Patent Application
20210155612
The present patent application claims priority to Japanese Patent Application No. 2017-123231 filed on Jun. 23, 2017, the entire disclosure of which is incorporated herein by reference.
The present invention relates to an α,β-unsaturated amide compound or a pharmaceutically acceptable salt or the like thereof having anticancer activity and the like.
Mesothelioma is the general term for tumors derived from mesothelial cells, wherein the sites of occurrence are mainly pleura, peritoneum and pericardium. Although there are malignant and benign types, malignant mesothelioma is associated with poor prognosis and a 5-year survival rate of 10% or less. Therefore, the establishment of its treatment modality is strongly desired.
Most mesothelioma occurring in pleura and peritoneum is caused by exposure to asbestos, and it is known that the average incubation period of mesothelioma is 40 years or more (Annals of Oncology, 2015, 26, 1649-1660). Furthermore, mesothelioma is often treatment-resistant and has low response to surgical remedy, radiotherapy or chemotherapy. For chemotherapy, a combination therapy of cisplatin and pemetrexed is used (Journal of Clinical Oncology, 2003, 21, 2636-2644), but the mean survival time is only approximately 12 months.
Lung cancer is defined as canceration of part of cells belonging to trachea, bronchi, or alveoli of lung for some reason. Early detection is difficult, and the 5-year survival rate is 15% or less with poor prognosis (OncoTargets and Therapy, 2016, 9, 1023-1028). The establishment of a further treatment modality is desired.
Ovarian cancer occurs in ovaries which sit at both sides of the uterus, and there is a great variety of types of ovarian cancers such as epithelial, germ cell or sex cord-stromal tumor depending on the site of occurrence. However, 90% or more of ovarian cancer cases are epithelial tumors. The 5-year survival rate is 45% or less. It is reported that there are 15,000 fatal cases among ovarian cancers each year in the world (Best Practice & Research Clinical Obstetrics and Gynaecology, 2016, S1521-6934, 30091-30098). The establishment of a treatment modality is desired.
Liver cancer is classified roughly into two types: primary liver cancer and metastatic liver cancer that has metastasized from other organs. Primary liver cancer is classified as hepatoma and cholangioma. Most primary liver cancer is hepatoma. Primary liver cancer has a poor-prognosis, and it has been reported that the 5-year survival rate is 12 to 28% for hepatoma and, 25 to 40% for cholangioma (Journal of Gastrointestinal surgery, 2014, 18, 2136-2148). There are many cases of recurrence and the disease is resistant to systemic chemotherapy. Therefore, the establishment of a further treatment modality is desired.
As α,β-unsaturated amide compounds, known are, for example, an α,β-unsaturated amide compound having a phenyl group substituted with an aryloxy group as a melatonin receptor agonist (refer to patent document 1), an α,β-unsaturated amide compound having a phenyl group substituted with an aryloxy group as a synthetic rubber component (refer to patent document 2), an α,β-unsaturated amide compound having a phenyl group substituted with a heteroarylamino group as a protein kinase inhibitor (refer to patent document 3), an α,β-unsaturated amide compound having a phenyl group substituted with a heteroarylthio group as a Heat shock protein 70 inhibitor (refer to patent document 4), an α,β-unsaturated amide compound having a pyridyl group substituted with an aryloxy group as a sodium-potassium exchanger inhibitor (refer to non-patent document 1), an α,β-unsaturated amide compound having a quinolyl group substituted with an anilino group as an epidermal growth factor receptor inhibitor (refer to patent document 5), an α,β-unsaturated amide compound having a 3-cyanoquinolyl group as a tyrosine kinase inhibitor (refer to patent document 6), an α,β-unsaturated amide compound having an aminopyrimidyl group as an epidermal growth factor receptor inhibitor (refer to patent document 7), an α,β-unsaturated amide compound having a benzimidazolyl group as an ion channel modulator (refer to patent document 8), and an α,β-unsaturated amide compound having a 2,3-dihydrobenzo furyl group as a therapeutic drug for hepatic disease (refer to patent document 9) and the like.
An object of the present invention is to provide an α,β-unsaturated amide compound or a pharmaceutically acceptable salt or the like thereof having anticancer activity and the like.
The present invention relates to the following clauses (1) to (36).
[wherein,
“A” represents optionally substituted heterocyclic diyl,
R1 represents hydrogen atom or optionally substituted lower alkyl,
R2 represents optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aliphatic heterocyclic group or optionally substituted aromatic heterocyclic group,
X represents —O—, —S—, —SO2—, —NRX1— (wherein, RX1 represents hydrogen atom or lower alkyl), —CHRX2— (wherein, RX2 represents hydrogen atom or hydroxy), —CH═CH—, —CO— or —NH—CO—, and
n1 and n2 are the same or different, and each represents 0 or 1].
{wherein, —[X] represents bonding position of the group represented in formula (A-1):
(wherein, X, R2 and n2 are each the same as the definition described in clause (1))
-[ACP] represents bonding position of the group represented in formula (A-2):
(wherein, R1 and n1 are each the same as the definition described in clause (1))}.
(wherein, —[X] and -[ACP] are each the same as the definition described in clause (4)).
(wherein, —[X] and -[ACP] are each the same as the definitions described in clause (4)).
(wherein, —[X] and -[ACP] are each the same as the definition described in clause (4)).
(wherein, —[X] and -[ACP] are each the same as the definition described in clause (4)).
(wherein, —[X] and -[ACP] are each the same as the definition described in clause (4)).
(wherein, —[X] and -[ACP] are each the same as the definition described in clause (4)).
The present invention provides an α,β-unsaturated amide compound or a pharmaceutically acceptable salt thereof or the like thereof having anticancer activity and the like.
According to the present invention, an 0,13-unsaturated amide compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof is provided:
[wherein,
“A” represents optionally substituted heterocyclic diyl,
R1 represents hydrogen atom or optionally substituted lower alkyl,
R2 represents optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aliphatic heterocyclic group or optionally substituted aromatic heterocyclic group,
X represents —O—, —S—, —SO2—, —NRX1— (wherein, RX1 represents hydrogen atom or lower alkyl), —CHRX2— (wherein, RX2 represents hydrogen atom or hydroxy), —CH═CH—, —CO— or —NH—CO—, and
n1 and n2 are the same or different, and each represents 0 or 1].
A compound represented by general formula (I) is hereinafter referred to as compound (I). The same applies to a compound of other formula number.
In the above general formula (I), “A” represents optionally substituted heterocyclic diyl.
A heterocyclic diyl group includes, for example, a group formed by removing one hydrogen atom from the group exemplified in the aliphatic heterocyclic group and the aromatic heterocyclic group in R2 mentioned below, and more specifically aziridinediyl, azetidinediyl, pyrrolidinediyl, piperidinediyl, azepanediyl, 1,2,5,6-tetrahydropyridinediyl, imidazolidinediyl, pyrazolidinediyl, piperazinediyl, homopiperazinediyl, pyrazolinediyl, oxiranediyl, tetrahydrofurandiyl, tetrahydro-2H-pyrandiyl, 5,6-dihydro-2H-pyrandiyl, oxazolidinediyl, morpholinediyl, thioxazolidinediyl, thiomorpholinediyl, 2H-oxazolediyl, 2H-thioxazolediyl, dihydroindolediyl, dihydroisoindolediyl, dihydrobenzofurandiyl, benzimidazolinediyl, dihydrobenzoxazolediyl, dihydrobenzothioxazolediyl, benzodioxolediyl, 1,2,3,4-tetrahydroquinolinediyl, 5,6,7,8-tetrahydroquinolinediyl, 1,2,3,4-tetrahydroisoquinolinediyl, chromanediyl, isochromanediyl, coumarinediyl, isocoumarinediyl, 1,2,3,4-tetrahydroquinoxalinediyl, 5,6,7,8-tetrahydroquinoxalinediyl, 5,6,7,8-tetrahydroquinazolinediyl, benzodioxanediyl, furandiyl, thiophenediyl, pyrrolediyl, imidazolediyl, pyrazolediyl, oxazolediyl, isoxazolediyl, oxadiazolediyl, thiazolediyl, isothiazolediyl, thiadiazolediyl, triazolediyl, tetrazolediyl, pyridinediyl, pyridazinediyl, pyrimidinediyl, pyrazinediyl, triazinediyl, benzofurandiyl, benzothiophenediyl, benzoxazolediyl, benzothiazolediyl, isoindoledlyl, indolediyl, indazoledlyl, benzimidazolediyl, benzotriazolediyl, oxazolopyrimidinediyl, thiazolopyrimidinediyl, pyrrolopyridinediyl, pyrrolopyrimidinediyl imidazopyridinediyl purinediyl quinolinediyl isoquinolinediyl cinnolinediyl phthalazinediyl quinazolinediyl, quinoxalinediyl, naphthyridinediyl, and the like. The one hydrogen atom removed may be any hydrogen atom on the aliphatic heterocyclic group or the aromatic heterocyclic group.
According to a preferred embodiment of the present invention, the heterocyclic diyl is heterocyclic diyl selected from the group consisting of benzoxazolediyl, benzothiazolediyl, 2,3-dihydrobenzothiophenediyl, 3,4-dihydropyranopyridinediyl, 2,3,4,5-tetrahydrobenzoxazepinediyl, 2,3,4,5-tetrahydrobenzoxepinediyl and 2,3-dihydrobenzofurandiyl.
According to a preferred embodiment of the present invention, the heterocyclic diyl is benzoxazolediyl.
According to a preferred embodiment of the present invention, the benzoxazolediyl is benzoxazolediyl selected from the group consisting of the following formulae (A1-1), (A1-2), (A1-3), and (A1-4):
{wherein, —[X] represents bonding position of the group represented in formula (A-1):
(wherein, X, R2 and n2 are each the same as the definition described above)
-[ACP] represents bonding position of the group represented in formula (A-2):
(wherein, R1 and n1 are each the same as the definition described above)}.
According to a preferred embodiment of the present invention, the heterocyclic diyl is benzothiazolediyl.
According to a preferred embodiment of the present invention, the benzothiazolediyl is benzothiazolediyl represented by the following formula (A2-1) or (A2-2):
(wherein, —[X] and -[ACP] are each the same as the definition described above).
According to a preferred embodiment of the present invention, the heterocyclic diyl is 2,3-dihydrobenzothiophenediyl.
According to a preferred embodiment of the present invention, the 2,3-dihydrobenzothiophenediyl is 2,3-dihydrobenzothiophenediyl represented by the following formula (A4-1):
(wherein, —[X] and -[ACP] are each the same as the definitions described above).
According to a preferred embodiment of the present invention, the heterocyclic diyl is 3,4-dihydropyranopyridinediyl.
According to a preferred embodiment of the present invention, the 3,4-dihydropyranopyridinediyl is 3,4-dihydropyranopyridinediyl represented by the following formula (A5-1):
(wherein, —[X] and -[ACP] are each the same as the definition described above).
According to a preferred embodiment of the present invention, the heterocyclic diyl is 2,3,4,5-tetrahydrobenzoxazepinediyl.
According to a preferred embodiment of the present invention, the 2,3,4,5-tetrahydrobenzoxazepinediyl is 2,3,4,5-tetrahydrobenzoxazepinediyl represented by the following formula (A6-1):
(wherein, —[X] and -[ACP] are each the same as the definition described above).
According to a preferred embodiment of the present invention, the heterocyclic diyl is 2,3,4,5-tetrahydrobenzoxepinediyl.
According to a preferred embodiment of the present invention, the 2,3,4,5-tetrahydrobenzoxepinediyl is 2,3,4,5-tetrahydrobenzoxepinediyl represented by the following formula (A7-1):
(wherein, —[X] and -[ACP] are each the same as the definition described above).
According to a preferred embodiment of the present invention, the heterocyclic diyl is 2,3-dihydrobenzofurandiyl.
According to a preferred embodiment of the present invention, the 2,3-dihydrobenzofurandiyl is 2,3-dihydrobenzofurandiyl selected from the group consisting of the following formulae (A8-1), (A8-2) and (A8-3):
(wherein, —[X] and -[ACP] are each the same as the definition described above).
In general formula (I) mentioned above, R1 represents hydrogen atom or optionally substituted lower alkyl, and is preferably hydrogen atom.
Lower alkyl in the present description includes, for example, straight or branched chain alkyl having 1-10 carbon atoms and more specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
In general formula (I) mentioned above, R2 represents optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aliphatic heterocyclic group or optionally substituted aromatic heterocyclic group, and preferably optionally substituted aryl or optionally substituted aromatic heterocyclic group.
Aryl in the present description includes, for example, aryl having 6-14 carbon atoms, and more specifically includes phenyl, naphthyl, azulenyl, and anthryl and the like.
Aryl in R2 is preferably phenyl.
Cycloalkyl in the present description includes, for example, cycloalkyl having 3-10 carbon atoms, and more specifically includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecanyl and the like.
Aliphatic heterocyclic group in the present description includes, for example, 5- or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from nitrogen atom, oxygen atom, and sulfur atom, and ring-fused aliphatic heterocyclic group and the like formed by fusing 3- to 8-membered rings in a bicyclic or tricyclic ring and containing at least one atom selected from nitrogen atom, oxygen atom, and sulfur atom; and more specifically includes aziridinyl, azetidinyl, pyrrolidinyl, piperidine, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxanyl, 5,6-dihydro-2H-pyranyl, oxazolidinyl, morpholine, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzodioxolyl, 1,2,3,4-tetrahydroquinolyl, 5,6,7,8-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, chromanyl, isochromanyl, 2H-chromenyl, 4H-chromenyl, 1,2,3,4-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinazolinyl, and benzodioxanyl and the like.
Aromatic heterocyclic group in the present description includes, for example, 5- or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from nitrogen atom, oxygen atom, and sulfur atom, and ring-fused aromatic heterocyclic group and the like formed by fusing 3- to 8-membered rings in a bicyclic or tricyclic ring and containing at least one atom selected from nitrogen atom, oxygen atom and sulfur atom, and more specifically includes furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and the like.
Substituents in the optionally substituted lower alkyl are the same or different, and each include, for example, with the number of substitution of 1-3, a substituent selected from the group consisting of halogen, hydroxy, mercapto, nitro, cyano, carboxy, carbamoyl, C3-10 cycloalkyl, C6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, C1-10 alkoxy, C3-10 cycloalkoxy, C6-14 aryloxy, C7-16 aralkyloxy, C2-11 alkanoyloxy, C7-15 aroyloxy, C1-10 alkylthio, —NRXRY (wherein, RX and RY are the same or different and each represent hydrogen atom, C1-10 alkyl, C3-10 cycloalkyl, C6-14 aryl, aromatic heterocyclic group, C7-16 aralkyl, C2-11 alkanoyl, C7-15 aroyl, C1-10 alkoxycarbonyl or C7-16 aralkyloxycarbonyl), C2-11 alkanoyl, C7-15 aroyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C1-10 alkylcarbamoyl, and di-C1-10 alkylcarbamoyl.
Substituents in the optionally substituted aryl and the optionally substituted aromatic heterocyclic group are the same or different, and each include, for example, with the number of substitution of 1-3, a substituent selected from the group consisting of halogen, hydroxy, mercapto, nitro, cyano, carboxy, carbamoyl, optionally substituted C1-10 alkyl (substituents in the optionally substituted C1-10 alkyl are the same or different, and each include, for example, halogen with the number of substitution of 1-3 and the like), C2-10 alkenyl, C2-10 alkynyl, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyl, trifluoromethanesulfonyloxy, C3-10 cycloalkyl, C6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, optionally substituted C1-10 alkoxy (substituents in the optionally substituted C1-10 alkoxy are the same or different, and each include, for example, halogen with the number of substitution of 1-3 and the like), C3-10 cycloalkoxy, C6-14 aryloxy, C7-16 aralkyloxy, C2-11 alkanoyloxy, C7-15 aroyloxy, C1-10 alkylthio optionally substituted (substituents in the C1-10 alkylthio optionally substituted are the same or different, and each include, for example, halogen with the number of substitution of 1-3), —NRXaRYa (wherein, RXa and RYa are the same or different, and each represent hydrogen atom, C1-10 alkyl, cycloalkyl, C6-14 aryl, aromatic heterocyclic group, C7-16 aralkyl, C2-11 alkanoyl, C7-15 aroyl, C1-10 alkoxycarbonyl or C7-16 aralkyloxycarbonyl), C2-11 alkanoyl, C7-15 aroyl, alkoxycarbonyl, C6-14 aryloxycarbonyl, C1-10 alkylcarbamoyl, and di-C1-10 alkylcarbamoyl.
Substituents in the optionally substituted cycloalkyl and the optionally substituted aliphatic heterocyclic group are the same or different, and each include, for example, with the number of substitution of 1-3, a substituent selected from the group consisting of oxo, halogen (preferably fluorine atom), hydroxy, mercapto, nitro, cyano, carboxy, carbamoyl, C1-10 alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, C3-10 cycloalkyl, C6-14 aryl, optionally substituted aliphatic heterocyclic group (substituents in the optionally substituted aliphatic heterocyclic group are the same or different, and include, for example, halogen with the number of substitution of 1-3 and the like), aromatic heterocyclic group, C1-10 alkoxy, C3-10 cycloalkoxy, C6-14 aryloxy, C7-16 aralkyloxy, C2-11 alkanoyloxy, C7-15 aroyloxy, C1-10 alkylthio, —NRXbRYb (wherein, RXb and RYb are the same or different, and each represent hydrogen atom, C1-10 alkyl, C3-10 cycloalkyl, C6-14 aryl, aromatic heterocyclic group, C7-16 aralkyl, C2-11 alkanoyl, C7-15 aroyl, C1-10 alkoxycarbonyl or C7-16 aralkyloxycarbonyl), C2-11 alkanoyl, C7-15 aroyl, C1-10 alkoxycarbonyl, C6-14 aryloxy carbonyl, C1-10 alkylcarbamoyl and di-C1-10 alkylcarbamoyl.
Substituents in the optionally substituted heterocyclic diyl are the same or different, and each include, for example, with the number of substitution of 1 -3, a substituent selected from the group consisting of halogen (preferably chlorine atom, fluorine atom or bromine atom), hydroxy, mercapto, nitro, cyano, carboxy, carbamoyl, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, trifluoromethyl, p-toluenesulfonyloxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, C3-10 cycloalkyl, C6-14 aryl, optionally substituted aliphatic heterocyclic group (substituents in the optionally substituted aliphatic heterocyclic group are the same or different, and each include, for example, halogen with the number of substitution of 1-3 and the like), aromatic heterocyclic group, optionally substituted C1-10 alkoxy (substituents in the optionally substituted C1-10 alkoxy are the same or different, and each include, for example, halogen with the number of substitution of 1-3 and the like), C3-10 cycloalkoxy, C6-14 aryloxy, C7-16 aralkyloxy, C2-11 alkanoyloxy, C7-15 aroyloxy, C1-10 alkylthio, —NRXcRYc (wherein, RXc and RYc are the same or different, and each represent hydrogen atom, optionally substituted C1-10 alkyl (substituents in the optionally substituted C1-10 alkyl are the same or different, and each include for example, with the number of substitution of 1-3, C1-10 alkylamino, and di-C1-10 alkylamino and the like), C3-10 cycloalkyl, C6-14 aryl, aromatic heterocyclic group, C7-16 aralkyl, C2-11 alkanoyl, C7-15 aroyl, C1-10 alkoxycarbonyl or C7-16 aralkyloxycarbonyl), C2-11 alkanoyl, C7-15 aroyl, C1-10 alkoxycarbonyl, C6-14 aryloxy carbonyl, C1-10 alkylcarbamoyl, and di-C1-10 alkylcarbamoyl.
In general formula (I) mentioned above, X represents —O—, —S—, —SO2—, —NRX1— (wherein, RX1 represents hydrogen atom or lower alkyl), —CHRX2— (wherein, RX2 represents hydrogen atom or hydroxy), —CH═CH—, —CO— or —NH—CO—, preferably —O—, —S—, —NX1— (wherein, RX1 represents hydrogen atom or lower alkyl), —CHRX2— (wherein, RX2 represents hydrogen atom), —CH═CH— or —CO. According to a preferred embodiment of the present invention, X is —O—.
In general formula (I) mentioned above, n1 and n2 are the same or different, and each represent 0 or 1. According to a preferred embodiment of the present invention, n2 is 0.
When substituents in the optionally substituted heterocyclic diyl are bonded to an sp3 carbon constituting the heterocyclic diyl, the above substituent may be, for example, substituted with oxo with the number of substitution of 1-3. Here, the sp3 carbon refers to a carbon atom forming an sp3 hybrid orbit. In the present description, a sp2 carbon also similarly refers to a carbon atom forming sp2 hybrid orbit.
Alkyl moieties of C1-3 alkyl and C1-10 alkyl, C1-3 alkoxy, C1-5 alkoxy, C2-11 alkanoyloxy, C1-3 alkylthio, C1-10 alkylthio, C2-11 alkanoyl, C1-10 alkoxycarbonyl, C1-10 alkylamino, di-C1-3 alkylamino, di-C1-10 alkylamino, C1-10 alkylcarbamoyl, and di-C1-10 alkylcarbamoyl, as shown here, are exemplified, for example, by the groups given in the above lower alkyl examples. Two alkyl moieties in di-C1-3 alkylamino, di-C1-10 alkylamino, and di-C1-10 alkylcarbamoyl may be the same or different.
C3-5 cycloalkyl and C3-10 cycloalkyl and cycloalkyl moieties of C3-10 cycloalkoxy are exemplified, for example, by the groups given in the above cycloalkyl examples.
C6-14 aryl and aryl moieties of C6-14 aryloxy, C7-15 aroyl, C7-15 aroyloxy and C6-14 aryloxycarbonyl are exemplified by the groups given in the above aryl examples.
Aryl moieties of C7-9 aralkyloxy, C7-16 aralkyloxy, C7-16 aralkyl, and C7-16 aralkyloxycarbonyl are exemplified by the groups given in the above aryl examples. Alkyl moiety thereof include, for example, C1-10 alkylene, and more specifically a group formed by removing one hydrogen atom from the groups given in the above lower alkyl examples.
C2-10 alkenyl represents, for example, straight or branched chain alkenyl having 2-10 carbon atoms, and more specifically includes vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl and the like.
In the present description, C2-10 alkynyl represents, for example, straight or branched chain alkynyl having 2-10 carbon atoms, and more specifically includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl and the like.
In the present description, aliphatic heterocyclic group and aromatic heterocyclic group are the same as defined above, respectively.
In the present description, halogen means fluorine, chlorine, bromine or iodine atom.
According to a preferred embodiment of the compound (compound (I)) represented by general formula (I), in the above formula (I),
“A” represents optionally substituted heterocyclic diyl, wherein the heterocyclic diyl is heterocyclic diyl selected from the group consisting of benzoxazolediyl, benzothiazolediyl, and 2,3-dihydrobenzofurandiyl,
the heterocyclic diyl is optionally substituted with the number of substitution of 1 or 2 (preferably the number of substitution of 1), with halogen (preferably chlorine atom, fluorine atom or bromine atom), trifluoromethyl, C1-3 alkyl, or phenyl,
R1 represents hydrogen atom or optionally substituted C1-3 alkyl (preferably hydrogen atom or trifluoromethyl),
R2 represents optionally substituted aryl (preferably phenyl), optionally substituted aromatic heterocyclic group (preferably pyridyl), or C3-C10 cycloalkyl (preferably cyclohexyl),
wherein,
the aryl in R2 is optionally substituted with the number of substitution of 1 or 2, with halogen (preferably chlorine atom or fluorine atom), cyano, trifluoromethyl, C1-5 alkoxy (preferably methoxy), or —NRXaRYa (wherein, RXa and RYa are the same or different and represent C1-3 alkyl) (preferably dimethylamine),
the aromatic heterocyclic group in R2 is optionally substituted with the number of substitution of 1, with trifluoromethyl,
X represents —O—, —S—, —SO2—, —NRX1— (wherein, RX1 represents hydrogen atom or C1-3 alkyl), —CHRX2— (wherein, RX2 represents hydrogen atom or hydroxy), —CH═CH— or —NH—CO—, and
n1 and n2 are the same or different and each represent 0 or 1.
According to a more preferred embodiment of the compound (compound (I)) represented by general formula (I), in the above formula (I),
“A” represents optionally substituted benzoxazolediyl, the heterocyclic diyl is optionally substituted with the number of substitution of 1 or 2 (preferably the number of substitution of 1), with trifluoromethyl, C1-3 alkyl, or phenyl,
R1 represents hydrogen atom or optionally substituted C1-3 alkyl (preferably hydrogen atom),
R2 represents optionally substituted aryl (preferably phenyl), optionally substituted aromatic heterocyclic group (preferably pyridyl), or C3-C10 cycloalkyl (preferably cyclohexyl),
wherein,
the aryl in R2 is optionally substituted with the number of substitution of 1 or 2, with halogen (preferably chlorine atom or fluorine atom), cyano, trifluoromethyl, C1-5 alkoxy (preferably methoxy), or —NRXaRYa (wherein, RXa and RYa are the same or different and represent C1-3 alkyl) (preferably dimethylamine),
the aromatic heterocyclic group in R2 is optionally substituted with the number of substitution of 1, with trifluoromethyl,
X represents —O—, —S—, —SO2—, —NRX1— (wherein, RX1 represents hydrogen atom or lower alkyl), —CHRX2— (wherein, RX2 represents hydrogen atom or hydroxy), —CH═CH— or —NH—CO—, and
n1 and n2 are the same or different and each represent 0 or 1.
According to a further preferred embodiment of the compound (compound (I)) represented by general formula (I), in the above formula (I),
“A” represents optionally substituted benzoxazolediyl, the heterocyclic diyl is optionally substituted with the number of substitution of 1, with trifluoromethyl, C1-3 alkyl, or phenyl,
R1 represents hydrogen atom,
R2 represents optionally substituted phenyl, or optionally substituted pyridyl,
wherein,
the phenyl in R2 is optionally substituted with the number of substitution of 1 or 2, with halogen (preferably chlorine atom or fluorine atom), cyano, trifluoromethyl, C1-5 alkoxy (preferably methoxy), or—NRXaRYa (wherein, RXa and RYa are the same or different and represent C1-3 alkyl) (preferably dimethylamine),
the pyridyl in R2 is optionally substituted with the number of substitution of 1, with trifluoromethyl,
X represents —O—, —S—, —SO2—, —NRX1— (wherein, RX1 represents hydrogen atom or lower alkyl), —CHRX2— (wherein, RX2 represents hydrogen atom or hydroxy) or —CH═CH—(preferably X represents —O—, —S—, (wherein, RX1 represents hydrogen atom or lower alkyl), or —CHRX2— (wherein, RX2 represents hydroxy)), and
n1 and n2 are the same or different and each represent 0 or 1.
According to another more preferred embodiment of the compound (compound (I)) represented by general formula (I), in the above formula (I),
“A” represents optionally substituted benzothiazolediyl,
the heterocyclic diyl is optionally substituted with the number of substitution of 1 or 2 (preferably the number of substitution of 1), with C1-3 alkyl,
R1 represents hydrogen atom,
R2 represents optionally substituted aryl (preferably phenyl), or optionally substituted aromatic heterocyclic group (preferably pyridyl),
wherein,
the aryl in R2 is optionally substituted with the number of substitution of 1, with trifluoromethyl,
the aromatic heterocyclic group in R2 is optionally substituted with the number of substitution of 1, with trifluoromethyl,
X represents —O—, and
n1 represents 1 and n2 represents 0.
According to another more preferred embodiment of the compound (compound (I)) represented by general formula (I), in the above formula (I),
“A” represents optionally substituted 2,3-dihydrobenzofurandiyl (here, 2,3-dihydrobenzofurandiyl is preferably represented by above formula (A8-1)),
the heterocyclic diyl is optionally substituted with the number of substitution of 1 or 2 (preferably the number of substitution of 1), with halogen (preferably bromine atom) or C1-3 alkyl,
R1 represents hydrogen atom,
R2 represents optionally substituted aryl (preferably phenyl),
wherein,
the aryl in R2 is optionally substituted with the number of substitution of 1, with trifluoromethyl,
X represents —O—, and
n1 represents 0 and n2 represents 0.
The pharmaceutically acceptable salt of compound (I) includes, for example, pharmaceutically acceptable acid addition salt, metal salt, ammonium salt, organic amine addition salt, and amino acid addition salt and the like. Pharmaceutically acceptable acid addition salt of compound (I) includes, for example, inorganic acid salt such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate and the like, and organic acid salt such as acetate, oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate and the like; pharmaceutically acceptable metal salt includes, for example, alkali metal salt such as sodium salt and potassium salt and the like, and alkali earth metal salt such as magnesium salt, and calcium salt and the like, aluminum salt, and zinc salt and the like; pharmaceutically acceptable ammonium salt include, for example, salt of such as ammonium and tetramethylammonium and the like; pharmaceutically acceptable organic amine addition salt includes, for example, addition salt of such as morpholine and piperidine and the like; pharmaceutically acceptable amino acid addition salt includes, for example, addition salt of such as lysine, glycine, phenylalanine, aspartic acid, and glutaminic acid and the like.
The wavy line between R1 and the carbon atom adjacent to R1 in compound (I) indicates a cis- or trans-configuration.
The compound of the present invention involves a compound having preferred properties on one or more evaluation items required for a pharmaceutical composition, or a prophylactic or therapeutic agent for cancer such as pharmacological activity, physical stability, stability under physiological conditions, safety for living body, and the like.
Next, manufacturing methods of compound (I) will be explained.
For the manufacturing method described below, when the defined groups are altered under the conditions of the manufacturing method or the method is not appropriate to conduct, target compounds can be manufactured by using a method of introducing or removing a protecting group commonly used in synthetic organic chemistry [e.g., a method described in Protective Groups in Organic Synthesis, third edition by T. W. Greene, John Wiley & Sons Inc. (1999), and the like] and the like. Furthermore, the order of the reaction steps such as the introduction of substituents and the like can be changed as needed.
The compounds (I) can be manufactured according to the following steps.
In manufacturing method 10, among compounds (II) that are precursors of compounds (I), compounds (II-a), (II-b) and (II-c) as 4-aminochromane derivatives and compound (II-d) as a 4-aminomethylchromane derivative can be manufactured according to the following steps:
(wherein R2 and n2 are the same as the definition described above; R2A represents optionally substituted aryl or optionally substituted aromatic heterocyclic group in R2; R3 represents lower alkyl; R4 represents lower alkyl, fluorine atom, chlorine atom, bromine atom or iodine atom; R5 represents the substituent mentioned above as the substituent of optionally substituted heterocyclic diyl or hydrogen atom; E1 represents CRaRb (wherein Ra and Rb are the same or different, and each represents the substituent mentioned above as the substituent of optionally substituted heterocyclic diyl or hydrogen atom); X1 and X2 are the same or different, and each represents a leaving group such as chlorine atom, bromine atom, iodine atom, p-toluenesulfonyloxy, methanesulfonyloxy, or trifluoromethanesulfonyloxy or the like; and M1 represents MgI, MgBr, MgCl, Li, and the like).
Compound (III-b) can be manufactured by reacting compound (III-a) in a solvent with an ammonia source preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a reducing agent preferably in 1 to 10 equivalent amount, an acid preferably in 1 to 10 equivalent amount, and if needed, a metallic catalyst preferably in 0.01 to 1 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (III-a) can be obtained as a commercially available product, or by well-known methods (e.g., WO2015/051447, WO2001/18006, WO1998/13356, Bioorganic & Medicinal Chemistry, 2007, 17, 1288-1290, and the like) or their equivalent methods.
The ammonia sources include, for example, ammoniacal water, ammonium formate, and ammonium acetate and the like.
The reducing agents include, for example, sodium triacetoxyborohydride, and sodium cyanoborohydride and the like.
The acids include, for example, hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid and the like.
The metallic catalysts include, for example, dichloro(pentamethylcyclopentadienyl)rhodium(III), and chloro[N-{4-(dimethylamino)phenyl}-2-pyridine carboxyamidate](pentamethylcyclopentadienyl)iridium(III) and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane (DME), 1,4-dioxane, N,N-dimethylformamide (DMF), N,N-dimethyl acetamide (DMA), N-methyl-2-pyrrolidone (NMP), and water and the like. They are used alone or in mixtures.
Compound (II-a), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured by reacting compound (III-b) in a solvent with compound (a-3) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a copper reagent in preferably 0.01 to 1 equivalent amount, a ligand in preferably 0.01 to 1 equivalent amount, and a base in preferably 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (a-3) can be obtained as a commercially available product.
The copper reagents include, for example, copper(0), copper(I) iodide, copper(II) acetate, copper(II) oxide, and copper(I) chloride and the like.
The ligands include, for example, phenanthroline, trans-1,2-cyclohexanediamine, and picolinic acid and the like.
The bases include, for example, potassium carbonate, cesium carbonate, lithium chloride, potassium chloride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, potassium acetate, sodium ethoxide, sodium carbonate, sodium hydroxide, potassium phosphate, ethylenediamine, glycine, N-methylpyrrolidine, pyridine, and 1,2-diaminocyclohexane and the like.
The solvents include, for example, methanol, ethanol, THF, pyridine, collidine, dichloromethane, 1,2-dichloroethane, DMF, acetonitrile, 1,4-dioxane, N,N-dimethylsulfoxide (DMSO), DMA, NMP, toluene, and hexamethylphosphoric triamide (HMPA). They are used alone or in mixtures and the like.
Compound (III-c) wherein n2 is 0 can be manufactured by reacting compound (III-a) in a solvent with compound (a-4) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a copper reagent preferably in 1 to 10 equivalent amount and a base in 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (a-4) can be obtained as a commercially available product, or by well-known methods [e.g., “Jikken Kagaku Koza 18, 5th Ed., Synthesis of organic compounds VI, Organic synthesis using metals” p. 97, Maruzen (2005)] or its equivalent methods.
Copper reagents include, for example, copper(0), copper(I) iodide, copper(II) acetate, copper(II) oxide, and copper(I) chloride and the like.
The bases include, for example, potassium carbonate, cesium carbonate, lithium chloride, potassium chloride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, potassium acetate, sodium ethoxide, sodium carbonate, sodium hydroxide, potassium phosphate, ethylenediamine, glycine, N-methylpyrrolidine, pyridine, and 1,2-diaminocyclohexane and the like.
The solvents include, for example, methanol, ethanol, THF, pyridine, collidine, dichloromethane, 1,2-dichloroethane, DMF, acetonitrile, 1,4-dioxane, DMSO, DMA, NMP, toluene, and HMPA and the like. They are used alone or in mixtures.
Compound (II-a) can be manufactured using compound (III-c) by a method similar to step 1.
Compound (III-d) can be manufactured by reacting compound (III-c) in a solvent with compound (a-5) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours at a temperature between −78° C. and the boiling point of the solvent used.
Compound (a-5) can be obtained as a commercially available product, or by well-known methods [e.g., “Jikken Kagaku Koza 18, 5th Ed., Synthesis of organic compounds VI, organic synthesis using metals” p. 59, Maruzen (2005)] or its equivalent methods.
The solvents include, for example, toluene, diethyl ether, THF, DME, 1,4-dioxane, and hexane and the like. They are used alone or in mixtures.
Compound (III-e) can be manufactured by reacting compound (III-d) in a solvent with an azidation reagent preferably in 1 equivalent to a large excess amount, for 5 minutes to 72 hours in the presence of, if needed, a base preferably in 1 equivalent to a large excess amount or if needed, an acid preferably in 1 equivalent to a large excess amount, at a temperature between 0° C. and the boiling point of the solvent used.
The azidation agents include, for example, sodium azide, potassium azide, and diphenylphosphoryl azide and the like.
The bases include, for example, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and the like.
The acids include, for example, trifluoroacetic acid and the like.
