for 24 hours. Water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (50mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by thin layer chromatography (4. 1 H NMR(400MHz,CDCl 3 ) Delta 7.30-7.26 (M, 2H), 7.21-7.17 (M, 1H), 7.14-7.12 (M, 2H), 3.45-3.38 (M, 2H), 2.99-2.95 (M, 1H), 2.17-2.12 (M, 1H), 1.44 (s, 9H), 1.35-1.25 (M, 4H), 1.05-0.99 (M, 2H), MS-ESI calculation [ M + H ]] + 313, measured value 313.
The fifth step
Compounds No. 1-6 (70.0 mg, 0.224)mmol) was dissolved in ethyl acetate (2 mL), hydrochloric acid/ethyl acetate (4 mol/L,4 mL) was added dropwise at 0 deg.C, the reaction was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the crude product was separated and purified by preparative high performance liquid chromatography to give compound 1 (38.0 mg). 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.37-7.30 (M, 2H), 7.25-7.23 (M, 1H), 7.20-7.17 (M, 2H), 3.47-3.39 (M, 2H), 3.08-3.04 (M, 1H), 2.58-2.53 (M, 1H), 1.61-1.55 (M, 1H), 1.49-1.42 (M, 3H), 1.31-1.28 (M, 2H), MS-ESI calculation [ M + H ]] + 213, found 213.
Example 2
The synthetic route is as follows:
first step of
Compound 1-6 (100mg, 0.321mmol), trimethylsilylazide (147mg, 1.28mmol) and di-n-butyltin oxide (26.3mg, 0.105mmol) were dissolved in anhydrous dioxane (2 mL), heated to 140 ℃ with a microwave, and reacted for 2.5 hours. The reaction mixture was concentrated to give Compound 2-2 (120 mg). MS-ESI calculated [ M + H ] +356, found 356.
Second step of
Compound 2-2 (80mg, 0.225mmol) was dissolved in anhydrous dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added dropwise at 0 ℃. The reaction solution was stirred at 0 ℃ for 1 hour, concentrated under reduced pressure, and the resulting crude product was purified by preparative high performance liquid chromatography to give Compound 2 (46.0 mg). 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.32-7.28 (M, 2H), 7.24-7.20 (M, 1H), 7.17-7.15 (M, 2H), 3.78-3.70 (M, 2H), 3.11-3.06 (M, 1H), 2.57-2.54 (M, 1H), 1.59-1.54 (M, 1H), 1.43-1.38 (M, 5H). MS-ESI calculated value [ M + H ]] + 256, found 256.
Example 3
The synthetic route is as follows:
the second step of reference example 2 gave compound 3 (12.0 mg). 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.33-7.29 (M, 2H), 7.25-7.23 (M, 1H), 7.18-7.16 (M, 2H), 3.78-3.70 (M, 2H), 3.12-3.08 (M, 1H), 2.58-2.55 (M, 1H), 1.72 (s, 9H), 1.58-1.55 (M, 1H), 1.43-1.36 (M, 5H). MS-ESI calculation [ M + H] + 312, measured value 312.
Example 4
The synthetic route is as follows:
first step of
Compounds 1 to 6 (70.0mg, 0.224mmol) were dissolved in methanol (5 mL), and sodium borohydride (67.8mg, 1.79mmol) and cobalt dichloride (116mg, 0.896 mmol) were added in portions at 0 ℃ to stir the reaction solution at room temperature for 3 hours. Ethyl acetate (20 mL) and a 1N NaOH solution (1 mL) were added to the reaction mixture in this order, and the mixture was filtered through celite. The filtrate was diluted with water (10 mL), extracted with ethyl acetate (20mL × 3), and the organic phases combined. The organic phase was washed with saturated brine (30mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by thin layer chromatography (10. 1 H NMR(400MHz,CDCl 3 )δ7.28-7.25(m,2H),7.19-7.16(m,1H),7.08-7.06(m,2H),3.54-3.50(m,1H),3.03(brs,2H),2.76-2.74(m,1H),2.60(d,J＝13.6Hz,1H),2.41(d,J＝13.6Hz,1H),2.11-2.06(m,1H),1.04(s,9H),1.28-1.17(m,3H),0.50-0.46(m,2H),0.39-0.30(m,2H).
Second step of
Compound 4 (24.0 mg) was obtained in the fifth step of referential example 1. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.31-7.28 (M, 2H), 7.23-7.18 (M, 3H), 3.39-3.28 (M, 2H), 3.17-3.12 (M, 2H), 3.06-3.02 (M, 1H), 2.75-2.70 (M, 1H), 1.73-1.68 (M, 1H), 1.38-1.33 (M, 1H), 0.95-0.92 (M, 2H), 0.89-0.86 (M, 2H), MS-ESI calculation [ M + H ] MS-ESI] + 217, found value 217.
Example 5
The synthetic route is as follows:
first step of
Compound 4-2 (100mg, 0.316mmol) was dissolved in dichloromethane (5 mL), paraformaldehyde (42.7mg, 0.474mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. Acetic acid (18.9mg, 0.316mmol) and sodium triacetoxyborohydride (200mg, 0.316mmol) were added thereto, and the reaction solution was stirred at room temperature for 23 hours. Water (10 mL) was added to the reaction mixture, extracted with dichloromethane (50mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated brine (50mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product which was isolated and purified by preparative high performance liquid chromatography to give compound 5-2 (30.0 mg). 1 H NMR(400MHz,CDCl 3 ) Δ 7.30-7.24 (M, 2H), 7.18-7.15 (M, 1H), 7.11-7.09 (M, 2H), 3.52-3.44 (M, 1H), 3.30-3.26 (M, 1H), 2.79-2.75 (M, 1H), 2.14 (s, 6H), 2.09-2.05 (M, 1H), 1.34 (s, 9H), 1.32-1.17 (M, 4H), 0.59-0.51 (M, 2H), 0.40-0.35 (M, 2H), MS-ESI [ M + H ] calculated] + 345, found 345.
Second step of
Compound 5 (13.0 mg) was obtained in the fifth step of referential example 1. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.32-7.28 (M, 2H), 7.23-7.19 (M, 3H), 3.45-3.30 (M, 4H), 3.10-3.06 (M, 1H), 2.95 (s, 6H), 2.80-2.75 (M, 1H), 1.77-1.72 (M, 1H), 1.37-1.32 (M, 1H), 1.03-1.01 (M, 2H), 0.95-0.90 (M, 2H), MS-ESI calculated value [ M + H ], [ M ] + 245, found 245.
Example 6
The synthetic route is as follows:
first step of
Reference example 5 gave compound 6-2 (38.0 mg) in the first step. 1 H NMR(400MHz,CDCl 3 ) Δ 7.30-7.25 (M, 2H), 7.21-7.17 (M, 1H), 7.06-7.03 (M, 2H), 3.49-3.45 (M, 1H), 3.08-3.01 (M, 2H), 2.99-2.92 (M, 1H), 2.80-2.74 (M, 2H), 2.68-2.65 (M, 1H), 2.16-2.11 (M, 1H), 1.50-1.40 (M, 12H), 1.29-1.24 (M, 3H), 0.96-0.90 (M, 2H), 0.73-0.68 (M, 1H), 0.59-0.54 (M, 1H). MS-ESI calculation [ M + H ]] + 345, found 345.
Second step of
Reference example 1 gave 6 (18 mg) in the fifth step. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.32-7.28 (M, 2H), 7.23-7.18 (M, 3H), 3.44-3.31 (M, 2H), 3.19-3.06 (M, 5H), 2.77-2.72 (M, 1H), 1.75-1.70 (M, 1H), 1.38-1.33 (M, 4H), 0.95-0.90 (M, 4H), MS-ESI calculated value [ M + H ]] + 245, found 245.
Example 7
The synthetic route is as follows:
first step of
Compound 4-2 (84.0mg, 0.265mmol) was dissolved in anhydrous N, N-dimethylformamide (1 mL), and sodium hydride (31.8mg, 0.796mmol, 60%) was added thereto at 0 ℃ and stirred for 1 hour, and ethyl iodide (91.1mg, 0.584 mmol) and tetrabutylammonium iodide (9.81mg, 0.0265mmol) were further added thereto, and the reaction solution was stirred at room temperature for 2 hours. Water (10 mL) was added to the reaction mixture, followed by addition of dichloroMethane (50mL x 3) extraction and combining the organic phases. The organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by thin layer chromatography (10. MS-ESI calculated value [ M + H% ] + 373, found 373.
Second step of
Compound 7 (8.00 mg) was obtained by the fifth step of referential example 1. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.32-7.28 (M, 2H), 7.24-7.18 (M, 3H), 3.47-3.37 (M, 4H), 3.31-3.25 (M, 4H), 3.13-3.09 (M, 1H), 2.76-2.71 (M, 1H), 1.74-1.69 (M, 1H), 1.38-1.29 (M, 7H), 1.04-0.97 (M, 2H), 0.96-0.93 (M, 2H), MS-ESI calculation [ M + H ] M] + 273, found 273.
Example 8
The synthesis route is as follows:
first step of
Compound 1-1 (5.30g, 46.8mmol) was dissolved in anhydrous N, N-dimethylformamide (20 mL), and 1, 8-diazabicyclo [5.4.0 ] was added]Undec-7-ene (15.7g, 103mmol) was stirred for 0.5 hour, then Compound 8-2 (10.4g, 51.5mmol) was added thereto, and the reaction mixture was stirred at 80 ℃ for 12 hours. After cooling to room temperature, water (150 mL) was added to the reaction mixture, extracted with ethyl acetate (250mL. Times.2), and the organic phases were combined. The organic phase was washed with saturated brine (250mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ4.26(q,J＝6.8Hz,2H),2.74-2.67(m,2H),2.64-2.57(m,2H),2.29-2.11(m,2H),1.31(t,J＝6.8Hz,3H).
Second step of
The second step of reference example 1 gave 8-4 (1.54 g). 1 H NMR(400MHz,CDCl 3 )δ3.80(s,2H),2.54-2.47(m,2H),2.35-2.15(m,4H).
The third step
The third step of reference example 1 gave 8-5 (1.81 g). 1 H NMR(400MHz,CDCl 3 )δ4.35(s,2H),3.13(s,3H),2.62-2.57(m,2H),2.28-2.10(m,4H).
The fourth step
The fourth step of reference example 1 gave 8-6 (450 mg). 1 H NMR(400MHz,CDCl 3 )δ7.30-7.21(m,2H),7.19-7.16(m,1H),7.14-7.06(m,2H),3.45-3.41(m,1H),2.89-2.81(m,1H),2.51-2.25(m,2H),2.23-2.05(m,6H),1.41(s,9H),1.34-1.31(m,2H).
The fifth step
Reference example the fifth step was carried out to give Compound 8 (38.0 mg). 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.34-7.30 (M, 2H), 7.26-7.19 (M, 3H), 3.68 (s, 2H), 3.13-3.09 (M, 1H), 2.61-2.56 (M, 3H), 2.43-2.36 (M, 2H), 2.29-2.12 (M, 2H), 1.63-1.57 (M, 1H), 1.45-1.40 (M, 1H). MS-ESI calculation [ M + H] + 227, found 227.
Example 9
The synthetic route is as follows:
first step of
Compound 9-2 (150 mg) was obtained according to the first step of example 4. 1 H NMR(400MHz,CDCl 3 )δ7.28-7.24(m,2H),7.19-7.15(m,1H),7.08-7.06(m,2H),3.53(d,J＝14.4Hz,1H),3.23(d,J＝14.4Hz,1H),2.78(d,J＝13.6Hz,1H),2.65(d,J＝13.6Hz,1H),2.60-2.58(m,4H),2.14-2.09(m,1H),2.05-2.00(m,1H),191-1.82(m,2H),1.76-1.70(m,2H),1.39(s,9H),1.34-1.29(m,1H),1.23-1.18(m,1H).
Second step of
Reference was made to example 1, which gave 9 (18.0 mg) in the fifth step. 1 H NMR(400MHz,Methonal-d 4 )δ7.37-7.30(m,2H) 7.25-7.20 (M, 3H), 3.49 (s, 2H), 3.28 (s, 2H), 3.12-3.09 (M, 1H), 2.77-2.72 (M, 1H), 2.13-2.05 (M, 6H), 1.76-1.70 (M, 1H), 1.42-1.36 (M, 1H), MS-ESI calculation [ M + H] + 231, measured value 231.
Example 10
The synthesis route is as follows:
first step of
Compound 4-2 (80.0mg, 0.253mmol) and 10-2 (31.4mg, 0.253mmol) were dissolved in anhydrous dichloromethane (2 mL), acetic acid (45.5mg, 0.758mmol) was added to the reaction liquid, and after 1 hour of reaction at 30 ℃, sodium triacetoxyborohydride (161mg, 0.758mmol) was added, followed by 1 hour of reaction at 30 ℃. Dichloromethane (10 mL) was added to the reaction solution to dilute the solution, and the reaction solution was washed with a saturated aqueous sodium carbonate solution (5mL × 3), water (5mL × 2) and a saturated common salt solution (10mL × 2) in this order, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained crude product was separated and purified by thin layer chromatography (dichloromethane/methanol = 10) to obtain compound 10-3 (56.0 mg. 1 H NMR(400MHz,CDCl 3 ) δ 7.46-7.40 (M, 1H), 7.30-7.28 (M, 1H), 7.24-7.04 (M, 6H), 7.03-6.97 (M, 1H), 3.89-3.76 (M, 2H), 3.60-3.45 (M, 1H), 3.13-3.00 (M, 1H), 2.81-2.72 (M, 1H), 2.54 (d, J =12.8hz, 1h), 2.37 (d, J =12.8hz, 1h), 2.12-2.05 (M, 1H), 1.40 (s, 9H), 1.25-1.12 (M, 2H), 0.60-0.52 (M, 1H), 0.46-0.33 (M, 3H), MS-ESI calculated value [ M + H ], [ M + H ]] + 425, found 425.
Second step of
Compound 10-3 (56.0 mg, 132. Mu. Mol) was dissolved in ethyl acetate (1 mL), hydrochloric acid/ethyl acetate (4 mol/L,3 mL) was added at 0 ℃ and the reaction mixture was stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure, and the obtained crude product was separated and purified by preparative high performance liquid chromatography to give compound 10 (28.0 mg). 1 H NMR(400MHz,D 2 O)δ7.50-7.39(m,2H),7.36-7.29(m,2H),7.29-7.09(m,5H),4.26 (s, 2H), 3.33-3.19 (M, 2H), 3.19-3.07 (M, 2H), 2.95-2.85 (M, 1H), 2.53-2.44 (M, 1H), 1.51-1.42 (M, 1H), 1.37-1.30 (M, 1H), 0.84 (s, 4H), MS-ESI calculated value [ M + H] + 325, found value 325.
Example 11
The synthetic route is as follows:
first step of
Compound 11-3 (26.0 mg) was obtained by the first step of referential example 10. 1 H NMR(400MHz,CDCl 3 ) δ 7.30-7.26 (M, 2H), 7.26-7.23 (M, 1H), 7.06-7.02 (M2H), 6.88-6.81 (M, 1H), 6.12-6.06 (M, 2H), 4.11-4.00 (M, 2H), 3.46 (d, J =15.2hz, 1H), 3.01 (d, J =15.2hz, 1H), 2.82-2.72 (M, 1H), 2.66-2.59 (M, 1H), 2.53-2.42 (M, 1H), 2.16-2.09 (M, 1H), 1.45 (s, 9H), 1.23-1.14 (M, 2H), 0.72-0.61 (M, 3H), 0.53-0.42 (M, 1H), MS-ESI [ M + H ], (M, 1H) (+ M, 1H) } M + ESI ] + 396, found 396.
Second step of
The second step of reference example 10 gave 11 (8.00 mg). 1 H NMR(400MHz,D 2 O) delta 7.39-7.34 (M, 2H), 7.32-7.27 (M, 1H), 7.21-7.17 (M, 2H), 6.94-6.90 (M, 1H), 6.38-6.30 (M, 1H), 6.25-6.18 (M, 1H), 4.27-4.19 (M, 2H), 3.31-3.20 (M, 2H), 3.13-3.03 (M, 2H), 2.95-2.89 (M, 1H), 2.56-2.47 (M, 1H), 1.56-1.48 (M, 1H), 1.42-1.34 (M, 1H), 0.88-0.81 (M, 4H). MS-ESI] + 296, found 296.
Example 12
The synthesis route is as follows:
first step of
Compound 12-3 (30.0 mg) was obtained by the first step of referential example 10. 1 H NMR(400MHz,CDCl 3 ) Δ 7.31-7.27 (M, 1H), 7.26-7.15 (M, 3H), 7.13-6.98 (M, 3H), 4.19-3.97 (M, 1H), 3.78-3.40 (M, 2H), 3.32-2.82 (M, 2H), 2.80-2.65 (M, 2H), 2.18-2.10 (M, 1H), 1.43-1.38 (M, 9H), 1.24-1.12 (M, 2H), 0.96-0.77 (M, 2H), 0.72-0.67 (M, 1H), 0.62-0.49 (M, 1H). MS-ESI calculation [ M + H ]] + 397, found 397.
Second step of
The second step in reference example 10 gave compound 12 (6.00 mg). 1 H NMR(400MHz,D 2 O) delta 8.77-8.73 (M, 1H), 7.69 (s, 1H), 7.40-7.33 (M, 2H), 7.33-7.26 (M, 1H), 7.22-7.17 (M, 2H), 4.42 (s, 2H), 3.40-3.28 (M, 2H), 3.28-3.17 (M, 2H), 3.03-2.96 (M, 1H), 2.60-2.57 (M, 1H), 1.60-1.50 (M, 1H), 1.45-1.37 (M, 1H), 0.92 (s, 4H), MS-ESI calculated value [ M + H ], [ M + H ]] + 297, found 297.
Example 13
The synthetic route is as follows:
first step of
Compound 13-3 (50.0 mg) was obtained by the first step of referential example 10. 1 H NMR(400MHz,CDCl 3 ) Δ 7.31-7.27 (M, 1H), 7.26-7.22 (M, 1H), 7.21-7.15 (M, 1H), 7.10-7.00 (M, 2H), 3.64-3.37 (M, 4H), 3.40-3.20 (M, 1H), 3.10-2.91 (M, 2H), 2.82-2.72 (M, 1H), 2.65-2.46 (M, 3H), 2.40-2.30 (M, 1H), 2.13-1.97 (M, 2H), 1.65-1.55 (M, 1H), 1.45 (s, 9H), 1.42 (s, 9H), 1.29-1.10 (M, 2H), 0.64-0.30 (M, 4H). MS-ESI [ M + H ] calculated value of M + 4H ], MS-ESI] + 500, found 500.
Second step of
The second step in reference example 10 gave compound 13 (9.00 mg). 1 H NMR(400MHz,D 2 O)δ7.41-7.35(m,2H),7.33-7.27(m,1H),7.24-7.17(m,2H),3.68-3.57 (M, 1H), 3.51-3.43 (M, 1H), 3.42-3.29 (M, 3H), 3.25-3.11 (M, 4H), 3.09-2.99 (M, 2H), 2.84-2.72 (M, 1H), 2.63-2.57 (M, 1H), 2.41-2.29 (M, 1H), 1.89-1.73 (M, 1H), 1.65-1.52 (M, 1H), 1.48-1.39 (M, 1H), 0.97-0.86 (M, 4H), MS-ESI [ M + H calculated for M + H ]] + 300, found 300.
Example 14
The synthetic route is as follows:
first step of
Compound 14-3 (30.0 mg) was obtained by the first step of reference example 10. MS-ESI calculated value [ M + H%] + 426, found value 426.
Second step of
The second step of reference example 10 gave compound 14 (1.30 mg). 1 H NMR(400MHz,D 2 O) δ 8.02 (s, 1H), 7.39-7.34 (M, 2H), 7.32-7.27 (M, 1H), 7.21-7.17 (M, 2H), 4.56-4.50 (M, 2H), 4.19 (q, J =7.2hz, 2h), 3.50-3.36 (M, 2H), 3.34-3.23 (M, 2H), 3.07-3.00 (M, 1H), 2.61-2.53 (M, 1H), 1.61-1.53 (M, 1H), 1.47-1.42 (M, 1H), 1.39 (t, J =7.2hz, 3h), 0.95 (s, 4H), MS-ESI calculation [ M + H ], M + H] + 326, found 326.
Example 15
The synthesis route is as follows:
first step of
The first step of reference example 10 gave compound 15-3 (40.0 mg). 1 H NMR(400MHz,CDCl 3 )δ8.66(s,1H),7.91(d,J＝8.0Hz,1H),7.63 (d, J =8.0hz, 1h), 7.29-7.25 (M, 2H), 7.21-7.15 (M, 1H), 7.11-7.03 (M, 2H), 3.87-3.78 (M, 2H), 3.64-3.52 (M, 1H), 3.12-2.96 (M, 1H), 2.84-2.74 (M, 1H), 2.54 (d, J =12.4hz, 1h), 2.27 (d, J =12.4hz, 1h), 2.13-2.05 (M, 1H), 1.42 (s, 9H), 1.27-1.18 (M, 2H), 0.60-0.51 (M, 1H), 0.42-0.29 (M, 3H), MS-ESI calculation [ M + H ], [ M + H ]] + 476, found 476.
Second step of
The second step of reference example 10 gave compound 15 (23.0 mg). 1 H NMR(400MHz,D 2 O)δ8.74(d,J＝1.6Hz,1H),8.20(dd,J 1 ＝1.6Hz,J 2 =8.4Hz, 1H), 7.93 (d, J =8.4Hz, 1H), 7.37-7.30 (M, 2H), 7.29-7.22 (M, 1H), 7.19-7.12 (M, 2H), 4.42-4.32 (M, 2H), 3.40-3.27 (M, 2H), 3.27-3.16 (M, 2H), 3.02-2.93 (M, 1H), 2.59-2.50 (M, 1H), 1.55-1.48 (M, 1H), 1.42-1.33 (M, 1H), 0.95-0.85 (M, 4H). MS-ESI calculation [ M + H ], (M + H) ]] + 376, found 376.
Example 16
The synthesis route is as follows:
first step of
Compound 16-3 (50.0 mg) was obtained by the first step of referential example 10. 1 H NMR(400MHz,CDCl 3 ) Δ 7.76-7.69 (M, 1H), 7.35-7.27 (M, 2H), 7.27-7.23 (M, 1H), 7.23-7.15 (M, 1H), 7.15-7.03 (M, 2H), 4.18-3.99 (M, 2H), 3.77-3.42 (M, 1H), 3.10-2.98 (M, 1H), 2.86-2.48 (M, 3H), 2.19-2.03 (M, 1H), 1.54-1.32 (M, 9H), 1.31-1.04 (M, 3H), 0.60-0.52 (M, 1H), 0.46-0.34 (M, 2H). MS-ESI calculation [ M + H ], M + H ] + 414, measured value 414.
Second step of
The second step of reference example 10 gave compound 16 (14.0 mg). 1 H NMR(400MHz,D 2 O)δ7.82(d,J＝3.6Hz,1H),7.66(d,J＝3.6Hz,1H),7.34-7.29(m,2H),7.27-7.22(m,1H),7.16-7.12(m,2H),4.59(s,2H),3.37-3.27(m,2H),3.25-3.16(m,2H),2.97-2.92 (M, 1H), 2.55-2.47 (M, 1H), 1.54-1.46 (M, 1H), 1.40-1.33 (M, 1H), 0.87 (s, 4H). Calculated as MS-ESI [ M + H] + 314, measured value 314.
Example 17
The synthesis route is as follows:
first step of
Compound 17-3 (40.0 mg) was obtained by the first step of referential example 10. 1 H NMR(400MHz,CDCl 3 ) Δ 7.29-7.24 (M, 2H), 7.21-7.13 (M, 1H), 7.10-7.03 (M, 2H), 6.95 (s, 1H), 4.15-4.05 (M, 2H), 3.66-3.58 (M, 2H), 3.55-3.45 (M, 1H), 3.30-3.17 (M, 2H), 3.02-2.90 (M, 1H), 2.80-2.71 (M, 1H), 2.70-2.59 (M, 2H), 2.53-2.42 (M, 1H), 2.26-2.12 (M, 2H), 1.41 (s, 9H), 1.28-1.13 (M, 2H), 0.60-0.48 (M, 1H), 0.40-0.23 (M, 3H), MS-ESI [ M + H ], [ M + E ]] + 437, found 437.
Second step of
The second step of referential example 10 gave compound 17 (14.0 mg). 1 H NMR(400MHz,D 2 O) delta 7.55 (s, 1H), 7.37-7.31 (M, 2H), 7.30-7.23 (M, 1H), 7.20-7.13 (M, 2H), 4.33 (s, 2H), 4.28-4.23 (M, 2H), 3.39-3.25 (M, 2H), 3.22-3.09 (M, 4H), 3.00-2.94 (M, 1H), 2.81-2.71 (M, 2H), 2.57-2.50 (M, 1H), 1.57-1.46 (M, 1H), 1.42-1.37 (M, 1H), 0.89 (s, 4H). MS-ESI calculation [ M + H ] calculation] + 337, found 337.
Example 18
The synthetic route is as follows:
first step of
Compound 18-3 (80.0 mg) was obtained by the first step of referential example 10. 1 H NMR(400MHz,CDCl 3 ) δ 8.03-8.00 (M, 1H), 7.99-7.96 (M, 1H), 7.48 (d, J =8.4Hz, 2H), 7.42 (d, J =8.4Hz, 1H), 7.25-7.23 (M, 1H), 7.21-7.14 (M, 1H), 7.07-7.03 (M, 2H), 3.90 (s, 3H), 3.57-3.48 (M, 1H), 3.08-2.97 (M, 1H), 2.79-2.73 (M, 1H), 2.61 (d, J =12.4Hz, 1H), 2.42 (d, J =12.4Hz, 1H), 2.12-2.05 (M, 1H), 2.01-1.93 (M, 1H), 1.40 (s, 9H), 1.25-1.13 (M, 3H), 0.61-0.47 (M, 3H), 0.43-0.36 (M, 1H), MS-ESI calculated value [ M + H [ ], MS-ESI ] + 465, found 465.
Second step of
The second step of referential example 10 gave compound 18-4 (60.0 mg). MS-ESI calculated value [ M + H%] + 365, found 365.
The third step
Compound 18-4 (60.0 mg, 0.165mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide (139mg, 3.29mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours and at 50 ℃ for 16 hours. The reaction solution is cooled to room temperature, diluted hydrochloric acid (1 mol/L) is used for adjusting the pH value to 5, the pressure reduction and the concentration are carried out, and the obtained crude product is separated and purified by preparative high performance liquid chromatography to obtain 18 (7.00 mg). 1 H NMR(400MHz,Methonal-d 4 ) δ 8.02 (d, J =8.0hz, 2h), 7.47 (d, J =8.0hz, 2h), 7.27-7.22 (M, 2H), 7.16-7.11 (M, 1H), 7.07-7.02 (M, 2H), 4.20 (s, 2H), 3.13 (s, 2H), 2.87 (s, 2H), 2.42-2.36 (M, 1H), 1.94-1.88 (M, 1H), 1.10-1.02 (M, 2H), 0.68-0.61 (M, 4H), MS-ESI calculation value [ M + H, H ]] + 351, found value 351.
Example 19
The synthetic route is as follows:
first step of
Compounds 8-6 (1.8g, 5.51mmol) were dissolved in anhydrous ethanol (20 mL), and hydroxylamine hydrochloride (767mg, 11.1mmol) and diisopropylethylamine (20 mL) were added2.85g, 22.2mmol), the reaction mixture was stirred at 80 ℃ for 12 hours. The solvent was removed by concentration under reduced pressure, the remaining mixture was dissolved in water (100 mL), extracted with ethyl acetate (80mL x 3), and the organic phase was washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was isolated and purified by silica gel column chromatography (1 petroleum ether/ethyl acetate, rf1=0.5, rf2= 0.3) to give compound 19-2 (760 mg). 1 H NMR(400MHz,CDCl 3 ) δ 7.25-7.23 (m, 2H), 7.17-7.14 (m, 1H), 7.08-7.07 (m, 2H), 4.51 (brs, 2H), 3.79-3.75 (m, 1H), 3.50-3.47 (m, 1H), 2.83-2.79 (m, 1H), 2.39-2.26 (m, 2H), 2.11-1.87 (m, 5H), 1.39 (s, 9H), 1.30-1.16 (m, 2H). MS-ESI calculated value [ M + H%] + 360, measured value 360.
Second step of
Benzoic acid (24.5mg, 0.201mmol) and carbonyldiimidazole (35.2mg, 0.217mmol) were dissolved in anhydrous N, N-dimethylformamide (2 mL), and stirred at 30 ℃ for 2 hours under nitrogen. Compound 19-2 (60.0 mg, 0.167mmol) was added to the reaction solution, and the reaction solution was heated to 110 ℃ and stirred for 10 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20mL. Times.3), and the organic phases were combined, washed with saturated brine (20mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 19-3 (80.0 mg). MS-ESI calculated value [ M + H%] + 446, found 446.
The third step
Compound 19-3 (80mg, 0.179mmol) was dissolved in anhydrous dichloromethane (2 mL) and trifluoroacetic acid (2 mL) was added dropwise at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour, the solvent was removed by concentration under reduced pressure, and the crude product was separated and purified by preparative high performance liquid chromatography to give compound 19 (30.0 mg). 1 H NMR(400MHz,Methonal-d 4 ) δ 8.17 (d, J =7.2hz, 2h), 7.68-7.58 (M, 3H), 7.28-7.15 (M, 5H), 3.88 (s, 2H), 3.09-3.08 (M, 1H), 2.69-2.69 (M, 2H), 2.59-2.57 (M, 1H), 2.43-2.41 (M, 2H), 2.24-2.21 (M, 2H), 1.60-1.57 (M, 1H), 1.39-1.32 (M, 1H). MS-ESI calculation [ M + H, 2H ], (M, 1H) ] ] + 346, found 346.
Example 20
The synthetic route is as follows:
first step of
Compound 20-2 (300 mg) was obtained according to the first step of example 19. MS-ESI calculated value [ M + H%] + 345, found 345.
Second step of
Compound 20 (60.0 mg) was obtained by the third step of reference example 19. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.31-7.27 (m, 2H), 7.22-7.17 (m, 3H), 3.58 (s, 2H), 3.04-3.01 (m, 1H), 2.65-2.61 (m, 1H), 2.52-2.47 (m, 2H), 2.21-2.01 (m, 4H), 1.65-1.55 (m, 1H), 1.36-1.31 (m, 1H). MS-ESI calculated value [ M + H%] + 245, found 245.
Example 21
The synthesis route is as follows:
first step of
The second step of referential example 19 gave compound 21-2 (75.0 mg). MS-ESI calculated value [ M + H%] + 480, found 480.
Second step of
Reference example 19 gave 21 (38.0 mg) in the third step. 1 H NMR(400MHz,Methonal-d 4 ) δ 8.14 (d, J =8.8hz, 2h), 7.63 (d, J =8.8hz, 2h), 7.29-7.25 (m, 2H), 7.20-7.14 (m, 3H), 3.87 (s, 2H), 3.07-3.05 (m, 1H), 2.67-2.65 (m, 2H), 2.58-2.56 (m, 1H), 2.44-2.41 (m, 2H), 2.23-2.19 (m, 2H), 1.59-1.57 (m, 1H), 1.38-1.36 (m, 1H). MS-ESI calculated value [ M + H%] + 380, found 380.
Example 22
The synthetic route is as follows:
first step of
The second step of referential example 19 gave compound 22-2 (80.0 mg). MS-ESI calculated value [ M + H%] + 480, found 480.
Second step of
Reference example 19 gave 22 (35.0 mg) in the third step. 1 H NMR(400MHz,Methonal-d 4 ) δ 8.15 (d, J =8.4hz, 1h), 7.67-7.63 (m, 2H), 7.55-7.53 (m, 1H), 7.28-7.26 (m, 2H), 7.21-7.15 (m, 3H), 3.89 (s, 2H), 3.09-3.08 (m, 1H), 2.70-2.67 (m, 3H), 2.47-2.42 (m, 2H), 2.25-2.21 (m, 2H), 1.62-1.59 (m, 1H), 1.39-1.37 (m, 1H). MS-ESI calculated value [ M + H% ] + 380, found 380.
Example 23
The synthetic route is as follows:
first step of
The second step of referential example 19 gave compound 23-2 (70.0 mg). MS-ESI calculated value [ M + H%] + 464, found 464.
Second step of
The third step of referential example 19 gave 23 (31.0 mg). 1 H NMR(400MHz,Methonal-d 4 ) δ 8.19 (t, J =1.6hz, 1h), 7.73-7.71 (m, 1H), 7.42-7.38 (m, 2H), 7.27-7.25 (m, 2H), 7.20-7.15 (m, 3H), 3.89 (s, 2H), 3.09-3.08 (m, 1H), 2.69-2.67 (m, 2H), 2.59-2.58 (m, 1H), 2.46-2.43 (m, 2H), 2.24-2.21 (m, 2H), 1.62-1.59 (m, 1H), 1.38-1.36 (m, 1H). MS-ESI calculated value [ M + H%] + 364, measured value 364.
Example 24
The synthetic route is as follows:
first step of
The second step of referential example 19 gave compound 24-2 (70.0 mg). MS-ESI calculated value [ M + H%] + 464, found 464.
Second step of
Compound 24 (36.0 mg) was obtained by the third step of reference example 19. 1 H NMR(400MHz,Methonal-d 4 ) δ 8.00 (d, J =8.0hz, 1h), 7.89-7.88 (m, 1H), 7.65-7.64 (m, 1H), 7.45-7.44 (m, 1H), 7.27-7.25 (m, 2H), 7.21-7.15 (m, 3H), 3.88 (s, 2H), 3.09-3.07 (m, 1H), 2.69-2.66 (m, 2H), 2.59-2.58 (m, 1H), 2.45-2.43 (m, 2H), 2.25-2.21 (m, 2H), 1.62-1.60 (m, 1H), 1.39-1.37 (m, 1H). MS-ESI calculated value [ M + H%] + 364, measured value 364.
Example 25
The synthetic route is as follows:
first step of
The second step of referential example 19 gave compound 25-2 (70.0 mg). MS-ESI calculated value [ M + H% ] + 464, found 464.
Second step of
Obtained in the third step in reference example 19 (31.0 mg). 1 H NMR(400MHz,Methonal-d 4 )δ8.25-8.19(m,2H),7.38-7.33(m,2H),7.28-7.26(m,2H),7.21-7.15(m,3H),3.87(s,2H),3.09-3.07(m,1H),2.67-2.65(m,2H),2.59-2.56(m, 1H), 2.42-2.41 (m, 2H), 2.24-2.20 (m, 2H), 1.60-1.58 (m, 1H), 1.39-1.35 (m, 1H). MS-ESI calculated value [ M + H%] + 364, measured value 364.
Example 26
The synthetic route is as follows:
first step of
The second step of referential example 19 gave compound 26-2 (70.0 mg). MS-ESI calculated value [ M + H%] + 447, found 447.
Second step of
Compound 26 (42.0 mg) was obtained by the third step of reference example 19. 1 H NMR(400MHz,Methonal-d 4 ) δ 9.62 (s, 1H), 9.26 (d, J =8.0hz, 1h), 9.16 (d, J =5.6hz, 1h), 8.36-8.32 (m, 1H), 7.26-7.23 (m, 2H), 7.16-7.13 (m, 3H), 3.91 (s, 2H), 3.08-3.06 (m, 1H), 2.70-2.63 (m, 3H), 2.50-2.49 (m, 2H), 2.23-2.22 (m, 2H), 1.67-1.65 (m, 1H), 1.35-1.34 (m, 1H). MS-ESI calculated value [ M + H%] + 347, found 347.
Example 27
The synthetic route is as follows:
first step of
The second step of referential example 19 gave compound 27-2 (80.0 mg). MS-ESI calculated value [ M + H%] + 515, found 515.
Second step of
The third step of reference example 19 gave compound 27 (42.0 mg). 1 H NMR(400MHz,Methonal-d 4 ) δ 9.42 (s, 1H), 8.75-8.73 (m, 1H), 8.08 (d, J =8.4hz, 1h), 7.27-7.23 (m, 2H), 7.17-7.13 (m, 3H), 3.91 (s, 2H), 3.07-3.06 (m, 1H), 2.72-2.67 (m, 2H), 2.56-2.55 (m, 1H), 2.48-2.46 (m, 2H), 2.26-2.22 (m, 2H), 1.61-1.60 (m, 1H), 1.38-1.36 (m, 1H). MS-ESI calculated value [ M + H% ] + 415, found value 415.
Example 28
The synthetic route is as follows:
first step of
Compounds 9-2 (50.0 mg, 0.151mmol) and 28-2 (16.2 mg, 0.151mmol) were dissolved in anhydrous dichloromethane (2.00 mL), acetic acid (27.3 mg, 0.454mmol) was added to the reaction solution, stirring was performed at 30 ℃ for 1 hour, sodium triacetoxyborohydride (96.2 mg, 0.454mmol) was added, and stirring was continued at 30 ℃ for 16 hours. The reaction mixture was diluted with dichloromethane (10 mL), washed with saturated aqueous sodium carbonate (5mL × 3), water (5mL × 2), and saturated brine (10mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was isolated and purified by thin layer chromatography (dichloromethane/methanol =10, 1, rf = 0.34) to give compound 28-3 (35.0 mg). 1 H NMR(400MHz,CDCl 3 ) δ 8.54 (s, 1H), 8.47 (d, J =4.8hz, 1h), 7.71 (d, J =6.8hz, 1h), 7.26-7.23 (M, 3H), 7.18-7.15 (M, 1H), 7.06-7.04 (M, 2H), 3.78-3.69 (M, 2H), 3.69-3.51 (M, 1H), 3.26-3.23 (M, 1H), 2.64-2.57 (M, 1H), 2.56 (s, 2H), 2.09-2.02 (M, 2H), 1.82-1.75 (M, 5H), 1.38 (s, 9H), 1.32-1.31 (M, 1H), 1.30-1.19 (M, 1H), MS-ESI [ M + H ] calculation value] + 422, measured value 422.
Second step of
Compound 28-3 (35.0 mg, 83.0. Mu. Mol) was dissolved in anhydrous dichloromethane (2 mL), trisilyl trifluoromethanesulfonate (36.9 mg, 0.166mmol) was added at 0 ℃ and the reaction solution was stirred at 0 ℃ for 30 minutes. Adding a drop of water to the reaction solution for quenching, and concentrating under reduced pressure to obtain The crude product of (2) was isolated and purified by preparative high performance liquid chromatography to give compound 28 (32.0 mg). 1 H NMR(400MHz,D 2 O) δ 8.93 (s, 1H), 8.80 (d, J =6.0hz, 1h), 8.69 (d, J =8.4hz, 1h), 8.07-8.04 (M, 1H), 7.32-7.28 (M, 2H), 7.24-7.22 (M, 1H), 7.21-7.13 (M, 2H), 4.52 (s, 2H), 3.46 (s, 2H), 3.40 (s, 2H), 3.00-2.95 (M, 1H), 2.58-2.51 (M, 1H), 2.03-1.94 (M, 6H), 1.53-1.50 (M, 1H), 1.39-1.35 (M, 1H)% calculated value MS-ESI [ M + H, H ]] + 322, measured value 322.
Example 29
The synthetic route is as follows:
first step of
Reference example 28 gave compound 29-3 (40.0 mg) in the first step. 1 H NMR(400MHz,CDCl 3 ) δ 7.49 (d, J =6.8hz, 1h), 7.33 (d, J =8.0hz, 1h), 7.26-7.19 (M, 3H), 7.17-7.14 (M, 2H), 7.08-7.06 (M, 2H), 3.87 (s, 2H), 3.60-3.56 (M, 1H), 3.30-3.26 (M, 1H), 2.68-2.63 (M, 3H), 2.12-2.09 (M, 1H), 2.04-1.99 (M, 1H), 1.87-1.74 (M, 5H), 1.38 (s, 9H), 1.33-1.29 (M, 1H), 1.22-1.16 (M, 1H). MS-ESI calculation [ M + H ], M + H] + 455, found value 455.
Second step of
The second step of referential example 28 gave compound 29 (31 mg). 1 H NMR(400MHz,D 2 O) delta 7.49-7.47 (M, 2H), 7.41-7.29 (M, 4H), 7.25-7.22 (M, 1H), 7.14-7.13 (M, 2H), 4.42 (s, 2H), 3.40 (s, 2H), 3.35 (s, 2H), 2.93-2.89 (M, 1H), 2.51-2.50 (M, 1H), 2.00-1.95 (M, 6H), 1.49-1.46 (M, 1H), 1.37-1.33 (M, 1H), MS-ESI calculated value [ M + H ]] + 355, found 355.
Example 30
The synthesis route is as follows:
first step of
Reference example 28 gave compound 30-3 (33.0 mg) in the first step. 1 H NMR(400MHz,CDCl 3 ) δ 8.88 (d, J =6.8hz, 1h), 7.62-7.60 (M, 1H), 7.55-7.53 (M, 1H), 7.49 (d, J =6.8hz, 1h), 7.25-7.22 (M, 2H), 7.14-7.10 (M, 3H), 4.78-4.77 (M, 2H), 4.42-4.48 (M, 1H), 4.10-4.07 (M, 1H), 3.67-3.63 (M, 1H), 3.44-3.38 (M, 1H), 2.93-2.90 (M, 1H), 2.20-1.89 (M, 7H), 1.45-1.41 (M, 1H), 1.33 (s, 9H), 1.28-1.27 (M, 1H), MS-ESI [ M + H ], [ M + ESI ], [ M + H ]] + 446, found 446.
Second step of
The second step of reference example 28 gave compound 30 (21.0 mg). 1 H NMR(400MHz,D 2 O) δ 7.89 (d, J =8.0hz, 1h), 7.72-7.70 (M, 1H), 7.61-7.56 (M, 2H), 7.26-7.20 (M, 3H), 7.11-7.08 (M, 2H), 4.92 (s, 2H), 3.84 (s, 2H), 3.43 (s, 2H), 2.97-2.94 (M, 1H), 2.54-2.48 (M, 1H), 2.18-1.85 (M, 6H), 1.55-1.50 (M, 1H), 1.40-1.35 (M, 1H), MS-ESI calculation value [ M + H ], 1H ]] + 346, found value 346.
Example 31
The synthetic route is as follows:
first step of
The first step of reference example 28 gave compound 31-3 (70.0 mg). 1 H NMR(400MHz,CDCl 3 ) δ 7.98 (d, J =8.0hz, 2h), 7.43 (d, J =8.0hz, 2h), 7.26-7.23 (m, 2H), 7.16-7.15 (m, 1H), 7.06-7.05 (m, 2H), 3.90 (s, 3H), 3.81-3.76 (m, 2H), 3.57-3.53 (m, 1H), 3.28-3.24 (m, 1H), 2.64-2.62 (m, 1H), 2.57-2.56 (m, 2H), 2.12-2.07 (m, 1H), 2.06-1.99 (m, 1H), 1.83-1.76 (m, 5H), 1.38 (s, 9H), 1.33-1.30 (m, 1H), 1.19-1.17 (MS, 1H-ESI) Value [ M + H] + 479, found 479.
Second step of
The second step of referential example 28 gave compound 31-4 (50.0 mg). MS-ESI calculated value [ M + H%] + 379, found 379.
The third step
Compound 31-4 (50.0 mg, 0.132mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), lithium hydroxide (111mg, 2.64mmol) was added to the reaction solution, and the reaction solution was stirred at room temperature overnight. The reaction solution was adjusted to pH 6 with 1N hydrochloric acid and directly concentrated under reduced pressure, and the crude product was separated and purified by preparative high performance liquid chromatography to give compound 31 (31.0 mg). 1 H NMR(400MHz,D 2 O) δ 7.90 (d, J =8.8hz, 2h), 7.49 (d, J =8.8hz, 2h), 7.24-7.20 (M, 2H), 7.17-7.15 (M, 1H), 7.05-7.03 (M, 2H), 4.25 (s, 2H), 3.31 (s, 2H), 3.21 (s, 2H), 2.81-2.78 (M, 1H), 2.42-2.38 (M, 1H), 1.90-1.84 (M, 6H), 1.41-1.30 (M, 1H), 1.26-1.22 (M, 1H), MS-ESI calcd [ M + H [ ] [ M + H ] ]] + 365, found 365.
Example 32
The synthetic route is as follows:
first step of
Compound 32-3 (27.0 mg) was obtained by the first step of referential example 28. 1 H NMR(400MHz,CDCl 3 ) δ 8.31 (d, J =4.8Hz, 1H), 7.39 (d, J =8.8Hz, 1H), 7.32 (s, 1H), 7.26-7.23 (M, 2H), 7.17-7.13 (M, 1H), 7.06-7.04 (M, 2H), 6.67-6.65 (M, 1H), 6.51-6.50 (M, 1H), 4.22-4.13 (M, 2H), 3.53-3.50 (M, 1H), 3.22-3.14 (M, 1H), 2.63-2.61 (M, 1H), 2.58 (s, 2H), 2.08-2.05 (M, 1H), 1.98-1.93 (M, 1H), 1.76-1.59 (M, 5H), 1.37 (s, 9H), 1.31-1.28 (M, 1H), 1.17-1.13 (M, 1H). MS-ESI calculated value [ M + H ] + 461, measured value 461.
Second step of
The second step of referential example 28 gave compound 32 (3.0 mg). 1 H NMR(400MHz,Methonal-d 4 ) δ 8.30 (d, J =7.2hz, 1h), 7.50 (d, J =9.2hz, 1h), 7.34 (s, 1H), 7.25-7.21 (M, 2H), 7.17-7.13 (M, 1H), 7.03-6.98 (M, 2H), 6.78-6.75 (M, 1H), 6.64-6.62 (M, 1H), 4.21 (s, 2H), 2.76 (s, 2H), 2.69 (s, 2H), 2.19-2.15 (M, 1H), 1.90-1.85 (M, 2H), 1.79-1.74 (M, 5H), 0.94-0.89 (M, 2H), MS-ESI calculation value [ M + H ], 1.5H ], 1.1H, 1H, and MS-ESI] + 361, found 361.
Example 33
The synthetic route is as follows:
first step of
Compound 33-3 (25.0 mg) was obtained by the first step in reference example 28. MS-ESI calculated value [ M + H%] + 489, found 489.
Second step of
The second step of referential example 28 gave compound 33 (20.0 mg). 1 H NMR(400MHz,D 2 O) δ 7.76 (d, J =8.0hz, 1h), 7.64-7.63 (M, 2H), 7.58-7.52 (M, 1H), 7.31-7.27 (M, 2H), 7.23-7.21 (M, 1H), 7.14-7.12 (M, 2H), 4.44 (s, 2H), 3.41 (s, 2H), 3.39 (s, 2H), 2.95-2.92 (M, 1H), 2.54-2.49 (M, 1H), 2.00-1.94 (M, 6H), 1.50-1.49 (M, 1H), 1.36-1.33 (M, 1H) MS-ESI calculation value [ M + H [ ]] + 389, found 389.
Example 34
The synthetic route is as follows:
first step of
Compound 34-3 (20.0 mg) was obtained by the first step of referential example 28. MS-ESI meterCalculate the value [ M + H] + 489, found 489.
Second step the second step of reference example 28 gave compound 34 (12.0 mg). 1 H NMR(400MHz,D 2 O) δ 7.68 (d, J =8.4hz, 2h), 7.58 (d, J =8.4hz, 2h), 7.27-7.24 (M, 2H), 7.20-7.18 (M, 1H), 7.10-7.08 (M, 2H), 4.29 (s, 2H), 3.36 (d, J =2.0hz, 2h), 3.23 (s, 2H), 2.90-2.87 (M, 1H), 2.49-2.47 (M, 1H), 1.93-1.85 (M, 6H), 1.45-1.42 (M, 1H), 1.31-1.27 (M, 1H). MS-ESI calculation [ M + H [ ] ] + 389, found 389.
Example 35
The synthetic route is as follows:
first step of
Reference example 28 gave compound 35-3 (77.0 mg) in the first step. MS-ESI calculated value [ M + H%] + 439, found 439.
Second step of
The second step of reference example 28 gave compound 35 (12.2 mg). 1H NMR (400MHz, D2O). Delta.7.47-7.43 (M, 2H), 7.43-7.29 (M, 2H), 7.24-7.12 (M, 5H), 4.33 (s, 2H), 3.39 (s, 2H), 3.29 (s, 2H), 2.91-2.88 (M, 1H), 2.50-2.47 (M, 1H), 1.96-1.94 (M, 6H), 1.48-1.45 (M, 1H), 1.36-1.33 (M, 1H), MS-ESI calculated [ M + H ] +339, found 339.
Example 36
The synthesis route is as follows:
first step of
Under the protection of nitrogen, the mixture is preparedCompound 35-3 (30.0mg, 0.680mmol) was dissolved in methanol, 37% aqueous formaldehyde (27.7mg, 0.342mmol) and acetic acid (20.5mg, 0.342mmol) were added, and the reaction mixture was stirred at 25 ℃ for 10 minutes, followed by addition of sodium cyanoborohydride (12.9mg, 0.205mmol), and the reaction mixture was stirred at 25 ℃ for 50 minutes. To the reaction solution, 50mL of water was added, extracted with ethyl acetate (50mL × 2), and the organic phases were combined, washed with saturated brine (80mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by thin layer chromatography (4. MS-ESI calculated value [ M + H%] + 453, found 453.
Second step of
The second step of referential example 28 gave compound 36 (14.5 mg). 1 H NMR(400MHz,D 2 O) delta 7.43-7.42 (M, 2H), 7.29-7.21 (M, 2H), 7.16-7.10 (M, 5H), 4.34 (s, 2H), 3.44 (s, 2H), 3.34 (s, 2H), 2.92-2.89 (M, 1H), 2.79 (s, 3H), 2.53-2.47 (M, 1H), 1.91-1.90 (M, 4H), 1.89-1.88 (M, 2H), 1.50-1.48 (M, 1H), 1.35-1.32 (M, 1H), MS-ESI calculation [ M + H ] M + H] + 353, measured value 353.
Example 37
The synthetic route is as follows:
first step of
Compound 37-3 (127 mg) was obtained according to the first synthesis procedure of example 28. MS-ESI calculated value [ M + H%] + 490, found 490.
Second step of
The second step of referential example 28 gave compound 37 (12.5 mg). 1 H NMR(400MHz,CH 3 OD)δ9.03(d,J＝1.6Hz,1H),8.46(dd,J 1 ＝1.6,J 2 ＝8.0Hz,1H),7.94(d,J＝8.0Hz,1H),7.34-7.31(m,2H),7.24-7.21(m,3H),4.56(s,2H),3.59(d,J＝4.0Hz,2H),3.54(s,2H),3.18-3.16(m,1H),2.82-2.80(m,1H),2.15-2.13(m,6H)1.82-1.76 (m, 1H), 1.41-1.38 (m, 1H). MS-ESI calculated value [ M + H%] + 390, found 390.
Example 38
The synthesis route is as follows:
first step of
Compound 38-3 (53.0 mg) was obtained by the first step in reference to example 36. MS-ESI calculated value [ M + H%] + 504, found 504.