The solvents include, for example, THF, DME, benzene, toluene, xylene, 1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or in mixtures.
Compound (II-b) can be manufactured by reacting compound (III-e) in a solvent with a reducing agent preferably in 1 to 10 equivalent amount for 5 minutes to 72 hours at a temperature between −78° C. and the boiling point of the solvent used.
The reducing agents include, for example, lithium aluminum hydride, borane dimethyl sulfide complex, triphenylphosphine, and tetrabutyltin hydride and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or in mixtures.
Furthermore, as an alternative method, compound (II-b) can be manufactured by reacting compound (III-e) in a solvent (i) with a hydrogen source preferably in 2 equivalents to a large excess amount for 5 minutes to in 72 hours, or (ii) with hydrogen under the hydrogen atmosphere preferably at 1 to 20 atmospheric pressure for 5 minutes to 72 hours, in the presence of a catalyst preferably in 0.01 to 50% by weight relative to compound (III-e), at a temperature between −20° C. and the boiling point of the solvent used.
The catalysts include, for example, palladium carbon, and palladium hydroxide and the like.
The hydrogen sources include, for example, formic acid, amammonium formate, sodium formate, cyclohexadiene, and hydrazine and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Compound (III-f) can be manufactured using compound (III-c), for example, by methods equivalent to a method described in “Jikken Kagaku Koza 13, 5th Ed., Synthesis of organic compounds I, hydrocarbon/halogen compounds”, Maruzen (2005), “Jikken Kagaku Koza 15, 5th Ed., Synthesis of organic compounds III, aldehydes/ketones/quinones”, Maruzen (2005), and the like.
Compound (III-f) can be manufactured by reacting compound (III-c) in a solvent with 1 equivalent to a large excess amount of a halogenating agent or an alkylating agent for 5 minutes to 72 hours at a temperature between −78° C. and the boiling point of the solvent used.
The halogenating agents include, for example, (diethylamino)sulfur trifluoride (DAST), bis(2-methoxyethyl)aminosulfur trifluoride, 1-fluoro-4-hydroxy-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate, N-chlorosuccinimide, N-bromosucciniide, N-iodosuccinimide, chlorine, bromine, and iodine and the like.
Alkylating agents include, for example, methyl iodide, ethyl iodide, and methyl trifluoromethanesulfonate and the like.
The solvents include, for example, dichloromethane, 1,2-dichloroethane, and methanol and the like. They are used alone or in mixtures.
Compound (II-c) can be manufactured by a method similar to step 1 using compound (III-f).
Compound (III-g) can be manufactured by reacting compound (III-c) in a solvent with a reducing agent preferably in 1 to 10 equivalent amount for 5 minutes to 72 hours at a temperature between −78° C. and the boiling point of the solvent used.
The reducing agents include, for example, lithium aluminum hydride, diisobutylaluminium hydride, bis(2-methoxyethoxy)aluminum sodium hydride, borane dimethyl sulfide complex, lithium borohydride, and sodium borohydride and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or in mixtures.
Compound (III-h) can be manufactured by reacting compound (III-g) in a solvent with a cyanating agent preferably in 1 to 10 equivalent amount for 5 minutes to 72 hours in the presence of, if needed, an additive preferably in 1 to 10 equivalent amount at a temperature between 0° C. and the boiling point of the solvent used.
The additives include, for example, zinc iodide and the like.
The cyanating agents include, for example, sodium cyanide, potassium cyanide, tetrabutyl ammonium cyanide, and trimethylsilyl cyanide and the like.
The solvents include, for example, dichloromethane, 1,2-dichloroethane, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, and toluene and the like. They are used alone or in mixtures.
Compound (II-d) can be manufactured by reacting compound (III-h) in a solvent with a reducing agent preferably in 1 to 10 equivalent amount for 5 minutes to 72 hours at a temperature between 0° C. and the boiling point of the solvent used.
The reducing agents include, for example, lithium aluminum hydride, and diborane and the like.
The solvents include, for example, toluene, diethyl ether, THF, DME, 1,4-dioxane, and the like. They are used alone or in mixtures.
Furthermore, as an alternative method, compound (II-d) can be manufactured by reacting compound (III-h) in a solvent or without solvent (i) with a hydrogen source preferably in 2 equivalents to a large excess amount for 5 minutes to 72 hours, or (ii) with hydrogen under the hydrogen atmosphere preferably at 1 to 20 atmospheric pressure for 5 minutes to 72 hours, by adding, if needed, an acid preferably in 1 equivalent to a large excess amount or if needed, an ammonia-alcoholic solution preferably in 1 equivalent to a large excess amount, in the presence of a catalyst preferably in 0.01 to 50% by weight relative to compound (III-h), at a temperature between −20° C. and the boiling point of the solvent used (between 0° C. and 150° C. when without solvent),.
The acids include, for example, acetic acid, and hydrochloric acid and the like.
The ammonia-alcoholic solutions include, for example, an ammonia-methanol solution, an ammonia-ethanol solution, and an ammonia-2-propanol solution and the like.
The catalysts include, for example, palladium carbon, and Raney nickel and the like.
The hydrogen sources include, for example, formic acid, ammonium formate, sodium formate, cyclohexadiene, and hydrazine and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Compound (III-c) wherein n2 is 1 can be manufactured by reacting compound (III-a) in a solvent with compound (a-6) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a phosphine compound preferably in 1 to 10 equivalent amount and an azo compound preferably in 1 to 10 equivalent amount, at a temperature between −78° C. and the boiling point of the solvent used.
Compound (a-6) can be obtained as a commercially available product.
The phosphine compounds include, for example, triphenylphosphine, and tributylphosphine and the like.
The azo compounds include, for example, diethyl azodicarboxylate (DEAD), di-tert-butyl azadicarboxylate, diisopropyl azadicarboxylate, N,N,N′,N′-tetramethyl azadicarboxamide, 1,1′-(azadicarbonyl)dipiperazine, and N,N,N′,N′-tetraisopropyl azadicarboxamide and the like.
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or in mixtures.
Furthermore, as an alternative method, compound (III-c) can be manufactured by reacting compound (III-a) in a solvent with compound (a-7) preferably in 1 to 10 equivalent amount, in the presence of a base preferably in 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 72 hours.
Compound (a-7) can be obtained as a commercially available product.
The bases include, for example, sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, diisopropylethylamine, and DBU and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, and water and the like. They are used alone or in mixtures.
Among compounds (II), compound (II-i) that is a 3-aminochromane derivative wherein X is —O— can be manufactured according to the following steps:
(wherein R2, R2A, R5, X1 and n2 are the same as the definition described above; R6 represents lower alkyl; and BOC represents tert-butoxycarbonyl).
Compound (III-p) can be manufactured by reacting compound (III-o) in a solvent or without solvent with acrylonitrile preferably in 1 equivalent to a large excess amount, in the presence of a base preferably in 1 to 10 equivalent amount, at a temperature between 0° C. and the boiling point of the solvent used (at 0° C. and 150° C. when without solvent) for 5 minutes to 72 hours.
Compound (III-o) can be obtained as a commercially available product, or by well-known methods (e.g., “Jikken Kagaku Koza 15, 5th Ed., Synthesis of organic compounds III, aldehydes/ketones/quinones” p. 78, Maruzen (2005)] or by its equivalent methods.
The bases include, for example, 1,4-diazabicyclo[2.2.2]octane and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, DMF, and water and the like. They are used alone or in mixtures.
Compound (III-q) can be manufactured by treating compound (III-p) in a solvent with a base preferably in 1 equivalent to a large excess amount, for 5 minutes to 72 hours at a temperature between 0° C. and the boiling point of the solvent used.
The bases include, for example, potassium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, and sodium methoxide and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine and the like. They are used by mixing with water, or mixing each solvent and further adding water thereto.
Compound (III-r) can be manufactured by reacting compound (III-q) in a solvent or without solvent with an azidation reagent preferably in 1 equivalent to a large excess amount and tert-butanol preferably in 1 equivalent to a large excess amount, in the presence of, if needed, a base preferably in 1 equivalent to a large excess amount, at a temperature between 0° C. and the boiling point of the solvent used (between 0° C. and 150° C. when without solvent) for 5 minutes to 72 hours.
The azidation reagents include, for example, sodium azide, potassium azide, and diphenylphosphoryl azide and the like.
The bases include, for example, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and the like.
The solvents include, for example, THF, DME, benzene, toluene, xylene, 1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or in mixtures.
Compound (III-s) can be manufactured by reacting compound (III-r) in a solvent (i) with hydrogen under the hydrogen atmosphere preferably at 1 to 20 atmospheric pressure for 5 minutes to 72 hours, or (ii) with a hydrogen source preferably in 2 equivalent to a large excess amount for 5 minutes to 72 hours, in the presence of preferably 0.01 to 50% by weight of a catalyst, at a temperature between −20° C. and the boiling point of the solvent used.
The catalysts include, for example, palladium carbon, palladium, palladium hydroxide, palladium acetate, and palladium black and the like.
The hydrogen sources include, for example, formic acid, ammonium formate, sodium formate, cyclohexadiene, and hydrazine and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Compound I can be manufactured by treating compound (III-s) in a solvent or without solvent with an additive preferably in 1 equivalent to a large excess amount, at a temperature between 0° C. and the boiling point of the solvent used (between 0° C. and 150° C. when without solvent), or if needed, using a microwave reaction device and at a temperature between 0° C. and 200° C., for one minute to 72 hours.
The additives include, for example, pyridine hydrochloride, boron tribromide, boron trifluoride diethyl ether complex, and aluminum chloride and the like.
The solvents include, for example, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or in mixtures.
Compound (II-i) wherein n2 is 1 can be manufactured using compounds (III-t) and (a-6) by a method similar to step 13.
Compound (II-i), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured using compounds (III-t) and (a-3) by a method similar to step 2.
Among compounds (III-r) described in manufacturing method 2, compound (III-r-2) can be also manufactured according to the following step:
(wherein R5A represents chlorine atom, bromine atom, iodine atom, p-toluene sulfonyloxy, methanesulfonyloxy or trifluoro-methanesulfonyloxy, and the like; R6 is the same as the definition described above; and R7 represents lower alkyl in R5).
Compound (III-r-2) can be manufactured by reacting compound (III-r-1) in a solvent with compound (a-8) preferably in 1 to 5 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 0.1 to 10 equivalent amount and a palladium catalyst preferably in 0.001 to 0.5 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (III-r-1) can be obtained according to step 16 of manufacturing method 2.
Compound (a-8) can be obtained as a commercially available product, or by well-known methods [e.g., Jikken Kagaku Koza 18, 5th Ed., Synthesis of organic compounds VI, Organic synthesis using metals” p. 97, Maruzen (2005)] or by its equivalent methods.
The bases include, for example, sodium carbonate, potassium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and the like.
The palladium catalysts include, for example, palladium acetate, tris(dibenzylidene acetone)dipalladium, tetrakis(triphenylphosphine)palladium, and 1,1′-bis(diphenylphosphino)ferrocene dichloropalladiumidichloromethane 1:1 adduct and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Among compounds (II), compound (II-j), that is a 3-aminochroman-4-one derivative, can be manufactured according to the following steps:
(wherein R2, R5, n2 and E1 are each the same as the definition described above; R8 represents phenyl optionally substituted with a substituent selected from the group consisting of fluorine atom, chlorine atom, bromine atom, iodine atom, lower alkyl and lower alkoxy; and X3 represents chlorine atom, bromine atom or iodine atom).
Compound (IV-a) can be manufactured by reacting compound (III-c) obtained in step 3 or step 13 of manufacturing method 1 in a solvent with hydroxylamine or a salt thereof preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a base or acid preferably in 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
The bases include, for example, potassium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and the like.
The acids include, for example, hydrochloric acid, and acetic acid and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, acetone, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and water and the like. They are used alone or in mixtures.
The hydroxylamine or salts thereof include, for example, hydroxylamine, hydroxylamine hydrochloride, and hydroxylamine sulfate and the like. Also, an aqueous hydroxylamine solution can be used.
Compound (IV-b) can be manufactured by reacting compound (IV-a) in a solvent with compound (a-9) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (a-9) can be obtained as a commercially available product.
The bases include, for example, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium bicarbonate, sodium hydride, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, acetone, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and water and the like. They are used alone or in mixtures.
Compound (II-j) can be manufactured by treating compound (IV-b) in a solvent with a base preferably in 1 to 10 equivalent amount for 5 minutes to 72 hours at a temperature between −20° C. and the boiling point of the solvent used.
The bases include, for example, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, and pyridine and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, acetone, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine and the like. They are used by mixing with water or mixing each solvent and further adding water thereto.
Among compounds (II), compound (II-k), that is a 5,6,7,8-tetrahydroquinoline derivative, can be manufactured according to the following steps:
[wherein R2, R2A, X2 and n2 each are the same as the definition described above; in R2, R2B represents (i) optionally substituted cycloalkyl, or (ii) aliphatic heterocyclic group wherein X4 is bonded to the sp3 carbon constituting the aliphatic heterocyclic group among optionally substituted aliphatic heterocyclic groups; X4 represents leaving group such as chlorine atom, bromine atom, iodine atom, p-toluene sulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy, or the like; represents the substituent mentioned above as a substituent of optionally substituted heterocyclic diyl or hydrogen atom; and R11 and R12 are the same or different, and each represents hydrogen atom or lower alkyl].
Compound (V-b) can be manufactured by reacting compound (V-a) in a solvent with compound (a-10) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of an additive preferably in 0.1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
The additives include, for example, pyridinium p-toluenesulfonate, p-toluenesulfonic acid, hydrochloric acid, and acetic acid and the like.
The solvents include, for example, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, and acetonitrile and the like.
Compound (V-a) can be obtained as a commercially available product, or by well-known methods (e.g., Synthetic Communications, 2010 Vol. 40, p. 1708-1716) or its equivalent methods.
Compound (a-10) can be obtained as a commercially available product. Other than the methods above, compound (V-b), for example, can be manufactured by methods equivalent to a method described in Protective Groups in Organic Synthesis, the third edition, by T. W. Greene, John Wiley & Sons Inc. (1999) and the like.
Compound (V-c) can be manufactured by reacting compound (V-b) in a solvent with an oxidizing agent preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours at a temperature between −20° C. and the boiling point of the solvent used.
The oxidizing agents include, for example m-chloroperoxybenzoic acid (m-CPBA), benzoyl peroxide, peracetic acid, and hydrogen peroxide and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Compound (V-d) can be manufactured by the following method.
Compound (V-c) is subjected to a reaction in a solvent with an acid anhydride preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 1 to 10 equivalent amount, at a temperature between −78° C. and the boiling point of the solvent used.
The compound obtained in step 27-1 is subjected to a reaction in a solvent with a base in 1 equivalent to a large excess amount relative to compound (V-c) for 5 minutes to 72 hours at a temperature between 0° C. and the boiling point of the solvent used.
The acid anhydrides include acetic anhydride, and trifluoroacetic acid anhydride and the like.
The bases used in steps 27-1 and 27-2 are the same or different, and each include, for example, potassium carbonate, potassium hydroxide, sodium hydroxide, triethylamine, diisopropylethylamine, N-methylmorpholine, and pyridine and the like.
The solvents used in step 27-1 are the same or different, and each include, for example, dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine and the like. They are used alone or in mixtures.
The solvents used in step 27-2 are the same or different, and each include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and water and the like. They are used alone or in mixtures.
Compound (V-e), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured by reacting compound (V-d) in a solvent with compound (a-11) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a phosphine compound preferably in 1 to 10 equivalent amount and an azo compound preferably in 1 to 10 equivalent amount, at a temperature between −78° C. and the boiling point of the solvent used.
Compound (a-11) can be obtained as a commercially available product.
The phosphine compounds include, for example, triphenylphosphine, and tributylphosphine and the like.
The azo compounds include, for example, DEAD, di-tert-butyl azadicarboxylate, diisopropyl azadicarboxylate, N,N,N′,N′-tetramethyl azadicarboxamide, 1,1′-(azadicarbonyl)dipiperazine, and N,N,N′,N′-tetraisopropyl azadicarboxamide and the like.
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or in mixtures.
Compound (V-e) wherein n2 is 1 can be manufactured by reacting compound (V-d) in a solvent with compound (a-7) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (a-7) can be obtained as a commercially available product.
The bases include, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium tert-butoxide, diisopropylethylamine, and DBU and the like.
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, DMF, 1,4-dioxane, and water and the like. They are used alone or in mixtures.
Compound (V-e) wherein n2 is 0 and R2 is optionally substituted cycloalkyl, or compound (V-e) wherein n2 is 0 and R2 is optionally substituted aliphatic heterocyclic group wherein the spa carbon constituting the aliphatic heterocyclic group is bonded to —O—, can be manufactured by reacting compound (V-d) in a solvent with compound (a-12) preferably in 1 to 10 equivalent amount, in the presence of a base preferably in 1 to 10 equivalent amount at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 72 hours.
Compound (a-12) can be obtained as a commercially available product.
The bases include, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, potassium tert-butoxide, diisopropylethylamine, and DBU and the like.
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, DMF, 1,4-dioxane, and water and the like. They are used alone or in mixtures.
Compound (V-f) can be manufactured using compound (V-e), for example, by methods equivalent to a method described in Protective Groups in Organic Synthesis, third edition by T. W. Greene, John Wiley & Sons Inc. (1999), and the like.
Compound (II-k) can be manufactured using compound (V-f) by a method similar to step 1.
Among compounds (II-k), compound (II-L) wherein in the position 2 of 5,6,7,8-tetrahydroquinoline is lower alkoxy or —NRcRd [wherein Rc and Rd are the same or different, and each represent hydrogen atom or low alkyl, or form an optionally substituted nitrogen-containing heterocyclic group together with the adjacent nitrogen atom (the nitrogen-containing heterocyclic groups include, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidine, azepanyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl, 2H-thioxazolyl, morpholino, and thiomorpholinyl and the like; and the substituents of the optionally substituted nitrogen-containing heterocyclic group together with the adjacent nitrogen atom are the same or different, and each include, for example, the substituent exemplified as the substituent of the aliphatic heterocyclic group optionally substituted with the number of substitution of 1-3)] can also be manufactured according to the following steps:
(wherein R2 and n2 are the same as the definition described above; R10A corresponds to R10 of compound (V-f), and represents fluorine atom, chlorine atom, bromine atom or iodine atom in R10, R13 represents lower alkoxy or —NRcRd [wherein Rc and Rd each are the same as the definition described above] in R10).
Compound (V-f-2) can be manufactured by reacting compound (V-f-1) in a solvent with compound (a-13) or an alkali metal salt of compound (a-13) preferably in 1 to 10 equivalent amount, in the presence of, if needed, a base preferably in 1 to 10 equivalent amount, at a temperature between 0° C. and the boiling point of the solvent used, or if needed, using a microwave reaction device and at a temperature between 0° C. and 200° C. for one minute to 72 hours.
The bases include, for example, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and the like.
Compound (V-f-1) can be obtained according to step 30 of manufacturing method 5. Compound (a-13) or an alkali metal salt of compound (a-13) can be obtained as a commercially available product.
The alkali metal salts of compound (a-13) include, for example, lithium salt, sodium salt or potassium salt or the like of compound (a-13).
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and water and the like. They are used alone or in mixtures.
Compound (II-L) can be manufactured using compound (V-f-2) by a method similar to step 1.
Among compounds (II), compounds (II-m), (II-n) and (II-o) can be manufactured according to the following steps:
(wherein AA represents heterocyclic diyl wherein X5 is bonded to the sp2 carbon constituting the heterocyclic diyl in the optionally substituted heterocyclic diyl; R2 and n2 each are the same as the definition described above; R14 represents amino, nitro or cyano; and X5 represents fluorine atom, chlorine atom, bromine atom or iodine atom).
Compound (II-m) can be manufactured by reacting compound (VII-a) in a solvent or without solvent with compound (a-6) preferably in 1 to 10 equivalent amount for one minute to 72 hours, if needed, in the presence of sodium iodide or potassium iodide preferably in 1 to 10 equivalent amount, and if needed, in the presence of a base preferably in 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used (between −20° C. and 180° C. when without solvent), or if needed, using a microwave reaction device and at a temperature between 0° C. and 200° C.
Compound (VII-a) can be obtained as a commercially available product or manufactured by methods equivalent to a method described in well-known methods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, John Wiley & Sons Inc. (2008), CN101983961A, WO2007/036743, and the like].
Compound (a-6) can be obtained as a commercially available product.
The bases include, for example, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and the like.
The solvents include, for example, toluene, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and water and the like. They are used alone or in mixtures.
Furthermore, as an alternative method, when reacting with compound (a-6), wherein n2 is 0 and R2 is an optionally substituted aromatic heterocyclic group or optionally substituted aryl, a method similar to step 2 of manufacturing method 1 can be used.
Compound (II-n) can be manufactured by reacting compound (II-m), wherein R14 is nitro, in a solvent, (i) with hydrogen under the hydrogen atmosphere preferably at 1 to 20 atmospheric pressure for 5 minutes to 72 hours, or (ii) with a hydrogen source preferably 2 equivalent to a large excess amount relative to compound (II-m) for 5 minutes to 72 hours, in the presence of a catalyst preferably in 0.01 to 50% by weight, at a temperature between −20° C. and the boiling point of the solvent used.
The catalysts include, for example, palladium carbon, palladium, palladium hydroxide, palladium acetate, palladium black, platinum oxide, and Raney nickel and the like.
The hydrogen sources include, for example, formic acid, ammonium formate, sodium formate, cyclohexadiene, and hydrazine and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Furthermore, as an alternative method, compound (II-n) can be manufactured by reacting compound (II-m) in a solvent with a metal or metal salt preferably in 1 to 10 equivalent amount, in the presence of an additive preferably in 1 equivalent to large excess amount, at a temperature between 0° C. and the boiling point of the solvent used for 5 minutes to 72 hours.
The metals or metal salts include, for example, tin, zinc, iron, samarium, indium, and tin dichloride and the like.
The additives include, for example, hydrochloric acid, acetic acid, and ammonium chloride and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Compound (II-o) can be manufactured using compound (II-m) wherein R14 is cyano by a method similar to step 12.
Among compounds (II), compound (II-n) can also be manufactured according to the following steps:
(wherein AA, R2, R2A, X1 and n2 are each the same as the definition described above).
Compound (II-n) wherein n2 is 1 can be manufactured by reacting compound (VIII-a) in a solvent with compound (a-6) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a phosphine compound preferably in 1 to 10 equivalent amount and an azo compound preferably in 1 to 10 equivalent amount, at a temperature between −78° C. and the boiling point of the solvent used.
Compound (a-6) can be obtained as a commercially available product.
Compound (VIII-a) can be obtained as a commercially available product or manufactured by methods equivalent to a method described in well-known methods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, John Wiley & Sons Inc. (2008), WO2011/025546, and the like].
The phosphine compounds include, for example, triphenylp osphine, and tributylphosphine and the like.
The azo compounds include, for example, DEAD, di-tert-butyl azadicarboxylate, diisopropyl azadicarboxylate, N,N,N′,N′-tetramethyl azadicarboxamide, 1,1′-(azadicarbonyl)dipiperazine, and N,N,N′,N′-tetraisopropyl azadicarboxamide and the like.
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or in mixtures.
Compound (II-n) wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group can be manufactured by a method similar to step 2 of manufacturing method 1 using compounds (VIII-a) and (a-3).
Compound (VIII-a) can be obtained in the method similar to the above.
Compound (a-3) can be obtained as a commercially available product.
Among compounds (II), compound (II-n) can also be manufactured according to the following steps:
(wherein AA, R2, R2A, R2B, X1, X2, X4 and n2 are each the same as the definition described above).
Compound (IX-b) wherein n2 is 1 can be manufactured by reacting compound (IX-a) in a solvent with compound (a-7) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (a-7) can be obtained as a commercially available product.
Compound (IX-a) can be obtained as a commercially available product or manufactured by methods equivalent to a method described in well-known methods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, John Wiley & Sons Inc. (2008), and the like].
The bases include, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, diisopropylethylamine, and DBU and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, DMF, 1,4-dioxane, water, and the like. They are used alone or in mixtures.
Compound (IX-b) wherein n2 is 0 and R2 is optionally substituted cycloalkyl, or compound (IX-b) wherein n2 is 0 and R2 is optionally substituted aliphatic heterocyclic group wherein the spa carbon constituting the aliphatic heterocyclic group is bonded to —O—, can be manufactured by reacting compound (IX-a) in a solvent with compound (a-12) preferably in 1 to 10 equivalent amount, in the presence of a base preferably in 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 72 hours.
Compound (a-12) can be obtained as a commercially available product.
The bases include, for example, sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, diisopropylethylamine, and DBU and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, DMF, 1,4-dioxane, and water and the like. They are used alone or in mixtures.
Compound (IX-b), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured using compounds (IX-a) and (a-3) by a method similar to step 2 of manufacturing method 1.
Compound (II-n) can be manufactured by a method similar to step 34 using compound (IX-b).
Compound (I) can be manufactured according to the following manufacturing method.
(wherein R1, R2, X, n1, n2 and A are each the same as the definition described above, and the wavy line part between R1 and the adjacent carbon atom represents cis or trans configuration).
Compound (I) can be manufactured by reacting compound (II) in a solvent with compound (a-1) preferably in 1 to 5 equivalent amount, for 5 minutes to 72 hours in the presence of a condensation agent preferably in 1 to 5 equivalent amount, and if needed, in the presence of an additive preferably in 1 to 5 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (a-1) can be obtained as a commercially available product or also manufactured by methods equivalent to a method described in well-known methods [e.g., “Jikken Kagaku Koza 16, 5th Ed., Synthesis of organic compounds IV, carboxylic acid, amino acid, peptide” Maruzen (2005), and the like].
Compound (II) can be manufactured according to any one of manufacturing methods 1, 2, 4-9, 11-15, 17-19, and 21-28.
The condensation agents include, for example, 1,3-dicyclohexane carbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), carbonyldiimidazole (CDT), and 2-chloro-1-methyl pyridinium iodide and the like.
The additives include, for example, 1-hydroxybenzotriazole monohydrate (HOBt) and the like.
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine and the like. They are used alone or in mixtures.
Furthermore, as an alternative method, compound (I) can be manufactured by reacting compound (II) in a solvent or without solvent with compound (a-2) preferably in 1 to 10 equivalent amount, if needed, in the presence of a base preferably in 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used (between −20° C. and 150° C. when without solvent) for 5 minutes to 72 hours.
Compound (a-2) can be obtained as a commercially available product, or obtained by well-known methods [e.g., “Jikken Kagaku Koza 16, 5th Ed., Synthesis of organic compounds IV” p. 101, Maruzen (2005)] or by its equivalent methods.
The bases include, for example, potassium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, DBU, and 4-dimethylaminopyridine (DMAP) and the like.
The solvents include, for example, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine and the like. They are used alone or in mixtures.
Among compounds (II), compound (II-p), (II-q) or (II-r) as a 5-aminochromane derivative or a 5-aminomethylchromane derivative can be manufactured according to the following steps:
(wherein R2, R2A, R14, X1, X2, X5, n2 and E1 are the same as the definition described above; and X6 represents hydroxy, fluorine atom, chlorine atom, bromine atom or iodine atom).
Compound (X-b) can be manufactured by reacting compound (X-a) in a solvent or without solvent, (i) with 1 equivalent to a large excess amount of a reducing agent for 5 minutes to 72 hours in the presence of 1 equivalent to a large excess amount of an acid at a temperature between −20° C. and the boiling point of the solvent used, or (ii) with hydrogen under the hydrogen atmosphere at 1 to 20 atmospheric pressure or with 2 equivalents to a large excess amount of a hydrogen source for 5 minutes to 72 hours in the presence of a catalyst preferably in 0.01 to 50% by weight, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (X-a) can be obtained as a commercially available product, or obtained by well-known methods [Chemistry of Heterocyclic Compounds, Volume 31, John Wiley & Sons Inc. (2008) and the like] or their equivalent methods.
The acids include, for example, acetic acid, hydrochloric acid, and trifluoroacetic acid and the like.
The reducing agents include, for example, triethylsilane, and zinc amalgam and the like.
The catalysts include, for example, palladium carbon, palladium, palladium hydroxide, palladium acetate, palladium black, platinum oxide, and Raney nickel and the like.
The hydrogen sources include, for example, formic acid, ammonium formate, sodium formate, cyclohexadiene, and hydrazine and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Compound (II-p) wherein n2 is 0 can be manufactured using compound (X-b) wherein X6 is hydroxy by a method similar to step 2 or 3 of manufacturing method 1.
Compound (II-p) wherein n2 is 1 can be manufactured by a method similar to step 13 of manufacturing method 1 using compound (X-b) wherein X6 is hydroxy.
Compound (II-p) can be manufactured by a method similar to step 34 using compound (X-b) wherein X6 is fluorine atom, chlorine atom, bromine atom or iodine atom.
Compound (II-q) can be manufactured by a method similar to step 35 using compound (II-p) wherein R14 is nitro.
Compound (II-r) can be manufactured by a method similar to step 12 using compound (II-p) wherein R14 is cyano.
Among compounds (II), compound (II-s) that is a 5,6,7,8-tetrahydroquinoline derivative can be manufactured according to the following steps:
(wherein R2, R10A and n2 are the same as the definition described above).
Compound (V-g) can be manufactured by a method similar to step 34 of manufacturing method 7 using compound (V-a-1).
Compound (V-a-1) can be obtained as a commercially available product, or by well-known methods [e.g., Synthetic Communications, 2010 Vol. 40, p. 1708-1716] or its equivalent methods.
Compound (II-s) can be manufactured by a method similar to step 1 of manufacturing method 1 using compound (V-g).
Among compounds (II), compound (II-t) that is a 5,6,7,8-tetrahydroisoquinoline derivative can be manufactured according to the following steps:
(wherein R2, R2A, R2B, R5, X2, X4 and n2 are the same as the definition described above).
Compound (XI-b), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured by a method similar to step 28 of manufacturing method 5 using compound (XI-a).
Compound (XI-a) can be obtained as a commercially available product or by well-known methods [e.g., US2013/0274287, WO2013/079452 and the like] or its equivalent methods.
Compound (XI-b) wherein n2 is 1 and R2 is optionally substituted cycloalkyl or optionally substituted aliphatic heterocyclic group, and compound (XI-b) wherein n2 is 0 and R2 is optionally substituted cycloalkyl, or compound (XI-b) wherein n2 is 0 and R2 is aliphatic heterocyclic group wherein the sp3 carbon constituting the aliphatic heterocyclic group is bonded to —O—, can be manufactured by a method similar to step 29 of manufacturing method 5 using compound (XI-a).
Compound (XI-c) can be manufactured by a method similar to step 26 of manufacturing method 5 using compound (XI-b).
Compound (XI-d) can be manufactured by a method similar to steps 27-1 and 27-2 of manufacturing method 5 using compound (XI-c).
Compound (XI-e) can be manufactured by treating compound (XI-d) in a solvent with an oxidation agent preferably in 1 to 10 equivalent amount for 5 minutes to 72 hours at a temperature between −20° C. and the boiling point of the solvent used.
The oxidizing agent includes, for example, manganese dioxide, chromic acid, pyridinium chlorochromate (PCC), pyridinium dichlorochromate (PDC), potassium permanganate, sulfur trioxide-pyridine, axone (registered trademark), DMSO/oxalyl chloride, and cess-Martin periodinane and the like.
The solvents include, for example, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, DMSO, pyridine, hydrochloric acid, acetic acid, propionic acid, acetic anhydride, sulfuric acid, and water and the like. They are used alone or in mixtures.
Compound (II-t) can be manufactured by a method similar to step 1 of manufacturing method 1 using compound (XI-e).
Among compounds (II), compounds (II-u), (II-v), (II-w), (II-x) and (II-y), wherein X is —O—, —S—,—NRX1— (wherein RX1 represents hydrogen atom or lower alkyl), —CH═CH—, —NH—CO— or —SO2—; and X is bonded to the sp3 carbon constituting A; can be manufactured according to the following steps:
[wherein R2, R14 and n2 are the same as the definition described above; AB represents heterocyclic diyl wherein X7 is bonded to the sp3 carbon constituting the heterocyclic diyl among optionally substituted heterocyclic diyl groups; X7 represents fluorine atom, chlorine atom, bromine atom, iodine atom, p-toluene sulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy; XA represents —O—, —S— or —NRX1— (wherein RX1 represents hydrogen atom or lower alkyl); and XB represents —O—, —S—, —NRX1— (wherein RX1 represents hydrogen atom or lower alkyl), —CH═CH— or —NH—CO—)].
Compound (II-u) wherein XB is XA can be manufactured by a method similar to step 29 of manufacturing method 5 using compounds (XII-a) and (a-6a).
Compound (XII-a) can be obtained as a commercially available product or manufactured by methods equivalent to a method described in well-known methods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, John Wiley & Sons Inc. (2008), and the like].
Compound (a-6a) can be obtained as a commercially available product.
Compound (II-u) wherein XB is —NH—CO— can be manufactured by reacting compound (XII-a) in a solvent with compound (a-14) preferably in 1 to 10 equivalent amount under exposure of light, for 5 minutes to 72 hours in the presence of a copper reagent preferably in 0.01 to 1 equivalent amount and a base preferably in 1 to 10 equivalent amount at a temperature between −20° C. and the boiling point of the solvent used.
The copper reagents include, for example, copper(0), copper(I) iodide, copper(II) acetate, copper(II) oxide, and copper(I) chloride and the like.
The bases include, for example, potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, and potassium phosphate and the like.
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, DMF, HMPA, DMSO, 1,4-dioxane, and water and the like. They are used alone or in mixtures.
Compound (a-14) can be obtained as a commercially available product.
Compound (II-u) wherein XB is —CH═CH— can be manufactured by reacting compound (XII-a) in a solvent with compound (a-15) preferably in 1 to 5 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 0.1 to 10 equivalent amount and a metallic catalyst preferably 0.001 to 0.5 equivalent amount at a temperature between −20° C. and the boiling point of the solvent used.
Compound (a-15) can be obtained as a commercially available product or by well-known methods [e.g., “Jikken Kagaku Koza 18, 5th Ed., Synthesis of organic compounds VI, Organic synthesis using metals” p. 97, Maruzen (2005)], or its equivalent methods.
The bases include, for example, potassium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, DBU, and sodium hexamethyldisilazide and the like.
The metallic catalysts include, for example, palladium acetate, tris(dibenzylidene acetone)dipalladium, tetrakis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane 1:1 adduct, nickel dicyclooctadiene, nickel chloride, nickel bromide, and nickel iodide and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Compound (II-v) can be manufactured by a method similar to step 35 of manufacturing method 7 using compound (II-u) wherein R14 is nitro.
Compound (II-w) can be manufactured by a method similar to step 12 of manufacturing method 1 using compound (II-u) wherein R14 is cyano.
Compound (II-x) can be manufactured by treating compound (II-v) wherein X6 is —S— in a solvent with an oxidizing agent preferably in 2 to 10 equivalent amount for 5 minutes to 72 hours at a temperature between 0° C. and the boiling point of the solvent used.
The oxidizing agents include, for example, m-chloroperoxybenzoic acid, benzoyl peroxide, peracetic acid, hydrogen peroxide solution, sodium periodate, and potassium permanganate and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine, and water and the like. They are used alone or in mixtures.
Compound (II-y) can be manufactured by a method similar to step 62 using compound (II-w) wherein X6 is —S—.
Among compounds (II), compounds (II-z), (II-A), (II-B), (II-C) and (II-D), wherein X is —O—, —S—,—NRX1— (wherein RX1 represents hydrogen atom or lower alkyl), —CH═CH—, —NH—CO— or —SO2 —; and X is bonded to the sp2 carbon constituting A; can be manufactured according to the following steps:
(wherein R2, R14, X7, XA, XB and n2 are the same as the definition described above; Ac represents a heterocyclic diyl wherein X7 is bonded to the sp2 carbon constituting the heterocyclic diyl among the optionally substituted heterocyclic diyl groups).
Compound (II-u) wherein XB is XA can be manufactured by a method in similar to step 34 using compounds (XII-b) and (a-6a).
Compound (XII-b) can be obtained as a commercially available product, or manufactured by methods equivalent to a method described in well-known methods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, John Wiley & Sons Inc. (2008), and the like].
Compound (II-z) wherein XB is —NH—CO— can be manufactured by reacting compound (XII-b) in a solvent with compound (a-14) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a copper reagent preferably 0.01 to 1 equivalent amount or palladium catalyst in 0.001 to 0.5 equivalent amount, a ligand preferably in 0.001 to 1 equivalent amount and a base preferably in 1 to 10 equivalent amount at a temperature between −20° C. and the boiling point of the solvent used.
The copper reagents include, for example, copper(0), copper(I) iodide, copper(II) acetate, copper(II) oxide, and copper(I) chloride and the like.
The palladium catalysts include, for example, palladium acetate, tris(dibenzylidene acetone)dipalladium, tetrakis(triphenylphosphine)palladium, and 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane 1:1 adduct and the like.
The ligands include, for example, phenanthroline, trans-1,2-cyclohexane diamine, picolinic acid, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, o-tolylphosphine, tributylphosphine, di-tert-butydiphenylphosphine, 2-(di-tert-butylphosphino)biphenyl, and 2-(dicyclohexylphosphino)biphenyl and the like.
The bases include, for example, potassium carbonate, cesium carbonate, potassium phosphate, potassium tert-butoxide, sodium tert-butoxide, sodium disilazide, triethylamine, potassium acetate, sodium ethoxide, sodium carbonate, sodium hydroxide, potassium phosphate, ethylenediamine, glycine, N-methylpyrrolidine, pyridine, and 1,2-diaminocyclohexane and the like.
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, DMF, HMPA, DMSO, 1,4-dioxane, and water and the like. They are used alone or in mixtures.
Compound (II-z) wherein XB is —CH═CH— can be manufactured by reacting in a solvent compound (XII-b) with compound (a-15) preferably in 1 to 5 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 0.1 to 10 equivalent amount and a palladium catalyst preferably in 0.001 to 0.5 equivalent amount at a temperature between −20° C. and the boiling point of the solvent used.
The bases include, for example, potassium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and the like.
The palladium catalysts include, for example, palladium acetate, tris(dibenzylidene acetone)dipalladium, tetrakis(triphenylphosphine)palladium, and 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane 1:1 adduct and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Compound (II-A) can be manufactured by a method similar to step 35 of manufacturing method 7 using compound (II-z) wherein R14 is nitro.
Compound (II-B) can be manufactured by a method similar to step 12 of manufacturing method 1 using compound (II-z) wherein R14 is cyano.
Compound (II-C) can be manufactured by a method similar to step 62 of manufacturing method 14 using compound (II-A) wherein XB is —S—.
Compound (II-D) can be manufactured by a method similar to step 62 of manufacturing method 14 using compound (II-B) wherein XB is —S—.
Among compounds (XII-a) and (XII-b), compound (XII-d) wherein X7 is p-toluenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy, can be manufactured according to the following step:
(wherein A and R14 are the same as the definition described above; X7A represents p-toluenesulfonyloxy, methanesulfonyloxy or trifluoromethanesulfonyloxy).
Compound (XII-d) can be manufactured by treating compound (XII-c) in a solvent or without solvent with a sulfonylation agent preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours if needed, in the presence of a base preferably in the equal amount of a catalyst to 10 equivalent amount at a temperature between −20° C. and 150° C.
The sulfonylation agents include, for example, trifluoromethanesulfonic anhydride, methanesulfonic anhydride, methanesulfonyl chloride, and p-toluenesulfonyl chloride and the like.
The bases include, for example, triethylamine, diisopropylethylamine, and pyridine and the like.
The solvents include, for example, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine and the like. They are used alone or in mixtures.
Compound (XII-c) can be obtained as a commercially available product, or also manufactured by methods equivalent to a method described in well-known methods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, John Wiley & Sons Inc. (2008), WO2011/025546, and the like].
Among compounds (II), compound (II-E) wherein X is —CH(OH)— or —CH═CH— can be manufactured according to the following steps:
[wherein A, AB, AC, R2, X7, M1 and n2 are the same as the definition described above; and XC represents —CH(OH)— or —CH═CH—].
Compound (XII-f) wherein XC is —CH(OH)— can be manufactured by reacting compound (XII-e) in a solvent with compound (a-16) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours at a temperature between −78° C. and the boiling point of the solvent used.
Compound (XII-e) can be obtained as a commercially available product or also manufactured by methods equivalent to a method described in well-known methods [e.g., Chemistry of Heterocyclic Compounds, Volume 1-64, John Wiley & Sons Inc. (2008), and the like].
Compound (a-16) can be obtained as a commercially available product or by well-known methods [e.g., “Jikken Kagaku Koza 18, 5th Ed., Synthesis of organic compounds VI, Organic synthesis using metal” p. 59, Maruzen (2005)] or its equivalent methods.
The solvents include, for example, toluene, diethyl ether, THF, DME, 1,4-dioxane, and hexane and the like. They are used alone or in mixtures.
Compound (XII-f) wherein XC is —CH═CH— can be manufactured by reacting compound (XII-e) in a solvent with compound (a-17) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 0.1 to 10 equivalent amount at a temperature between −78° C. and the boiling point of the solvent used.
The bases include, for example, potassium acetate, sodium bicarbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP. They are used alone or in mixtures.
Compound (a-17) can be obtained as a commercially available product, or by well-known methods [e.g., “Jikken Kagaku Koza 24, 4th Ed.” p. 252, Maruzen (2000)] or its equivalent methods.
When compound (XII-f) wherein X7 is bonded to the sp3 carbon constituting A is used, compound (XII-g) can be manufactured by reacting compound (XII-f) in a solvent with a cyanating agent preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of, if needed, a base preferably in 1 to 10 equivalent amount at a temperature between −20° C. and 150° C.
The cyanating agents include, for example, sodium cyanide, potassium cyanide, tetrabutylammonium cyanide, and trimethylsilyl cyanide and the like.
The bases include, for example, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and the like.
The solvents include, for example, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, and NMP and the like. They are used alone or in mixtures.
When compound (XII-f) wherein X7 is bonded to the sp2 carbon constituting A is used, compound (XII-g) can be manufactured by reacting compound (XII-f) in a solvent with a cyanating agent preferably in 1 equivalent to 10 equivalent amount for 5 minutes to 72 hours, in the presence of a base preferably in 0.1 to 10 equivalent amount and a palladium catalyst preferably in 0.001 to 0.5 equivalent amount at a temperature between −20° C. and the boiling point of the solvent used, or if needed, using a microwave reaction device and at a temperature between 0° C. and 200° C.
The cyanating agents include, for example, zinc cyanide, sodium cyanide, and potassium cyanide and the like.
The bases include, for example, sodium carbonate, potassium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, and DBU and the like.
The palladium catalysts include, for example, palladium acetate, tris(dibenzylidene acetone)dipalladium, tetrakis(triphenylphosphine)palladium, and 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane 1:1 adduct and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and water and the like. They are used alone or in mixtures.
Compound (II-E) can be manufactured by a method similar to step 12 of manufacturing method 1 using compound (XII-g).
Among compounds (II), compounds (II-F), (II-G) and (II-H) wherein X is —CHRX2— (wherein RX2 represents hydrogen atom or hydroxy) or —CO— can be manufactured according to the following steps:
(wherein A, R2 and n2 are the same as the definition described above).
Compound (II-F) can be manufactured by a method similar to step 12 of manufacturing method 1 using compound (XII-g-1).
Compound (XII-g-1) can be obtained according to step 72 of manufacturing method 17.
Compound (XII-h) can be manufactured by treating compound (XII-g-1) in a solvent or without solvent with a chlorinating agent preferably in 1 to a large excess amount, in the presence of, if needed, an additive preferably in the equal amount of a catalyst to 1 equivalent amount at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours.
The chlorinating agents include, for example, phosphorus oxychloride, phosphorus pentachioride, phosphorus trichloride, and thionyl chloride and the like.
The additives include, for example, DMF, pyridine, and diisopropylethylamine and the like.
The solvents include, for example, dichloromethane, chloroform, 1,2-dichloroethane, toluene, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, and pyridine and the like. They are used alone or in mixtures.
Compound (II-G) can be manufactured by a method similar to step 12 of manufacturing method 1 using compound (XII-h).
Compound (XII-i) can be manufactured by a method similar to step 55 of manufacturing method 13 using compound (XII-g-1).
Compound (II-H) can be manufactured by a method similar to step 12 of manufacturing method 1 using compound (XII-i).
Among compounds (II), compound (II-J) wherein n is 1 and X is —CH2— can be manufactured according to the following step:
(wherein A and R2 are the same as the definition described above).
Compound (II-J) can be manufactured by a method similar to step 12 using compound (XII-g-2).
Compound (XII-g-2) can be obtained according to the method of step 73 of manufacturing method 17.
Among compounds (I), compound (I-b) wherein X is —SO2— can also be manufactured according to the following step:
(wherein R1, R2, n1, n2 and A are each the same as the definition described above, and the wavy line part between R1 and the adjacent carbon atom indicates cis or trans configuration).
Compound (I-a) can be obtained according to the method of step 42 of manufacturing method 10.
Compound (I-b) can be manufactured by a method similar to step 62 using compound (I-a).
Among compounds (II), compound (II-K) and compound (II-M) as a benzoxazole derivative or a benzothiazole derivative can be manufactured according to the following steps:
(wherein R2, R2A, R5, R6, X1, X2, X3, and n2 are the same as the definition described above; and X8 represents —O— or —S—).
Compound (XIII-b) can be manufactured using compound (XIII-a), for example, by methods equivalent to a method described in “Jikken Kagaku Koza 13, 5th Ed., Synthesis of organic compounds I, hydrogen/halogen compounds”, Maruzen (2005) and the like.
For example, compound (XIII-b) can be manufactured by reacting compound (XIII-a) in a solvent with 1 equivalent to a large excess amount of a halogenating agent for 5 minutes to 72 hours at a temperature between −78° C. and the boiling point of the solvent used.
Compound (XIII-a) can be obtained as a commercially available product or by well-known methods (e.g., Japanese Unexamined Patent Application Publication No. 2009-40711 and the like) or their equivalent methods.
The halogenating agents include, for example, chlorine, bromine, iodine, N,N,N,N-tetra-n-butylammonium tribromide, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, and the like.
The solvents include, for example, acetone, 1,4-dioxane, acetonitrile, chloroform, dichloromethane, THF, DME, ethyl acetate, methanol, ethanol, DMF, acetic acid, water, and the like. They are used alone or in mixtures.
Compound (XIII-c) can be manufactured by a method similar to step 18 using compound (XIII-b).
Compound (XIII-d) wherein n2 is 1 can be manufactured using compounds (XIII-c) and (a-6) or compounds (XIII-c) and (a-7) by a method similar to step 13.
Compound (XIII-d) wherein n2 is 0 can be manufactured using compounds (XIII-c) and (a-4) by a method similar to step 3.
Furthermore, as an alternative method, compound (XIII-d), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured using compounds (XIII-c) and (a-3) by a method similar to step 2.
Compound (II-K) can be manufactured by reacting compound (XIII-d) in a solvent with an ammonia source preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a metallic catalyst preferably in 0.01 to 1 equivalent amount, and if needed, a base preferably in 1 equivalent to a large excess amount, and if needed, a ligand preferably in 0.01 to 1 equivalent amount, at a temperature between 0° C. and the boiling point of the solvent used.
The metallic catalysts include, for example, copper(0) copper(I) iodide, copper(II) acetate, copper(II) oxide, copper(I) chloride, copper(II) sulfate, palladium acetate, tris(dibenzylidene acetone)dipalladium, tetrakis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane 1:1 adduct and the like.
The bases include, for example, potassium carbonate, cesium carbonate, lithium chloride, potassium chloride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, potassium acetate, sodium ethoxide, sodium carbonate, sodium hydroxide, potassium phosphate, ethylenediamine, glycine, N-methylpyrrolidine, pyridine, 1,2-diaminocyclohexane and the like.
The ligands include, for example, phenanthroline, trans-1,2-cyclohexane diamine, picolinic acid, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, o-tolylphosphine, tributylphosphine, di-tert-butydiphenylphosphine, 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl and the like. Ligands are preferably used when palladium catalysts such as palladium acetate, tris(dibenzylidene acetone)dipalladium, tetrakis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene dichloropalladiu dichloromethane 1:1 adduct, and the like are used as metalic catalysts.
The ammonia sources include, for example, ammoniacal water, ammonium formate, ammonium acetate and the like.
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, DMF, HMPA, DMSO, 1,4-dioxane, water and the like. They are used alone or in mixtures.
Compound (X III-e) can be manufactured by treating compound (XIII-d) in a solvent with a cyano source preferably in 1 to 10 equivalent amount for 1 minute to 72 hours, if needed, in the presence of a palladium catalyst preferably in 0.01 to 1 equivalent amount, at a temperature between 0° C. and the boiling point of the solvent used (between 0° C. and 200° C. when a microwave reaction device is used).
The cyano sources include, for example, zinc(II) cyanide, copper(I) cyanide and the like.
The palladium catalysts include, for example, palladium acetate, tris(dibenzylidene acetone)dipalladium, tetrakis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene dichloropalladiumidichloromethane 1:1 adduct and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water and the like. They are used alone or in mixtures.
Compound (II-M) can be manufactured by a method similar to step 12 using compound (XIII-e).
Among compounds (II), compound (II-N) or compound (II-O) as a benzoxazole derivative or a benzothiazole derivative can be manufactured according to the following steps:
(wherein R2, R2A, R5, R6, X1, X2, X8, and n2 are the same as the definition described above).
Compound (XIII-g) can be manufactured by a method similar to step 83 using compound (XIII-f).
Compound (XIII-f) can be obtained as a commercially available product or by well-known methods (e.g., Japanese Unexamined Patent Application Publication No, 2009-40711 and the like) or their equivalent methods.
Compound (XIII-h) can be manufactured by a method similar to step 18 using compound (XIII-g).
Compound (XIII-i) wherein n2 is 1 can be manufactured using compounds (XIII-h) and (a-6) or compounds (XIII-h) and (a-7) by a method similar to step 13.
Compound (XIII-i) wherein n2 is 0 can be manufactured using compounds (XIII-h) and (a-4) by a method similar to step 3.
Furthermore, as an alternative method, compound (XIII-i), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured using compounds (XIII-h) and (a-3) by a method similar to step 2.
Compound (II-N) can be manufactured by a method similar to step 87 using compound (XIII-i).
Compound (XIII-j) can be manufactured using compound (XIII-i) by a method similar to step 88.
Compound (II-O) can be manufactured by a method similar to step 12 using compound (XIII-j).
Among compounds (II), compound (II-P) or compound (II-Q) as a benzoxazole derivative can be manufactured according to the following steps:
(wherein R2, R2A, X1, X2 and n2 are the same as the definition described above; and R15 represents an amino group or chloromethyl group).
Compound (II-P) wherein n2 is 1 can be manufactured using compounds (XIII-k) and (a-6) or compounds (XIII-k) and (a-7) by a method similar to step 13.
Compound (XIII-k) can be obtained as a commercially available product.
Compound (II-P) wherein n2 is 0 can be manufactured using compounds (XIII-k) and (a-4) by a method similar to step 3.
Furthermore, as an alternative method, compound (II-P), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured using compounds (XIII-k) and (a-3) by a method similar to step 2.
Compound (XIII-m) can be manufactured by reacting compound (II-P), wherein R15 is chloromethyl, in a solvent with potassium phthalimide in 1 to 20 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 1 to 20 equivalent amount, at a temperature between −78° C. and the boiling point of the solvent used.
The bases include, for example, potassium carbonate, potassium hydroxide and the like.
The solvents include, for example, methanol, ethanol, propanol, THF, 1,4-dioxane, DME, toluene, dichloromethane, DMF, water, and the like. They are used alone or in mixtures.
Compound (II-Q) can be manufactured by reacting compound (XIII-m) in a solvent in the presence of a base in 1 equivalent to a large excess amount for 5 minutes to 72 hours at a temperature between 0° C. and the boiling point of the solvent used.
The bases include, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, hydrazine monohydrate and the like.
The solvents include, for example, water-containing solvents. Said solvents are, for example, methanol, ethanol, propanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine and the like. They are used by mixing with water, or mixing each solvent and further adding water thereto.
Among compounds (II) including 2,3-dihydrobenzofuran derivative, 2,3-dihydrobenzothiophene derivative or 2,3-dihydrobenzothiophene 1,1-dioxide derivative, compound (II-R) wherein X is —O—, compound (II-S) wherein X is —NH—CO—, compound (II-T) wherein X is —CH═CH—, and (II-U) wherein X is —CH2— can be manufactured according to the following steps:
(wherein R2, R2A, X1, X2, X3, and n2 are the same as the definition described above; R16 represents a hydrogen atom or substituents except a halogen atom which are described above as the substituents for the optionally substituted heterocyclic diyl; and X9 represents —O—, —S— or —SO2—).
Compound (XIV-b) can be manufactured by a method similar to step 22 using compound (XIV-a).
Compound (XIV-a) can be obtained as a commercially available product or by well-known methods (e.g., WO2010/104194, WO2014/146493 and the like) or their equivalent methods.
Compound (XIV-c) can be manufactured by reacting compound (XIV-b) in a solvent or without solvent (i) with a hydrogen source preferably in 2 equivalents to a large excess amount for 5 minutes to 72 hours, or (ii) with hydrogen under the hydrogen atmosphere preferably at 1 to 20 atmospheric pressure for 5 minutes to 72 hours, by adding, if needed, an acid preferably in 1 equivalent to a large excess amount or if needed, an ammonia-alcoholic solution preferably in 1 equivalent to a large excess amount, in the presence of a catalyst preferably in 0.01 to 50% by weight relative to compound (XIV-b), at a temperature between −20° C. and the boiling point of the solvent used (between 0° C. and 150° C. when without solvent).
The acids include, for example, acetic acid, hydrochloric acid and the like.
The ammonia-alcoholic solutions include, for example, an ammonia-methanol solution, an ammonia-ethanol solution, an ammonia-2-propanol solution and the like.
The catalysts include, for example, palladium carbon, Raney nickel and the like.
The hydrogen sources include, for example, formic acid, ammonium formate, sodium formate, cyclohexadiene, hydrazine and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water and the like. They are used alone or in mixtures.
Furthermore, as an alternative method, compound (XIV-c) can be manufactured by reacting compound (XIV-b) in a solvent with a metal or metal salt preferably in 1 to 10 equivalent amount, by adding, if needed, an acid preferably in 1 equivalent to a large excess amount, at a temperature between −20° C. and the boiling point of the solvent used for 5 minutes to 72 hours.
The acids include, for example, acetic acid, hydrochloric acid and the like.
The metals or metal salts include, for example, tin, zinc, iron, samarium, indium, tin dichloride and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water and the like. They are used alone or in mixtures.
Compound (XIV-d) can be manufactured by reacting compound (XIV-c) in a solvent with pinacol diborane preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 0.1 to 10 equivalent amount and a palladium catalyst preferably in 0.001 to 0.5 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
The bases include, for example, potassium acetate, sodium acetate, potassium carbonate, potassium phosphate and the like.
The palladium catalysts include, for example, palladium acetate, tris(dibenzylidene acetone)dipalladium, tetrakis(triphenylphosphine)palladium, 1,1′-bis(diphenylphosphino)ferrocene dichloropalladium/dichloromethane 1:1 adduct and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water and the like. They are used alone or in mixtures.
Compound (XIV-e) can be manufactured by reacting compound (XIV-d) in a solvent with an oxidizing agent preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours at a temperature between −20° C. and the boiling point of the solvent used.
The oxidizing agents include, for example, hydrogen peroxide, urea hydrogen peroxide adduct and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water and the like. They are used alone or in mixtures.
Compound (II-R) wherein n2 is 1 can be manufactured using compounds (XIV-e) and (a-6), or compounds (XIV-e) and (a-7) by a method similar to step 13.
Compound (II-R) wherein n2 is 0 can be manufactured using compounds (XIV-e) and (a-4) by a method similar to step 3.
Furthermore, as an alternative method, compound (II-R), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured using compounds (XIV-e) and (a-3) by a method similar to step 2.
Compound (II-S) can be manufactured using compounds (XIV-c) and (a-14) by a method similar to step 65.
Compound (II-T) can be manufactured using compounds (XIV-c) and (a-15) by a method similar to step 66.
Compound (II-U) can be manufactured using compound (II-T) by a method similar to step 17.
Among compounds (II), compound (II-V) as a 2,3-dihydrobenzofuran derivative having a halogen atom as a substituent, 2,3-dihydrobenzothiophene derivative having a halogen atom as a substituent or 2,3-dihydrobenzothiophene 1,1-dioxide derivative having a halogen atom as a substituent, can be manufactured according to the following steps:
(wherein R2, R2A, X1, X2, X9 and n2 are the same as the definition described above; and R17 represents fluorine atom, chlorine atom, bromine atom or iodine atom).
Compound (XVI-g) can be manufactured by a method similar to step 101 using compound (XIV-f).
Compound (XIV-f) can be obtained as a commercially available product or by well-known methods (e.g., WO2014/146493 and the like) or their equivalent methods.
Compound (XVI-h) can be manufactured by a method similar to step 102 using compound (XIV-g).
Compound (II-V) wherein n2 is 1 can be manufactured using compounds (XIV-h) and (a-6) or compounds (XIV-h) and (a-7) by a method similar to step 13.
Compound (II-V) wherein n2 is 0 can be manufactured using compounds (XIV-h) and (a-4) by a method similar to step 3.
Furthermore, as an alternative method, compound (II-V), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured using compounds (XIV-h) and (a-3) by a method similar to step 2.
Among compounds (II), compounds (II-W) and (II-X), that are each dihydropyranopyridine derivative, can be manufactured according to the following steps:
(wherein R2, XA, XB and n2 are the same as the definition described above; and R10 represents chlorine atom or bromine atom; XD represents —SO2— or —CH2CH2—).
Compound (XV-b) wherein XB is XA can be manufactured by a method similar to step 34 using compounds (XV-a) and (a-6a).
Compound (XV-a) can be obtained as a commercially available product.
Compound (XV-b) wherein XB is —NH—CO— can be manufactured using compounds (XV-a) and (a-14) by a method similar to step 65.
Compound (XV-b) wherein X5 is —CH═CH— can be manufactured using compounds (XV-a) and (a-15) by a method similar to step 66.
Compound (II-W) can be manufactured by a method similar to step 1 using compound (XV-b).
Compound (XV-c) can be manufactured by a method similar to step 17 using compound (XV-b) wherein XB is —CH═CH—.
Compound (II-X) wherein XD is —CH2CH2— can be manufactured using compound (XV-c) by a method similar to step 1.
Compound (11-X) wherein XD is —SO2— can be manufactured by a method similar to step 62 using compound (II-W) wherein XB is —S—.
Among compounds (II), compound (II-Y) and compound (II-Z) that are each benzoxazepine derivative can be manufactured according to the following steps:
(wherein R2, R2A, R6, X1, X2, X5 and n2 are the same as the definition described above; and R18 represents optionally substituted alkyl).
Compound (XVI-b) can be manufactured by reacting compound (XVI-a) in a solvent with compound (a-18) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a reducing agent preferably in 1 to 10 equivalent amount, an acid preferably in 1 to 10 equivalent amount, and if needed, a metallic catalyst preferably in 0.01 to 1 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (XVI-a) can be obtained as a commercially available product.
Compound (a-18) can be obtained as a commercially available product, or obtained by well-known methods [e.g., “Jikken Kagaku Koza 14, 5th Ed., Synthesis of organic compounds II, alcohol/amine”, Maruzen (2005)] or by its equivalent methods.
The reducing agents include, for example, sodium triacetoxyborohydride, sodium cyanoborohydride and the like.
The acids include, for example, hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid and the like.
The metallic catalysts include, for example, dichloro(pentamethylcyclopentadienyl)rhodium(III), chloro[N-{4-(dimethylamino)phenyl}-2-pyridine carboxyamidate](pentamethylcyclopentadienyl)iridium(III) and the like.
The solvents include, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water and the like. They are used alone or in mixtures.
Compound (XVI-c) can be manufactured by reacting compound (XVI-b) in a solvent for 5 minutes to 72 hours in the presence of a phosphine compound preferably in 1 to 10 equivalent amount and an azo compound preferably in 1 to 10 equivalent amount, at a temperature between −78° C. and the boiling point of the solvent used.
The phosphine compounds include, for example, triphenylphosphine, tributylphosphine and the like.
The azo compounds include, for example, DEAD, di-tert-butyl azadicarboxylate, diisopropyl azadicarboxylate, N,N,N′,N′-tetramethyl azadicarboxamide, 1,1′-(azadicarbonyl)dipiperazine, N,N,N′,N′-tetraisopropyl azadicarboxamide and the like.
The solvents include, for example, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP and the like. They are used alone or in mixtures.
Compound (XVI-d) can be manufactured using compound (XVI-c) by a method similar to step 18.
Compound (XVI-e) wherein n2 is 1 can be manufactured using compounds (XVI-d) and (a-6) or compounds (XVI-d) and (a-7) by a method similar to step 13.
Compound XVI-e wherein n2 is 0 can be manufactured using compounds (XVI-d) and (a-4) by a method similar to step 3.
Furthermore, as an alternative method, compound (XVI-e), wherein n2 is 0 and R2 is optionally substituted aryl or optionally substituted aromatic heterocyclic group, can be manufactured using compounds (XVI-d) and (a-3) by a method similar to step 2.
Compound (XVI-f) can be manufactured using compound (XVI-e) by a method similar to step 88.
Compound (II-Y) can be manufactured using compound (XVI-e) by a method similar to step 87.
Compound (II-Z) can be manufactured by a method similar to step 12 using compound (XVI-f).
Among compounds (II), compound (II-Aa) that is a tetrahydrobenzoxepin derivative can be manufactured according to the following steps:
(wherein R2, R2A, X1, X2 and n2 are the same as the definition described above).
Compound (XVII-b) wherein n2 is 1 can be manufactured using compounds (XVII-a) and (a-6) or compounds (XVII-a) and (a-7) by a method similar to step 13.
Compound (XVII-a) can be obtained as a commercially available product.
Compound (XVII-b) wherein n2 is 0 can be manufactured using compounds (XVII-a) and (a-3) by a method similar to step 2.
Compound (XVII-c) can be manufactured by reacting compound (XVII-b) in a solvent with compound (a-19) preferably in 1 to 10 equivalent amount, for 5 minutes to 72 hours in the presence of a base preferably in 1 to 10 equivalent amount, at a temperature between −20° C. and the boiling point of the solvent used.
Compound (a-19) can be obtained as a commercially available product.
The bases include, for example, sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, diisopropyle hylamine, DBU and the like.
The solvents include, for example, methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, water and the like. They are used alone or in mixtures.
Compound (XVII-d) can be manufactured by treating compound (XVII-c) in a solvent in the presence of a base preferably in 1 equivalent to a large excess amount, for 5 minutes to 72 hours at a temperature between 0° C. and the boiling point of the solvent used.
The bases include, for example, potassium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium methoxide and the like.
The solvents include, for example, water-containing solvents. Said solvents are, for example, methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine and the like. They are used by mixing with water, or mixing each solvent and further adding water thereto.
Compound (XVII-e) can be manufactured by reacting compound (XVII-d) in a solvent or without solvent in the presence of an acid preferably in 1 equivalent to a large excess amount and if needed, a chlorinating agent in 1 equivalent to a large excess amount, at a temperature between 0° C. and the boiling point of the solvent used (between 0° C. and 150° C. when without solvent) for 5 minutes to 72 hours.
The acids include, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid and the like.
The chlorinating agents include, for example, thionyl chloride, phosphorus oxychloride, oxalyl chloride, phosphorus pentoxide and the like.
The solvents include, for example, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, pyridine and the like. They are used alone or in mixtures.
Compound (II-Aa) can be manufactured using compound (XVII-e) by a method similar to step 1.
Conversion of functional groups contained in R1 or R2 of compound (I) can be conducted by well-known methods [methods described in Comprehensive Organic Transformations 2nd Ed., by R. C. Larock, Vch Verlagsgesellschaft Mbh (1999), and the like] or their equivalent methods.
The intermediate and the target compound in each manufacturing method mentioned above can be isolated and purified by an isolation/purification procedure commonly used in synthetic organic chemistry, for example, by subjecting to filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography and the like. Furthermore, the intermediates can be supplied to the next reactions without being particularly purified.
Among compounds (I), stereoisomers such as geometric isomer, optical isomer, and the like, and tautomer and the like can be present, but the present invention includes all possible isomers and mixtures thereof.
A part or all of each atom in compound (I) may be substituted with the corresponding isotope, and the present invention includes these compounds substituted with these isotopes. For example, a part or all of hydrogen atom(s) in compound (I) may be hydrogen atom having an atomic weight of 2 (deuterium atom).
Compound (I), wherein a part or all of each atom is substituted with the corresponding isotope, can be manufactured by a method similar to the manufacturing method mentioned above using commercially available building blocks. Furthermore, a compound wherein a part or all of each hydrogen atom in compound (I) is substituted with deuterium can be synthesized by, for example, 1) a method by which carboxylic acid and the like are deuterated under the basic conditions using deuterium peroxide (refer to U.S. Pat. No. 3,849,458), 2) a method by which alcohol, carboxylic acid and the like are deuterated using an iridium complex as a catalyst and heavy water as a deuterium source [refer to J. Am. Chem. Soc., Vol. 124, No. 10, 2092 (2002)], 3) a method by which aliphatic acid is deuterated using palladium carbon as a catalyst and only deuterium gas as a deuterium source [refer to LIPIDS, Vol. 9, No. 11, 913 (1974)], 4) a method by which acrylic acid, methyl acrylate, methacrylic acid, methyl methacrylate, and the like are deuterated using a metal such as platinum, palladium, rhodium, ruthenium, iridium, and the like as a catalyst, and using heavy water or heavy water and deuterium gas as a deuterium source (refer to Japanese Examined Patent Application 5-19536, Japanese Unexamined Patent Application Publication No. 61-277648 and Japanese Unexamined Patent Application Publication No. 61-275241), 5) a method by which acrylic acid, methyl methacrylate, and the like are deuterated using a catalyst such as palladium, nickel, copper or copper chromite, and the like, and heavy water as a deuterium source (refer to Japanese Unexamined Patent Application Publication No. 63-198638), and the like.
When a salt of compound (I) is desired, in the case where compound (I) is obtained in the form of a salt, it can be purified as it is, or in the case where it is obtained in a free form, compound (I) can be dissolved or suspended in a suitable solvent and an acid or a base may be added to form a salt thereof followed by isolation and purification.
Furthermore, compound (I) and a pharmaceutically acceptable salt thereof may be present in the form of an adduct with water or various solvents, but these adducts are also included in the present invention.
Compounds represented in formula (I) of the present invention (compounds (I)) are preferably compounds described in the following Tables 1 to 32.
Compound (I) or a pharmaceutically acceptable salt thereof can be administered alone, but generally it is desirable to provide it as various pharmaceutical preparations. In addition, these pharmaceutical preparations are used for animals or humans, preferably humans.
The pharmaceutical preparation related to the present invention can contain compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient by itself, or as a mixture with any other active ingredients used for the treatment. Furthermore, those pharmaceutical preparations are manufactured by a well-known method in the technical field of pharmaceutics by mixing the active ingredient with one kind or more pharmaceutically acceptable carriers (e.g., an attenuant, a solvent, a diluent and the like).
The most effective administration route is desirably used for the treatment. For example, it includes an oral or parental administration route such as intravenous injection and the like.
Administration forms include, for example, tablets, injection and the like.
Suitable formulation for the oral administration, for example, such as tablets, can be manufactured using a diluent such as lactose, a disintegrant such as starch, a lubricant such as magnesium stearate, a binder such as hydroxypropylcellulose, and the like.
Suitable formulation for the parenteral administration, for example, such as injection, can be manufactured using an attenuant such as a salt solution, glucose solution or mixed solution of saline and glucose solutions; a solvent or the like.
Dose and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof differ depending on administration form, age, body weight, the nature of the symptoms to be treated or severity of them or the like of the patient. Generally, they are administered for oral administration at a dosage of 0.01 to 1000 mg per adult, preferably at a dosage of 0.05 to 100 mg once daily or several times a day. In the case of parenteral administrations such as intravenous administration, they are administered at a dosage of 0.001 to 1000 mg per adult, preferably at a dosage of 0.01 to 100 mg once daily or several times a day. However, the dose and frequency of the administration vary depending on the above-mentioned conditions.
According to another embodiment of the present invention, provided is a pharmaceutical composition comprising compound (I) or a pharmaceutically acceptable salt thereof and a carrier. The pharmaceutical composition of the present invention is used in administration routes and dosage forms and the like similar to the pharmaceutical preparation mentioned above. Furthermore, the carrier contained in the pharmaceutical composition of the present invention may be an attenuant, solvent, diluent, and the like that are similar to the case of the pharmaceutical preparation mentioned above. Furthermore, the pharmaceutical composition of the present invention is used preferably for the treatment or prevention of cancers, more preferably for the treatment or prevention of one or two or more cancers selected from the group consisting of mesothelioma, lung cancer, ovarian cancer and liver cancer. Here, prevention means that the clinical condition of a disease, the outcome of biological symptoms or the severity of the disease is substantially reduced, or that development of such condition or the biological symptoms is delayed, and the like. The situation is similar to the following prevention.
According to another embodiment of the present invention, provided is a method for the treatment or prevention comprising administering compound (I) of the present invention or a pharmaceutically acceptable salt thereof to a subject (preferably a subject in need thereof). The subject includes, for example, an animal other than a human, but is preferably a human. This is also the same in the following subjects. The method for the treatment or prevention in the present invention is preferably used for the treatment or prevention of cancers, more preferably is used for the treatment or prevention of one or two or more cancers selected from the group consisting of mesothelioma, lung cancer, ovarian cancer and liver cancer.
According to another embodiment, provided is compound (I) of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament.
According to another embodiment, provided is compound (I) of the present invention or a pharmaceutically acceptable salt thereof for use of treating or preventing cancers. Here, cancers are preferably one or two or more cancers selected from the group consisting of mesothelioma, lung cancer, ovarian cancer and liver cancer.
According to another embodiment, provided is use of compound (I) of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of drugs for the treatment or prevention of cancers. Here, cancers are preferably one or two or more cancers selected from the group consisting of mesothelioma, lung cancer, ovarian cancer and liver cancer.
According to another embodiment, provided is use of compound (I) of the present invention or a pharmaceutically acceptable salt thereof for the treatment or prevention of cancers.
According to another embodiment, provided is a medicament comprising compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
According to another embodiment, provided is a preventive or therapeutic agent for cancers comprising compound (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
The present invention will be explained by examples more specifically below, but the scope of the present invention is not limited to these examples.
The pharmacological action of the typical compound (I) will be specifically explained by a test example.