Second step the second step of reference example 28 gave compound 38 (20.4 mg). 1 H NMR(400MHz,D 2 O)δ8.72(d,J＝2.0Hz,1H),8.17(dd,J 1 ＝2.0,J 2 =8.0hz, 1h), 7.87 (d, J =8.0hz, 1h), 7.29-7.25 (m, 2H), 7.21-7.18 (m, 1H), 7.12-7.10 (m, 2H), 4.45 (s, 2H), 3.47-3.43 (m, 4H), 2.97-2.95 (m, 1H), 2.73 (s, 3H), 2.53-2.52 (m, 1H), 2.04-1.92 (m, 6H), 1.52-1.49 (m, 1H), 1.36-1.32 (m, 1H). MS-ESI calculated value [ M + H%] + 404, measured value 404.
Example 39
The synthetic route is as follows:
first step of
Compound 9-2 (100mg, 0.302mmol) was dissolved in isopropanol (5 mL) under a nitrogen atmosphere, triethylamine (153mg, 1.51mmol) and methyl acrylate (78.2mg, 0.907 mmol) were further added, and the reaction mixture was heated to 80 ℃ in a sealed tube and stirred for 12 hours. Water (20 mL) was added to the reaction mixture, which was extracted with ethyl acetate (20mL. Times.1). The organic phases are combined withThe crude product was separated and purified by silica gel column chromatography (1. 1 H NMR(400MHz,CDCl 3 )δ7.26-7.23(m,2H),7.17-7.15(m,1H),7.07-7.05(m,2H),3.66(s,3H),3.51-3.47(m,1H),3.24-3.20(m,1H),2.83(t,J＝7.2Hz,2H),2.66-2.62(m,1H),2.57-2.56(m,2H),2.46(t,J＝7.2Hz,2H),2.10-2.05(m,1H),1.84-1.74(m,8H),1.38(s,9H).
Second step of
Compound 39-2 (30.0 mg, 72. Mu. Mol) was dissolved in water (1 mL) and tetrahydrofuran (4 mL), and then, water and lithium hydroxide (8.6 mg, 0.360mmol) were added to stir the reaction solution at 25 ℃ for 12 hours. The aqueous phase was adjusted to pH 5 with 1M aqueous hydrochloric acid, extracted with dichloromethane/methanol (10) (20mL × 2), and the organic phases were combined, washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 39-3 (20.0 mg). MS-ESI calculated value [ M + H%] + 403, measured value 403.
The third step
The second step of reference example 28 gave compound 39 (11.1 mg). 1 H NMR(400MHz,D 2 O) δ 7.32-7.29 (M, 2H), 7.25-7.23 (M, 1H), 7.16-7.14 (M, 2H), 3.44 (s, 2H), 3.32 (t, J =6.8hz, 2h), 3.28 (s, 2H), 2.98-2.97 (M, 1H), 2.78 (t, J =6.8hz, 2h), 2.56-2.51 (M, 1H), 2.00-1.95 (M, 6H), 1.53-1.52 (M, 1H), 1.38-1.36 (M, 1H), MS-ESI calculation [ M + H, 1H ] ] + 303, found value 303.
Example 40
The synthesis route is as follows:
first step of
Compound 40-2 (70.0 mg) was obtained by the first step of referential example 36. MS-ESI calculated value [ M + H%] + 431, found 431.
Second step of
The second step of referential example 39 gave compound 40-3 (70.0 mg). MS-ESI calculated value [ M + H%] + 417, found 417.
The third step
The second step of reference example 28 gave compound 40 (22.5 mg). 1 H NMR(400MHz,D 2 O) delta 7.35-7.31 (M, 2H), 7.27-7.23 (M, 1H), 7.19-7.17 (M, 2H), 3.58 (s, 2H), 3.44-3.34 (M, 4H), 3.06-3.03 (M, 1H), 2.90-2.80 (M, 5H), 2.63-2.58 (M, 1H), 2.14-1.98 (M, 6H), 1.59-1.58 (M, 1H), 1.41-1.39 (M, 1H), MS-ESI calculation [ M + H ] M + H] + 317, measured value 317.
EXAMPLE 41
The synthetic route is as follows:
first step of
Compound 9-2 (35mg, 0.106mmol) was dissolved in tetrahydrofuran (5 mL) under nitrogen, p-fluoroacetophenone (14.6 mg, 0.106mmol) and tetraethyltitanyl (48.3mg, 0.212mmol) were added, the reaction was stirred at 60 ℃ for 11 hours, then sodium borohydride (12.0mg, 0.317mmol) and methanol (1 mL) were added, and the reaction was stirred at 25 ℃ for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20mL. Times.1). The organic phase was washed with saturated brine (20mLx 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained crude product was isolated and purified by thin layer chromatography (20. MS-ESI calculated value [ M + H% ] + 453, actual measurement value 453.
Second step of
The second step of referential example 28 gave compound 41 (3.2 mg). 1 H NMR(400MHz,D 2 O)δ7.42-7.40(m,2H),7.24-7.22(m,2H),7.18-7.14(m,1H),7.07-7.05(m,4H),4.38-4.33(m,1H),3.29-3.11(m,3H),2.88-2.85(m,1H),2.79-2.76(m,1H),2.46-2.37 (m, 1H), 1.89-1.70 (m, 6H), 1.57 (d, J =6.8hz, 3h), 1.44-1.35 (m, 1H), 1.27-1.21 (m, 1H). MS-ESI calculated value [ M + H%] + 353, measured value 353.
Example 42
The synthesis route is as follows:
first step of
Compound 42-3 (25.0 mg) was obtained by the first step of referential example 41. MS-ESI calculated value [ M + H%] + 453, found 453.
Second step of
The second step of referential example 28 gave compound 42 (4.0 mg). 1 H NMR(400MHz,D 2 O) δ 7.44-7.43 (m, 1H), 7.28-7.25 (m, 1H), 7.21-7.19 (m, 2H), 7.10-7.08 (m, 5H), 4.64-4.59 (m, 1H), 3.32-3.27 (m, 3H), 2.97-2.93 (m, 1H), 2.84-2.80 (m, 1H), 2.48-2.39 (m, 1H), 1.91-1.80 (m, 6H), 1.62 (d, J =6.8hz, 3h), 1.47-1.37 (m, 1H), 1.29-1.25 (m, 1H). MS-ESI calculated value [ M + H%] + 353, measured value 353.
Example 43
The synthesis route is as follows:
first step of
Compound 43-3 (30.0 mg) was obtained by the first step of referential example 41. MS-ESI calculated value [ M + H%] + 460, found value 460.
Second step of
The second step of referential example 28 gave compound 43 (3.4 mg). 1H NMR (400mhz, d2 o) δ 7.82 (d, J =1.6hz, 1H), 7.76-7.70 (m, 2H), 7.57-7.53 (m, 1H), 7.30-7.28 (m, 2H), 7.24-7.20 (m, 1H), 7.12-7.10 (m, 2H), 4.51-4.45 (m, 1H), 3.31-3.17 (m, 3H), 2.94-2.91 (m, 1H), 2.85-2.84 (m, 1H), 2.50-2.40 (m, 1H), 1.94-1.80 (m, 6H), 1.65 (d, J =6.8hz, 3h), 1.48-1.40 (m, 1H), 1.32-1.28 (m, 1H). MS-ESI calculated [ M + H ] +360, found 360.
Example 44
The synthetic route is as follows:
first step of
Compound 9-2 (70.0mg, 0.212mmol) was dissolved in dimethylsulfoxide (5 mL) under a nitrogen atmosphere, diisopropylethylamine (82.1mg, 0.635mmol) and compound 44-2 (49.3mg, 0.318mmol) were added at 25 ℃ and the reaction solution was stirred at 100 ℃ for 12 hours. Water (20 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (20mL × 1), the organic phase was washed with saturated brine (20mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was isolated and purified by thin layer chromatography (1. MS-ESI calculated value [ M + H%] + 466, found 466.
Second step of
The second step of reference example 39 gave compound 44-4.MS-ESI calculated value [ M + H%] + 452, found 452.
The third step
The second step of reference example 28 gave compound 44. 1 H NMR(400MHz,D 2 O) δ 7.90-7.86 (m, 1H), 7.30 (d, J =6.8hz, 1h), 7.16-7.07 (m, 4H), 7.00-6.98 (m, 2H), 3.52 (s, 2H), 3.39 (s, 2H), 2.89-2.85 (m, 1H), 2.44-2.39 (m, 1H), 1.99-1.93 (m, 6H), 1.49-1.44 (m, 1H), 1.30-1.25 (m, 1H). MS-ESI calculated value [ M + H%] + 352, found value 352.
Example 45
The synthetic route is as follows:
first step of
Compound 45-1 (2.00g, 28.5 mmol) was dissolved in methanol (20 mL) under nitrogen, ammonia (17.0g, 485 mmol), sodium cyanide (1.75g, 35.7 mmol) and ammonium chloride (3.05g, 57.1mmol) were added at 25 ℃ and the reaction was stirred at 25 ℃ for 12 hours. Water (30 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (80mL x 1), and the organic phase was washed with saturated brine (80mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 45-2. 1 H NMR(400MHz,CDCl 3 )δ2.66-2.58(m,2H),2.17-2.02(m,4H),1.84(br s,2H).
Second step of
Compound 45-2 (1.65g, 17.2mmol) was dissolved in di-tert-butyl dicarbonate (5 mL), and the reaction solution was stirred at 90 ℃ for 12 hours. The reaction solution was separated and purified by silica gel column chromatography (5. 1 H NMR(400MHz,CDCl 3 )δ2.78-2.73(m,2H),2.42-2.33(m,2H),2.20-2.08(m,1H),1.91-1.83(m,1H),1.53(s,18H).
The third step
Compound 45-3 (500mg, 1.69mmol) was dissolved in dichloromethane (20 mL) under nitrogen, diisobutylaluminum hydride (1M in toluene, 6.76mL, 6.76mmol) was added at-78 deg.C, and the reaction was stirred at-78 deg.C for 3 hours. Water (20 mL) was added to the reaction mixture, which was filtered, extracted with dichloromethane (20mL × 1), and the organic phase was washed with saturated brine (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 45-4. 1 H NMR(400MHz,CDCl 3 )δ9.53(s,1H),2.39-2.35(m,2H),2.28-2.26(m,2H),1.86-1.81(m,2H),1.36(s,18H).
The fourth step
Reference example 28 gave compound 45-6 in the first step. MS-ESI calculated value [ M + H%] + 317, measured value 317.
The fifth step
The second step of reference example 28 gave compound 45. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.36-7.30 (m, 2H), 7.27-7.22 (m, 3H), 3.73 (s, 2H), 3.19-3.15 (m, 1H), 2.78-2.73 (m, 1H), 2.49-2.37 (m, 4H), 2.20-2.07 (m, 2H), 1.78-1.72 (m, 1H), 1.48-1.42 (m, 1H). MS-ESI calculated value [ M + H%] + 217, found value 217.
Example 46
The synthetic route is as follows:
first step of
Under nitrogen protection, compound 46-1 (200mg, 1.39mmol) was dissolved in dimethyl malonate (3 mL), p-toluenesulfonic acid (12.0 mg, 69.5. Mu. Mol) was added at 25 ℃, and the reaction solution was stirred at 140 ℃ for 12 hours. The reaction solution was separated and purified by silica gel column chromatography (5. 1 H NMR(400MHz,CDCl 3 )δ7.63(d,J＝2.0Hz,1H),7.38(d,J＝8.4Hz,1H),7.26(dd,J＝2.0,8.4Hz,1H),3.96(s,2H),3.72(s,3H)。
Second step of
Compound 46-3 was obtained according to the first step of example 1. 1 H NMR(400MHz,CDCl 3 )δ7.69(d,J＝2.0Hz,1H),7.46(d,J＝8.4Hz,1H),7.34(dd,J＝2.0,8.4Hz,1H),3.78(s,3H),1.84-1.81(m,2H),1.71-1.68(m,2H)
The third step
The second step of reference example 1 gave compound 46-4.MS-ESI calculated value [ M + H%] + 224, measured value 224.
The fourth step
Under nitrogen protection, compound 46-4 (24.0mg, 0.11mmol) was dissolved in methylene chloride (2 mL), and then Desmatine reagent (91.0mg, 0.215mmol) was added at 25 ℃ to stir the reaction solution at 25 ℃Stirring for 1 hour. Saturated sodium carbonate (20 mL) was added to the reaction mixture, the mixture was extracted with dichloromethane (20mL × 1), and the organic phase was washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 46-5.MS-ESI calculated value [ M + H%] + 222, measured value 222.
The fifth step
Compound 46-5 (24.0mg, 0.180mmol) and A-2 (40.0mg, 0.180mmol) were dissolved in anhydrous dichloromethane (10 mL), acetic acid (32.5mg, 0.541mmol) was added to the reaction solution, and stirring was performed at 25 ℃ for 1 hour, sodium triacetoxyborohydride (115mg, 0.541mmol) was added, and stirring was continued at 25 ℃ for 11 hours. The reaction mixture was diluted with dichloromethane (20 mL), washed successively with saturated aqueous sodium carbonate (20mL × 1) and saturated brine (20mL × 1), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated and purified by high performance liquid chromatography to obtain compound 46. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.58 (d, J =2.0hz, 1h), 7.46 (d, J =8.4hz, 1h), 7.31 (d, J =2.0hz, 1h), 7.20-7.19 (m, 2H), 7.10-7.09 (m, 1H), 7.01-6.99 (m, 2H), 3.25-3.13 (m, 2H), 2.49-2.45 (m, 1H), 1.95-1.90 (m, 1H), 1.46-1.43 (m, 2H), 1.22-1.16 (m, 2H), 1.11-1.09 (m, 1H), 1.02-0.97 (m, 1H). MS-ESI calculated value [ M + H%] + 339, found 339.
Example 47
The synthetic route is as follows:
first step of
Compound 47-2 was obtained in the first step of reference example 46. 1 H NMR(400MHz,CDCl 3 )δ7.65(d,J＝8.4Hz,1H),7.57(d,J＝2.0Hz,1H),7.35(dd,J＝2.0,8.4Hz,1H),4.04(s,2H),3.81(s,3H).
Second step of
Compound 47-3 was obtained in the first step of reference example 1. 1 H NMR(400MHz,CDCl 3 )δ7.61(d,J＝8.4Hz,1H),7.56(d,J＝2.0Hz,1H),7.33(dd,J＝2.0,8.4Hz,1H),3.78(s,3H),1.83-1.80(m,2H),1.70-1.67(m,2H).
The third step
The second step of reference example 1 gave compound 47-4.MS-ESI calculated value [ M + H%] + 224, found 224.
The fourth step
The fourth step in reference example 46 gave compound 47-5.MS-ESI calculated value [ M + H%] + 222, measured value 222.
The fifth step
Compound 47 is obtained in the fifth step of reference example 46. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.55-7.52 (m, 2H), 7.32 (dd, J =2.0,8.4hz, 1H), 7.20-7.16 (m, 2H), 7.10-7.06 (m, 1H), 7.00-6.98 (m, 2H), 3.23-3.14 (m, 2H), 2.48-2.44 (m, 1H), 1.94-1.90 (m, 1H), 1.47-1.41 (m, 2H), 1.19-1.10 (m, 3H), 1.09-0.96 (m, 1H). MS-ESI calculated value [ M + H%] + 339, found 339.
Example 48
The synthetic route is as follows:
first step of
Compound 45-6 (4.00g, 12.6 mmol) was dissolved in anhydrous dichloromethane (40 mL) and triethylamine (3.84g, 37.9 mmol) and allyl chloroformate (1.83g, 15.2 mmol) were added at 0 ℃. The reaction mixture was stirred at 25 ℃ for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (20mL. Times.1). The organic phase was washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (5. MS-ESI calculated value [ M + H% ] + 401, found value 401.
Second step of
Compound 48-3 (4.00 g)9.99 mmol) was dissolved in anhydrous dichloromethane (50 mL) and trimethylsilyl trifluoromethanesulfonate (4.44g, 20.0 mmol) was added at 0 ℃. The reaction solution was stirred at 0 ℃ for 0.5 hour. Water (1 mL) was added to the reaction solution, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (1. MS-ESI calculated value [ M + H%] + 301, found value 301.
The third step
Reference example 28 gave compound 48-6 in the first step. MS-ESI calculated value [ M + H%] + 416, found 416.
The fourth step
Compound 48-6 (32mg, 77.0. Mu. Mol) was dissolved in tetrahydrofuran (5 mL) under nitrogen, diethylamine (56.3mg, 0.077mmol) and tetratriphenylphosphine palladium (8.90mg, 7.70. Mu. Mol) were added to the solution, the reaction solution was stirred at 70 ℃ for 12 hours, water (20 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (20mL. Times.3). The organic phases were combined, washed with saturated brine (20mL. Times.1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was isolated and purified by high performance liquid chromatography to give compound 48. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.81-7.79 (M, 2H), 7.75-7.73 (M, 2H), 7.24-7.20 (M, 2H), 7.16-7.12 (M, 3H), 4.35-4.27 (M, 2H), 3.84 (s, 2H), 3.14-3.04 (M, 1H), 2.78-2.66 (M, 1H), 2.55-2.47 (M, 2H), 2.41-2.28 (M, 2H), 2.13-1.96 (M, 2H), 1.76-1.66 (M, 1H), 1.35-1.30 (M, 1H), MS-ESI calculation [ M + H ] ] + 332, found 332.
Example 49
The synthetic route is as follows:
first step of
Under the protection of nitrogen, compound 1-6 (4.00g, 12.8mmol) was dissolved in methylene chloride (50 mL) and diisobutylaluminum hydride (1M in toluene, 25.6mL,25.6 mmol) was added at-78 ℃ to stir the reaction mixture at-78 ℃For 3 hours. To the reaction solution was added a saturated aqueous solution of sodium potassium tartrate (100 mL), stirred at 25 ℃ for 12 hours, the mixture was extracted with dichloromethane (100mL x 1), the organic phase was washed with a saturated brine (100mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (4. 1 H NMR(400MHz,CDCl 3 )δ9.00(s,1H),7.26-7.24(m,2H),7.12-7.08(m,1H),7.03-7.01(m,2H),3.71-3.63(m,2H),2.63-2.59(m,1H),2.07-2.02(m,1H),1.34(s,9H),1.25-1.19(m,2H),1.14-1.08(m,4H).
Second step of
Compound 49-4 was obtained in the first step of referential example 28. MS-ESI calculated value [ M + H%] + 434, found 434.
The third step
The second step of reference example 28 gave compound 49. 1 H NMR(400MHz,Methonal-d 4 ) δ 8.94 (s, 1H), 8.77 (d, J =6.0hz, 1h), 8.05 (d, J =6.0hz, 1h), 7.32-7.28 (M, 2H), 7.24-7.20 (M, 3H), 4.91-4.66 (M, 2H), 4.3-3.3 (M, 8H), 3.18-3.14 (M, 1H), 2.85-2.75 (M, 1H), 1.80-1.75 (M, 1H), 1.39-1.34 (M, 1H), 1.15-1.08 (M, 4H), MS-ESI calculated value [ M + H, H ], M + 1H, M] + 334, measured value 334.
Example 50
The synthesis route is as follows:
first step of
Compound 50-2 was obtained in the first step of reference example 28. MS-ESI calculated value [ M + H% ] + 477, measured 477.
Second step of
The second step of reference example 28 gave compound 50. 1 H NMR(400MHz,Methonal-d 4 )δ7.33-7.30(m,6H),7.26-7.18(m,3H),4.69-4.49(m,4H),3.70-3.47(m,2H),3.41-3.35(m,1H),3.26-3.05(m,3H),2.73-2.68 (M, 1H), 1.73-1.64 (M, 1H), 1.42-1.35 (M, 1H), 1.00-0.84 (M, 4H). MS-ESI calculated value [ M + H] + 377, found 377.
Example 51
The synthetic route is as follows:
first step of
Compound 51-2 (45.2mg, 0.190mmol) was dissolved in anhydrous dichloromethane (10 mL), triethylamine (19.3mg, 0.190mmol) was added, the reaction mixture was stirred for 0.5 hour, compound 49-2 (50.0 mg, 0.159mmol) and acetic acid (28.6mg, 0.476mmol) were added to the reaction mixture, stirred at 25 ℃ for 0.5 hour, sodium triacetoxyborohydride (101mg, 0.176mmol) was added, and stirring was continued at 25 ℃ for 11 hours. The reaction mixture was diluted with dichloromethane (20 mL), washed with saturated aqueous sodium carbonate (20mL × 1) and saturated brine (20mL × 1), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the residue was separated and purified by thin layer chromatography (2. MS-ESI calculated value [ M + H%] + 501, measured value 501.
Second step of
The second step of reference example 28 gave compound 51. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.66-7.62 (M, 2H), 7.51-7.49 (M, 1H), 7.33-7.29 (M, 2H), 7.25-7.19 (M, 3H), 4.88-4.86 (M, 1H), 4.53-4.49 (M, 1H), 4.10-3.90 (M, 1H), 3.85-3.47 (M, 5H), 3.27-3.22 (M, 2H), 3.13-3.12 (M, 1H), 2.79-2.72 (M, 1H), 1.82-1.68 (M, 1H), 1.36-1.31 (M, 1H), 1.11-0.96 (M, 4H). MS-ESI calculation [ M + H ] ] + 401, found value 401.
Example 52
The synthesis route is as follows:
first step of
The first step of reference example 51 gave compound 52-2.MS-ESI calculated value [ M + H%] + 495, found value 495.
Second step of
The second step of reference example 28 gave compound 52. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.37-7.31 (M, 6H), 7.26-7.22 (M, 3H), 3.87-3.82 (M, 2H), 3.55-3.52 (M, 1H), 3.45-3.40 (M, 1H), 3.37-3.34 (M, 1H), 3.30-3.27 (M, 1H), 3.20-3.12 (M, 3H), 2.96-2.90 (M, 1H), 2.83-2.77 (M, 1H), 2.36-2.27 (M, 2H), 2.12-2.09 (M, 2H), 1.79-1.74 (M, 1H), 1.41-1.35 (M, 1H), 1.06-1.03 (M, 2H), 1.00-0.95 (M, 2H), MS-ESI [ M + H ], [ M,2H ]] + 395, found 395.
Example 53
The synthesis route is as follows:
first step of
Compound 53-2 is obtained by the first step of reference example 51. MS-ESI calculated value [ M + H%] + 491, found 491.
Second step of
The second step of reference example 39 gave compound 53-3.MS-ESI calculated value [ M + H%] + 477, measured 477.
The third step
The second step of reference example 28 gave compound 53. 1 H NMR(400MHz,Methonal-d 4 )δ7.97-7.96(m,2H),7.42-7.39(m,1H),7.33-7.29(m,2H),7.25-7.19(m,3H),4.87-4.80(m,1H),4.51-7.48(m,1H),4.12-3.88(m 1H),3.86-3.46(m,4H),3.33-3.21(m,3H),3.15-3.05(m,1H),2.88-2.79(m,1H),1.82-1.67(M, 1H), 1.38-1.31 (M, 1H), 1.11-0.97 (M, 4H). Calculated values of MS-ESI [ M + H ]]+377, found 377.
Example 54
The synthetic route is as follows:
first step of
Compound 54-2 was obtained by the first step of reference example 28. MS-ESI calculated value [ M + H%] + 443, found 443.
Second step of
The second step of reference example 39 gave compound 54-3.MS-ESI calculated value [ M + H% ] + 429, found 429.
The third step
The second step of reference example 28 gave compound 54. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.34-7.30 (M, 2H), 7.26-7.21 (M, 3H), 3.80-3.64 (M, 2H), 3.50-3.46 (M, 1H), 3.39-3.36 (M, 1H), 3.29-3.22 (M, 2H), 3.15-3.11 (M, 1H), 3.06-2.91 (M, 2H), 2.79-2.74 (M, 1H), 2.70-2.58 (M, 1H), 2.28-2.13 (M, 4H), 1.77-1.72 (M, 1H), 1.40-1.35 (M, 1H), 1.03-0.93 (M, 4H). MS-ESI calculation [ M + H ]] + 329 found, value 329.
Example 55
The synthesis route is as follows:
first step of
Compound 55-2 was obtained in the first step of reference example 28. MS-ESI calculated value [ M + H%] + 487, measured value 487.
Second step of
The second step of reference example 28 gave compound 55. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.38-7.35 (M, 2H), 7.29-7.20 (M, 3H), 7.11-7.09 (M, 2H), 6.81 (d, J =8.0hz, 1h), 3.59-3.53 (M, 2H), 3.39-3.36 (M, 2H), 3.30-3.20 (M, 2H), 3.08-3.04 (M, 2H), 3.02-2.98 (M, 1H), 2.60-2.50 (M, 1H), 1.64-1.58 (M, 1H), 1.39-1.34 (M, 1H), 0.95-0.86 (M, 2H), 0.81-0.73 (M, 2H), MS-calculated value [ M + H ], ESI] + 387, found 387.
Example 56
The synthetic route is as follows:
first step of
Compound 56-2 was obtained in the first step of reference example 28. MS-ESI calculated value [ M + H%] + 505, measured value 505.
Second step of
The second step of reference example 28 gave compound 56. 1 H NMR(400MHz,Methonal-d 4 ) δ 8.03 (d, J =8.0hz, 2h), 7.45 (d, J =8.0hz, 2h), 7.35-7.31 (M, 2H), 7.27-7.22 (M, 3H), 3.93-3.81 (M, 2H), 3.55-3.52 (M, 1H), 3.45-3.41 (M, 2H), 3.30-3.26 (M, 1H), 3.18-3.15 (M, 2H), 3.08-2.94 (M, 1H), 2.81-2.76 (M, 1H), 2.37-2.34 (M, 2H), 2.18-2.13 (M, 2H), 1.78-1.73 (M, 1H), 1.42-1.31 (M, 2H), 1.05-1.03 (M, 2H), 0.99-0.97H (MS-2H) (+ M, 1H) ] + 405, found value 405.
Example 57
The synthesis route is as follows:
first step of
Compound 57-2 is obtained in the first step of reference example 28. MS-ESI calculated value [ M + H%] + 477, measured 477.
Second step of
The second step of reference example 28 gave compound 57. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.39-7.30 (M, 6H), 7.28-7.20 (M, 3H), 4.81-4.77 (M, 2H), 4.70-4.51 (M, 1H), 3.88-3.62 (M, 3H), 3.47-3.43 (M, 1H), 3.24-3.21 (M, 2H), 3.09-3.08 (M, 1H), 2.78-2.70 (M, 1H), 1.80-1.68 (M, 1H), 1.43-1.34 (M, 1H), 1.04-0.97 (M, 3H), 0.95-0.80 (M, 1H). MS-ESI calculated value [ M + H ]] + 377, found 377.
Example 58
The synthesis route is as follows:
first step of
Compound 58-2 is obtained by the first step of reference example 28. MS-ESI calculated value [ M + H%] + 447, found 447.
Second step of
The second step of reference example 28 gave compound 58. 1 H NMR(400MHz,Methonal-d 4 ) Delta 7.34-7.30 (M, 2H), 7.26-7.22 (M, 7H), 3.97-3.95 (M, 2H), 3.63-3.57 (M, 2H), 3.54-3.47 (M, 2H), 3.36-3.33 (M, 2H), 3.22-3.18 (M, 1H), 3.10-3.00 (M, 4H), 2.82-2.78 (M, 1H), 1.80-1.76 (M, 1H), 1.41-1.37 (M, 1H), 1.10-1.06 (M, 2H), 0.95-0.91 (M, 2H). MS-ESI calculated value [ M + H ]] + 347, found 347.
Example 59
The synthetic route is as follows:
first step of
Reference example 28 gave compound 59-2 in the first step. MS-ESI calculated value [ M + H%] + 433, measured value 433.
Second step of
The second step of reference example 28 gave compound 59. 1 H NMR(400MHz,Methonal-d 4 ) Delta 7.35-7.26 (M, 6H), 7.25-7.20 (M, 3H), 4.76-4.46 (M, 2H), 3.97-3.45 (M, 5H), 3.20-3.16 (M, 2H), 3.10-3.09 (M, 2H), 2.84-2.70 (M, 1H), 1.81-1.67 (M, 1H), 1.38-1.31 (M, 1H), 1.11-0.97 (M, 4H), MS-ESI calculation [ M + H ] M] + 333, found value 333.
Example 60
The synthesis route is as follows:
first step of
Compound 60-2 was obtained in the first step of reference example 28. MS-ESI calculated value [ M + H%] + 447, found 447.
Second step of
The second step of reference example 28 gave compound 60. 1 H NMR(400MHz,Methonal-d 4 ) Delta 7.39-7.28 (M, 6H), 7.24-7.14 (M, 3H), 4.33-3.77 (M, 2H), 3.75-3.34 (M, 2H), 3.20-2.87 (M, 5H), 2.75-2.37 (M, 2H), 2.09-1.96 (M, 2H), 1.86-1.48 (M, 2H), 1.31-1.29 (M, 1H), 0.86-0.10 (M, 4H), MS-ESI calculation [ M + H ] M] + 347, found 347.
Example 61
The synthetic route is as follows:
first step of
Compound 61-2 is obtained by the first step of reference example 51. MS-ESI calculated value [ M + H%] + 420, found value 420.
Second step of
Compound 61 was obtained by the third step of reference example 19. 1 H NMR(400MHz,Methonal-d 4 ) Δ 9.10-8.93 (M, 2H), 8.22-8.21 (M, 1H), 7.32-7.21 (M, 5H), 5.28-5.21 (M, 4H), 3.92-3.80 (M, 2H), 3.67-3.49 (M, 2H), 3.14-3.12 (M, 1H), 2.84-2.81 (M, 1H), 1.81-1.77 (M, 1H), 1.40-1.30 (M, 1H), 1.12-1.09 (M, 4H), MS-ESI calculation [ M + H ] M + H] + 320, measured value 320.
Example 62
The synthetic route is as follows:
first step of
Compound 1-6 (500mg, 1.60mmol) was dissolved in absolute ethanol (10 mL), hydroxylamine hydrochloride (222mg, 3.20mmol) and diisopropylethylamine (827mg, 6.40mmol) were added under nitrogen protection, and the reaction mixture was stirred at 80 ℃ for 12 hours. The reaction was cooled to 0 ℃, water (30 mL) was added, the mixture was extracted with ethyl acetate (25mL × 2), the organic phases were combined, washed with saturated brine (25mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (2. MS-ESI calculated value [ M + H%] + 346, found 346.
Second step of
Compound 62-3 (63.7mg, 0.278mmol) was dissolved in anhydrous N, N-dimethylformamide (2 mL), and carbonyldiimidazole (48.8mg, 0)301 mmol), stirred at 30 ℃ for 2 hours, compound 62-2 (80.0 mg, 0.232mmol) was added, and stirred at 110 ℃ for 12 hours. The reaction was cooled to 0 ℃, water (20 mL) was added, the mixture was extracted with ethyl acetate (25mL x 2), the organic phases were combined, washed with saturated brine (25mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin layer chromatography (2. MS-ESI calculated value [ M + Na ]] + 561, found, 561.
The third step
Compound 62-4 (91.0mg, 0.1699 mmol) was dissolved in anhydrous dichloromethane (5 mL), trifluoroacetic acid (77.0mg, 0.676mmol) was added thereto, and the mixture was stirred at 20 ℃ for 2 hours, concentrated under reduced pressure, and the crude product was isolated and purified by high performance liquid chromatography to give 62. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.32-7.29 (m, 2H), 7.24-7.21 (m, 1H), 7.18-7.16 (m, 2H), 3.74-3.64 (m, 2H), 3.49-3.40 (m, 3H), 3.24-3.19 (m, 2H), 3.11-3.07 (m, 1H), 2.67-2.62 (m, 1H), 2.35-2.32 (m, 2H), 2.15-2.02 (m, 2H), 1.68-1.63 (m, 1H), 1.45-1.35 (m, 5H). MS-ESI calculated value [ M + H%] + 339, found value 339.
Example 63
The synthetic route is as follows:
first step of
P-fluorobenzoic acid (73.0mg, 0.521mmol) was dissolved in anhydrous N, N-dimethylformamide (2 mL), carbonyldiimidazole (91.5mg, 0.564mmol) was added under nitrogen protection at 30 ℃ and stirred for 2 hours, compound 62-2 (150mg, 0.434mmol) was added to the reaction solution, and the reaction solution was heated to 110 ℃ and stirred for 10 hours. Cooling the reaction solution to room temperature, adding water (30 mL), extracting with ethyl acetate (20mL × 3), mixing organic phases, washing with saturated brine (20mL × 2), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, separating and purifying the crude product by preparative thin layer chromatography to obtain a compound 63-2. MS-ESI calculated value [ M + Na ]] + 472, measured value 472.
Second step of
Compound 63-2 (160mg, 0.356mmol) was dissolved in anhydrous dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was added dropwise at 0 ℃. The reaction solution was stirred at 0 ℃ for 1 hour, concentrated under reduced pressure, and the crude product was separated and purified by high performance liquid chromatography to give compound 63. 1 H NMR(400MHz,Methonal-d 4 ) δ 8.17-8.14 (m, 2H), 7.36-7.26 (m, 4H), 7.25-7.14 (m, 3H), 3.79-3.68 (m, 2H), 3.13-3.11 (m, 1H), 2.57-2.52 (m, 1H), 1.59-1.54 (m, 3H), 1.43-1.38 (m, 3H). MS-ESI calculated value [ M + H%] + 350, found 350.
Example 64
The synthetic route is as follows:
first step of
The first step of reference example 63 gave compound 64-2.MS-ESI calculated value [ M + Na ]] + 479, found 479.
Second step of
The second step of reference example 63 gave compound 64. 1 H NMR(400MHz,Methonal-d 4 ) δ 8.26 (d, J =8.0hz, 2h), 7.97 (d, J =8.0hz, 2h), 7.27-7.23 (m, 2H), 7.18-7.12 (m, 3H), 3.80-3.66 (m, 2H), 3.11-3.08 (m, 1H), 2.53-2.49 (m, 1H), 1.58-1.54 (m, 3H), 1.40-1.36 (m, 3H). MS-ESI calculated value [ M + H%] + 357, measured value 357.
Example 65
The synthetic route is as follows:
first step of
Reference example 63 gave compound 65-2 in the first step. MS-ESI calculated value [ M + Na ]] + 488, found 488.
Second step of
The second step of reference example 63 gave compound 65. 1 H NMR(400MHz,Methonal-d 4 ) δ 8.09 (d, J =8.4hz, 2h), 7.63 (d, J =8.4hz, 2h), 7.29-7.25 (m, 2H), 7.20-7.13 (m, 3H), 3.79-3.67 (m, 2H), 3.13-3.10 (m, 1H), 2.56-2.52 (m, 1H), 1.59-1.53 (m, 3H), 1.43-1.39 (m, 3H). MS-ESI calculated value [ M + H%] + 366, found value 366.
Example 66
The synthesis route is as follows:
first step of
Compound 66-2 is obtained in the first step of reference example 63. MS-ESI calculated value [ M + Na ] ] + 523, found 523.
Second step of
The second step of reference example 63 gave compound 66. 1 H NMR(400MHz,Methonal-d 4 ) δ 9.36 (s, 1H), 8.68 (d, J =8.0hz, 1h), 8.06 (d, J =8.0hz, 1h), 7.26-7.22 (m, 2H), 7.16-7.12 (m, 3H), 3.85-3.70 (m, 2H), 3.23-3.15 (m, 1H), 2.56-2.52 (m, 1H), 1.62-1.57 (m, 3H), 1.45-1.39 (m, 3H). MS-ESI calculated value [ M + H%] + 401, found value 401.
Example 67
The synthetic route is as follows:
first step of
Compound 67-2 was obtained in the first step of reference example 63. MS-ESI calculated value [ M + H%] + 496, found 496.
Second step of
Compound 67-2 (130mg, 0.262mol) was dissolved in water (8 mL) and tetrahydrofuran (2 mL), sodium hydroxide (41.9mg, 1.05mmol) was added, and the reaction was stirred at 40 ℃ for 4 hours. The reaction mixture was cooled to 0 ℃ and water (50 mL) was added to the reaction mixture to adjust the pH to 3 with hydrochloric acid (1 mol/L). The mixture was extracted with ethyl acetate (30mL x 3), the organic phases combined, washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 67-3.MS-ESI calculated value [ M + Na ]] + 504, found 504.
The third step
The second step of reference example 63 gave compound 67. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.34-7.30 (m, 2H), 7.26-7.22 (m, 1H), 7.19-7.17 (m, 2H), 3.73-3.64 (m, 2H), 3.11-3.07 (m, 1H), 2.97-2.90 (m, 1H), 2.64-2.59 (m, 1H), 2.39-2.33 (m, 1H), 2.19-2.11 (m, 4H), 1.67-1.51 (m, 5H), 1.45-1.37 (m, 5H). MS-ESI calculated value [ M + H% ] + 382, measured value 382.
Example 68
The synthetic route is as follows:
first step of
Compound 68-1 (4.50g, 19.6 mmol) was dissolved in absolute ethanol (50 mL), hydroxylamine hydrochloride (2.73g, 39.3 mmol) and diisopropylethylamine (10.2g, 78.6 mmol) were added, and the reaction mixture was stirred at 80 ℃ for 12 hours. The mixture was concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (1Compound 68-2. 1 H NMR(400MHz,DMSO-d 6 )δ9.72(s,1H),7.74-7.65(m,2H),7.47-7.44(m,2H),5.84(brs,2H)。
Second step of
Compound 1 (640mg, 3.01mmol) was dissolved in anhydrous dichloromethane (10 mL), and diisopropylethylamine (778mg, 6.02mmol) and allyl chloroformate (544mg, 4.51mmol) were added. The reaction solution was stirred at 20 ℃ for 1 hour. Concentrating under reduced pressure to obtain compound 68-4.MS-ESI calculated value [ M + H%] + 297, found 297.
The third step
Compound 68-4 (900mg, 3.04mmol) was dissolved in hydrochloric acid/methanol (4 mol/L10 mL) and stirred at 30 ℃ for 1 hour. The temperature was raised to 60 ℃ and stirred for 11 hours. The reaction was cooled to 0 ℃ and concentrated sulfuric acid (1 mL) was added dropwise to the reaction solution, and the reaction solution was heated to 70 ℃ and stirred for 36 hours. Concentrated under reduced pressure and the residue was taken up in water (50 mL), adjusted to pH 9 with saturated sodium carbonate, extracted with ethyl acetate (30mL x 3), the organic phases combined, washed with saturated brine (30mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and the crude product isolated and purified by thin layer chromatography (3. MS-ESI calculated value [ M + H% ] + 330, measured value 330.
The fourth step
The second step of reference example 67 gave compound 68-6.MS-ESI calculated value [ M + H%] + 316, found 316.
The fifth step
The first step of reference example 63 gave compound 68-7.MS-ESI calculated value [ M + H%] + 542, measured value 542.
The sixth step
Compound 68-7 (110mg, 0.203mmol) was dissolved in anhydrous N, N-dimethylformamide (5 mL), and zinc cyanide (47.7 mg,0.406 mmol), 2-dicyclohexylphosphonium-2 ',4',6' -triisopropylbiphenyl (9.7 mg, 20.3. Mu. Mol) and bis (dibenzylideneacetone) palladium (5.8mg, 10.2. Mu. Mol) were added under nitrogen protection. The reaction solution was stirred at 90 ℃ for 12 hours. Concentration under reduced pressure and isolation and purification of the crude product by thin layer chromatography (3. MS-ESI calculated value [ M + H%] + 441, measured value 441.
Seventh step
Compound 68-8 (47.0 mg, 0.107mmol) was dissolved in dry tetrahydrofuran (5 mL), and diethylamine (78.0 mg, 1.07mmol) and tetrakistriphenylphosphine palladium (12.3 mg, 10.6. Mu. Mol) were added under nitrogen. The reaction solution was stirred at 80 ℃ for 2 hours. Filtering the reaction solution, concentrating the filtrate under reduced pressure, and separating and purifying the crude product by high performance liquid chromatography to obtain a compound 68. 1 H NMR(400MHz,Methonal-d 4 ) δ 8.22 (d, J =8.4hz, 2h), 7.90 (d, J =8.4hz, 2h), 7.28-7.24 (m, 2H), 7.20-7.14 (m, 3H), 3.90-3.77 (m, 2H), 3.21-3.17 (m, 1H), 2.59-2.55 (m, 1H), 1.75-1.73 (m, 2H), 1.62-1.59 (m, 3H), 1.44-1.42 (m, 1H). MS-ESI calculated value [ M + H% ] + 357, found value 357.
Example 69
The synthetic route is as follows:
first step of
Compound 69-2 was obtained by the first step of reference example 68. 1 H NMR(400MHz,DMSO-d 6 ) Δ 9.74 (s, 1H), 7.69-7.67 (m, 2H), 7.45-7.42 (m, 2H), 5.87 (brs, 2H). MS-ESI calculated value [ M + H%] + 171, found value 171.
Second step of
Compound 69-3 was obtained by the first step of reference example 63. MS-ESI calculated value [ M + H%] + 450, found 450.
The third step
The seventh step of reference example 68 gave compound 69. 1 H NMR(400MHz,Methonal-d 4 ) δ 8.04 (d, J =8.8hz, 2h), 7.54 (d, J =8.8hz, 2h), 7.29-7.26 (m, 2H), 7.21-7.15 (m, 3H), 3.88-3.76 (m, 2H), 3.20-3.16 (m, 1H), 2.60-2.55 (m, 1H), 1.73-1.71 (m, 2H), 1.64-1.58 (m, 3H), 1.45-1.40 (m, 1H). MS-ESI calculated value [ M + H%] + 366, found value 366.
Example 70
The synthetic route is as follows:
first step of
Compound 68-6 (88.0mg, 0.279mmol) was dissolved in phosphorus oxychloride (1 mL), 4-chlorobenzoyl hydrazine (47.6mg, 0.279mmol) was added under the protection of nitrogen, and the reaction solution was stirred at 100 ℃ for 2 hours. The reaction was cooled to 0 ℃, added dropwise to water (30 mL), and adjusted to pH =8 with saturated sodium carbonate. The mixture was extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by thin layer chromatography (2. MS-ESI calculated value [ M + H% ] + 450, found 450.
Second step of
Compound 70 is obtained by the seventh step of reference example 68. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.98 (d, J =8.4hz, 2h), 7.59 (d, J =8.4hz, 2h), 7.28-7.24 (m, 2H), 7.19-7.14 (m, 3H), 3.85-3.72 (m, 2H), 3.17-3.13 (m, 1H), 2.59-2.57 (m, 1H), 1.65-1.59 (m, 3H), 1.55-1.53 (m, 2H), 1.41-1.39 (m, 1H). MS-ESI calculated value [ M + H%] + 366, found value 366.
Example 71
The synthetic route is as follows:
first step of
Compound 71-1 (1.70g, 9.60mmol) was dissolved in anhydrous methanol (20 mL) and concentrated sulfuric acid (2 mL) was added dropwise at 0 ℃. The reaction solution is at 80 DEG CStirred for 12 hours. The reaction was concentrated under reduced pressure, the residue was dissolved in water, adjusted to pH =9 with saturated sodium carbonate, the mixture was extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 71-2.MS-ESI calculated value [ M + H%] + 192, found 192.
Second step of
Compound 71-2 (1.00g, 5.23mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL), cesium carbonate (6.82g, 20.9 mmol) and 1, 2-dibromoethane (1.97g, 10.5 mmol) were added, and the reaction mixture was stirred at 50 ℃ for 12 hours. After cooling to room temperature, water (100 mL) was added to the reaction solution, extracted with ethyl acetate (50mL × 3), and the organic phases were combined, washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by silica gel column chromatography (3. MS-ESI calculated value [ M + H% ] + 218, found value 218.
The third step
Compound 71-3 (800mg, 3.68mmol) was dissolved in methanol (10 mL), lithium borohydride (321mg, 14.7 mmol) was added portionwise at 0 deg.C, the reaction was warmed to 20 deg.C and stirred for 1 hour, 50 deg.C and 11 hours. The reaction was cooled to room temperature, water (100 mL) was added, the mixture was extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ7.61-7.53(m,3H),7.30-7.28(m,1H),3.95(d,J＝6.8Hz,2H),2.60(t,J＝6.8Hz,1H),1.50(dd,J 1 ＝5.2Hz,J 2 ＝1.2Hz,2H),1.18(dd,J 1 ＝5.2Hz,J 2 Calculation of MS-ESI [ M + H ] =1.2Hz, 2H)] + 190, found 190.
The fourth step
Compound 71-4 (250mg, 1.32mmol) was dissolved in anhydrous dichloromethane (10 mL), and dess-Martin reagent (649mg, 1.45mmol, 95%) was added at 0 ℃ and the reaction was stirred at 25 ℃ for 12 hours. To the reaction mixture were added saturated sodium bicarbonate (30 mL) and saturated sodium thiosulfate (30 mL), and the mixture was extracted with ethyl acetate (50mL. Times.3)And the organic phases were combined, washed with saturated brine (30mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by thin layer chromatography (3. MS-ESI calculated value [ M + H% ] + 188, found 188.
The fifth step
Compound 71-5 (140mg, 0.751mmol) was dissolved in anhydrous dichloromethane (10 mL), compound A-2 (100mg, 0.751mmol) and acetic acid (135mg, 2.25mmol) were added, and the reaction solution was stirred at 30 ℃ for 1 hour. Sodium bundroxide acetate (477mg, 2.25mmol) was added and the reaction was stirred at 30 ℃ for 1 hour. Methylene chloride (50 mL) was added to the reaction mixture. The organic phase was washed successively with saturated sodium bicarbonate (20mL x 3), water (20mL x 2), saturated brine (20mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated and purified by high performance liquid chromatography to give compound 71. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.72-7.71 (m, 1H), 7.68-7.66 (m, 2H), 7.41-7.37 (m, 1H), 7.32-7.22 (m, 3H), 7.16-7.14 (m, 2H), 3.71 (s, 2H), 3.15-3.09 (m, 1H), 2.54-2.48 (m, 1H), 1.74-1.69 (m, 2H), 1.57-1.52 (m, 1H), 1.47-1.37 (m, 3H). MS-ESI calculated value [ M + H%] + 305, measured value 305.
Example 72
The synthetic route is as follows:
first step of
The second step of reference example 71 gave compound 72-2.MS-ESI calculated value [ M + H%] + 232, found 232.
Second step of
The second step of reference example 1 gave compound 72-3. 1 H NMR(400MHz,CDCl 3 )δ7.80-7.78(m,1H),7.60-7.57(m,2H),7.35-7.33(m,1H),4.12(s,2H),2.77-2.71(m,2H),2.41-2.40(m,2H),2.26-2.20(m,2H)。
The third step
Referring to the fourth step of example 46, compound 72-4 was obtained. MS-ESI calculated value [ M + H%] + 202, measured value 202.
The fourth step
Compound 72 is obtained by the fifth step of reference example 46. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.75-7.74 (m, 1H), 7.57-7.56 (m, 2H), 7.32-7.30 (m, 1H), 7.15-7.13 (m, 2H), 7.06-7.05 (m, 1H), 6.89-6.87 (m, 2H), 3.36-3.35 (m, 2H), 2.67-2.63 (m, 2H), 2.47-2.36 (m, 2H), 2.25-2.21 (m, 1H), 2.18-1.95 (m, 2H), 1.71-1.69 (m, 1H), 0.92-0.88 (m, 1H), 0.83-0.79 (m, 1H). MS-ESI calculated value [ M + H%] + 319, found 319.
Example 73
The synthetic route is as follows:
first step of
Compound 73-1 (2.00g, 12.9mmol) and compound 73-2 (685mg, 6.43mmol) were dissolved in acetic acid (1 mL) and the mixture was stirred at 120 ℃ for 48 hours. The reaction was cooled to room temperature, water (30 mL) was added, and pH =9 was adjusted with a saturated sodium bicarbonate solution, extracted with ethyl acetate (30mL × 3), the organic phases were combined, washed with a saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ7.92(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),2.31(s,3H),2.15(s,3H)。
Second step of
Compound 73-3 (420mg, 2.02mmol) was dissolved in acetonitrile (5 mL), and N-chlorosuccinimide (269mg, 2.02mmol) was added. The reaction solution was stirred at 60 ℃ for 12 hours. Water (50 mL) was added to the reaction mixture, extracted with ethyl acetate (30mL. Times.2), the organic phases combined and washed with brine Washing (20mL × 2), drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and separating and purifying the obtained crude product by silica gel column chromatography (10. 1 H NMR(400MHz,CDCl 3 )δ7.95(d,J＝8.4Hz,2H),7.43(d,J＝8.4Hz,2H),4.55(s,2H),2.43(s,3H)。
The third step
Compound 73-4 (300mg, 1.24mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL), and potassium cyanide (121mg, 1.86mmol) and potassium iodide (144mg, 0.869mmol) were added. The reaction solution was stirred at 85 ℃ for 12 hours. The reaction was cooled to 0 ℃, water (50 mL) was added, extraction was performed with ethyl acetate (30mL x 3), the organic phases were combined, washed with saturated brine (30mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting crude product was isolated and purified by thin layer chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ7.93(d,J＝8.8Hz,2H),7.44(d,J＝8.8Hz,2H),3.65(s,2H),2.45(s,3H)。
The fourth step
The second step of reference example 71 gave compound 73-6. 1 H NMR(400MHz,CDCl 3 )δ7.87(d,J＝8.8Hz,2H),7.41(d,J＝8.8Hz,2H),2.58(s,3H),1.66-1.60(m,4H)。
The fifth step
Compound 73-6 (45.0mg, 0.174mmol) was dissolved in anhydrous dichloromethane (2 mL), -diisobutylaluminum hydride (1M toluene solution, 696 μ L,0.696 mmol) was added dropwise at 78 ℃, reacted at 78 ℃ for 2 hours, water (10 mL) was added to the reaction solution, filtered, extracted with dichloromethane (10mL × 2), the organic phases were combined, washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by thin layer chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ9.12(s,1H),7.95-7.82(m,2H),7.34-7.32(m,2H),2.30(s,3H),1.58-1.56(m,2H),1.47-1.46(m,2H)。
The sixth step referring to the fifth step of example 46 gave compound 73. 1 H NMR(400MHz,Methonal-d 4 )δ7.94-7.92(m,2H),7.52-7.49(m,2H),7.26-7.24(m,2H),7.20-7.19(m,1H),7.14-7.12(m,2H),3.46-3.40(m,2H),3.11-3.10(m,1H),2.50-2.47 (m, 1H), 2.43 (s, 3H), 1.53-1.50 (m, 1H), 1.37-1.35 (m, 1H), 1.15-1.08 (m, 4H). MS-ESI calculated value [ M + H%] + 379, found 379.
Example 74
The synthetic route is as follows:
first step of
Compound 74-1 (5.00g, 30.3mmol) was dissolved in anhydrous N, N-dimethylformamide (100 mL), sodium hydrogen (60%, 2.54g,63.6 mmol) was added at 0 deg.C, stirring was continued for 0.5h, and 2, 2-dimethoxy-1, 3-dibromopropane (9.51g, 36.3mmol) was added. The reaction solution was heated to 60 ℃ and stirred for 16h. After cooling to room temperature, water (300 mL) was added to the reaction mixture, and extraction was performed with ethyl acetate (100mL × 2), and the organic phases were combined, washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (3. 1 H NMR(400MHz,CDCl 3 ) δ 8.59-8.50 (m, 2H), 7.66-7.62 (m, 1H), 7.27-7.25 (m, 1H), 4.14 (q, J =7.2hz, 2h), 3.21 (s, 3H), 3.19-3.17 (m, 2H), 3.14 (s, 3H), 2.59-2.55 (m, 2H), 1.22-1.18 (t, J =7.2hz, 3h). MS-ESI calculated value [ M + H%] + 266, found 266.