NCI-H226 cells, a human mesothelioma cell line (ATCC, CRL-5826), NCI-H322cells, a human lung cancer cell line (the European Collection of Authenticated Cell Cultures, 95111734), OUTOKO cells, a human ovarian cancer cell line (JCRB cell bank, KRB1048) and HuH28, a human liver cancer cell line (JCRB cell bank, KRB0426) were each subcultured by keeping the cell density under 80% in a RPMI1640 culture medium with 10% fetal bovine serum (FBS). NCI-H226 cells, NCI-H322 cells and SSP-25 cells were each suspended in the RPMI1640 culture medium mentioned above, and plated to a 96-well flat-bottom plate at 500 cells/well in each well, and incubated at 37° C. in an incubator with 5% CO2 for one day. After the incubation, the evaluation of cell growth inhibitory activity was started. OVTOKO cells were suspended in the RPMI1640 culture medium mentioned above, and plated to a 96-well flat-bottom plate at 250 cells/well in each well, and incubated it at 37° C. in an incubator with 5% CO2 for one day. After the incubation, the evaluation of the cell growth inhibitory activity was started. The next day, a test compound was serially diluted to 5 times of its final concentration in the RPM11640 culture medium mentioned above, and the diluted solution was added to each well. In this case, the final concentration of DMSO in each well was adjusted to 0.1%. After the test compound was added, cells were incubated at 37° C. in an incubator with 5% CO2 for 6 days. At the addition of the test compound and 6 days after the addition, the cell counting measurement was performed using a cell counting kit 8 (made by DOJINDO) according to a protocol equivalent to DOJINDO's recommendation. A reagent contained in the kit was added to each plate and and color reaction was performed for 2 or 3 hours at 37° C. in an incubator with 5% CO2. After the reaction, an absorbance at wavelength of 450 nm was measured using a microplate reader. A growth inhibition rate was calculated according to the following formula, from which the concentration of a test compound at which cell growth was inhibited by 50% (GI50 value) was determined.
Among compounds described in the following examples, compounds 1, 3, 5, 11, 19-22, 27, 28, 30-35, 39-44, 50, 51, 56, 59, 60, 68, 70, 71, 76, 82, 95, 96, 100, 107-109, 111, 112, 114, 117, 126, 133, 134, 137-139, 143, 149-151, 155, 157, 163, 167, 168, 169, 176, 178, 179, 184, 185, 187, 189, 190, 199, 200, 201, 202, 203, 211, 212, 214, 216, 219, 222, 223, 224, 225, 226, 227, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 243-245, 247, 249-253, 256, 257, 262-264, 270, 272, 276, 277 and 279-288 exhibited a GI50 value of less than 100 nmol/L and compounds 14, 16, 23, 24, 26, 29, 49, 67, 81, 92-94, 101-103, 105, 106, 110, 116, 120, 123, 135, 136, 142, 144, 146, 147, 153, 156, 159, 162, 164, 166, 172, 181, 186, 192, 196, 206, 208, 220, 221, 246, 248, 254, 255, 259, 261, 265-269, 273, 275 and 278 exhibited a GI50 value of 100 nmol/L to 1 μmol/L against the human mesothelioma cell line, NCI-H226 cells.
Among compounds described in the following examples, compounds 5, 21, 22, 27, 28, 31-33, 35, 37, 40-42, 44, 50, 51, 59, 61, 64, 68, 70, 71, 76, 82, 95, 96, 106-109, 111, 112, 114, 117, 126, 134, 137-139, 143, 149-151, 155, 157, 162-164, 168, 169, 176, 179, 184, 185, 187, 189, 190, 192, 199-203, 206, 208, 211, 212, 214, 216, 219, 220, 222-230, 241, 243-253, 256, 257, 259, 262-266, 268-270, 272, 275 and 277-288 exhibited a GI50 value of less than 1000 nmol/L against the human lung cancer cell line, NCI-H322 cells.
Among compounds described in the following examples, compounds 5, 21, 22, 27, 28, 31-33, 35, 37, 40-42, 44, 51, 59, 61, 68, 70, 71, 76, 82, 95, 96, 100, 105-109, 111, 112, 114, 117, 126, 134, 137, 138, 143, 149-151, 155, 157, 162-164, 168, 169, 176, 179, 184, 185, 187, 189, 190, 192, 199, 200-203, 206, 208, 211, 212, 216, 219, 222-224, 226, 227, 229, 230, 241, 243, 244, 247, 249,250, 256, 267-273 and 275-288 exhibited a GI50 value of 3000 nmol/L or less against the human ovarian cancer cell line, OVTOKO cells.
Among compounds described in the following examples, compounds 5, 22, 28, 31, 33, 40, 68, 95, 96, 107, 108, 111, 112, 114, 117, 126, 134, 137, 138, 139, 143, 149-151, 155, 163, 164, 168, 169, 176, 179, 185, 187, 189, 190, 192, 199, 200-203, 206, 208, 211, 212 and 222-227, 243-247, 249-253, 256, 257, 268-273 and 275-288 exhibited a GI50 value of less than 3000 nmol/L against human liver cancer cell line, HuH28 cells.
As mentioned above, compound (I) of the present invention represented in test compounds exhibited a high growth inhibitory effect on NCI-H226 cells as the human mesothelioma cell line, on NCI-H322 cells as the human lung cancer cell line, on OVTOKO cells as the human ovarian cancer cell line, and on HuH28 cells as the human liver cancer cell line. Therefore, compound (I) of the present invention was found to be useful as a preventive or therapeutic agent or the like for cancers.
The proton nuclear magnetic resonance spectrum (1H NMR) used in the following examples is measured at 300 MHz or 400 MHz, and sometimes an exchangable proton may not be clearly observed depending on compounds and measurement conditions. In addition, commonly used notation is used as one for the multiplicity of signals, but br expresses an apparent wide signal.
To a mixture of resorcinol (5.00 g, 45.4 mmol) and 3-chloropropionic acid (4.90 g, 45.4 mmol), trifluoromethanesulfonic acid (15 mL) was added, and the mixture was stirred at 80° C. for 0.5 hours. A reaction liquid obtained by adding dichloromethane (100 mL) to the mixture left to cool to room temperature was gradually added to water (100 mL). The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1-1 (6.00 g) as a crude product.
1H NMR (400 MHz, CDCl3, δ): 12.48 (s, 1H), 7.62 (d, J=11.6 Hz, 1H), 6.43-6.39 (m, 2H), 3.90 (t, J=9.2 Hz, 2H), 3.40 (t, J=9.2 Hz, 2H).
To compound 1-1 (6.00 g), a 2 mol/L aqueous sodium hydroxide solution (250 mL) was added at −5° C., and the mixture was stirred at room temperature for 2 hours. The mixture was cooled to −5° C., and 2 mol/L sulfuric acid was added to the mixture to adjust pH to 2. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1-2 (3.00 g, 40% over two steps).
1H NMR (400 MHz, DMSO-d6, 5): 12.48 (s, 1H), 7.62 (d, J=11.6 Hz, 1H), 6.43-6.39 (m, 2H), 3.90 (t, J=9.2 Hz, 2H), 3.40 (t, J=9.2 Hz, 2H).
Compound 1-2 (0.50 g, 3.04 mmol) was dissolved in dichloromethane (15 mL), and phenylboronic acid (0.74 g, 6.09 mmol), pyridine (1.22 mL, 15.2 mmol), and copper(II) acetate (0.82 g, 4.57 mmol) were added to the solution. The solution was stirred at room temperature for 18 hours. Dichloromethane (30 mL) was added to the mixture, followed by filtration with Celite(R), and the solid on the Celite was washed with dichloromethane (50 mL). The organic layer in the filtrate was washed with 2 mol/L hydrochloric acid, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>70/30) to obtain compound 1-3 (0.075 g, 10%).
1H NMR (400 MHz, CDCl3, 6): 7.87 (d, J=8.8 Hz, 1H), 7.42-7.38 (m, 2H), 7.09-7.07 (m, 2H), 6.84-6.82 (m, 1H), 6.63 (dd, J=8.8, 2.4 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 4.50 (t, J=6.4 Hz, 2H), 2.76 (t, J=6.4 Hz, 2H);
ESIMS m/z: [M+H]+241.
Compound 1-3 (0.05 g, 0.21 mmol) was dissolved in methanol (3 mL), and ammonium acetate (0.24 g, 3.12 mmol) and sodium cyanoborohydride (0.04 g, 0.62 mmol) were added to the solution. The mixture was stirred at 80° C. for 18 hours in a sealed tube. The mixture was left to cool to room temperature, and water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1-4 (0.03 g, 60%).
1H NMR (400 MHz, CDCl3, δ): 7.39-7.34 (m, 3H), 7.12 (t, J=7.6 Hz, 1H), 6.99-6.97 (m, 2H), 6.50 (dd, J=8.4, 2.4 Hz, 1H), 6.30 (d, J=2.4 Hz, 1H), 4.26-4.20 (m, 1H), 4.14-4.09 (m, 1H), 3.86 (t, J=5.2 Hz, 1H), 2.01-1.94 (m, 1H), 1.75-1.68 (m, 1H).
Compound 1-4 (0.15 g, 0.62 mmol) was dissolved in dichloromethane (5 mL), and diisopropylethylamine (0.23 mL, 1.24 mmol) and acryloyl chloride (0.075 mL, 0.93 mmol) were added to the solution under cooling at 0° C. The mixture was stirred at 0° C. for 0.5 hours. A saturated aqueous sodium bicarbonate solution was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10−>50/50) to obtain compound 1 (0.08 g, 44%).
1H NMR (400 MHz, DMSO-d6, δ): 8.55 (d, J=8.0 Hz, 1H), 7.41-7.36 (m, 2H), 7.16-7.13 (m, 2H), 7.00-6.98 (m, 2H), 6.54 (dd, J=8.4, 2.4 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 6.26 (dd, J=16.8, 9.6 Hz, 1H), 6.15 (dd, J=16.8, 2.4 Hz, 1H), 5.62 (dd, J=10.0, 2.4 Hz, 1H), 5.04 (q, J=5.6 Hz, 1H), 4.26-4.13 (m, 2H), 2.10-1.86 (m, 2H)
ESIMS m/z: [M−70]+225.
The following compounds were synthesized in accordance with the synthesis method of compound 1.
ESIMS m/z: [M−70]+259.
ESIMS m/z: [M−70]+239.
Compound 2-1 (0.26 g, 26%) was obtained in the same manner as step 3 of example 1, using compound 1-2.
1H NMR (300 MHz, CDCl3, δ): 7.87 (d, J=8.7 Hz, 1H), 7.36 (dd, J=6.9, 2.1 Hz, 2H), 7.01 (dd, J=6.9, 2.4 Hz, 2H), 6.62 (dd, J=9.0, 2.4 Hz, 1H), 6.42 (d, J=2.1 Hz, 1H), 4.51 (t, J=6.3 Hz, 2H), 2.77 (t, J=6.3 Hz, 2H).
Compound 2-2 (0.20 g, 80%) was obtained in the same manner as in step 4 of example 1, using compound 2-1 obtained in step 1.
1H NMR (400 MHz, CDCl3, δ): 7.28-7.24 (m, 3H), 6.95-6.93 (m, 2H), 6.55 (dd, J=8.4, 2.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 4.30-4.18 (m, 2H), 4.04-4.02 (m, 1H), 2.18-2.10 (m, 1H), 1.86-1.79 (m, 1H).
Compound 3 (0.11 g, 55%) was obtained in the same manner as step 5 of example 1, using compound 2-2.
1H NMR (400 MHz, DMSO-d6, δ): 8.58 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.4Hz, 1H), 6.99 (d, J=8.8Hz, 2H), 6.57 (dd, J=8.4, 2.4 Hz, 1H), 6.44 (d, J=2.0 Hz, 1H), 6.29-6.13 (m, 2H), 5.63 (dd, J=10.0, 2.4 Hz, 1H), 5.07-5.02 (m, 1H), 4.26-4.14 (m, 2H), 2.10-1.87 (m, 2H);
ESIMS m/z: [M−70]+259.
Compound 3 was optically resolved under the following chiral preparative conditions to obtain compound 13 (17 mg, 34%) having a retention time of 3.31 minutes and compound 12 (15 mg, 31%) having a retention time of 4.17 minutes.
Compound 1-2 (0.80 g, 4.87 mmol) was dissolved in dichloromethane (20 mL), and 4-trifluoromethylphenylboronic acid (7.40 g, 39.0 mmol), pyridine (1.96 mL, 24.4 mmol), and copper(II) acetate (1.77 g, 9.75 mmol) were added to the solution. The mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the mixture. The mixture was filtered with Celite(R). The organic layer in the filtrate was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20−>20/80) to obtain compound 3-1 (0.18 g, 12%).
1H NMR (400 MHz, CDCl3, δ): 7.91 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.5 Hz, 2H), 7.16 (d, J=8.5 Hz, 2H), 6.67 (dd, J=8.8, 2.2 Hz, 1H), 6.51 (d, J=2.2 Hz, 1H), 4.54 (t, J=6.5 Hz, 2H), 2.80 (t, J=6.5 Hz, 2H).
Compound 3-1 (0.45 g, 1.44 mmol) was dissolved in methanol (14 mL). Added to the solution were ammonium formate (1.82 g, 28.9 mmol), acetic acid (0.12 mL, 2.17 mmol), and chloro[N-{4-(dimethylamino)phenyl}-2-pyridinecarboxyamidate](pentame thylcyclopentadienyl)iridium(III) (0.026 g, 0.043 mmol), and the mixture was stirred at 80° C. for 2.5 hours. The mixture was left to cool to room temperature, methanol was concentrated under reduced pressure, and water and ethyl acetate were added to the mixture. The mixture was filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=50/50−>chloroform/methanol=90/10) to obtain compound 3-2 (0.43 g, 97%).
Compound 5 (0.26 g, 51%) was obtained in the same manner as step 5 of example 1, using compound 3-2.
1H NMR (400 MHz, CDCl3, δ): 7.58 (d, J=8.8 Hz, 2H), 7.21 (d, J=8.6 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 6.61 (dd, J=8.6, 2.4 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 6.36 (dd, J=17.0, 1.2 Hz, 1H), 6.11 (dd, J=17.0, 10.4 Hz, 1H), 5.77 (d, J=6.8 Hz, 1H), 5.72 (dd, J=10.4, 1.2 Hz, 1H), 5.26-5.20 (m, 1H), 4.33-4.26 (m, 1H), 4.20-4.13 (m, 1H), 2.28-2.23 (m, 1H), 2.16-2.08 (m, 1H);
ESIMS m/z: [M−H]+ 362.
The following compounds were synthesized in accordance with the synthesis method of compound 5.
ESIMS m/z: [M−H]+ 396.
ESIMS m/z: [M−H]+ 378.
ESIMS m/z: [M−H]+ 346.
Compound 1-2 (1.50 g, 9.14 mmol) was dissolved in DMF (15 mL). Benzyl bromide (1.62 g, 13.7 mmol) and potassium carbonate (3.78 g, 27.4 mmol) were added to the solution, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>85/15) to obtain compound 4-1 (2.00 g, 86%).
1H NMR (300 MHz, DMSO-d6, δ): 7.68 (d, J=8.7 Hz, 1H), 7.45-7.30 (m, 5H), 6.70 (dd, J=8.7, 2.4 Hz, 1H), 6.20 (d, J=2.4 Hz, 1H), 5.17 (s, 2H), 4.50 (t, J=6.3 Hz, 2H), 2.70 (t, J=6.3 Hz, 2H).
Compound 4-2 (1.50 g, 75%) was obtained in the same manner as step 4 of example 1, using compound 4-1.
1H NMR (300 MHz, DMSO-d6, δ): 7.39-7.30 (m, 5H), 7.22 (d, J=8.7 Hz, 1H), 6.51 (dd, J=8.4, 2.4 Hz, 1H), 6.33 (d, J=2.4 Hz, 1H), 5.03 (s, 2H), 4.22-4.16 (m, 1H), 4.10-4.05 (m, 1H), 3.80 (t, J=5.1 Hz, 1H), 1.97-1.88 (m, 1H), 1.72-1.64 (m, 1H).
Compound 4-2 (1.50 g, 5.88 mmol) was dissolved in ethanol (50 mL), and 10% palladium carbon (0.15 g) was added to the solution. The mixture was stirred under hydrogen atmosphere at a pressure of 60 psi at room temperature for 16 hours. The mixture was filtered with Celite(R), and the filtrate was concentrated under reduced pressure to obtain compound 4-3 (0.60 g, 61%).
1H NMR (400 MHz, DMSO-d6, δ): 7.10 (d, J=8.4 Hz, 1H), 6.27 (dd, J=8.1, 2.4 Hz, 1H), 6.09 (d, J=2.4 Hz, 1H), 4.20-4.08 (m, 1H), 4.07-4.02 (m, 1H), 3.80 (t, J=5.1 Hz, 1H), 1.96-1.92 (m, 1H), 1.72-1.64 (m, 1H).
4-Iodo-N,N-dimethylaniline (0.20 g, 1.21 mmol) was dissolved in DMSO (10 mL), and compound 4-3 (0.44 g, 1.81 mmol), tripotassium phosphate (0.51 g, 2.42 mmol), picolinic acid (0.014 g, 0.12 mmol), and copper(I) iodide (0.012 g, 0.06 mmol) were added to the solution under argon atmosphere. The mixture was stirred at 90° C. for 16 hours. Water was added to the mixture, and the mixture was filtered with Celite(R). The organic layer in the filtrate was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40−>40/60) to obtain compound 4-4 (0.13 g, 37%).
1H NMR (400 MHz, DMSO-d6, δ): 7.27 (d, J=7.2 Hz, 1H), 6.88 (d, J=9.2 Hz, 2H), 6.74 (d, J=9.2 Hz, 2H), 6.39 (dd, J=8.0, 2.4 Hz, 1H), 6.15 (d, J=2.4 Hz, 1H), 4.22-4.18 (m, 1H), 4.09-4.07 (m, 1H), 3.80-3.78 (m, 1H), 2.86 (s, 6H), 1.98-1.95 (m, 1H), 1.72-1.70 (m, 1H).
Compound 6 (0.055 g, 35%) was obtained in the same manner as step 5 of example 1, using compound 4-4.
1H NMR (400 MHz, DMSO-d6, δ): 8.51 (d, J=7.6 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.88 (d, J=9.2 Hz, 2H), 6.74 (d, J=8.8 Hz, 2H), 6.43 (dd, J=8.8, 2.8 Hz, 1H), 6.28-6.21 (m, 2H), 6.14 (dd, J=16.8, 2.4 Hz, 1H), 5.61 (dd, J=9.6, 2.4 Hz, 1H), 5.02-4.98 (m, 1H), 4.21-4.08 (m, 2H), 2.87 (m, 6H), 2.09-2.00 (m, 1H), 1.98-L84 (m, 1H);
ESIMS m/z: [M+H]+ 339.
The following compound was synthesized in accordance with the synthesis method of compound 6.
ESIMS m/z: [M−70]+ 250.
Compound 1-2 (70.0 mg, 0.426 mmol) was dissolved in DMF (1 mL), and potassium carbonate (431 mg, 3.41 mmol) and 2,6-dichloro-3-(trifluoromethyl)pyridine (0.092 mL, 0.853 mmol) were added to the solution. The mixture was stirred at 50° C. overnight. Water and ethyl acetate were added to the mixture. The mixture was filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL), and the filtrate was concentrated. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>heptane/ethyl acetate=70/30) to obtain compound 5-1 (41.0 mg, 28%).
1H NMR (400 MHz, CDCl3, δ): 8.02 (d, J=8.2 Hz, 1H), 7.96 (d, J=8.2 Hz, 1H), 6.97 (d, J=8.2 Hz, 1H), 6.82 (d, J=2.3 Hz, 1H), 6.80-6.79 (m, 1H), 4.58 (t, J=6.6 Hz, 2H), 2.83 (t, J=6.6 Hz, 2H).
Compound 5-2 was obtained as a crude product in the same manner as step 2 of example 3, using compound 5-1, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 344.
Compound 11 (20.3 mg, 43% over two steps) was obtained in the same manner as step 5 of example 1, using compound 5-2.
1H NMR (400 MHz, CDCl3, δ): 7.96 (d, J=8.6 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.70 (dd, J=8.6, 2.4 Hz, 1H), 6.64 (d, J=2.4 Hz, 1H), 6.36 (dd, J=16.8, 1.4 Hz, 1H), 6.13 (dd, J=16.8, 10.4 Hz, 1H), 5.98 (d, J=7.2 Hz, 1H), 5.71 (dd, J=10.4, 1.4 Hz, 1H), 5.25-5.23 (m, 1H), 4.32-4.29 (m, 1H), 4.21-4.15 (m, 1H), 2.30-2.20 (m, 1H), 2.16-2.09 (m, 1H);
ESIMS m/z: [M−H]+ 397.
Compound 14 (0.075 g, 45%) was obtained in the same manner as step 5 of example 1, using compound 4-2.
1H NMR (400 MHz, CDCl3, δ): 7.43-7.30 (m, 5H), 7.10 (d, J=8.4 Hz, 1H), 6.57 (dd, J=8.4, 2.6 Hz, 1H), 6.45 (d, J=2.6 Hz, 1H), 6.33 (dd, J=16.9, 1.5 Hz, 1H), 6.07 (dd, J=16.9, 10.3 Hz, 1H), 5.74 (d, J=7.3 Hz, 2H), 5.68 (dd, J=10.3, 1.5 Hz, 2H), 5.14 (dd, J=12.5, 5.1 Hz, 1H), 5.02 (s, 2H), 4.27-4.24 (m, 1H), 4.15-4.07 (m, 1H);
ESIMS m/z: [M+H]+ 310.
The following compound was synthesized in accordance with the synthesis method of compound 14.
ESIMS m/z: [M−70]+ 273.
Compound 1-2 (0.10 g, 0.61 mmol) was dissolved in THF (3 mL), and, triphenylphosphine (0.32 g, 1.22 mmol), diethyl azodicarboxylate (a 2.2 mol/L toluene solution, 0.55 mL, 1.22 mmol), and cyclohexanemethanol (0.15 mL, 1.22 mmol) were added to the solution. The mixture was stirred at room temperature for 3 hours. After the mixture was concentrated under reduced pressure, the mixture was purified by silica gel column chromatography (heptane/ethyl acetate=90/10) to obtain compound 7-1 as a crude product, which was used as it is in the next reaction.
Compound 7-2 was obtained as a crude product in the same manner as step 4 of example 1, using compound 7-1, and used as it is in the next reaction.
Compound 16 (0.12 g, 62% over three steps) was obtained in the same manner as step 5 of example 1, using compound 7-2.
1H NMR (300 MHz, CDCl3, δ): 7.08 (d, J=8.4 Hz, 1H), 6.49 (dd, J=8.4, 2.6 Hz, 1H), 6.33 (dd, J=17.2, 1.8 Hz, 2H), 6.07 (dd, J=16.9, 10.3 Hz, 1H), 5.74 (d, J=7.0 Hz, 1H), 5.68 (dd, J=10.3, 1.5 Hz, 1H), 5.13 (dd, J=12.3, 4.9 Hz, 1H), 4.30-4.21 (m, 1H), 4.15-4.07 (m, 1H), 3.70 (d, J=6.2 Hz, 2H), 2.28-2.16 (m, 1H), 2.14-2.03 (m, 1H), 1.89-1.67 (m, 5H), 1.35-1.18 (m, 4H), 1.08-0.95 (m, 2H);
ESIMS m/z: [M+H]+ 316.
Compound 1-3 (0.10 g, 0.41 mmol) was dissolved in THF (3 mL), and a 1.6 mol/L methyllithium solution in diethyl ether (0.78 mL, 1.25 mmol) was added dropwise to the solution, at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the mixture. The organic layer was extracted with ethyl acetate , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-1 (0.10 g, 95%).
1H NMR (400 MHz, CDCl3, δ): 7.45-7.36 (m, 3H), 7.15-7.11 (m, 1H), 6.99 (d, J=7.6 Hz, 2H), 6.52 (dd, J=8.8, 2.4 Hz, 1H), 6.30 (d, J=2.4 Hz, 1H), 5.10 (s, 1H), 4.25-4.11 (m, 2H), 1.97-1.88 (m, 2H), 1.46 (s, 3H).
Compound 8-1 (0.10 g, 0.39 mmol) was dissolved in chloroform (3 mL), and sodium azide (0.25 g, 3.90 mmol) was added to the solution. A mixed liquid of trifluoroacetic acid (0.15 mL, 1.95 mmol) and chloroform (3 mL) were added dropwise to the mixture at 0° C. The mixture was stirred at room temperature for 3 hours. Water was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10−>80/20) to obtain compound 8-2 (0.06 g, 51%).
1H NMR (400 MHz, CDCl3, δ): 7.48-7.36 (m, 3H), 7.20-7.16 (m, 1H), 7.05-7.00 (m, 2H), 6.59 (dd, J=8.4, 2.4 Hz, 1H), 6.39 (d, J=2.8 Hz, 1H), 4.28-4.11 (m, 2H), 2.18-1.89 (m, 2H), 1.65 (s, 3H).
Compound 8-2 (0.05 g, 0.17 mmol) was dissolved in THF (3 mL), and a 2 mol/L lithium aluminum hydride solution in THF (0.44 mL, 0.88 mmol) was added dropwise to the solution at 0° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The mixture was cooled to 0° C., and water was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 8-3 (0.02 g, 65%).
1H NMR (400 MHz, CDCl3, δ): 7.50 (d, J=8.4 Hz, 1H), 7.39-7.35 (m, 2H), 7.14-7.10 (m, 1H), 7.02-6.97 (m, 2H), 6.50 (dd, J=8.4, 2.4 Hz, 1H), 6.27 (d, J=2.8 Hz, 1H), 4.25-4.10 (m, 2H), 1.77-1.74 (m, 2H), 1.36 (s, 3H).
Compound 17 (0.08 g, 40%) was obtained in the same manner as step 5 of example 1, using compound 8-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.14 (s, 1H), 7.42-7.32 (m, 3H), 7.15 (t, J=7.2 Hz, 1H), 7.01 (d, J=8.0 Hz, 2H), 6.51 (dd, J=8.4, 2.0 Hz, 1H), 6.36-6.29 (m, 2H), 6.01 (dd, J=17.2, 2.0 Hz, 1H), 5.51 (dd, J=10.0, 1.6 Hz, 1H), 4.16-4.13 (m, 2H), 2.84-2.78 (m, 1H), 1.80-1.74 (m, 1H), 1.65 (s, 3H);
ESIMS m/z: [M−70]+ 239.
Compound 9-1 (170 mg, 72%) was obtained in the same manner as step 1 of example 3, using commercially available 7-hydroxy-2,2-dimethylchroman-4-one.
1H NMR (400 MHz, CDCl3, δ): 7.84 (d, J=8.6 Hz, 1H), 7.37-7.35 (m, 2H), 7.04-7.02 (m, 2H), 6.59 (dd, J=8.6, 2.3 Hz, 1H), 6.36 (d, J=2.3 Hz, 1H), 2.68 (s, 2H), 1.44 (s, 6H).
Compound 9-2 was obtained as a crude product in the same manner as step 2 of example 3, using compound 9-1, and used as it is in the next reaction.
ESIMS m/z: [M−17]+ 287.
Compound 18 (38.0 mg, 35% over two steps) was obtained in the same manner as step 5 of example 1, using compound 9-2.
1H NMR (400 MHz, CDCl3, δ): 7.31-7.26 (m, 2H), 7.16 (d, J=8.6 Hz, 1H), 6.96-6.93 (m, 2H), 6.54 (dd, J=8.6, 2.7 Hz, 1H), 6.38 (d, J=2.7 Hz, 1H), 6.34 (dd, J=17.0, 1.4 Hz, 1H), 6.14 (dd, J=17.0, 10.4 Hz, 1H), 5.81 (d, J=8.6 Hz, 1H), 5.70 (dd, J=10.4, 1.4 Hz, 1H), 5.35-5.32 (m, 1H), 2.23 (dd, J=13.3, 6.3 Hz, 1H), 1.71 (dd, J=13.3, 10.9 Hz, 1H), 1.40 (s, 3H), 1.33 (s, 3H);
ESIMS m/z: [M−H]+ 356.
Trifluoromethanesulfonic acid (3.2 mL) was added to a mixture of resorcinol (500 mg, 4.54 mmol) and crotonic acid (430 mg, 4.99 mmol),and the mixture was stirred at 80° C. for 2 hours. The mixture left to cool to room temperature was gradually added to a 2 mol/L aqueous sodium hydroxide solution. The organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>heptane/ethyl acetate=50/50) to obtain compound 10-1 (55.0 mg, 7%).
1H NMR (400 MHz, DMSO-d6, δ): 7.59 (d, J=8.6 Hz, 1H), 6.46 (dd, J=8.6, 2.3 Hz, 1H), 6.28 (d, J=2.3 Hz, 1H), 4.58-4.55 (m, 1H), 2.62-2.58 (m, 2H), 1.39 (d, J=6.3 Hz, 3H).
Compound 10-2 (66.5 mg, 83%) was obtained in the same manner as step 1 of example 3, using compound 10-1.
1H NMR (400 MHz, CDCl3, δ): 7.65 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.5 Hz, 1H), 7.16 (d, J=8.5 Hz, 2H), 6.67 (dd, J=8.5, 2.5 Hz, 1H), 6.49 (d, J=2.5 Hz, 1H), 4.62-4.59 (m, 1H), 2.68-2.67 (m, 2H), 1.50 (d, J=6.3 Hz, 3H).
Compound 10-3 was obtained as an unpurified crude product in the same manner as step 2 of example 3, using compound 10-2, and used as it is in the next reaction.
ESIMS m/z: [M−16]+ 307.
Compound 19 (16.8 mg, 22% over two steps) and compound 20 (12.9 mg, 17% over two steps) were obtained in the same manner as step 5 of example 1, using compound 10-3.
Compound 19: 1H NMR (400 MHz, CDCl3, δ): 7.57 (d, J=8.6 Hz, 2H), 7.21 (dd, J=8.6, 0.9 Hz, 1H), 7.06 (d, J=8.6 Hz, 2H), 6.60 (dd, J=8.6, 2.5 Hz, 1H), 6.48 (d, J=2.5 Hz, 1H), 6.38 (dd, J=17.0, 1.1 Hz, 1H), 6.14 (dd, J=17.0, 10.4 Hz, 1H), 5.74 (dd, J=10.4, 1.4 Hz, 1H), 5.64 (d, J=8.6 Hz, 1H), 5.47-5.41 (m, 1H), 4.34-4.28 (m, 1H), 2.43-2.40 (m, 1H), 1.65-1.62 (m, 1H), 1.41 (d, J=6.3 Hz, 3H)
ESIMS m/z: [M−H]+ 376.
Compound 20: 1H NMR (400 MHz, CDCl3, δ): 7.58 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.6 Hz, 1H), 7.07 (d, J=8.6 Hz, 2H), 6.62 (dd, J=8.6, 2.5 Hz, 1H), 6.51 (d, J=2.5 Hz, 1H), 6.35 (dd, J=17.0, 1.4 Hz, 1H), 6.08 (dd, J=17.0, 10.4 Hz, 1H), 5.81 (d, J=6.8 Hz, 1H), 5.70 (dd, J=10.4, 1.4 Hz, 1H), 5.15-5.11 (m, 1H), 4.20-4.13 (m, 1H), 2.23 (dt, J=14.3, 2.0 Hz, 1H), 1.90-1.86 (m, 1H), 1.43 (d, J=6.3 Hz, 3H)
ESIMS m/z: [M−H]+ 376.
Compound 3-1 (110 mg, 0.357 mmol) was dissolved in methanol (1 mL), and 1-fluoro-4-hydroxy-1,4-diazabicyclo[2.2.2]octane-1,4-diium tetrafluoroborate (50% on aluminum oxide, 276 mg, 0.428 mmol) was added to the solution. The mixture was stirred at 80° C. for 2 hours, followed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>heptane/ethyl acetate=60/40) to obtain compound 114 (90.0 mg, 77%).
1H NMR (400 MHz, CDCl3, δ): 7.94 (d, J=8.6 Hz, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.6 Hz, 2H), 6.74 (dd, J=8.6, 2.3 Hz, 1H), 6.52 (d, J=2.3 Hz, 1H), 5.11 (ddd, J=47.1, 4.2, 2.1 Hz, 1H), 4.62-4.56 (m, 2H).
Compound 11-2 was obtained as a crude product in the same manner as step 2 of example 3, using compound 11-1, and used as it is in the next reaction.
Compound 21 (44.5 mg, 41% over two steps) and compound 22 (5.5 mg, 5% over two steps) were obtained in the same manner as step 5 of example 1, using compound 11-2.
Compound 21: 1H NMR (400 MHz, CDCl3, δ): 7.58 (d, J=8.6 Hz, 2H), 7.20 (d, J=8.6 Hz, 1H), 7.06 (d, J=8.6 Hz, 2H), 6.65 (dd, J=8.6, 2.7 Hz, 1H), 6.55 (d, J=2.7 Hz, 1H), 6.43 (dd, J=17.0, 0.9 Hz, 1H), 6.23 (dd, J=17.0, 10.2 Hz, 1H), 6.10 (d, J=9.1 Hz, 1H), 5.80 (dd, J=10.2, 0.9 Hz, 1H), 5.58 (ddd, J=29.9, 9.5, 3.2 Hz, 1H), 5.02 (dt, J=48.5, 3.2 Hz, 1H), 4.59-4.52 (m, 1H), 4.26 (dd, J=39.0, 13.1 Hz, 1H);
ESIMS m/z: [M−H]+ 380.
Compound 22: 1H NMR (400 MHz, CDCl3, δ): 7.59 (d, J=8.6 Hz, 2H), 7.23 (d, J=8.2 Hz, 1H), 7.08 (d, J=8.6 Hz, 2H), 6.68 (dd, J=8.4, 2.5 Hz, 1H), 6.58 (d, J=2.3 Hz, 1H), 6.38 (dd, J=16.8, 1.4 Hz, 1H), 6.09 (dd, J=17.0, 10.2 Hz, 1H), 5.75 (dd, J=10.4, 1.4 Hz, 1H), 5.65 (d, J=5.4 Hz, 1H), 5.21-5.19 (m, 1H), 5.03 (dtd, J=45.2, 3.4, 1.4 Hz, 1H), 4.49-4.42 (m, 1H), 4.15 (ddd, J=36.0, 12.9, 1.1 Hz, 1H);
ESIMS m/z: [M−H]+ 380.
Compound 12-1 (0.25 g, 48%) was obtained in the same manner as step 1 of example 1, using 4-methylbenzene-1,3-diol.
1H NMR (300 MHz, DMSO-d6, δ): 10.68 (s, 1H), 12.29 (s, 1H), 7.66 (s, 1H), 6.31 (s, 1H), 3.91 (t, J=6.3 Hz, 2H), 3.48 (t, J=6.3 Hz, 2H), 2.06 (s, 3H).
Compound 12-2 (0.15 g, 72%) was obtained in the same manner as step 2 of example 1, using compound 12-1.
1H NMR (300 MHz, DMSO-d6, δ): 10.54 (s, 1H), 7.46 (s, 1H), 6.34 (s, 1H), 4.42 (t, J=6.3 Hz, 2H), 2.63 (t, J=6.3 Hz, 2H), 2.05 (s, 3H).
Compound 12-3 (0.55 g, 76%) was obtained in the same manner as step 1 of example 4, using compound 12-2.
1H NMR (300 MHz, DMSO-d6, δ): 7.53 (s, 1H), 7.47-7.31 (m, 5H), 6.62 (s, 1H), 5.19 (s, 2H), 4.47 (t, J=6.3 Hz, 2H), 2.67 (t, J=6.3 Hz, 2H), 2.13 (s, 3H).
Compound 12-4 (0.40 g, 78%) was obtained in the same manner as step 4 of example 1, using compound 12-3.
1H NMR (300 MHz, DMSO-d6, δ): 7.43-7.30 (m, 5H), 7.09 (s, 1H), 6.34 (s, 1H), 5.04 (s, 2H), 4.20-4.02 (m, 2H), 3.77 (t, J=5.1 Hz, 1H), 2.10 (s, 3H), 2.10-1.83 (m, 1H), 1.96-1.83 (m, 1H).
Compound 12-5 (0.18 g, 65%) was obtained in the same manner as step 3 of example 4, using compound 12-4.
1H NMR (400 MHz, DMSO-d6, δ): 7.02 (s, 1H), 6.18 (s, 1H), 4.17-3.99 (m, 2H), 3.92 (bs, 1H), 2.01 (s, 3H), 1.96-1.92 (m, 1H), 1.84-1.71 (m, 1H).
Compound 12-6 (0.09 g, 56%) was obtained in the same manner as step 4 of example 4, using compound 12-5.
ESIMS m/z: [M−16]+ 273.
Compound 23 (0.025 g, 23%) was obtained in the same manner as step 5 of example 1, using compound 12-6.
1H NMR (400 MHz, DMSO-d6, δ): 8.56 (d, J=8.0 Hz, 1H), 7.40 (d, J=9.2 Hz, 2H), 7.08 (s, 1H), 6.89 (d, J=9.2 Hz, 2H), 6.34-6.24 (m, 2H), 6.16 (d, J=17.2, 2.4 Hz, 1H), 5.63 (dd, J=10.0, 2.4 Hz, 1H), 5.06-5.01 (m, 1H), 4.23-4.10 (m, 2H), 2.09-2.03 (m, 4H), 1.92-1.85 (m, 1H)
ESIMS m/z: [M−70]+ 273.
A 33% hydrogen bromide solution in acetic acid (10.0 mL) was added to commercially available 6-methoxychroman-4-one (0.30 g, 1.68 mmol), and the mixture was stirred at 100° C. for 12 hours. The mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=70/30−>60/40) to obtain compound 13-1 (0.20 g, 72%).
1H NMR (300 MHz, DMSO-d6, δ): 9.36 (s, 1H), 7.07 (d, J=3.0 Hz, 1H), 6.99 (dd, J=8.7, 3.0 Hz, 1H), 6.87 (d, J=9.0 Hz, 1H), 4.42 (t, J=6.6 Hz, 2H), 2.72 (t, J=6.6 Hz, 2H).
Compound 13-2 (0.310 g, 32%) was obtained in the same manner as step 3 of example 1, using compound 13-1.
1H NMR (300 MHz, DMSO-d6, δ): 7.44-7.41 (m, 2H), 7.34 (dd, J=9.0, 3.3 Hz, 1H), 7.25 (d, J=3.0 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 7.11-6.99 (m, 2H), 4.54 (t, J=6.3 Hz, 2H), 2.79 (t, J=6.3 Hz, 2H).
Compound 13-3 was obtained as a crude product in the same manner as step 4 of example 1, using compound 13-2, and used as it is in the next reaction.
ESIMS m/z: [M−16]+ 259.
Compound 24 (0.120 g, 35% over two steps) was obtained in the same manner as step 5 of example 1, using compound 13-3.
1H NMR (300 MHz, DMSO-d6, δ): 8.59 (d, J=8.1 Hz, 1H), 7.37 (d, J=9.0 Hz, 2H), 6.94-6.89 (m, 3H), 6.85-6.83 (m, 2H), 6.28-6.19 (m, 1H), 6.15-6.09 (m, 1H), 5.61 (dd, J=9.6, 2.4 Hz, 1H), 5.10-5.03 (m, 1H), 4.24-4.18 (m, 2H), 2.09-2.06 (m, 1H), 1.95-1.87 (m, 1H)
ESIMS m/z: [M+H]+ 330.
A saturated aqueous sodium bicarbonate solution was added to commercially available 8-methoxychroman-4-amine hydrochloride (500 mg, 2.32 mol). The organic layer was extracted with chloroform and filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (4 mL) and the solution was cooled to −78° C. A 1 mol/L boron tribromide solution in dichloromethane (4.64 mL, 4.64 mmol) was added to the solution, and the mixture was stirred at −78° C. for 2 hours. To the reaction liquid, methanol was added at −78° C., and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=90/10−>chloroform/methanol=70/30) to obtain compound 14-1 (403 mg, 71%).
1H NMR (400 MHz, DMSO-d6, δ): 8.35 (br, 2H), 6.89-6.88 (m, 1H), 6.78 (s, 1H), 6.77 (s, 1H), 4.49-4.48 (m, 1H), 4.27-4.22 (m, 2H), 2.28-2.23 (m, 1H), 2.12-2.05 (m, 1H).
Compound 14-2 (20.7 mg, 17%) was obtained in the same manner as step 4 of example 4, using compound 14-1 and 1-iodo-4-(trifluoromethyl)benzene.
1H NMR (400 MHz, CDCl3, δ): 7.53 (d, J=8.6 Hz, 2H), 7.21 (dd, J=6.3, 3.2 Hz, 1H), 6.98 (d, J=8.6 Hz, 2H), 6.92-6.91 (m, 2H), 4.31-4.20 (m, 2H), 4.12 (t, J=5.0 Hz, 1H), 2.20-2.12 (m, 1H), 1.90-1.82 (m, 1H).
Compound 25 (17.3 mg, 87%) was obtained in the same manner as step 5 of example 1, using compound 14-2.
1H NMR (400 MHz, CDCl3, δ): 7.55 (d, J=8.5 Hz, 2H), 7.13 (dt, J=7.6, 0.9 Hz, 1H), 6.98 (d, J=8.1 Hz, 3H), 6.93-6.91 (m, 1H), 6.38 (d, J=16.8 Hz, 1H), 6.12 (dd, J=16.8, 10.5 Hz, 1H), 5.79-5.77 (m, 1H), 5.74 (d, J=10.5 Hz, 1H), 5.32 (dd, J=13.2, 5.6 Hz, 1H), 4.32-4.26 (m, 1H), 4.18-4.14 (m, 1H), 2.29-2.26 (m, 1H), 2.14-2.11 (m, 1H)
ESIMS m/z: [M−H]+ 362.
Compound 2-1 (0.24 g, 0.87 mmol) was dissolved in methanol (5 mL), and sodium borohydride (0.16 g, 4.37 mmol) was added to the solution at 0° C. The mixture was stirred at room temperature for 2 hours. Water was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 15-1 (0.10 g, 41%).
1H NMR (300 MHz, DMSO-d6, δ): 7.42 (dd, J=6.6, 2.1 Hz, 2H), 7.31 (d, J=8.4 Hz, 1H), 7.00 (d, J=6.9 Hz, 2H), 6.54 (dd, J=8.1, 2.4 Hz, 1H), 6.38 (d, J=2.4 Hz, 1H), 5.37 (d, J=4.5 Hz, 1H), 4.61-4.59 (m, 1H), 4.20-4.16 (m, 2H), 2.04-1.81 (m, 2H).
Compound 15-1 (0.10 g, 0.36 mmol) was dissolved in dichloromethane (3 mL), and zinc(II) iodide (0.34 g, 1.08 mmol) and trimethylsilyl cyanide (0.06 mL, 0.54 mmol) were added to the solution. The mixture was stirred at room temperature for 18 hours. Water was is added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 15-2 (0.06 g, 58%).
1H NMR (400 MHz, DMSO-d6, δ): 7.20 (d, J=8.8 Hz, 2H), 7.09 (d, J=8.8 Hz, 1H), 6.82 (d, J=9.2 Hz, 2H), 6.39 (dd, J=8.4, 2.0 Hz, 1H), 6.23 (d, J=2.4 Hz, 1H), 4.19 (t, J=6.0 Hz, 1H), 3.99-3.95 (m, 2H), 2.09-1.94 (m, 2H).
Compound 15-2 (0.06 g, 0.21 mmol) was dissolved in ethanol (5 mL), and Raney nickel (0.05 g) and ammonia water (0.1 mL) were added to the solution. The mixture was stirred under hydrogen atmosphere at room temperature for 2 hours. The mixture was filtered with Celite(R), and the filtrate was concentrated under reduced pressure to obtain compound 15-3 (0.06 g) as a crude product.
ESIMS m/z: [M+H]+ 290.
Compound 26 (0.03 g, 42% over two steps) was obtained in the same manner as step 5 of example 1, using compound 15-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.34 (bs, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.8 Hz, 2H), 6.54 (dd, J=8.0, 2.0 Hz, 1H), 6.4 (d, J=2.0 Hz, 1H), 6.26 (dd, J=17.2, 10.0 Hz, 1H), 6.10 (dd, J=17.2, 2.0 Hz, 1H), 5.61 (dd, J=10.0, 1.6 Hz, 1H), 4.18-4.09 (m, 2H), 3.49-3.44 (m, 1H), 3.30-3.25 (m, 1H), 2.91-2.90 (m, 1H), 1.93-1.88 (m, 1H), 1.81-1.78 (m, 1H);
ESIMS m/z: [M+H]+ 344.
Compound 16-1 (0.60 g, 34%) was obtained in the same manner as step 1 of example 1, using 2-methylbenzene-1,3-diol.
ESIMS m/z: [M+H]+ 214.
Compound 16-2 (0.30 g, 60%) was obtained in the same manner as step 2 of example 1, using compound 16-1.
1H NMR (300 MHz, DMSO-d6, δ): 10.4 (s, 1H), 7.48 (d, J=8.7 Hz, 1H), 6.55 (d, J=8.7 Hz, 1H), 4.50-4.46 (m, 2 H), 2.65 (t, J=6.0 Hz, 2H), 1.97 (s, 3H).
Compound 16-3 (0.20 g, 45%) was obtained in the same manner as step 3 of example 1, using compound 16-2.
1H NMR (300 MHz, DMSO-d6, δ): 7.46 (d, J=8.7 Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.7 Hz, 1H), 6.76 (d, J=8.7 Hz, 2H), 4.60 (t, J=6.3 Hz, 2H), 3.39 (t, J=6.0 Hz, 1H), 2.77 (d, J=6.3 Hz, 1H), 2.09 (s, 3H).
Compound 16-4 (0.30 g, 60%) was obtained in the same manner as step 4 of example 1, using compound 16-3.
1H NMR (300 MHz, DMSO-d6, δ): 7.36 (d, J=9.0 Hz, 2H), 7.25 (d, J=8.4 Hz, 1H), 6.85 (d, J=9.0 Hz, 2H), 6.50 (d, J=8.4 Hz, 1H), 4.35-4.18 (m, 2H), 3.88 (t, J=5.1 Hz, 1H), 2.00-1.94 (m, 1H), 1.92 (s, 3H), 1.79-1.70 (m, 1H).
Compound 27 (0.17 g, 48%) was obtained in the same manner as step 5 of example 1, using compound 16-4.
1H NMR (300 MHz, DMSO-d6, δ): 8.60 (d, J=7.8 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.86 (d, J=8.7 Hz, 2H), 6.54 (d, J=8.7 Hz, 1H), 6.30-6.12 (m, 2H), 5.63 (dd, J=9.6, 2.7 Hz, 1H), 5.10-5.08 (m, 1H), 4.34-4.09 (m, 2H), 2.11-2.06 (m, 1H), 1.96-1.88 (m, 4H)
ESIMS m/z: [M−70]+ 273.
Compound 17-1 (177 mg, 65%) was obtained in the same manner as step 1 of example 3, using compound 16-2.
1H NMR (400 MHz, CDCl3, δ): 7.78 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.03 (d, J=8.6 Hz, 2H), 6.56 (d, J=8.8 Hz, 1H), 4.61 (t, J=6.3 Hz, 2H), 2.82 (t, J=6.3 Hz, 2H), 2.14 (s, 3H).
Compound 17-2 (140 mg, 73%) was obtained in the same manner as step 2 of example 3, using compound 17-1.
1H NMR (400 MHz, CDCl3, δ): 7.52 (d, J=8.6 Hz, 2H), 7.16 (d, J=8.3 Hz, 1H), 6.93 (d, J=8.6 Hz, 2H), 6.57 (d, J=8.3 Hz, 1H), 4.38-4.28 (m, 2H), 4.08 (t, J=5.1 Hz, 1H), 2.18-2.15 (m, 1H), 2.02 (s, 3H), 1.89-1.82 (m, 1H).
Compound 17-2 (70 mg, 0.22 mmol) was dissolved in DMA (2 mL), and acryloyl chloride (0.026 mL, 0.33 mmol) was added to the mixed solution. The mixture was stirred at room temperature for 2 hours. Water was added to the mixture, and a precipitated solid was filtered off, washed with water, and dried to obtain a crude product. The crude product was purified by silica gel column chromatography (heptane/ethyl acetate=80/20−>50/50) to obtain compound 28 (34 mg, 42%).
1H NMR (400 MHz, CDCl3, δ): 7.53 (d, J=8.6 Hz, 2H), 7.08 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.6 Hz, 2H), 6.56 (d, J=8.8 Hz, 1H), 6.36 (dd, J=17.0, 1.5 Hz, 1H), 6.10 (dd, J=17.0, 10.4 Hz, 1H), 5.77 (s, 1H), 5.71 (dd, J=10.4, 1.5 Hz, 1H), 5.25-5.22 (m, 1H), 4.39-4.34 (m, 1H), 4.24-4.18 (m, 1H), 2.30-2.22 (m, 1H), 2.17-2.10 (m, 1H), 2.03 (s, 3H)
ESIMS m/z: [M−H]+ 376.
Compound 29 (61 mg, 63%) was obtained in the same manner as step 3 of example 17, using compound 17-2 and commercially available (E)-4,4,4-trifluoro-2-butenoyl chloride.
1H NMR (400 MHz, CDCl3, δ): 7.54 (d, J=8.8 Hz, 2H), 7.05 (d, J=8.3 Hz, 1H), 6.93 (d, J=8.8 Hz, 2H), 6.85-6.81 (m, 1H), 6.57 (d, J=8.3 Hz, 1H), 6.50-6.46 (m, 1H), 6.00 (d, J=7.8 Hz, 1H), 5.25-5.22 (m, 1H), 4.41-4.37 (m, 1H), 4.23-4.17 (m, 1H), 2.31-2.26 (m, 1H), 2.17-2.11 (m, 1H), 2.04 (s, 3H);
ESIMS m/z: [M H]+ 444.
2-Fluoro-3-methoxyphenol (0.50 g, 3.52 mmol) was dissolved in dichloromethane (10 mL). A 1 mol/L boron tribromide in dichloromethane (17.6 mL, 17.6 mmol) was added dropwise to the mixture at −78° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 18 hours. The mixture was cooled to −78° C., and water was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 19-1 (0.45 g, 89%).
1H NMR (400 MHz, DMSO-d6, δ): 9.57 (s, 2H), 6.73-6.68 (m, 1H), 6.38-6.34 (m, 2H).
Compound 19-2 (0.65 g, 85%) was obtained in the same manner as step 1 of example 1, using compound 19-1.
1H NMR (400 MHz, DMSO-d6, δ): 12.24 (s, 1H), 11.18 (s, 1H), 7.64-7.61 (m, 1H), 6.56-6.52 (m, 1H), 3.91 (t, J=6.4 Hz, 2H), 3.52 (t, J=6.4 Hz, 2H).
Compound 19-3 (0.45 g, 83%) was obtained in the same manner as step 2 of example 1, using compound 19-2.
1H NMR (400 MHz, DMSO-d6, δ): 11.05 (s, 1H), 7.44-7.41 (m, 1H), 6.66-6.62 (m, 1H), 4.57 (t, J=6.4 Hz, 2H), 2.73 (t, J=6.4 Hz, 2H).
Compound 19-4 was obtained as a crude product in the same manner as step 1 of example 3, using compound 19-3.
1H NMR (300 MHz, DMSO-d6, δ): 7.57 (dd, J=9.0, 2.1 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 6.72-6.67 (m, 1H), 4.68 (t, J=6.3 Hz, 2H), 2.85 (t, J=6.6 Hz, 2H).
Compound 19-5 was obtained as a crude product in the same manner as step 4 of example 1, using compound 19-4.
1H NMR (400 MHz, DMSO-d6, δ): 7.40-7.30 (m, 3H), 6.95 (d, J=8.8 Hz, 2H), 6.68-6.64 (m, 1H), 4.34-4.09 (m, 3H), 2.04-2.00 (m, 1H), 1.80-1.76 (m, 1H);
ESIMS m/z: [M−16]+ 277.
Compound 30 (0.025 g, 4% over three steps) was obtained in the same manner as step 5 of example 1, using compound 19-5.
1H NMR (400 MHz, CDCl3, δ): 7.29-7.25 (m, 2H), 6.97-6.89 (m, 3H), 6.59-6.55 (m, 1H), 6.36 (dd, J=16.8, 1.2 Hz, 1H), 6.10 (dd, J=16.8, 10.0 Hz, 1H), 5.81-5.71 (m, 2H), 5.30-5.20 (m, 1H), 4.43-4.38 (m, 1H), 4.29-4.23 (m, 1H), 2.32-2.24 (m, 1H), 2.18-2.11 (m, 1H);
ESIMS m/z: [M−70]+ 277.
Compound 20-1 (0.02 g, 11%) was obtained in the same manner as step 1 of example 3, using compound 19-3.
1H NMR (400 MHz, CDCl3, δ): 7.70-7.62 (m, 3H), 7.12 (d, J=8.4 Hz, 2H), 6.69-6.65 (m, 1H), 4.70-4.66 (m, 2H), 2.89-2.86 (m, 2H).
Compound 20-2 (0.12 g, 67%) was obtained in the same manner as step 4 of example 1, using compound 20-1.
1H NMR (300 MHz, CDCl3, δ): 7.57-7.11 (m, 3H), 7.02 (d, J=8.7 Hz, 2H), 6.68-6.62 (m, 1H), 4.41-4.08 (m, 3H), 2.25-2.15 (m, 1H), 1.95-1.87 (m, 1H).
Compound 31 (0.05 g, 39%) was obtained in the same manner as step 5 of example 1, using compound 20-2.
1H NMR (400 MHz, DMSO-d6, δ): 8.66 (d, J=7.6 Hz, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.8 Hz, 1H), 6.82 (t, J=7.6 Hz, 1H), 6.30-6.15 (m, 2H), 5.66 (dd, J=9.6, 2.4 Hz, 1H), 5.15-5.13 (m, 1H), 4.39-4.30 (m, 2H), 2.16-2.12 (m, 1H), 1.98-1.96 (m, 1H);
ESIMS m/z: [M−70]+ 311.
Benzene-1,2,3-triol (2.00 g, 15.87 mmol) was dissolved in acetone (20 mL), and potassium hydrogen carbonate (1.74 g, 17.46 mmol) and methyl iodide (2.25 g, 15.83 mmol) were added to the solution. The mixture was stirred at 50° C. for 24 hours. The mixture was filtered with Celite(R), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>70/30) to obtain compound 21-1 (0.50 g, 22%).
1H NMR (400 MHz, DMSO-d6, δ): 8.98 (s, 2H), 6.65 (t, J=8.4 Hz, 1H), 6.27 (d, J=8.0 Hz, 2H), 3.65 (s, 3H).
Compound 21-2 (0.77 g, 46%) was obtained in the same manner as step 1 of example 1, using compound 21-1.
1H NMR (400 MHz, DMSO-d6, δ): 12.39 (s, 1H), 10.50 (s, 1H), 7.57 (d, J=8.8 Hz, 1H),6.46 (d, J=8.8 Hz, 1H), 3.90-3.88 (m, 2H), 3.71 (s, 3H), 3.51-3.48 (m, 2H).
Step 3
Compound 21-3 (0.10 g, 59%) was obtained in the same manner as step 2 of example 1, using compound 21-2.
1H NMR (400 MHz, DMSO-d6, δ): 10.30 (s, 1H), 7.38 (d, J=8.8 Hz, 1H), 6.55 (d, J=8.8 Hz 1H), 4.52 (t, J=6.4 Hz, 2H), 3.70 (s, 3H), 2.68 (t, J=5.6 Hz, 2H).
Compound 21-4 (0.30 g, 58%) was obtained in the same manner as step 1 of example 3, using compound 21-3.
1H NMR (300 MHz, DMSO-d6, δ): 7.54-7.46 (m, 3H), 7.06 (d, J=8.7 Hz, 2H), 6.63 (d, J=9.0 Hz, 1H), 4.62 (t, J=6.6 Hz, 2H), 3.73 (s, 3H), 2.80 (t, J=6.3 Hz, 2H).
Compound 21-5 (0.20 g, 70%) was obtained in the same manner as step 4 of example 1, using compound 21-4.
1H NMR (300 MHz, DMSO-d6, δ): 7.36 (d, J=9.0 Hz, 2H), 7.15 (d, J=9.0 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 6.58 (d, J=8.7 Hz, 1H), 4.32-4.10 (m, 2H), 3.90-3.86 (m, 1H), 3.59 (s, 3H), 2.03-1.96 (m, 1H), 1.79-1.71 (m, 1H).
Compound 32 (0.09 g, 38%) was obtained in the same manner as step 5 of example 1, using compound 21-5.
1H NMR (300 MHz, DMSO-d6, δ): 8.62 (d, J=8.1 Hz, 1H), 7.38 (d, J=9.0 Hz, 2H), 6.91-6.88 (m, 3H), 6.62 (d, J=8.7 Hz, 1H), 6.31-6.12 (m, 2H), 5.63 (dd, J=8.7, 2.7 Hz, 1H), 5.08 (d, J=7.8 Hz, 1H) 4.36-4.20 (m, 2H), 3.6 (s, 3H), 2.12-2.06 (m, 1H), 1.94-1.90 (m, 1H);
ESIMS m/z: [M−70]+ 289.
Compound 22-1 (0.38 g, 66%) was obtained in the same manner as step 1 of example 3, using compound 21-3.
1H NMR (300 MHz, DMSO-d6, δ): 7.75 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 6.79 (d, J=8.7 Hz, 1H), 4.65 (t, J=6.6 Hz, 2H), 3.72 (s, 3H), 2.82 (t, J=6.6 Hz, 2H).
Compound 22-2 (0.34 g, 90%) was obtained in the same manner as step 4 of example 1, using compound 22-1.
1H NMR (300 MHz, DMSO-d6, δ): 7.60 (d, J=8.7 Hz, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 1H), 4.34-4.19 (m, 2H), 3.92-3.88 (m, 1H), 3.59 (s, 3H), 2.06-1.99 (m, 1H), 1.82-1.73 (m,1H).
Compound 33 (0.12 g, 28%) was obtained in the same manner as step 5 of example 1, using compound 22-2.
1H NMR (300 MHz, DMSO-d6, δ): 8.60 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.4 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.32-6.13 (m, 2H), 5.64 (dd, J=9.6, 2.7 Hz, 1H), 5.13 (d, J=5.7 Hz, 1H), 4.37-4.22 (m, 2H), 3.60 (s, 3H), 2.14-2.08 (m, 1H) 1.99-1.91 (m, 1H);
ESIMS m/z: [M−70]+ 323.
Acrylonitrile (10 mL) and 1,4-diazabicyclo[2.2.2]octane (0.55 g, 4.93 mmol) were added to commercially available 2-hydroxy-6-methoxybenzaldehyde(0.50 g, 3.28 mmol), and the mixture was stirred at 85° C. for 16 hours, The mixture was cooled to room temperature, and water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20−>70/30) to obtain compound 23-1 (0.30 g, 48%).
1H NMR (400 MHz, DMSO-d6, δ): 7.55 (d, J=0.8 Hz, 1H), 7.30 (t, J=8.4 Hz, 1H), 6.67 (dd, J=8.4, 0.4 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 4.80 (d, J=1.2 Hz, 2H), 3.83 (s, 3H)
A 3 mol/L aqueous sodium hydroxide solution (10 mL) was added to compound 23-1 (0.30 g, 1.64 mmol), and the mixture was refluxed for 5 hours. The mixture was cooled to room temperature, and 2 mol/L hydrochloric acid (10.0 mL) was added to the mixture. The precipitated solid was filtered off, washed with water, and dried under reduced pressure to obtain compound 23-2 (0.25 g, 72%).
1H NMR (400 MHz, DMSO-d6, δ): 12.75 (s, 1H), 7.56 (d, J=0.8 Hz, 1H), 7.24 (t, J=8.4 Hz, 1H), 6.62 (dd, J=8.4, 0.4 Hz, 1H), 6.49-6.47 (m, 1H), 4.84 (d, J=1.6 Hz, 2H), 3.82 (s, 3H).
tert-Butanol (25 mL) and triethylamine (1.3 mL, 9.70 mmol) were added to compound 23-2 (0.50 g, 3.28 mmol). Diphenylphosphoryl azide (1.3 mL, 5.82 mmol) was added to the solution at room temperature, and the mixture was stirred at 90° C. for 16 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40−>40/60) to obtain compound 23-3 (0.95 g, 73%).
1H NMR (300 MHz, DMSO-d6, δ): 8.97 (s, 1H), 6.93 (t, J=8.1 Hz, 1H), 6.72 (s, 1H), 6.54 (d, J=8.1 Hz, 1H), 6.30 (d, J=8.1Hz, 1H), 4.60 (s, 2H), 3.76 (s, 3H), 1.44 (s, 9H).
Compound 23-3 (0.95 g, 3.42 mmol) was dissolved in ethanol (20 mL), and palladium/carbon (0.90 g) was added to the solution. The mixture was stirred under hydrogen atmosphere at room temperature for 16 hours. The reaction liquid was filtered with Celite(R). The filtrate was concentrated under reduced pressure to obtain compound 23-4 as a crude product, which was used as it is in the next reaction.
1H NMR (300 MHz, DMSO-d6, δ): 7.04 (t, J=8.1 Hz, 1H), 6.96 (d, J=6.6 Hz, 1H), 6.51 (d, J=8.1 Hz, 1H), 6.40 (d, J=8.1Hz, 1H), 4.08-4.05 (m, 1H), 3.82 (s, 3H), 3.59-3.82 (m, 2H), 2.80 (dd, J=16.8, 5.4 Hz, 1H), 2.44-2.38 (m, 1H), 1.40 (s, 9H).
Pyridine hydrochloride (150 mg) was added to compound 23-4, and the mixture was stirred at 150° C. for 30 minutes using a microwave reactor, Initiator, manufactured by Biotage. The mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=40/60−>30/70) to obtain compound 23-5 (40.0 mg, 62% over two steps).
1H NMR (300 MHz, DMSO-d6, δ): 9.31 (s, 1H), 6.82 (t, J=8.1 Hz, 1H), 6.33 (d, J=7.8 Hz, 1H), 6.20 (d, J=8.1 Hz, 1H), 4.01-3.98 (m, 1H), 3.48 (t, J=9.0 Hz, 1H), 3.05-3.02 (m, 1H), 2.78 (dd, J=16.8, 4.8 Hz, 1H), 2.19-2.11 (m, 1H).
Compound 23-6 (0.110 g, 26%) was obtained in the same manner as step 4 of example 4, using compound 23-5.
ESIMS m/z: [M+H]+ 276.
Compound 34 (21 mg, 18%) was obtained in the same manner as step 5 of example 1, using compound 23-6.
1H NMR (300 MHz, DMSO-d6, δ): 8.25 (d, J=6.6 Hz, 1H), 7.40 (d, J=9.0 Hz, 2H), 7.14 (t, J=8.1 Hz, 1H), 6.96 (d, J=9.0 Hz, 2H), 6.70 (d, J=8.1 Hz, 1H), 6.50 (d, J=7.8 Hz, 1H), 6.26 (dd, J=17.1, 9.9 Hz, 1H), 6.10 (dd, J=17.1, 2.4 Hz, 1H), 5.59 (dd, J=9.9, 2.4 Hz, 1H), 4.21-4.13 (m, 2H), 3.93-3.88 (m, 1H), 2.87 (dd, J=17.1, 5.7 Hz, 1H), 2.57-2.50 (m, 1H); ESIMS m/z: [M+H]+ 330.
The following compounds were synthesized in accordance with the synthesis method of compound 34.
ESIMS m/z: [M+H]+ 330.
ESIMS m/z: [M+H]+ 330.
ESIMS m/z: [M+H]+ 364.
Compound 24-1 (0.13 g, 46%) was obtained in the same manner as step 4 of example 4, using compound 23-5.
ESIMS m/z: [M+H]+ 310.
Compound 35 (70 mg, 46%) was obtained in the same manner as step 5 of example 1, using compound 24-1.
1H NMR (400 MHz, DMSO-d6, δ): 8.26 (d, J=6.8 Hz, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.20 (t, J=8.4 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H), 6.78-6.76 (m, 1H), 6.64 (dd, J=8.0, 0.8 Hz, 1H), 6.24 (dd, J=17.2, 10.4 Hz, 1H), 6.09 (dd, J=16.8, 2.0 Hz, 1H), 5.59 (dd, J=10.0, 2.4 Hz, 1H), 4.20-4.15 (m, 2H), 3.94-3.89 (m, 1H), 2.83 (dd, J=16.8, 6.4 Hz, 1H), 2.56-2.54 (m, 1H);
ESIMS m/z: [M+H]+ 364.
Compound 35 was optically resolved under the following chiral preparative conditions to obtain compound 65 (17 mg, 25%) having a retention time of 6.65 minutes and compound 66 (19 mg, 29%) having a retention time of 8.25 minutes.
DMF (10 mL) was added to sodium hydride (65% liquid paraffin dispersion, 1.73 g, 48.38 mmol). A solution prepared by adding DMF (20 mL) to 2-methoxyphenol (5.00 g, 40.32 mmol) was added dropwise to the mixture under nitrogen atmosphere at 0° C., and the mixture was stirred for minutes. A solution prepared by adding DMF (20 mL) to 3-bromopropionic acid (7.40 g, 48.38 mmol) was added dropwise to the mixture, and the mixture was stirred under nitrogen atmosphere at room temperature for 18 hours. Water was added to the mixture. The mixture was acidified by the addition of a 2 mol/L aqueous hydrochloric acid solution (20 mL). The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 25-1 as a crude product, which was used as it is in the next reaction.
1H NMR (400 MHz, DMSO-d6, δ): 12.34 (br, 1H), 6.97-6.86 (m, 2H), 6.76-6.73 (m, 1H), 4.13 (t, J=6.0 Hz, 2H), 3.73 (5, 3H), 2.68 (t, J=6.0 Hz, 2H).
Trifluoromethanesulfonic acid (1 mL) was added to compound 25-1, and the mixture was stirred at 80° C. for 30 minutes. A solution prepared by adding dichloromethane to the mixture left to cool to room temperature was slowly added to water. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>70/30) to obtain compound 25-2 (0.15 g, 13% over two steps).
1H NMR (400 MHz, DMSO-d6, δ): 7.32-7.30 (m, 1H), 7.23-7.21 (m, 1H), 6.97 (t, J=8.0 Hz, 1H), 4.53 (t, J=6.4 Hz, 2H), 3.79 (s, 3H), 2.77 (t, J=6.8 Hz, 2H).
Compound 25-2 (0.10 g, 0.56 mmol) was dissolved in dichloromethane (3 mL), and the solution was cooled to −78° C. A 1 mol/L boron tribromide solution in dichloromethane (2.80 mL, 2.80 mmol) was added dropwise to the solution under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The mixture was cooled to −78° C., and water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 25-3 as a crude product, which was used as it is in the next reaction.
1H NMR (400 MHz, DMSO-d6, δ): 9.52 (s, 1H), 7.19 (dd, J=8.0, 1.6 Hz, 1H), 7.04-7.02 (m, 1H), 6.84 (t, J=7.6 Hz, 1H), 4.53 (t, J=6.4 Hz, 2H), 2.77 (t, J=6.4 Hz, 2H).
Compound 25-4 (0.10 g, 39% over two steps) was obtained in the same manner as step 1 of example 3, using compound 25-3 and 4-chlorophenylboronic acid.
1H NMR (400 MHz, DMSO-d6, δ): 7.65 (dd, J=8.0, 1.2 Hz, 1H), 7.39-7.37 (m, 3H), 7.08 (t, J=8.0 Hz, 1H), 6.94 (d, J=8.8 Hz, 2H), 4.53 (t, J=6.4 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H).
Compound 25-4 (0.10 g, 0.364 mmol) was dissolved in pyridine (2 mL), and hydroxylamine hydrochloride (0.05 g, 0.72 mmol) was added to the solution. The mixture was stirred at 80° C. for 2 hours. The mixture was cooled to room temperature, and a 2 mol/L aqueous hydrochloric acid solution (5 mL) was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtained compound 25-5 as a crude product, which was used as it is in the next reaction.
1H NMR (400 MHz, DMSO-d6, δ): 11.39 (s, 1H), 7.69-7.67 (m, 1H), 7.35 (d, J=9.2 Hz, 2H), 7.08-7.06 (m, 1H), 7.00-6.96 (m, 1H), 6.89 (d, J=9.2 Hz, 2H), 4.14 (t, J=6.0 Hz, 2H), 2.83 (t, J=6.0 Hz, 2H).
A solution prepared by adding THF (2 mL) to compound 25-5 (0.10 g, in 0.34 mmol) was added dropwise to a suspension solution prepared by adding THF (1 mL) to sodium hydride (65% liquid paraffin dispersion, 0.025 g, 0.69 mmol) under nitrogen atmosphere at room temperature, and the mixture was stirred for 30 minutes. A solution prepared by adding THF (2 mL) to p-toluenesulfonyl chloride (0.10 g, 0.519 mmol) was added dropwise to the mixture. The mixture was stirred under nitrogen atmosphere at room temperature for one hour. Water was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 25-6 as a crude product, which was used as it is in the next reaction.
1H NMR (400 MHz, DMSO-d6, δ): 7.93 (d, J=8.0 Hz, 2H), 7.57-7.45 (m, 3H), 7.34 (d, J=8.0 Hz, 2H), 7.24-7.22 (m, 1H), 7.06-7.00 (m, 1H), 6.89 (d, J=8.8 Hz, 2H), 4.18 (t, J=6.0 Hz, 2H), 3.00 (t, J=6.4 Hz, 2H), 2.43 (s, 3H).
Compound 25-6 (0.10 g, 0.22 mmol) was dissolved in toluene (5 mL), and a 24% potassium ethoxide solution in ethanol (0.11 mL, 0.338 mmol) was added to the solution. The mixture was stirred under argon atmosphere at room temperature for 18 hours. tert-Butylmethyl ether (20 mL) was added to the mixture, and the mixture was filtered with Celite(R). Concentrated hydrochloric acid (0.2 mL) was added to the filtrate, and the mixture was stirred at room temperature for one hour. The liquid mixture was concentrated under reduced pressure, and tert-butylmethyl ether was added to the residue for reslurrying to obtain compound 25-7 (0.02 g, 14% over three steps).
1H NMR (400 MHz, DMSO-d6, δ): 8.76 (s, 3H), 7.70 (dd, J=7.6, 1.2 Hz, 1H), 7.46 (dd, J=7.6, 1.2 Hz, 1H), 7.41 (d, J=8.8 Hz, 2H), 7.19 (t, J=8.0 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 4.79-4.71 (m, 2H), 4.50-4.42 (m, 1H).
Compound 39 (0.11 g, 52%) was obtained in the same manner as step 5 of example 1, using compound 25-7.
1H NMR (400 MHz, DMSO-d6, δ): 8.58 (d, J=7.6 Hz, 1H), 7.68 (dd, J=7.6, 1.2 Hz, 1H), 7.42-7.38 (m, 3H), 7.14 (t, J=8.0 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.35 (dd, J=17.2, 10.4 Hz, 1H), 6.15 (dd, J=17.2, 1.6 Hz, 1H), 5.69 (dd, J=10.0, 1.6 Hz, 1H), 5.02-4.96 (m, 1H), 4.55-4.51 (m, 1H), 4.36-4.30 (m, 1H);
ESIMS m/z: [M+H]+ 344.
Compound 26-1 (0.05 g, 27%) was obtained in the same manner as step 1 of example 3, using compound 25-3 and 4-(trifluoromethyl)phenylboronic acid.