Second step of
Compound 74-2 (600mg, 2.26mmol) was dissolved in acetone (10 mL), sulfuric acid (2 mol/L,11.3 mL) was added, and the reaction mixture was stirred at 30 ℃ for 12 hours. To the reaction solution was added a saturated aqueous sodium bicarbonate solution to adjust pH =8, and extraction was performed with ethyl acetate (50mL × 2), and the organic phases were combined, washed with a saturated saline solution (25mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (1. MS-ESI calculated [ M + Na ] +242, found 242.
The third step
Compound 74-3 (13)0mg,0.590 mmol) was dissolved in methylene chloride (5 mL), and diethylaminosulfur trifluoride (0.200mL, 1.48mmol) was added dropwise at 0 ℃. The reaction solution was stirred at 30 ℃ for 12h. To the reaction solution was added saturated aqueous sodium bicarbonate (20 mL), the mixture was extracted with dichloromethane (50mL × 2), the organic phases were combined, washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin layer chromatography (1. 1 H NMR(400MHz,CDCl 3 )δ8.53-8.47(m,2H),7.61-7.55(m,1H),7.28-7.22(m,1H),4.11-4.05(q,J＝7.2Hz,2H),3.50-3.39(m,2H),3.05-2.93(m,2H),1.14-1.11(t,J＝7.2Hz,3H)。
The fourth step
Compound 74-4 (50mg, 0.210mmol) was dissolved in dry methanol (3 mL) and lithium borohydride (9.03mg, 0.410mmol) was added at 0 ℃. The reaction was stirred at 30 ℃ for 3h. The reaction solution was diluted with ethyl acetate (10 mL), hydrochloric acid (1 mol/L,5 mL) was added, the mixture was extracted with ethyl acetate (20mL × 3), the organic phases were combined, washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin layer chromatography (1. 1 H NMR(400MHz,CDCl 3 )δ8.31-8.26(m,2H),7.52-7.50(m,1H),7.26-7.21(m,1H),3.76(s,2H),2.99-2.80(m,4H)。
The fifth step
Oxalyl chloride (105mg, 0.831mmol) was dissolved in anhydrous dichloromethane (2 mL), and a solution of dimethyl sulfoxide (130mg, 1.66mmol) in anhydrous dichloromethane (2 mL) was added dropwise at 78 ℃. The reaction mixture was stirred at-78 ℃ for 0.5h, a solution of compound 74-5 (36.0mg, 0.181mmol) in dry dichloromethane (1 mL) was added dropwise, stirring was continued at-78 ℃ for 1h, triethylamine (0.440mL, 3.18mmol) was added dropwise, and the reaction mixture was stirred at-78 ℃ for 2h. After warming to 0 ℃, saturated aqueous ammonium chloride (10 mL) was added, extraction was performed with dichloromethane (25mL × 2), the organic phases were combined, washed with saturated brine (25mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin layer chromatography (1. 1 H NMR(400MHz,CDCl 3 )δ9.80(s,1H),8.62-8.51(m,2H),7.55(d,J＝8.0Hz,1H),7.39-7.36(m,1H),3.47-3.38(m,2H),3.05-2.95(m,2H)。
The sixth step
Compound 74-6 (20.0 mg, 0.101mmol) and compound A-2 (13.5mg, 0.101mmol) were dissolved in anhydrous dichloromethane (2 mL), glacial acetic acid (18.3 mg, 0.304mmol) was added, the reaction mixture was stirred at 30 ℃ for 1h, sodium borohydride acetate (64.5mg, 0.304mmol) was added, and stirring was continued for 1h. The reaction was diluted with dichloromethane (10 mL), saturated aqueous sodium bicarbonate (30 mL) was added, the mixture was extracted with dichloromethane (10mL × 2), the organic phases were combined, washed with saturated brine (25mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by high performance liquid chromatography to give compound 74. 1 H NMR(400MHz,Methonal-d 4 ) δ 9.12 (s, 1H), 8.88 (d, J =8.0hz, 1h), 8.80 (d, J =8.0hz, 1h), 8.21-8.17 (m, 1H), 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.18 (d, J =7.2hz, 2h), 3.90 (s, 2H), 3.39-3.33 (m, 2H), 3.31-3.24 (m, 2H), 3.05-3.01 (m, 1H), 2.73-2.69 (m, 1H), 1.72-1.66 (m, 1H), 1.38-1.34 (m, 1H). MS-ESI calculated value [ M + H%] + 315, measured value 315.
Example 75
The synthetic route is as follows:
first step of
75-1 (10.0 g,68.0 mmol) was dissolved in dichloromethane (50 mL), carbonyl diimidazole (11.0 g,68.0 mmol) was added in portions at 0 ℃, the reaction solution was stirred at 0 ℃ for 0.5 hours, hydroxylamine hydrochloride (6.63g, 68.0 mmol) and triethylamine (6.88g, 68.0 mmol) were added in portions, the reaction solution was further stirred at 0 ℃ for 1 hour, and the temperature was raised to 25 ℃ and stirred for 12 hours. Cooled to 0 ℃, quenched by addition of hydrochloric acid (1 mol/L,50 mL), the mixture extracted with dichloromethane (50mL × 2), the organic phases combined, washed with brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was purified by silica gel column chromatography (2 And (4) carrying out cyclization to obtain a compound 75-2. 1 H NMR(400MHz,CDCl 3 )δ7.80(d,J＝8.0Hz,2H),7.73(d,J＝8.0Hz,2H),3.54(s,3H),3.40(s,3H)。
Second step of
Sodium hydride (60%, 1.77g,44.2 mmol) was added to anhydrous tetrahydrofuran (50 mL), ethyl acetoacetate (4.93g, 37.9 mmol) was added dropwise at 0 ℃, the reaction solution was stirred at 0 ℃ for 0.5 hour, the temperature was reduced to-78 ℃, n-butyllithium (2 mol/L n-hexane solution, 13.9mL,34.7 mmol) was added dropwise, the mixture was stirred at-78 ℃ for 10 minutes, compound 75-2 (6.00g, 31.2 mmol) was added dropwise, stirring was continued for 30 minutes, the mixture was stirred at 0 ℃ for 1 hour, quenched by addition of water (50 mL), extracted with ethyl acetate (mL 50x 2), the organic phases were combined, washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (3.
The third step
Compound 75-3 (8.00g, 30.9mmol) and hydroxylamine hydrochloride (2.36g, 34.0mmol) were dissolved in pyridine (50 mL), and the reaction solution was stirred at 25 ℃ for 0.5 hour under nitrogen protection, heated to 110 ℃ and stirred for 1 hour. The reaction was cooled to 0 ℃, hydrochloric acid (1 mol/L,200 mL) was added dropwise, the mixture was extracted with ethyl acetate (100mL x 2), the organic phases were combined, washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (3.
The fourth step
Cesium carbonate (2.54g, 7.80mmol) was added to anhydrous tetrahydrofuran (5 mL), a solution of compound 75-4 (400mg, 1.56mmol) in anhydrous N, N-dimethylformamide (15 mL) was added dropwise at 0 ℃, stirred for 0.5 hours, and 1, 2-dibromoethane (351mg, 1.87mmol) was added dropwise. The reaction was warmed to 50 ℃, stirred for 16 hours, cooled to 0 ℃, and saturated aqueous ammonium chloride (15 mL) was added, extracted with ethyl acetate (50mL × 2), the organic phases were combined, washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin layer chromatography (3.
Fifth step the third step of reference example 46 gave Compound 75-6。 1 H NMR(400MHz,CDCl 3 )δ7.86(d,J＝8.0Hz,2H),7.76(d,J＝8.0Hz,2H),6.42(s,1H),3.85(s,2H),1.51-1.08(m,4H)。
The sixth step
Compound 75-6 (50.0 mg, 0.208mmol) was dissolved in anhydrous dichloromethane (5 mL), and Desmatine reagent (97.1mg, 0.229mmol) was added thereto at 25 ℃ and the reaction solution was stirred at 25 ℃ for 2 hours. To the reaction solution was added saturated sodium carbonate (5 mL), the mixture was extracted with dichloromethane (10mL × 3), the organic phases were combined, washed with saturated brine (10mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin layer chromatography (1. 1 H NMR(400MHz,CDCl 3 )δ9.15(s,1H),7.96(d,J＝8.0Hz,2H),7.78(d,J＝8.0Hz,2H),7.03(s,1H),1.86-1.84(m,2H),1.77-1.75(m,2H).
Step seven
The sixth step of reference example 74 gave compound 75. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.93 (d, J =8.0hz, 2h), 7.83 (d, J =8.0hz, 2h), 7.20-7.16 (m, 2H), 7.08-7.04 (m, 1H), 7.01-6.99 (m, 2H), 6.80 (s, 1H), 3.08-3.01 (m, 2H), 2.45-2.42 (m, 1H), 1.92-1.88 (m, 1H), 1.14-0.94 (m, 6H). MS-ESI calculated value [ M + H%] + 356, found 356.
Example 76
The synthetic route is as follows:
first step of
Compound 76-2 was obtained by the first step of reference example 46. 1 H NMR(400MHz,CDCl3)δ7.76-7.71(m,1H),7.56-7.51(m,1H),7.39-7.32(m,2H),4.04(s,2H),3.79(s,3H)。
Second step of
The first step of reference example 1 gave compound 76-3. 1 H NMR(400MHz,CDCl3)δ7.72-7.68(m,1H),7.54-7.52(m,1H),7.38-7.31(m,2H),3.76(s,3H),1.81-1.78(m,2H),1.69-1.66(m,2H)。
The third step
The second step of reference example 1 gave compound 76-4.MS-ESI calculated value [ M + H%] + 190, found 190.
Fourth step the crude compound 76-5 was obtained in the fourth step of example 46. MS-ESI calculated value [ M + H%] + 188, found 188.
The fifth step
Referring to the sixth step of example 74, compound 76 was obtained. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.58-7.57 (m, 1H), 7.52-7.45 (m, 1H), 7.33-7.29 (m, 2H), 7.21-7.17 (m, 2H), 7.10-7.07 (m, 1H), 7.02-6.99 (m, 2H), 3.20-3.13 (m, 2H), 2.48-2.44 (m, 1H), 1.96-1.90 (m, 1H), 1.46-1.42 (m, 2H), 1.18-1.08 (m, 3H), 1.01-0.95 (m, 1H). MS-ESI calculated value [ M + H%] + 305, measured value 305.
Example 77
The synthetic route is as follows:
first step of
Compound 77-2 was obtained by the first step of reference example 28. MS-ESI calculated value [ M + H%] + 371, found 371.
Second step of
Reference example 62 gave compound 77 in the third step. 1 H NMR(400MHz,Methonal-d 4 ) Delta 7.32-7.29 (m, 2H), 7.24-7.19 (m, 3H), 3.83 (s, 2H), 3.50-3.35 (m, 4H), 3.11-3.07 (m, 3H), 2.78-2.70 (m, 1H), 2.20-2.05 (m, 4H), 1.74-1.71 (m, 1H), 1.39-1.36 (m, 1H), 0.98-0.93 (m, 4H). MS-ESI calculated value [ M + H%] + 271, found value 271.
Example 78
The synthetic route is as follows:
first step of
Compound 78-2 was obtained in the first step of referential example 28. MS-ESI calculated value [ M + H%] + 385, measured value 385.
Second step of
Compound 78 was obtained by the third step of reference example 62. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.34-7.30 (M, 2H), 7.26-7.20 (M, 3H), 3.70-3.65 (M, 2H), 3.48-3.44 (M, 1H), 3.38-3.36 (M, 1H), 3.26-3.23 (M, 2H), 3.14-3.12 (M, 1H), 2.97-2.92 (M, 2H), 2.76-2.74 (M, 1H), 2.01-1.92 (M, 5H), 1.75-1.74 (M, 1H), 1.54-1.51 (M, 1H), 1.40-1.35 (M, 1H), 1.02-0.91 (M, 4H). MS-ESI calculation [ M + H ]] + 285, found value 285.
Example 79
The synthesis route is as follows:
first step of
Compound 79-2 is obtained in the first step with reference to example 51. MS-ESI calculated value [ M + H%] + 421, measured value 421.
Second step of
The third step of reference example 62 gave compound 79. 1 H NMR(400MHz,Methonal-d 4 ) Δ 7.31-7.28 (M, 2H), 7.23-7.20 (M, 3H), 3.85-3.77 (M, 2H), 3.58-3.55 (M, 1H), 3.47-3.42 (M, 2H), 3.38-3.34 (M, 1H), 3.31-3.24 (M, 2H), 3.21-3.17 (M, 1H), 2.84-2.79 (M, 1H), 2.74-2.59 (M, 2H), 2.44-2.30 (M, 2H), 1.80-1.74 (M, 1H), 1.36-1.29 (M, 1H), 1.07 (s, 2H), 0.95 (s, 2H). Calculated value of MS-ESI [ M + H ] is ] + 321, found value 321.
Example 80
The synthesis route is as follows:
first step of
Compound 80-2 was obtained by the first step of reference example 51. MS-ESI calculated value [ M + H%] + 453, found 453.
Second step of
Compound 80 was obtained by the third step of reference example 62. 1 H NMR(400MHz,Methonal-d 4 ) δ 7.30-7.28 (m, 2H), 7.23-7.19 (m, 3H), 3.87-3.84 (m, 2H), 3.51-3.47 (m, 1H), 3.40-3.32 (m, 2H), 3.27-3.24 (m, 1H), 3.15-3.12 (m, 1H), 3.07-3.05 (m, 2H), 2.77-2.74 (m, 1H), 2.62-2.56 (m, 1H), 2.17-2.13 (m, 4H), 1.75-1.73 (m, 1H), 1.35-1.34 (m, 1H), 1.02-1.00 (m, 2H), 0.96-0.93 (m, 2H). MS-ESI calculated value [ M + H%] + 353, measured value 353.
Example 81
The synthetic route is as follows:
first step of
Compound 81-2 was obtained by the first step of reference example 28. MS-ESI calculated value [ M + H%] + 410, found value 410.
Second step of
The third step of reference example 62 gave compound 81. 1 H NMR(400MHz,Methonal-d 4 )δ7.32-7.28(m,2H),7.24-7.19(m,3H),3.77-3.74(m,2H),3.50 to 3.48 (m, 1H), 3.40 to 3.37 (m, 2H), 3.28 to 3.13 (m, 3H), 3.04 to 3.02 (m, 2H), 2.78 to 2.73 (m, 1H), 2.48 to 2.34 (m, 3H), 2.23 to 2.19 (m, 1H), 1.75 to 1.70 (m, 1H), 1.38 to 1.33 (m, 1H), 1.02 to 1.00 (m, 2H), 0.94 to 0.91 (m, 2H). MS-ESI calculated value [ M + H%] + 310, measured value 310.
Example 82
The synthesis route is as follows:
first step of
Compound 82-2 was obtained by the first step of reference example 62. MS-ESI calculated value [ M + H%] + 330, measured value 330.
Second step of
The second step of referential example 62 gave compound 82-3.MS-ESI calculated value [ M + Na ] ] + 545, found 545.
The third step
Compound 82-3 (460mg, 0.880mmol) was dissolved in anhydrous dichloromethane (5 mL), trifluoroacetic acid (200mg, 1.76mmol) was added, the reaction was stirred at 20 ℃ for 0.5 hour, cooled to 0 ℃, saturated aqueous sodium carbonate solution (20 mL) was added dropwise to the reaction, the mixture was extracted with dichloromethane (25mL x 2), the organic phases were combined, washed with saturated brine (25mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 82-4.MS-ESI calculated value [ M + H%] + 423, measured value 423.
The fourth step
Compound 82-5 was obtained according to the first step of example 28. MS-ESI calculated value [ M + H%] + 571, found 571.
The fifth step
Compound 82-6 was obtained by the fourth step of EXAMPLE 48. MS-ESI calculated value [ M + H%] + 487, measured value 487.
The sixth step
The second step of reference example 54 gave compound 82.1H NMR (400MHz,Methonal-d 4 ) δ 8.13 (d, J =8.4hz, 2h), 7.75 (d, J =8.4hz, 2h), 7.32-7.28 (m, 2H), 7.24-7.15 (m, 3H), 4.49-4.47 (m, 2H), 3.74-3.60 (m, 3H), 3.54-3.31 (m, 3H), 3.27-3.24 (m, 1H), 3.09-3.05 (m, 1H), 2.69-2.56 (m, 1H), 2.45-2.12 (m, 4H), 1.71-1.58 (m, 1H), 1.41-1.36 (m, 5H). MS-ESI calculated value [ M + H%] + 473, found 473.
Example 83
The synthetic route is as follows:
first step of
The first step of reference example 51 gave compound 83-2.MS-ESI calculated value [ M + H% ] + 435, found 435.
Second step of
The second step of reference example 28 gave compound 83. 1 H NMR(400MHz,Methonal-d 4 ) Δ 9.19 (s, 1H), 8.85 (s, 1H), 7.30-7.29 (M, 2H), 7.23-7.20 (M, 3H), 4.69-4.43 (M, 1H), 4.07-3.47 (M, 7H), 3.19-2.80 (M, 3H), 1.80-1.73 (M, 1H), 1.39-1.10 (M, 6H). MS-ESI calculation [ M + H] + 335, measured value 335.
Example 84
The synthetic route is as follows:
first step of
Under nitrogen protection, compound 9-2 (50.0mg, 0.151mmol) was dissolved in dimethyl sulfoxide (1 mL), diisopropylethylamine (58.7mg, 0.454mmol) and compound 84-1 (32.0mg, 0.227mmol) were added at 25 deg.C, and trans-The reaction mixture was stirred at 110 ℃ for 12 hours, water (10 mL) and 1N aqueous hydrochloric acid (10 mL) were added to the reaction mixture, and extracted with dichloromethane (20mL × 5), the organic phase was washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was separated and purified by thin layer chromatography (10. MS-ESI calculated value [ M + H%] + 452, measured value 452.
Second step of
Under nitrogen protection, compound 84-2 (50.0 mg, 0.111mmol) was dissolved in anhydrous dichloromethane (5 mL), trimethylsilyl trifluoromethanesulfonate (49.2 mg, 0.222mmol) was added dropwise at 0 ℃ and the reaction mixture was stirred at 0 ℃ for 0.5 hour, quenched with 0.5 mL of water at 25 ℃, concentrated under reduced pressure, and separated and purified by preparative high performance liquid chromatography (hydrochloric acid) to give compound 84 (4.40 mg). 1 H NMR(400MHz,D 2 O) delta 8.28 (s, 1H), 8.12-8.10 (m, 1H), 7.21-7.12 (m, 3H), 7.04-7.02 (m, 2H), 6.97-6.94 (m, 1H), 3.52 (s, 2H), 3.41 (s, 2H), 2.93-2.89 (m, 1H), 2.46-2.40 (m, 1H), 2.03-1.86 (m, 6H), 1.49-1.43 (m, 1H), 1.32-1.27 (m, 1H). MS-ESI calculated value [ M + H%] + 352, found value 352.
Example 85
The synthesis route is as follows:
first step of
Dissolving compound 85-1 (2.00g, 16.9mmol) in anhydrous tetrahydrofuran (30 mL) under the protection of nitrogen, adding methyllithium (1M methyltetrahydrofuran solution, 20.3mL, 20.3mmol) at-78 deg.C, stirring the reaction solution at-78 deg.C for 1 hr, adding bromohydrin (2.78g, 20.3mmol) dissolved in tetrahydrofuran (15 mL) dropwise at-78 deg.C, stirring the reaction solution at-78 deg.C for 1 hr, adding methylmagnesium bromide (3M tetrahydrofuran solution, 6.8mL, 20.3mmol) at-70 deg.C, stirring the reaction solution at 25 deg.C for 12 hr, adding saturated aqueous ammonium chloride (60 mL), and adding saturated aqueous ammonium chloride (60 mL) to the reaction solutionExtraction with ethyl acetate (60mL x 1), washing of the organic phase with saturated brine (60mL x 1), drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure gave compound 85-2.MS-ESI calculated value [ M + H%] + 175, found 175.
Second step of
Compound 85-2 (1.44g, 8.30mmol) was dissolved in anhydrous dichloromethane (10 mL) under nitrogen protection, diethylaminosulfur trifluoride (2.66g, 16.5 mmol) was added dropwise at-78 ℃, the reaction mixture was stirred at 25 ℃ for 12 hours, a saturated aqueous sodium bicarbonate solution (50 mL) was added to the reaction mixture, extraction was performed with dichloromethane (50mL × 1), drying was performed with anhydrous sodium sulfate, filtration was performed, concentration was performed under reduced pressure, and separation and purification was performed by silica gel column chromatography (1. 1 H NMR(400MHz,CDCl 3 )δ8.68(d,J＝2.0Hz,1H),8.57-8.56(m,1H),7.71-7.68(m,1H),7.33-7.30(m,1H),5.47-5.27(m,1H),3.31-3.24(m,2H),2.83-2.73(m,2H)。
The third step
Under nitrogen protection, compound 85-3 (300mg, 1.70mmol) was dissolved in anhydrous dichloromethane (10 mL), diisobutylaluminum hydride (1M toluene solution, 3.4mL, 3.40mmol) was added at-78 ℃, the reaction solution was stirred at-78 ℃ for 3 hours, water (20 mL) was added to the reaction solution, filtered, the mother liquor was extracted with dichloromethane (20mL × 1), the organic phase was washed with saturated brine (30mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by thin layer chromatography (1. 1 H NMR(400MHz,CDCl 3 )δ9.59(s,1H),8.58-8.57(m,1H),8.45(d,J＝2.0Hz,1H),7.50-7.48(m,1H),7.36-7.33(m,1H),5.19-5.05(m,1H),3.26-3.19(m,2H),2.68-2.59(m,2H)。
The fourth step
Dissolving compound 85-4 (70.0mg, 0.391mmol) in anhydrous dichloromethane (10 mL) under nitrogen protection, adding acetic acid (70.4mg, 1.17mmol) and compound A-2 (52.0mg, 0.391mmol), stirring the reaction solution at 25 ℃ for 1 hour, adding sodium triethoxyborohydride (248mg, 1.17mmol), stirring the reaction solution at 25 ℃ for 11 hours, adding saturated aqueous sodium carbonate (20 mL), extracting with dichloromethane (20mL x 1), washing the organic phase with saturated brine (20mL x 1), drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and performing thin layer chromatography to obtain the residue(10: 1 dichloromethane/methanol, rf = 0.5) to give a product, which is isolated and purified by preparative high performance liquid chromatography (hydrochloric acid) to give compound 85. 1 H NMR(400MHz,D 2 O) delta 8.70-8.69 (m, 1H), 8.53-8.52 (m, 1H), 8.49-8.47 (m, 1H), 7.93-7.89 (m, 1H), 7.27-7.18 (m, 3H), 6.97-6.95 (m, 2H), 5.37-5.17 (m, 1H), 3.70 (s, 2H), 3.05-2.93 (m, 2H), 2.79-2.62 (m, 3H), 2.35-2.29 (m, 1H), 1.41-1.36 (m, 1H), 1.26-1.21 (m, 1H). MS-ESI calculated value [ M + H%] + 297, found 297.
Example 86
The synthesis route is as follows:
first step of
The third step of referential example 85 gave compound 86-1. 1 H NMR(400MHz,CDCl 3 ) Δ 9.61 (s, 1H), 8.59-8.56 (m, 2H), 7.60-7.57 (m, 1H), 7.37-7.34 (m, 1H), 4.44-4.38 (m, 1H), 2.89-2.81 (m, 2H), 2.74-2.69 (m, 2H). MS-ESI calculated value [ M + H%] + 178, found 178.
Second step of
Compound 86 is obtained by the fourth step of EXAMPLE 85. 1 H NMR(400MHz,D 2 O) δ 8.79 (d, J =1.6hz, 0.5h), 8.64 (d, J =1.6hz, 0.5h), 8.60-8.58 (m, 0.5H), 8.50-8.47 (m, 1H), 8.45-8.43 (m, 0.5H), 7.91-7.86 (m, 1H), 7.24-7.16 (m, 3H), 6.94-6.92 (m, 2H), 4.51-4.43 (m, 0.5H), 4.12-4.05 (m, 0.5H), 3.73-3.68 (m, 2H), 2.92-2.81 (m, 2H), 2.68-2.64 (m, 1H), 2.39-2.28 (m, 3H), 1.39-1.34 (m, 1H), 1.23-1.17 (m, 1H). MS-ESI calculated value [ M + H%] + 295, found 295.
Example 87
The synthesis route is as follows:
first step of
Under nitrogen protection, compound 19-2 (90.2mg, 0.501mmol) was dissolved in anhydrous N, N-dimethylformamide (4 mL), N-carbonyldiimidazole (88.0mg, 0.543mmol) was added in one portion, the reaction solution was stirred at 30 ℃ for 2 hours, compound 19-2 (150mg, 0.417mmol) was added in one portion, the reaction solution was stirred at 110 ℃ for 10 hours, the reaction solution was cooled to 25 ℃, water (30 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20mL × 1), the organic phase was washed with saturated brine (20mL × 2), anhydrous sodium sulfate was dried, filtration was performed, concentration was performed under reduced pressure, and (4.1 petroleum ether/ethyl acetate, rf = 0.7) was prepared by thin layer chromatography to obtain compound 87-2.MS-ESI calculated value [ M + H% ] + 504, found 504.
Second step of
The second step of reference example 84 gave compound 87. 1 H NMR(400MHz,CD 3 OD) δ 8.09 (d, J =9.2hz, 2h), 7.32-7.29 (m, 2H), 7.24-7.22 (m, 1H), 7.19-7.17 (m, 2H), 7.10 (d, J =9.2hz, 2h), 4.80-4.73 (m, 1H), 3.87 (s, 2H), 3.11-3.06 (m, 1H), 2.70-2.65 (m, 2H), 2.58-2.52 (m, 1H), 2.45-2.37 (m, 2H), 2.28-2.20 (m, 2H), 1.61-1.53 (m, 1H), 1.43-1.41 (m, 1H), 1.39-1.37 (m, 6H). MS-ESI calculated value [ M + H%] + 404, measured value 404.
Example 88
The synthetic route is as follows:
first step of
Reference example 87 gave compound 88-2 in the first step. MS-ESI calculated value [ M + H%] + 530, measured value 530.
Second step of
Second step of reference example 84Compound 88 is obtained. 1 H NMR(400MHz,CD 3 OD) delta 8.30-8.28 (m, 2H), 7.55-7.53 (m, 2H), 7.31-7.27 (m, 2H), 7.22-7.17 (m, 3H), 3.90 (s, 2H), 3.12-3.08 (m, 1H), 2.74-2.66 (m, 2H), 2.59-2.54 (m, 1H), 2.49-2.38 (m, 2H), 2.29-2.21 (m, 2H), 1.63-1.57 (m, 1H), 1.43-1.37 (m, 1H). MS-ESI calculated value [ M + H%] + 430, measured value 430.
Example 89
The synthetic route is as follows:
first step of
The first step of reference example 87 gave compound 89-2.MS-ESI calculated value [ M + H%] + 512, found 512.
Second step the second step, referred to example 84, gave compound 89. 1 H NMR(400MHz,CD 3 OD) Δ 8.24-8.20 (m, 2H), 7.39-7.37 (m, 2H), 7.32-7.28 (m, 2H), 7.24-7.22 (m, 0.25H), 7.21-7.17 (m, 3H), 7.06 (s, 0.5H), 6.88 (s, 0.25H), 3.90 (s, 2H), 3.12-3.09 (m, 1H), 2.73-2.66 (m, 2H), 2.59-2.54 (m, 1H), 2.48-2.39 (m, 2H), 2.28-2.21 (m, 2H), 1.62-1.57 (m, 1H), 1.43-1.38 (m, 1H). MS-ESI calculated value [ M + H% ] + 412, found 412.
Example 90
The synthetic route is as follows:
first step of
Under the protection of nitrogen, compound 90-1 (76.2mg, 0.501mmol) was dissolved in anhydrous N, N-dimethylformamide (4 mL) and added in one portionN, N-carbonyldiimidazole (88.0mg, 0.543mmol) was added, the reaction solution was stirred at 30 ℃ for 2 hours, then, compound 19-2 (150mg, 0.417mmol) was added all at once, the reaction solution was stirred at 110 ℃ for 10 hours, the reaction solution was cooled to 25 ℃ and water (30 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20mL x 1), the organic phase was washed with saturated brine (20mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 90-2.MS-ESI calculated value [ M + H%] + 476, found 476.
Second step the second step, referred to example 84, gave compound 90. 1 H NMR(400MHz,CD 3 OD) delta 8.09-8.07 (m, 1H), 7.68-7.64 (m, 1H), 7.33-7.13 (m, 7H), 3.98 (s, 3H), 3.89 (s, 2H), 3.14-3.10 (m, 1H), 2.73-2.66 (m, 2H), 2.59-2.55 (m, 1H), 2.44-2.38 (m, 2H), 2.28-2.20 (m, 2H), 1.62-1.56 (m, 1H), 1.44-1.39 (m, 1H). MS-ESI calculated value [ M + H%] + 376, found 376.
Example 91
The synthetic route is as follows:
first step of
Compound 91-2 was obtained by the first step of reference example 87. MS-ESI calculated value [ M + Na ]] + 493, found 493.
Second step of
The second step of reference example 84 gave compound 91. 1 H NMR(400MHz,CD 3 OD) δ 8.35 (dd, J =0.8,8.0hz, 1h), 8.05 (dd, J =0.8,8.0hz, 1h), 7.97-7.93 (m, 1H), 7.90-7.86 (m, 1H), 7.30-7.26 (m, 2H), 7.21-7.18 (m, 3H), 3.91 (s, 2H), 3.16-3.12 (m, 1H), 2.74-2.66 (m, 2H), 2.61-2.56 (m, 1H), 2.52-2.44 (m, 2H), 2.32-2.18 (m, 2H), 1.64-1.59 (m, 1H), 1.43-1.37 (m, 1H). MS-ESI calculated value [ M + H% ] + 371, found 371.
Example 92
The synthetic route is as follows:
first step of
The first step of reference example 90 gave compound 92-2.MS-ESI calculated value [ M + Na ]] + 493, found 493.
Second step of
The second step of reference example 84 gave compound 92. 1 H NMR(400MHz,CD 3 OD) Δ 8.50-8.49 (m, 1H), 8.46-8.43 (m, 1H), 8.06-8.04 (m, 1H), 7.85-7.81 (m, 1H), 7.30-7.27 (m, 2H), 7.22-7.16 (m, 3H), 3.92 (s, 2H), 3.13-3.09 (m, 1H), 2.75-2.67 (m, 2H), 2.58-2.53 (m, 1H), 2.50-2.41 (m, 2H), 2.29-2.21 (m, 2H), 1.62-1.57 (m, 1H), 1.43-1.38 (m, 1H). MS-ESI calculated value [ M + H%] + 371, found 371.
Example 93
The synthetic route is as follows:
first step of
The first step of reference example 90 gave compound 93-2.MS-ESI calculated value [ M + Na ]] + 548, found 548.
Second step of
The second step of reference example 84 gave compound 93. 1 H NMR(400MHz,CD 3 OD) delta 8.07-8.05 (m, 1H), 7.99-7.98 (m, 1H), 7.48-7.46 (m, 1H), 7.31-7.27 (m, 2H), 7.22-7.16 (m, 3H), 3.90 (s, 2H), 3.12-3.08 (m, 1H), 2.73-2.65 (m, 2H), 2.61-2.56 (m, 1H), 2.49-2.41 (m, 2H), 2.29-2.20 (m, 2H), 1.64-1.56 (m, 1H), 1.42-1.37 (m, 1H). MS-ESI calculated value [ M + H%] + 426, found value 426.
Example 94
The synthetic route is as follows:
first step of
Compound 94-2 was obtained in the first step of referential example 87. MS-ESI calculated value [ M + Na ]] + 555, found 555.
Second step of
The second step of reference example 84 gave compound 94. 1 H NMR(400MHz,CD 3 OD) delta 8.08-8.06 (m, 1H), 7.68-7.67 (m, 1H), 7.30-7.26 (m, 3H), 7.21-7.17 (m, 3H), 3.94 (s, 3H), 3.93 (s, 2H), 3.13-3.09 (m, 1H), 2.73-2.68 (m, 2H), 2.60-2.55 (m, 1H), 2.51-2.44 (m, 2H), 2.30-2.22 (m, 2H), 1.64-1.58 (m, 1H), 1.44-1.38 (m, 1H). MS-ESI calculated value [ M + H%] + 433, measured value 433.
Example 95
The synthesis route is as follows:
first step of
Compound 95-1 was obtained by the first step of reference example 87. MS-ESI calculated value [ M + Na ]] + 493, found 493.
Second step of
Compound 95-1 (50.0mg, 0.106mmol) was dissolved in dimethyl sulfoxide (5 mL) under nitrogen protection, 30% hydrogen peroxide (120mg, 1.06mmol) and potassium carbonate (29.4mg, 0.213mmol) were added, the reaction solution was stirred at 25 ℃ for 2 hours, sodium thiosulfate (20 mL) was added to the reaction solution, and ethyl acetate was usedThe ester (20mL. Times.1) was extracted, and the organic phase was washed with saturated brine (20mL. Times.1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 95-2.MS-ESI calculated value [ M + Na ]] + 511, found value 511.
The third step
The second step of reference example 84 gave compound 95. 1 H NMR(400MHz,CD 3 OD) delta 8.20-8.18 (m, 2H), 8.07-8.05 (m, 2H), 7.17-7.13 (m, 2H), 7.05-7.02 (m, 1H), 6.99-6.97 (m, 2H), 3.32-3.31 (m, 2H), 2.62-2.50 (m, 2H), 2.36-2.32 (m, 1H), 2.31-2.22 (m, 2H), 2.14-2.06 (m, 2H), 1.87-1.83 (m, 1H), 1.06-1.01 (m, 1H), 0.95-0.90 (m, 1H). MS-ESI calculated value [ M + H% ] + 389, found 389.
Example 96
The synthetic route is as follows:
first step of
Compound 96-1 (2.50g, 19.6 mmol) was dissolved in acetonitrile (10 mL), and tert-butyl nitrite (3.03g, 29.4 mmol) and trimethylsilyl azide (3.39g, 29.4 mmol) were added at 0 ℃ and stirred at 0 ℃ for 2 hours, and N, N-dimethylformamide (30 mL) was added to the reaction solution to dilute it, followed by concentration under reduced pressure to give a solution of compound 96-2 in N, N-dimethylformamide (30 mL).
Second step of
Under nitrogen protection, copper sulfate pentahydrate (1M aqueous solution, 4.3mL, 4.30mmol), sodium ascorbate (1.94g, 9.77mmol) and compound 96-3 (2.30g, 27.4 mmol) were added to a solution of compound 96-2 (3.00g, 19.5 mmol) in N, N-dimethylformamide (30 mL), the reaction mixture was stirred at 25 ℃ for 12 hours, water (30 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (40mL x 1), the aqueous phase was adjusted to pH =3-5 with 1M aqueous hydrochloric acid, extraction was performed with ethyl acetate (30mL x 4), anhydrous sodium sulfate was dried, filtration and concentration under reduced pressure was performed to give compound 96-4.MS-ESI calculated value [ M + H%] + 238, found value 238.
The third step
Compound 96-4 (2.30g, 4.26mmol) was dissolved in methanol (20 mL), concentrated sulfuric acid (0.209g, 2.13mmol) was added at 0 ℃, the reaction solution was stirred at 80 ℃ for 4 hours, cooled to 25 ℃, saturated aqueous sodium carbonate solution (50 mL) was added to the reaction solution, extracted with ethyl acetate (50mL × 1), the organic phase was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (2. MS-ESI calculated value [ M + H% ] + 252, measured value 252.
The fourth step
Compound 96-5 (2454 mg, 0.974mmol) was dissolved in N, N-dimethylformamide (5 mL), cesium carbonate (1.27g, 3.89mmol) and 1,2 dibromoethane (365.8mg, 1.95mmol) were added at 25 ℃, the reaction solution was stirred at 65 ℃ for 12 hours, cooled to 25 ℃, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20mL × 1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (2. MS-ESI calculated value [ M + H%] + 278, found in 278.
The fifth step
Compound 96-6 (113mg, 0.407mmol) was dissolved in anhydrous methanol (5 mL), lithium borohydride (35.5mg, 1.63mmol) was added at 25 ℃, the reaction solution was stirred at 65 ℃ for 12 hours, the temperature was reduced to 25 ℃, water (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20mL × 1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by thin layer chromatography (2. MS-ESI calculated value [ M + H%] + 250, found 250.
The sixth step
Compound 96-7 (8.00mg, 0.032mmol) was dissolved in anhydrous dichloromethane (2 mL), dess-martin reagent (27.2mg, 0.064mmol) was added at 25 ℃, the reaction mixture was stirred at 25 ℃ for 1 hour, saturated aqueous sodium carbonate solution (20 mL) was added to the reaction mixture, extraction was performed with dichloromethane (20mL × 1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 96-8.MS-ESI calculated value [ M + H% ] + 248, found 248.
Seventh step
Compound 96 is obtained by the fourth step of EXAMPLE 85. 1 H NMR(400MHz,CD 3 OD) delta 8.44 (s, 1H), 7.86-7.83 (m, 2H), 7.63-7.60 (m, 2H), 7.32-7.28 (m, 2H), 7.24-7.19 (m, 1H), 7.18-7.16 (m, 2H), 3.73-3.65 (m, 2H), 3.14-3.10 (m, 1H), 2.57-2.52 (m, 1H), 1.59-1.55 (m, 1H), 1.43-1.38 (m, 1H), 1.31-1.27 (m, 4H). MS-ESI calculated value [ M + H%] + 365, found 365.
Example 97
The synthesis route is as follows:
first step of
Under nitrogen protection, compound 97-1 (26.9mg, 0.183mmol) was dissolved in N, N-dimethylformamide (5 mL), 1-hydroxybenzotriazole (27.0mg, 0.200mmol), 1- (3-dimethylaminopropyl) -3-acetaldehyde hydrochloride (38.3mg, 0.200mmol) and diisopropylethylamine (43.0mg, 0.333mmol) were added, the reaction mixture was stirred at 25 ℃ for 0.5 hour, compound 48-4 (50.0mg, 0.166mmol) was added, the reaction mixture was stirred at 25 ℃ for 11.5 hours, water (20 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20mL × 1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by silica gel column chromatography (1. MS-ESI calculated value [ M + H%] + 430, measured value 430.
Second step of
Under nitrogen protection, compound 97-2 (14.0mg, 0.033mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), diethylamine (23.8mg, 0.222mmol) and tetratriphenylphosphine palladium (3.80mg, 0.003mmol) were added, the reaction mixture was stirred at 70 ℃ for 12 hours, water (20 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20mL. Times.1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and used for preparation of a drug Separation and purification by high performance liquid chromatography (hydrochloric acid) to obtain the compound 97. 1 H NMR (400MHz, CD3OD) delta 8.06-8.04 (m, 2H), 7.89-7.87 (m, 2H), 7.34-7.30 (m, 2H), 7.26-7.22 (m, 1H), 7.20-7.17 (m, 2H), 3.79 (s, 2H), 3.10-3.06 (m, 1H), 2.56-2.52 (m, 1H), 2.47-2.42 (m, 4H), 2.10-2.04 (m, 2H), 1.59-1.53 (m, 1H), 1.41-1.38 (m, 1H). MS-ESI calculated value [ M + H%] + 346, found 346.
Example 98
The synthesis route is as follows:
first step of
Compound 98-1 (100mg, 0.822mmol) was dissolved in anhydrous dichloromethane (10 mL), triethylamine (83.4 mg, 0.824mmol) was added, the reaction mixture was stirred for 0.5 hour, compound 49-2 (100mg, 0.317mmol) and acetic acid (57.1mg, 0.951mmol) were added to the reaction mixture, and stirring was continued at 25 ℃ for 0.5 hour, sodium triacetoxyborohydride (202mg, 0.951mmol) was added, and stirring was continued at 25 ℃ for 11 hours. Dichloromethane (20 mL) was added to the reaction mixture to dilute the mixture, and the mixture was washed with a saturated aqueous sodium carbonate solution (20mL × 1) and a saturated brine (20mL × 1), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by thin layer chromatography (3. MS-ESI calculated value [ M + H%] + 385, measured value 385.
Second step of
The second step of reference example 84 gave compound 98. 1 H NMR(400MHz,CD 3 OD) delta 7.34-7.30 (m, 2H), 7.25-7.21 (m, 3H), 3.95-3.77 (m, 1.5H), 3.58-3.56 (m, 0.5H), 3.45-3.38 (m, 3H), 3.33-3.16 (m, 2.5H), 3.14-3.10 (m, 1H), 2.78-2.75 (m, 1.5H), 2.70-2.50 (m, 1H), 2.35-2.25 (m, 1H), 1.76-1.72 (m, 2H), 1.38-1.36 (m, 1H), 1.19-1.18 (m, 3H), 1.00-0.96 (m, 4H). MS-ESI calculated value [ M + H%] + 285, found value 285.
Example 99
The synthetic route is as follows:
first step of
Under nitrogen protection, compound 99-1 (0.930g, 3.97mmol) was dissolved in N, N-dimethylformamide (30 mL), di-tert-butyl dicarbonate (1.73g, 7.93mmol), p-dimethylaminopyridine (48.5mg, 0.3972 mmol) and diisopropylethylamine (0.602g, 5.95mmol) were added, and the reaction mixture was stirred at 25 ℃ for 12 hours, water (20 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (2ml × 1), the organic phase was washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (4 petroleum ether/ethyl acetate, rf = 0.6) to obtain compound 99-2. 1 H NMR(400MHz,CDCl 3 )δ7.42-7.36(m,2H),7.16-7.08(m,1H),4.67-4.59(m,4H),1.51(s,9H)。
Second step of
Under nitrogen protection, compound 99-2 (0.450g, 1.51mmol) was dissolved in dimethyl sulfoxide (4.5 mL) and methanol (4.5 mL), 1, 3-bis (diphenylphosphino) propane (125mg, 0.302mmol), palladium acetate (67.8mg, 0.302mmol) and triethylamine (1.53g, 15.09mmol) were added, the reaction mixture was stirred at 80 ℃ for 12 hours under a carbon monoxide atmosphere at 15PSI, the reaction mixture was concentrated under reduced pressure, water (20 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20mL × 2), the organic phase was washed with saturated brine (2ml × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (4. MS-ESI calculated value [ M + H% ] + 278, found in 278.
The third step
The compound 99-3 (410mg, 1.48mmol) was dissolved in ethyl acetate (5 mL), hydrochloric acid (4M in ethyl acetate, 5mL, 20mmol) was added at 25 ℃, the reaction mixture was stirred at 25 ℃ for 1 hour, and the reaction mixture was concentrated under reduced pressure to give the compound 99-4.MS-ESI calculated value [ M + H%] + 178, found 178.
The fourth step
Compound 99-5 was obtained in the first step of EXAMPLE 98. MS-ESI calculated value [ M + H%] + 477, measured 477.
The fifth step
Compound 99-5 (85.0mg, 0.178mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and water (1 mL), sodium hydroxide (100mg, 2.50mmol) was added, the reaction mixture was stirred at 40 ℃ for 46 hours, the temperature was reduced to 25 ℃ and water (20 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20mL. Times.1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 99-6.MS-ESI calculated value [ M + H%] + 463, found 463.
The sixth step
The second step of reference example 84 gave compound 99. 1 H NMR(400MHz,CD 3 OD) delta 8.10-8.08 (m, 2H), 7.56-7.54 (m, 1H), 7.33-7.29 (m, 2H), 7.25-7.20 (m, 3H), 5.25-5.05 (m, 2H), 4.86-4.60 (m, 2H), 3.77-3.74 (m, 2H), 3.56-3.53 (m, 1H), 3.45-3.42 (m, 1H), 3.13-3.09 (m, 1H), 2.84-2.79 (m, 1H), 1.81-1.75 (m, 1H), 1.39-1.34 (m, 1H), 1.09-1.05 (m, 4H). MS-ESI calculated value [ M + H% ] + 363, measured value 363.
Example 100
The synthetic route is as follows:
first step of
Dissolving 100-1 (100mg, 0.335mmol) in acetonitrile (10 mL) under nitrogen protection, adding zinc cyanide (78.8mg, 0.671mmol) and tetratriphenylphosphoropadium (77.5mg, 0.067mmol), stirring the reaction solution at 80 deg.C for 12 hours, adding saturated aqueous sodium carbonate (20 mL) to the reaction solution, extracting with ethyl acetate (20mL. Times.1), washing the organic phase with saturated brine (20mL. Times.1), drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and subjecting the residue to thin layer chromatographyPreparative (3. 1 H NMR(400MHz,CDCl 3 )δ7.51-7.45(m,2H),7.33-7.26(m,1H),4.67-4.62(m,4H),1.45(s,9H)。
Second step of
Under nitrogen protection, compound 100-2 (52.0 mg, 0.213mmol) was dissolved in anhydrous dichloromethane (4 mL), trifluoroacetic acid (1.54g, 13.5 mmol) was added, the reaction was stirred at 25 ℃ for 2 hours, and the reaction was concentrated under reduced pressure to give compound 100-3. 1 H NMR(400MHz,CDCl 3 )δ7.83(s,1H),7.79-7.77(m,1H),7.64-7.62(m,1H),4.74-4.72(m,4H)。
The third step
Reference example 98 gave compound 100-4 in the first step. MS-ESI calculated value [ M + H%] + 444, found value 444.
The fourth step
The second step of reference example 84 gave compound 100. 1 H NMR(400MHz,CD 3 OD) δ 7.84-7.81 (m, 2H), 7.66-7.64 (m, 1H), 7.35-7.30 (m, 2H), 7.26-7.20 (m, 3H), 5.25-4.96 (m, 2H), 4.86-4.65 (m, 2H), 3.74-3.66 (m, 2H), 3.51-3.41 (m, 2H), 3.14-3.08 (m, 1H), 2.71-2.66 (m, 1H), 1.71-1.66 (m, 1H), 1.43-1.38 (m, 1H), 1.13-1.05 (m, 4H). MS-ESI calculated value [ M + H% ] + 344, found 344.
Example 101
The synthetic route is as follows:
first step of
The second step of referential example 99 gave compound 101-2.MS-ESI calculated value [ M + H%] + 292, found 292.
Second step of
Compound 101-3 was obtained by the third step of referential example 99. MS-ESI calculated value [ M + H%] + 192, found 192.
The third step
Compound 101-4 was obtained by the first step in accordance with example 98. MS-ESI calculated value [ M + H%] + 491, measured value 491.
The fourth step
Compound 101-4 (67.0 mg, 0.137mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and water (1 mL), sodium hydroxide (100mg, 2.50mmol) was added, the reaction mixture was stirred at 25 ℃ for 168 hours, water (20 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20mL. Times.1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 101-5.MS-ESI calculated value [ M + H%] + 477, measured 477.
The fifth step
The second step of reference example 84 gave compound 101. 1 H NMR(400MHz,CD 3 OD) delta 7.95-7.93 (m, 2H), 7.40-7.38 (m, 1H), 7.3-7.29 (m, 2H), 7.25-7.19 (m, 3H), 4.75-4.40 (m, 2H), 4.00-3.50 (m, 6H), 3.12-3.10 (m, 3H), 2.90-2.70 (m, 1H), 1.84-1.70 (m, 1H), 1.38-1.33 (m, 1H), 1.12-0.90 (m, 4H). MS-ESI calculated value [ M + H%] + 377, found 377.
Example 102
The synthetic route is as follows:
first step of
The third step of reference example 87 gave compound 102-2.MS-ESI calculated value [ M + H%] + 512, found 512.
Second step of
The second step of reference example 99 gave compound 102-3.MS-ESI calculated value [ M + H%] + 491, measured value 491.
The third step
Compound 102-3 (67.0 mg, 0.137mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and water (1 mL), lithium hydroxide monohydrate (57.3 mg, 1.37mmol) was added, and the reaction mixture was heated at 25 deg.CAfter stirring for 48 hours, water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20mL. Times.1), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 102-4.MS-ESI calculated value [ M + Na ]] + 499, measured value 499.
The fourth step
The second step of reference example 84 gave compound 102. 1 H NMR(400MHz,CD 3 OD) delta 9.35-9.33 (m, 1H), 8.77-8.68 (m, 1H), 8.44-8.37 (m, 1H), 7.28-7.24 (m, 2H), 7.17-7.14 (m, 3H), 3.89-3.85 (m, 1H), 3.76-3.73 (m, 1H), 3.17-3.16 (m, 1H), 2.61-2.59 (m, 1H), 1.64-1.59 (m, 2H), 1.50-1.38 (m, 4H). MS-ESI calculated value [ M + H%] + 377, found 377.
Example 103
The synthetic route is as follows:
first step of
Under nitrogen protection, compound 103-1 (400mg, 1.99mmol) was dissolved in methanol (10 mL), concentrated sulfuric acid (97.6 mg, 0.995mmol) was added at 0 deg.C, and the reaction mixture was stirred at 80 deg.C for 2 hours. Cooling to 25 deg.C, concentrating the reaction solution under reduced pressure, adding saturated sodium carbonate aqueous solution (20 mL), extracting with ethyl acetate (20mL x 1), washing the organic phase with saturated saline solution (20mL x 1), drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain compound 103-2. 1 H NMR(400MHz,CDCl 3 )δ7.94-7.91(m,2H),7.62-7.59(m,2H),3.94(s,3H)。
Second step of
Under the protection of nitrogen, compound 103-3 (200mg, 0.902mmol) was dissolved in N, N-dimethylformamide (10 mL), triethylamine (95.8mg, 0.947mmol) was added, the reaction mixture was stirred at 25 ℃ for 0.5 hour, and then compound 103-2 (213mg, 0.992mmol), cesium carbonate (588mg, 1.80mmol), tris (dibenzylideneacetone) dipalladium (41.3mg, 0.045mmol) and 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene (52.2 mg, 52.045 mmol) were added0.090 mmol), the reaction mixture was stirred at 100 ℃ for 11.5 hours, water (20 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20mL × 1), the organic phase was washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (3: 1 petroleum ether/ethyl acetate, rf = 0.5) to give compound 103-4.MS-ESI calculated value [ M + H%] + 320, measured value 320.
The third step
The third step of reference example 99 gave compound 103-5.MS-ESI calculated value [ M + H%] + 264, found 264.
The fourth step
The third step of reference example 87 gave compound 103-6.MS-ESI calculated value [ M + H%] + 573, found 573.
The fifth step
Compound 103-6 (56.0mg, 0.098mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and water (1 mL), and sodium hydroxide (100mg, 2.5mmol) was added thereto, the reaction mixture was stirred at 50 ℃ for 72 hours, the temperature was decreased to 25 ℃, water (20 mL) was added to the reaction mixture, the aqueous phase was adjusted to pH =5 with 1M hydrochloric acid aqueous solution, extraction was performed with ethyl acetate (20mL × 1), the organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 103-7.MS-ESI calculated value [ M + H% ] + 559, found 559.
The sixth step
The second step of reference example 84 gave compound 103. 1 H NMR(400MHz,CD 3 OD) Δ 8.13-8.11 (m, 2H), 7.54-7.52 (m, 2H), 7.35-7.31 (m, 2H), 7.27-7.24 (m, 1H), 7.19-7.17 (m, 2H), 3.95-3.91 (m, 2H), 3.75-3.67 (m, 2H), 3.60-3.55 (m, 2H), 3.49-3.42 (m, 1H), 3.13-3.09 (m, 1H), 2.59-2.54 (m, 1H), 2.42-2.39 (m, 2H), 2.30-2.21 (m, 2H), 1.62-1.57 (m, 1H), 1.50-1.49 (m, 2H), 1.45-1.40 (m, 1H), 1.38-1.35 (m, 2H). MS-ESI calculated value [ M + H%] + 459, found value 459.