1H-NMR (400 MHz, H, CDCl3) δ: 7.80 (dd, J=8.0, 1.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.28-7.26 (m, 1H), 7.06-6.91 (m, 3H), 4.54 (t, J=6.4 Hz, 2H), 2.85 (t, J=6.4 Hz, 2H).
Compound 26-2 was obtained as a crude product in the same manner as step 5 of example 25, using compound 26-1, and used as it is in the next reaction.
1H NMR (300 MHz, DMSO-d6, δ): 11.43 (s, 1H), 7.74 (dd, J=7.8, 1.2 Hz, 1H), 7.68 (d, J=8.7 Hz, 2H), 7.18 (dd, J=8.1, 1.5 Hz, 1H), 7.05-7.03 (m, 3H), 4.14 (t, J=6.0 Hz, 2H), 2.83 (t, J=6.3 Hz, 2H).
Compound 26-3 was obtained as a crude product in the same manner as step 6 of example 25, using compound 26-2, and used as it is in the next reaction.
1H NMR (300 MHz, DMSO-d6, δ): 7.94 (d, J=8.1 Hz, 2H), 7.80 (t, J=7.8 Hz, 1H), 7.68-7.61 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.36-7.33 (m, 1H), 7.10-7.01 (m, 3H), 4.18 (t, J=6.3 Hz, 2H), 3.01 (t, J=6.3 Hz, 2H), 2.43 (s, 3H).
Compound 26-4 (0.03 g, 31% over three steps) was obtained in the same manner as step 7 of example 25, using compound 26-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.90 (s, 3H), 7.78-7.71 (m, 3H), 7.59 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 4.80-4.72 (m, 2H), 4.52-4.46 (m, 1H).
Compound 40 (0.18 g, 69%) was obtained in the same manner as step 5 of example 1, using compound 26-4 (0.25 g, 0.70 mmol).
1H NMR (400 MHz, DMSO-d6, δ): 8.58 (d, J=7.6 Hz, 1H), 7.75-7.70 (m, 3H), 7.53-7.51 (m, 1H), 7.18 (t, J=7.6 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 6.35 (dd, J=17.2, 10.0 Hz, 1H), 6.15 (dd, J=17.2, 1.6 Hz, 1H), 5.68 (dd, J=10.0, 1.2 Hz, 1H), 5.04-4.97 (m, 1H), 4.54-4.50 (m, 1H), 4.37-4.31 (m, 1H);
ESIMS m/z: [M+H]+ 378.
Compound 27-1 (0.12 g, 21%) was obtained in the same manner as step 1 of example 23, using commercially available 6-bromo-2-hydroxy-3-methoxybenzaldehyde.
1H NMR (300 MHz, DMSO-d6, δ): 7.53 (s, 1H), 7.25 (d, J=9.0 Hz, 1H), 7.05 (d, J=8.7 Hz, 1H), 4.87(d, J=1.2 Hz, 2H), 3.77 (s, 3H).
Compound 27-2 (0.10 g, 85%) was obtained in the same manner as step 2 of example 23, using compound 27-1.
1H NMR (300 MHz, DMSO-d6, δ): 13.18 (br, 1H), 7.45 (s, 1H), 7.20 (d, J=8.7 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 4.89(d, J=1.2 Hz, 2H), 3.77 (s, 3H).
Compound 27-3 (0.10 g, 80%) was obtained in the same manner as step 3 of example 23, using compound 27-2.
1H-NMR (300 MHz, DMSO-d6, δ): 9.22 (s, 1H), 7.08 (d, J=9.0 Hz, 1H), 6.77 (s, 1H), 6.72 (d, J=8.7 Hz, 1H), 4.64 (s, 2H), 3.72 (s, 3H), 1.46 (s, 9H).
Compound 27-3 (0.90 g, 2.52 mmol) was dissolved in 1,4-dioxane (20 mL), and trimethylboroxine (0.41 g, 5.05 mmol), potassium carbonate (0.69 g, 5.05 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol) were added to the solution. The mixture was stirred at 199° C. for 16 hours. The liquid mixture was filtered, and water was added to the filtrate. The organic layer was extracted with tert-butyl methyl ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40 ->50/50) to obtain compound 27-4 (0.65 g, 88%).
1H NMR (300 MHz, DMSO-d6, δ): 9.06 (s, 1H), 6.64-6.61 (m, 3H), 4.58 (s, 2H), 3.68 (s, 3H), 2.12 (s, 3H), 1.45 (s, 9H).
Compound 27-5 was obtained as a crude product in the same manner as step 4 of example 23, using compound 27-4, and used as it is in the next reaction.
1H NMR (400 MHz, DMSO-d6, δ): 6.97 (d, J=6.80 Hz, 1H), 6.66 (q, J=8.4 Hz, 2H), 4.06 (d, J=9.6 Hz, 1H), 3.80-3.61 (m, 5H), 2.79 (dd, J=16.4, 5.6 Hz, 1H), 2.46-2.44 (m, 1H), 2.06 (s, 3H), 1.40 (s, 9H).
Compound 27-5 was dissolved in dichloromethane (10 mL), and the solution was cooled to 0° C. A 1 mol/L boron tribromide solution in dichloromethane (8.5 mL, 8.53 mmol) was added dropwise to the solution under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. The mixture was cooled to 0° C., and methanol (15 mL) was added to the mixture. The mixture was concentrated under reduced pressure, and tert-butyl methyl ether was added to the residue for reslurrying to obtain compound 27-6 (0.38 g, 62% over three steps).
1H NMR (400 MHz, DMSO-d6, δ): 8.82 (br, 1H), 8.14 (br, 3H), 6.59 (q, J=8.0 Hz, 2H), 4.11 (s, 2H), 3.81 (br, 1H), 2.99 (dd, J=17.2, 5.6 Hz, 1H), 2.63-2.58 (m, 1H), 2.05 (s, 3H).
Compound 27-7 (0.150 g, 39%) was obtained in the same manner as step 4 of example 4, using compound 27-6.
1H NMR (300 MHz, DMSO-d6, δ): 7.31 (d, J=9.0 Hz, 2H), 6.85-6.76 (m, 4H), 4.00-3.98 (m, 1H), 3.59-3.47 (m, 2H), 2.72 (br, 1H), 2.27-2.25 (m, 1H), 2.17 (s, 3H).
Compound 41 (0.18 g, 26%) was obtained in the same manner as step 5 of example 1, using compound 27-7.
1H NMR (300 MHz, DMSO-d6, δ): 8.28 (d, J=6.6 Hz, 1H), 7.31 (d, J=9.0 Hz, 2H), 6.91-6.78 (m, 4H), 6.28 (dd, J=17.1, 10.2 Hz, 1H), 6.11 (dd, J=17.1, 2.1 Hz, 1H), 5.60 (dd, J=9.9, 2.4 Hz, 1H), 4.24-4.20 (m, 1H), 4.04-3.99 (m, 1H), 3.86-3.80 (m, 1H), 3.00-2.93 (m, 1H), 2.64-2.56 (m, 1H), 2.18 (s, 3H);
ESIMS m/z: [M+H]+ 344.
Compound 28-1 was obtained as a crude product in the same manner as step 4 of example 1, using commercially available 8-methoxychroman-3-one, and was used as it is in the next reaction.
1H NMR (300 MHz, DMSO-d6, δ): 6.74 (br, 2H), 6.62-6.61 (m, 1H), 4.09-4.03 (m, 1H), 3.66 (s, 3H), 3.79-3.66 (m, 1H), 3.08-3.06 (m, 1H), 2.96-2.83 (m, 1H), 2.61-2.41 (m, 1H).
Compound 28-2 (0.25 g, 30% over two steps) was obtained in the same manner as step 6 of example 27, using compound 28-1.
ESIMS m/z: [M+H]+ 166.
Compound 28-3 (0.150 g, 36%) was obtained in the same manner as step 4 of example 4, using compound 28-2.
ESIMS m/z: [M+H]+ 276.
Compound 42 (35 mg, 19%) was obtained in the same manner as step 5 of example 1, using compound 28-3.
1H NMR (300 MHz, DMSO-d6, δ): 8.29 (d, J=6.9 Hz, 1H), 7.33 (d, J=8.7 Hz, 2H), 7.03-7.01 (m, 1H), 6.91-6.86 (m, 4H), 6.29 (dd, J=17.1, 10.2 Hz, 1H), 6.10 (dd, J=16.8, 2.1 Hz, 1H), 5.60 (dd, J=10.2, 2.4 Hz, 1H), 4.21-4.17 (m, 1H), 4.09-4.05 (m, 1H), 3.92-3.86 (m, 1H), 3.15-309 (m, 1H), 2.82-2.74 (m, 1H);
ESIMS m/z: [M+H]+ 330.
The following compounds were synthesized in accordance with the synthesis method of compound 42.
ESIMS m/z: [M−H]+ 362.
ESIMS m/z: [M−H]+ 378.
ESIMS m/z: [M−H]+ 362, 364.
ESIMS m/z: [M−H]+ 396.
ESIMS m/z: [M+H]+ 331.
ESIMS m/z: [M+H]+ 331.
ESIMS m/z: [M+H]+ 365, 367.
ESIMS m/z: [M+H]+ 365, 367.
ESIMS m/z: [M+H]+ 345.
ESIMS m/z: [M+H]+ 345.
ESIMS m/z: [M+H]+ 399.
ESIMS m/z: [M+H]+ 433.
ESIMS m/z: [M+H]+ 355.
Compound 42 was optically resolved under the following chiral preparative conditions to obtain compound 59 (63 mg, 31%) having a retention time of 148 minutes and compound 60 (68 mg, 33%) having a retention time of 4.57 minutes.
Compound 29-1 was obtained as a crude product in the same manner as step 4 of example 4, using compound 28-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 310.
Compound 44 (0.17 g, 33% over two steps) was obtained in the same manner as step 5 of example 1, using compound 29-1.
1H NMR (400 MHz, DMSO-d6, δ): 8.28 (d, J=6.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.08-6.92 (m, 5H), 6.28 (dd, J=17.2, 10.4 Hz, 1H), 6.10 (d, J=17.2, 2.0 Hz, 1H), 5.60 (dd, J=10.0, 2.0 Hz, 1H), 4.21-4.19 (m, 1H), 4.08-4.05 (m, 1H), 3.91-3.87 (m, 1H), 3.17-3.10 (m, 1H), 2.83-2.77 (m, 1H)
ESIMS m/z: [M+H]+ 364.
Compound 44 was optically resolved under the following chiral preparative conditions to obtain compound 61 (46 mg, 34%) having a retention time of 4.17 minutes and compound 62 (66 mg, 48%) having a retention time of 5.74 minutes.
Compound 30-1 was obtained as a crude product in the same manner as step 4 of example 4, using compound 28-2 and commercially available 2-chloro-5-(trifluoromethyl)pyridine, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 311.
Compound 50 (82.0 mg, 55% over two steps) was obtained in the same manner as step 5 of example 1, using compound 30-1.
1H NMR (400 MHz, CDCl3, δ): 8.35 (br, 1H), 7.90 (dd, J=8.6, 2.5 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.00-6.95 (m, 3H), 6.27 (dd, J=17.0, 1.6 Hz,1H), 6.25-6.22 (m, 1H), 6.05 (dd, J=17.0, 10.2 Hz, 1H), 5.63 (dd, J=10.2, 1.6 Hz, 1H), 4.59-4.54 (m, 1H), 4.12 (ddd, J=10.9, 2.0, 1.0 Hz, 1H), 4.05 (dd, J=10.9, 2.0 Hz, 1H), 3.19 (dd, J=17.0, 5.2 Hz, 1H), 2.87-2.85 (m, 1H);
ESIMS m/z: [M+H]+ 365.
Compound 50 was optically resolved under the following chiral preparative conditions to obtain compound 63 (23 mg, 34%) having a retention time of 5.95 minutes and compound 64 (26 mg, 38%) having a retention time of 7.82 minutes.
Compound 31-1 was obtained as a crude product in the same manner as step 4 of example 4, using compound 28-2 and commercially available 5-bromo-2-(trifluoromethyl)pyridine, and was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 311.
Compound 51 (43.4 mg, 29% over two steps) was obtained in the same manner as step 5 of example 1, using compound 31-1.
1H NMR (400 MHz, CDCl3, δ): 8.39 (d, J=2.7 Hz, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.27 (dd, J=8.6, 2.7 Hz, 1H), 7.01-6.92 (m, 3H), 6.29 (dd, J=16.8, 1.4 Hz, 1H), 6.12 (d, J=8.2 Hz, 1H), 6.07 (dd, J=16.8, 10.4 Hz, 1H), 5.66 (dd, J=10.4, 1.4 Hz, 1H), 4.59-4.53 (m, 1H), 4.16 (ddd, J=11.1, 2.0, 1.0 Hz, 1H), 4.10 (dd, J=11,1, 2.0 Hz, 1H), 3.20 (dd, J=17.0, 5.4 Hz, 1H), 2.90 (dd, J=17.0, 2.0 Hz, 1H);
ESIMS m/z: [M+H]+ 365.
Compound 32-1 was obtained as a crude product in the same manner as step 4 of example 4, using compound 28-2 and commercially available 2-chloro-5-iodo-3-methylpyridine, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 290.
Compound 56 (2.7 mg, 7%) was obtained in the same manner as step 5 of example 1, using compound 32-1.
1H NMR (400 MHz, CDCl3, δ): 7.92 (d, J=3.2 Hz, 1H), 7.17 (d, J=3.2 Hz, 1H), 6.94-6.89 (m, 3H), 6.31 (dd, J=17.0, 1.4 Hz, 1H), 6.05 (dd, J=17.0, 10.2 Hz, 1H), 5.88 (d, J=8.2 Hz, 1H), 5.67 (dd, J=10.2, 1.1 Hz, 1H), 4.61-4.58 (m, 1H), 4.23 (ddd, J=11.1, 2.0, 1.0 Hz, 1H), 4.12 (dd, J=11.1, 2.0 Hz, 1H), 3.20 (dd, J=17.0, 5.2 Hz, 1H), 2.90 (dt, J=17.0, 2.5 Hz, 1H), 2.36 (s, 3H);
ESIMS m/z: [M+H]+ 345.
In toluene (34 mL), 7,8-dihydroquinolin-5(6H)-one (0.50 g, 3.40 mmol) was dissolved. Ethylene glycol (0.38 mL, 6.79 mmol) and p-toluenesulfonic acid monohydrate (0.13 mg, 0.679 mmol) were added to the solution. The mixture was refluxed overnight using a Dean-Stark apparatus. The mixture was left to cool to room temperature, and triethylamine (0.14 mL) was added to the mixture. The mixture was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (heptane/ethyl acetate=100/0−>80/20) to obtain compound 33-1 (374 mg, 58%).
1H NMR (400 MHz, CDCl3, δ): 8.49 (dd, J=4.8, 1.8 Hz, 1H), 7.79 (dd, J=8.1, 1.8 Hz, 1H), 7.15 (ddt, J=8.1, 4.8, 0.7 Hz, 1H), 4.20-4.12 (m, 4H), 2.98-2.96 (m, 2H), 2.08-1.95 (m, 4H); ESIMS m/z: [M+H]+ 192.
Compound 33-1 (0.374 g, 1.95 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (674 mg, 2.93 mmol) was added to the solution. The mixture was stirred at room temperature for one hour. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the mixture. The mixture was filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL), and the filtrate was concentrated under reduced pressure to obtain compound 33-2 (415 mg) as a crude product.
ESIMS m/z: [M+H]+ 208.
Compound 33-2 (415 mg) as a crude product was dissolved in ethyl acetate (15 mL), and triethylamine (0.84 mL, 6.01 mmol) was added to the solution. Trifluoroacetic anhydride (0.57 mL, 4.01 mmol) dissolved in ethyl acetate (5 mL) was added to the mixture at −78° C. After stirred at −78° C. for one hour, the mixture was stirred at room temperature overnight. A saturated aqueous sodium bicarbonate solution was added to the mixture. The mixture was filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL), and the filtrate was concentrated under reduced pressure. Ethanol (1.0 mL) and a 2 mol/L aqueous sodium hydroxide solution (1.0 mL) were added to the residue, and the mixture was stirred at room temperature for one hour. Water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=97/3−>93/7) to obtain compound 33-3 (325 mg, 78% over two steps).
1H NMR (400 MHz, CDCl3, δ): 8.56 (dd, J=4.8, 1.8 Hz, 1H), 7.81 (dd, J=8.2, 1.8 Hz, 1H), 7.27 (dd, J=8.2, 4.8 Hz, 1H), 4.69 (dd, J=9.1, 5.4 Hz, 1H), 4.25-4.06 (m, 4H), 3.98 (br, 1H), 2.39-2.36 (m, 1H), 2.22-2.19 (m, 1H), 2.01-1.94 (m, 2H);
ESIMS m/z: [M+H]+ 208.
Compound 33-3 (36.0 mg, 0.174 mmol), triphenylphosphine (91.0 mg, 0.347 mmol), and phenol (33.0 mg, 0.347 mmol) were dissolved in THF (0.7 mL), and diisopropyl azodicarboxylate (0.068 mL) was added to the solution. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20−>50/50) to obtain compound 33-4 (93.0 mg) as a crude product.
ESIMS m/z: [M+H]+ 284.
A 2 mol/L hydrochloric acid 1,4-dioxane solution (1 mL) was added to compound 33-4 as a crude product, and the mixture was stirred at 50° C. overnight. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>70/30) to obtain compound 33-5 (16.3 mg, 39% over two steps).
1H NMR (400 MHz, CDCl3, δ): 8.80 (dd, J=4.8, 2.1 Hz, 1H), 8.35 (dd, J=7.9, 2.1 Hz, 1H), 7.45 (dd, J=7.9, 4.8 Hz, 1H), 7.32 (tt, J=7.9, 2.1 Hz, 2H), 7.16-7.15 (m, 2H), 7.01 (td, J=7.9, 1.1 Hz, 1H), 5.63 (t, J=3.4 Hz, 1H), 3.16-3.13 (m, 1H), 2.72-2.59 (m, 2H), 2.43-2.34 (m, 1H);
ESIMS m/z: [M+H]+ 240.
Compound 33-6 (13.8 mg) was obtained as a crude product in the same manner as step 4 of example 1, using compound 33-5 (15.0 mg, 0.063 mmol).
ESIMS m/z: [M+H]+ 241.
Compound 33-6(13.8 mg) as a crude product was dissolved in dichloromethane (0.6 mL), and triethylamine (0.03 mL, 0.189 mmol) and acryloyl chloride (0.075 mL, 0.93 mmol) were added to the solution. The mixture was stirred at 0° C. for one hour. A saturated aqueous sodium bicarbonate solution was added to the mixture. The mixture was filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=70/30−>40/60) to obtain compound 67 (3.20 mg, 17% over two steps).
1H NMR (400 MHz, CDCl3, δ): 8.58 (dt, J=4.5, 1.5 Hz, 1H), 7.71 (dd, J=8.2, 4.5 Hz, 1H), 7.31-7.27 (m, 3H), 7.10 (dd, J=8.6, 1.1 Hz, 2H), 6.99 (tt, J=7.2, 1.1 Hz, 1H), 6.39 (dd, J=17.0, 1.4 Hz, 1H), 6.16 (dd, J=17.0, 10.2 Hz, 1H), 5.93 (d, J=9.1 Hz, 1H), 5.75 (dd, J=10.2, 1.4 Hz, 1H), 5.45-5.38 (m, 2H), 2.44-2.42 (m, 1H), 2.18-1.98 (m, 3H);
ESIMS m/z: [M+H]+ 295.
Compound 34-1 (207 mg) was obtained as a crude product in the same manner as step 4 of example 33, using compound 33-3 (80.0 mg, 0.386 mmol) and 3-chlorophenol (99.0 mg, 0.772 mmol).
1H NMR (400 MHz, CDCl3, δ): 8.64 (dd, J=4.8, 1.8 Hz, 1H), 7.88 (dd, J=7.9, 1.8 Hz, 1H), 7.33 (dd, J=7.9, 4.8 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 7.11 (t, J=2.3 Hz, 1H), 7.00-6.94 (m, 2H), 5.41 (t, J=3.4 Hz, 1H), 4.23-4.14 (m, 4H), 2.35-2.30 (m, 3H), 2.00-1.97 (m, 1H); ESIMS m/z: [M+H]+ 318.
Compound 34-2 (180 mg) was obtained as a crude product in the same manner as step 5 of example 33, using compound 34-1 (207 mg) as a crude product.
1H NMR (400 MHz, CDCl3, δ):8.80 (dd, J=4.5, 1.8 Hz, 1H), 8.36 (dd, J=8.2, 1.8 Hz, 1H), 7.46 (dd, J=8.2, 4.5 Hz, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.19 (t, J=2.3 Hz, 1H), 7.07-7.05 (m, 1H), 7.00-6.98 (m, 1H), 5.60 (t, J=3.9 Hz, 1H), 3.17-3.08 (m, 1H), 2.73-2.68 (m, 1H), 2.64-2.57 (m, 1H), 2.45-2.37 (m, 1H);
ESIMS m/z: [M+H]+ 274.
Compound 34-3 (59.2 mg) was obtained as a crude product in the same manner as step 6 of example 33, using compound 34-2 (180 mg) as a crude product.
ESIMS m/z: [M+H]+ 275.
Compound 68 (26.8 mg, 38% in four stages) and compound 79 (5.50 mg, 8% in four stages) were obtained in the same manner as step 7 of example 33, using compound 34-3 (59.2 mg) as a crude product. Compound 68: 1H NMR (400 MHz, CDCl3, δ): 8.59 (d, J=4.9 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.30 (d, J=4.9 Hz, 1H), 7.23 (t, J=8.3 Hz, 1H), 7.12-7.11 (m, 1H), 7.01-6.97 (m, 2H), 6.40 (dd, J=17.1, 1.5 Hz, 1H), 6.16 (dd, J=17.1, 10.2 Hz, 1H), 5.82 (d, J=10.0 Hz, 1H), 5.76 (dd, J=10.2, 1.5 Hz, 1H), 5.42-5.40 (m, 2H), 2.42-2.40 (m, 1H), 2.15-2.09 (m, 3H);
ESIMS m/z: [M+H]+ 329.
Compound 79: 1H NMR (400 MHz, CDCl3, δ): 8.62 (d, J=6.8 Hz, 1H), 7.74 (d, J=6.8 Hz, 1H), 7.22-7.14 (m, 3H), 7.00-6.98 (m, 2H), 6.37 (dd, J=17.1, 1.9 Hz, 1H), 6.08 (dd, J=17.1, 10.2 Hz, 1H), 5.74-5.71 (m, 2H), 5.46-5.44 (m, 2H), 2.45-2.42 (m, 1H), 2.27-2.18 (m, 2H), 1.96-1.90 (m, 1H);
ESIMS m/z: [M+H]+ 329.
The following compounds were synthesized in accordance with the synthesis method aforementioned.
ESIMS m/z: [M+H]+ 329.
ESIMS m/z: [M+H]+ 329.
ESIMS m/z: [M+H]+ 397.
Commercially available 2-chloro-7,8-dihydroquinolin-5(6H)-one (1.50 g, 8.26 mmol) was dissolved in toluene (83 mL). Ethylene glycol (0.92 mL, 16.5 mmol) and pyridinium p-toluenesulfonate (208 mg, 0.826 mmol) were added to the solution,. The mixture was refluxed for three hours using a Dean-Stark apparatus during which ethylene glycol (0.92 mL, 16.5 mmol) was added four times every 30 minutes. The mixture was cooled to and triethylamine (0.35 mL) was added to the mixture. The mixture was concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (heptane/ethyl acetate=90/10−>70/30) to obtain compound 35-1 (1.75 g, 94%).
1H NMR (400 MHz, CDCl3, δ): 7.73 (d, J=8.2 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 4.21-4.08 (m, 4H), 2.93 (t, J=6.1 Hz, 2H), 2.03-1.93 (m, 4H);
ESIMS m/z: [M+H]+ 226.
Compound 35-1 (2.35 g, 10.4 mmol) was dissolved in dichloromethane (104 mL), and m-chloroperoxybenzoic acid (4.79 g, 20.8 mmol) was added to the solution. After the mixture was stirred at room temperature overnight, m-chloroperoxybenzoic acid (2.39 g, 10.4 mmol) was further added to the mixture. The mixture was stirred at room temperature for one hour. The mixture was basified by the addition of a 4 mol/L aqueous sodium hydroxide solution, and a saturated aqueous sodium thiosulfate solution was added to the mixture. The organic layer was extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (104 mL), and trifluoroacetic acid anhydride (0.57 mL, 4.01 mmol) was added to the mixture at −78° C. The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. Ethanol (20 mL) and a 4 mol/L aqueous sodium hydroxide o solution (2.0 mL) were added to the residue, and the mixture was stirred at room temperature for one hour. Water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>50/50) to obtain compound 35-2 (1.63 g, 65%).
1H NMR (400 MHz, CDCl3, δ): 7.76 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.2 Hz, 1H), 4.67 (dd, J=8.6, 5.4 Hz, 1H), 4.16-4.12 (m, 4H), 2.38-2.31 (m, 1H), 2.18 (ddd, J=13.4, 6.8, 2.5 Hz, 1H), 2.07-1.98 (m, 1H), 1.90 (ddd, J=14.0, 11.1, 2.3 Hz, 1H);
ESIMS m/z: [M+H]+ 242.
Compound 35-3 (68.5 mg) was obtained as a crude product in the same manner as step 4 of example 33, using compound 35-2 (110 mg, 0.455 mmol) and 4-chlorophenol (117 mg, 9.10 mmol).
ESIMS m/z: [M+H]+ 352.
Compound 35-4 (57.5 mg, 41% over two steps) was obtained in the same manner as step 5 of example 33, using compound 35-3 (422 mg) as a crude product.
1H NMR (400 MHz, CDCl3, δ): 8.29 (d, J=8.1 Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.29-7.28 (m, 2H), 7.08 (td, J=6.1, 3.8 Hz, 2H), 5.49 (t, J=3.5 Hz, 1H), 3.17-3.05 (m, 1H), 2.69-2.59 (m, 2H), 2.41-2.31 (m, 1H);
ESIMS m/z: [M+H]+ 308.
Compound 35-5 (23.5 mg) was obtained as a crude product in the same manner as step 4 of example 1, using compound 35-4 (57.5 mg, 0.185 mmol).
ESIMS m/z: [M+H]+ 309.
Compound 70 (10.2 mg, 15% over two steps) was obtained in the same manner as step 7 of example 33, using compound 35-5 (23.5 mg) as a crude product.
1H NMR (400 MHz, CDCl3, δ): 7.66 (d, J=8.6 Hz, 1H), 7.27 (d, J=5.4 Hz, 1H), 7.24 (t, J=2.9 Hz, 2H), 7.02 (td, J=6.2, 3.8 Hz, 2H), 6.39 (dd, J=16.8, 1.4 Hz, 1H), 6.16 (dd, J=16.8, 10.4 Hz, 1H), 5.95 (d, J=9.5 Hz, 1H), 5.75 (dd, J=10.4, 1.4 Hz, 1H), 5.36-5.33 (m, 1H), 5.28-5.28 (m, 1H), 2.42-2.33 (m, 1H), 2.08-2.01 (m, 3H);
ESIMS m/z: [M+H]+ 363.
The following compound was synthesized in accordance with the synthesis method of compound 70.
ESIMS m/z: [M+H]+ 397.
Compound 35-4 (50 mg, 0.162 mmol) was dissolved in methanol (0.5 mL), and a 28% sodium methoxide solution in methanol (1 mL) was added to the solution. The mixture was subjected to a reaction at a temperature of 120° C. for 3 minutes, using a microwave reactor manufactured by Biotage. The mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>50/50) to obtain compound 36-1 (39 mg, 79%).
1H NMR (400 MHz, CDCl3, δ): 8.20 (d, J=8.6 Hz, 1H), 7.25 (td, J=6.1, 3.6 Hz, 2H), 7.13 (td, J=6.1, 3.6 Hz, 2H), 6.79 (d, J=8.6 Hz, 1H), 5.42 (dd, J=4.5, 3.6 Hz, 1H), 3.90 (s, 3H), 3.08-3.03 (m, 1H), 2.66-2.61 (m, 1H), 2.56-2.49 (m, 1H), 2.44-2.36 (m, 1H);
ESIMS m/z: [M+H]+ 304.
Compound 36-2 was obtained as a crude product in the same manner as step 4 of example 1, using compound 36-1 (39 mg, 0.128 mmol).
ESIMS m/z: [M+H]+ 305.
Compound 71 (9.2 mg, 20% over two steps) and compound 81 (1.8 mg, 4% over two steps) were obtained in the same manner as step 7 of example 33, using compound 36-2 as a crude product. Compound 71: 1H NMR (400 MHz, CDCl3, δ): 7.55 (d, J=8.6 Hz, 1H), 7.24-7.23 (m, 2H), 7.14 (td, J=6.2, 3.8 Hz, 2H), 6.70 (d, J=8.6 Hz, 1H), 6.36 (dd, J=17.2, 1.4 Hz, 1H), 6.12 (dd, J=17.2, 10.4 Hz, 1H), 5.74 (d, J=9.5 Hz, 1H), 5.72 (dd, J=10.4, 1.4 Hz, 1H), 5.31-5.29 (m, 1H), 5.23-5.22 (m, 1H), 3.82 (s, 3H), 2.32-2.28 (m, 1H), 2.18-2.01 (m, 3H);
ESIMS m/z: [M+H]+ 359.
Compound 81: 1H NMR (400 MHz, CDCl3, δ): 7.55 (d, J=8.6 Hz, 1H), 7.24-7.23 (m, 2H), 7.12 (td, J=6.1, 3.9 Hz, 2H), 6.70 (d, J=8.6 Hz, 1H), 6.34 (dd, J=16.8, 1.4 Hz, 1H), 6.06 (dd, J=16.8, 10.4 Hz, 1H), 5.69 (dd, J=10.4, 1.4 Hz, 1H), 5.63 (d, J=8.2 Hz, 1H), 5.34-5.32 (m, 1H), 5.26-5.24 (m, 1H), 3.79 (s, 3H), 2.48-2.38 (m, 1H), 2.26-2.08 (m, 2H), 1.95-1.88 (m, 1H);
ESIMS m/z: [M+H]+ 359.
The following compounds were synthesized in accordance with the synthesis method of compound 71.
ESIMS m/z: [M+H]+ 372.
ESIMS m/z: [M+H]+ 420.
ESIMS m/z: [M+H]+ 414.
ESIMS m/z: [M+H]+ 407.
Compound 37-1 was obtained as a crude product in the same manner as step 4 of example 33, using compound 35-2 (250 mg, 1.03 mmol) and 4-(trifluoromethyl)phenol (335 mg, 2.07 mmol).
ESIMS m/z: [M+H]+ 386.
Compound 37-2 was obtained as a crude product in the same manner as step 5 of example 33, using compound 37-1 (339 mg) as a crude product.
ESIMS m/z: [M+H]+ 342.
Compound 37-3 was obtained as a crude product in the same manner as step 2 of example 3, using compound 37-2 (70 mg) as a crude product.
ESIMS m/z: [M+H]+ 343.
Compound 76 (33.7 mg, 52% in four stages) and compound 82 (21.6 mg, 33% in four stages) were obtained in the same manner as step 3 of example 17, using compound 37-3 as a crude product. Compound 76: 1H NMR (400 MHz, CDCl3, δ): 7.70 (d, J=8.5 Hz, 1H), 7.57 (dt, J=9.3, 2.4 Hz, 2H), 7.31 (d, J=8.5 Hz, 1H), 7.17 (dt, J=9.3, 2.4 Hz, 2H), 6.41 (dd, J=17.1, 1.3 Hz, 1H), 6.16 (dd, J=17.1, 10.3 Hz, 1H), 5.82 (d, J=9.4 Hz, 1H), 5.77 (dd, J=10.3, 1.3 Hz, 1H), 5.41-5.38 (m, 2H), 2.43-2.41 (m, 1H), 2.20-2.00 (m, 3H);
ESIMS m/z: [M+H]+ 397.
Compound 82: 1H NMR (400 MHz, CDCl3, δ): 7.73 (d, J=8.5 Hz, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz, 1H), 7.17 (d, J=8.5 Hz, 2H), 6.37 (dd, J=16.6, 1.3 Hz, 1H), 6.08 (dd, J=16.6, 10.5 Hz, 1H), 5.73 (dd, J=10.5, 1.3 Hz, 1H), 5.72 (d, J=9.0 Hz, 1H), 5.45-5.42 (m, 2H), 2.47-2.42 (m, 1H), 2.31-2.28 (m, 1H), 2.19-2.10 (m, 1H), 1.94-1.90 (m, 1H);
ESIMS m/z: [M+H]+ 397.
The following compound was synthesized in accordance with the synthesis method of compound 76.
ESIMS m/z: [M+H]+ 398.
2-Amino-6-chloropyridine (100 mg, 0.778 mmol) was dissolved in DMF (4.00 mL), and 4-chlorophenol (150 mg, 1.17 mmol) and cesium carbonate (507 mg, 1.56 mmol) were added to the solution. The mixture was heated to 180° C. and stirred for one hour using a microwave reactor, Initiator, manufactured by Biotage. A saturated aqueous sodium bicarbonate solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified using a preparative HPLC [Waters Xbridge Prep C18 OBD column, 5 μm silica, diameter 19 mm, length 100 mm; acetonitrile/0.05% aqueous TFA solution (30/70−>40/60)] to obtain compound 38-1 (92.0 mg, 54%).
1H NMR (400 MHz, CDCl3, δ): 7.41 (t, J=8.2 Hz, 1H), 7.34-7.29 (m, 2H), 7.08-7.02 (m, 2H), 6.20 (d, J=8.2 Hz, 1H), 6.13 (d, J=8.2 Hz, 1H), 4.35 (br, 2H);
ESIMS m/z: [M+H]+ 221.
Compound 38-1 (47.0 mg, 0.213 mmol) was dissolved in dichloromethane (2.00 mL), and triethylamine (0.0890 mL, 0.639 mmol) and acryloyl chloride (0.0270 mL, 0.320 mmol) were added to the solution under ice cooling. The mixture was stirred at room temperature for 1.5 hours. Water and ethyl acetate were added to the mixture. The mixture was filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>60/40) to obtain compound 83 (34.0 mg, 58%).
1H NMR (400 MHz, CDCl3, δ): 7.99 (d, J=7.7 Hz, 1H), 7.76-7.65 (m, 2H), 7.38-7.32 (m, 2H), 7.09-7.02 (m, 2H), 6.63 (d, J=7.7 Hz, 1H), 6.43 (dd, J=16.8, 1.1 Hz, 1H), 6.18 (dd, J=16.8, 10.2 Hz, 1H), 5.79 (dd, J=10.2, 1.1 Hz, 1H);
ESIMS m/z: [M+H]+ 275.
The following compounds were synthesized in accordance with the synthesis method of compound 83.
ESIMS m/z: [M+H]+ 275.
ESIMS m/z: [M+H]+ 289.
ESIMS m/z: [M+H]+ 289.
ESIMS m/z: [M+H]+ 289.
ESIMS m/z: [M+H]+ 289.
ESIMS m/z: [M+H]+ 289.
ESIMS m/z: [M+H]+ 289.
ESIMS m/z: [M+H]+ 289.
ESIMS m/z: [M+H]+ 275.
Compound 39-1 (38.0 mg, 44%) was obtained in the same manner as step 1 of example 38, using 2-amino-4-chloropyridine.
1H NMR (400 MHz, CDCl3, δ): 7.95 (d, J=5.9 Hz, 1H), 7.39-7.33 (m, 2H), 7.05-6.99 (m, 2H), 6.27 (dd, J=5.9, 2.3 Hz, 1H), 5.95 (d, J=2.3 Hz, 1H), 4.39 (br, 2H);
ESIMS m/z: [M+H]+ 221.