Example 104
The synthesis route is as follows:
first step of
The second step of referential example 103 gave compound 104-3.MS-ESI calculated value [ M + H%] + 321, found value 321.
Second step of
The third step of reference example 99 gave compound 104-4.MS-ESI calculated value [ M + H%] + 265, found value 265.
The third step
The third step of reference example 87 gave compound 104-5.MS-ESI calculated value [ M + H%] + 574, measured value 574.
The fourth step
Compound 104-5 (35.0mg, 0.061mmol) was dissolved in anhydrous tetrahydrofuran (4 mL) and water (1 mL), sodium hydroxide (62.4mg, 1.56mmol) was added, the reaction mixture was stirred at 50 ℃ for 12 hours, the temperature was decreased to 25 ℃, water (20 mL) was added to the reaction mixture, the aqueous phase was adjusted to pH =5 with 1M aqueous hydrochloric acid solution, extraction was performed with ethyl acetate (20mL × 1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 104-6.MS-ESI calculated value [ M + H% ] + 560, found 560.
The fifth step
The second step of reference example 84 gave compound 104. 1 H NMR(400MHz,CD 3 OD) delta 8.39-8.38 (m, 1H), 8.30-8.28 (m, 1H), 8.07-8.04 (m, 1H), 7.35-7.31 (m, 2H), 7.27-7.23 (m, 1H), 7.18-7.16 (m, 2H), 4.18-4.15 (m, 2H), 3.74-3.65 (m, 2H), 3.44-3.38 (m, 3H), 3.12-3.08 (m, 1H), 2.58-2.53 (m, 1H), 2.29-2.27 (m, 2H), 2.03-1.94 (m, 2H), 1.60-1.57 (m, 1H), 1.47-1.45 (m, 2H), 1.43-1.39 (m, 1H), 1.36-1.35 (m, 2H). MS-ESI calculated value [ M + H%] + 460, found value 460.
Example 105
The synthetic route is as follows:
first step of
The third step of reference example 87 gave compound 105-2.MS-ESI calculated value [ M + Na ]] + 503, found 503.
Second step of
The second step of reference example 84 gave compound 105. 1 H NMR(400MHz,CD 3 OD) Δ 7.35-7.31 (m, 2H), 7.27-7.23 (m, 1H), 7.19-7.17 (m, 2H), 4.46-4.42 (m, 1H), 4.02-3.99 (m, 1H), 3.74-3.65 (m, 2H), 3.42-3.35 (m, 2H), 3.12-3.02 (m, 2H), 2.60-2.55 (m, 1H), 2.23-2.19 (m, 3H), 2.18-2.12 (m, 2H), 1.90-1.85 (m, 1H), 1.79-1.71 (m, 1H), 1.63-1.57 (m, 1H), 1.47-1.44 (m, 2H), 1.42-1.40 (m, 1H), 1.38-1.35 (m, 2H). MS-ESI calculated value [ M + H%] + 381, found value 381.
Example 106
The synthetic route is as follows:
first step of
Compound 106-1 (320mg, 1.53mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), triethylamine (279mg, 2.75mmol) was added, methanesulfonyl chloride (228mg, 1.99mmol) was added at 0 ℃, the reaction mixture was stirred at 25 ℃ for 1 hour, water (20 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (20mL. Times.1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a mixture of compound 106-2 and compound 106-3. 1 H NMR(400MHz,CDCl 3 )δ7.82-7.79(m,1H),4.60-4.57(m,2H),4.36-4.33(m,2H),3.55-3.54(m,3H),1.46-1.45(m,9H)。
Second step of
A mixture (340mg, 1.18mmol) of compound 106-2 and compound 106-3 was dissolved in isopropyl acetate (5 mL), and the solution was added dropwise to the solutionBenzenesulfonic acid (205.9mg, 1.30mmol), the reaction mixture was stirred at 30 ℃ for 1 hour and at 15 ℃ for 12 hours, the reaction mixture was filtered, and the filter cake was washed once with isopropyl acetate (5 mL) to give compound 106-4. 1 H NMR(400MHz,CDCl 3 )δ10.03-9.91(m,2H),7.83(s,1H),7.63-7.61(m,5H),4.59-4.53(m,2H),4.33-4.25(m,2H),3.62(s,3H)。
The third step
The first step of reference example 98 gave compound 106-5.MS-ESI calculated value [ M + H%] + 487, measured value 487.
The fourth step
Under the protection of nitrogen, compound 106-5 (50.0mg, 0.103mmol) was dissolved in anhydrous dichloromethane (10 mL), trimethylsilyl trifluoromethanesulfonate (45.7mg, 0.206mmol) was added dropwise at 0 ℃, the reaction solution was stirred at 0 ℃ for 0.5 hour, the reaction solution was quenched with a saturated aqueous solution of sodium hydrogencarbonate (20 mL) at 25 ℃, dichloromethane (10mL. Times.2) was extracted, anhydrous sodium sulfate was dried, filtered, concentrated under reduced pressure, and separated and purified by preparative high performance liquid chromatography (neutral) to give compound 106. 1 H NMR(400MHz,CD 3 OD) δ 7.60 (s, 1H), 7.22 to 7.19 (m, 2H), 7.12 to 7.08 (m, 1H), 7.04 to 7.02 (m, 2H), 4.08 to 4.02 (m, 2H), 3.84 to 3.78 (m, 2H), 3.37 (s, 3H), 2.81 to 2.67 (m, 4H), 2.44 to 2.40 (m, 1H), 1.93 to 1.86 (m, 1H), 1.10 to 1.05 (m, 1H), 1.01 to 0.96 (m, 1H), 0.51 to 0.37 (m, 4H). MS-ESI calculated value [ M + H% ] + 387, found 387.
Example 107
The synthetic route is as follows:
first step of
Under nitrogen protection, compound 82-4 (60.0mg, 0.142mmol) was dissolved in anhydrous dichloromethane (10 mL), and 2- (7-azobenzotriazol) -N, N, N, N-tetramethyluronium hexafluorophosphate (70.2mg, 0.185mmol), diisopropylethylamine (36.7mg, 0.284mmol) and compound 107-1 (38.4 mmol) were addedmg,0.213 mmol), the reaction solution was stirred at 25 ℃ for 1 hour, water (20 mL) was added to the reaction solution, extraction was performed with dichloromethane (20mL × 1), the organic phase was washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and prepared by thin layer chromatography (1: 1 petroleum ether/ethyl acetate, rf = 0.4) to give compound 107-2.MS-ESI calculated value [ M + H%] + 585, found 585.
Second step of
Compound 107-2 (55.0mg, 0.094mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) under nitrogen protection, diethylamine (68.8mg, 0.941mmol) and tetratriphenylphosphine palladium (10.9mg, 0.009mmol) were added, the reaction mixture was stirred at 70 ℃ for 12 hours, water (20 mL) was added to the reaction mixture, pH =5 was adjusted with 1M aqueous hydrochloric acid, extraction was performed with ethyl acetate (20mL. Times.1), the aqueous phase was adjusted to pH =8 with saturated sodium bicarbonate, extraction was performed with ethyl acetate (20mL. Times.2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 107-3.MS-ESI calculated value [ M + H% ] + 501, measured value 501.
The third step
Compound 107-3 (40.0 mg, 0.080mmol) was dissolved in anhydrous tetrahydrofuran (10 mL) and water (4 mL), sodium hydroxide (160mg, 4.0 mmol) was added, the reaction mixture was stirred at 50 ℃ for 12 hours, concentrated under reduced pressure, and isolated and purified by preparative high performance liquid chromatography (hydrochloric acid) to give compound 107. 1 H NMR(400MHz,CD 3 OD) Δ 8.15-8.13 (m, 2H), 7.55-7.53 (m, 2H), 7.35-7.31 (m, 2H), 7.27-7.24 (m, 1H), 7.19-7.17 (m, 2H), 4.60-4.52 (m, 1H), 3.74-3.65 (m, 3H), 3.39-3.36 (m, 2H), 3.21-3.19 (m, 1H), 3.12-3.08 (m, 1H), 2.56-2.51 (m, 1H), 2.28-2.16 (m, 1H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 2H), 1.59-1.54 (m, 1H), 1.49-1.45 (m, 2H), 1.43-1.40 (m, 1H), 1.35-1H (m, 1H). MS-ESI calculated value [ M + H%] + 487, measured value 487.
Example 108
The synthetic route is as follows:
first step of
Under the protection of nitrogen, compound 108-1 (500mg, 3.49mmol) was dissolved in anhydrous methanol (10 mL), thionyl chloride (1.66g, 14.0 mmol) was added, the reaction solution was stirred at 25 ℃ for 2 hours, and the reaction solution was concentrated under reduced pressure to give compound 108-2. 1 H NMR(400MHz,CDCl 3 )δ8.68-8.22(m,3H),3.69(s,3H),3.25-3.11(m,1H),2.37-2.34(m,1H),2.28-2.25(m,2H),2.15-2.11(m,2H),1.63-1.47(m,4H)。
Second step of
Under nitrogen protection, compound 108-2 (470mg, 2.99mmol) was dissolved in methanol (10 mL), 37% aqueous formaldehyde (594mg, 7.32mmol), sodium acetate (2450 mg, 2.99mmol) and 10% wet palladium on carbon (70.0 mg) were added, the reaction solution was stirred at 25 ℃ for 4 hours under a hydrogen atmosphere of 15PSI, the reaction solution was filtered, the organic phase was concentrated under reduced pressure, a saturated aqueous potassium carbonate solution (20 mL) was added to the reaction solution, extraction was performed with chloroform (2ml × 1), drying was performed with anhydrous sodium sulfate, filtration and concentration under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (10 dichloromethane/methanol 1, basification with a few drops of ammonia water, rf = 0.1) to obtain compound 108-3. 1 H NMR(400MHz,CDCl 3 )δ3.60(s,3H),2.21(s,6H),2.19-2.06(m,2H),2.00-1.89(m,4H),1.44-1.34(m,2H),1.19-1.11(m,2H)。
The third step
Compound 108-3 (270mg, 1.46mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) and water (1 mL), lithium hydroxide monohydrate (306mg, 7.29mmol) was added, the reaction solution was stirred at 25 ℃ for 12 hours, concentrated under reduced pressure, the residue was adjusted to pH =5 with 1M aqueous hydrochloric acid solution, concentrated under reduced pressure, dichloromethane: methanol =10 (1) (20 mL) was added, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 108-4. 1 H NMR(400MHz,CDOD)δ2.15(s,6H),2.09-2.03(m,1H),1.89-1.84(m,3H),1.78-1.75(m,2H),1.30-1.19(m,2H),1.15-1.05(m,2H)。
The fourth step
Compound 108-4 (200mg, 0.963 mmol) was dissolved in anhydrous dichloromethane (5 mL), thionyl chloride (458mg, 3.85mmol) was added, the reaction solution was stirred at 25 ℃ for 2 hours, and concentrated under reduced pressure to give compound 108-5.
The fifth step
Protection with nitrogenThen, compound 108-5 (131mg, 0.579mmol) was dissolved in chloroform (6 mL), pyridine (980mg, 12.4mmol) and compound 62-2 (100mg, 0.289mmol) were added, the reaction solution was stirred at 80 ℃ for 1 hour, the reaction solution was concentrated under reduced pressure, 1M aqueous hydrochloric acid solution was added to the reaction solution to adjust pH =5, extraction was performed with dichloromethane: methanol =10 (20mL × 1), the organic phase was washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 108-6.MS-ESI calculated value [ M + H%] + 481, found 481.
The sixth step
The second step of reference example 84 gave compound 108. 1 H NMR(400MHz,CD 3 OD) δ 7.35-7.31 (m, 2H), 7.28-7.22 (m, 1H), 7.19-7.17 (m, 2H), 3.73-3.64 (m, 2H), 3.11-3.08 (m, 1H), 3.05-2.98 (m, 1H), 2.90 (s, 6H), 2.59-2.54 (m, 1H), 2.35-2.33 (m, 2H), 2.26-2.20 (m, 2H), 1.79-1.68 (m, 4H), 1.61-1.56 (m, 1H), 1.46-1.44 (m, 2H), 1.42-1.38 (m, 2H), 1.36-1.34 (m, 2H). MS-ESI calculated value [ M + H% ] + 381, found value 381.
Example 109
The synthetic route is as follows:
first step of
Compound 109-1 (500mg, 2.39mmol) was dissolved in N, N dimethylformamide (10 mL), cesium carbonate (1.56g, 4.78mmol) and iodomethane (509mg, 3.58mmol) were added, the reaction solution was stirred at 25 ℃ for 12 hours, water (20 mL) was added to the reaction solution, extraction was performed with ethyl acetate (20mL × 1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (1. 1 H NMR(400MHz,CDCl 3 ) Δ 7.04-7.00 (M, 1H), 4.42-4.33 (M, 4H), 3.83 (s, 3H), 1.44-1.43 (M, 9H). MS-ESI calculated value [ M + H] + 224, found 224.Compound 109-3. 1 H NMR(400MHz,CDCl 3 ) Δ 7.18-7.14 (M1H), 4.42-4.31 (M, 4H), 3.75-3.74 (M, 3H), 1.44-1.43 (M, 9H). MS-ESI Calculations [ M + H] + 224, measured value 224.
Second step of
Compound 109-2 (180mg, 0.806 mmol) was dissolved in ethyl acetate (5 mL), hydrochloric acid (4M ethyl acetate solution, 5mL, 20mmol) was added dropwise, the reaction solution was stirred at 25 ℃ for 2 hours, and the reaction solution was concentrated under reduced pressure to give compound 109-4.MS-ESI calculated value [ M + H%] + 124, found value 124.
The third step
The first step of reference example 98 gave compound 109-5.MS-ESI calculated value [ M + H% ] + 423, measured value 423.
The fourth step
The second step of reference example 84 gave compound 109. 1 H NMR(400MHz,CD 3 OD) δ 7.56 (s, 1H), 7.38-7.30 (m, 2H), 7.26-7.20 (m, 3H), 4.98-4.95 (m, 2H), 4.50-4.42 (m, 2H), 3.93 (s, 3H), 3.83-3.38 (m, 4H), 3.12-3.08 (m, 1H), 2.82-2.77 (m, 1H), 1.80-1.74 (m, 1H), 1.40-1.35 (m, 1H), 1.06-1.03 (m, 4H). MS-ESI calculated value [ M + H%] + 323, found value 323.
Example 110
The synthetic route is as follows:
first step of
The second step of referential example 109 gave compound 110-2.MS-ESI calculated value [ M + H%] + 124, measured value 124.
Second step of
Compound 110-3 was obtained in the first step with reference to example 98. MS-ESI calculated value [ M + H%] + 423, measured value 423.
The third step
Second step of reference example 84 gave Compound 110。 1 H NMR(400MHz,CD 3 OD) δ 7.41 (s, 1H), 7.34 to 7.30 (m, 2H), 7.26 to 7.21 (m, 3H), 5.10 to 5.00 (m, 2H), 4.64 to 4.47 (m, 2H), 3.90 (s, 3H), 3.75 to 3.72 (m, 2H), 3.57 to 3.38 (m, 2H), 3.14 to 3.10 (m, 1H), 2.83 to 2.78 (m, 1H), 1.80 to 1.75 (m, 1H), 1.41 to 1.36 (m, 1H), 1.07 to 1.03 (m, 4H). MS-ESI calculated value [ M + H%] + 323, found 323.
Example 111
The synthetic route is as follows:
first step of
Compound 111-1 (48.4 mg, 0.285mmol) was dissolved in anhydrous methanol (10 mL), triethylamine (28.9mg, 0.285mmol) was added, the reaction solution was stirred for 0.5 hour, compound 49-2 (100mg, 0.285mmol) and acetic acid (57.4mg, 0.856 mmol) were further added to the reaction solution, stirring was performed at 50 ℃ for 0.5 hour, sodium cyanoborohydride (53.8mg, 0.856 mmol) was added, stirring was continued at 50 ℃ for 11 hours, a saturated aqueous sodium carbonate solution (20 mL) was added to the reaction solution, methanol was removed by spin-drying, the residue was washed with dichloromethane/methanol (10) (20mL. Times.1), the organic phase was washed with a saturated brine (20mL. Times.1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by thin layer chromatography (2. MS-ESI calculated value [ M + H% ] + 433, measured value 433.
Second step of
The second step of reference example 84 gave compound 111. 1 H NMR(400MHz,CD 3 OD) δ 7.34-7.31 (m, 2H), 7.27-7.21 (m, 3H), 5.50-5.36 (m, 1H), 4.56-4.48 (m, 1H), 4.34-4.24 (m, 1H), 3.58-3.55 (m, 2H), 3.50-3.43 (m, 1H), 3.38 (s, 2H), 3.07-3.03 (m, 1H), 2.82-2.73 (m, 2H), 2.44-2.28 (m, 1H), 1.72-1.66 (m, 1H), 1.42-1.37 (m, 1H), 0.98-0.87 (m, 4H). MS-ESI calculated value [ M + H%] + 333, found value 333.
Example 112
The synthetic route is as follows:
first step of
The first step of reference example 98 gave compound 112-2.MS-ESI calculated value [ M + H%] + 479, found 479.
Second step of
Compound 112-2 (97.0 mg, 0.203mmol) was dissolved in anhydrous tetrahydrofuran (8 mL) and water (2 mL), sodium hydroxide (200mg, 20.0 mmol) was added, the reaction mixture was stirred at 25 ℃ for 12 hours, water (20 mL) was added to the reaction mixture, ph =5 was adjusted with 1N aqueous hydrochloric acid solution, extraction was performed with ethyl acetate (20mL × 1), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 112-3.MS-ESI calculated value [ M + H%] + 465, found 465.
The third step
The second step of reference example 84 gave compound 112. 1 H NMR(400MHz,CD 3 OD) δ 7.38-7.31 (m, 7H), 7.27-7.25 (m, 1H), 7.22-7.20 (m, 2H), 4.34-4.30 (m, 1H), 3.60-3.57 (m, 1H), 3.50-3.41 (m, 2H), 3.29-3.23 (m, 2H), 3.07-3.04 (m, 1H), 3.01-2.98 (m, 1H), 2.75-2.73 (m, 1H), 1.69-1.64 (m, 1H), 1.43-1.37 (m, 1H), 0.99-0.91 (m, 4H). MS-ESI calculated value [ M + H% ] + 365, found 365.
Example 113
The synthesis route is as follows:
first step of
Reference to realThe first step of example 111 affords compound 113-2.MS-ESI calculated value [ M + H%] + 451, found value 451.
Second step of
The second step of reference example 84 gave compound 113. 1 H NMR(400MHz,CD 3 OD) δ 7.34 to 7.30 (m, 2H), 7.26 to 7.19 (m, 3H), 3.84 to 3.78 (m, 2H), 3.49 to 3.41 (m, 2H), 3.15 to 3.11 (m, 1H), 3.03 to 2.92 (m, 2H), 2.89 to 2.78 (m, 1H), 2.75 to 2.70 (m, 1H), 2.49 to 2.36 (m, 1H), 2.24 to 2.21 (m, 1H), 1.535 to 1.50 (m, 1H), 1.42 to 1.37 (m, 1H), 0.87 to 0.82 (m, 1H), 0.79 to 0.74 (m, 1H), 0.68 to 0.63 (m, 1H), 0.59 to 0.54 (m, 1H). MS-ESI calculated value [ M + H%] + 351, found value 351.
Example 114
The synthetic route is as follows:
first step of
Compound 114-2 was obtained by the first step in reference example 111. MS-ESI calculated value [ M + H%] + 429, found 429.
Second step of
The second step of reference example 84 gave compound 114. 1 H NMR(400MHz,CD 3 OD) δ 7.35-7.31 (m, 2H), 7.27-7.11 (m, 3H), 4.12-4.06 (m, 3H), 3.50-3.42 (m, 1H), 3.11-3.05 (m, 2H), 2.97-2.93 (m, 1H), 2.73-2.68 (m, 1H), 2.33-2.31 (m, 3H), 2.26-2.19 (m, 1H), 1.84-1.79 (m, 1H), 1.64 (s, 3H), 1.45-1.39 (m, 1H), 1.07-1.03 (m, 3H), 0.96-0.94 (m, 1H). MS-ESI calculated value [ M + H%] + 329 found, value 329.
Example 115
The synthesis route is as follows:
first step of
Compound 115-2 was obtained by the fifth step in accordance with example 108. MS-ESI calculated value [ M + H% ] + 481, found 481.
Second step of
Compound 115 was obtained by the sixth step in accordance with example 108. 1 H NMR(400MHz,CD 3 OD) δ 7.35-7.31 (m, 2H), 7.27-7.24 (m, 1H), 7.19-7.17 (m, 2H), 3.73-3.64 (m, 2H), 3.37-3.34 (m, 1H), 3.11-3.03 (m, 2H), 2.90 (s, 6H), 2.59-2.54 (m, 1H), 2.35-2.33 (m, 2H), 2.25-2.23 (m, 2H), 1.79-1.68 (m, 4H), 1.62-1.56 (m, 1H), 1.46-1.34 (m, 5H). MS-ESI calculated value [ M + H%] + 381, found value 381.
Example 116
The synthesis route is as follows:
first step of
The second step of reference example 108 gave compound 116-2. 1 H NMR(400MHz,CDCl 3 )δ3.69(s,3H),2.26(s,6H),2.15-2.14(m,2H),1.76-1.54(m,8H)。
Second step of
The third step in reference example 108 gave compound 116-3. 1 H NMR(400MHz,CDOD)δ3.30-3.23(m,1H),2.85(s,6H),2.74-2.69(m,1H),2.33-2.31(m,2H),2.05-1.99(m,2H),1.75-1.64(m,4H)。
The third step
Compound 116-4 is obtained by the fourth step in EXAMPLE 108.
The fourth step
The fifth step in reference example 108 gave compound 116-5.MS-ESI calculated value [ M + H%] + 481, found 481.
The fifth step
The second step of reference example 84 gave compound 116. 1 H NMR(400MHz,CD 3 OD) Δ 7.35-7.31 (m, 2H), 7.27-7.24 (m, 1H), 7.20-7.18 (m, 2H), 3.76-3.66 (m, 2H), 3.38-3.36 (m, 1H), 3.31-3.28 (m, 1H), 3.13-3.09 (m, 1H), 2.84 (s, 6H), 2.64-2.58 (m, 1H), 2.41-2.38 (m, 2H), 2.07-2.03 (m, 2H), 2.01-1.93 (m, 2H), 1.80-1.71 (m, 2H), 1.65-1.60 (m, 1H), 1.51-1.49 (m, 2H), 1.41-1.41 (m, 1H), 1.39-1.36 (m, 2H). MS-ESI calculated value [ M + H%] + 381, found value 381.
Example 117
The synthetic route is as follows:
first step of
Compound 117-1 (200mg, 1.03mmol) was dissolved in anhydrous dichloromethane (4 mL), triethylamine (313mg, 3.10 mmol) and cyclopropylcarbonyl chloride (119mg, 1.1 4mmol) were added, the reaction solution was stirred at 25 ℃ for 12 hours, water (20 mL) was added to the reaction solution, extraction was performed with dichloromethane (20mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (2. MS-ESI calculated value [ M + H%] + 226, found value 226.
Second step of
The third step of referential example 108 gave compound 117-3.MS-ESI calculated value [ M + H%] + 265, found 265.
The third step
The first step of reference example 87 gave compound 117-4.MS-ESI calculated value [ M + H%] + 521, found value 521.
The fourth step
The second step of reference example 84 gave compound 117. 1 H NMR(400MHz,CD 3 OD)δ7.35-7.31(m,2H),7.27-7.24(m,1H),7.19-7.17(m,2H),3.89-3.85(m,1H),3.74-3.66(m,2H),3.18-3.16 (m, 1H), 3.11-3.08 (m, 1H), 2.58-2.53 (m, 1H), 2.14-2.11 (m, 2H), 1.95-1.89 (m, 2H), 1.81-1.76 (m, 2H), 1.69-1.56 (m, 4H), 1.50-1.47 (m, 2H), 1.45-1.40 (m, 1H), 1.37-1.34 (m, 2H), 0.86-0.82 (m, 2H), 0.76-0.71 (m, 2H). MS-ESI calculated value [ M + H%] + 421, measured value 421.
Example 118
The synthetic route is as follows:
first step of
Compound 118-1 (2.00g, 17.7 mmol) was dissolved in anhydrous N, N-dimethylformamide (30 mL), 1, 8-diazabicycloundec-7-ene (5.92g, 38.9 mmol) was added dropwise, stirring was performed at 0 ℃ for 0.5 hour, and 1, 5-dibromopentane (4.47g, 19.5 mmol) was added dropwise. The temperature was raised to 80 ℃ and stirred for 2 hours. The reaction mixture was cooled to 25 ℃, water (300 mL) was added to the reaction mixture, and extraction was performed with ethyl acetate (400mL × 2), and the organic phases were combined, washed with saturated brine (250mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (5. 1 H NMR(400MHz,CDCl 3 )δ4.29-4.21(q,J＝7.2Hz,2H),2.13-2.09(m,2H),1.83-1.68(m,8H),1.34-1.30(t,J＝7.2Hz,3H)。
Second step of
Compound 118-2 (3.00g, 16.6 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), lithium borohydride (721mg, 33.1mmol) was added at 0 ℃ and the reaction mixture was stirred at 25 ℃ for 2 hours. To the reaction mixture were added ethyl acetate (200 mL) and aqueous hydrochloric acid (50mL, 1mol/L). Then, water (300 mL) was added, extraction was performed with ethyl acetate (200mL × 3), and the organic phases were combined, washed with saturated brine (300mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 118-3. 1 H NMR(400MHz,CDCl 3 )δ3.62(s,2H),2.04-2.01(m,3H),1.80-1.76(m,3H),1.64-1.61(m,2H),1.31-1.26(m,2H)。
The third step
Oxalyl chloride (2.31g, 18.2 mmol) was dissolved in dry dichloromethane (30 mL), and a solution of dimethyl sulfoxide (2.84g, 36.3 mmol) in dry dichloromethane (6 mL) was added dropwise at 78 ℃. Stirring was carried out at 78 ℃ for 0.5 hour, a solution of compound 118-3 (550mg, 3.95mmol) in dry dichloromethane (12 mL) was added dropwise, stirring was carried out at 78 ℃ for 1 hour, then triethylamine (7.03g, 69.5mmol) was added dropwise, and stirring was carried out at 78 ℃ for 2 hours. Aqueous hydrochloric acid (30mL, 1 mol/L) was added, extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated brine (30mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by preparative thin layer chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ9.48(s,1H),2.04-2.03(m,2H),1.81-1.78(m,3H),1.66-1.62(m,3H),1.28-1.23(m,2H)。
The fourth step
Compound 118-4 (100mg, 0.729mmol) and compound A-2 (97.1mg, 0.729mmol) were dissolved in dry dichloromethane (1 mL), and acetic acid (131mg, 2.19mmol) was added. The reaction mixture was stirred at 30 ℃ for 1 hour. Then, sodium borohydride acetate (0.46g, 2.19mmol) was added thereto, and the reaction solution was stirred at 30 ℃ for 1 hour. The reaction solution was diluted with dichloromethane (10 mL), washed successively with saturated aqueous sodium carbonate (10mL × 3), water (10mL × 2), and saturated brine (10mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by thin layer chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ7.18-7.10(m,2H),7.09-7.07(m,1H),6.97-6.95(m,2H),2.79(s,2H),2.37-2.35(m,1H),2.04-1.93(m,2H),1.85-1.80(m,1H),1.78-1.71(m,2H),1.71-1.61(m,3H),1.20-1.13(m,3H),1.03-0.90(m,2H)。
The fifth step
Compound 118-5 (86.0mg, 0.338mmol) was dissolved in anhydrous methanol (2 mL), and sodium borohydride (102mg, 2.70mmol) and cobalt dichloride (0.18g, 1.35mmol) were added at 0 ℃ and stirred at 25 ℃ for 2 hours. The reaction mixture was diluted with ethyl acetate (15 mL), an aqueous sodium hydroxide solution (10mL, 1mol/L) was added thereto, the mixture was filtered through celite, water (10 mL) was added to the filtrate, ethyl acetate (15mL. Times.3) was extracted, the organic phase was washed with a saturated brine (20mLx 2), and the mixture was dried over anhydrous sodium sulfateFiltering, concentrating under reduced pressure, and performing high performance liquid chromatography (acidic, hydrochloric acid system) to obtain compound 118. 1 H NMR(400MHz,CD 3 OD) Δ 7.24-7.20 (m, 2H), 7.15-7.13 (m, 3H), 3.30-3.24 (m, 1H), 3.12-3.12 (m, 1H), 2.76-2.74 (m, 2H), 2.74-2.72 (m, 1H), 2.72-2.71 (m, 1H), 1.71-1.67 (m, 1H), 1.49-1.45 (m, 10H), 1.29-1.27 (m, 1H). MS-ESI calculated value [ M + H%] + 259, found 259.
Example 119
The synthetic route is as follows:
first step of
Cesium carbonate (9.86g, 30.3mmol) was dissolved in anhydrous dimethylformamide (15 mL), and Compound 119-1 (1.00g, 6.05mmol) was added at 0 deg.C, and the reaction was stirred at 0 deg.C for 0.5 hours, after which 1, 3-dibromopropane (1.47g, 7.26mmol) was added in portions at 0 deg.C, and the reaction was stirred at 50 deg.C for 12 hours. The reaction was then quenched with water (100 mL) at 0 ℃, extracted with ethyl acetate (50mL x 2), the organic phases were combined, washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ8.48-8.39(m,2H),7.53-7.51(m,1H),7.17-7.14(m,1H),4.01(q,J＝6.8Hz,2H),2.78-2.75(m,2H),2.44-2.41(m,2H),2.02-1.98(m,1H),1.85-1.83(m,1H),1.08(t,J＝6.8Hz,3H)。
Second step of
Compound 119-2 (780mg, 3.80mmol) was dissolved in anhydrous methanol (10 mL), lithium borohydride (165mg, 7.60mmol) was added in portions at 0 ℃, the reaction mixture was stirred at 30 ℃ for 3 hours, an aqueous hydrochloric acid solution (20ml, 1mol/L) was added to the reaction solution at 0 ℃, extraction was performed with ethyl acetate (50mL × 2), the organic phases were combined, washed with a saturated saline solution (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography (3Ethyl acetate, rf = 0.2) to give compound 119-3. 1 H NMR(400MHz,CDCl 3 )δ8.44-8.38(m,2H),7.56-7.46(m,1H),7.25-7.21(m,1H),3.81(s,2H),2.39-2.29(m,4H),2.28-2.17(m,2H)。
The third step
The third step of reference example 118 gave compound 119-4. 1 H NMR(400MHz,CDCl 3 )δ9.64(s,1H),8.57-8.47(m,2H),7.51-7.48(m,1H),7.35-7.32(m,1H),2.83-2.78(m,2H),2.52-2.47(m,2H),2.13-2.03(m,2H)。
The fourth step
The fourth step of reference example 118 gave compound 119. 1 H NMR (400mhz, cd3od) δ 8.92 (s, 1H), 8.81 (d, J =5.6hz, 1h), 8.65 (d, J =8.0hz, 1h), 8.14 (dd, J =5.6,8.0hz, 1h), 7.33-7.29 (m, 2H), 7.24-7.20 (m, 1H), 7.18-7.16 (m, 2H), 3.91 (s, 2H), 3.06-3.02 (m, 1H), 2.68-2.56 (m, 5H), 2.40-2.27 (m, 1H), 2.10-2.00 (m, 1H), 1.70-1.62 (m, 1H), 1.38-1.34 (m, 1H). MS-ESI calculated value [ M + H%] + 279, found 279.
Example 120
The synthetic route is as follows:
first step of
Compound 120-1 (200mg, 1.15mmol) was dissolved in anhydrous dichloromethane (5 mL), -diisobutylaluminum hydride (2.30ml, 1mol/L) was added at 78 ℃, reaction was carried out at 78 ℃ for 2 hours, -saturated aqueous ammonium chloride solution (10 mL) was added at 78 ℃, the reaction solution was warmed to room temperature, pH was adjusted to 7 with sodium carbonate, dichloromethane (20mL × 3) was extracted, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and compound 120-2 was obtained by thin layer chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ9.23(s,1H),7.26-7.24(m,2H),6.92-6.89(m,2H),3.81(s,3H),1.56-1.53(m,2H),1.38-1.36(m,2H)。
Second step of
Compound 120 was obtained by the fourth step in accordance with example 118. 1 H NMR (400MHz, CD3OD) delta 7.40-7.38 (m, 2H), 7.31-7.28 (m, 2H), 7.24-7.21 (m, 1H), 7.12-7.10 (m, 2H), 6.94-6.90 (m, 2H), 3.79 (s, 3H), 3.46-3.39 (m, 2H), 2.89-2.85 (m, 1H), 2.48-2.43 (m, 1H), 1.51-1.45 (m, 1H), 1.31-1.26 (m, 1H), 1.09-1.00 (m, 4H). MS-ESI calculated value [ M + H%] + 294, found 294.
Example 121
The synthetic route is as follows:
first step of
The first step of reference example 120 gave compound 121-2. 1 H NMR(400MHz,CDCl 3 )δ9.41(s,1H),7.38-7.35(m,2H),7.29-7.24(m,3H),2.55-2.51(m,2H),1.91-1,83(m,2H),1.82-1.64(m,4H)。
Second step of
Compound 121 was obtained by the fourth step in example 118. 1 H NMR(400MHz,CD 3 OD) δ 7.50-7.48 (m, 2H), 7.42 (t, J = 7.6hz2h), 7.33-7.27 (m, 3H), 7.24-7.20 (m, 1H), 7.09 (d, J =7.6hz, 2h), 3.58 (s, 2H), 2.75-2.72 (m, 1H), 2.47-2.42 (m, 1H), 2.18-2.15 (m, 2H), 2.05-1.99 (m, 2H), 1.88-1.83 (m, 2H), 1.73-1.72 (m, 2H), 1.49-1.43 (m, 1H), 1.24-1.21 (m, 1H). MS-ESI calculated value [ M + H%] + 292, found 292.
Example 122
The synthesis route is as follows:
first step of
The first step of reference example 120 gave compound 122-2. 1 H NMR(400MHz,CDCl 3 )δ9.54(s,1H),7.40-7.37(m,2H),7.30-7.28(m,1H),7.19-7.15(m,2H),2.75-2.71(m,2H),2.46-2.37(m,2H),2.05-1.94(m,2H)。
Second step of
Compound 122 was obtained in the fourth step of example 118. 1 H NMR(400MHz,CD 3 OD) δ 7.42-7.38 (m, 2H), 7.33 (d, J =7.6hz, 2h), 7.30-7.26 (m, 3H), 7.22-7.19 (m, 1H), 7.09 (d, J =7.6hz, 2h), 3.66 (s, 2H), 2.78-2.78 (m, 1H), 2.54-2.37 (m, 5H), 2.25-2.13 (m, 1H), 1.98-1.88 (m, 1H), 1.50-1.45 (m, 1H), 1.28-1.24 (m, 1H). MS-ESI calculated value [ M + H% ] + 278, found 278.
Example 123
The synthetic route is as follows:
first step of
Compound 123-2 was obtained in the first step of referential example 120. 1 H NMR(400MHz,CDCl 3 )δ9.46(s,1H),7.29-7.26(m,2H),7.03-7.00(m,2H),2.68-2.63(m,2H),2.32-2.29(m,2H),1.97-1.88(m,2H)。
Second step of
Compound 123-2 (138mg, 0.709mmol) and compound A-2 (94.4mg, 0.709mmol) were dissolved in dry dichloromethane (2 mL), and acetic acid (128mg, 2.13mmol) was added. The reaction mixture was stirred at 30 ℃ for 1h. After that, sodium borohydride acetate (451mg, 2.13mmol) was added, and the reaction mixture was stirred at 30 ℃ for 1 hour. The reaction was quenched with saturated aqueous sodium bicarbonate (10 mL) at 0 ℃, extracted with dichloromethane (25mL x 2), the organic phase collected, washed with saturated brine (25mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by high performance liquid chromatography (acidic, hydrochloric acid system) to give compound 123. 1 H NMR(400MHz,CD 3 OD) δ 7.40 (d, J =8.4hz, 2h), 7.35-7.28 (m, 4H), 7.24-7.21 (m, 1H), 7.12 (d, J =8.4hz, 2h), 3.68 (s, 2H), 2.83-2.81 (m, 1H), 2.53-2.42 (m, 5H), 2.26-2.15 (m, 1H), 2.00-1.90 (m, 1H), 1.54-1.49 (m, 1H), 1.32-1.28 (m, 1H). MS-ESI calculated value [ M + H%] + 312, measured value 312.
Example 124
The synthetic route is as follows:
compound 123 (45.0mg, 0.144mmol), compound 124-1 (28.0mg, 0.144mmol), potassium carbonate (59.8mg, 0.433mmol), tris (dibenzylideneacetone) dipalladium (6.61mg, 7.22. Mu. Mol), 2-dicyclohexyl-phosphorus-2 ',4',6' -triisopropyl-biphenyl (6.88mg, 14.4. Mu. Mol) were added to anhydrous N, N-dimethylformamide (2 mL) and water (0.5 mL) under nitrogen protection, the reaction solution was cooled to 25 ℃ under nitrogen protection, water (10 mL) was added to the reaction solution, extraction was performed with ethyl acetate (25mL. Times.2), the organic phases were combined, a saturated brine (25mL. Times.2) was washed, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 124 was prepared by preparative high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR(400MHz,CD 3 OD) δ 8.21 (br, 2H), 7.65 (d, J =8.4hz, 2h), 7.36 (d, J =8.4hz, 2h), 7.28-7.24 (m, 2H), 7.21-7.18 (m, 1H), 7.09-7.07 (m, 2H), 3.68 (s, 2H), 2.82-2.78 (m, 1H), 2.57-2.48 (m, 2H), 2.40-2.38 (m, 2H), 2.25-2.14 (m, 1H), 2.01-1.97 (m, 1H), 1.46-1.40 (m, 1H), 1.32-1.31 (m, 1H), 0.93-0.88 (m, 1H). MS-ESI calculated value [ M + H%] + 344, found 344.
Example 125
The synthetic route is as follows:
first step of
Dissolving compound 125-1 (61.7mg, 0.501mmol) in anhydrous dimethylformamide (4 mL), adding carbonyldiimidazole (88.0 mg, 0.542mmol), reacting the reaction mixture at 30 ℃ for 2 hours, adding compound 19-2 (150mg, 0.417mmol), reacting at 110 ℃ for 12 hours, adding water (20 mL) at 0 ℃ to quench the reaction mixture, extracting with ethyl acetate (25mL x 2), collecting the organic phase, washing with saturated brine (25mL x 2), drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 125-2.MS-ESI calculated value [ M + Na ]] + 469, found 469.
Second step of
125-2 (120mg, 0.269mmol) was dissolved in anhydrous dichloromethane (3 mL), trimethylsilyl trifluoromethanesulfonate (120mg, 0.537mmol) was added at 0 deg.C, the reaction mixture was reacted at 0 deg.C for 0.5 hour, water (0.2 mL) was added to the reaction mixture at 0 deg.C and quenched, concentrated under reduced pressure, and prepared by high performance liquid chromatography (acidic, hydrochloric acid system) to give 125. 1 H NMR(400MHz,CD 3 OD) δ 8.90 (d, J =8.0hz, 1h), 8.48 (d, J =8.0hz, 1h), 8.37-8.33 (m, 1H), 7.93-7.90 (m, 1H), 7.33-7.27 (m, 2H), 7.22-7.17 (m, 3H), 3.93 (s, 2H), 3.14-3.10 (m, 1H), 2.76-2.68 (m, 2H), 2.63-2.57 (m, 1H), 2.53-2.45 (m, 2H), 2.30-2.22 (m, 2H), 1.86-1.60 (m, 1H), 1.43-1.39 (m, 1H). MS-ESI calculated value [ M + H%] + 347, found 347.
Example 126
The synthesis route is as follows:
first step of
Compound 126-2 was obtained in the first step of referential example 125. MS-ESI calculated value [ M + Na ]] + 537, found 537.
Second step of
The second step of reference example 125 gave compound 126. 1 H NMR(400MHz,CD 3 OD) δ 9.09 (d, J =5.2hz, 1h), 8.54 (s, 1H), 8.04 (d, J =5.2hz, 1h), 7.30-7.26 (m, 2H), 7.20-7.15 (m, 3H), 3.93 (s, 2H), 3.13-3.09 (m, 1H), 2.78-2.69 (m, 2H), 2.55-2.42 (m, 3H), 2.31-2.23 (m, 2H), 1.60-1.54 (m, 1H), 1.43-1.40 (m, 1H). MS-ESI calculated value [ M + H%] + 415, measured value 415.
Example 127
The synthesis route is as follows:
first step of
The first step of reference example 125 gave compound 127-2.MS-ESI calculated value [ M + Na ]] + 525, found value 525.
Second step of
The second step of reference example 125 gave compound 127. 1 H NMR(400MHz,CD 3 OD) delta 9.49 (s, 1H), 8.95 (s, 1H), 8.35-8.26 (m, 2H), 7.31-7.28 (m, 2H), 7.22-7.17 (m, 3H), 3.93 (m, 2H), 3.15-3.11 (m, 1H), 3.28-3.69 (m, 2H), 2.57-2.55 (m, 1H), 2.49-2.41 (m, 2H), 2.31-2.23 (m, 2H), 1.61-1.56 (m, 1H), 1.45-1.39 (m, 1H). MS-ESI calculated value [ M + H% ] + 403, measured value 403.
Example 128
The synthetic route is as follows:
first step of
Reference example 125 gave compound 128-2 in the first step. MS-ESI calculated value [ M + Na ]] + 470, found 470.
Second step of
The second step of reference example 125 gave compound 128. 1 H NMR(400MHz,CD 3 OD) delta 9.10-9.09 (m, 2H), 7.79-7.77 (m, 1H), 7.32-7.28 (m, 2H), 7.23-7.18 (m, 3H), 3.93 (s, 2H), 3.15-3.09 (m, 1H), 2.76-2.69 (m, 2H), 2.60-2.54 (m, 1H), 2.51-2.43 (m, 2H), 2.31-2.22 (m, 2H), 1.63-1.54 (m, 1H), 1.44-1.41 (m, 1H). MS-ESI calculated value [ M + H%] + 348, found value 348.
Example 129
The synthetic route is as follows:
first step of
Compound 129-2 was obtained in the first step of referential example 125. MS-ESI calculated value [ M + Na ]] + 499, found 499.
Second step of
The second step of reference example 125 gave compound 129. 1 H NMR(400MHz,CD 3 OD) δ 8.97 (d, J =2.4hz, 1H), 8.38 (dd, J =2.4,8.8hz, 1H), 7.32-7.29 (m, 2H), 7.24-7.21 (m, 3H), 7.03-7.01 (d, J =8.8hz, 1H), 4.07 (s, 3H), 3.90 (s, 2H), 3.12-3.08 (m, 1H), 2.73-2.66 (m, 2H), 2.56-2.51 (m, 1H), 2.46-2.40 (m, 2H), 2.28-2.23 (m, 2H), 1.60-1.54 (m, 1H), 1.44-1.39 (m, 1H). MS-ESI calculated value [ M + H%] + 377, found 377.
Example 130
The synthesis route is as follows:
first step of
Compound 130-2 was obtained in the first step of referential example 125. MS-ESI calculated value [ M + Na ] ] + 469, found 469.
Second step of
The second step of reference example 125 gave compound 130. 1 H NMR(400MHz,CD 3 OD) δ 9.65 (s, 1H), 9.30 (d, J =7.6hz, 1h), 9.18 (d, J =7.6hz, 1h), 8.39-8.36 (m, 1H), 7.29-7.25 (m, 2H), 7.19-7.16 (m, 3H), 3.94 (s, 2H), 3.10-3.09 (m, 1H), 2.77-2.63 (m, 3H), 2.52-2.49 (m, 2H), 2.29-2.22 (m, 2H), 1.68-1.65 (m, 1H), 1.40-1.37 (m, 1H). MS-ESI calculated value [ M + H%] + 347, found 347.
Example 131
The synthetic route is as follows:
first step of
Compound 131-2 was obtained in the first step of referential example 125. MS-ESI calculated value [ M + Na ]] + 537, found 537.
Second step of
The second step of reference example 125 gave compound 131. 1 H NMR(400MHz,CD 3 OD) δ 9.04 (d, J =4.8hz, 1h), 8.43 (s, 1H), 8.34 (d, J =4.8hz, 1h), 7.29-7.25 (m, 2H), 7.19-7.08 (m, 3H), 3.97 (s, 2H), 3.11-3.08 (m, 1H), 2.73-2.68 (m, 2H), 2.55-2.43 (m, 3H), 2.30-2.22 (m, 2H), 1.61-1.55 (m, 1H), 1.42-1.39 (m, 1H). MS-ESI calculated value [ M + H%] + 415, found value 415.
Example 132
The synthetic route is as follows:
first step of
The first step of reference example 125 gave compound 132-2.MS-ESI calculated value [ M + Na ]] + 536, found 536.
Second step of
The second step of reference example 125 gave compound 132. 1 H NMR(400MHz,CD 3 OD) δ 8.37 (d, J =8.0hz, 2h), 7.95 (d, J =8.0hz, 2h), 7.31-7.27 (m, 2H), 7.24-7.16 (m, 3H), 3.91 (s, 2H), 3.12-3.08 (m, 1H), 2.75-2.67 (m, 2H), 2.56-2.51 (m, 1H), 2.49-2.41 (m, 2H), 2.29-2.22 (m, 2H), 1.60-1.55 (m, 1H), 1.43-1.39 (m, 1H). MS-ESI calculated value [ M + H% ] + 414, measured value 414.
Example 134
The synthetic route is as follows:
first step of
Compound 134-2 was obtained in the first step with reference to example 125. MS-ESI calculated value [ M + Na ]] + 568, found 568.
Second step of
Compound 134-2 (46.0mg, 0.843mmol) was dissolved in anhydrous dichloromethane (3 mL), and trifluoroacetic acid (127mg, 1.11mmol) was added thereto, and the mixture was stirred at 25 ℃ for 2 hours, concentrated under reduced pressure, and subjected to high performance liquid chromatography (acidic, hydrochloric acid system) to give compound 134. 1 H NMR(400MHz,CD 3 OD) Δ 8.01-8.00 (m, 1H), 7.87-7.85 (m, 1H), 7.80-7.77 (m, 2H), 7.32-7.28 (m, 2H), 7.24-7.22 (m, 1H), 7.21-7.17 (m, 2H), 3.88 (s, 2H), 3.11-3.07 (m, 1H), 2.72-2.65 (m, 2H), 2.59-2.53 (m, 1H), 2.43-2.37 (m, 2H), 2.27-2.22 (m, 2H), 1.59-1.58 (m, 1H), 1.40-1.38 (m, 1H). MS-ESI calculated value [ M + H%] + 390, found 390.
Example 135
The synthesis route is as follows:
first step of
The first step of reference example 125 gave compound 135-2.MS-ESI calculated value [ M + Na ]] + 526, measured value 526.
Second step of
The compound 135-2 (56.0mg, 0.111mmol) and lithium hydroxide (13.3mg, 0.556 mmol) were dissolved in tetrahydrofuran (3 mL) and water (1 mL), and the mixture was stirred at 25 ℃ for 2 hours, and the reaction mixture was quenched by adding an aqueous hydrochloric acid solution (5mL, 1mol/L), extracted with ethyl acetate (5mLx 2), the organic phase was collected, washed with a saturated brine (5mLx 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the compound 135-3.MS-ESI calculated value [ M + Na ] ] + 512, found 512.
The third step
Compound 135-3 (45.0 mg, 91.9. Mu. Mol) was dissolved in anhydrous dichloromethane (2 mL), trifluoroacetic acid (52.4 mg, 0.460mmol) was added, and the mixture was stirred at 25 ℃ for 2 hours, concentrated under reduced pressure, and subjected to high performance liquid chromatography (acidic, hydrochloric acid system) to prepare Compound 135. 1 H NMR(400MHz,CD 3 OD) delta 8.75 (s, 1H), 8.38-8.31 (m, 2H), 7.77-7.73 (m, 1H), 7.30-7.26 (m, 2H), 7.21-7.15 (m, 3H), 3.90 (s, 2H), 3.10-3.08 (m, 1H), 2.75-2.68 (m, 2H), 2.62-2.57 (m, 1H), 2.50-2.42 (m, 2H), 2.29-2.21 (m, 2H), 1.65-1.60 (m, 1H), 1.39-1.37 (m, 1H). MS-ESI calculated value [ M + H%] + 390, found 390.
Example 136
The synthesis route is as follows:
first step of
The first step of reference example 125 gave compound 136-2.MS-ESI calculated value [ M + H%] + 513, found value 513.
Second step of
The third step of reference example 135 gave compound 136. 1 H NMR(400MHz,CD 3 OD) δ 9.96 (s, 2H), 8.46 (d, J =8.4hz, 2h), 8.08 (d, J =8.4hz, 2h), 7.31-7.28 (m, 2H), 7.23-7.18 (m, 3H), 3.93 (s, 2H), 3.13-3.10 (m, 1H), 2.76-2.68 (m, 2H), 2.66-2.61 (m, 1H), 2.53-2.47 (m, 2H), 2.30-2.23 (m, 2H), 1.68-1.63 (m, 1H), 1.43-1.40 (m, 1H). MS-ESI calculated value [ M + H%] + 413, found value 413.
Example 137
The synthesis route is as follows:
first step of
Compound 137-1 (700mg, 3.03mmol) was dissolved in anhydrous methanol (10 mL), lithium borohydride (132mg, 6.06mmol) was added in portions at 0 ℃, the reaction was stirred for 16 hours at 30 ℃, water (10 mL) was added to the reaction solution at 0 ℃, extracted with ethyl acetate (25mL x 2), the organic phases were combined, washed with saturated brine (25mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by preparative thin layer chromatography (2. 1 H NMR(400MHz,CD 3 OD)δ7.80(d,J＝6.8Hz,1H),7.62-7.54(m,2H),7.35-7.33(m,1H),4.12(d,J＝6.8Hz,2H),2.79-2.71(m,2H),2.44-2.37(m,2H),2.31-2.14(m,2H)。
Second step of
Compound 137-2 (210mg, 1.03mmol) was dissolved in anhydrous dichloromethane (5 mL), and dess-Martin oxidant (482mg, 1.14mmol), 15, was addedStirring at room temperature for 2 hours, adding saturated aqueous sodium bicarbonate (10 mL) to quench the reaction until no gas is evolved, adding saturated aqueous sodium thiosulfate (10 mL), extracting with dichloromethane (20mL x 3), collecting the organic phase, washing with saturated brine (20mL x 2), drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain compound 137-3.MS-ESI calculated value [ M + H%] + 202, measured value 202.
The third step
Compound 137-3 (215mg, 1.07mmol) and compound A-2 (157mg, 1.18mmol) were dissolved in anhydrous dichloromethane (5 mL), and acetic acid (193mg, 3.21mmol) was added. The reaction mixture was stirred at 20 ℃ for 1 hour. Then, sodium borohydride acetate (680 mg, 3.21mmol) was added thereto, and the reaction mixture was stirred at 20 ℃ for 1 hour. The reaction solution was diluted with dichloromethane (10 mL), washed successively with saturated aqueous sodium carbonate (10mL × 3), water (10mL × 2), and saturated brine (10mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, separated by high performance liquid chromatography (neutral system), salified with aqueous hydrochloric acid (0.5ml, 4mol/L), and concentrated under reduced pressure to give compound 137. 1 H NMR(400MHz,CD 3 OD) δ 7.76-7.74 (m, 1H), 7.60-7.55 (m, 2H), 7.32-7.29 (m, 1H), 7.16-7.13 (m, 2H), 7.08-7.04 (m, 1H), 6.89-6.87 (m, 2H), 3.36-3.35 (m, 2H), 2.70-2.63 (m, 2H), 2.43-2.35 (m, 2H), 2.25-2.20 (m, 1H), 2.17-2.02 (m, 2H), 1.71-1.67 (m, 1H), 0.92-0.88 (m, 1H), 0.83-0.80 (m, 1H). MS-ESI calculated value [ M + H% ] + 319, found 319.
Example 138
The synthetic route is as follows:
first step of
The first step of reference example 125 gave compound 138-2.MS-ESI calculated value [ M + Na ]] + 561, found, 561.
Second step of
Compound 138-2 (100mg, 0)186 mmol) was dissolved in anhydrous dichloromethane (5 mL), trifluoroacetic acid (84.7mg, 0.743mmol) was added, stirring at 20 ℃ for 2 hours, concentration under reduced pressure, and preparation by high performance liquid chromatography (acidic, hydrochloric acid system) gave compound 138. 1 H NMR(400MHz,CD 3 OD) Δ 7.33-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.18-7.16 (m, 2H), 3.75-3.57 (m, 4H), 3.42-3.36 (m, 2H), 3.14-3.07 (m, 2H), 2.68-2.62 (m, 1H), 2.29-2.25 (m, 1H), 2.03-1.88 (m, 3H), 1.68-1.63 (m, 1H), 1.47-1.37 (m, 5H). MS-ESI calculated value [ M + H%] + 339, found 339.
Example 139
The synthesis route is as follows:
first step of
The first step of reference example 125 gave compound 139-2.MS-ESI calculated value [ M + Na ]] + 561, measured value 561.
Second step of
The second step of reference example 138 gave compound 139. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.24-7.21 (m, 1H), 7.18-7.16 (m, 2H), 3.74-3.49 (m, 4H), 3.42-3.36 (m, 2H), 3.14-3.07 (m, 2H), 2.70-2.61 (m, 1H), 2.28-2.26 (m, 1H), 2.03-1.88 (m, 3H), 1.67-1.62 (m, 1H), 1.47-1.37 (m, 5H). MS-ESI calculated value [ M + H%] + 339, found value 339.
Examples 140 and 141
The synthetic route is as follows:
first step of
Reference example 125 prepared crude product by the first step and purified by thin layer chromatography to give compound 140-2 (2. MS-ESI calculated value [ M + Na ]] + 490, found 490. 140-3 (2. MS-ESI calculated value [ M + Na ]] + 490, found 490.
Second step of
Dissolving the compound 140-2 (115mg, 0.246mmol) in tetrahydrofuran (2 mL) and water (0.5 mL), adding lithium hydroxide (103mg, 2.46mmol), stirring at 50 ℃ for 12 hours, adding an aqueous hydrochloric acid solution (5 mL,1 mol/L) to the reaction solution at 0 ℃ for quenching, extracting with ethyl acetate (10mLx 2), collecting the organic phase, washing with saturated brine (10mLx 2), drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain the compound 140-4.MS-ESI calculated value [ M + Na ]] + 476, found 476. According to the same manner, compound 140-3 was prepared to give compound 141-1.MS-ESI calculated value [ M + Na ]] + 476, found 476.
The third step
Compound 140-4 (108mg, 0.238mmol) was dissolved in anhydrous dichloromethane (2 mL), and trifluoroacetic acid (54.3mg, 0.476mmol) was added thereto, and the mixture was stirred at 20 ℃ for 0.5 hour, concentrated under reduced pressure, and subjected to high performance liquid chromatography (acidic, hydrochloric acid system) to prepare compound 140, i.e., example 140. 1 H NMR(400MHz,CD 3 OD) delta 7.33-7.30 (m, 2H), 7.25-7.22 (m, 1H), 7.19-7.17 (m, 2H), 3.76-3.65 (m, 3H), 3.39-3.31 (m, 1H), 3.13-3.10 (m, 1H), 2.77-2.71 (m, 2H), 2.67-2.59 (m, 3H), 1.69-1.64 (m, 1H), 1.48-1.38 (m, 5H). MS-ESI calculated value [ M + H% ] + 354, found 354. Compound 141-1 was prepared according to the same procedure as that described for compound 141, example 141. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.24-7.21 (m, 1H), 7.17-7.15 (m, 2H), 3.72-3.62 (m, 3H), 3.28-3.21 (m, 1H), 3.10-3.06 (m, 1H), 2.77-2.55 (m, 5H), 1.67-1.58 (m, 1H), 1.45-1.36 (m, 5H). MS-ESI calculated value [ M + H%] + 354, found 354.
Example 142
The synthetic route is as follows:
first step of
Compound 142-1 (200mg, 1.40mmol) was dissolved in acetone (5 mL) and water (1 mL), di-tert-butyl dicarbonate (396mg, 1.82mmol) and potassium carbonate (232mg, 1.68mmol) were added, stirring was carried out at 20 ℃ for 12 hours, aqueous hydrochloric acid (10ml, 1mol/L) was added to the reaction solution at 0 ℃, ethyl acetate (10mLx 2) was extracted, the organic phase was collected, and saturated brine (10mLx 2) was washed, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by preparative thin layer chromatography (10. 1 H NMR(400MHz,CDCl3)δ3.48-3.47(m,1H),2.51-2.48(m,1H),1.98-1.94(m,2H),1.72-1.54(m,6H),1.45(s,9H)。
Second step of
The first step of reference example 125 gave compound 142-3.MS-ESI calculated value [ M + Na ]] + 575, found 575.
The third step
The third step of reference example 140 gave compound 142. 1 H NMR(400MHz,CD 3 OD) δ 7.34-7.30 (m, 2H), 7.26-7.22 (m, 1H), 7.21-7.19 (m, 2H), 3.76-3.66 (m, 2H), 3.32-3.27 (m, 2H), 3.13-3.09 (m, 1H), 2.71-2.66 (m, 1H), 2.30-2.26 (m, 2H), 2.00-1.92 (m, 4H), 1.78-1.64 (m, 3H), 1.52-1.47 (m, 2H), 1.43-1.38 (m, 3H). MS-ESI calculated value [ M + H% ] + 353, measured value 353.
Example 143
The synthetic route is as follows:
first step of
First step of preparation of referential example 142Compound No. 143-2. 1 H NMR(400MHz,CDCl3)δ4.40(s,1H),3.43(m,1H),2.30-2.24(m,2H),2.07-2.04(m,6H),1.45(s,9H)。
Second step of
Compound 143-3 was obtained in the first step of referential example 125. MS-ESI calculated value [ M + Na ]] + 575, found 575.
The third step
The third step of referential example 140 gave compound 143. 1 H NMR(400MHz,CD 3 OD) delta 7.32-7.29 (m, 2H), 7.24-7.22 (m, 1H), 7.15-7.13 (m, 2H), 3.54-3.43 (m, 3H), 3.06-2.94 (m, 3H), 2.10-2.06 (m, 4H), 1.60-1.44 (m, 7H), 1.23-1.23 (m, 3H). MS-ESI calculated value [ M + H%] + 353, measured value 353.
Example 144
The synthetic route is as follows:
first step of
Under nitrogen protection, compound 144-1 (5.80g, 59.7 mmol) was dissolved in anhydrous dichloromethane (100 mL), dessimutant reagent (26.6 g,62.7 mmol) was added, the reaction solution was stirred at 25 ℃ for 1 hour, saturated aqueous sodium carbonate solution (200 mL) was added to the reaction solution, extraction was performed with dichloromethane (100mL x 1), the organic phase was washed with saturated saline (100mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (5. 1 H NMR(400MHz,CDCl 3 )δ9.31(s,1H),1.71-1.68(m,4H)。
Second step of
Dissolving a compound 144-3 (41.2g, 288mmol) in anhydrous dichloromethane (400 mL), adding acetic acid (1.73g, 28.8mmol) and a compound 144-2 (33.8g, 316mmol) to the reaction solution, stirring the reaction solution at 25 ℃ for 1 hour, further adding sodium triacetoxyborohydride (91.5g, 432mmol), stirring the reaction solution at 25 ℃ for 11 hours, and adding the mixture to the reaction solution To this solution, saturated sodium bicarbonate (500 mL) was added, extraction was performed with dichloromethane (500mL × 2), organic phases were combined, water (500 mL) was added after spin-drying, pH =3 about with 1N aqueous hydrochloric acid, extraction was performed with methyl tert-butyl ether (500mL × 1), pH =8 about with saturated aqueous sodium carbonate, extraction was performed with dichloromethane (500mL × 2), and the organic phase was washed with saturated brine (500mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 144-4. 1 H NMR(400MHz,CDCl 3 )δ7.29-7.26(m,2H),7.19-7.16(m,1H),7.06-7.04(m,2H),2.83(s,2H),2.51-2.48(m,1H),2.01-1.96(m,1H),1.28-1.24(m,2H),1.18-1.13(m,1H),1.05-1.01(m,1H),0.88-0.79(m,2H).
The third step
Compound 144-4 (3.80g, 17.9 mmol) was dissolved in tetrahydrofuran (30 mL) and water (6 mL), di-tert-butyl dicarbonate (4.30g, 19.7 mmol) and lithium hydroxide monohydrate (0.901g, 21.5 mmol) were added to the reaction mixture, the reaction mixture was stirred at 25 ℃ for 12 hours, the reaction mixture was concentrated under reduced pressure, pH =5 was adjusted with 1N aqueous hydrochloric acid solution, extraction was performed with ethyl acetate (30mL × 2), the organic phase was washed with saturated brine (40mL × 1), dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (5. 1 H NMR(400MHz,CDCl 3 )δ7.23-7.21(m,2H),7.13-7.10(m,1H),7.07-7.05(m,2H),3.42-3.31(m,2H),2.90-2.88(m,1H),2.10-2.05(m,1H),1.37(s,9H),1.28-1.16(m,4H),1.00-0.90(m,2H).
The fourth step
Compound 144-5 (2.00g, 5.89mmol) was dissolved in absolute ethanol (40 mL), and hydroxylamine hydrochloride (818mg, 11.8mmol) and diisopropylethylamine (3.04g, 23.6 mmol) were added to the reaction solution, and the reaction solution was stirred at 80 ℃ for 12 hours. The solvent was removed by concentration under reduced pressure, the resulting crude product was dissolved in ethyl acetate (50 mL) and water (50 mL), and the organic phase was washed with saturated ammonium chloride solution (50mL. Times.1), saturated sodium chloride solution (50mL. Times.1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 144-6.MS-ESI calculated value [ M + H% ] + 346, found 346.
The fifth step
The compound 143-2 (174mg, 0.715mmol) was dissolved in anhydrous N, N-dimethylformamide (5 mL), and carbonyl was added under nitrogen protection at 30 deg.CDiylbiimidazole (127mg, 0.781mmol) was stirred for 2 hours, compound 144-6 (250mg, 0.651mmol) was added to the reaction mixture, and the reaction mixture was heated to 110 ℃ and stirred for 10 hours. The reaction was cooled to room temperature, water (50 mL) was added to the reaction, extraction was performed with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by preparative thin layer chromatography (2. MS-ESI calculated value [ M + Na ]] + 575, found 575.
The sixth step
Compound 144-7 (260mg, 0.470mmol) was dissolved in anhydrous dichloromethane (8 mL), and trifluoroacetic acid (4 mL) was added dropwise at 0 ℃. The reaction solution was stirred at 0 ℃ for 0.5 hour, concentrated under reduced pressure, and subjected to high performance liquid chromatography (acidic, hydrochloric acid system) to obtain compound 144. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.17-7.14 (m, 2H), 3.70-3.62 (m, 2H), 3.21-3.14 (m, 1H), 3.09-3.05 (m, 1H), 3.01-2.95 (m, 1H), 2.57-2.52 (m, 1H), 2.26-2.22 (m, 2H), 2.18-2.15 (m, 2H), 1.75-1.64 (m, 2H), 1.61-1.54 (m, 3H), 1.44-1.41 (m, 2H), 1.39-1.36 (m, 1H), 1.34-1.32 (m, 2H). MS-ESI calculated value [ M + H% ] + 353, measured value 353.
Example 145
The synthetic route is as follows:
first step of
The third step of reference example 144 gave compound 145-2. 1 H NMR(400MHz,CDCl 3 ) Δ 4.64 (brs, 1H), 3.63-3.58 (m, 1H), 2.53-2.51 (m, 1H), 1.92-1.89 (m, 2H), 1.76-1.59 (m, 6H), 1.45 (s, 9H). MS-ESI calculated value [ M-Boc + H] + 144, found 144.
Second step of
Reference example 144 the fifth step gave the compound145-3.MS-ESI calculated value [ M + Na ]] + 575, found 575.
The third step
The sixth step of EXAMPLE 144 gave compound 145. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.17-7.15 (m, 2H), 3.73-3.63 (m, 2H), 3.28-3.25 (m, 2H), 3.08-3.07 (m, 1H), 2.61-2.55 (m, 1H), 2.26-2.22 (m, 2H), 1.98-1.92 (m, 4H), 1.72-1.66 (m, 2H), 1.62-1.57 (m, 1H), 1.48-1.45 (m, 2H), 1.42-1.36 (m, 1H), 1.35-1.34 (m, 2H). MS-ESI calculated value [ M + H%] + 353, measured value 353.
Example 146
The synthetic route is as follows:
first step of
The third step of EXAMPLE 144 gave compound 146-2. 1 H NMR(400MHz,CDCl 3 ) δ 4.76 (brs, 1H), 4.36-4.30 (m, 1H), 3.08-3.04 (m, 1H), 2.72-2.60 (m, 2H), 2.26-2.20 (m, 2H), 1.45 (s, 9H). MS-ESI calculated value [ M-56+H] + 160, found 160.
Second step of
The fifth step in reference example 144 gave compound 146-3.MS-ESI calculated value [ M + Na ]] + 547, found value 547.
The third step
Compound 146 can be obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) delta 7.32-7.28 (m, 2H), 7.24-7.21 (m, 1H), 7.16-7.14 (m, 2H), 4.08-4.05 (m, 1H), 3.92-3.87 (m, 1H), 3.73-3.63 (m, 2H), 3.09-3.06 (m, 1H), 2.77-2.70 (m, 4H), 2.59-2.54 (m, 1H), 1.61-1.56 (m, 1H), 1.47-1.45 (m, 2H), 1.41-1.34 (m, 3H). MS-ESI calculated value [ M + H%] + 325, found value 325.
Example 147
The synthetic route is as follows:
first step of
The third step in reference example 144 gave compound 147-2. 1 H NMR(400MHz,CDCl 3 ) δ 4.89 (brs, 1H), 4.11-3.95 (m, 1H), 2.90-2.83 (m, 1H), 2.30-2.19 (m, 1H), 1.98-1.65 (m, 5H), 1.45 (s, 9H). MS-ESI calculated value [ M-56+H] + 174, measured value 174.
Second step of
Compound 147-3 was obtained in the fifth step in accordance with example 144. MS-ESI calculated value [ M + Na ]] + 561, measured value 561.
The third step
The sixth step in reference example 144 gave compound 147. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.16-7.15 (m, 2H), 3.77-3.74 (m, 1H), 3.71-3.62 (m, 2H), 3.56-3.50 (m, 1H), 3.08-3.05 (m, 1H), 2.68-2.63 (m, 1H), 2.59-2.54 (m, 1H), 2.28-2.20 (m, 2H), 2.16-2.08 (m, 1H), 2.04-1.96 (m, 1H), 1.90-1.84 (m, 1H), 1.61-1.56 (m, 1H), 1.44-1.41 (m, 2H), 1.40-1.36 (m, 1H), 1.35-1.33 (m, 2H). MS-ESI calculated value [ M + H%] + 339, found 339.
Example 148
The synthesis route is as follows:
first step of
The third step of EXAMPLE 144 gave compound 148-2. 1 H NMR(400MHz,CDCl 3 )δ4.73(brs,1H),3.46-3.32(m,1H),2.90-2.83(m,1H),2.29-226 (m, 1H), 1.99-1.96 (m, 2H), 1.87-1.84 (m, 1H), 1.44 (s, 9H), 1.34-1.28 (m, 3H), 1.24-1.06 (m, 1H). MS-ESI calculated value [ M + Na ]] + 266, found 266.
Second step of
The fifth step of reference example 144 gave compound 148-3.MS-ESI calculated value [ M + Na ]] + 575, found 575.
The third step
The sixth step of referential example 144 gave compound 148 (60.0 mg). 1 H NMR(400MHz,CD 3 OD) Δ 7.32-7.29 (m, 2H), 7.25-7.23 (m, 1H), 7.16-7.14 (m, 2H), 3.71-3.62 (m, 2H), 3.28-3.24 (m, 1H), 3.18-3.11 (m, 1H), 3.08-3.04 (m, 1H), 2.57-2.52 (m, 1H), 2.44-2.41 (m, 1H), 2.16-2.08 (m, 2H), 2.04-1.99 (m, 1H), 1.70-1.64 (m, 1H), 1.61-1.54 (m, 2H), 1.49-1.32 (m, 7H). MS-ESI calculated value [ M + H%] + 353, measured value 353.
Example 149 and example 150
The synthetic route is as follows:
first step of
The crude product was prepared according to the fifth step of reference example 144 and purified by thin layer chromatography to give compound 149-1, (3. MS-ESI calculated value [ M + Na ]] + 490, found 490. Compound 149-2, (3. MS-ESI calculated value [ M + Na ]] + 490, found 490.
Second step of
Compound 149-1 (200mg, 0.427mol) was dissolved in water (8 mL) and tetrahydrofuran (2 mL), sodium hydroxide (68.4 mg, 1.71mmol) was added, and the reaction mixture was stirred at 40 ℃ for 4 hours. The reaction was cooled to 0 ℃, water (50 mL) was added to the reaction, the pH was adjusted to 3 with hydrochloric acid (1 mol/L), the mixture was extracted with ethyl acetate/tetrahydrofuran =3/1 (50mL × 3), and the organic phase was extracted with saturated brine Washed (50mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide 149-3.MS-ESI calculated value [ M + Na ]] + 476, found 476. According to the same manner, compound 149-2 was prepared to give compound 150-1.MS-ESI calculated value [ M + Na ]] + 476, found 476.
The third step
Compound 149 was prepared according to the sixth step of 149-3 of example 144, example 149. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.16-7.14 (m, 2H), 3.77-3.70 (m, 1H), 3.67-3.61 (m, 2H), 3.28-2.23 (m, 1H), 3.09-3.05 (m, 1H), 2.71-2.57 (m, 4H), 2.55-2.49 (m, 1H), 1.58-1.52 (m, 1H), 1.46-1.44 (m, 2H), 1.42-1.36 (m, 1H), 1.32-1.30 (m, 2H). MS-ESI calculated value [ M + H%] + 354, found 354. According to the same manner, compound 150-1 was produced to obtain compound 150, i.e., example 150. 1 H NMR(400MHz,CD 3 OD) Δ 7.32-7.28 (m, 2H), 7.24-7.21 (m, 1H), 7.16-7.14 (m, 2H), 3.85-3.77 (m, 1H), 3.72-3.62 (m, 2H), 3.29-2.26 (m, 1H), 3.10-3.06 (m, 1H), 2.77-2.69 (m, 2H), 2.66-2.59 (m, 2H), 2.57-2.51 (m, 1H), 1.59-1.54 (m, 1H), 1.48-1.44 (m, 2H), 1.42-1.36 (m, 1H), 1.35-1.32 (m, 2H). MS-ESI calculated value [ M + H%] + 354, found 354.
Example 151
The synthesis route is as follows:
first step of
The fifth step in reference example 144 gave compound 151-2.MS-ESI calculated value [ M + Na ] ] + 587, found 587.
Second step of
Compound 151 is obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD)δ7.32-7.28(m,2H),7.25-7.21(m,1H),7.16-7.14(m,2H),3.73-3.61(m,4H),3.09-3.05(m,1H),2.66-2.59(m, 2H), 2.56-2.40 (m, 5H), 2.29-2.24 (m, 1H), 2.20-2.15 (m, 1H), 1.59-1.53 (m, 1H), 1.44-1.41 (m, 2H), 1.40-1.36 (m, 1H), 1.33-1.31 (m, 2H). MS-ESI calculated value [ M + H%] + 365, found 365.
Example 152
The synthesis route is as follows:
first step of
The fifth step of reference example 144 gave compound 152-2.MS-ESI calculated value [ M + Na ]] + 621, measured value 621.
Second step of
In the sixth step of EXAMPLE 144, compound 152 was obtained. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.17-7.15 (m, 2H), 4.57 (t, J =6.4hz, 1h), 3.72-3.64 (m, 2H), 3.60-3.50 (m, 2H), 3.05-3.04 (m, 1H), 2.61-2.56 (m, 1H), 1.63-1.58 (m, 1H), 1.49-1.46 (m, 2H), 1.41-1.36 (m, 3H). MS-ESI calculated value [ M + H%] + 343, found value 343.
Example 153
The synthetic route is as follows:
first step of
The fifth step in reference example 144 gave compound 153-2.MS-ESI calculated value [ M + Na ]] + 635, found 635.
Second step of
The sixth step of reference example 144 gave compound 153. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.16-7.14 (m, 2H), 4.13 (t, J =6.8hz, 1h), 3.74-3.61 (m, 2H), 3.16-3.05 (m, 3H), 2.56-2.51 (m, 1H), 2.44-2.33 (m, 2H), 1.59-1.54 (m, 1H), 1.46-1.33 (m, 5H). MS-ESI calculated value [ M + H% ] + 357, found value 357.
Example 154
The synthesis route is as follows:
first step of
Compound 154-2 is obtained by the fifth step in accordance with example 144. MS-ESI calculated value [ M + Na ]] + 549, found 549.
Second step of
Compound 154 is obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) δ 7.33-7.28 (m, 2H), 7.25-7.21 (m, 1H), 7.20-7.15 (m, 2H), 4.70 (d, J =6.0hz, 1h), 3.77-3.66 (m, 2H), 3.10-3.06 (m, 1H), 2.66-2.61 (m, 1H), 2.44-2.35 (m, 1H), 1.66-1.61 (m, 1H), 1.52-1.49 (m, 2H), 1.45-1.37 (m, 3H), 1.12 (t, J =6.8hz, 3h), 1.03 (t, J =6.8hz, 3h). MS-ESI calculated value [ M + H%] + 327, measured value 327.
Example 155
The synthetic route is as follows:
first step of
The fifth step of reference example 144 gave compound 155-2.MS-ESI calculated value [ M + H%] + 579, found 579.
Second step of
Compound 155 was obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) delta 7.33-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.17-7.15 (m, 2H), 3.69-3.61 (m, 2H), 3.08-3.04 (m, 1H), 2.55-2.50 (m, 1H), 2.16-2.12 (m, 6H), 1.94-1.90 (m, 6H), 1.58-1.52 (m, 1H), 1.43-1.37 (m, 3H), 1.32-1.30 (m, 2H). MS-ESI calculated value [ M + H%] + 379, found 379.
Example 156
The synthetic route is as follows:
first step of
The fifth step of EXAMPLE 144 gave compound 156-2.MS-ESI calculated value [ M + Na ]] + 587, found 587.
Second step of
The sixth step of reference example 144 gave compound 156. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.24-7.21 (m, 1H), 7.17-7.15 (m, 2H), 3.70-3.61 (m, 2H), 3.51-3.43 (m, 1H), 3.42-3.35 (m, 2H), 3.27-3.23 (m, 2H), 3.13-3.04 (m, 3H), 2.60-2.48 (m, 3H), 1.87-1.79 (m, 2H), 1.62-1.56 (m, 1H), 1.44-1.41 (m, 2H), 1.39-1.36 (m, 1H), 1.34-1.32 (m, 2H). MS-ESI calculated value [ M + H%] + 365, found 365.
Example 157
The synthetic route is as follows:
first step of
The fifth step of referential example 144 gave compound 157-2.MS-ESI calculated value [ M + Na ]] + 587, found 587.
Second step of
The sixth step of referential example 144 gave compound 157. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.16-7.15 (m, 2H), 3.70-3.61 (m, 3H), 3.57-3.53 (m, 2H), 3.09-3.02 (m, 5H), 2.57-2.52 (m, 1H), 2.24-2.16 (m, 2H), 2.10-2.05 (m, 2H), 1.60-1.54 (m, 1H), 1.44-1.36 (m, 3H), 1.34-1.32 (m, 2H). MS-ESI calculated value [ M + H%] + 365, found 365.
Example 158
The synthetic route is as follows:
first step of
The fifth step of EXAMPLE 144 gave compound 158-2.MS-ESI calculated value [ M + Na ]] + 601, measured value 601.
Second step of
In the sixth step of EXAMPLE 144, compound 158 was obtained. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.28 (m, 2H), 7.24-7.20 (m, 1H), 7.16-7.14 (m, 2H), 3.86 (s, 2H), 3.80 (s, 2H), 3.70-3.61 (m, 2H), 3.08-3.04 (m, 1H), 3.00-2.93 (m, 1H), 2.57-2.52 (m, 1H), 2.14-2.11 (m, 2H), 2.07-2.03 (m, 2H), 1.75-1.61 (m, 4H), 1.60-1.54 (m, 1H), 1.42-1.35 (m, 3H), 1.34-1.31 (m, 2H). MS-ESI calculated value [ M + H% ] + 379, found 379.
Example 159
The synthesis route is as follows:
first step of
Compound 159-1 (2.00g, 9.99mmol) was dissolved in dry dichloromethane (30 mL), a sodium bicarbonate solution (2.52g, 29.9mmol, 6mL water) was added at 0 deg.C, and a cyanogen bromide solution (1.27g, 11.9mmol, 3mL dichloromethane) was added dropwise. Stirring at 0 deg.C for 10 min, heating to 25 deg.C, and stirring for 3 hr. The reaction solution was diluted with water (50 mL), extracted with dichloromethane (20mL × 3), and the organic phase was washed successively with a saturated sodium bicarbonate solution (30mL × 1), a saturated sodium chloride solution (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 159-2.MS-ESI calculated value [ M-56+ H] + 170, found value 170.
Second step of
Compound 144-6 (100mg, 0.260mmol) and compound 159-2 (117mg, 0.520mmol) were dissolved in anhydrous tetrahydrofuran (15 mL), and zinc dichloride in diethyl ether (1M, 312. Mu.L) was added dropwise thereto at room temperature, followed by stirring at 25 ℃ for 3 hours. P-toluenesulfonic acid monohydrate (54.5mg, 0.286mmol) was added at room temperature, and the reaction solution was heated to 70 ℃ and stirred for 10 hours. Water (50 mL) was added to the reaction mixture, and extraction was performed with ethyl acetate (20mL × 3), and the organic phase was washed with a saturated sodium chloride solution (20mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by preparative thin layer chromatography (2. MS-ESI calculated value [ M + H% ] + 554, found 554.
The third step
Compound 159 is obtained by the sixth step of EXAMPLE 144. 1 H NMR(400MHz,CD 3 OD) delta 7.32-7.28 (m, 2H), 7.25-7.21 (m, 1H), 7.15-7.14 (m, 2H), 4.18-4.14 (m, 2H), 3.61-3.51 (m, 2H), 3.24-3.17 (m, 2H), 3.07-3.03 (m, 1H), 2.55-2.50 (m, 1H), 2.11-2.08 (m, 2H), 1.69-1.53 (m, 4H), 1.40-1.36 (m, 3H), 1.22-1.16 (m, 2H). MS-ESI calculated value [ M + H%] + 354, found 354.
Example 160
The synthetic route is as follows:
first step of
Compound 144-6 (500mg, 1.45mmol) and pyridine (194mg, 2.46mmol) were dissolved in anhydrous dichloromethane (10 mL), the mixture was cooled to-15 deg.C, and trichloroacetyl chloride (316mg, 1.74mmol) was slowly added dropwise. The reaction mixture was heated to 25 ℃ and stirred for 10 hours. Water (50 mL) was added to the reaction solution, stirred at room temperature for 30 minutes, extracted with dichloromethane (50mL × 2), the organic phase was washed with saturated sodium chloride solution (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by preparative thin layer chromatography (2. MS-ESI calculated value [ M + Na ]] + 494, found 494.
Second step of
Compound 160-1 (200mg, 0.423mmol), diisopropylethylamine (164mg, 1.27mmol) and compound 160-2 (1699 mg, 0.846. Mu. Mol) were dissolved in anhydrous N, N-dimethylformamide (5 mL), and the mixture was heated to 60 ℃ and stirred for 12 hours. After the reaction solution was cooled to 0 ℃, water (50 mL) was added, and extracted with ethyl acetate (20mL × 3), and the organic phase was washed with a saturated sodium chloride solution (20mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by preparative thin layer chromatography (2. MS-ESI calculated value [ M + Na ] ] + 604, found value 604.
The third step
The sixth step of reference example 144 gave compound 160. 1 H NMR(400MHz,CD 3 OD) δ 7.33-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.17-7.15 (m, 2H), 4.70-4.66 (m, 1H), 4.30-4.27 (m, 1H), 3.77-3.69 (m, 2H), 3.51-3.45 (m, 1H), 3.36-3.33 (m, 1H), 3.11-2.99 (m, 2H), 2.58-2.53 (m, 1H), 2.18-2.09 (m, 2H), 1.69-1.55 (m, 3H), 1.49-1.47 (m, 2H), 1.44-1.38 (m, 3H). MS-ESI calculated value [ M + H%] + 382, measured value 382.
Example 161
The synthetic route is as follows:
first step of
The fifth step in reference example 144 gave compound 161-2.MS-ESI calculated value [ M + H%] + 476, found 476.
Second step of
Compound 161 can be obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) delta 8.74 (s, 1H), 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.16-7.14 (m, 2H), 3.72-3.63 (m, 2H), 3.62-3.57 (m, 1H), 3.23-3.18 (m, 1H), 3.09-3.04 (m, 2H), 2.88-2.78 (m, 2H), 2.57-2.52 (m, 1H), 2.48-2.42 (m, 1H), 2.22-2.13 (m, 1H), 1.60-1.54 (m, 1H), 1.44-1.35 (m, 5H). MS-ESI calculated value [ M + H%] + 376, found 376.
Example 162
The synthetic route is as follows:
first step of
In the fifth step of EXAMPLE 144, compound 162-2 was obtained. MS-ESI calculated value [ M + H%] + 476, found 476.
Second step of
The sixth step of reference example 144 gave compound 162. 1 H NMR(400MHz,CD 3 OD) δ 8.36 (s, 1H), 7.29-7.26 (m, 2H), 7.21-7.17 (m, 1H), 7.15-7.12 (m, 2H), 4.27 (t, J =6.0hz, 2h), 3.81-3.70 (m, 2H), 3.14-3.09 (m, 3H), 2.58-2.53 (m, 1H), 2.18-2.07 (m, 4H), 1.62-1.51 (m, 3H), 1.45-1.38 (m, 3H). MS-ESI calculated value [ M + H% ] + 376, found 376.
Example 163
The synthesis route is as follows:
first step of
The fifth step in reference example 144 gave compound 163-2.MS-ESI calculated value [ M + Na ]] + 575, found 575.
Second step of
Compound 163 was obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.17-7.15 (m, 2H), 3.72-3.62 (m, 2H), 3.41-3.38 (m, 2H), 3.10-2.97 (m, 3H), 2.92 (d, J =7.2hz, 2H), 2.59-2.54 (m, 1H), 2.24-2.15 (m, 1H), 2.04-1.97 (m, 2H), 1.61-1.50 (m, 3H), 1.45-1.33 (m, 5H). MS-ESI calculated value [ M + H%] + 353, measured value 353.
Example 164
The synthetic route is as follows:
first step of
The fifth step of EXAMPLE 144 gave compound 164-2.MS-ESI calculated value [ M + Na ]] + 559, found 559.
Second step of
The sixth step of EXAMPLE 144 gave compound 164-3.MS-ESI calculated value [ M + H%] + 437, found 437.
The third step
Compound 164-3 (130mg, 0.298mmol) and compound 164-4 (58.7mg, 0.357mmol) were dissolved in anhydrous dichloromethane (20 mL), and acetic acid (53.7mg, 0.893mmol) was added.The reaction mixture was stirred at 30 ℃ for 1 hour, and sodium borohydride acetate (189mg, 0.893 mmol) was added to continue the reaction with stirring for 1 hour. Dichloromethane (100 mL) was added to the reaction solution, and the organic phase was washed successively with saturated sodium carbonate (50mL × 3), saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and isolated and purified by preparative thin layer chromatography (1. MS-ESI calculated value [ M + H% ] + 585, found 585.
The fourth step
Compound 164-5 (80mg, 0.137mmol) was dissolved in tetrahydrofuran (5 mL) under a nitrogen atmosphere, and diethylamine (100mg, 1.37mmol) and tetrakistriphenylphosphine palladium (15.8mg, 13.7. Mu. Mol) were added to stir the reaction mixture at 80 ℃ for 2 hours, followed by filtration and concentration under reduced pressure to give compound 164-6.MS-ESI calculated value [ M + H%] + 501, measured value 501.
The fifth step gave compound 164 in the second step with reference to example 149. 1 H NMR(400MHz,CD 3 OD) δ 8.12 (d, J =8.0hz, 2h), 7.66 (d, J =8.0hz, 2h), 7.32-7.28 (m, 2H), 7.24-7.21 (m, 1H), 7.16-7.14 (m, 2H), 4.38 (s, 2H), 3.71-3.61 (m, 2H), 3.51-3.48 (m, 2H), 3.13-3.05 (m, 3H), 2.90 (d, J =6.8hz, 2h), 2.57-2.51 (m, 1H), 2.22-2.16 (m, 1H), 2.04-2.01 (m, 2H), 1.70-1.54 (m, 3H), 1.45-1.32 (m, 5H). MS-ESI calculated value [ M + H%] + 487, measured value 487.
Example 165
The synthetic route is as follows:
the compound 82-6 is separated by a chiral column, a chromatographic column OD (particle size of 3 um), a mobile phase of ethanol (0.05% diethylamine), the proportion of ethanol is eluted in a gradient from 5% to 40%, and the flow rate is as follows: 2.5ml/min, (retention time: 4.894 min). After separation, compound 165 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1 H NMR(400MHz,CD 3 OD)δ8.14(d,J＝8.0Hz, 2H), 7.70 (d, J =8.0hz, 2h), 7.32-7.28 (m, 2H), 7.25-7.21 (m, 1H), 7.16-7.14 (m, 2H), 4.41 (s, 2H), 3.93 (s, 3H), 3.71-3.48 (m, 5H), 3.20-3.13 (m, 2H), 3.07-3.05 (m, 1H), 2.57-2.48 (m, 1H), 2.40-2.32 (m, 2H), 2.20-2.00 (m, 2H), 1.63-1.59 (m, 1H), 1.42-1.29 (m, 5H). MS-ESI calculated value [ M + H% ] + 487, measured value 487.
Example 166
The synthetic route is as follows:
separating compound 82-6 with chiral column, chromatographic column OD (particle size of 3 um), mobile phase of ethanol (0.05% diethylamine), gradient eluting with ethanol ratio of 5% to 40%, flow rate: 2.5ml/min, (retention time: 5.225 min). After separation, compound 166 is prepared by high performance liquid chromatography (acidic, hydrochloric acid system). 1H NMR (400MHz, CD 3 OD) δ 8.13 (d, J =8.0hz, 2h), 7.68 (d, J =8.0hz, 2h), 7.32-7.28 (m, 2H), 7.25-7.21 (m, 1H), 7.16-7.14 (m, 2H), 4.39 (s, 2H), 3.93 (s, 3H), 3.70-3.48 (m, 5H), 3.17-3.13 (m, 2H), 3.06-3.05 (m, 1H), 2.55-2.48 (m, 1H), 2.38-2.29 (m, 2H), 2.17-2.01 (m, 2H), 1.59-1.52 (m, 1H), 1.41-1.29 (m, 5H). MS-ESI calculated value [ M + H%] + 487, measured value 487.
Example 167
The synthetic route is as follows:
first step of
Reference example 63 gave compound 167-2 in the first step. MS-ESI calculated value [ M + H%] + 496, found 496.
Second step of
Compound 167-2 (1.50g, 3.03mol) was dissolved in water (8 mL) and tetrahydrofuran (2 mL), sodium hydroxide (484mg, 12.1mmol) was added, and the reaction mixture was stirred at 40 ℃ for 4 hours. The reaction mixture was cooled to 0 ℃ and water (100 mL) was added to the reaction mixture to adjust the pH to 3 with hydrochloric acid (1 mol/L). The mixture was extracted with ethyl acetate tetrahydrofuran =3 (50mL x 3), the organic phases were combined, washed with saturated brine (50mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 167-3.MS-ESI calculated value [ M + Na ] ] + 504, found 504.
The third step
The second step of reference example 63 gave compound 167-4.MS-ESI calculated value [ M + H%] + 382, measured value 382.
The fourth step
Separating the compound 167-4 by a chiral column, separating by a chromatographic column Chiralpak AD (particle size is 3 um), wherein the mobile phase comprises A: CO2, B: methanol (0.05% diethylamine), the proportion of the methanol is firstly kept at 5%, the mobile phase is 0.2min, then the gradient elution is carried out for 1.05min from 5% to 40%, and finally the methanol is changed into 5% and washed for 0.35min; the flow rate was 4mL/min (retention time: 1.627 min), and after separation, compound 167 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system). Optically active [ a ]]＝-76.753(0.07g/100mL 26℃)。 1 H NMR (400MHz, CD3OD) delta 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.19-7.15 (m, 2H), 3.70-3.61 (m, 2H), 3.09-3.05 (m, 1H), 2.96-2.90 (m, 1H), 2.56-2.51 (m, 1H), 2.37-2.31 (m, 1H), 2.18-2.10 (m, 4H), 1.66-1.50 (m, 5H), 1.42-1.36 (m, 3H), 1.32-1.27 (m, 2H). MS-ESI calculated value [ M + H%] + 382, measured value 382.
Example 168
The synthetic route is as follows:
the compound 167-4 is separated by a chiral column and chromatographed on a Chiralpak AD (particle size 3 um)) The mobile phase comprises A, CO2, B, methanol (0.05% diethylamine), the proportion of the methanol is kept at 5% for 0.2min, then the gradient elution is carried out for 1.05min from 5% to 40%, and finally the methanol is changed into 5% to wash for 0.35min; the compound 168 was prepared by high performance liquid chromatography (acidic, hydrochloric acid system) at a flow rate of 4mL/min (retention time: 1.867 min). Optically active [ a ] ]＝+22.530(0.03g/100mL 26℃)。 1 H NMR(400MHz,CD 3 OD) delta 7.33-7.29 (m, 2H), 7.22-7.22 (m, 1H), 7.17-7.15 (m, 2H), 3.70-3.61 (m, 2H), 3.07-3.06 (m, 1H), 2.97-2.90 (m, 1H), 2.55-2.50 (m, 1H), 2.34-2.32 (m, 1H), 2.18-2.10 (m, 4H), 1.66-1.54 (m, 5H), 1.43-1.37 (m, 3H), 1.31-1.26 (m, 2H). MS-ESI calculated value [ M + H%] + 382, measured value 382.
Example 169
The synthesis route is as follows:
the second step of reference example 149 gave compound 169.1H NMR (400MHz, CD 3 OD) δ 8.14 (d, J =8.0hz, 2h), 7.71 (d, J =8.0hz, 2h), 7.32-7.28 (m, 2H), 7.24-7.21 (m, 1H), 7.18-7.14 (m, 2H), 4.45 (s, 2H), 3.73-3.60 (m, 3H), 3.54-3.34 (m, 3H), 3.26-3.20 (m, 1H), 3.08-3.04 (m, 1H), 2.64-2.51 (m, 1H), 2.44-2.31 (m, 4H), 1.66-1.54 (m, 1H), 1.42-1.34 (m, 5H). MS-ESI calculated value [ M + H%] + 473, found 473.
Example 170
The synthesis route is as follows:
first step second step of reference example 149 gaveAnd (3) an object 170.1H NMR (400MHz, CD 3 OD) δ 8.14 (d, J =8.4hz, 2h), 7.73 (d, J =8.4hz, 2h), 7.31-7.28 (m, 2H), 7.24-7.14 (m, 3H), 4.46 (s, 2H), 3.74-3.59 (m, 3H), 3.54-3.33 (m, 3H), 3.28-3.22 (m, 1H), 3.08-3.05 (m, 1H), 2.59-2.54 (m, 1H), 2.44-2.11 (m, 4H), 1.61-1.56 (m, 1H), 1.41-1.28 (m, 5H). MS-ESI calculated value [ M + H%] + 473, found 473.
Example 171
The synthesis route is as follows:
compound 167 (58.0 mg, 0.152mmol) was dissolved in methanol (5 mL), concentrated sulfuric acid (0.1 mL) was added dropwise at 0 ℃ and the reaction mixture was heated to 70 ℃ and stirred for 1 hour. Concentrating under reduced pressure, and separating and purifying by high performance liquid chromatography (acidic, hydrochloric acid system) to obtain compound 171. 1 H NMR(400MHz,CD 3 OD) δ 7.33-7.29 (m, 2H), 7.25-7.22 (m, 1H), 7.16-7.14 (m, 2H), 3.69-3.61 (m, 5H), 3.08-3.06 (m, 1H), 2.96-2.94 (m, 1H), 2.52-2.49 (m, 1H), 2.40-2.38 (m, 1H), 2.18-2.03 (m, 4H), 1.66-1.51 (m, 5H), 1.43-1.37 (m, 3H), 1.31-1.25 (m, 2H). MS-ESI calculated value [ M + H%] + 396, found 396.
Example 172
The synthetic route is as follows:
compound 172 was obtained by reference to example 171. 1 H NMR(400MHz,CD 3 OD)δ7.33-7.29(m,2H),7.25-7.21(m,1H),7.16-7.14(m,2H),3.69-3.61(m,5H),3.09-3.05(m,1H),2.96-2.94(m,1H),2.53-2.48(m,1H),2.40-2.38(m, 1H), 2.17-2.08 (m, 4H), 1.66-1.51 (m, 5H), 1.43-1.37 (m, 3H), 1.30-1.29 (m, 2H). MS-ESI calculated value [ M + H%] + 396, found 396.
Example 173
The synthetic route is as follows:
first step of
Compound 173-2 is obtained in the fifth step in accordance with example 144. MS-ESI calculated value [ M + Na ]] + 530, measured value 530.
Second step of
The second step of reference example 149 gave compound 173-3.MS-ESI calculated value [ M + Na ]] + 516, found 516.
The third step
The sixth step of referential example 144 gave the compound 173. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.16-7.14 (m, 2H), 3.70-3.58 (m, 3H), 3.09-2.97 (m, 2H), 2.60-2.47 (m, 2H), 2.45-2.31 (m, 5H), 2.25-2.23 (m, 2H), 1.57-1.51 (m, 1H), 1.45-1.42 (m, 2H), 1.40-1.37 (m, 1H), 1.31-1.29 (m, 2H). MS-ESI calculated value [ M + H%] + 394, found 394.
Example 174
The synthesis route is as follows:
first step of
The fifth step of referential example 144 gave compound 174-2.MS-ESI calculated value [ M + H% ] + 482, found 482.
Second step of
The second step of referential example 149 gave compound 174-3.MS-ESI calculated value [ M + Na ]] + 490, found 490.
The third step
Compound 174 was obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.24-7.21 (m, 1H), 7.16-7.15 (m, 2H), 3.70-3.61 (m, 2H), 3.55-3.40 (m, 1H), 3.10-3.06 (m, 1H), 3.02-2.93 (m, 1H), 2.58-2.51 (m, 1H), 2.46-2.33 (m, 1H), 2.26-1.90 (m, 5H), 1.59-1.54 (m, 1H), 1.45-1.42 (m, 2H), 1.40-1.35 (m, 1H), 1.32-1.30 (m, 2H). MS-ESI calculated value [ M + H%] + 368, measured value 368.
Example 175
The synthetic route is as follows:
first step of
In the fifth step of EXAMPLE 144, compound 175-2 was obtained. MS-ESI calculated value [ M + Na ]] + 504, found 504.
Second step of
Compound 175 is obtained by the sixth step of EXAMPLE 144. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.17-7.15 (m, 2H), 3.65 (s, 2H), 3.43-3.39 (m, 1H), 3.12-3.04 (m, 2H), 2.54-2.49 (m, 1H), 2.13-2.00 (m, 3H), 1.90-1.85 (m, 1H), 1.58-1.49 (m, 5H), 1.43-1.35 (m, 3H), 1.31-1.25 (m, 2H). MS-ESI calculated value [ M + H%] + 382, measured value 382.
Example 176
The synthesis route is as follows:
first step of
In the fifth step of EXAMPLE 144, compound 176-2 was obtained. MS-ESI calculated value [ M + Na ]] + 502, measured value 502.
Second step of
The second step of referential example 149 gave compound 176-3.MS-ESI calculated value [ M + Na ] ] + 488, found 488.
The third step
The sixth step of reference example 144 gave compound 176. 1 H NMR(400MHz,CD 3 OD) delta 7.33-7.29 (m, 2H), 7.25-7.22 (m, 1H), 7.16-7.14 (m, 2H), 3.71-3.61 (m, 2H), 3.09-3.06 (m, 1H), 2.52-2.46 (m, 7H), 1.56-1.50 (m, 1H), 1.45-1.35 (m, 3H), 1.32-1.29 (m, 2H). MS-ESI calculated value [ M + H%] + 366, found value 366.
Example 177
The synthesis route is as follows:
first step of
The fifth step of reference example 144 gave compound 177-2.MS-ESI calculated value [ M + H%] + 522, measured value 522.
Second step of
Reference example 149 second step gave compound 177-3.MS-ESI calculated value [ M + Na ]] + 530, measured value 530.
The third step
Reference to example 144 gave compound 177 in the sixth step. 1 H NMR(400MHz,CD 3 OD)δ7.33-7.31(m,2H),7.25-7.22(m,1H),7.17-7.15(m,2H),3.68-3.61(m,2H),3.09-3.05(m,1H),2.54-2.49(m,1H),2.03-1.90(m,12H),1.57-1.52(m,1H),1.44-1.37(m,3H),1.32-1.27 (m, 2H). MS-ESI calculated value [ M + H%] + 408, found value 408.
Example 178
The synthesis route is as follows:
first step of
The fifth step of EXAMPLE 144 gave compound 178-2.MS-ESI calculated value [ M + Na ]] + 504, found 504.
Second step of
The second step of reference example 149 gave compound 178-3.MS-ESI calculated value [ M + Na ]] + 490, found 490.
The third step
Compound 178 was obtained by the sixth step of EXAMPLE 144. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.24-7.21 (m, 1H), 7.16-7.15 (m, 2H), 3.71-3.62 (m, 2H), 3.55-3.40 (m, 1H), 3.10-3.06 (m, 1H), 3.03-2.95 (m, 1H), 2.57-2.52 (m, 1H), 2.46-2.33 (m, 1H), 2.26-1.88 (m, 5H), 1.60-1.51 (m, 1H), 1.45-1.41 (m, 2H), 1.40-1.36 (m, 1H), 1.34-1.31 (m, 2H). MS-ESI calculated value [ M + H% ] + 368, measured value 368.
Example 179
First step of
Compound 179-1 (5g, 35.7mmol) was dissolved in anhydrous dichloromethane (200 mL) and m-chloroperoxybenzoic acid (9.23g, 42.8mmol,80% purity) was added at 0 ℃. The reaction solution was heated to 25 ℃ and stirred for further reaction for 24 hours. Chloroform (100 mL) and saturated sodium carbonate (100 mL) were added to the reaction mixture, the mixture was stirred for 30 minutes, the solution was separated, the organic phase was washed with saturated sodium carbonate (3X 100 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then filtered through silica gelColumn chromatography (10. 1 H NMR(400MHz,CDCl 3 )δ3.66(s,3H),3.22-3.12(m,2H),2.53-2.49(m,0.5H),2.25-2.14(m,2H),2.03-1.86(m,2H),1.80-1.72(m,1H),1.65-1.52(m,1H),1.45-1.35(m,0.5H)。
Second step of
Compound 179-2 (5.00g, 32.0 mmol) was dissolved in N, N-dimethylformamide (50 mL), and sodium azide (2.71g, 41.6 mmol) and ammonium chloride (3.08g, 57.6 mmol) were added to the reaction solution. The mixture was stirred at 70 ℃ for 6 hours. The reaction was quenched with water (300 mL), extracted with ethyl acetate (200mL x 3), the organic phases combined, washed with saturated brine (100mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 179-3. 1 H NMR(400MHz,CDCl 3 )δ3.70-3.61(m,4H),3.57-3.28(m,1H),2.78-2.72(m,1H),2.37-2.23(m,1H),2.12-1.85(m,1H),1.69-1.31(m,4H)。
The third step
Compound 179-3 (7.00g, 35.1mmol) and di-tert-butyl carbonate (7.67g, 35.1mmol) were dissolved in methanol (150 mL), wet palladium on carbon (700mg, 10% purity) was added under nitrogen protection, the reaction solution was purged with hydrogen several times, and the reaction solution was stirred under hydrogen (15 psi) at 25 ℃ for 12 hours. The palladium on carbon was removed by filtration, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (5. MS-ESI calculated value [ M + Na ] ] + 296, found 296.
The fourth step
Compound 179-4 (1.60g, 5.85mmol) was dissolved in anhydrous dichloromethane (30 mL), and bis (2-methoxyethyl) aminosulfur trifluoride (1.94g, 8.78mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at 25 ℃ for 12 hours. The reaction was quenched with water (50 mL), adjusted to pH 9 with saturated sodium bicarbonate, extracted with dichloromethane (30mL x 3), the organic phases combined, washed with saturated brine (30mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by silica gel column chromatography (3. MS-ESI calculated value [ M-Boc + H] + 176, found 176.
The fifth step
Second step of reference example 149Compound 179-6 is obtained. MS-ESI calculated value [ M-56+ H] + 206, measured value 206.
The sixth step
The fifth step of reference example 144 gave compound 179-7.MS-ESI calculated value [ M + Na ]] + 593, found 593.
Step seven
In the sixth step of EXAMPLE 144, compound 179 was obtained. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.16-7.14 (m, 2H), 4.68-4.51 (m, 1H), 3.75-3.49 (m, 5H), 3.07-3.05 (m, 1H), 2.58-2.51 (m, 2H), 2.34-2.20 (m, 2H), 2.04-1.94 (m, 1H), 1.86-1.55 (m, 3H), 1.42-1.34 (m, 4H). MS-ESI calculated value [ M + H%] + 371, found 371.
Example 180
First step of
The second step of referential example 149 gave compound 180-1.MS-ESI calculated value [ M + Na ]] + 282, measured value 282.
Second step of
The fifth step of reference example 144 gave compound 180-2.MS-ESI calculated value [ M + Na ]] + 591, found 591.