Compound 84 (18.0 mg, 38%) was obtained in the same manner as step 2 of example 38, using compound 39-1.
1H NMR (400 MHz, CDCl3, δ): 8.14 (d, J=5.9 Hz, 1H), 8.01 (br, 1H), 7.90 (d, J=2.3 Hz, 1H), 7.41-7.36 (m, 2H), 7.09-7.03 (m, 2H), 6.62 (dd, J=2.3 Hz, 1H), 6.43 (dd, J=17.0, 1.1 Hz, 1H), 6.22 (dd, J=16.8, 10.4 Hz, 1H), 5.81 (dd, J=10.4, 1.1 Hz, 1H);
ESIMS m/z: [M+H]+ 275.
Compound 90 (16.0 mg, 25%) was obtained in the same manner as step 2 of example 38, using compound 39-1 and (E)-2-butenoyl chloride.
1H NMR (400 MHz, CDCl3, δ): 8.12 (d, J=5.4 Hz, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.82 (br, 1H), 7.40-7.36 (m, 2H), 7.08-6.95 (m, 3H), 6.60 (dd, J=2.3 Hz, 1H), 5.91 (dd, J=15.0, 1.6 Hz, 1H), 1.92 (dd, J=7.0, 1.6 Hz, 3H);
ESIMS m/z: [M+H]+ 289.
In DMSO (2.00 mL), 3-iodobenzotrifluoride (0.0530 mL, 0.357 mmol) was dissolved, and copper(I) iodide (3.40 mg, 0.0180 mmol), picolinic acid (4.39 mg, 0.0360 mmol), tripotassium phosphate (151 mg, 0.713 mmol), and 3-amino-5-hydroxypyridine (47.0 mg, 0.428 mmol) were added to the solution. The mixture was stirred at 80° C. for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified using a preparative HPLC [Waters Xbridge Prep C18 OBD column, 5 μm silica, diameter 19 mm, length 100 mm; acetonitrile/0.05% aqueous TFA solution (30/70−>40/60)] to obtain compound 41-1 (36.0 mg, 40%).
1H NMR (400 MHz, CDCl3, δ): 7.92 (s, 1H), 7.82 (s, 1H), 7.51-7.35 (m, 2H), 7.30-7.16 (m, 2H), 6.63 (s, 1H), 3.79 (br, 2H)
ESIMS m/z: [M+H]+ 255.
Compound 95 (26.0 mg, 60%) was obtained in the same manner as step 2 of example 38, using compound 41-1.
1H NMR (400 MHz, CDCl3, δ): 8.37 (s, 1H), 8.17 (s, 1H), 8.08 (s, 1H), 7.56-7.17 (m, 5H), 6.46 (d, J=16.8 Hz, 1H), 6.25 (dd, J=16.8, 10.0 Hz, 1H), 5.85 (d, J=10.0 Hz, 1H);
ESIMS m/z: [M+H]+ 309.
Compound 42-1 (30.0 mg, 33%) was obtained in the same manner as step 1 of example 41, using 4-iodobenzotrifluoride.
1H NMR (400 MHz, CDCl3, δ): 7.93 (d, J=2.3 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.60 (d, J=8.2 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H), 6.65 (t, J=2.3 Hz, 1H), 3.79 (br, 2H);
ESIMS m/z: [M+H]+ 255.
Compound 96 (24.0 mg, 66%) was obtained in the same manner as step 2 of example 38, using compound 42-1.
1H NMR (400 MHz, DMSO-d6, δ): 10.55 (br, 1H), 8.64 (d, J=2.3 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.94 (t, J=2.3 Hz, 1H), 7.80 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.6 Hz, 2H), 6.41 (dd, J=16.8, 10.0 Hz, 1H), 6.28 (dd, J=16.8, 1.8 Hz, 1H), 5.82 (dd, J=10.0, 1.8 Hz, 1H); ESIMS m/z: [M+H]+ 309.
Compound 43-1 (33.0 mg, 36%) was obtained in the same manner as step 1 of example 41, using 1-iodo-4-(trifiuoromethoxy)benzene.
1H-NMR (400 MHz, CDCl3, δ): 7.88 (d, J=2.3 Hz, 1H), 7.80 (d, J=2.3 Hz, 1H), 7.24-7.17 (m, 2H), 7.06-7.00 (m, 2H), 6.59 (t, J=2.3 Hz, 1H), 3.75 (br, 2H);
ESIMS m/z: [M+H]+ 271.
Compound 100 (26.0 mg, 66%) was obtained in the same manner as step 2 of example 38, using compound 43-1.
1H NMR (400 MHz, DMSO-d6, δ): 10.50 (br, 1H), 8.61 (d, J=2.3 Hz, 1H), 8.15 (d, J=2.3 Hz, 1H), 7.84 (t, J=2.3 Hz, 1H), 7.45 (d, J=8.6 Hz, 2H), 7.24 (d, J=8.6 Hz, 2H), 6.40 (dd, J=16.8, 10.0 Hz, 1H), 6.27 (dd, J=16.8, 1.8 Hz, 1H), 5.81 (dd, J=10.0, 1.8 Hz, 1H); ESIMS m/z: [M+H]+ 325.
Compound 44-1 (15.0 mg, 17%) was obtained in the same manner as step 1 of example 41, using 1-ethoxy-4-iodobenzene.
1H NMR (400 MHz, CDCl3, δ): 7.79 (d, J=2.3 Hz, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.00-6.95 (m, 2H), 6.91-6.86 (m, 2H), 6.50 (t, J=2.3 Hz, 1H), 4.02 (q, J=7.0 Hz, 2H), 3.67 (br, 2H), 1.42 (t, J=7.0 Hz, 3H);
ESIMS m/z: [M+H]+ 231.
Compound 102 (9.90 mg, 54%) was obtained in the same manner as step 2 of example 38, using compound 44-1.
1H NMR (400 MHz, DMSO-d6, δ): 10.41 (br, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.68 (t, J=2.3 Hz, 1H), 7.10-7.05 (m, 2H), 7.02-6.96 (m, 2H), 6.38 (dd, J=17.0, 10.0 Hz, 1H), 6.25 (dd, J=17.0, 1.8 Hz, 1H), 5.79 (dd, J=10.0, 1.8 Hz, 1H), 4.03 (q, J=7.0 Hz, 2H), 1.34 (t, J=7.0 Hz, 3H)
ESIMS m/z: [M+H]+ 285.
Compound 45-1 (31.0 mg, 34%) was obtained in the same manner as step 1 of example 41, using 3-iodo-5-(trifluoromethyl)pyridine.
1H NMR (400 MHz, CDCl3, δ): 8.66 (br, 1H), 8.59 (d, J=2.3 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H), 7.84 (d, J=2.3 Hz, 1H), 7.50 (br, 1H), 6.66 (t, J=2.3 Hz, 1H), 3.86 (br, 2H); ESIMS m/z: [M+H]+ 256.
Compound 107 (13.0 mg, 34%) was obtained in the same manner as step 2 of example 38, using compound 45-1.
1H NMR (DMSO-d6, δ): 10.56 (br, 1H), 8.84 (br, 1H), 8.79 (d, J=2.3 Hz, 1H), 8.65 (d, J=2.3 Hz, 1H), 8.23 (d, J=2.7 Hz, 1H), 8.05 (br, 1H), 7.94 (t, J=2.3 Hz, 1H), 6.42 (dd, J=17.2, 10.0 Hz, 1H), 6.28 (dd, J=17.2, 1.8 Hz, 1H), 5.82 (dd, J=10.0, 1.8 Hz, 1H); ESIMS m/z: [M+H]+ 310.
Compound 46-1 (53.0 mg, 43%) was obtained in the same manner as step 1 of example 41, using 4-iodo-2-(trifluoromethyl)pyridine.
1H NMR (400 MHz, CDCl3, δ): 8.59 (d, J=5.9 Hz, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H), 7.28-7.24 (m, 1H), 7.01 (dd, J=5.9, 2.3 Hz, 1H), 6.72 (t, J=2.3 Hz, 1H), 3.91 (br, 2H);
ESIMS m/z: [M+H]+ 256.
Compound 108 (40.0 mg, 63%) was obtained in the same manner as step 2 of example 38, using compound 46-1.
1H NMR (400 MHz, DMSO-d6, δ): 10.64 (br, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.68 (d, J=5.4 Hz, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.11 (t, J=2.3 Hz, 1H), 7.59 (d, J=2.3 Hz, 1H), 7.29 (dd, J=5.4, 2.3 Hz, 1H), 6.44 (dd, J=17.0, 10.0 Hz, 1H), 6.30 (dd, J=17.0, 1.8 Hz, 1H), 5.84 (dd, J=10.0, 1.8 Hz, 1H);
ESIMS m/z: [M+H]+ 310.
Compound 47-1 (99.0 mg, 73%) was obtained in the same manner as step 1 of example 41, using 2-iodo-5-(trifluoromethyl)pyridine.
1H NMR (400 MHz, CDCl3, δ): 8.44 (br, 1H), 8.00 (br, 1H), 7.95-7.89 (m, 2H), 7.06 (d, J=8.6 Hz, 1H), 6.83 (t, J=2.3 Hz, 1H), 3.81 (br, 2H);
ESIMS m/z: [M+H]+ 256.
Compound 109 (82.0 mg, 68%) was obtained in the same manner as step 2 of example 38, using compound 47-1.
1H NMR (400 MHz, DMSO-d6, δ): 10.57 (br, 1H), 8.66 (d, J=2.3 Hz, 1H), 8.59 (br, 1H), 8.33-8.23 (m, 2H), 8.10 (t, J=2.3 Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 6.44 (dd, J=16.8, 10.0 Hz, 1H), 6.29 (dd, J=16.8, 1.8 Hz, 1H), 5.83 (dd, J=10.0, 1.8 Hz, 1H);
ESIMS m/z: [M+H]+ 310.
Compound 48-1 (26.0 mg, 23%) was obtained in the same manner as step 1 of example 41, using 5-iodo-2-(isopropoxy)pyridine.
1H NMR (400 MHz, CDCl3, δ): 7.95 (d, J=3.2 Hz, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.77 (d, J=2.3 Hz, 1H), 7.33-7.26 (m, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.52 (t, J=2.3 Hz, 1H), 5.29-5.20 (m, 1H), 3.71 (br, 2H), 1.36 (d, J=6.8 Hz, 6H);
ESIMS m/z: [M+H]+ 246.
Compound 110 (17.0 mg, 54%) was obtained in the same manner as step 2 of example 38, using compound 48-1.
1H-NMR (400 MHz, DMSO-d6, δ): 10.45 (br, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.11 (d, J=2.3 Hz, 1H), 8.07 (d, J=2.7 Hz, 1H), 7.71 (t, J=2.3 Hz, 1H), 7.59 (dd, J=9.1, 2.7 Hz, 1H), 6.84 (d, J=9.1 Hz, 1H), 6.39 (dd, J=16.8, 10.0 Hz, 1H), 6.26 (dd, J=16.8, 1.8 Hz, 1H), 5.80 (dd, J=10.0, 1.8 Hz, 1H), 5.26-5.15 (m, 1H), 1.31 (d, J=5.9 Hz, 6H);
ESIMS m/z: [M+H]+ 300.
The following compounds were synthesized in accordance with the synthesis method of compound 95.
ESIMS m/z: [M+H]+ 271.
ESIMS m/z: [M+H]+ 271.
ESIMS m/z: [M+H]+ 266.
ESIMS m/z: [M+H]+ 285.
ESIMS m/z: [M+H]+ 299.
ESIMS m/z: [M+H]+ 347.
ESIMS m/z: [M+H]+ 309.
ESIMS m/z: [M+H]+ 327.
Compound 49-1 (17.9 mg, 10%) was obtained in the same manner as step 4 of example 4, using 5-aminoguinolin-8-ol.
1H NMR (300 MHz, CDCl3, δ): 8.94 (dd, J=4.0, 1.5 Hz, 1H), 8.22 (dd, J=8.6, 1.6 Hz, 1H), 7.44-7.40 (m, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.06-7.00 (m, 4H), 6.77 (d, J=8.4 Hz, 1H)
ESIMS m/z: [M+H]+ 237.
Compound 111 (8.3 mg, 40%) was obtained in the same manner as step 5 of example 1, using compound 49-1.
1H NMR (300 MHz, CDCl3, δ): 9.02 (s, 1H), 8.23 (d, J=7.3 Hz, 1H), 7.70-7.62 (m, 1H), 7.54-7.46 (m, 2H), 7.39 (t, J=7.7 Hz, 2H), 7.21-7.13 (m, 3H), 7.05 (d, J=8.4 Hz, 1H), 6.57-6.43 (m, 2H), 5.87 (d, J=9.9 Hz, 1H)
ESIMS m/z: [M+H]+ 291.
8-Chloro-2-methylquinoline (0.50 g, 2.28 mmol) was added to a liquid mixture of concentrated sulfuric acid (2.5 mL), concentrated nitric acid (5.0 mL), and fuming nitric acid (1.0 mL) under ice cooling. The mixture was slowly stirred at 65° C. for 16 hours. The mixture was cooled to room temperature, and water was added to the mixture. The organic layer was extracted with tert-butyl methyl ether, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>80/20) to obtain compound 50-1 (0.35 g, 56%).
1H NMR (400 MHz, DMSO-d6, δ): 8.77 (d, J=8.8 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.78 (d, J=9.2 Hz, 1H), 2.76 (s, 3H).
Compound 50-1 (0.35 g, 1.57 mmol) was dissolved in DMF (5.0 mL), and phenol (0.11 g, 1.89 mmol) and cesium carbonate (1.20 g, 3.94 mmol) were added to the solution. The mixture was stirred at 90° C. for 3 hours. The mixture was cooled to room temperature, and water was added to the mixture. The organic layer was extracted with tert-butyl methyl ether, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20−>70/30) to obtain compound 50-2 (0.29 g, 56%).
1H NMR (400 MHz, DMSO-d6, δ): 8.91 (d, J=9.2 Hz, 1H), 8.38 (d, J=8.8 Hz, 1H), 7.78 (d, J=9.2 Hz, 1H), 7.52 (t, J=8.0 Hz, 2H), 7.32 (t, J=7.2 Hz, 1H), 7.25 (d, J=7.6 Hz, 2H), 6.99 (d, J=8.8 Hz, 1H), 2.72 (s, 3H).
Compound 50-2 (0.28 g, 1.00 mmol) was suspended in ethanol (5.0 mL) and water (2.5 mL), and iron (0.27 g, 5.00 mmol) and ammonium chloride (0.26 g, 5.00 mmol) were added to the suspension. The mixture was refluxed for 2 hours. The mixture was cooled to room temperature, and dichloromethane (30 mL) was added to the mixture. The mixture was filtered with Celite(R). The organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 50-3 (0.16 g, 66%).
1H NMR (400 MHz, DMSO-d6, δ): 8.43 (d, J=8.8 Hz, 1H), 7.29-7.20 (m, 3H), 7.12 (d, J=8.4 Hz, 1H), 6.92 (t, J=7.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 2H), 6.62 (d, J=8.0 Hz, 1H), 5.81 (s, 2H), 2.50 (s, 3H).
Compound 112 (51.0 mg, 28%) was obtained in the same manner as step 5 of example 1, using compound 50-3 (0.15 g, 0.60 mmol).
1H NMR (400 MHz, DMSO-d6, δ): 10.16 (s, 1H), 8.36 (d, J=8.7 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.38-7.33 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.09 (t, J=7.2 Hz, 1H), 6.97 (d, J=7.8 Hz, 2H), 6.66 (dd, J=16.8, 10.2 Hz, 1H), 6.31 (dd, J=17.1, 1.8 Hz, 1H), 5.82 (dd, J=10.2, 1.5 Hz, 1H), 2.60 (s, 3H)
ESIMS m/z: [M+H]+ 305.
The following compounds were synthesized in accordance with the synthesis method of compound 112.
ESIMS m/z: [M+H]+ 339.
ESIMS m/z: [M+H]+ 339.
Compound 51-1 (30.0 mg, 40%) was obtained in the same manner as step 2 of example 50, using 8-fluoro-5-nitroquinoline.
1H NMR (400 MHz, CDCl3, δ): 9.24 (dd, J=9.2, 1.6 Hz, 1H), 9.14 (dd, J=4.0, 1.2 Hz, 1H), 8.37 (d, J=8.8 Hz, 1H), 7.76 (dd, J=8.8, 4.0 Hz, 1H), 7.58-7.55 (m, 1H), 7.40-7.38 (m, 1H), 7.32-7.26 (m, 2H), 6.74 (d, J=8.8 Hz, 1H).
Compound 51-2 (20.0 mg, 60%) was obtained in the same manner as step 3 of example 50, using compound 51-1.
1H NMR (400 MHz, CDCl3, δ): 8.95 (dd, J=4.4, 1.6 Hz, 1H), 8.21 (dd, J=8.4, 1.2 Hz, 1H), 7.47-7.41 (m, 2H), 7.12-7.10 (m, 1H), 7.04-7.00 (m, 2H), 6.84-6.82 (m, 1H), 6.73 (d, J=8.4 Hz, 1H), 4.11 (bs, 2H).
Compound 113 (150 mg, 70%) was obtained in the same manner as step 5 of example 1, using compound 51-2.
1H-NMR (400 MHz, DMSO-d6, δ): 10.22 (s, 1H), 8.90-8.89 (m, 1H), 8.51-8.49 (m, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.66-7.58 (m, 2H), 7.29-7.21 (m, 2H), 7.15-7.11 (m, 1H), 6.77-6.75 (m, 1H), 6.67 (dd, J=16.8, 10.0 Hz, 1H), 6.33 (dd, J=16.8, 1.6 Hz, 1H), 5.85-5.82 (m, 1H)
ESIMS m/z: [M+H]+ 325.
The following compounds were synthesized in accordance with the synthesis method of compound 113.
ESIMS m/z: [M+H]+ 325.
ESIMS m/z: [M+H]+ 325.
ESIMS m/z: [M+H]+ 359.
ESIMS m/z: [M+H]+ 333.
ESIMS m/z: [M+H]+ 299.
ESIMS m/z: [M+H]+ 299.
ESIMS m/z: [M+H]+ 329.
ESIMS m/z: [M+H]+ 379.
ESIMS m/z: [M+H]+ 379.
ESIMS m/z: [M+H]+ 313.
ESIMS m/z: [M+H]+ 313.
ESIMS m/z: [M+H]+ 313.
ESIMS m/z: [M+H]+ 341.
5-Nitroquinolin-8-ol (0.25 g, 1.31 mmol) was dissolved in DMF (5.0 mL), and cyclohexyl bromide (0.42 g, 2.63 mmol) and cesium carbonate (1.20 g, 3.94 mmol) were added to the liquid mixture. The liquid mixture was stirred at 90° C. for 16 hours. The mixture was cooled to room temperature, and water was added to the mixture. The organic layer was extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>80/20) to obtain compound 52-1 (0.24 g, 67%).
1H-NMR (300 MHz, DMSO-d6, δ): 9.05-9.00 (m, 2H), 8.52 (d, J=9.0 Hz, 1H), 7.85-7.81 (m, 1H), 7.42 (d, J=9.0 Hz, 1H), 4.84-4.78 (m, 1H), 2.06-1.37 (m, 10H).
Compound 52-2 (0.17 g, 83%) was obtained in the same manner as step 3 of example 50, using compound 52-1.
1H-NMR (300 MHz, DMSO-d6, δ): 8.78 (dd, J=3.9, 1.5 Hz, 1H), 8.44 (dd, J=8.4, 1.2 Hz, 1H), 7.37 (dd, J=8.7, 4.2 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 5.47 (s, 2H), 4.35-4.29 (m, 1H), 1.98-1.90 (m, 2H), 1.78-1.75 (m, 2H), 1.52-1.46 (m, 3H), 1.33-1.23 (m, 3H).
Compound 119 (89 mg, 46%) was obtained in the same manner as step 5 of example 1, using compound 52-2.
1H-NMR (300 MHz, DMSO-d6, δ): 10.04 (s, 1H), 8.88 (dd, J=3.9, 1.5 Hz, 1H), 8.30 (dd, J=8.7, 1.8 Hz, 1H), 7.63-7.55 (m, 2H), 7.24 (d, J=8.7 Hz, 1H), 6.62 (dd, J=17.1, 10.2Hz, 1H), 6.28 (dd, J=17.1, 1.8 Hz, 1H), 5.80 (dd, J=10.2, 1.8 Hz, 1H), 4.62-4.56 (m, 1H), 2.05-2.01 (m, 2H), 1.81-1.77 (m, 2H), 1.60-1.23 (m, 6H)
ESIMS m/z: [M+H]+ 297.
The following compounds were synthesized in accordance with the synthesis method of compound 119.
ESIMS m/z: [M+H]+ 305.
ESIMS m/z: [M+H]+ 311.
Compound 53-1 (0.25 g, 38%) was obtained in the same manner as step 2 of example 50, using 8-fluoro-5-nitroquinoline.
1H-NMR (400 MHz, DMSO-d6, δ): 9.04-9.02 (m, 2H), 8.54 (d, J=9.2 Hz, 1H), 7.85-7.82 (m, 1H), 7.36 (d, J=8.8 Hz, 1H), 4.22 (d, J=6.8 Hz, 2H), 2.10-1.86 (m, 7H), 1.45-1.41(m, 2H).
Compound 53-2 (0.17 g, 78%) was obtained in the same manner as step 3 of example 50, using compound 53-1.
1H-NMR (400 MHz, DMSO-d6, δ): 8.79-8.78 (m, 1H), 8.45 (dd, J=8.4, 1.6 Hz, 1H), 7.41-7.38 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 5.40 (s, 2H), 3.92 (d, J=6.0 Hz, 2H), 2.07-1.78 (m, 7H), 1.40-1.31(m, 2H).
Compound 126 (78 mg, 38%) was obtained in the same manner as step 5 of example 1, using compound 53-2.
1H-NMR (400 MHz, DMSO-d6, δ): 8.89 (dd, J=4.0, 1.2 Hz, 1H), 8.31 (d, J=7.6 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.60-7.57 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.61 (dd, J=17.2, 10.4 Hz, 1H), 6.28 (dd, J=17.2, 2.0 Hz, 1H), 5.79 (d, J=10.8 Hz, 1H), 4.06 (d, J=6.4 Hz, 2H), 2.07-1.81 (m, 7H), 1.44-1.36 (m, 2H); ESIMS m/z: [M+H]+ 347.
5-Bromo-8-fluoroquinoline (0.50 g, 2.21 mmol) was dissolved DMF (11 mL), and tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.22 mmol) and zinc cyanide (0.39 g, 3.32 mmol) were added to the solution. The mixture was subjected to a reaction at a temperature of 150° C. for 30 minutes using a microwave reactor, Initiator, manufactured by Biotage. The mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution was added to the mixture. The mixture was filtered with Celite(R). The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>60/40) to obtain compound 54-1 (0.36 g, 94%).
1H NMR (400 MHz, CDCl3, δ): 9.12 (dd, J=4.5, 1.5 Hz, 1H), 8.58 (dt, J=8.5, 1.5 Hz, 1H), 7.99 (dd, J=8.3, 4.5 Hz, 1H), 7.72 (dd, J=8.5, 4.0 Hz, 1H), 7.50 (dd, J=9.6, 8.3 Hz, 1H)
ESIMS m/z: [M+H]+ 173.
Compound 54-2 (73.9 mg, 91%) was obtained in the same manner as step 2 of example 50, using compound 54-1 (50.0 mg, 0.29 mmol).
1H NMR (400 MHz, CDCl3, δ): 9.12 (dd, J=4.0, 1.8 Hz, 1H), 8.59 (dd, J=8.5, 1.8 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.72 (dd, J=8.5, 4.0 Hz, 1H), 7.40 (t, J=8.1 Hz, 1H), 7.28 (dd, J=1.9, 1.0 Hz, 1H), 7.22 (q, J=1.9 Hz, 1H), 7.11 (dq, J=8.1, 1.0 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H)
ESIMS m/z: [M+H]+ 281.
Lithium aluminum hydride (35.2 mg, 0.93 mmol) was suspended in THF (4.0 mL), and compound 54-2 (86.8 mg, 0.31 mmol) dissolved in THF (1.0 mL) was added to the suspension under ice cooling. The mixture was stirred at 60° C. for 2 hours. The mixture was cooled to 0° C., and water (0.04 mL), a 4 mol/L aqueous sodium hydroxide solution (0.04 mL), and water (0.12 mL) were sequentially added to the mixture. The mixture was stirred at room temperature for 30 minutes. The mixture was filtered with Celite(R). The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (chloroform/methanol=100/0−>95/5) to obtain compound 54-3 as a crude product, which was used as it is in the next reaction.
Compound 133 (3.0 mg, 3% over two steps) was obtained in the same manner as step 3 of example 17, using compound 54-3.
1H NMR (400 MHz, CDCl3, δ): 8.99 (dd, J=4.0, 1.3 Hz, 1H), 8.47 (dd, J=8.5, 1.8 Hz, 1H), 7.54 (dd, J=8.5, 4.5 Hz, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.13-7.10 (m, 2H), 7.06 (t, J=2.0 Hz, 1H), 7.03-7.00 (m, 1H), 6.37 (dd, J=16.9, 1.3 Hz, 1H), 6.09 (dd, J=17.1, 10.3 Hz, 1H), 5.81 (br, 1H), 5.70 (dd, J=10.3, 1.3 Hz, 1H), 4.96 (d, J=5.8 Hz, 2H)
ESIMS m/z: [M+H]+ 339.
Compound 55-1 (0.64 g, 98%) was obtained in the same manner as step 2 of example 50, using compound 54-1 (0.40 g, 2.32 mmol) and 4-chlorophenol.
1H NMR (400 MHz, CDCl3, δ): 9.12 (dd, J=4.5, 1.8 Hz, 1H), 8.58 (dd, J=8.5, 1.8 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.5, 4.5 Hz, 1H), 7.44 (dq, J=12.6, 2.8 Hz, 2H), 7.16 (dq, J=12.6, 2.8 Hz, 2H), 6.96 (d, J=8.5 Hz, 1H)
ESIMS m/z: [M+H]+ 281.
Compound 55-2 was obtained as a crude product in the same manner as step 3 of example 54, using compound 55-1 (20.0 mg, 0.071 mmol), and used as it is in the next reaction.
Compound 134 (2.2 mg, 9% over two steps) was obtained in the same manner as step 3 of example 17, using compound 55-2.
1H NMR (400 MHz, CDCl3, δ): 9.00 (dd, J=4.0, 1.3 Hz, 1H), 8.46 (dd, J=8.8, 1.6 Hz, 1H), 7.54 (dd, J=8.5, 4.0 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.34-7.33 (m, 2H), 7.06-7.02 (m, 3H), 6.36 (dd, J=16.9, 1.0 Hz, 1H), 6.08 (dd, J=16.9, 10.3 Hz, 1H), 5.79 (br, 1H), 5.70 (dd, J=10.3, 1.0 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H)
ESIMS m/z: [M+H]+ 339.
Compound 135 (60.0 mg, 60%) was obtained in the same manner as step 3 of example 17, using compound 55-2 (70.0 mg, 0.25 mmol) and commercially available (E)-4,4,4-trifluoro-2-butenoyl chloride (46.8 mg, 0.30 mmol).
1H NMR (400 MHz, CDCl3, δ): 8.96 (dd, J=4.0, 1.8 Hz, 1H), 8.39 (dd, J=8.5, 1.8 Hz, 1H), 7.52 (dd, J=8.5, 4.0 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.33 (dd, J=7.0, 2.0 Hz, 2H), 7.04-7.00 (m, 3H), 6.88-6.79 (m, 1H), 6.46 (dd, J=15.3, 1.8 Hz, 1H), 6.15 (br, 1H), 4.95 (d, J=5.4 Hz, 2H)
ESIMS m/z: [M+H]+ 407.
Compound 57-1 (0.12 g, 94%) was obtained in the same manner as step 2 of example 50, using compound 54-1 (70.0 mg, 0.41 mmol) and 4-bromophenol (84.0 mg, 0.49 mmol).
1H NMR (400 MHz, CDCl3, δ): 9.12 (dd, J=4.3, 1.6 Hz, 1H), 8.58 (dd, J=8.5, 1.3 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.3, 4.3 Hz, 1H), 7.59-7.57 (m, 2H), 7.12-7.08 (m, 2H), 6.97 (d, J=8.1 Hz, 1H)
ESIMS m/z: [M+H]+ 324.
Compound 57-1 (125.0 mg, 0.38 mmol) was dissolved in a 2 mol/L ammonia solution in methanol (12 mL), and the solution was subjected to a reaction using Raney Nickel CatCart(R) (manufactured by ThalesNano Technologies, Inc., 30 mm) in the full H2 mode of H-cube(R) at 25° C. The solvent was concentrated under reduced pressure to obtain compound 57-2 as a crude product.
Compound 57-3 (0.10 g, 70% over two steps) was obtained in the same manner as step 3 of example 17, using compound 57-2.
1H NMR (400 MHz, CDCl3, δ): 8.99 (dd, J=4.0, 1.8 Hz, 1H), 8.46 (dd, J=8.5, 1.8 Hz, 1H), 7.54 (dd, J=8.5, 4.0 Hz, 1H), 7.48-7.47 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 7.04-6.95 (m, 3H), 6.36 (dd, J=17.0, 1.3 Hz, 1H), 6.07 (dd, J=17.0, 10.3 Hz, 1H), 5.75 (br, 1H), 5.70 (dd, J=10.3, 1.3 Hz, 1H), 4.95 (d, J=5.8 Hz, 2H)
ESIMS m/z: [M+H]+ 383.
Compound 57-3 (50.0 mg, 0.13 mmol) was dissolved in 1,4-dioxane (1.0 mL), and added to the solution were bis(triphenylphosphine)palladium(II) chloride dichloromethane adduct (10.7 mg, 0.013 mmol), cyclopropylboronic acid (33.6 mg, 0.391 mmol), cesium carbonate (0.26 g, 0.783 mmol), and water (0.1 mL). The mixture was fluxed for 1.5 hours. The mixture was cooled to room temperature, and saturated saline was added to the mixture. The mixture was filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10 ->50/50) to obtain compound 136 (12.8 mg, 28%).
1H NMR (400 MHz, CDCl3, δ): 9.02 (dd, J=4.1, 1.4 Hz, 1H), 8.44 (dd, J=8.6, 1.4 Hz, 1H), 7.53 (dd, J=8.6, 4.1 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.11-7.04 (m, 4H), 6.90 (d, J=8.2 Hz, 1H), 6.35 (dd, J=17.2, 1.4 Hz, 1H), 6.06 (dd, J=17.2, 10.2 Hz, 1H), 5.73 (br, 1H), 5.69 (dd, J=10.2, 1.4 Hz, 1H), 4.92 (d, J=5.9 Hz, 2H), 1.92 (tt, J=8.4, 3.9 Hz, 1H), 0.98-0.96 (m, 2H), 0.70-0.69 (m, 2H)
ESIMS m/z: [M+H]+ 345.
Compound 58-1 (86.4 mg, 95%) was obtained in the same manner as step 2 of example 50, using compound 54-1 (50.0 mg, 0.29 mmol) and 3-(trifluoromethyl)phenol (56.0 mg, 0.35 mmol).
1H NMR (400 MHz, CDCl3, δ): 9.12 (dd, J=4.0, 1.5 Hz, 1H), 8.60 (dd, J=8.5, 1.5 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.73 (dd, J=8.5, 4.0 Hz, 1H), 7.61-7.53 (m, 2H), 7.47 (s, 1H), 7.39 (dt, J=8.2, 1.7 Hz, 1H), 7.02 (d, J=8.1 Hz, 1H)
ESIMS m/z: [M+H]+ 315.
Compound 58-2 was obtained as a crude product in the same manner as step 2 of example 57, using compound 58-1 (86.4 mg, 0.28 mmol).
ESIMS m/z: [M+H]+ 319.
Compound 137 (65.3 mg, 64% over two steps) was obtained in the same manner as step 3 of example 17, using compound 58-2.
1H NMR (400 MHz, CDCl3, δ): 8.98 (dd, J=4.4, 1.6 Hz, 1H), 8.48 (dd, J=8.8, 1.6 Hz, 1H), 7.55 (dd, J=8.8, 4.4 Hz, 1H), 7.46-7.44 (m, 2H), 7.40 (d, J=8.1 Hz, 1H), 7.34 (br, 1H), 7.26-7.26 (m, 1H), 7.12 (d, J=7.6 Hz, 1H), 6.38 (dd, J=16.9, 1.3 Hz, 1H), 6.09 (dd, J=16.9, 10.3 Hz, 1H), 5.82 (br, 1H), 5.71 (dd, J=10.3, 1.3 Hz, 1H), 4.97 (d, J=5.8 Hz, 2H)
ESIMS m/z: [M+H]+ 373.
The following compounds were synthesized in accordance with the synthesis method of compound 137.
ESIMS m/z: [M+H]+ 373.
ESIMS m/z: [M+H]+ 373.
Compound 59-1 (91.1 mg, 100%) was obtained in the same manner as step 2 of example 50, using compound 54-1 (50.0 mg, 0.29 mmol) and 4-(trifluoromethyl)phenol (56.0 mg, 0.35 mmol).
ESIMS m/z: [M+H]+ 315.
Compound 59-2 was obtained as a crude product in the same manner as step 2 of example 57, using compound 59-1 (91.1 mg, 0.29 mmol).
ESIMS m/z: [M+H]+ 319.
Compound 138 (22.8 mg, 21% over two steps) was obtained in the same manner as step 3 of example 17, using compound 59-2.
1H NMR (400 MHz, CDCl3, δ): 8.97 (dd, J=4.0, 1.5 Hz, 1H), 8.49 (dd, J=8.5, 1.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.54 (dd, J=8.8, 4.3 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.19 (d, J=7.6 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H), 6.38 (dd, J=17.1, 1.3 Hz, 1H), 6.09 (dd, J=17.1, 10.3 Hz, 1H), 5.79 (br, 1H), 5.71 (dd, J=10.3, 1.3 Hz, 1H), 4.98 (d, J=5.4 Hz, 2H)
ESIMS m/z: [M+H]+ 373.
Compound 59-1 (0.15 g, 0.48 mmol) was dissolved in dichloromethane (5.0 mL), and m-chloroperoxybenzoic acid (0.13 g, 0.57 mmol) was added to the solution. After the mixture was stirred at room temperature overnight, m-chloroperoxybenzoic acid (0.13 g, 0.57 mmol) was further added to the mixture. The mixture was stirred at room temperature overnight. The mixture was basified by the addition of a 4 mol/L aqueous sodium hydroxide solution, and a saturated aqueous sodium thiosulfate solution to the mixture for quenching. The organic layer was extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 60-1 as a crude product.
Compound 60-1 was dissolved in toluene (4.8 mL), and phosphoryl chloride (0.22 mL, 2.39 mmol) and diisopropylethylamine (0.42 mL, 2.39 mmol) were added to the solution. The mixture was subjected to a reaction at 80° C. for one hour. The mixture was cooled to room temperature, diluted with acetonitrile, and added dropwise to ice-cooled water. A saturated aqueous sodium bicarbonate solution was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>80/20) to obtain compound 60-2 (31.8 mg, 19% over two steps).
1H NMR (400 MHz, CDCl3, δ): 8.52 (d, J=9.0 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.5 Hz, 1H), 7.30-7.28 (m, 2H), 7.06 (d, J=8.5 Hz, 1H)
ESIMS m/z: [M+H]+ 349.
Compound 60-3 was obtained as a crude product in the same manner as step 2 of example 57, using compound 60-2 (31.8 mg, 0.091 mmol).
ESIMS m/z: [M+H]+ 353.
Compound 139 (27.5 mg, 29% over two steps) was obtained in the same manner as step 3 of example 17, using compound 60-3.