The third step
The sixth step of reference example 144 gave compound 180. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.24-7.21 (m, 1H), 7.17-7.15 (m, 2H), 3.78-3.63 (m, 3H), 3.57-3.49 (m, 1H), 3.25-3.20 (m, 0.5H), 3.08-3.06 (m, 1H), 3.01-2.94 (m, 0.5H), 2.63-2.47 (m, 2H), 2.27-2.18 (m, 1H), 2.02-1.79 (m, 3H), 1.70-1.58 (m, 2H), 1.46-1.35 (m, 5H). MS-ESI calculated value [ M + H%] + 369, found 369.
Example 181
The synthetic route is as follows:
first step of
The fifth step in accordance with example 144 gave compound 181-2.MS-ESI calculated value [ M + Na ]] + 512, found 512.
Second step of
The second step of referential example 149 gave compound 181-3.MS-ESI calculated value [ M + Na ]] + 498, found 498.
The third step
Compound 181 was obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) delta 8.23-8.15 (m, 4H), 7.27-7.23 (m, 2H), 7.18-7.13 (m, 3H), 3.82-3.69 (m, 2H), 3.15-3.11 (m, 1H), 2.61-2.58 (m, 1H), 1.65-1.49 (m, 3H), 1.45-1.37 (m, 3H). MS-ESI calculated value [ M + H%] + 376, found 376.
Example 182
The synthesis route is as follows:
First step of
Compound 64-2 (260mg, 0.569mmol) and anhydrous potassium carbonate (157mg, 1.14mmol) were dissolved in dimethyl sulfoxide (2 mL), and hydrogen peroxide (645mg, 5.70mmol,30% purity) was added dropwise at 0 ℃. The mixture was stirred at room temperature 25 ℃ for 12 hours. To the reaction solution were added a saturated sodium thiosulfate solution (50 mL) and a saturated sodium bicarbonate solution (50 mL) at 0 ℃ and stirred for 30 minutes, extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with a saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by preparative thin layer chromatography (ethyl acetate, rf = 0.5) to give compound 182-1. 1 H NMR(400MHz,CDCl 3 )δ8.13(d,J＝8.4Hz,2H),7.94(d,J＝8.4Hz,2H),7.18-7.15(m,2H),7.09-7.01(m, 3H), 6.16 (brs, 1H), 5.73 (brs, 1H), 3.96-3.76 (m, 2H), 2.83-2.79 (m, 1H), 2.11-2.05 (m, 1H), 1.40 (s, 9H), 1.34-1.29 (m, 2H), 1.22-1.06 (m, 4H). MS-ESI calculated value [ M + Na ]] + 497, found 497.
The second step refers to the sixth step of example 144 to provide compound 182. 1 H NMR(400MHz,CD 3 OD) δ 8.18 (d, J =8.4hz, 2h), 8.06 (d, J =8.4hz, 2h), 7.28-7.25 (m, 2H), 7.19-7.14 (m, 3H), 3.82-3.69 (m, 2H), 3.15-3.11 (m, 1H), 2.59-2.54 (m, 1H), 1.62-1.50 (m, 3H), 1.42-1.38 (m, 3H). MS-ESI calculated value [ M + H%] + 375, found 375.
Example 183
The synthetic route is as follows:
first step of
Compound 181-3 (100mg, 0.210mmol) was dissolved in anhydrous N, N-dimethylformamide (2 mL), and dimethylamine hydrochloride (18.9mg, 0.231mmol), 2- (7-azobisbenzotriazol) -N, N, N, N-tetramethyluronium hexafluorophosphate (79.9mg, 0.210mmol), and diisopropylethylamine (81.5mg, 0.630mmol) were added to the reaction solution. The mixture was stirred at room temperature at 25 ℃ for 12 hours. Water (30 mL) was added to the reaction mixture at 0 ℃, and extracted with ethyl acetate (20mL × 3), and the organic phases were combined, washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by preparative thin layer chromatography (1. MS-ESI calculated value [ M + Na ] ] + 525, found value 525.
The second step, referring to example 144, provides compound 183 in the sixth step. 1 H NMR(400MHz,CD 3 OD) δ 8.18 (d, J =8.4hz, 2h), 7.65 (d, J =8.4hz, 2h), 7.28-7.24 (m, 2H), 7.16-7.13 (m, 3H), 3.82-3.69 (m, 2H), 3.14-3.11 (m, 4H), 3.01 (s, 3H), 2.62-2.57 (m, 1H), 1.65-1.60 (m, 1H), 1.58-1.51 (m, 2H), 1.47-1.36 (m, 3H). MS-ESI calculated value [ M + H%] + 403, measured value 403.
Example 184
The synthesis route is as follows:
first step of
The first step of reference example 183 gave compound 184-2.MS-ESI calculated value [ M + Na ]] + 537, found 537.
Second step of
Compound 184 is obtained by the sixth step of EXAMPLE 144. 1 H NMR(400MHz,CD 3 OD) δ 8.15 (d, J =8.4hz, 2h), 7.98 (d, J =8.4hz, 2h), 7.33-7.24 (m, 2H), 7.19-7.07 (m, 3H), 3.90-3.57 (m, 2H), 3.15-3.11 (m, 1H), 2.90-2.86 (m, 1H), 2.60-2.55 (m, 1H), 1.67-1.54 (m, 3H), 1.45-1.32 (m, 3H), 0.87-0.78 (m, 2H), 0.69-0.62 (m, 2H). MS-ESI calculated value [ M + H%] + 415, found value 415.
Example 185
The synthetic route is as follows:
first step of
The fifth step of EXAMPLE 144 was followed to give compound 185-2.MS-ESI calculated value [ M + Na ]] + 472, measured value 472.
Second step of
Compound 185 is obtained by the sixth step of EXAMPLE 144. 1 H NMR(400MHz,CD 3 OD)δ8.12-8.09(m,1H),7.74-7.69(m,1H),7.42-7.35(m,2H),7.29-7.25(m,2H),7.20-7.13(m,3H),3.79-3.67(m,2H),3.12-3.10 (m, 1H), 2.53-2.49 (m, 1H), 1.58-1.50 (m, 3H), 1.43-1.38 (m, 3H). MS-ESI calculated value [ M + H%] + 350, found 350.
Example 186
The synthetic route is as follows:
first step of
Compound 1 (600mg, 2.65mmol) was dissolved in anhydrous dichloromethane (5 mL), diisopropylethylamine (685mg, 5.30mmol) and allyl chloroformate (479mg, 3.98mmol) were added at 25 deg.C, and the reaction mixture was stirred at 20 deg.C for 1 hour. The reaction solution was concentrated under reduced pressure, and separated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,CDCl 3 ) δ 7.28-7.26 (m, 2H), 7.19-7.15 (m, 3H), 5.96-5.90 (m, 1H), 5.30-5.19 (m, 2H), 4.70-4.61 (m, 2H), 3.97-3.94 (m, 1H), 3.51-3.47 (m, 1H), 2.89-2.85 (m, 1H), 2.52-2.41 (m, 2H), 2.28-2.16 (m, 4H), 2.05-2.03 (m, 1H), 1.38-1.26 (m, 2H). MS-ESI calculated value [ M + H%] + 311, measured value 311.
Second step of
The first step of reference example 182 gave compound 186-2. 1 H NMR(400MHz,CDCl 3 ) δ 7.28-7.24 (m, 2H), 7.20-7.16 (m, 1H), 7.12-7.11 (m, 2H), 5.96-5.86 (m, 1H), 5.30-5.18 (m, 2H), 4.66-4.56 (m, 2H), 3.92 (d, J =14.8hz, 1h), 3.62 (d, J =14.8hz, 1h), 2.76-2.72 (m, 1H), 2.44-2.28 (m, 2H), 2.21-2.01 (m, 3H), 1.95-1.86 (m, 2H), 1.31-1.26 (m, 2H). MS-ESI calculated value [ M + Na ]] + 351, found value 351.
The third step
Compound 186-2 (110mg, 0.335mmol) and compound 186-3 (140mg, 0.670mmol) were dissolved in dichloroethane, and silver hexafluoroantimonate (115mg, 0.335mmol) was added thereto, followed by heating to 100 ℃ and stirring for reaction for 48 hours. Concentrated under reduced pressure by filtration and the pure product isolated by thin layer chromatography (3 The compound 186-4 is obtained by reaction. MS-ESI calculated value [ M + H%] + 439, found 439.
The fourth step
Compound 186-4 (50.0mg, 0.114mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), diethylamine (83.4mg, 1.14mmol) and tetratriphenylphosphine palladium (13.2mg, 11.4. Mu. Mol) were added, and the reaction solution was stirred at 80 ℃ for 3 hours. Filtering, concentrating under reduced pressure to obtain compound 186-5.MS-ESI calculated value [ M + H%] + 355, found 355.
The fifth step
The second step of reference example 149 gave compound 186. 1 H NMR(400MHz,CD 3 OD) Δ 7.33-7.29 (m, 2H), 7.25-7.18 (m, 3H), 3.82 (s, 2H), 3.17-3.13 (m, 1H), 2.67-2.59 (m, 6H), 2.36-2.14 (m, 4H), 1.64-1.59 (m, 1H), 1.42-1.37 (m, 1H). MS-ESI calculated value [ M + H%] + 327, measured value 327.
Example 187
The synthesis route is as follows:
first step of
The fifth step of reference example 144 gave compound 187-2.MS-ESI calculated value [ M + Na ]] + 504, found 504.
Second step of
The sixth step of referential example 144 gave compound 187. 1 H NMR(400MHz,CD 3 OD) delta 8.27-8.21 (m, 1H), 7.31-7.14 (m, 7H), 3.88 (s, 2H), 3.08-3.06 (m, 1H), 2.72-2.64 (m, 2H), 2.56-2.52 (m, 1H), 2.45-2.40 (m, 2H), 2.26-2.18 (m, 2H), 1.61-1.55 (m, 1H), 1.40-1.35 (m, 1H). MS-ESI calculated value [ M + H%] + 382, measured value 382.
Example 188
The synthetic route is as follows:
first step of
In the fifth step of EXAMPLE 144, compound 188-2 was obtained. MS-ESI calculated value [ M + Na ] ] + 526, found value 526.
Second step of
The second step of referential example 149 gave compound 188-3.MS-ESI calculated value [ M + Na ]] + 512, found 512.
The third step
In the sixth step of EXAMPLE 144, compound 188 was obtained. 1 H NMR(400MHz,CD 3 OD) delta 8.28-8.21 (m, 4H), 7.30-7.26 (m, 2H), 7.22-7.15 (m, 3H), 3.89 (s, 2H), 3.11-3.07 (m, 1H), 2.74-2.66 (m, 2H), 2.56-2.51 (m, 1H), 2.47-2.38 (m, 2H), 2.28-2.20 (m, 2H), 1.59-1.54 (m, 1H), 1.42-1.33 (m, 1H). MS-ESI calculated value [ M + H%] + 390, found 390.
Example 189
The synthesis route is as follows:
first step of
In the fifth step of EXAMPLE 144, compound 189-2 was obtained. MS-ESI calculated value [ M + Na ]] + 551, measured value 551.
Second step of
Compound 189 was obtained by the sixth step of EXAMPLE 144. 1 H NMR(400MHz,CD 3 OD)δ8.37(s,1H),8.34(d,J＝9.2Hz,1H),7.34(d,J＝9.2Hz,1H),7.29-7.25(m,2H),7.20-7.14(m,3H),4.98-4.91(m,1H),3.67(s,2H),3.08-3.06(m,1H),2.71-2.62(m,2H),2.57-2.52(m,1H),2.46-2.37(m,2H),2.26-2.18(m,2H),1.61-156 (m, 1H), 1.45 (d, J =6.0hz, 6H), 1.40-1.35 (m, 1H). MS-ESI calculated value [ M + H%] + 429, found 429.
Example 190
The synthesis route is as follows:
first step of
The fifth step of EXAMPLE 144 gave compound 190-2.MS-ESI calculated value [ M + Na ]] + 511, found value 511.
Second step of
The sixth step of reference example 144 gave compound 190. 1 H NMR(400MHz,CD 3 OD) δ 8.34 (s, 1H), 8.20 (d, J =8.4hz, 1h), 7.93 (d, J =6.8hz, 1h), 7.33-7.24 (m, 2H), 7.19-7.14 (m, 3H), 3.89 (s, 2H), 3.08-3.06 (m, 1H), 2.72-2.64 (m, 2H), 2.58-2.53 (m, 1H), 2.47-2.42 (m, 2H), 2.26-2.21 (m, 2H), 1.62-1.57 (m, 1H), 1.40-1.34 (m, 1H). MS-ESI calculated value [ M + H% ] + 389, found 389.
Example 191
The synthetic route is as follows:
first step of
Compound 191-2 is obtained in the fifth step in accordance with example 144. MS-ESI calculated value [ M + Na ]] + 522, measured value 522.
Second step of
Compound 191 was obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD)δ7.31-7.15(m,7H)3.89 (s, 2H), 3.09-3.05 (m, 1H), 2.72-2.65 (m, 2H), 2.53-2.48 (m, 1H), 2.44-2.38 (m, 2H), 2.25-2.21 (m, 2H), 1.57-1.52 (m, 1H), 1.42-1.37 (m, 1H). MS-ESI calculated value [ M + H%] + 400, found value 400.
Example 192
The synthetic route is as follows:
first step of
The fifth step in reference example 144 gave compound 192-2.MS-ESI calculated value [ M + Na ]] + 493, found 493.
Second step of
Compound 192 is obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) δ 8.31 (d, J =8.4hz, 2h), 7.98 (d, J =8.4hz, 2h), 7.29-7.25 (m, 2H), 7.20-7.14 (m, 3H), 3.89 (s, 2H), 3.10-3.06 (m, 1H), 2.73-2.65 (m, 2H), 2.58-2.53 (m, 1H), 2.48-2.40 (m, 2H), 2.27-2.19 (m, 2H), 1.61-1.58 (m, 1H), 1.41-1.35 (m, 1H). MS-ESI calculated value [ M + H%] + 371, found 371.
Example 193
The synthetic route is as follows:
first step of
Compound 193-2 can be obtained by the fifth step of EXAMPLE 144. MS-ESI calculated value [ M + Na ]] + 511, found value 511.
Second step of
Reference example 144 the sixth step to obtain the Compound193。 1 H NMR(400MHz,CD 3 OD) δ 8.35 (t, J =6.8hz, 1h), 7.90 (dd, J =10.0hz, J =1.2hz, 1h), 7.81 (dd, J =10.0hz, J =1.2hz, 1h), 7.29-7.25 (m, 2H), 7.20-7.13 (m, 3H), 3.90 (s, 2H), 3.09-3.05 (m, 1H), 2.73-2.65 (m, 2H), 2.54-2.49 (m, 1H), 2.47-2.39 (m, 2H), 2.27-2.19 (m, 2H), 1.58-1.53 (m, 1H), 1.41-1.36 (m, 1H). MS-ESI calculated value [ M + H% ] + 389, found 389.
Example 194
The synthetic route is as follows:
first step of
Compound 186-1 (100mg, 0.322mmol) was dissolved in ethyl acetate (10 mL), compound 194-1 (120mg, 0.644mmol) was added, and the reaction solution was stirred at 30 ℃ for 12 hours. Ethyl acetate (50 mL) was added to the reaction mixture, and the organic phase was washed with saturated sodium bicarbonate (20mL. Times.2) and saturated brine (20mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 194-2.MS-ESI calculated value [ M + H%] + 345, found 345.
Second step of
Compound 194-2 (100mg, 0.290mmol) was dissolved in anhydrous toluene (5 mL), and compound 194-3 (62.1mg, 0.377mmol) was added at 25 ℃. The reaction mixture was heated to 100 ℃ and stirred for 3 hours. The reaction solution was concentrated under reduced pressure to obtain compound 194-4.MS-ESI calculated value [ M + H%] + 455, found value 455.
The third step
The fourth step of reference example 186 gave compound 194-5.MS-ESI calculated value [ M + H%] + 371, found 371.
The fourth step
The second step of reference example 149 gave compound 194. 1 H NMR(400MHz,CD 3 OD)δ7.32-7.28(m,2H),7.24-7.16(m,3H),3.87(s,2H),3.17-3.13(m,1H),2.67(m,3H),2.58-2.51(m,5H),2.23-2.17 (m, 2H), 1.64-1.59 (m, 1H), 1.42-1.38 (m, 1H). MS-ESI calculated value [ M + H%] + 343, found value 343.
Example 195
The synthetic route is as follows:
first step of
Compound 49-2 (100mg, 0.317 mmol) was dissolved in anhydrous dichloromethane (10 mL), and compound 195-1 (81.5mg, 0.380mmol) and acetic acid (57.1mg, 0.951mmol) were added to the reaction solution, followed by stirring at 30 ℃ for 1 hour, sodium triacetoxyborohydride (201mg, 0.951mmol) was added, and stirring was continued at 30 ℃ for 1 hour. Dichloromethane (30 mL) was added to the reaction solution for dilution, and washed with saturated aqueous sodium carbonate solution (30mL x 3), water (30mL x 2), saturated brine (30mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was prepared by thin layer chromatography (3. MS-ESI calculated value [ M + H% ] + 514, measured value 514.
Second step of
In the sixth step of EXAMPLE 144, compound 195 was obtained. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.24-7.18 (m, 3H), 3.52-3.45 (m, 2H), 3.38-3.33 (m, 2H), 3.29-3.25 (m, 1H), 3.19-3.10 (m, 2H), 2.74-2.69 (m, 1H), 2.06-1.91 (m, 8H), 1.72-1.67 (m, 1H), 1.39-1.34 (m, 1H), 0.98-0.94 (m, 4H). MS-ESI calculated value [ M + H%] + 314, measured value 314.
Example 196
The synthesis route is as follows:
first step of
Compound 196-2 was obtained in the first step of reference example 195. MS-ESI calculated value [ M + H%] + 471, found 471.
Second step of
The second step of reference example 149 gave compound 196-3.MS-ESI calculated value [ M + H%] + 443, found 443.
The third step
Compound 196 is obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.28 (m, 2H), 7.24-7.18 (m, 3H), 3.69-3.64 (m, 2H), 3.52-3.38 (m, 2H), 3.26-3.10 (m, 3H), 3.00-2.94 (m, 2H), 2.76-2.71 (m, 1H), 2.38-2.34 (m, 2H), 2.03-1.91 (m, 2H), 1.73-1.68 (m, 1H), 1.39-1.31 (m, 4H), 1.01-0.86 (m, 4H). MS-ESI calculated value [ M + H%] + 343, found value 343.
Example 197
The synthetic route is as follows:
first step of
The first step of reference example 195 gave compound 197-2.MS-ESI calculated value [ M + H%] + 457, found 457.
Second step of
Reference example 149 second step gave compound 197-3.MS-ESI calculated value [ M + H% ] + 443, found 443.
The third step
The sixth step of reference example 144 gave compound 197. 1 H NMR(400MHz,CD 3 OD)δ7.32-7.28(m,2H),7.24-7.18(m,3H),3.44-3.34(m,2H),3.25-3.14(m,3H),3.09-3.05(m,1H),2.75-2.70(m,1H),2.34-2.22(m,3H),2.15-2.12(m,2H),1.74-1.68(m,1H),1.60-1.44(m,4H),1.39-1.34 (m, 1H), 0.97-0.90 (m, 4H). MS-ESI calculated value [ M + H%] + 343, found value 343.
Example 198
The synthetic route is as follows:
first step of
Reference example 195 gave compound 198-1 as the first step. MS-ESI calculated value [ M + H%] + 433, found value 433.
Second step of
The sixth step of reference example 144 gave compound 198. 1 H NMR(400MHz,CD 3 OD) delta 7.34-7.30 (m, 4H), 7.26-7.19 (m, 6H), 3.48-3.34 (m, 4H), 3.06-3.02 (m, 2H), 2.72-2.68 (m, 2H), 1.77-1.66 (m, 2H), 1.38-1.33 (m, 2H), 0.93 (s, 4H). MS-ESI calculated value [ M + H%] + 333, found value 333.
Example 199
The synthesis route is as follows:
first step of
Compound 199-1 (20.0g, 177mmol) was dissolved in anhydrous acetonitrile (300 mL), anhydrous potassium carbonate (61.1g, 442mmol) and compound 199-2 (66.4g, 354mmol) were added at 0 ℃ and the reaction mixture was stirred at 70 ℃ for 24 hours. The reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ4.27(q,J＝6.8Hz,2H),1.67-1.64(m,2H),1.58-1.54(m,2H),1.34(t,J＝6.8Hz,3H)。
Second step of
Compound 199-3 (6.00g, 43.1mmol) was dissolved in ethanol (60 mL), concentrated hydrochloric acid (8.73g, 86.2mmol,8.6mL,36% purity) was added dropwise to the reaction solution, and the reaction solution was stirred at 25 ℃ for 24 hours. The reaction solution was concentrated under reduced pressure to give compound 199-4. 1 H NMR(400MHz,CDCl 3 )δ4.13(q,J＝6.8Hz,2H),1.98(brs,2H),1.29-1.23(m,5H),0.99-0.96(m,2H)。
The third step
Compound 199-4 (2.00g, 15.5 mmol) was dissolved in anhydrous dichloromethane (40 mL), and triethylamine (1.57g, 15.5 mmol) and di-tert-butyl carbonate (3.38g, 15.5 mmol) were added. The reaction mixture was stirred at 20 ℃ for 24 hours. Concentrated under reduced pressure, and isolated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,CDCl 3 )δ5.11(brs,1H),4.15(q,J＝7.2Hz,2H),1.56-1.48(m,2H),1.45(s,9H),1.24(t,J＝7.2Hz,3H),1.17-1.08(m,2H)。
The fourth step
Compound 199-5 (1.80g, 7.85mmol) was dissolved in anhydrous methanol (20 mL), lithium borohydride (513mg, 23.6 mmol) was added at 0 ℃ and the reaction solution was stirred at 70 ℃ for 12 hours. To the reaction mixture was added a saturated ammonium chloride solution (200 mL), extracted with ethyl acetate (100mL × 3), and the organic phase was washed with a saturated brine (100x 2mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (1. 1 H NMR(400MHz,CDCl 3 )δ5.07(brs,1H),3.59(s,2H),3.42(brs,1H),1.45(s,9H),0.84-0.83(m,4H)。
The fifth step
Compound 199-6 (250mg, 1.34mmol) was dissolved in anhydrous dichloromethane (10 mL), and Desmatin's reagent (597 mg, 1.41mmol) was added at 0 ℃ to stir the reaction solution at 25 ℃ for 12 hours. To the reaction mixture were added a saturated sodium bicarbonate solution (30 mL) and a saturated sodium thiosulfate solution (30 mL), and the mixture was extracted with dichloromethane (30mL × 3), and the organic phase was washed with a saturated brine (30x 2mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by thin layer chromatography (3 Compound 199-7. 1 H NMR(400MHz,CDCl 3 )δ9.18(brs,1H),5.15(brs,1H),1.52-1.48(m,2H),1.46(s,9H),1.34-1.28(m,2H)。
The sixth step
Reference example 195 the first step provided compound 199-8.MS-ESI calculated value [ M + H%] + 303, found value 303.
Step seven
Compound 199 was obtained by the sixth step of reference example 144. 1 H NMR(400MHz,CD 3 OD) Δ 7.33-7.29 (m, 2H), 7.25-7.18 (m, 3H), 3.60 (s, 2H), 3.06-3.02 (m, 1H), 2.78-2.73 (m, 1H), 1.78-1.72 (m, 1H), 1.43-1.38 (m, 1H), 1.22 (s, 4H). MS-ESI calculated value [ M + H%] + 203, found value 203.
Example 200
The synthetic route is as follows:
first step of
The first step of reference example 186 gave compound 200-2.MS-ESI calculated value [ M-56+H] + 331, found value 331.
Second step of
The sixth step of EXAMPLE 144 was followed to give compound 200-3. 1 H NMR(400MHz,CDCl 3 ) δ 7.30-7.29 (m, 2H), 7.22-7.18 (m, 1H), 7.15-7.14 (m, 2H), 6.00-5.90 (m, 1H), 5.33-5.20 (m, 2H), 4.70-4.60 (m, 2H), 3.61-3.50 (m, 1H), 3.21-3.17 (m, 1H), 2.84-2.81 (m, 1H), 2.23-2.16 (m, 1H), 1.32-1.24 (m, 2H), 0.66-0.53 (m, 3H), 0.45-0.40 (m, 1H). MS-ESI calculated value [ M + H%] + 287, found 287.
The third step
Reference example 195 the first step gave compound 200-5.MS-ESI calculated value [ M + H%] + 435, found 435.
The fourth step
Fourth step of reference example 186To obtain the compound 200-6.MS-ESI calculated value [ M + H%] + 351, found value 351.
The fifth step
Reference example 149 second step gave compound 200. 1 H NMR(400MHz,CD 3 OD) δ 8.09 (d, J =8.4hz, 2h), 7.79 (d, J =8.4hz, 2h), 7.33-7.29 (m, 2H), 7.25-7.19 (m, 3H), 4.62-4.54 (m, 2H), 3.81-3.68 (m, 2H), 3.09-3.05 (m, 1H), 2.79-2.74 (m, 1H), 1.81-1.76 (m, 1H), 1.43-1.31 (m, 5H). MS-ESI calculated value [ M + H%] + 337, found 337.
Example 201
The synthesis route is as follows:
first step of
The first step of reference example 195 gave compound 201-2.MS-ESI calculated value [ M + H%] + 415, found value 415.
Second step of
Compound 201 is obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) delta 7.32-7.26 (m, 2H), 7.24-7.19 (m, 3H), 4.15-3.89 (m, 2H), 3.53-3.34 (m, 6H), 3.22-3.09 (m, 2H), 2.77-2.72 (m, 1H), 2.51-2.30 (m, 2H), 1.73-1.72 (m, 1H), 1.39-1.34 (m, 1H), 0.98-0.95 (m, 4H). MS-ESI calculated value [ M + H%] + 315, measured value 315.
Example 202
The synthesis route is as follows:
first step of
Compound 202-2 was obtained in the first step of reference example 195. MS-ESI calculated value [ M + H%] + 399, measured value 399.
Second step of
The sixth step of EXAMPLE 144 gave compound 202. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.28 (m, 2H), 7.23-7.19 (m, 3H), 3.89-3.84 (m, 1H), 3.62 (d, J =11.2hz, 1h), 3.52-3.33 (m, 5H), 3.12-3.11 (m, 1H), 2.97-2.94 (m, 1H), 2.79-2.72 (m, 1H), 1.99-1.95 (m, 2H), 1.76-1.69 (m, 1H), 1.37-1.31 (m, 1H), 1.28 (s, 3H), 1.24 (s, 3H), 0.97-0.94 (m, 4H). MS-ESI calculated value [ M + H% ] + 299, measured value 299.
Example 203
The synthesis route is as follows:
first step of
The first step of reference example 195 gave compound 203-2.MS-ESI calculated value [ M + H%] + 401, found value 401.
Second step of
Compound 203 is obtained by the sixth step in accordance with example 144. 1 H NMR(400MHz,CD 3 OD) delta 7.32-7.28 (m, 2H), 7.23-7.19 (m, 3H), 4.61-4.51 (m, 2H), 4.44-4.26 (m, 2H), 3.88-3.64 (m, 1H), 3.58-3.34 (m, 4H), 3.07-3.01 (m, 1H), 2.77-2.72 (m, 1H), 1.76-1.69 (m, 1H), 1.38-1.32 (m, 1H), 0.95-0.92 (m, 4H). MS-ESI calculated value [ M + H%] + 301, found value 301.
Example 204
The synthetic route is as follows:
first step of
Compound 49-2 (80.0mg, 0.254mmol) and compound 204-1 (46.2mg, 0.279mmol) were dissolved in dichloromethane (6 mL) under nitrogen protection, acetic acid (45.7mg, 0.761mmol) was added, the reaction mixture was stirred at 26 ℃ for 1 hour, sodium borohydride acetate (161mg, 0.761mmol) was added, and stirring of the reaction mixture was continued at 26 ℃ for 1 hour. To the reaction solution was added a saturated sodium carbonate solution (15 mL), extracted with dichloromethane (25mL × 2), and the organic phases were combined, washed with a saturated brine (50mLx 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by thin layer chromatography (5. MS-ESI calculated value [ M + H%] + 429, found 429.
Second step of
Compound 204-2 (60.0 mg, 0.140mmol) was dissolved in a mixed solution of tetrahydrofuran (6 mL) and water (2 mL) under nitrogen protection, and water and lithium hydroxide (29.4 mg, 0.700mmol) were added in one portion, and the reaction solution was stirred at 26 ℃ for 12 hours. Adding hydrochloric acid aqueous solution (1 mol/L) to adjust the pH value to 3-4, extracting by dichloromethane (25mL x 3), and combining organic phases. The organic phase was washed with saturated brine (40mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by thin layer chromatography (8. MS-ESI calculated value [ M + H%] + 415, found value 415.
The third step
Compound 204-3 (56.0 mg, 0.135mmol) was dissolved in dichloromethane (5 mL) under nitrogen, trifluoroacetic acid (46.2mg, 0.405mmol) was added, and the reaction mixture was stirred at 18 ℃ for 1 hour. Concentrating under reduced pressure, and separating and purifying by preparative high performance liquid chromatography (hydrochloric acid) to obtain the compound 204. 1 H NMR(400MHz,CH 3 OD) δ 7.34-7.27 (m, 2H), 7.26-7.17 (m, 3H), 4.53-4.40 (m, 1H), 4.11-4.00 (m, 1H), 3.80-3.35 (m, 4H), 3.29-3.21 (m, 1H), 3.12-2.97 (m, 1H), 2.85-2.69 (m, 1H), 2.56-2.68 (m, 1H), 2.31-2.10 (m, 3H), 1.81-1.68 (m, 1H), 1.43-1.34 (m, 1H), 1.08-0.88 (m, 4H). MS-ESI calculated value [ M + H%] + 315, measured value 315.
Example 205
The synthetic route is as follows:
first step of
Compound 205-1 (66.0mg, 0.328mmol) was dissolved in anhydrous N, N-dimethylformamide (8 mL) under a nitrogen atmosphere, N-carbonyldiimidazole (57.6mg, 0.355mmol) was added, and the reaction mixture was stirred at 30 ℃ for 2 hours. Then, 82-2 (90.0 mg,0.273 mmol) was added, and the reaction mixture was stirred at 110 ℃ for 10 hours. Water (10 mL) was added to the reaction mixture, extracted with ethyl acetate (20mL. Times.2), and the organic phases were combined. The organic phase was washed with saturated brine (40mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 205-2.MS-ESI calculated value [ M + Na ]] + 517, found value 517.
Second step of
Compound 205-2 (110mg, 0.222mmol) was dissolved in dichloromethane (4 mL) under nitrogen protection, trifluoroacetic acid (101mg, 0.890 mmol) was added, and the reaction mixture was stirred at 20 ℃ for 0.5 hour. Concentrating under reduced pressure to obtain compound 205-3.MS-ESI calculated value [ M + H%] + 395, found 395.
The third step
The first step of reference example 204 gave compound 205-5.MS-ESI calculated value [ M + Na ]] + 565, found 565.
The fourth step
Compound 205-5 (104mg, 0.192mmol) was dissolved in anhydrous tetrahydrofuran (6 mL) under nitrogen, tetrakis (triphenylphosphine) palladium (0) (22.1mg, 19.1. Mu. Mol) and diethylamine (140mg, 1.92mmol) were added, and the reaction was stirred at 80 ℃ for 3 hours. Concentration under reduced pressure and isolation and purification by thin layer chromatography (1. MS-ESI calculated value [ M + H% ] + 459, found 459.
The fifth step
Compound 205-6 (63.0 mg, 0.137mmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and water (2 mL) under nitrogenTo the solution was added sodium hydroxide (11.0 mg, 0.275mmol) in one portion, and the reaction mixture was stirred at 50 ℃ for 36 hours. Adding hydrochloric acid solution (1 mol/L) to adjust the pH value to 1-2, decompressing and concentrating, and separating and purifying by preparative high performance liquid chromatography (hydrochloric acid) to obtain the compound 205. 1 H NMR(400MHz,D 2 O) δ 8.06 (d, J =8.2hz, 2h), 7.61-7.51 (m, 2H), 7.32-7.20 (m, 3H), 7.08-7.00 (m, 2H), 4.61-4.46 (m, 4H), 4.42-4.19 (m, 3H), 3.84-3.76 (m, 1H), 3.66-3.54 (m, 1H), 3.08-3.00 (m, 1H), 2.48-2.39 (m, 1H), 1.53-1.39 (m, 2H), 1.36-1.24 (m, 4H). MS-ESI calculated value [ M + H%] + 445, found value 445.
Example 206
The synthetic route is as follows:
first step of
The first step of reference example 205 gave compound 206-2.MS-ESI calculated value [ M + Na ]] + 585, found 585.
Second step of
Compound 206-2 (170mg, 302. Mu. Mol) was dissolved in methylene chloride (20 mL) under nitrogen, trifluoroacetic acid (138mg, 121mmol) was added, and the reaction mixture was stirred at 20 ℃ for 1 hour. Concentrating under reduced pressure to obtain compound 206-3.MS-ESI calculated value [ M + H%] + 463, found value 463.
The third step
In the first step of reference example 204, compound 206-5 was obtained. MS-ESI calculated value [ M + H% ] + 611, found value 611.
The fourth step
The fourth step of EXAMPLE 205 gave compound 206-6.MS-ESI calculated value [ M + H%] + 527, found 527.
The fifth step
Compound 206-6 (50.0 mg, 95.0. Mu. Mol) was dissolved in a mixed solution of tetrahydrofuran (4 mL) and water (4 mL) under nitrogen atmosphere and used onceSodium hydroxide (19.0 mg, 0.475mmol) was added, and the reaction mixture was stirred at 50 ℃ for 9 hours. Adding 1N hydrochloric acid solution to adjust the pH value to 1-2, decompressing and concentrating, and separating and purifying by preparative high performance liquid chromatography (hydrochloric acid) to obtain the compound 206. 1 H NMR(400MHz,CH 3 OD) δ 8.13 (d, J =8.2hz, 2h), 7.68 (d, J =8.2hz, 2h), 7.36-7.27 (m, 2H), 7.27-7.19 (m, 1H), 7.19-7.12 (m, 2H), 4.44-4.35 (m, 2H), 3.87-3.74 (m, 1H), 3.74-3.61 (m, 2H), 3.48-3.33 (m, 2H), 3.20-2.95 (m, 3H), 2.61-2.48 (m, 2H), 2.40-2.14 (m, 4H), 2.04-1.80 (m, 3H), 1.64-1.53 (m, 1H), 1.50-1.27 (m, 5H). MS-ESI calculated value [ M + H%] + 513, found value 513.
Example 207
The synthetic route is as follows:
first step of
Compound 207-2 was obtained in the first step of example 204. MS-ESI calculated value [ M + H%] + 512, found 512.
Second step of
Compound 207-2 (55.0 mg, 0.107mmol) was dissolved in dichloromethane (6 mL) under nitrogen, trifluoroacetic acid (49.0 mg, 0.440mol) was added, and the reaction was stirred at 20 ℃ for 1 hour. Concentrating under reduced pressure, and separating and purifying by preparative high performance liquid chromatography (hydrochloric acid) to obtain the compound 207. 1 H NMR(400MHz,CH 3 OD) δ 7.34-7.26 (m, 2H), 7.26-7.17 (m, 3H), 4.17-4.05 (m, 1H), 4.01-3.86 (m, 1H), 3.74-3.61 (m, 2H), 3.61-3.33 (m, 10H), 3.22-3.07 (m, 1H), 2.82-2.70 (m, 1H), 1.79-1.66 (m, 1H), 1.42-1.31 (m, 1H), 1.07-0.87 (m, 4H). MS-ESI calculated value [ M + H%] + 312, measured value 312.
Example 208
The synthesis route is as follows:
first step of
Compound 208-1 (292mg, 1.28mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL) under nitrogen protection, N-carbonyldiimidazole (241mg, 1.49mmol) was added, and the reaction mixture was stirred at 30 ℃ for 2 hours. Then, compound 82-2 (350mg, 1.06mmol) was added thereto, and the reaction mixture was stirred at 110 ℃ for 12 hours. Water (10 mL) was added to the reaction mixture, which was extracted with ethyl acetate (20mL. Times.2), and the organic phases were combined. The organic phase was washed with saturated brine (40mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 208-2.MS-ESI calculated value [ M + Na ]] + 545, found 545.
Second step of
The second step of reference example 207 gave compound 208-3.MS-ESI calculated value [ M + H%] + 424, measured value 424.
The third step
Compound 208-3 (67.0mg, 0.159mmol) was dissolved in anhydrous dichloromethane (12 mL) under nitrogen protection, and compound 208-4 (33.2mg, 0.317mmol), 4-dimethylaminopyridine (3.87mg, 31.7. Mu. Mol) and N, N-diisopropylethylamine (82.0mg, 0.634mmol) were added in one portion at 0 ℃, and the reaction solution was stirred at 20 ℃ for 1.5 hours. Concentration under reduced pressure and isolation and purification by thin layer chromatography (3. MS-ESI calculated value [ M + H% ] + 491, measured value 491.
The fourth step
In the fourth step of EXAMPLE 205, compound 208 was obtained. 1 H NMR(400MHz,CH 3 OD) δ 7.35-7.28 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.13 (m, 2H), 4.46-4.30 (m, 2H), 3.72-3.61 (m, 2H), 3.48-3.32 (m, 2H), 3.12-3.04 (m, 1H), 3.03-2.89 (m, 1H), 2.56-2.46 (m, 1H), 2.23-2.03 (m, 2H), 2.02-1.95 (m, 1H), 1.88-1.62 (m, 2H), 1.59-1.51 (m, 1H), 1.47-1.37 (m, 3H), 1.35-1.29 (m, 2H), 0.94-0.77 (m, 4H). MS-ESI calculated value [ M + H%] + 407, measured value 407.
Example 209
The synthetic route is as follows:
first step of
Compound 209-1 (1.89g, 17.3mmol) and 144-8 (2.31g, 17.3mmol) were dissolved in dichloromethane (8 mL) under nitrogen, acetic acid (104mg, 1.73mmol) was added, the reaction stirred at 30 ℃ for 1h, sodium borohydride acetate (5.51mg, 26.0mmol) was added and stirring at 30 ℃ was continued for 4 h. To the reaction solution, a saturated sodium carbonate solution was added to adjust the PH to 9 to 10, followed by extraction with dichloromethane (40mL × 2), and the organic phases were combined, washed with a saturated saline solution (70mLx 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by silica gel column chromatography (2. 1 H NMR(400MHz,CDCl 3 )δ7.20-7.15(m,2H),7.12-7.04(m,1H),7.00-6.93(m,2H),2.98-2.90(m,2H),2.45-2.34(m,3H),2.16-1.95(m,4H),1.89-1.84(m,1H),1.09-0.98(m,1H),0.97-0.87(m,1H)。
Second step of
Boc anhydride (964mg, 4.42mmol) was added to compound 209-2 (0.50g, 2.21mmol) under nitrogen protection, and the mixture was stirred at 90 ℃ for 12 hours. This mixture was subjected to column chromatography separation and purification (5. 1 H NMR(400MHz,CDCl 3 )δ7.23-7.18(m,2H),7.13-6.97(m,3H),3.95-3.70(m,1H),3.44-3.27(m,1H),2.85-2.72(m,1H),2.52-2.30(m,2H),2.20-2.08(m,3H),2.07-1.90(m,2H),1.37-1.29(m,9H),1.27-1.14(m,2H)。
The third step
Compound 209-3 (0.70g, 2.14mmol) was dissolved in absolute ethanol (20 mL) under nitrogen, hydroxylamine hydrochloride (298mg, 4.29mmol) and N, N-dimethylisopropylamine (1.11g, 8.58mmol) were added, and the reaction mixture was stirred at 80 ℃ for 12 hours. The reaction was quenched with water (30 mL), extracted with ethyl acetate (30mL. Times.2), the organic phases combined and washed with saturated brine (30 mL)x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (2: 1 petroleum ether/ethyl acetate, rf = 0.4) to yield compound 209-4.MS-ESI calculated value [ M + H%] + 360, measured value 360.
The fourth step
Reference example 205 gave compound 209-6 in the first step. MS-ESI calculated value [ M + Na ]] + 589, found 589.
The fifth step
The second step of referential example 207 gave compound 209. 1 H NMR(400MHz,CH 3 OD) delta 7.36-7.27 (m, 2H), 7.27-7.21 (m, 1H), 7.23-7.16 (m, 2H), 3.83 (s, 2H), 3.37-3.32 (m, 2H), 3.11-3.01 (m, 1H), 2.69-2.53 (m, 3H), 2.44-2.29 (m, 4H), 2.23-2.12 (m, 2H), 2.06-1.92 (m, 4H), 1.84-1.71 (m, 2H), 1.68-1.55 (m, 1H), 1.42-1.32 (m, 1H). MS-ESI calculated value [ M + H%] + 367, found 367.
Example 210
The synthesis route is as follows:
first step of
Compound 210-2 was obtained in the first step of example 204. MS-ESI calculated value [ M + H%] + 429, found 429.
Second step of
The second step of reference example 204 gave compound 210-3.MS-ESI calculated value [ M + H%] + 415, found value 415.
The third step
The third step of reference example 204 gave compound 210. 1 H NMR(400MHz,CH 3 OD) δ 7.34-7.26 (m, 2H), 7.25-7.18 (m, 3H), 4.55-4.49 (m, 1H), 4.12-3.99 (m, 1H), 3.80-3.35 (m, 4H), 3.30-3.19 (m, 1H), 3.12-2.93 (m, 1H), 2.84-2.71 (m, 1H), 2.63 (m, 1H), 2.29-2.05 (m, 3H), 1.82-1.68 (m, 1H), 1.44-1.33 (m, 1H), 1.08-0.89 (m, 4H). MS-ESI calculated value [ M + H%] + 315, measured value 315.
Example 211
The synthetic route is as follows:
first step of
Reference example 204 gave compound 211-2 in the first step. MS-ESI calculated value [ M + H%] + 357, found value 357.
Second step of
The third step of reference example 204 gave compound 211 (14.1 mg). 1 H NMR(400MHz,CH 3 OD) Δ 7.33-7.26 (m, 2H), 7.26-7.17 (m, 3H), 4.39-4.14 (m, 4H), 3.48-3.33 (m, 3H), 3.30-3.24 (m, 1H), 3.11-3.01 (m, 1H), 2.81-2.74 (m, 1H), 2.73-2.61 (m, 1H), 2.44-2.29 (m, 1H), 1.79-1.68 (m, 1H), 1.42-1.30 (m, 1H), 0.91 (s, 4H). MS-ESI calculated value [ M + H%] + 257, found 257.
Example 212
The synthesis route is as follows:
first step of
Reference example 204 gave compound 212-2 in the first step. MS-ESI calculated value [ M + H%] + 385, measured value 385.
Second step of
The third step of reference example 204 gave compound 212. 1 H NMR(400MHz,CH 3 OD)δ7.37-7.29(m,2H),7.28-7.19(m,3H),3.92-3.71(m,3H),3.61-3.42(m,1H),3.24-3.07(m,2H),3.00-2.85(m,1H),2.842.68 (m, 1H), 2.43-2.28 (m, 1H), 2.23-2.08 (m, 2H), 1.93-1.66 (m, 2H), 1.65-1.51 (m, 3H), 1.50-1.09 (m, 2H), 1.09-0.84 (m, 4H). MS-ESI calculated value [ M + H%] + 285, found value 285.
Example 213
The synthetic route is as follows:
first step of
Compound 213-2 was obtained in the first step of reference example 204. MS-ESI calculated value [ M + H%] + 385, measured value 385.
Second step of
The third step of reference example 204 gave compound 213. 1 H NMR(400MHz,CH 3 OD) δ 7.33 to 7.26 (m, 2H), 7.25 to 7.18 (m, 3H), 3.90 to 3.73 (m, 3H), 3.58 to 3.42 (m, 1H), 3.23 to 3.04 (m, 2H), 2.97 to 2.85 (m, 1H), 2.83 to 2.68 (m, 1H), 2.40 to 2.25 (m, 1H), 2.22 to 2.07 (m, 2H), 1.92 to 1.65 (m, 2H), 1.64 to 1.52 (m, 3H), 1.43 to 1.08 (m, 2H), 1.07 to 0.97 (m, 3H), 0.94 to 0.85 (m, 1H). MS-ESI calculated value [ M + H%] + 285, found value 285.
Example 214
The synthetic route is as follows:
first step of
The first step of reference example 205 gave compound 214-2.MS-ESI calculated value [ M + Na ]] + 575, found 575.
Second step of
Second step of reference example 207Compound 214 (13.4 mg). 1 H NMR(400MHz,CH 3 OD) δ 7.34-7.27 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.13 (m, 2H), 3.76-3.61 (m, 2H), 3.58-3.40 (m, 2H), 3.12-3.03 (m, 1H), 2.63-2.53 (m, 1H), 2.49-2.39 (m, 1H), 2.15-1.96 (m, 2H), 1.96-1.75 (m, 3H), 1.64-1.48 (m, 3H), 1.47-1.33 (m, 5H). MS-ESI calculated value [ M + H% ] + 353, measured value 353.
Example 215
The synthetic route is as follows:
first step of
Compound 215-2 was obtained in the first step of referential example 205. MS-ESI calculated value [ M + Na ]] + 531, found 531.
Second step of
The second step in reference example 205 gave compound 215-3.MS-ESI calculated value [ M + H%] + 409, measured value 409.
The third step
The first step of reference example 204 gave compound 215-5.MS-ESI calculated value [ M + Na ]] + 579, found 579.
The fourth step
The fourth step of EXAMPLE 205 gave compound 215-6.MS-ESI calculated value [ M + H%] + 473, found 473.
The fifth step
The fifth step of reference example 205 gave compound 215. 1 H NMR(400MHz,D 2 O) δ 8.07 (d, J =8.0hz, 2h), 7.60 (d, J =8.0hz, 2h), 7.30-7.18 (m, 3H), 7.07-6.09 (m, 2H), 4.73-3.39 (m, 3H), 4.00-3.73 (m, 3H), 3.64-3.46 (m, 3H), 3.10-2.98 (m, 1H), 2.64-2.19 (m, 3H), 1.52-1.37 (m, 2H), 1.36-1.27 (m, 4H). MS-ESI calculated value [ M + H%] + 459, found 459.
Example 216
The synthetic route is as follows:
first step of
Reference example 204 gave compound 216-2 as a first step. MS-ESI calculated value [ M + H%] + 414, measured value 414.
Second step of
The third step of reference example 204 gave compound 216. 1 H NMR(400MHz,D 2 O) delta 7.41-7.24 (m, 3H), 7.23-7.16 (m, 2H), 3.85-3.55 (m, 4H), 3.38-3.30 (m, 2H), 3.29-3.07 (m, 2H), 3.04-2.97 (m, 1H), 2.95-2.70 (m, 2H), 2.61-2.51 (m, 1H), 1.61-1.51 (m, 1H), 1.46-1.28 (m, 7H), 1.03-0.80 (m, 4H). MS-ESI calculated value [ M + H% ] + 314, measured value 314.
Example 217
The synthetic route is as follows:
first step of
Compound 217-2 was obtained by the first step of EXAMPLE 204. MS-ESI calculated value [ M + H%] + 415, found value 415.
Second step of
The third step of reference example 204 gave compound 217. 1 H NMR(400MHz,CH 3 OD) δ 7.34-7.27 (m, 2H), 7.26-7.15 (m, 3H), 4.18-4.05 (m, 2H), 3.68-3.45 (m, 4H), 3.43-3.33 (m, 2H), 3.16-3.10 (m, 1H), 2.80-2.64 (m, 3H), 1.77-1.66 (m, 1H), 1.44-1.32 (m, 1H), 1.28-1.20 (m, 6H), 1.09-0.84 (m, 4H). MS-ESI calculated value [ M + H%] + 315, measured value 315.
Example 218
The synthetic route is as follows:
first step of
Compound 218-2 was obtained in the first step of example 205. MS-ESI calculated value [ M + Na ]] + 490, found 490.
Second step of
The third step of reference example 204 gave compound 218. 1 H NMR(400MHz,CH 3 OD) delta 7.35-7.28 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.11 (m, 2H), 3.73-3.47 (m, 4H), 3.45-3.35 (m, 1H), 3.12-3.02 (m, 1H), 2.86-2.63 (s, 3H), 2.87-2.62 (m, 2H), 2.59-2.50 (m, 1H), 2.40-2.28 (m, 1H), 2.18-2.03 (m, 1H), 1.62-1.52 (m, 1H), 1.47-1.31 (m, 5H). MS-ESI calculated value [ M + H%] + 367, measured value 367.
Example 219
The synthetic route is as follows:
first step of
Compound 219-2 was obtained in the first step of reference example 205. MS-ESI calculated value [ M + Na ]] + 601, measured value 601.
Second step of
The third step of reference example 204 gave compound 219. 1 H NMR(400MHz,CH 3 OD)δ7.35-7.27(m,2H),7.27-7.20(m,1H),7.19-7.12(m,2H),3.86-3.74(m,1H),3.74-3.60(m,2H),3.22-3.15(m,2H),3.14-3.04(m,3H),2.62-2.51(m,1H),2.48-2.36(m,2H),2.33-2.20(m, 2H), 2.04-1.94 (m, 2H), 1.91-1.83 (m, 2H), 1.63-1.52 (m, 1H), 1.50-1.29 (m, 5H). MS-ESI calculated value [ M + H%] + 379, found 379.
Example 220
The synthetic route is as follows:
first step of
The first step of reference example 205 gave compound 220-2.MS-ESI calculated value [ M + Na ]] + 575, found 575.
Second step of
The second step of reference example 207 gave compound 220. 1 H NMR(400MHz,CH 3 OD) δ 7.36-7.27 (m, 2H), 7.27-7.19 (m, 1H), 7.18-7.12 (m, 2H), 3.73-3.62 (m, 2H), 3.29-3.25 (m, 1H), 3.19-3.05 (m, 2H), 2.58-2.49 (m, 1H), 2.47-2.36 (m, 1H), 2.17-1.99 (m, 3H), 1.70-1.54 (m, 3H), 1.52-1.32 (m, 7H). MS-ESI calculated value [ M + H%] + 353, measured value 353.
Example 221
The synthetic route is as follows:
first step of
Compound 49-2 (150mg, 0.476 mmol) and 221-1 (61.0mg, 0.476 mmol) were dissolved in methylene chloride (8 mL) under nitrogen protection, acetic acid (85.7mg, 1.43mmol) was added, the reaction mixture was stirred at 26 ℃ for 20 hours, sodium borohydride acetate (302mg, 1.43mmol) was added, and the reaction mixture was further stirred at 26 ℃ for 36 hours. To the reaction solution was added a saturated sodium carbonate solution (15 mL)Extraction with dichloromethane (25mL × 2), combination of organic phases, washing with saturated brine (50mLx 1), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, and isolation and purification by thin layer chromatography (1. MS-ESI calculated value [ M + H% ] + 429, found 429.
Second step of
Compound 221-2 (60.0 mg, 0.140mmol) was dissolved in dichloromethane (6 mL) under nitrogen, trifluoroacetic acid (64.0 mg, 0.561mmol) was added, and the reaction mixture was stirred at 20 ℃ for 3 hours. Concentrating under reduced pressure, and separating and purifying by preparative high performance liquid chromatography (hydrochloric acid) to obtain the compound 221. 1 H NMR(400MHz,CH 3 OD) δ 7.34-7.26 (m, 2H), 7.26-7.16 (m, 3H), 4.40-4.07 (m, 3H), 4.07-3.85 (m, 2H), 3.84-3.67 (m, 2H), 3.55-3.37 (m, 1H), 3.29-3.18 (m, 1H), 3.03 (s, 3H), 2.96-2.56 (m, 3H), 1.88-1.60 (m, 1H), 1.60-1.46 (m, 6H), 1.41-1.29 (m, 1H), 1.23-1.01 (m, 3H), 0.93-0.80 (m, 1H). MS-ESI calculated value [ M + H%] + 328, found 328.
Example 222
The synthesis route is as follows:
first step of
Compound 222-2 was obtained in the first step of referential example 205. MS-ESI calculated value [ M + Na ]] + 496, found 496.
Second step of
The second step of reference example 207 gave compound 222. 1 H NMR(400MHz,CH 3 OD) Δ 7.34-7.27 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.12 (m, 2H), 3.72-3.62 (m, 2H), 3.20-3.11 (m, 1H), 3.10-3.04 (m, 1H), 2.57-2.48 (m, 1H), 2.19-2.07 (m, 4H), 2.04-1.88 (m, 4H), 1.56 (m, 1H), 1.46-1.37 (m, 3H), 1.35-1.32 (m, 2H). MS-ESI calculated value [ M + H%] + 374, found value 374.
Example 223
The synthetic route is as follows:
first step of
Compounds 223-1 (153mg, 0.919mmol) and 223-1a (150mg, 0.707mmol) were dissolved in anhydrous N, N-dimethylformamide (8 mL) under nitrogen, potassium carbonate (195mg, 1.41mmol) was added all at once, and the reaction mixture was stirred at 20 ℃ for 2 hours. The solid was removed by filtration, water (40 mL) was added to the mother liquor, the reaction solution was extracted with ethyl acetate (40mL × 3), the organic phases were combined, washed with saturated brine (90mLx 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 223-2. 1 H NMR(400MHz,CDCl 3 )δ4.11(q,J＝7.0Hz,2H),3.48-3.40(m,2H),3.28-3.23(m,2H),3.23-3.12(m,2H),2.89-2.84(m,2H),2.81-2.72(m,2H),2.42-2.32(m,2H),1.38(s,9H),1.20(t,J＝7.0Hz,3H)。
Second step of
Compound 223-2 (203mg, 0.680 mmol) was dissolved in dichloromethane (4 mL) under nitrogen protection, trifluoroacetic acid (155mg, 1.36mmol) was added, and the reaction mixture was stirred at 20 ℃ for 1.5 hours. Concentrating under reduced pressure to obtain compound 223-3. 1 H NMR(400MHz,CH 3 OD)δ4.89-4.58(m,2H),4.38-4.26(m,2H),4.24(s,1H),3.92-3.61(m,2H),3.61-3.51(m,2H),3.50-3.32(m,5H),1.37-1.30(m,3H)。
The third step
Compound 223-4 was obtained in the first step of reference example 204. MS-ESI calculated value [ M + H%] + 498 found therein.
The fourth step
The fifth step of reference example 206 gave compound 223-5.MS-ESI calculated value [ M + H%] + 470, found 470.
The fifth step
The second step of reference example 207 gave compound 223. 1 H NMR(400MHz,CH 3 OD)δ7.34-7.27(m,2H),7.26-7.17 (m, 3H), 4.43-4.16 (m, 2H), 4.16-3.98 (m, 2H), 3.97-3.88 (m, 2H), 3.87-3.56 (m, 3H), 3.55-3.35 (m, 7H), 3.25-3.06 (m, 1H), 2.80-2.69 (m, 1H), 1.78-1.63 (m, 1H), 1.42-1.30 (m, 1H), 1.08-0.87 (m, 4H). MS-ESI calculated value [ M + H%] + 370, found 370.
Example 224
The synthesis route is as follows:
first step of
The first step of reference example 205 gave compound 224-2.MS-ESI calculated value [ M + Na ]] + 589, found 589.
Second step of
The second step of reference example 207 gave compound 224. 1 H NMR(400MHz,CH 3 OD) δ 7.36-7.28 (m, 2H), 7.28-7.21 (m, 1H), 7.24-7.16 (m, 2H), 3.76-3.64 (m, 2H), 3.21-3.11 (m, 1H), 3.10-3.02 (m, 1H), 2.68-2.56 (m, 1H), 2.48-2.39 (m, 2H), 1.99-1.92 (m, 2H), 1.75-1.60 (m, 3H), 1.57-1.39 (m, 5H), 1.37-1.31 (m, 5H). MS-ESI calculated value [ M + H% ] + 367, measured value 367.
Example 225
The synthetic route is as follows:
first step of
Compound 225-2 was obtained in the first step of reference example 208. MS-ESI calculated value [ M + Na ]] + 589, found 589.
Second step of
Compound 225-2 (130mg, 0.229 mmol) was dissolved in dichloromethane (6 mL) under nitrogen, trifluoroacetic acid (26.2 mg,0.229 mmol) was added, and the reaction was stirred at 20 ℃ for 1.5 hours. Concentrating under reduced pressure, and separating and purifying by preparative high performance liquid chromatography to obtain compound 225. 1 H NMR(400MHz,CH 3 OD) δ 7.34-7.28 (m, 2H), 7.26-7.20 (m, 1H), 7.20-7.12 (m, 2H), 3.73-3.61 (m, 2H), 3.13-3.01 (m, 2H), 2.81 (d, J =6.8hz, 2h), 2.60-2.51 (m, 1H), 2.10-2.00 (m, 2H), 1.95-1.79 (m, 3H), 1.64-1.54 (m, 1H), 1.49-1.33 (m, 7H), 1.30-1.20 (m, 2H). MS-ESI calculated value [ M + H%] + 367, found 367.
Example 226
The synthetic route is as follows:
first step of
Compound 224-3 (97.0 mg, 0.230mmol) was dissolved in anhydrous dichloromethane (16 mL) under nitrogen, triethylamine (46.5 mg, 0.459mmol) and trifluoroacetic anhydride (96.4 mg, 0.459mmol) were added in one portion at 0 ℃, and the reaction solution was stirred at 20 ℃ for 18 hours. Concentration under reduced pressure and isolation and purification by thin layer chromatography (5. MS-ESI calculated value [ M + Na ]] + 541, found value 541.
Second step of
Compound 226-1 (50.0mg, 96.4. Mu. Mol) was dissolved in anhydrous tetrahydrofuran (8 mL) under a nitrogen atmosphere, tetrakis (triphenylphosphine) palladium (0) (11.1mg, 9.64. Mu. Mol) and diethylamine (70.5mg, 0.964mmol) were added, and the reaction solution was stirred at 80 ℃ for 2.5 hours. Concentration under reduced pressure and isolation and purification by thin layer chromatography (1. 1 H NMR(400MHz,CH 3 OD)δ7.34-7.27(m,2H),7.27-7.20(m,1H),7.22-7.12(m,2H),4.38(m,1H),4.44-4.30(m,1H),3.74-3.59(m,2H),3.51-3.34(m,2H),3.23-3.04(m,2H),2.57-2.45(m,1H),2.27-2.12(m,2H),1.90-1.72(m,2H),1.601.50 (m, 1H), 1.48-1.37 (m, 3H), 1.35-1.28 (m, 2H). MS-ESI calculated value [ M + H%] + 435, found 435.
Example 227
The synthetic route is as follows:
first step of
Compound 114-10 (5.00g, 16.0 mmol) was dissolved in dichloromethane (16 mL) under nitrogen, diisobutylaluminum hydride (2.49g, 17.6 mmol) was added at-78 ℃ and the reaction was stirred at-78 ℃ for 1.5 hours. To the reaction mixture were added a saturated sodium potassium tartrate solution (150 mL) and methylene chloride (70 mL), and the mixture was stirred at room temperature for 30 minutes. Extraction with dichloromethane (200mL x 2), combining the organic phases, washing with saturated brine (300mLx 3), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure, isolation and purification by column chromatography (5. MS-ESI calculated value [ M-100+ H] + 216, found value 216.
Second step of
Compound 227-1 (80.0mg, 0.254mmol) and 227-2 (90.5mg, 0.355mmol) were dissolved in dichloromethane (8 mL) under nitrogen protection, acetic acid (30.5mg, 0.507mmol) was added, the reaction solution was stirred at 30 ℃ for 1 hour, sodium borohydride acetate (161mg, 0.761mmol) was added, and the reaction solution was further stirred at 30 ℃ for 3 hours. To the reaction solution was added a saturated sodium carbonate solution (30 mL), extracted with dichloromethane (40mL × 2), and the organic phases were combined, washed with a saturated saline solution (70mLx 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by thin layer chromatography (2. MS-ESI calculated value [ M + H% ] + 518, found 518.
The third step
Compound 227-3 (70.0 mg, 0.135mmol) was dissolved in a mixed solution of tetrahydrofuran (4 mL) and water (4 mL) under nitrogen, oneSodium hydroxide (27.0 mg,0.676 mmol) was added in portions, and the reaction mixture was stirred at 50 ℃ for 20 hours. Adding 1N hydrochloric acid solution to adjust the pH value to be 1-2, and concentrating under reduced pressure to obtain a compound 227-4.MS-ESI calculated value [ M + H%] + 504, found 504.
The fourth step
The second step of reference example 205 gave compound 227. 1 H NMR(400MHz,CH 3 OD) δ 7.69 (d, J =7.8hz, 1h), 7.37 (d, J =7.8hz, 1h), 7.34-7.27 (m, 3H), 7.26-7.20 (m, 1H), 7.17 (d, J =7.2hz, 2h), 7.13 (t, J =7.2hz, 1h), 7.08-7.02 (m, 1H), 4.36-4.28 (m, 1H), 3.57 (d, J =6.0hz, 2h), 3.43-3.32 (m, 2H), 3.18-3.12 (m, 1H), 3.08-3.02 (m, 1H), 2.99-2.92 (m, 1H), 2.73-2.64 (m, 1H), 1.67-1.54 (m, 1H), 1.36-1.30 (m, 1H), 0.79-0H (m, 1H). MS-ESI calculated value [ M + H%] + 404, measured value 404.
Example 228
The synthetic route is as follows:
first step of
Compounds 227-1 (120mg, 0.380mmol) and 228-1 (53.9mg, 0.533mmol) were dissolved in absolute ethanol (8 mL) under nitrogen, acetic acid (45.7mg, 0.761mmol) was added, the reaction mixture was stirred at 50 ℃ for 1 hour, sodium cyanoborohydride (71.7mg, 1.14mmol) was added, and stirring was continued at 50 ℃ for 15 hours. Concentration under reduced pressure and isolation and purification by thin layer chromatography (4. MS-ESI calculated value [ M + H% ] + 401, found value 401.
Second step of
Compound 228-2 (76.0 mg, 0.190mmol) was dissolved in dichloromethane (8 mL) under nitrogen, trifluoroacetic acid (86.5 mg, 0.759mmol) was added, and the reaction mixture was stirred at 20 ℃ for 2 hours. Concentrating under reduced pressure, and separating and purifying by preparative high performance liquid chromatography to obtain compound 228. 1 H NMR(400MHz,CH 3 OD)δ7.35-7.27 (m, 2H), 7.27-7.17 (m, 3H), 5.44-5.34 (m, 1H), 4.27-4.06 (m, 2H), 3.92-3.77 (m, 2H), 3.18-3.12 (m, 1H), 3.07-2.95 (m, 2H), 2.82-2.69 (m, 3H), 1.73-1.62 (m, 1H), 1.40-1.30 (m, 1H), 1.04-0.92 (m, 2H), 0.90-0.77 (m, 2H). MS-ESI calculated value [ M + H%] + 301, found value 301.
Example 229
The synthetic route is as follows:
first step of
Compounds 227-1 (180mg, 0.571mmol) and 229-1 (121mg, 0.799mmol) were dissolved in absolute ethanol (8 mL) under nitrogen, acetic acid (68.5mg, 1.14. Mu. Mol) was added, the reaction was stirred at 30 ℃ for 1 hour, sodium borohydride acetate (363mg, 1.71mmol) was added, and stirring was continued at 30 ℃ for 2 hours. Concentration under reduced pressure and isolation and purification by thin layer chromatography (5. MS-ESI calculated value [ M + H%] + 415, found value 415.
Second step of
The second step of referential example 207 gave compound 229. 1 H NMR(400MHz,CH 3 OD) δ 7.34-7.28 (m, 2H), 7.27-7.17 (m, 3H), 4.52-4.40 (m, 1H), 4.10-3.98 (m, 1H), 3.74-3.57 (m, 2H), 3.48-3.32 (m, 2H), 3.30-3.24 (m, 1H), 3.09-2.99 (m, 1H), 2.80-2.70 (m, 1H), 2.68-2.55 (m, 1H), 2.27-2.08 (m, 3H), 1.78-1.67 (m, 1H), 1.44-1.36 (m, 1H), 1.06-0.92 (m, 4H). MS-ESI calculated value [ M + H% ] + 315, measured value 315.
Example 230
The synthetic route is as follows:
first step of
Compounds 227-1 (100mg, 0.317mmol) and 230-1 (88.9mg, 0.444mmol) were dissolved in anhydrous dichloromethane (8 mL) under nitrogen, acetic acid (38.1mg, 0.634mmol) was added, the reaction was stirred at 30 ℃ for 1 hour, sodium borohydride acetate (202mg, 0.951mmol) was added, and stirring was continued at 30 ℃ for 11 hours. Concentrating under reduced pressure to obtain compound 230-2.MS-ESI calculated value [ M + H%] + 500, found 500.
Second step of
The second step of reference example 206 gave compound 230. 1 H NMR (400MHz, CH3OD) delta 7.34-7.27 (m, 2H), 7.27-7.17 (m, 3H), 3.99-3.63 (m, 4H), 3.62-3.32 (m, 8H), 3.17-3.12 (m, 1H), 2.77-2.65 (m, 1H), 2.49-2.23 (m, 2H), 1.74-1.62 (m, 1H), 1.40-1.32 (m, 1H), 1.10-0.86 (m, 4H). MS-ESI calculated value [ M + H%] + 300, found 300.
Example 231
The synthesis route is as follows:
first step of
Compound 231-2 was obtained in the first step of referential example 205. MS-ESI calculated value [ M + Na ]] + 561, measured value 561.
Second step of
The second step of reference example 207 gave compound 231. 1 H NMR(400MHz,CH 3 OD) δ 7.36-7.27 (m, 2H), 7.27-7.20 (m, 1H), 7.20-7.14 (m, 2H), 3.75-3.62 (m, 2H), 3.52-3.37 (m, 3H), 3.25-3.14 (m, 2H), 3.11-3.04 (m, 1H), 2.62-2.53 (m, 1H), 2.38-2.27 (m, 2H), 2.13-1.97 (m, 2H), 1.64-1.55 (m, 1H), 1.48-1.32 (m, 5H). MS-ESI calculated value [ M + H% ] + 339, found 339.
Example 232
The synthetic route is as follows:
first step of
The first step of reference example 208 gave compound 232-2.MS-ESI calculated value [ M + Na ]] + 575, found 575.
Second step of
Compound 232-2 (112mg, 0.145mmol) was dissolved in anhydrous N, N-dimethylformamide (12 mL) under nitrogen, sodium hydride (8.71mg, 0.218mmol) was added, the reaction mixture was stirred at 0 ℃ for 0.5 hour, iodomethane (246mg, 1.73mmol) was added at 0 ℃ and stirring of the reaction mixture was continued at 20 ℃ for 2.5 hours. To the reaction solution was added a saturated ammonium chloride solution (30 mL), extracted with ethyl acetate (40mL × 2), and the organic phases were combined, washed with a saturated saline solution (80mLx 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated and purified by thin layer chromatography (3. MS-ESI calculated value [ M + Na ]] + 589, found 589.
The third step
The second step of referential example 207 gave compound 232. 1 H NMR(400MHz,CH 3 OD) δ 7.35-7.27 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.13 (m, 2H), 3.72-3.60 (m, 2H), 3.19-2.88 (m, 3H), 2.72 (s, 3H), 2.55 (m, 1H), 2.36-2.17 (m, 4H), 1.74-1.62 (m, 2H), 1.62-1.47 (m, 3H), 1.46-1.30 (m, 5H). MS-ESI calculated value [ M + H%] + 367, found 367.
Example 233
The synthesis route is as follows:
first step of
Compound 233-1 was obtained by the first step in reference example 205. MS-ESI calculated value [ M + Na ] ] + 589, found 589.
Second step of
The second step of referential example 207 gave compound 233. 1 H NMR (400MHz, CH3OD) delta 7.35-7.27 (m, 2H), 7.27-7.21 (m, 1H), 7.22-7.16 (m, 2H), 3.81 (s, 2H), 3.25-3.16 (m, 1H), 3.09-2.99 (m, 2H), 2.66-2.51 (m, 3H), 2.40-2.27 (m, 4H), 2.24-2.13 (m, 4H), 1.84-1.68 (m, 2H), 1.66-1.53 (m, 3H), 1.44-1.34 (m, 1H). MS-ESI calculated value [ M + H%] + 367, found 367.
Example 235
The synthesis route is as follows:
first step of
Compound 235-1 (1g, 6.94mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL), triethylamine (2.81g, 27.8mmol) was added thereto at 0 ℃ and stirred for 15 minutes, bromobenzyl (4.15g, 24.3mmol) was added thereto, and the mixture was stirred at 0 ℃ for 15 minutes and then heated to 25 ℃ and stirred for 11.5 hours. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50mL x 3), and the organic phase was washed with saturated sodium bicarbonate (50mL x 1), sodium chloride solution (50mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated and purified by preparative thin layer chromatography (10. 1 H NMR(400MHz,CDCl 3 )δ7.36-7.28(m,10H),5.18(s,4H),2.63-2.59(m,4H),2.07-1.98(m,2H)。
Second step of
Compound 235-2 (6.00g, 18.5 mmol) was dissolved in anhydrous dichloromethane (120 mL), and diisobutylaluminum hydride (1.5M in toluene, 24.7mL,36.9 mmol) was added dropwise at-78 deg.C to react The solution was stirred at-78 ℃ for 2 hours. The reaction was quenched by addition of hydrochloric acid (1M, 36.9mL) and water (100 mL) at-78 deg.C, and the mixture was stirred for 30 min at 25 deg.C and extracted with ethyl acetate (100mL. Times.3). The organic phase was washed with saturated sodium bicarbonate (100 mL), saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (10. 1 H NMR(400MHz,CDCl 3 )δ9.81(s,1H),7.40-7.34(m,5H),5.23(s,2H),2.52-2.48(m,4H),2.05-1.88(m,2H)。
The third step
Compound 144-4 (6.00g, 22.7 mmol) was dissolved in anhydrous dichloromethane (50 mL) and diisopropylethylamine (5.88g, 45.5 mmol) and allyl chloroformate (4.11g, 34.12mmol) were added at 0 ℃. The reaction mixture was stirred at 25 ℃ for 1 hour. The solvent was concentrated under reduced pressure, water (60 mL) was added, and extraction was performed with ethyl acetate (80mL. Times.3). The organic phases were combined, washed with citric acid (10%, 150 mL), brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 235-5.MS-ESI calculated value [ M + H%] + 297, found 297.
The fourth step
Compound 235-5 (8.71g, 21.51mmol) was dissolved in absolute ethanol (50 mL), hydroxylamine hydrochloride (3.74g, 53.77mmol) and diisopropylethylamine (13.90g, 107.54mmol) were added to the reaction solution, and the reaction solution was stirred at 80 ℃ for 11 hours. The solvent was removed by concentration under reduced pressure, the resulting crude product was dissolved in ethyl acetate (50 mL) and water (50 mL), extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed successively with saturated ammonium chloride solution (100mL × 1), saturated sodium chloride solution (100mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 235-6. 1 H NMR(400MHz,CDCl 3 ) δ 7.28 to 7.25 (m, 2H), 7.20 to 7.18 (m, 1H), 7.16 to 7.141 (m, 2H), 5.95 to 5.91 (m, 1H), 5.30 to 5.17 (m, 2H), 4.85 (s, 2H), 4.62 to 4.60 (m, 2H), 3.70 to 3.67 (m, 1H), 3.35 to 3.31 (m, 1H), 2.87 to 2.83 (m, 1H), 2.16 to 2.13 (m, 1H), 1.27 to 1.24 (m, 2H), 1.10 to 0.99 (m, 1H), 0.89 to 0.88 (m, 1H), 0.71 to 0.70 (m, 1H), 0.61 to 0.60 (m, 1H). MS-ESI calculated value [ M + H%] + 330, measured value 330.
The fifth step
Under the protection of nitrogen, compound 235-7 (681.12mg, 2.97mmol) The reaction mixture was dissolved in anhydrous N, N-dimethylformamide (15 mL), N-carbonyldiimidazole (578.06mg, 3.56mmol) was added thereto, and the reaction mixture was stirred at 30 ℃ for 2 hours. Then, compound 235-6 (1.1g, 2.97mmo) was added thereto, and the reaction mixture was stirred at 110 ℃ for 10 hours. The reaction was cooled to room temperature, water (50 mL) was added, extracted with ethyl acetate (50mL. Times.3), and the organic phases combined. The organic phase was washed with saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (1. MS-ESI calculated value [ M + Na ]] + 523, found 523.
The sixth step
Compound 235-8 (1.50g, 2.87mmol) was dissolved in ethyl acetate (5 mL) and ethyl acetate hydrochloride (4M 10 mL), and the reaction was stirred at 20 ℃ for 1h. Concentrating under reduced pressure to obtain compound 235-9.MS-ESI calculated value [ M + H% ] + 423, measured value 423.
Seventh step
Compound 235-9 (1.3g, 2.83mmol), triethylamine (859mg, 8.50mmol) and compound 235-3 (618mg, 2.83mmol) were dissolved in anhydrous dichloromethane (30 mL), anhydrous sodium sulfate (1.21g, 8.50mmol) was added, the reaction was stirred at 25 ℃ for 5h, sodium borohydride acetate (1.50g, 7.08mmol) was added, and stirring was continued for 7h. The reaction was diluted with dichloromethane (100 mL), and the organic phase was washed successively with saturated aqueous sodium carbonate (50mL × 2), saturated brine (50mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 235-10.MS-ESI calculated value [ M + H%] + 625, measured value 625.
The eighth step
Compound 235-10 (1.80g, 2.73mmol) was dissolved in tetrahydrofuran (10 mL) under nitrogen, diethylamine (2.00g, 27.3mmol) and tetrakistriphenylphosphine palladium (315mg, 0.273mmol) were added, and the reaction was stirred at 80 ℃ for 3 hours. After filtration, water (50 mL) was added to the filtrate, which was extracted with ethyl acetate (30mL. Times.3). The organic phases were combined, washed with saturated brine (30mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was isolated and purified by silica gel column chromatography (2. MS-ESI calculated value [ M + H%] + 541, found value 541.
The ninth step
Will be transformed intoCompound 235-11 (900mg, 1.01mmol) and sodium hydroxide (202mg, 5.06mmol) were dissolved in water (4 mL) and methanol (8 mL), and the reaction solution was stirred at 60 ℃ for 12 hours. The reaction was cooled to 0 ℃, the pH was adjusted to 5 with hydrochloric acid (1 mol/L), the mixture was extracted with dichloromethane/methanol =9/1 (20mL × 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated and purified by high performance liquid chromatography (acidic, hydrochloric acid system) to give compound 235. 1 H NMR(400MHz,D 2 O) delta 7.39-7.30 (m, 3H), 7.13-7.12 (m, 2H), 3.84-3.76 (m, 1H), 3.66-3.63 (m, 5H), 3.27-3.21 (m, 3H), 3.11-3.09 (m, 1H), 2.55-2.51 (m, 3H), 2.28-2.05 (m, 8H), 1.44-1.33 (m, 6H). MS-ESI calculated value [ M + Na ]] + 451, found value 451.
Example 236
The synthesis route is as follows:
first step of
Compound 236-1 (10.0g, 97.9 mmol) and diisopropylethylamine (41.8g, 323mmol) were dissolved in anhydrous dichloromethane (200 mL), sulfoxide chloride (12.8g, 108mmol) was added dropwise at-5 ℃ and the reaction mixture was stirred for 3 hours at-5 ℃ under nitrogen. The reaction was quenched with water (300 mL) at 0 ℃, the mixture was extracted with dichloromethane (200mL x 2), the organic phases were combined, the organic phase was washed with saturated brine (200mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (10. 1 H NMR(400MHz,CDCl 3 )5.28(d,J＝12.0Hz,2H),3.08(d,J＝12.0Hz,2H),0.87-0.83(m,2H),0.51-0.47(m,2H)。
Second step of
Compound 236-2 (3.00g, 20.3 mmol) was dissolved in N, N-dimethylformamide (5 mL), and sodium cyanide (1.19g, 24.3 mmol) and potassium iodide (0.672g, 4.05mmol) were added to the reaction solution, and the reaction solution was stirred at 110 ℃ for 12 hours. Trans formThe reaction was cooled to 0 ℃ and quenched with water (50 mL), extracted with ethyl acetate (30mL x 3), and the organic phase was washed with saturated brine (30mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 236-3. 1 H NMR(400MHz,CDCl 3 )3.50(s,2H),2.56(s,2H),0.63-0.57(m,4H)。
The third step
Compound 236-3 (1.75g, 15.8mmol) was dissolved in anhydrous dichloromethane (40 mL), and under the protection of nitrogen gas at 0 ℃ was added dropwise, to the solution, wearable martin iodoalkane (8.01g, 18.9mmol) was added, and the reaction solution was heated to 20 ℃ and stirred for 16 hours. To the reaction solution was added a saturated sodium bicarbonate solution (50 mL) until no bubbles were formed in the solution, and then a saturated sodium thiosulfate solution (50 mL) was added to the reaction solution until the color of the starch potassium iodide paper became blue, the solution was stirred for 30 minutes, extracted with dichloromethane (100mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude compound 236-4. 1 H NMR(400MHz,CDCl 3 )8.60(s,1H),2.78(s,2H),1.38-1.27(m,4H)。
The fourth step
Compound 236-4 (2.5g, 22.9mmol) was dissolved in dry dichloromethane (30 mL) and then acetic acid (125mg, 2.08mmol) and 144-3 (2.77g, 20.8mmol) were added. The reaction mixture was stirred at 25 ℃ for 1 hour, then sodium borohydride acetate (6.62g, 31.2mmol) was added and the reaction mixture was stirred for another 11 hours. After completion of the reaction, a saturated sodium carbonate solution (20 mL) was added to the reaction mixture until no bubbles were generated, extraction was performed with methylene chloride (20mL x 3), the organic phases were combined and concentrated under reduced pressure, water (20 mL) was added to the residue, pH =3 was adjusted with 1M hydrochloric acid, extraction was performed with methyl tert-butyl ether (20mL x 2), the aqueous phase was adjusted to pH =8 with a saturated sodium carbonate solution, ethyl acetate (20mL x 3), the organic phases were combined and washed with a saturated saline solution (20mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 236-5.MS-ESI calculated value [ M + H% ] + 227, found 227.
The fifth step
Compound 236-5 (1.6 g, 7.07mmol) was dissolved in anhydrous dichloromethane (20 mL), di-tert-butyl dicarbonate (1.85g, 8.48mmol) and diisopropylethylamine (1.43g, 14.1 mmol) were added, and the reaction mixture was stirred at 25 ℃ for 4 hours. 10% citric acid (10 m) was added to the reaction solutionL), water (100 mL), extraction with ethyl acetate (100mL x 2), drying over anhydrous sodium sulfate, filtration, and concentration under reduced pressure gave crude compound 236-6.MS-ESI calculated value [ M-56+H] + 271, found value 271.
The sixth step
Compound 236-6 (100mg, 0.306mmol) was dissolved in anhydrous methanol (3 mL), cobalt chloride (159mg, 1.23mmol) was added thereto at 0 deg.C, sodium borohydride (92.7mg, 2.45mmol) was slowly added, and the reaction mixture was stirred at 20 deg.C for 1 hour. The reaction solution was filtered through celite, water (10 mL) was added to the filtrate, followed by extraction with ethyl acetate (10mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 236-7.MS-ESI calculated value [ M + H%] + 331, found value 331.
Step seven
Compound 236-7 (80mg, 0.242mmol) was dissolved in ethyl acetate (2 mL) and ethyl acetate hydrochloride (0.5 mL) was added dropwise at 0 ℃. The reaction solution was stirred at 0 ℃ for 1 hour, the solvent was removed by concentration under reduced pressure, and the crude product was subjected to high performance liquid chromatography (acidic, hydrochloric acid system) to prepare compound 236. 1 H NMR (400MHz, meOD). Delta.7.33-7.29 (m, 2H), 7.25-7.22 (m, 1H), 7.21-7.18 (m, 2H), 3.15-3.11 (m, 4H), 3.02-2.98 (m, 1H), 2.68-2.63 (m, 1H), 1.83-1.79 (m, 2H), 1.67-1.62 (m, 1H), 1.39-1.34 (m, 1H), 0.75-0.72 (m, 2H), 0.65-0.63 (m, 2H). MS-ESI calculated value [ M + H%] + 231, found 231.
Example 237
The synthetic route is as follows:
first step of
Compound 235-9 (300mg, 0.653mmol) was dissolved in anhydrous dioxane (10 mL), and compound 237-1 (213mg, 0.980mmol) was added under nitrogen protection at 0 ℃. Tri-n-propyl phosphoric anhydride (50% ethyl acetate solution, 1.17mL, 1.96mmol) and diisopropyl group were then addedEthylamine (338mg, 0.980mmol). The reaction solution was stirred in an oil bath at 60 ℃ for one hour. Water (20 mL) was added to the reaction solution at 0 ℃, extracted with ethyl acetate (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin layer chromatography (2. MS-ESI calculated value [ M + H%] + 622, found 622.
Second step of
Referring to example 235, the eighth step gave compound 237-3.MS-ESI calculated value [ M-Boc + H] + 438, found value 438.
The third step
Example 236 step seven gave compound 237. 1 H NMR (400MHz, meOD). Delta.7.34-7.31 (m, 2H), 7.27-7.24 (m, 1H), 7.23-7.17 (m, 2H), 4.52-4.35 (m, 2H), 4.06-3.96 (m, 1H), 3.69-3.41 (m, 2H), 3.39-3.36 (m, 2H), 3.11-3.09 (m, 2H), 2.58-2.53 (m, 1H), 2.22-2.17 (m, 3H), 1.91-1.72 (m, 2H), 1.61-1.56 (m, 1H), 1.45-1.34 (m, 5H), 1.14-1.11 (m, 3H), 1.04-1.02 (m, 3H). MS-ESI calculated value [ M + H% ] + 438, found 438.
Example 238
The synthetic route is as follows:
first step of
The first step of referential example 237 gave compound 238-2.MS-ESI calculated value [ M + H%] + 594, found 594.
Second step of
The eighth step of reference example 235 gave compound 238-3.MS-ESI calculated value [ M + H%] + 510, measured value 510.
The third step
Compound 238 was obtained by the seventh step in accordance with example 236. 1 H NMR(400MHz,MeOD)δ7.35-7.31(m,2H),7.27-7.24(m,1H),7.19-7.16 (m, 2H), 4.49-4.39 (m, 2H), 3.97-3.90 (m, 1H), 3.73-3.64 (m, 2H), 3.51-3.35 (m, 2H), 3.15-3.08 (m, 2H), 2.59-2.53 (m, 1H), 2.23-2.14 (m, 2H), 1.90-1.77 (m, 2H), 1.61-1.56 (m, 1H), 1.49-1.34 (m, 8H). MS-ESI calculated value [ M + H%] + 410, found value 410.
Example 239
The synthetic route is as follows:
first step of
Compound 239-2 is obtained in the first step of reference example 237. MS-ESI calculated value [ M + H%] + 567, found 567.
Second step of
Compound 239-2 (40mg, 70.6. Mu. Mol) was dissolved in anhydrous dichloromethane (1 mL), trifluoroacetic acid (924mg, 8.1mmol) was added to the reaction solution, and the reaction solution was stirred at 0 ℃ for 1 hour. The solvent is removed by concentration under reduced pressure, and the crude product is subjected to high performance liquid chromatography (acidic, hydrochloric acid system) to prepare a compound 239. 1 H NMR(400MHz,CD 3 OD) δ 7.35-7.31 (m, 2H), 7.27-7.23 (m, 1H), 7.18-7.16 (m, 2H), 3.72-3.63 (m, 2H), 3.10-3.06 (m, 1H), 3.00-2.94 (m, 1H), 2.87-2.85 (m, 2H), 2.57-2.52 (m, 1H), 2.22-2.18 (m, 2H), 1.99-1.97 (m, 2H), 1.78-1.55 (m, 4H), 1.45-1.22 (m, 7H). MS-ESI calculated value [ M + H% ] + 367, measured value 367.
Example 240
The synthetic route is as follows:
first step of
Compound 240-2 is obtained in the first step of referential example 237. MS-ESI calculated value [ M + Na ]] + 589, found 589.
Second step of
The second step of reference example 239 gives compound 240. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.25-7.21 (m, 1H), 7.16-7.14 (m, 2H), 3.71-3.63 (m, 2H), 3.13-2.99 (m, 2H), 2.86-2.80 (m, 2H), 2.56-2.51 (m, 1H), 2.06-2.03 (m, 2H), 1.91-1.82 (m, 3H), 1.59-1.54 (m, 1H), 1.46-1.12 (m, 9H). MS-ESI calculated value [ M + H%] + 367, found 367.
Example 241
The synthetic route is as follows:
first step of
Hydroxylamine hydrochloride (1.61g, 23.1mmol) was added to absolute ethanol (30 mL), sodium hydrogencarbonate (2.65g, 31.5mmol) was added thereto, and the mixture was reacted at 0 ℃ for 15 minutes with stirring, and then compound 241-1 (2.00g, 21.0 mmol) was added thereto and reacted at 0 ℃ for 20 minutes with stirring. Water (60 mL) was added to the reaction solution, and extracted with ethyl acetate (30mL × 4), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (2. 1 H NMR(400MHz,CDCl 3 )δ8.26(s,1H),7.04(s,1H),1.65-1.62(m,2H),1.38-1.35(m,2H)。
Second step of
Compound 241-2 (890 mg, 8.08mmol) was dissolved in methylene chloride (40 mL), N-chlorosuccinimide (1.08g, 8.08mmol) was added to the reaction solution, and the reaction solution was stirred at 25 ℃ for 2 hours. Nuclear magnetic monitoring showed the raw material was remaining and stirring was continued at 25 ℃ for 12 hours, which indicated complete reaction. Water (50 mL) was added to the reaction mixture, extracted with dichloromethane (30mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure And (5) condensing to obtain a crude product 241-3. 1 H NMR(400MHz,CDCl 3 )δ8.71(s,1H),1.71-1.66(m,2H),1.65-1.60(m,2H)。
The third step
Compound 241-4 (1g, 4.40mmol) and potassium carbonate (1.82g, 13.2 mmol) were dissolved in methanol (30 mL), and 241-5 (929mg, 4.84mmol) was added. The reaction solution was stirred at 25 ℃ for 12 hours. The reaction was quenched by addition of saturated ammonium chloride solution (60 mL), extracted with ethyl acetate (30mL x 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 241-6. 1 H NMR(400MHz,CDCl 3 )δ4.41(brs,1H),3.45-3.35(m,1H),2.20-2.19(m,1H),2.03-1.95(m,5H),1.73-1.47(m,2H),1.43(s,9H),1.11-1.08(m,2H)。
The fourth step
Compound 241-6 (630mg, 2.82mmol) and compound 241-3 (816mg, 5.64mmol) were dissolved in tetrahydrofuran (20 mL), and potassium carbonate (780mg, 5.64mmol) and cuprous iodide (107mg, 0.564 mmol) were added. The reaction solution was stirred at 25 ℃ for 2 hours under nitrogen protection. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (5. 1 H NMR(400MHz,DMSO-d 6 ) δ 6.79 (d, J =7.6hz, 1h), 6.24 (s, 1H), 3.7-3.21 (m, 1H), 2.70-2.64 (m, 1H), 1.95-1.84 (m, 2H), 1.85-1.82 (m, 4H), 1.60-1.54 (m, 2H), 1.40-1.38 (m, 2H), 1.37 (s, 9H), 1.31-1.18 (m, 2H). MS-ESI calculated value [ M-56+H] + 276, found 276.
The fifth step
Compound 241-7 (496 mg, 1.50mmol) was dissolved in toluene (20 mL), cooled to-78 deg.C, diisobutylaluminum hydride (1.5M in toluene, 2.00mL, 3.00mmol) was added and the reaction stirred at-78 deg.C for 1 h. The reaction was quenched by addition of methanol (1 mL) at-78 deg.C, and after the temperature returned to 0 deg.C, 30% aqueous sodium potassium tartrate solution (30 mL) was added, stirred at 25 deg.C for 12 hours, and then extracted with ethyl acetate (30mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,DMSO-d 6 )δ9.17(s,1H),6.81(d,J7.6Hz, 1H), 6.41 (s, 1H), 3.25-3.22 (m, 1H), 2.71-2.68 (m, 1H), 2.07-1.94 (m, 2H), 1.89-1.82 (m, 2H), 1.71-1.64 (m, 2H), 1.59-1.53 (m, 2H), 1.49-1.41 (m, 2H), 1.40 (s, 9H), 1.38-1.25 (m, 2H). MS-ESI calculated value [ M-56+H] + 279, found 279.
The sixth step
Compound 241-8 (500mg, 1.50mmol) and compound 144-3 (199mg, 1.50mmol) were dissolved in dichloromethane (20 mL), and acetic acid (89.8mg, 1.50mmol) was added. After stirring for 2 hours at 25 ℃, sodium triacetoxyborohydride (634mg, 2.99mmol) was added and the reaction was stirred at 25 ℃ for 1 hour. Water (50 mL) was added to the reaction mixture, which was extracted with dichloromethane (30mL. Times.3). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,DMSO-d 6 ) δ 7.23-7.19 (m, 2H), 7.11-7.09 (m, 1H), 7.02-7.00 (m, 2H), 6.78 (d, J =7.6hz, 1h), 6.08 (s, 1H), 3.27-3.14 (m, 1H), 2.92-2.80 (m, 2H), 2.69-2.54 (m, 1H), 2.31-2.24 (m, 1H), 1.98-1.77 (m, 5H), 1.38 (s, 9H), 1.33 (br s, 2H), 1.31-1.21 (m, 2H), 0.96-0.82 (m, 6H). MS-ESI calculated value [ M + H%] + 452, measured value 452.
Seventh step
Compound 241-9 (415mg, 0.919mmol) was dissolved in hydrochloric acid (4M ethyl acetate solution, 5 mL) and stirring was continued at 25 ℃ for 0.5 hour. The solvent was removed by concentration under reduced pressure and the crude product was diluted with water (40 mL), adjusted to pH 8 with saturated aqueous sodium carbonate, extracted with ethyl acetate (30mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and subjected to high performance liquid chromatography (acidic, hydrochloric acid system) to afford compound 241. 1 H NMR(400MHz,CD 3 OD) δ 7.32-7.29 (m, 2H), 7.24-7.21 (m, 1H), 7.16-7.14 (m, 2H), 5.97 (s, 1H), 3.59 (s, 2H), 3.16-3.13 (m, 1H), 3.04-3.02 (m, 1H), 2.89-2.72 (m, 1H), 2.58-2.45 (m, 1H), 2.18-2.14 (m, 4H), 1.59-1.53 (m, 5H), 1.37-1.36 (m, 1H), 1.33-1.25 (m, 2H), 1.21-1.20 (m, 2H). MS-ESI calculated value [ M + H%] + 352, found value 352.
Example 242
The synthetic route is as follows:
first step of
Compound 242-1 (250mg, 1.11mmol) was dissolved in absolute ethanol (6 mL), hydroxylamine hydrochloride (194mg, 2.79mmol) and diisopropylethylamine (1M tetrahydrofuran solution, 5.57mL, 5.57mmol) were added to the reaction solution, and the reaction solution was stirred at 80 ℃ for 15 hours. The reaction solution was cooled to 30 ℃, the solvent was removed by concentration under reduced pressure, the obtained crude product was dissolved in ethyl acetate (30 mL) and water (20 mL), extracted with ethyl acetate (25mL x 3), and the organic phase was washed successively with a saturated ammonium chloride solution (30mL x 1), a saturated sodium chloride solution (30mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 242-2.MS-ESI calculated value [ M + H%] + 258, found 258.
Second step of
Compound 144-5 (8.00g, 25.6 mmol) was dissolved in anhydrous toluene (60 mL), diisobutylaluminum hydride (1M in toluene, 51.2mL,51.2 mmol) was added dropwise at-78 ℃ under nitrogen protection, and the reaction was stirred at-78 ℃ for 3 hours. The reaction was quenched with methanol (15 mL) at-60 ℃ and stirred for 30 min until no gas was produced. The pH was adjusted to 3 with hydrochloric acid (1N, 150mL) at room temperature and stirred for 16 hours at 30 ℃. After clarification, extraction with ethyl acetate (100mL x 3), washing of the organic phase successively with saturated ammonium chloride solution (80mL x 1), drying over anhydrous sodium sulfate, filtration, concentration under reduced pressure and isolation and purification of the crude product by preparative thin layer chromatography (5. MS-ESI calculated value [ M + Na ] ] + 338, measured value 338.
The third step
Compound 242-3 (3.08g, 9.76mmol) was dissolved in t-butanol (45 mL) and a solution of sodium chlorite (2.65g, 29.3 mmol), 2-methyl-2-butene (2.74g, 39.0 mmol) and sodium dihydrogen phosphate (3.51g, 29.3 mmol) in water (40 mL) was added at 0 ℃. The reaction mixture was stirred at 30 ℃ for 16 hours. The reaction mixture was concentrated under reduced pressure to remove t-butanol, water (15 mL) was added to the reaction mixture, and ethyl acetate (50 mL) was addedx 3), the organic phases are combined, washed with brine (50mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product is purified with (10: 1 petroleum ether/ethyl acetate, 11 mL) to obtain compound 242-4.MS-ESI calculated value [ M + Na ]] + 354, found 354.
The fourth step
Dissolving compound 242-4 (231mg, 0.6988 mmol) in anhydrous N, N-dimethylformamide (5 mL), adding carbonyldiimidazole (136mg, 0.837 mmol) under the protection of nitrogen at 30 ℃, stirring for 2 hours, adding compound 242-2 (214mg, 0.767 mmol) into the reaction solution, heating the reaction solution to 110 ℃, and stirring for reaction for 10 hours. The reaction was cooled to room temperature, water (60 mL) was added to the reaction, extracted with ethyl acetate (50mL × 3), the organic phases were combined, washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin layer chromatography (2. MS-ESI calculated value [ M + Na ] ] + 575, found 575.
The fifth step
Compound 242-5 (161mg, 0.277mmol) was dissolved in dry dichloromethane (16 mL) and trifluoroacetic acid (8 mL) was added dropwise at 0 ℃. The reaction solution is stirred and reacted for 1 hour at 0 ℃, the solvent is removed by decompression and concentration, and the crude product is subjected to high performance liquid chromatography (acidic, hydrochloric acid system) to prepare the compound 242. 1 H NMR(400MHz,CD 3 OD) Δ 7.33-7.29 (m, 2H), 7.25-7.22 (m, 1H), 7.18-7.16 (m, 2H), 3.79-3.72 (m, 2H), 3.15-3.10 (m, 2H), 2.80-2.75 (m, 1H), 2.62-2.58 (m, 1H), 2.20-2.17 (m, 4H), 1.67-1.54 (m, 9H), 1.43-1.37 (m, 1H). MS-ESI calculated value [ M + H%] + 353, measured value 353.
Example 243
The synthetic route is as follows:
first step of
Compound 243-1 (5.00g, 20.6mmol) was dissolved in N, N-dimethylformamide (100 mL), and hydrazine hydrate (1.57g, 85%,26.7 mmol), 1-hydroxybenzotriazole (4.17g, 30.8mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.91g, 30.8mmol) and the reaction was stirred at 25 ℃ for 60 hours. The reaction was quenched by adding water (150 mL) to the reaction solution, extracted with ethyl acetate (200mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (300mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (1. MS-ESI calculated value [ M-56+H ] + 202, measured value 202.
Second step of
Compound 242-4 (250mg, 0.754mmol), compound 243-2 (366mg, 0.830mmol) were dissolved in anhydrous dioxane (50 mL), tri-N-propylcyclic phosphoric anhydride (50% ethyl acetate solution, 1.35mL, 2.26mmol) and diisopropylethylamine (292mg, 2.26mmol) were added under nitrogen protection at 30 ℃ and the reaction was stirred at 70 ℃ for 1 hour, and tri-N-propylcyclic phosphoric anhydride (50% ethyl acetate solution, 1.35mL, 2.26mmol) and N, N-diisopropylethylamine (292mg, 2.26mmol) were added to the reaction solution and the reaction was stirred at 135 ℃ for 24 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to remove the solvent, the residue was dissolved with water (20 mL), extracted with ethyl acetate (25mL x 3), the organic phases were combined, washed with saturated brine (40mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by preparative thin layer chromatography (1. 1 H NMR(400MHz,CDCl 3 ) δ 7.16-7.24 (m, 2H), 7.11-7.07 (m, 1H), 6.98-6.96 (m, 2H), 4.34-43.1 (m, 1H), 3.75-3.52 (m, 2H), 3.41-3.39 (m, 1H), 2.72-2.70 (m, 1H), 2.60-2.55 (m, 1H), 2.06-2.03 (m, 4H), 1.45 (s, 9H), 1.36 (s, 9H), 1.27-0.87 (m, 10H). MS-ESI calculated value [ M + H%] + 553, found 553.
The third step
In the fifth step of EXAMPLE 242, compound 243 was obtained. 1 H NMR(400MHz,CD 3 OD)δ7.37-7.26(m,3H),7.04-7.02(m,2H),3.87-3.84(m,1H),3.61-3.57(m,1H),3.17-3.05(m,1H),3.04-3.02(m,1H),2.65-2.58(m,1H),2.46-2.43(m,1H),2.11-2.09(m4H), 1.59-1.39 (m, 10H). MS-ESI calculated value [ M + H%] + 353, measured value 353.
Example 244
The synthetic route is as follows:
first step of
Compound 244-1 (8.00g, 29.3 mmol) was dissolved in dichloromethane (100 mL) and cooled to 0 deg.C.Des-Martin periodinane 16.7g,32.2 mmol) was added to the solution and the reaction was stirred at 20 deg.C under nitrogen for 12 hours. To the reaction solution was added a saturated sodium bicarbonate solution (200 mL) and stirred until no bubble was generated, a saturated sodium thiosulfate solution (300 mL) was added to quench the reaction, extracted with ethyl acetate (500mL × 2), the organic phase was washed with a saturated sodium chloride solution (500mL × 1), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (2. MS-ESI calculated value [ M + Na ]] + 294, found 294.
Second step of
Compound 244-2 (1.00g, 3.00mmol) was dissolved in methylene chloride (10 mL), cooled to 0 deg.C, diethylaminosulfur trifluoride (2.42g, 15.0 mmol) was added to the solution, and the reaction was stirred at 20 deg.C for 12 hours. The reaction was quenched by addition of saturated sodium bicarbonate solution (30 mL), the aqueous phase was extracted with dichloromethane (20mL × 3), the organic phase was washed with saturated sodium bicarbonate solution to pH 7, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 244-3.MS-ESI calculated value [ M-56+ H ] + 238, found value 238.
The third step
The compound 244-3 (1.06g, 3.60mmol) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (5 mL), sodium hydroxide (432mg, 10.8mmol) was added thereto under nitrogen protection at 20 ℃ and stirring was carried out for 12 hours, and the reaction mixture was concentrated under reduced pressureThe solvent was removed, the pH was adjusted to 5 with hydrochloric acid (1M), extracted with ethyl acetate (15mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound 244-4.MS-ESI calculated value [ M-56+H] + 224, found 224.
The fourth step
Compound 244-4 (444mg, 1.59mmol) was dissolved in anhydrous N, N-dimethylformamide (5 mL), carbonyldiimidazole (352mg, 2.17mmol) was added under nitrogen protection at 20 ℃ and stirred for 2 hours, compound 144-6 (500mg, 1.45mmol) was added to the reaction solution, and the reaction solution was heated to 110 ℃ and stirred for 10 hours. The reaction was cooled to room temperature, water (50 mL) was added to the reaction, extraction was performed with ethyl acetate (30mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (50mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (3. MS-ESI calculated value [ M + Na ]] + 611, found value 611.
The fifth step
Compound 244-5 (388mg, 0.411mmol) was dissolved in ethyl acetate (3 mL), hydrochloric acid (4M ethyl acetate solution, 3mL,12.0 mmol) was added under nitrogen at 20 ℃ and stirred for 0.5 hour, the reaction solution was concentrated under reduced pressure, and the crude product was isolated and purified by high performance liquid chromatography (hydrochloric acid system) to give compound 244.1H NMR (400MHz, D 2 O) delta 7.31-7.21 (m, 3H), 7.06-7.04 (m, 2H), 3.84-3.71 (m, 2H), 3.58-3.54 (m, 1H), 3.45-3.40 (m, 1H), 3.03-3.00 (m, 1H), 2.51-2.42 (m, 2H), 2.20-1.98 (m, 4H), 1.92-1.82 (m, 1H), 1.50-1.40 (m, 2H), 1.37-1.23 (m, 4H). MS-ESI calculated value [ M + H%] + 389, found 389.
Example 245
The synthetic route is as follows:
first step of
Compound 245-1 (10.0 g,58.8 mmol) was dissolved in tetrahydrofuran (10 mL), and a saturated sodium hydroxide solution (20 mL) was added to the reaction solution, and the reaction solution was stirred at 60 ℃ for 10 hours. The pH was adjusted to 5 with hydrochloric acid (1M) at room temperature, then water (300 mL) was added, followed by extraction with ethyl acetate (300mL x 3), the organic phases were combined, washed with saturated sodium chloride solution (300mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 245-2.
Second step of
The fourth step in EXAMPLE 244 gave compound 245-3.MS-ESI calculated value [ M + Na ]] + 474, measured value 474.
The third step
Compound 245-3 (200mg, 387 μmol) and tetraethyl titanate (265mg, 1.16mmol) were dissolved in tetrahydrofuran (8 mL), and (R) - (+) -tert-butylsulfinamide (56.3mg, 0.464mmol) was dissolved in tetrahydrofuran (2 mL) and added dropwise to the system, followed by stirring at 75 ℃ for 2 hours, the reaction system was quenched dropwise into saturated sodium bicarbonate solution (20 mL), filtered, the filtrate was extracted with ethyl acetate (30mL x 1), the organic phase was washed with saturated sodium chloride solution (30mL x 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (2 petroleum ether/ethyl acetate, rf = 0.4) to give compound 245-4.
The fourth step
The compound 245-4 (154mg, 0.278mmol) is dissolved in tetrahydrofuran (3 mL), the system is cooled to-78 ℃, methylmagnesium bromide (3M diethyl ether solution, 99.3mg, 0.833mmol) is added into the system dropwise, the reaction is kept at-78 ℃ for 1 hour, then the system is gradually heated to 25 ℃ for three hours, saturated ammonium chloride solution (3 mL) is added for quenching, water (5 mL) is added for dilution, ethyl acetate (10mL x 3) is used for extraction, the combined organic phase is washed by saturated sodium chloride solution (10mL x 1), anhydrous sodium sulfate is dried, filtration and decompression and concentration are carried out to obtain the crude compound 245-5.MS-ESI calculated value [ M + Na ]] + 593, found 593.
The fifth step
In the fifth step in accordance with example 244, compound 245 was obtained. 1 H NMR(400MHz,D 2 O)δ7.29-7.19(m,3H),7.03-7.01(m,2H),3.70-3.53(m,2H),3.00-2.98(m,1H),2.91-2.86(m,1H),2.40-2.39(m,1H),1.96-1.90(m,2H),1.83-1.77(m,2H),1.69-1.66 (m, 4H), 1.48-1.43 (m, 1H), 1.34-1.22 (m, 8H). MS-ESI calculated value [ M + H%] + 367, found 367.
Example 246
The synthesis route is as follows:
first step of
Compound 246-1 (2.00g, 8.98mmol) was dissolved in dichloromethane (30 mL), sodium bicarbonate (2.26g, 26.9mmol) was dissolved in water (6 mL) and added to the reaction solution, after the system was cooled to 0 deg.C, cyanogen bromide (1.14g, 10.8mmol) was dissolved in dichloromethane (3 mL) and added dropwise to the reaction system, and the system was raised to 25 deg.C and stirred for 3 hours. Water (50 mL) was added at room temperature to dilute the precipitate and the precipitate was filtered, the aqueous phase was extracted with dichloromethane (20mL x 3), the organic phases were combined, washed with saturated sodium bicarbonate solution (30mL x 1) and saturated sodium chloride solution (30mL x 1), respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 246-2.MS-ESI calculated value [ M-56+ H] + 156, measured value 156.
Second step of
The compound 144-6 (200mg, 0.579mmol) and the compound 246-2 (2458 mg, 1.1699 mmol) are dissolved in tetrahydrofuran (30 mL), zinc chloride (1M diethyl ether solution, 1.16mL, 1.16mmol) is added into the reaction system dropwise, the reaction is stirred at 30 ℃ for 1 hour, then the temperature is raised to 70 ℃ for 3 hours, and then p-toluenesulfonic acid monohydrate (121mg, 0.637mmol) is added and stirred at 70 ℃ for 4 hours. The reaction solution was concentrated under reduced pressure, the resulting product was diluted with water (50 mL) and then extracted with ethyl acetate (40mL x 3), the organic phases were combined and washed with saturated sodium chloride solution (40mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (5. MS-ESI calculated value [ M + H% ] + 540, found 540.
The third step
In the fifth step of EXAMPLE 244, compound 246 was obtained. 1 H NMR(400MHz,CD 3 OD) δ 7.35-7.31 (m, 2H), 7.28-7.24 (m, 1H), 7.18-7.16 (m, 2H), 3.87 (t, J =5.6hz, 4H), 3.65-3.54 (m, 2H), 3.38 (t, J =5.6hz, 4H), 3.10-3.06 (m, 1H), 2.57-2.52 (m, 1H), 1.60-1.55 (m, 1H) 1.43-1.38 (m, 3H), 1.27-1.25 (m, 2H). MS-ESI calculated value [ M + H%] + 340, found 340.
Example 247
The synthetic route is as follows:
first step of
The first step of referential example 246 gave compound 247-2. 1 H NMR(400MHz,DMSO-d 6 ) δ 3.20 (t, J =5.2hz, 4h), 2.35 (t, J =5.2hz, 4h), 2.18 (s, 3H). MS-ESI calculated value [ M + H%] + 126, found value 126.
Second step of
The second step of referential example 246 gave compound 247-3.MS-ESI calculated value [ M + H%] + 454, found 454.
The third step
Compound 247 was obtained by the fifth step in EXAMPLE 244. 1 H NMR(400MHz,CD 3 OD) delta 7.35-7.31 (m, 2H), 7.28-7.24 (m, 1H), 7.18-7.16 (m, 2H), 3.65-3.50 (m, 6H), 3.35-3.30 (m, 4H), 3.10-3.06 (m, 1H), 2.99 (s, 3H), 2.57-2.52 (m, 1H) 1.60-1.55 (m, 1H), 1.43-1.38 (m, 3H), 1.27-1.25 (m, 2H). MS-ESI calculated value [ M + H%] + 354, found 354.
Example 248
The synthetic route is as follows:
first step of
Hydroxylamine hydrochloride (336mg, 4.84mmol) was added to a mixed solution of ethanol (6 mL) and water (2 mL), sodium carbonate (933mg, 8.80mmol) was added, and the reaction was stirred at 25 ℃ for 15 minutes, followed by addition of compound 248-1 (1g, 4.40mmol) and stirring at 25 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, water (50 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (40mL. Times.3), and the organic phase was washed with saturated brine (40mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 248-2. 1 H NMR(400MHz,CDCl 3 ) δ 7.48 (br s, 1H), 7.33 (d, J =6.0hz, 1h), 4.53-4.30 (m, 1H), 3.49-3.31 (m, 1H), 2.24-2.05 (m, 2H), 1.95-1.83 (m, 2H), 1.45 (s, 9H), 1.40-1.25 (m, 2H), 1.22-1.08 (m, 2H). MS-ESI calculated value [ M + H%] + 243, measured value 243.
Second step of
Compound 248-2 (600mg, 2.48mmol) was dissolved in methylene chloride (20 mL), N-chlorosuccinimide (331mg, 2.48mmol) was added to the reaction solution, and the reaction solution was stirred at 35 ℃ for 2 hours. Nuclear magnetic monitoring showed the raw material was remaining and stirring was continued at 35 ℃ for 12 hours, indicating complete reaction. Water (30 mL) was added to the reaction mixture, which was extracted with dichloromethane (30mL. Times.3), and the organic phase was washed with saturated brine (20mL. Times.1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product 248-3. 1 H NMR(400MHz,CDCl 3 )δ9.07(br s,1H),4.70-4.22(m,1H),3.62-3.26(m,1H),2.44-2.28(m,1H),2.20-2.00(m,4H),1.60-1.50(m,2H),1.45(s,9H),1.22-1.06(m,2H)。
The third step
Compound 242-3 (750mg, 2.38mmol) and potassium carbonate (986mg, 7.13mmol) were dissolved in methanol (10 mL), and 248-4 (503mg, 2.62mmol) was added. The reaction solution was stirred at 25 ℃ for 12 hours. The solvent was removed by concentration under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (30mL × 3), the organic phase was washed with saturated brine (20mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (5 -5。 1 H NMR(400MHz,CDCl 3 ) δ 7.29-7.25 (m, 2H), 7.22-7.09 (m, 3H), 3.60-3.14 (m, 2H), 3.05-2.95 (m, 1H), 2.18-2.05 (m, 1H), 1.78 (s, 1H), 1.45 (s, 9H), 1.34-1.18 (m, 2H), 0.99-0.67 (m, 4H). MS-ESI calculated value [ M + Na ]] + 334, measured value 334.
The fourth step
Compound 248-5 (200mg, 0.642mmol) and compound 248-3 (355mg, 1.28mmol) were dissolved in tetrahydrofuran (5 mL), and potassium carbonate (266mg, 1.93mmol) and cuprous iodide (24.5mg, 0.128mmol) were added. The reaction mixture was stirred at 25 ℃ for 12 hours under nitrogen. Water (50 mL) was added to the reaction solution, followed by extraction with ethyl acetate (30mL. Times.3). The organic phase was washed with saturated brine (20mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel preparative plate separation (3. 1 H NMR(400MHz,CDCl 3 ) δ 7.28-7.24 (m, 2H), 7.21-7.14 (m, 1H), 7.05-7.04 (m, 2H), 6.00 (s, 1H), 4.49-4.33 (m, 1H), 3.85-3.70 (m, 1H), 3.57-3.28 (m, 2H), 2.77-2.66 (m, 1H), 2.63-2.49 (m, 1H), 2.17-2.05 (m, 3H), 2.01-1.90 (m, 2H), 1.57-1.47 (m, 2H), 1.45 (s, 9H), 1.39 (s, 9H), 1.22-1.09 (m, 5H), 1.08-0.84 (m, 3H). MS-ESI calculated value [ M + Na ]] + 574, measured value 574.
The fifth step
Compound 248-6 (204mg, 370. Mu. Mol) was dissolved in methanol (4 mL) and then hydrochloric acid/methanol (4M, 4 mL) was added and stirred for 0.5 h at 20 ℃ with LCMS showing the starting material remaining and stirring continued at 20 ℃ for 12 h. The solvent was removed by concentration under reduced pressure, the resulting crude product was diluted with water (40 mL), adjusted to pH 8 with saturated aqueous sodium carbonate, extracted with ethyl acetate (30mL x 3), the organic phase was washed with saturated brine (20mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to high performance liquid chromatography (acidic, hydrochloric acid system) to give compound 248. 1 H NMR(400MHz,CD 3 OD) Δ 7.35-7.27 (m, 2H), 7.27-7.19 (m, 1H), 7.19-7.12 (m, 2H), 6.31 (s, 1H), 3.62 (s, 2H), 3.25-3.09 (m, 1H), 3.06-2.97 (m, 1H), 2.76-2.63 (m, 1H), 2.59-2.48 (m, 1H), 2.22-2.00 (m, 4H), 1.66-1.46 (m, 5H), 1.41-1.28 (m, 5H). MS-ESI calculated value [ M + H%] + 352, found value 352.
Example 249
The synthetic route is as follows:
first step of
Compound 144-5 (400mg, 1.12mmol) was dissolved in anhydrous methanol (12 mL), and sodium borohydride (339mg, 8.96mmol) and cobalt dichloride (582mg, 4.48mmol) were added to the reaction solution at 0 ℃ and the reaction solution was stirred at 20 ℃ for 1 hour. Celite was filtered, the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 249-1.MS-ESI calculated value [ M + H%] + 317, measured value 317.
Second step of
Compound 249-1 (413mg, 1.02mmol) was dissolved in ethyl acetate (2 mL) and hydrochloric acid/ethyl acetate (4M, 10.2mL) was added dropwise at 0 ℃. The reaction solution is stirred and reacted for 0.5 hour under the protection of nitrogen at 0 ℃, the solvent is removed by decompression and concentration, and the crude product is prepared into the compound 249 by high performance liquid chromatography (acidity, hydrochloric acid system). 1 H NMR(400MHz,D 2 O) delta 7.35-7.32 (m, 2H), 7.28-7.24 (m, 1H), 7.18-7.16 (m, 2H), 3.34-3.24 (m, 2H), 3.11-3.02 (m, 2H), 2.99-2.95 (m, 1H), 2.59-2.54 (m, 1H), 1.58-1.52 (m, 1H), 1.40-1.34 (m, 1H), 0.87-0.82 (m, 4H). MS-ESI calculated value [ M + H% ] + 217, found value 217.
Example 250
The synthetic route is as follows:
first step of
Reacting compound 143-2 (3.75g, 15.2mmol) was dissolved in anhydrous N, N-dimethylformamide (50 mL), carbonyldiimidazole (2.68g, 16.5 mmol) was added under nitrogen protection at 30 ℃ and stirred for 2 hours, compound 235-6 (5.00g, 13.8mmol) was added to the reaction solution, and the reaction solution was heated to 110 ℃ and stirred for reaction for 10 hours. The reaction was cooled to room temperature, concentrated under reduced pressure to remove the solvent DMF (10 mL), water (200 mL) was added to the reaction, extracted with ethyl acetate (150mL × 3), the organic phases were combined, washed with saturated brine (200mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by column chromatography (2. 1 H NMR(400MHz,CD 3 Cl) δ 7.28 to 7.24 (m, 2H), 7.20 to 7.16 (m, 1H), 7.11 to 7.09 (m, 2H), 5.98 to 5.88 (m, 1H), 5.30 to 5.18 (m, 2H), 4.66 to 4.57 (m, 2H), 4.51 to 4.42 (m, 1H), 3.93 (d, J =14.8hz, 1H), 3.73 (d, J =14.8hz, 1H), 3.51 to 3.38 (m, 1H), 2.76 to 2.66 (m, 2H), 2.18 to 2.09 (m, 5H), 1.82 to 1.70 (m, 1H), 1.67 to 1.57 (m, 2H), 1.46 (s, 9H), 1.22 to 1.18 (m, 3H), 1.16 to 1.00 (m, 1H), 1.07 to 0.85H). MS-ESI calculated value [ M + Na ]] + 537, found 537.
Second step of
Compound 250-1 (1.07g, 1.92mmol) was dissolved in ethyl acetate (3 mL) and hydrochloric acid/ethyl acetate (4M, 12mL) was added dropwise at 0 ℃. The reaction solution is stirred and reacted for 1 hour under the protection of nitrogen at the temperature of 0 ℃, and the compound 250-2 is obtained after decompression and concentration. MS-ESI calculated value [ M + H% ] + 437, found value 437.
The third step
Compound 250-2 (120mg, 0.252mmol), compound 250-3 (47.6 mg, 0.252mmol) were dissolved in anhydrous dioxane (3 mL), tri-N-propylcyclophosphonic anhydride (50% ethyl acetate solution, 449. Mu.L, 0.755 mmol) and N, N-diisopropylethylamine (130mg, 1.01mmol) were added to the reaction solution at 0 ℃ and the temperature was raised to 60 ℃ and the reaction was stirred under nitrogen for 1 hour. The reaction solution was cooled to 0 ℃ by LCMS to detect that the compound 250-2 did not react, and tri-N-propylcyclic phosphoric anhydride (50% ethyl acetate solution, 449. Mu.L, 0.755 mmol) and N, N-diisopropylethylamine (130mg, 1.01mmol) were added to the reaction solution and the reaction was stirred at 60 ℃ for 1 hour. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (20mL. Times.3), the organic phases were combined, washed with saturated brine (30mL. Times.1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 250-4. MS-ESI calculated value [ M + Na ]] + 630, found value 630.
The fourth step
Referring to example 235, the eighth step gave compound 250-5.MS-ESI calculated value [ M + H%] + 524, found 524.
The fifth step
Example 236 step seven gave compound 250. 1 H NMR(400MHz,D 2 O) δ 7.31-7.29 (m, 2H), 7.28-7.22 (m, 1H), 7.05-7.03 (m, 2H), 3.93 (q, J =7.2hz, 1h), 3.70-3.55 (m, 3H), 3.02-2.98 (m, 1H), 2.81-2.73 (m, 1H), 2.44-2.39 (m, 1H), 2.04-1.92 (m, 4H), 1.58-1.47 (m, 3H), 1.44 (d, J =7.2hz, 3h), 1.38-1.24 (m, 7H). MS-ESI calculated value [ M + H% ] + 424, measured value 424.
Example 251
The synthetic route is as follows:
first step of
The third step of referential example 250 gave compound 251-2.MS-ESI calculated value [ M + H%] + 636, found value 636.
Second step of
Referring to example 235, the eighth step gave compound 251-3.MS-ESI calculated value [ M + H%] + 552, found 552.
The third step
The seventh step of reference example 236 gave compound 251. 1 H NMR(400MHz,D 2 O) delta 7.33-7.29 (m, 2H), 7.27-7.24 (m, 1H), 7.06-7.04 (m, 2H), 3.72-3.57 (m, 4H), 3.04-3.00 (m, 1H), 2.85-2.75 (m, 1H), 2.46-2.41 (m, 1H), 2.18-2.10 (m, 1H), 2.07-1.94 (m, 4H), 1.58-1.46 (m, 3H), 1.42-1.26 (m, 7H), 1.00-0.97 (m, 6H). MS-ESI calculated value [ M + H%] + 452, found 452.
Example 252
The synthetic route is as follows:
first step of
The fourth step of reference example 235 gave compound 252-1.MS-ESI calculated value [ M + H%] + 360, measured value 360.
Second step of
The fifth step of reference example 235 gave compound 252-2.MS-ESI calculated value [ M + H%] + 567, found 567.
The third step
The seventh step of reference example 236 gave compound 252. 1 H NMR(400MHz,D 2 O) delta 7.36-7.32 (m, 2H), 7.28-7.25 (m, 1H), 7.16-7.15 (m, 2H), 3.21-3.12 (m, 3H), 3.03-2.97 (m, 2H), 2.86-2.82 (m, 2H), 2.53-2.48 (m, 1H), 2.21-2.17 (m, 2H), 2.12-2.09 (m, 2H), 1.65-1.47 (m, 5H), 1.40-1.34 (m, 1H), 0.75-0.68 (m, 4H). MS-ESI calculated value [ M + H% ] + 367, found 367.
Example 253
The synthesis route is as follows:
first step of
The first step of referential example 246 gave compound 253-2. 1 H NMR(400MHz,CDCl 3 ) δ 4.15 (q, J =6.8hz, 2h), 3.43-3.39 (m, 2H), 3.09-3.03 (m, 2H), 2.42-2.35 (m, 1H), 1.97-1.93 (m, 2H), 1.84-1.80 (m, 2H), 1.24 (t, J =6.8hz, 3h). MS-ESI calculated value [ M + H%] + 183, found value 183.
Second step of
The second step of reference example 246 gave compound 253-3.MS-ESI calculated value [ M + H%] + 511, found value 511.
The third step
The ninth step of referential example 235 gave compound 253-4.MS-ESI calculated value [ M + H%] + 483, found 483.
The fourth step
The fifth step in reference example 244 gave compound 253. 1 H NMR(400MHz,D 2 O) delta 7.30-7.22 (m, 3H), 7.01-6.99 (m, 2H), 3.74-3.71 (m, 2H), 3.65-3.44 (m, 2H), 3.06-3.03 (m, 3H), 2.62-2.59 (m, 1H), 2.45-2.39 (m, 1H), 1.93-1.89 (m, 2H) 1.59-1.47 (m, 3H), 1.29-1.16 (m, 5H). MS-ESI calculated value [ M + H%] + 383, found 383.
Example 254
The synthetic route is as follows:
first step of
Lithium diisopropylamide (2.0M THF solution, 32.9mL, 65.8mmol) was added to a tetrahydrofuran (150 mL) solution of compound 254-1 (10.0g, 41.1mmol) at-78 deg.C, the reaction solution was reacted at-78 deg.C for 10 minutes, then the temperature was raised to-40 deg.C within 1 hour, the reaction solution was cooled to-78 deg.C, chloromethyl ether (4.96g, 61.7mmol) was added dropwise, and after the addition, the reaction was continued at-78 deg.C for 2.5 hours, and then the temperature was raised to 25 deg.C within 1 hour. The reaction was quenched by adding saturated aqueous ammonium chloride (300 mL) to the reaction solution, followed by extraction with ethyl acetate (200mL × 3), the organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous magnesium sulfate (15 g), filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (10, petroleum ether/ethyl acetate, rf = 0.45) to give compound 254-2. 1 H NMR(400MHz,CDCl 3 )δ3.91-3.78(m,2H),3.74(s,3H),3.39(s,2H),3.31(s,3H),3.05-2.87(m,2H),2.10-2.07(m,2H),1.48-1.40(s,11H)。
Second step of
The ninth step of referential example 235 gave compound 254-3. 1 H NMR(400MHz,CDCl 3 )δ4.01-3.83(m,2H),3.44(s,2H),3.34(s,3H),3.16-2.98(m,2H),2.06-2.05(m,2H),1.49-1.38(m,11H)。
The third step
In the fifth step of referential example 235, a compound 254-4 was obtained. MS-ESI calculated value [ M + Na ]] + 589, found 589.
The fourth step
Compound 254-5 was obtained by the sixth step in EXAMPLE 235. MS-ESI calculated value [ M + H%] + 467, found 467.
The fifth step
Compound 254-6 was obtained by the seventh step in EXAMPLE 235. MS-ESI calculated value [ M + H%] + 669, found 669.
The sixth step
The eighth step in reference example 235 gave compound 254-7.MS-ESI calculated value [ M + H%] + 585, found 585.
Seventh step
In the ninth step of referential example 235, a compound 254 was obtained. 1 H NMR(400MHz,D 2 O) delta 7.36-7.31 (m, 2H), 7.26-7.25 (m, 1H), 7.15-7.13 (m, 2H), 3.71-3.58 (m, 4H), 3.50-3.39 (m, 4H), 3.22 (s, 3H), 3.05-2.97 (m, 2H), 2.52-2.40 (m, 5H), 2.27-2.20 (m, 1H), 2.11-1.94 (m, 6H), 1.54-1.49 (m, 1H), 1.42-1.25 (m, 5H). MS-ESI calculated value [ M + H%] + 495, found value 495.
Example 255
The synthesis route is as follows:
first step of
Sodium bicarbonate (442mg, 5.26mmol) was added to a solution of hydroxylamine hydrochloride (366mg, 5.26mmol) in water (5 mL). Without bubble generationThereafter, a mixture of compound 242-3 (1.58g, 5.01mmol) dissolved in absolute ethanol (10 mL) was added dropwise, and the reaction solution was stirred at 20 ℃ for 1 hour. The solvent was removed by concentration under reduced pressure, and the resulting crude product was dissolved in water (30 mL) and ethyl acetate (40mL. Times.3) and extracted, the organic phases were combined and washed with saturated sodium chloride solution (100mL. Times.1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 255-1.MS-ESI calculated value [ M + Na ] ] + 353, measured value 353.
Second step of
Compound 255-1 (1.65g, 4.99mmol) was dissolved in N, N-dimethylformamide (10 mL), N-chlorosuccinimide (667mg, 4.99mmol) was added, and the reaction mixture was stirred at 20 ℃ under nitrogen for 1 hour. The reaction was quenched with water (150 mL), extracted with ethyl acetate (150mL x 3), and the organic phase was washed with water (300mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 255-2. 1 H NMR(400MHz,DMSO-d 6 ) δ 11.63 (s, 1H), 7.28-7.24 (m, 2H), 7.18-7.10 (m, 3H), 3.62 (d, J =14.4hz, 1h), 3.28 (d, J =14.4hz, 1h), 2.67-2.63 (m, 1H), 2.08-2.04 (m, 1H), 1.33 (s, 9H), 1.24-1.15 (m, 2H), 0.96-0.91 (m, 2H), 0.85-0.80 (m, 1H), 0.75-0.74 (m, 1H). MS-ESI calculated value [ M + Na ]] + 387, found 387.
The third step
Compound 255-3 (5.00g, 20.6 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0 deg.C, and after adding sodium borohydride (1.55g, 41.1 mmol) to the solution, the system was warmed to 70 deg.C and stirred for reaction for 3 hours. The reaction was quenched by addition of water (50 mL), extracted with ethyl acetate (30mL x 3), the organic phase was washed with saturated sodium chloride solution (50mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (3. 1 H NMR(400MHz,CDCl 3 ) δ 3.51 (d, J =6.4hz, 2h), 1.74-1.60 (m, 4H), 1.52-1.41 (m, 12H), 1.20-1.10 (m, 2H). MS-ESI calculated value [ M-56+ H] + 160, found 160.
The fourth step
Compound 255-4 (1.43g, 6.65mmol) is dissolved in dichloromethane (15 mL) and cooled to 0 deg.C and then dess-Martin reagent (3.38g, 7.98mmol) is added to the solution and the reaction is stirred at 10 deg.C under nitrogen protectionFor 4 hours. The reaction was quenched by the addition of saturated sodium thiosulfate solution (50 mL) and saturated sodium bicarbonate solution (50 mL) to the reaction, extracted with ethyl acetate (80mL x 3), the organic phase was washed with saturated sodium chloride solution (100mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 255-5. 1 H NMR(400MHz,CDCl 3 )δ9.66(d,J＝4.8Hz,1H),4.13-3.99(m,2H),2.95-2.83(m,2H),2.74-2.38(m,1H),1.90-1.87(m,2H),1.70-1.50(m,2H),1.46(m,9H)。
The fifth step
Compound 255-5 (1.12g, 5.27mmol) and potassium carbonate (2.18g, 15.8mmol) were dissolved in methanol (10 mL), and dimethyl (1-diazo-2-oxopropyl) phosphonate (1.21g, 6.32mmol) was added and stirred at 20 ℃ for 12 hours. The reaction was quenched by adding saturated ammonium chloride solution (30 mL) to the reaction solution, followed by extraction with ethyl acetate (30mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (5. 1H NMR (400MHz, CDCl) 3 )δ3.72-3.68(m,2H),3.22-3.16(m,2H),2.62-2.56(m,1H),2.11(d,J＝2.4Hz,1H),1.82-1.77(m,2H),1.64-1.55(m,2H),1.46(s,9H)。
The sixth step
Compound 255-6 (558mg, 2.67mmol) was dissolved in methanol (5 mL), hydrochloric acid (4M methanol solution, 5mL,20.0 mmol) was added thereto at 15 ℃ and stirred for 0.5 hour, and the reaction solution was concentrated under reduced pressure to give crude compound 255-7. 1 H NMR(400MHz,CD 3 OD)δ3.36-3.31(m,2H),3.14-3.08(m,2H),2.85-2.79(m,1H),2.59(d,J＝2.4Hz,1H),2.09-2.03(m,2H),1.87-1.78(m,2H)。
Seventh step
Compound 255-7 (399mg, 2.74mmol), compound 235-3 (598mg, 2.74mmol) and triethylamine (832mg, 8.22mmol) were dissolved in dichloromethane (10 mL), anhydrous sodium sulfate (1.17g, 8.22mmol) was added, the system was stirred at 25 ℃ for 3 hours, then sodium borohydride acetate (1.45g, 6.85mmol) was added, and the system was stirred at 25 ℃ for 9 hours. The reaction was quenched by addition of water (20 mL), then extracted with dichloromethane (10mL x 3), the combined organic phases were washed with saturated sodium chloride solution (30mL x 1), the organic phases were dried over anhydrous sodium sulfate, filtered, and subtractedThe crude product was isolated and purified by silica gel column chromatography (10. 1 H NMR(400MHz,CDCl 3 ) δ 7.41-7.29 (m, 5H), 5.18 (s, 2H), 2.70 (s, 2H), 2.64-2.59 (m, 2H), 2.51-2.44 (m, 2H), 2.35-2.25 (m, 1H), 2.13-2.08 (m, 2H), 2.06-2.05 (m, 1H), 2.03-1.98 (m, 2H), 1.95-1.81 (m, 2H), 1.75-1.68 (m, 2H), 1.59-1.50 (m, 2H). MS-ESI calculated value [ M + H%] + 312, measured value 312.
Eighth step
Compound 255-8 (350mg, 1.12mmol) was dissolved in tetrahydrofuran (5 mL), and the mixture was stirred with a system of potassium carbonate (466 mg, 3.37mmol) and cuprous iodide (42.8mg, 0.225mmol) at 15 ℃ for 0.5 hour. Compound 255-2 (820mg, 2.25mmol) was added to the reaction system, and the system was further stirred at 15 ℃ for 5.5 hours. The reaction was quenched by adding saturated ammonium chloride solution (10 mL) to the reaction solution, followed by extraction with ethyl acetate (10mL × 3), the combined organic phases were washed with saturated sodium chloride solution (10mL × 1), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the crude product was isolated and purified by silica gel column chromatography (5. MS-ESI calculated value [ M + H% ] + 640, found value 640.
The ninth step
Compound 255-9 (320mg, 0.500mmol) was dissolved in methanol (10 mL), and a solution of sodium hydroxide (100mg, 2.5 mmol) dissolved in water (5 mL) was added. The reaction mixture was stirred at 60 ℃ for 12 hours. The reaction mixture was concentrated under reduced pressure to remove methanol, water (20 mL) was added to the reaction mixture, and extracted with ethyl acetate (20mL × 2), the aqueous phase was adjusted to pH =3 with 1M HCl, and further extracted with ethyl acetate (20mL × 4), and the organic phases were combined, washed with saturated brine (50mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 255-10.MS-ESI calculated value [ M + H%] + 550, found 550.
The tenth step
Compound 255-10 (340mg, 0.585mmol) was dissolved in anhydrous dichloromethane (8 mL), and trifluoroacetic acid (4 mL) was added dropwise at 0 ℃. The reaction solution is stirred and reacted for 2 hours under the protection of nitrogen at the temperature of 0 ℃, the solvent is removed by decompression and concentration, and the compound 255 is prepared from the crude product by high performance liquid chromatography (neutral system). 1 H NMR(400MHz,CD 3 OD)δ7.337.29 (m, 2H), 7.25-7.21 (m, 1H), 7.17-7.15 (m, 2H), 6.08 (s, 1H), 3.65-3.59 (m, 6H), 3.27-3.15 (m, 2H), 3.06-3.02 (m, 1H), 2.60-2.54 (m, 3H), 2.25-2.19 (m, 6H), 2.15-1.94 (m, 3H), 1.59-1.54 (m, 1H), 1.40-1.35 (m, 1H), 1.32-1.28 (m, 2H), 1.26-1.22 (m, 2H). MS-ESI calculated value [ M + H%] + 450, found 450.
And (3) biochemical detection:
experimental example 1: evaluation of enzyme Activity
The aim of this assay was to test the in vitro inhibitory activity of the compounds on LSD 1. The enzyme adopted in the test is human LSD1, the standard substrate is histone H3 (1-21) K4me2 peptide (10 mu M), HCI-2509 (SP 2509) is used as a reference compound, and the enzyme fluorescence coupling method is adopted to detect H generated after the demethylation activity generated by the combination of LSD1 and FAD is generated through the joint detection of Horseradish Peroxidase (HPR) and a fluorescent reagent Amplex Red 2 O 2 The method of (3) determining the activity of the compound. IC at 10 concentrations of test compound and control compound HCI-2509 starting from a 3-fold dilution at 10. Mu.M 50 The value is obtained. The compounds were preincubated with enzyme for 30 minutes before starting the reaction with substrate addition. A fluorescence detector: enVision, excitation wavelength: ex/Em =535/590nM.
The test compounds were classified for LSD1 inhibitory activity as: + represents IC 50 Less than or equal to 50nM; + represents IC 50 >50nM is less than or equal to 100nM; + + + + + + + +' denotes IC 50 >100nM and 500nM, the results are shown in Table 1.
Table 1: results of in vitro enzyme Activity screening test for Compounds of the invention
And (4) conclusion: the compound of the invention has obvious LSD1 inhibition activity.
Experimental example 2: evaluation of cell proliferation inhibitory Activity:
purpose of the experiment: detecting the inhibition activity of the test compound on the H1417 cell proliferation.
Experimental materials: RPMI 1640 medium, fetal bovine serum, promega CellTiter-Glo reagent. The H1417 cell line was purchased from ATCC. Envision multi-label analyzer (PerkinElmer).
The experimental method comprises the following steps: h1417 cells were seeded in black 384-well plates 1000 cells per well per 30 ml cell suspension. The test compound was diluted 3-fold with the Epmotion to the 10 th concentration, i.e., from 10 millimolar to 0.5 millimolar, setting up a duplicate well experiment. Add 198 μ l of medium to the intermediate plate, transfer 2 μ l of the diluted compounds per well to the intermediate plate according to the corresponding position, mix well and transfer 20 μ l of each well to the cell plate. The cell plates were placed in a carbon dioxide incubator for 10 days. Add 25. Mu.l of Promega CellTiter-Glo reagent to the cell plate and incubate for 10 min at room temperature to stabilize the luminescence signal. Readings were taken using a PerkinElmer Envision multi-label analyzer.
And (3) data analysis: the original data was converted to the inhibition rate, IC, using the equation (Max-Ratio)/(Max-Min) × 100% 50 The value of (d) can be obtained by curve fitting through four parameters. (XLFIT 5 model 205 out, iDBS)
The inhibitory activity of test compounds on H1417 cell growth was classified as: + denotes IC 50 Less than or equal to 100nM; + represents IC 50 >100nM and less than or equal to 500nM; + + + + + denotes IC 50 >500nM is less than or equal to 1000nM; the highest percent inhibition of cell viability was classified as: a is more than or equal to 90 percent when the content is 100 percent; b is more than 90% and more than or equal to 70%;70 percent more than C is more than or equal to 50 percent. The results are shown in Table 2.
Table 2: results of screening test for inhibitory Activity of Compound of the present invention on in vitro cell proliferation
And (4) conclusion: the compound has obvious inhibition activity on H1417 cell proliferation.
Experiment 3: compound pharmacokinetic evaluation
Purpose of the experiment: test Compounds pharmacokinetics in C57BL/6 mice
Experimental materials:
c57BL/6 mice (Male, 7-9 weeks old, shanghai Slek)
Experimental operation:
rodent pharmacokinetic characteristics of the compound after intravenous injection and oral administration are tested by a standard scheme, and the candidate compound is prepared into a clear solution in an experiment and is given to a mouse for single intravenous injection and oral administration. The intravenous injection and oral administration solvent is 10% hydroxypropyl beta cyclodextrin water solution or normal saline solution. The project uses six male C57BL/6 mice, three mice were administered intravenously at a dose of 1mg/kg, 0h (pre-dose) and 0.0833,0.25,0.5,1,2,4,7, 24h plasma samples were collected, three mice were administered orally by gavage at a dose of 2mg/kg, 0h (pre-dose) and 0.5,1,2,3,4,6, 24h plasma samples were collected over 24 hours, 3000g was centrifuged for 15 minutes, the supernatant was separated to obtain plasma samples, 4 volumes of acetonitrile solution containing internal standard was added to precipitate protein, the supernatant was centrifuged to obtain an equal volume of water and then centrifuged to obtain a supernatant sample, plasma concentrations were quantitatively analyzed by LC-MS/MS analysis, and drug substitution parameters such as peak concentration (Cmax), clearance rate (CL), half-life (T) were calculated 1/2 ) Tissue distribution (Vdss), area under the curve (AUC 0-last) at drug time, bioavailability (F), etc.
The results are shown in Table 3:
TABLE 3 pharmacokinetic testing results
And (4) conclusion: the compound of the invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life, clearance rate and the like.
Experiment 4 inhibition assay for hERG potassium channel
The purpose of the experiment is as follows: and detecting the influence of the embodiment to be detected on the hERG potassium ion channel by using a full-automatic patch clamp method.
Experimental method
4.1. Cell culture
4.1.1CHO-hERG cells were cultured in 175cm2 flasks, and after the cell density reached 60-80%, the culture medium was removed, washed once with 7mL PBS (Phosphate Buffered Saline Phosphate buffer), and digested with 3mL of digestion solution.
4.1.2 after digestion, add 7mL of medium to neutralize, then centrifuge, remove the supernatant, add 5mL of medium to resuspend, to ensure cell density of 2-5X 106/mL.
4.2 preparation of solutions
TABLE 4.1 composition of intracellular and extracellular fluids
Reagent Extracellular fluid (mM) Intracellular fluid (mM)
CaCl 2 2 5.374
MgCl 2 1 1.75
KCl 4 120
NaCl 145 -
Glucose 10 -
HEPES 10 10
EGTA - 5
Na 2 ATP - 4
pH pH was adjusted to 7.4 with NaOH Adjusting the pH to 7.4 with KOH
3 electrophysiological recording procedure
The process of single cell high impedance sealing and whole cell mode forming is automatically completed by Qpatch instrument, after obtaining whole cell recording mode, the cell is clamped at-80 millivolt, before a depolarization stimulation of +40 millivolt for 5 seconds, a 50 millivolt prepotential of-50 millivolt is given, then repolarization is carried out to-50 millivolt for 5 seconds, and then the voltage returns to-80 millivolt. This voltage stimulus was applied every 15 seconds, and 2 minutes after recording extracellular fluid was administered for 5 minutes, and then the dosing process was started, with compound concentrations starting at the lowest test concentration, each of which was administered for 2.5 minutes. At least 3 cells (n.gtoreq.3) were tested per concentration.
4.4 preparation of Compounds
4.4.1 dilution of 20mM compound stock solution with extracellular fluid, 5. Mu.L of 20mM compound stock solution was added to 2495. Mu.L of extracellular fluid, and 500-fold dilution was carried out to 40. Mu.M, followed by 3-fold serial dilutions in the 0.2-th% DMSO-containing extracellular fluid in order to obtain the final concentration to be tested.
4.4.2 the highest concentration tested was 40. Mu.M, in turn 6 concentrations of 40, 13.33,4.44,1.48,0.49, 0.16. Mu.M.
4.5 data analysis
Experimental data were analyzed by XLFit software.
4.6 test results
The results of the IC50 values of hERG of the example compounds are shown in Table 4.2.
TABLE 4.2 results of the hERG IC50 values for the compounds of the examples
And (4) conclusion: the compound of the invention has no inhibition effect on hERG potassium channel.
Experimental example 5 in vivo pharmacodynamic study of the Compound on a mouse model of human Small cell Lung cancer NCI-H1417 cell subcutaneous xenograft tumor CB-17SCID
5.1 purpose of experiment:
the purpose of this experiment was to investigate the efficacy of some compounds of the present invention on human small cell lung carcinoma NCI-H1417 cell subcutaneous xenograft tumors in a CB-17SCID mouse model for in vivo drug efficacy assessment.
5.2 Experimental animals:
the species is as follows: mouse
Strain: CB-17SCID mice
Week age and body weight: 6-8 weeks old, weight 18-23 g
Sex: female with a female
The supplier: beijing Huafukang Biotech GmbH Ltd
5.3 Experimental methods and procedures
5.3.1 cell culture
In vitro monolayer culture of human small cell lung carcinoma NCI-H1417 cells in RPMI-1640 medium (Sigma-aldrich, R0883) supplemented with 10% fetal bovine serum at 37 deg.C with 5% CO 2 And (5) culturing. When the saturation degree of the cells is 80% -90%, collecting the cells, counting and inoculating.
5.3.2 tumor cell inoculation
0.2mL of 10x 10 6 One NCI-H1417 cell was inoculated subcutaneously into the right dorsal back of each mouse (PBS: matrigel = 1. The mean volume reached 107mm 21 days after tumor inoculation 3 The grouped administration is started.
5.3.3 preparation of test substances
The solvent for experiments is 10% hydroxypropyl-beta-cyclodextrin solution, and the preparation method comprises the steps of weighing 100g of hydroxypropyl-beta-cyclodextrin, placing the hydroxypropyl-beta-cyclodextrin into a wide-mouth bottle with 1000mL, adding 800mL of ultrapure water, stirring overnight until the ultrapure water is completely dissolved, and then fixing the volume to 1000mL. Dissolving the test substance with solvent to obtain a uniform solution with a certain concentration, and storing at 4 deg.C.
5.3.4 tumor measurement and Experimental indices
The experimental index is to investigate whether the tumor growth is inhibited, delayed or cured. Tumor diameters were measured twice weekly using a vernier caliper. The formula for tumor volume is: v =0.5a × b 2 And a and b represent the major and minor diameters of the tumor, respectively.
Tumor suppressive therapeutic effect of the compounds TGI (%) evaluation. TGI (%), reflecting the rate of tumor growth inhibition. Calculation of TGI (%): TGI (%) = [ 1- (mean tumor volume at the end of administration of a treatment group-mean tumor volume at the start of administration of the treatment group)/(mean tumor volume at the end of treatment of solvent control group-mean tumor volume at the start of treatment of solvent control group) × 100%. Solvent control group: vehicle (10% hydroxypropyl-beta-cyclodextrin solution).
5.4 results of the experiment
TABLE 5.1 evaluation of tumor-inhibiting efficacy of test compounds on human small cell lung carcinoma NCI-H1417 xenograft tumor model (calculated based on tumor volume on day 34 post-dose)
(Cisplatin Cisplatin)。
TABLE 5.2 evaluation of the antitumor drug efficacy of the test compounds on the human small-cell lung carcinoma NCI-H1417 xenograft tumor model (calculated based on the tumor volume on day 27 after administration)
TABLE 5.3 evaluation of the antitumor drug efficacy of the test compounds on the human small-cell lung carcinoma NCI-H1417 xenograft tumor model (calculated based on the tumor volume on day 28 after administration)
And (4) conclusion: the compound has excellent tumor inhibition effect on a human small cell lung cancer NCI-H1417 xenograft tumor model.

Claims (33)

1. A compound of formula (I), a pharmaceutically acceptable salt thereof or a tautomer thereof,
Wherein, the first and the second end of the pipe are connected with each other,
f is 1 or 2;
r is 0, 1 or 2;
e is 0, 1 or 2;
p is 0 or 1;
m is 0, 1 or 2;
n is 1 or 2; or, a structural unitIs composed of
R 1 、R 2 Each independently selected from H, F, cl, br, I, OH, CN, NH 2 -COOH, or selected from C optionally substituted with 1, 2 or 3R 1-3 An alkyl group;
or R 1 And R 2 Joined together to form a 3-6 membered ring;
R 3 is-L-R 5 Or selected from phenyl optionally substituted by 1, 2 or 3R, 5-to 12-membered heteroaryl, C 3-7 Cycloalkyl and 4-to 8-membered heterocycloalkyl;
R 4 selected from H, or selected from C optionally substituted with 1, 2 or 3R 1-6 Alkyl and C 1-6 A heteroalkyl group;
R 5 selected from phenyl optionally substituted by 1, 2 or 3R, 5-to 10-membered heteroaryl, C 3-10 Cycloalkyl, cyclohexyl-CH 2 -, 4-to 10-membered heterocycloalkyl, 5-to 6-membered heterocycloalkyl-C (= O) -and 5-to 6-membered heterocycloalkyl-C 1-3 Alkyl-;
R 6 selected from H, or selected from C optionally substituted with 1, 2 or 3R 1-6 Alkyl and C 1-6 A heteroalkyl group;
l is selected from-C (= O) -, or-C optionally substituted with 1, 2 or 3R 1-6 Alkyl-, -5-to 9-membered heteroaryl-, -4-to 8-membered heterocycloalkyl-, -phenyl-and-C 3-6 Cycloalkyl-;
r is selected from H, F, cl, br, I, OH and NH 2 、CN、COOH、NH 2 -C (= O) -, or is selected from C optionally substituted with 1, 2 or 3R 1-6 Alkyl radical, C 1-6 Heteroalkyl, phenyl-C 1-6 Alkyl-, phenyl, 5-to 6-membered heteroaryl, phenyl-C (= O) -, C 3-6 cycloalkyl-C (= O) -, C 3-6 cycloalkyl-C (= O) -NH-, C 3-6 cycloalkyl-NH-C (= O) -and C 3-6 cycloalkyl-C 1-3 Alkyl-;
r' is selected from F, cl, br, I, OH and NH 2 、COOH、C 1-3 Alkyl, C substituted by 1 to 3 halogens 1-3 Alkyl radical, C 1-3 alkyl-NH-, N-di (C) 1-3 Alkyl) -amino, C 1-3 alkyl-O-C (= O) -, C 3-6 Cycloalkyl and C 1-3 An alkoxy group;
the 5-to 12-membered heteroaryl group, the 4-to 8-membered heterocycloalkyl group, C 1-6 The "hetero" of heteroalkyl, 5-to 10-membered heteroaryl, 5-to 6-membered heterocycloalkyl, 4-to 10-membered heterocycloalkyl is independently selected from: -NH-, -S-, N, -O-, = O, -C (= O) -, -NH-C (= O) -, -O-C (= O) -, -S (= O) 2 -、-S(＝O)-、-C(＝O)-NH-；
In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1, 2, 3, or 4;
and said compound is not:
2. the compound of formula (I), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 1, wherein R' is selected from F, cl, br, I, OH, NH 2 、Me、Et、CF 3 、CHF 2 、CH 2 F、NHCH 3 、N(CH 3 ) 2 、COOH、-C(＝O)-O-CH 3 、-O-CH 3 And
3. the compound of formula (I), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 1, wherein R is selected from H, F, cl, br, I, OH, NH 2 、CN、COOH、NH 2 -C (= O) -, or selected from methyl, ethyl, propyl, isobutyl, tert-butyl, C optionally substituted with 1,2 or 3R 1-6 Alkoxy, phenyl-C 1-3 Alkyl-, phenyl, pyridyl, 1,2, 4-triazolyl, phenyl-C (= O) -, C 1-3 alkyl-C (= O) -, C 1-3 alkyl-NH-, cyclopropanyl-C (= O) -, C 1-3 alkyl-O-C (= O) -C 1-3 Alkyl-, C 1-3 alkyl-O-C (= O) -, C 1-3 alkyl-S (= O) 2 -, cyclopropyl-C (= O) -NH-, cyclopropyl-NH-C (= O) -, C 1-3 alkyl-NH-C (= O) -, cyclobutyloxy-CH 2 -and C 1-3 alkyl-C (= O) -NH-.
4. A compound of formula (I), a pharmaceutically acceptable salt or tautomer thereof, as claimed in claim 3, wherein R is selected from H, F, cl, br, I, OH, NH 2 、CN、COOH、NH 2 -C (= O) -, or is selected from Me, et, optionally substituted with 1,2 or 3R
5. The compound of formula (I), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 4, wherein R is selected from H, F, cl, br, I, OH, NH 2 、Me、Et、-CF 3 、CN、COOH、
6. According to any one of claims 1 to 5The compound of formula (I), a pharmaceutically acceptable salt thereof, or a tautomer thereof, wherein R 1 、R 2 Each independently selected from H, F, cl, br, I, OH, CN, NH 2 COOH, -Me and Et.
7. The compound of formula (I), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to any one of claims 1 to 5, wherein L is selected from-C (= O) -, or-C optionally substituted with 1,2, or 3R 1-3 Alkyl-, -phenyl-, -5-to 6-membered heteroaryl-, -5-to 6-membered heterocycloalkyl-and-C 3-6 Cycloalkyl-.
8. A compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 7, wherein L is selected from-C (= O) -, or-1, 2, 4-oxadiazolyl-, -methylene-, -ethyl-, -1,3, 4-oxadiazolyl-, -isoxazolyl-, -oxazolyl-, -piperidinyl-, -1,2, 3-triazolyl-, -cyclopropylalkyl-, and-phenyl-optionally substituted with 1,2, or 3R.
9. The compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 8, wherein L is selected from-C (= O) -, or optionally substituted with 1,2, or 3R
10. The compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 9, wherein L is selected from the group consisting of
11. According to any of claims 1 to 5A compound of the formula (I), a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein R 5 Selected from phenyl, pyridyl, piperidyl, pyrrolidinyl, azetidinyl, cyclohexyl, cyclobutyl, benzo [ d ] optionally substituted by 1,2 or 3R][1,3]Dioxolyl, piperidinyl-2-keto, 7-azaspiro [3.5 ]]Nonyl, cyclohexyl-CH 2 -, 3a, 7a-dihydro-1H-indolyl, pyrazolyl, pyridinyl, 3a, 7a-dihydrobenzo [ d ] or]Thiazolyl, pyrimidinyl, cyclopentylalkyl, spiro [3.3 ]]Heptenyl, bicyclo [2.2.2]Octyl radical, octahydrocyclopenta [ c ]]Pyrrolyl, 2-azaspiro [3.5 ]]Nonanyl, piperidinyl-C (= O) -, 4,5,6, 7-tetrahydro-1H-benzo [ d ]]Imidazolyl, 5,6,7, 8-tetrahydroimidazo [1,2-a ]]Pyridyl, piperidyl-CH 2 -, bicyclo [1.1.1]Pentyl and piperazinyl.
12. The compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 11, wherein R 5 Selected from optionally substituted by 1,2 or 3R
13. The compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 12, wherein R is 5 Is selected from
14. The compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 9, wherein-L-R 5 Selected from optionally substituted by 1,2 or 3R
15. A compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof, according to claim 14, wherein-L-R 5 Selected from:
16. the compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to any one of claims 1 to 5, wherein R 3 is-L-R 5 Or selected from optionally substituted with 1,2 or 3R: phenyl, pyrrolidinyl, 1H-imidazolyl, 1H-1,2, 4-triazolyl, pyridyl, thiazolyl, thienyl, pyrrolyl, 2H-tetrazolyl, 6, 7-dihydro-5H-pyrrolo [1,2-a ]]Imidazolyl, imidazo [1,5-a ]]Pyridyl, oxazolyl, benzo [ d ]]Isoxazolyl, benzo [ d ]]Oxazolyl, 1,2,3,4-4H-2, 7-naphthyridinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 2,3,4, 5-tetrahydro-1H-benzo [ d]Azepine group, azetidinyl group, isoindolinyl group, piperidyl group, 2,3,4, 5-tetrahydro-1H-benzo [ b ]]Azepinyl, 2, 3-dihydro-1H-pyrrolo [3, 4-c)]Pyridyl, benzisoxazolyl, 5,6,7, 8-tetrahydropyridopyrimidinyl, 3a, 7a-dihydrobenzo [ d]Thiazolyl, 2,4,5, 6-tetrahydropyrrolo [3,4-c ]]Pyrazolyl, 1,4,5, 6-tetrahydropyrrolo [3,4-c ]]Pyrazolyl, piperazinyl, morpholinyl, octahydropyrrolo [3, 4-c)]Pyrrolyl, 1, 4-diazepinyl, cyclohexyl, 1,2, 4-oxadiazolyl.
17. The compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 16, wherein R 3 is-L-R 5 Or selected from optionally substituted with 1, 2 or 3R:
18. the compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 15, wherein R 3 Selected from the group consisting of:
19. the compound of formula (I), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to any one of claims 1 to 5, wherein R is 4 Selected from H, or selected from C optionally substituted with 1, 2 or 3R 1-3 Alkyl and C 1-4 alkyl-O-C (= O) -.
20. The compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 19, wherein R is 4 Selected from H, me, et and
21. the compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to any one of claims 1 to 5, wherein R 6 Selected from H, or selected from C optionally substituted with 1, 2 or 3R 1-3 Alkyl and C 1-4 alkyl-O-C (= O) -.
22. The compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to claim 21, wherein R is 6 Selected from H, me, et and
23. The compound of formula (I), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to any one of claims 1 to 5, wherein the structural unitIs selected from
24. A compound of formula (i) according to claim 23, which isA pharmaceutically acceptable salt or tautomer thereof, wherein the structural unitsIs selected from
25. A compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to any one of claims 1 to 5, selected from the group consisting of:
wherein the content of the first and second substances,
e. f, m and n are as defined in claim 1;
r is as defined in any one of claims 1, 3 to 5;
R 5 as defined in claim 1;
q 1 、q 2 each independently selected from: 1 or 2.
26. A compound of the formula, a pharmaceutically acceptable salt thereof, or a tautomer thereof, selected from the group consisting of:
27. a pharmaceutical composition comprising as an active ingredient a therapeutically effective amount of a compound of formula (i), a pharmaceutically acceptable salt thereof or a tautomer thereof according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt thereof, or a tautomer thereof, and cisplatin,
the compound is selected from:
Wherein, the first and the second end of the pipe are connected with each other,
f is 1;
e is 0;
m is 0,1 or 2;
n is 1 or 2;
R 5 is selected from C optionally substituted by 1, 2 or 3R 3-10 Cycloalkyl, R is selected from NH 2 and-COOH.
29. The pharmaceutical composition of claim 28, wherein said compound is selected from the group consisting of:
30. use of a compound of formula (i), a pharmaceutically acceptable salt thereof, or a tautomer thereof according to any one of claims 1-26, or a composition according to claim 27 or 28, for the manufacture of a medicament for the treatment of a LSD 1-associated disorder.
31. The use according to claim 30, wherein the LSD 1-associated disorder is lung cancer.
32. The use of claim 30, wherein the LSD 1-associated disorder is small cell lung cancer.
33. The use of claim 30, wherein the use of the compound, the pharmaceutically acceptable salt thereof, or the tautomer or the pharmaceutical composition for the preparation of a medicament for the treatment of small cell lung cancer,
the compound is selected from:
the pharmaceutical composition comprises the following compounds and cisplatin:
HK19131105.9A 2017-01-24 2018-01-24 Lsd1 inhibitor and preparation method and application thereof HK40007681B (en)

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