1H NMR (400 MHz, CDCl3, δ): 8.45 (d, J=9.1 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.51 (d, J=9.1 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.14 (dd, J=9.7, 7.9 Hz, 3H), 6.37 (dd, J=17.0, 1.1 Hz, 1H), 6.08 (dd, J=17.0, 10.4 Hz, 1H), 5.80 (br, 1H), 5.72 (dd, J=10.4, 1.1 Hz, 1H), 4.94 (d, J=5.9 Hz, 2H)
ESIMS m/z: [M+H]+ 407.
Compound 61-1 (71.9 mg, 88%) was obtained in the same manner as step 2 of example 50, using compound 54-1 (50.0 mg, 0.29 mmol) and 6-chloropyridin-3-ol (45.0 mg, 0.35 mmol).
1H NMR (400 MHz, CDCl3, δ): 9.10 (dd, J=4.0, 1.8 Hz, 1H), 8.60 (dd, J=8.5, 1.8 Hz, 1H), 8.32 (d, J=2.2 Hz, 1H), 7.91 (d, J=8.1 Hz, 1H), 7.74 (dd, J=8.5, 4.0 Hz, 1H), 7.49 (dd, J=8.8, 2.9 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H)
ESIMS m/z: [M+H]+ 282.
Compound 61-2 was obtained as a crude product in the same manner as step 2 of example 57, using compound 61-1 (71.0 mg, 0.25 mmol).
ESIMS m/z: [M+H]+ 286.
Compound 142 (27.7 mg, 32% over two steps) was obtained in the same manner as step 3 of example 17, using compound 61-2.
1H NMR (400 MHz, CDCl3, δ): 8.97 (dd, J=4.3, 1.3 Hz, 1H), 8.49 (dd, J=8.5, 1.3 Hz, 1H), 8.21 (d, J=2.7 Hz, 1H), 7.56 (dd, J=8.5, 4.0 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.36 (dd, J=8.8, 2.9 Hz, 1H), 7.30-7.29 (m, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.38 (dd, J=16.8, 1.3 Hz, 1H), 6.09 (dd, J=16.8, 10.3 Hz, 1H), 5.81 (s, 1H), 5.71 (dd, J=10.3, 1.3 Hz, 1H), 4.97 (d, J=5.8 Hz, 2H); ESIMS m/z: [M+H]+ 340.
Compound 62-1 (71.0 mg, 78%) was obtained in the same manner as step 2 of example 50, using compound 54-1 (50.0 mg, 0.29 mmol) and 6-(trifluoromethyl)pyridin-3-ol (57.0 mg, 0.35 mmol).
1H NMR (400 MHz, CDCl3, δ):9.06 (dd, J=4.0, 0.9 Hz, 1H), 8.62 (dd, J=8.5, 0.9 Hz, 1H), 8.58 (d, J=2.7 Hz, 1H), 7.74-7.72 (m, 2H), 7.52 (dd, J=8.7, 2.9 Hz, 1H), 7.30-7.29 (m, 1H)
ESIMS m/z: [M+H]+ 316.
Compound 62-2 was obtained as a crude product in the same manner as step 2 of example 57, using compound 62-1 (71.0 mg, 0.23 mmol).
ESIMS m/z: [M+H]+ 320.
Compound 143 (26.7 mg, 32% over two steps) was obtained in the same manner as step 3 of example 17, using compound 62-2.
1H NMR (400 MHz, CDCl3, δ): 8.93 (dd, J=3.8, 1.6 Hz, 1H), 8.52-8.50 (m, 2H), 7.61 (d, J=8.5 Hz, 1H), 7.56-7.52 (m, 2H), 7.34-7.29 (m, 2H), 6.38 (d, J=17.1 Hz, 1H), 6.10 (dd, J=17.1, 10.1 Hz, 1H), 5.81 (br, 1H), 5.72 (d, J=10.1 Hz, 1H), 5.00 (d, J=5.8 Hz, 2H)
ESIMS m/z: [M+H]+ 374.
2-Chloroquinoline-4-carbonitrile (0.10 g, 0.53 mmol) was dissolved in DMF (2 mL), and 4-chlorophenol (0.082 g, 0.64 mmol) was added to the solution. The mixture was stirred using a microwave reactor at 150° C. for 30 minutes. Water was added to the mixture. Precipitated crystals were filtered off, washed with water, and dried under reduced pressure to obtain compound 63-1 (145 mg, 97%).
1H NMR (400 MHz, CDCl3, δ): 8.13 (d, J=8.3 Hz, 1H), 7.83 (d, J=8.3 Hz, 1H), 7.75 (t, J=7.6 Hz, 1H), 7.62 (t, J=7.6 Hz, 1H), 7.50-7.40 (m, 2H), 7.24-7.18 (m, 3H).
Compound 63-2 (148 mg, quantitatively) was obtained in the same manner as step 3 of example 15, using compound 63-1.
1H NMR (400 MHz, CDCl3, δ): 7.91 (d, J=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.38 (t, J=8.8 Hz, 2H), 7.21-7.20 (m, 3H), 4.36 (s, 2H).
Compound 144 (118 mg, 68%) was obtained in the same manner as step 5 of example 1, using compound 63-2.
1H-NMR (400 MHz, DMSO-d6, δ): 8.81 (s, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.67 (s, 2H), 7.52 (d, J=8.8 Hz, 3H), 7.30 (d, J=8.8 Hz, 2H), 7.09 (s, 1H), 6.36 (dd, J=17.1, 10.2 Hz, 1H), 6.19 (d, J=17.1 Hz, 1H), 5.69 (d, J=10.2 Hz, 1H), 4.87 (d, J=5.4 Hz, 2H)
ESIMS m/z: [M+H]+ 339.
The following compounds were synthesized in accordance with the synthesis method of compound 144.
ESIMS m/z: [M+H]+ 407.
ESIMS m/z: [M+H]+ 340.
Compound 64-1 (129 mg, 52%) was obtained in the same manner as step 1 of example 63, using 2-chloroquinoline-4-carbonitrile.
1H NMR (400 MHz, CDCl3, δ): 8.16-8.12 (m, 1H), 7.86-7.71 (m, 4H), 7.66-7.62 (m, 1H), 7.52 (s, 1H), 7.39 (d, J=8.8 Hz, 2H).
Compound 64-2 (127 mg, quantitatively) was obtained in the same manner as step 3 of example 15, using compound 64-1.
1H NMR (400 MHz, CDCl3, δ): 7.92 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.68-7.61 (m, 3H), 7.47 (t, J=7.6 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.29-7.26 (m, 2H), 4.43-4.40 (m, 2H).
Compound 146 (29 mg, 41%) was obtained in the same manner as step 5 of example 1, using compound 64-2.
1H NMR (400 MHz, CDCl3, δ): 7.94 (d, J=8.3 Hz, 1H), 7.80 (d, J=8.3 Hz, 1H), 7.68-7.64 (m, 3H), 7.49 (t, J=8.3 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.08 (s, 1H), 6.40 (d, J=17.1 Hz, 1H), 6.18 (dd, J=17.1, 10.2 Hz, 1H), 5.98 (s, 1H), 5.75 (d, J=10.2 Hz, 1H), 5.01 (d, J=6.3 Hz, 2H)
ESIMS m/z: [M+H]+ 373.
Compound 147 (19 mg, 23%) was obtained in the same manner as in example 18, using compound 64-2.
1H NMR (400 MHz, CDCl3, δ): 7.90 (d, J=8.1 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.71-7.64 (m, 3H), 7.50 (t, J=8.1 Hz, 1H), 7.37 (d, J=8.8 Hz, 2H), 7.08 (s, 1H), 6.90-6.85 (m, 1H), 6.54 (dd, J=15.1, 2.0 Hz, 1H), 6.16 (br, 1H), 5.03 (d, J=5.9 Hz, 2H)
ESIMS m/z: [M+H]+ 441.
Compound 66-1 (76 mg, 91%) was obtained in the same manner as step 1 of example 63, using 2-chloroquinoline-4-carbonitrile.
1H NMR (400 MHz, CDCl3, δ): 8.76 (d, J=2.4 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 7.85-7.80 (m, 4H), 7.69-7.65 (m, 1H), 7.58 (s, 1H).
Compound 66-2 (70 mg, 91%) was obtained in the same manner as step 3 of example 15, using compound 66-1.
1H NMR (400 MHz, CDCl3, δ): 8.75 (d, J=2.3 Hz, 1H), 7.94(dd, J=8.4, 1.2 Hz, 1H), 7.86 (dd, J=8.4, 2.3 Hz, 1H), 7.81-7.75 (m, 2H), 7.68-7.63 (m, 1H), 7.50 (td, J=7.7, 1.2 Hz, 1H), 7.34 (s, 1H).
Compound 149 (72 mg, 90%) was obtained in the same manner as step 5 of example 1, using compound 66-2.
1H NMR (400 MHz, CDCl3, δ): 8.73 (d, J=2.4 Hz, 1H), 7.96 (d, J=8.3 Hz, 1H), 7.86 (dd, J=8.3, 2.4 Hz, 1H), 7.78-7.77 (m, 2H), 7.67 (t, J=7.8 Hz, 1H), 7.54-7.51 (m, 1H), 7.14 (s, 1H), 6.42 (dd, J=17.1, 1.5 Hz, 1H), 6.21 (dd, J=17.1, 10.2 Hz, 1H), 5,99 (br, 1H), 5.78 (dd, J=10.2, 1.5 Hz, 1H), 5.04 (d, J=5.9 Hz, 2H)
ESIMS m/z: [M+H]+ 374.
Compound 67-1 (75 mg, quantitatively) was obtained in the same manner as step 1 of example 63, using 2-chloroquinoline-4-carbonitrile.
1H NMR (400 MHz, CDCl3, δ): 8.45 (d, J=5.8 Hz, 1H), 8.19 (d, J=7.8 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 7.83 (td, J=7.8, 1.3 Hz, 1H), 7.72-7.69 (m, 1H), 7.54 (s, 1H), 7.37 (d, J=2.1 Hz, 1H), 7.23 (dd, J=5.8, 2.1 Hz, 1H).
Compound 67-2 (72 mg, 94%) was obtained in the same manner as step 3 of example 15, using compound 67-1.
1H NMR (400 MHz, CDCl3, δ): 8.37 (d, J=5.4 Hz, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.31 (d, J=5.9 Hz, 2H), 7.19 (d, J=5.9 Hz, 1H), 4.42 (s, 2H).
Compound 150 (63 mg, 75%) was obtained in the same manner as step 5 of example 1, using compound 67-2.
1H NMR (400 MHz, CDCl3, δ): 8.38 (d, J=5.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.74-7.69 (m, 1H), 7.58-7.54 (m, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.20 (dd, J=5.8, 2.1 Hz, 1H), 7.10 (s, 1H), 6.41 (dd, J=17.1, 1.3 Hz, 1H), 6.20 (dd, J=17.1, 10.2 Hz, 1H), 6.00 (br, 1H), 5.77 (dd, J=10.2, 1.3 Hz, 1H), 5.04 (d, J=5.8 Hz, 2H)
ESIMS m/z: [M+H]+ 340.
Compound 68-1 (73 mg, 87%) was obtained in the same manner as step 1 of example 63, using 2-chloroquinoline-4-carbonitrile.
1H NMR (400 MHz, CDCl3, δ): 8.79 (d, J=5.5 Hz, 1H), 8.19 (d, J=8.5 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.86-7.81 (m, 1H), 7.72-7.70 (m, 2H), 7.57 (s, 1H), 7.51 (dd, J=5.5, 2.2 Hz, 1H).
Compound 68-2 (69 mg, 94%) was obtained in the same manner as step 3 of example 15, using compound 68-1.
1H NMR (400 MHz, CDCl3, δ): 8.72 (d, J=5.5 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.71-7.69 (m, 2H), 7.54 (t, J=7.8 Hz, 1H), 7.47 (dd, J=5.5, 2.2 Hz, 1H), 7.34 (s, 1H), 4.43 (s, 2H).
Compound 151 (65 mg, 83%) was obtained in the same manner as step 5 of example 1, using compound 68-2.
1H NMR (400 MHz, CDCl3, δ): 8.72 (d, J=5.4 Hz, H), 7.99 (dd, J=8.3, 1.0 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.74-7.70 (m, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.59-7.55 (m, 1H), 7.47 (dd, J=5.4, 2.2 Hz, 1H), 7.13 (s, 1H), 6.42 (dd, J=16.9, 1.3 Hz, 1H), 6.20 (dd, J=16.9, 10.2 Hz, 1H), 5.99 (br, 1H), 5.78 (dd, J=10.2, 1.3 Hz, 1H), 5.05 (d, J=5.9 Hz, 2H)
ESIMS m/z: [M+H]+ 374.
Compound 69-1 (0.40g, 80%) was obtained in the same manner as step 1 of example 15, using compound 25-4.
1H NMR (400 MHz, DMSO-d6, δ): 7.34 (d, J=8.8 Hz, 2H), 7.22 (d, J=7.2 Hz, 1H), 6.97-6.89 (m, 2H), 6.83 (d, J=8.8 Hz, 2H), 5.47 (d, J=5.2 Hz, 1H), 4.68-4.64 (m, 1H), 4.14-4.12 (m, 2H), 2.02-1.88 (m, 2H).
Compound 69-2 (0.02g, 20%) was obtained in the same manner as step 2 of example 15, using compound 69-1.
1H NMR (400 MHz, DMSO-d6, δ): 7.36 (d, J=8.8 Hz, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.06-6.97 (m, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.53 (t, J=6.0 Hz, 1H), 4.18-4.14 (m, 2H), 2.33-2.24 (m, 2H).
Compound 69-3 (0.12g, 79%) was obtained in the same manner as step 3 of example 15, using compound 69-2.
1H NMR (400 MHz, DMSO-d6, δ): 7.33 (d, J=8.8 Hz, 2H), 7.10 (dd, J=6.4, 2.8 Hz, 1H), 6.87-6.81 (m, 4H), 4.10-3.98 (m, 2H), 2.93-2.89 (m, 1H), 2.75-2.64 (m, 2H), 2.03-1.89 (m, 2H).
Compound 152 (0.09g, 69%) was obtained in the same manner as step 5 of example 1, using compound 69-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.37 (br, 1H), 7.34 (d, J=8.8 Hz, 2H), 7.10-7.08 (m, 1H), 6.93-6.83 (m, 4H), 6.26 (dd, J=16.8, 10.0 Hz, 1H), 6.11 (dd, J=17.2, 2.0 Hz, 1H), 5.62 (dd, J=10.0, 1.6 Hz, 1H), 4.14-4.02 (m, 2H), 3.54-3.48 (m, 1H), 3.36-3.29 (m, 1H), 2.98-2.97 (m, 1H), 1.93-1.78 (m, 2H);
ESIMS m/z: [M+H]+ 344.
Compound 51 (50 mg, 0.137 mmol) was dissolved in acetonitrile (1 mL), and N-bromosuccinimide (26.9 mg, 0.151 mmol) was added to the solution. The mixture was stirred at room temperature for 72 hours. Methanol was added to the reaction liquid, and the mixture was concentrated under reduced pressure. The residue was purified using a preparative HPLC [Waters Xbridge Prep C18 OBD column, 5 μm silica, diameter 19 mm, length 100 mm; acetonitrile/0.05% aqueous TFA solution (30/70−>40/60)] to obtain compound 153 (26.9 mg, 47%).
1H NMR (400 MHz, CDCl3, δ): 8.33 (d, J=2.7 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.23 (dd, J=8.6, 2.7 Hz, 1H), 7.06 (dd, J=13.1, 2.3 Hz, 2H), 6.23 (dd, J=17.0, 1.1 Hz, 1H), 5.98 (dd, J=17.0, 10.2 Hz, 1H), 5.80 (d, J=7.2 Hz, 1H), 5.61 (dd, J=10.4, 1.4 Hz, 1H), 4.51-4.48 (m, 1H), 4.12-4.10 (m, 1H), 4.04-4.01 (m, 1H), 3.10 (dd, J=17.2, 5.4 Hz, 1H), 2.85-2.80 (m, 1H).
ESIMS m/z: [M+H]+ 443, 445.
Compound 71-1 was obtained as a crude product in the same manner as step 4 of example 4, using compound 28-2 and commercially available 5-bromo-2-(trifluoromethyl)pyrimidine, and was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 312.
Compound 155 (130 mg, 44% over two steps) was obtained in the same manner as step 5 of example 1, using compound 71-1.
1H NMR (400 MHz, CDCl3, δ): 8.37 (s, 2H), 6.94-6.90 (m, 3H), 6.26-6.17 (m, 2H), 6.00 (dd, J=17.0, 10.2 Hz, 1H), 5.56 (dd, J=10.4, 1.4 Hz, 1H), 4.50-4.44 (m, 1H), 4.05-4.02 (m, 2H), 3.12 (dd, J=17.0, 5.2 Hz, 1H), 2.82 (dd, J=17.2, 4.1 Hz, 1H).
ESIMS m/z: [M+H]+ 366.
Compound 72-1 was obtained as a crude product in the same manner as step 4 of example 4, using compound 28-2 and commercially available 3-chloro-6-(trifluoromethyl)pyridazine, and was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 312.
Compound 156 (158 mg, 53% over two steps) was obtained in the same manner as step 5 of example 1, using compound 72-1.
1H NMR (400 MHz, CDCl3, δ): 7.74 (d, J=9.1 Hz, 1H), 7.29 (d, J=9.1 Hz, 1H), 6.97-6.83 (m, 3H), 6.44 (d, J=8.2 Hz, 1H), 6.18 (dd, J=17.2, 1.4 Hz, 1H), 6.05 (dd, J=17.0, 10.2 Hz, 1H), 5.53 (dd, J=10.0, 1.4 Hz, 1H), 4.47-4.46 (m, 1H), 3.98-3.93 (m, 2H), 3.06 (dd, J=16.8, 5.4 Hz, 1H), 2.74 (dd, J=16.8, 3.2 Hz, 1H).
ESIMS m/z: [M+H]+ 366.
Compound 73-1 was obtained as a crude product in the same manner as step 4 of example 4, using compound 28-2 and commercially available 2-chloro-5-(trifluoromethyl)pyrazine, and was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 312.
Compound 157 (89 mg, 29% over two steps) was obtained in the same manner as step 5 of example 1, using compound 73-1.
1H NMR (400 MHz, CDCl3, δ): 8.45 (s, 1H), 8.29 (s, 1H), 6.97-6.95 (m, 2H), 6.89 (dd, J=9.1, 6.3 Hz, 1H), 6.18 (dd, J=17.7, 12.2 Hz, 2H), 5.98 (dd, J=16.8, 10.4 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.48-4.48 (m, 1H), 4.02-3.99 (m, 2H), 3.12 (dd, J=16.8, 5.4 Hz, 1H), 2.80 (d, J=16.8 Hz, 1H).
ESIMS m/z: [M+H]+ 366.
Compound 74-1 was obtained as a crude product in the same manner as step 4 of example 4, using compound 28-2 and commercially available (4-bromophenyl)(trifluoromethyl)sulfane, and was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 342.
Compound 158 (48 mg, 15% over two steps) was obtained in the same manner as step 5 of example 1, using compound 74-1.
1H NMR (400 MHz, CDCl3, δ): 7.50 (d, J=11.6 Hz, 2H), 6.87-6.84 (m, 5H), 6.22 (d, J=16.8 Hz, 1H), 5.97 (dd, J=17.0, 10.2 Hz, 2H), 5.59 (d, J=10.9 Hz, 1H), 4.52-4.49 (m, 1H), 4.14 (dt, J=11.2, 2.8 Hz, 1H), 4.03 (dd, J=11.3, 1.4 Hz, 1H), 3.13 (dd, J=17.0, 5.2 Hz, 1H), 2.83 (dt, J=17.2, 2.5 Hz, 1H).
ESIMS m/z: [M+H]+ 396.
Compound 75-1 was obtained as a crude product in the same manner as step 4 of example 4, using compound 28-2 and commercially available 1-bromo-4-{(trifluoromethyl)sulfonyl}benzene, and was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 374.
Compound 159 (34 mg, 10% over two steps) was obtained in the same manner as step 5 of example 1, using compound 75-1.
1H NMR (400 MHz, CDCl3, δ): 7.87 (d, J=9.3 Hz, 2H), 7.02 (dt, J=9.5, 2.5 Hz, 2H), 6.98-6.88 (m, 3H), 6.23 (dd, J=16.8, 1.4 Hz, 1H), 5.97 (dd, J=17.0, 10.2 Hz, 1H), 5.86 (d, J=7.7 Hz, 1H), 5.61 (dd, J=10.4, 1.4 Hz, 1H), 4.53-4.48 (m, 1H), 4.11 (dq, J=11.1, 2.0 Hz, 1H), 4.02 (dd, J=10.9, 1.8 Hz, 1H), 3.14 (dd, J=17.2, 5.4 Hz, 1H), 2.85 (dt, J=16.9, 2.8 Hz, 1H).
ESIMS m/z: [M+H]+ 428.
Compound 28-2 (0.20 g, 0.81 mmol) was dissolved in THF (4 mL) and water (4 mL), and sodium hydrogen carbonate (0.34 g, 4.06 mmol) and acryloyl chloride (0.079 mL, 0.98 mmol) were added to the solution. The mixture was stirred at room temperature for 1.5 hours. Water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with a 1 mol/L aqueous hydrochloric acid solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 76-1 (0.17 g, 93%). 1H NMR (400 MHz, DMSO-d6, δ): 8.90 (s, 1H), 8.27 (d, J=6.8 Hz, 1H), 6.68-6.59 (m, 2H), 6.51 (d, J=7.8 Hz, 1H), 6.35-6.23 (m, 1H), 6.12 (dd, J=17.1, 2.0 Hz, 1H), 5.62-5.57 (m, 1H), 4.27-4.10 (m, 2H), 3.92 (dd, J=9.5, 6.6 Hz, 1H), 3.01 (dd, J=16.5, 6.2 Hz, 1H), 2.69 (dd, J=16.5, 6.2 Hz, 1H);
ESIMS m/z: [M+H]+ 220.
Compound 76-1 (165 mg, 0.753 mmol), triphenylphosphine (237.0 mg, 0.903 mmol), and (4,4-difluorocyclohexyl)methanol (136.0 mg, 0.347 mmol) were dissolved in THF (4 mL). Diisopropyl azodicarboxylate (0.19 mL) was added to the solution under cooling at 0° C. The mixture was stirred at room temperature for 2 hours. Magnesium chloride hexahydrate (612 mg, 3.01 mmol) and heptane (3.8 mL) were added to the mixture. The mixture was stirred at 60° C. for 2 hours. Water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=99/1−>96/4) to obtain a crude product. The crude product obtained was purified using a preparative HPLC [Waters Xbridge Prep C18 OBD column, 5 μm silica, diameter 19 mm, length 100 mm; acetonitrile/0.05% aqueous TFA solution (30/70−>40/60)] to obtain compound 160 (37.0 mg, 13%).
1H NMR (400 MHz, CDCl3, δ): 6.84 (t, J=7.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.68 (d, J=7.6 Hz, 1H), 6.31 (dd, J=17.1, 1.3 Hz, 1H), 6.10-6.01 (m, 2H), 5.64 (dd, J=10.3, 1.3 Hz, 1H), 4.63-4.56 (m, 1H), 4.35-4.28 (m, 1H), 4.15 (dd, J=11.0, 2.0 Hz, 1H), 3.87-3.80 (m, 2H), 3.16 (dd, J=17.1, 5.4 Hz, 1H), 2.87-2.78 (m, 1H), 2.21-2.08 (m, 2H), 2.07-1.92 (m, 3H), 1.87-1.66 (m, 2H), 1.47-1.32 (m, 2H);
ESIMS m/z: [M+H]+ 352.
Compound 28-2 (0.20 g, 0.81 mmol) was dissolved in DMF (8 mL), and potassium carbonate (0.56 g, 4.06 mmol) and 2,5-dichloropyrimidine (0.13 g, 0.89 mmol) were added to the solution. The mixture was stirred at 100° C. for 17 hours. Water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 77-1 as a crude product, which was used as it is in the next reaction.
Compound 161 (10.0 mg, 5% over two steps) was obtained in the same manner as step 5 of example 1, using compound 77-1.
1H NMR (400 MHz, CDCl3, δ): 8.46 (s, 2H), 7.08 (dd, J=7.7, 1.6 Hz, 1H), 7.04-6.94 (m, 2H), 6.29 (dd, J=17.2, 1.5 Hz, 1H), 6.08-5.95 (m, 2H), 5.66 (dd, J=10.4, 1.5 Hz, 1H), 4.62-4.56 (m, 1H), 4.17-4.01 (m, 2H), 3.20 (dd, J=17.0, 5.0 Hz, 1H), 2.87 (d, J=17.0 Hz, 1H);
ESIMS m/z: [M+H]+ 332.
Commercially available 2-hydroxy-3-methoxybenzaldehyde (2.00 g, 13.15 mmol) was dissolved in chloroform (40 mL) and pyridine (20 mL), and silver nitrate (2.10 g, 13.15 mmol) was added to the solution. The mixture was stirred at room temperature for 10 minutes. Iodine monochloride (2.10 g, 12.15 mmol) was added to the mixture. The mixture was stirred at room temperature for 3 hours. A saturated aqueous sodium thiosulfate solution (50 mL) and a 2 mol/L aqueous hydrochloric acid solution (50 mL) were added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 78-1 (1.80 g, 50%).
1H NMR (300 MHz, DMSO-d6, δ): 10.42 (s, 1H), 10.18 (s, 1H), 7.49 (d, J=1.8 Hz, 1H), 7.45 (d, J=2.1 Hz, 1H), 3.86 (s, 3H).
Compound 78-2 (0.50 g, 22%) was obtained in the same manner as step 1 of example 23, using compound 78-1.
1H NMR (300 MHz, DMSO-d6, δ): 7.52 (s, 1H), 7.31 (s, 1H), 7.25 (d, J=1.5 Hz, 1H), 4.87 (s, 2H), 3.77 (s, 3H).
Compound 78-2 (1.50 g, 4.80 mmol) was dissolved in DMF (15 mL), and added to the solution were methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (4.50 g, 24.03 mmol), hexamethylphosphoric triamide (4.20 g, 24.03 mmol), and copper(I) iodide (0.76 g, 4.80 mmol). The mixture was stirred at 90° C. for 16 hours. Water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20−>70/30) to obtain compound 78-3 (0.65 g, 53%).
1H NMR (300 MHz, DMSO-d6, δ): 7.63 (s, 1H), 7.31 (d, J=4.2 Hz, 2H), 4.99 (d, J=1.2 Hz, 2H), 3.85 (s, 3H).
Compound 78-4 (0.60 g, 86%) was obtained in the same manner as step 2 of example 23, using compound 78-3.
1H NMR (400 MHz, DMSO-d6, δ): 13.01 (bs, 1H), 7.50 (s, 1H), 7.38 (d, J=1.2 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 4.99 (d, J=1.6 Hz, 2H), 3.84 (s, 3H).
Compound 78-5 (0.60 g, 79%) was obtained in the same manner as step 3 of example 23, using compound 78-4.
1H NMR (400 MHz, DMSO-d6, δ): 9.17 (s, 1H), 6.99 (d, J=0.8 Hz, 2H), 6.60 (s, 1H), 4.75 (d, J=1.2 Hz, 2H), 3.80 (s, 3H), 1.45 (s, 9H).
Compound 78-6 (0.55 g, 91%) was obtained in the same manner as step 4 of example 23, using compound 78-5.
1H NMR (400 MHz, CDCl3, δ): 6.95 (d, J=9.2 Hz, 2H), 4.85-4.83 (m, 1H), 4.33-4.16 (m, 3H), 3.92 (s, 3H), 3.15-3.10 (m, 1H), 2.80-2.76 (m, 1H), 1.43 (s, 9H).
Compound 78-7 (0.35 g, 86%) was obtained in the same manner as step 6 of example 27, using compound 78-6.
ESIMS m/z: [M+H]+ 234.
Compound 78-8 (0.07 g, 25%) was obtained in the same manner as step 1 of example 76, using compound 78-7.
1H NMR (300 MHz, DMSO-d6, δ): 9.65 (s, 1H), 8.28 (d, J=6.6 Hz, 1H), 6.90 (d, J=12.9 Hz, 2H), 6.29 (dd, J=17.1, 9.9 Hz, 1H), 6.12 (dd, J=17.1, 2.4 Hz, 1H), 5.60 (dd, J=9.9, 2.4 Hz, 1H), 4.25-4.18 (m, 2H), 4.04 (dd, J=11.1, 6.3 Hz, 1H), 3.11 (dd, J=16.5, 5.1 Hz, 1H), 2.75 (dd, J=16.8, 6.0 Hz, 1H).
Compound 162 (0.03 g, 34%) was obtained in the same manner as step 1 of example 3, using compound 78-8.
1H NMR (400 MHz, DMSO-d6, δ): 8.51 (d, J=2.8 Hz, 1H), 8.30 (d, J=6.8 Hz,1H),7.82(d,J=8.8Hz,1H),7.54(d,J=8.4Hz,2H),7.46(dd,J=8.4, 2.4 Hz, 1H), 6.26 (dd, J=16.8, 10.0 Hz, 1H), 6.10 (dd, J=16.8, 2.0 Hz, 1H), 5.60 (dd, J=10.4, 2.4 Hz, 1H), 4.29-4.27 (m, 1H), 4.16 (dd, J=10.8, 2.0 Hz, 1H), 4.06 (dd, J=10.0, 6.4 Hz, 1H), 3.21 (dd, J=16.4, 4.8 Hz, 1H), 2.87 (dd, J=17.6, 6.0 Hz, 1H);
ESIMS m/z: [M+H]+ 433.
Compound 79-1 (0.11 g, 64%) was obtained in the same manner as step 1 of example 3, using compound 21-3.
1H NMR (400 MHz, CDCl3, δ): 8.50 (d, J=2.5 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.34 (dd, J=8.6, 2.5 Hz, 1H), 6.73 (d, J=8.6 Hz, 1H), 4.68 (t, J=6.3 Hz, 2H), 3.84 (s, 3H), 2.87 (t, J=6.3 Hz, 2H);
ESIMS m/z: [M+H]+ 340.
Compound 79-2 was obtained as a crude product in the same manner as step 2 of example 3, using compound 79-1, and used as it is in the next reaction.
Compound 163 (0.013 g, 14% over two steps) was obtained in the same manner as step 3 of example 17, using compound 79-2.
1H NMR (400 MHz, CDCl3, δ): 8.44 (d, J=2.7 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.23 (dd, J=8.6, 2.7 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.37 (dd, J=17.1, 1.4 Hz, 1H), 6.13 (dd, J=17.1, 10.3 Hz, 1H), 6.01 (d, J=7.7 Hz, 1H), 5.73 (dd, J=10.3, 1.4 Hz, 1H), 5.31-5.24 (m, 1H), 4.45-4.37 (m, 1H), 4.32-4.22 (m, 1H), 3.77 (s, 3H), 2.34-2.22 (m, 1H), 2.21-2.10 (m, 1H);
ESIMS m/z: [M+H]+ 395.
Compound 80-1 (0.12 g, 79%) was obtained in the same manner as step 1 of example 3, using compound 21-3.
1H NMR (400 MHz, CDCl3, δ): 7.64 (d, J=9.2 Hz, 1H), 7.15 (q, J=9.2 Hz, 1H), 6.91-6.84 (m, 1H), 6.79-6.73 (m, 1H), 6.56 (d, J=9.2 Hz, 1H), 4.65 (t, J=6.6 Hz, 2H), 3.89 (s, 3H), 2.84 (t, J=6.6 Hz, 2H);
ESIMS m/z: [M+H]+ 307.
Compound 80-2 was obtained as a crude product in the same manner as step 2 of example 3, using compound 80-1, and used as it is in the next reaction.
Compound 164 (0.052 g, 39% over two steps) was obtained in the same manner as step 3 of example 17, using compound 80-2.
1H NMR (400 MHz, CDCl3, δ): 7.08 (q, J=9.2 Hz, 1H), 6.94 (dd, J=8.5, 0.9 Hz, 1H), 6.81-6.74 (m, 1H), 6.71-6.66 (m, 1H), 6.56 (d, J=9.2 Hz, 1H), 6.37 (dd, J=17.1, 1.3 Hz, 1H), 6.11 (dd, J=17.1, 10.3 Hz, 1H), 5.82 (d, J=7.2 Hz, 1H), 5.72 (dd, J=10.3, L3 Hz, 1H), 5.27-5.20 (m, 1H), 4.44-4.37 (m, 1H), 4.28-4.20 (m, 1H), 3.81 (s, 3H), 2.33-2.22 (m, 1H), 2.18-2.09 (m, 1H);
ESIMS m/z: [M+H]+ 362.
Compound 81-1 (0.16 g, 93%) was obtained in the same manner as step 2 of example 76, using compound 21-3.
1H NMR (400 MHz, CDCl3, δ): 7.67 (d, J=8.6 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H), 4.59 (t, J=6.3 Hz, 2H), 3.93 (d, J=6.3 Hz, 2H), 3.86 (s, 3H), 2.78 (t, J=6.3 Hz, 2H), 2.18-2.13 (m, 2H), 2.03-1.95 (m, 3H), 1.88-1.71 (m, 2H), 1.53-1.42 (m, 2H);
ESIMS m/z: [M+H]+ 327.
Compound 81-2 was obtained as a crude product in the same manner as step 2 of example 3, using compound 81-1, and used as it is in the next reaction.
Compound 165 (0.039 g, 24% over two steps) was obtained in the same manner as step 3 of example 17, using compound 81-2.
1H NMR (400 MHz, CDCl3, δ): 6.87 (d, J=8.5 Hz, 1H), 6.46 (d, J=8.5 Hz, 1H), 6.34 (dd, J=17.1, 1.3 Hz, 1H), 6.11 (dd, J=17.1, 10.3 Hz, 1H), 6.03 (d, J=7.2 Hz, 1H), 5.69 (dd, J=10.3, 1.3 Hz, 1H), 5.19-5.12 (m, 1H), 4.39-4.29 (m, 1H), 4.23-4.13 (m, 1H), 3.85-3.80 (m, 5H), 2.26-2.04 (m, 4H), 2.01-1.91 (m, 3H), 1.86-1.67 (m, 2H), 1.50-1.36 (m, 2H);
ESIMS m/z: [M+H]+ 382.
Compound 19-3 (0.50 g, 2.74 mmol) was dissolved in DMF (14 mL), and potassium carbonate (0.76 g, 5.49 mmol) and benzyl bromide (0.39 mL, 3.29 mmol) were added to the solution. The mixture was stirred at room temperature for 4 hours, Water was added to the mixture. Precipitated crystals were filtered off, washed with water, and dried under reduced pressure to obtain compound 82-1 (0.73 g, 98%).
1H NMR (400 MHz, CDCl3, δ): 7.64 (dd, J=8.9, 2.2 Hz, 1H), 7.46-7.32 (m, 5H), 6.70 (dd, J=8.9, 7.0 Hz, 1H), 5.22 (s, 2H), 4.62 (t, J=6.4 Hz, 2H), 2.81 (t, J=6.4 Hz, 2H);
ESIMS m/z: [M+H]+ 273.
Compound 82-2 (0.053 g, 53%) was obtained in the same manner as step 4 of example 1, using compound 82-1.
1H NMR (400 MHz, CDCl3, δ): 7.46-7.28 (m, 5H), 6.93 (dd, J=8.7, 2.0 Hz, 1H), 6.56 (dd, J=8.7, 7.6 Hz, 1H), 5.12 (s, 2H), 4.37-4.26 (m, 2H), 4.00 (t, J=5.2 Hz, 1H), 2.18-2.09 (m, 1H), 1.86-1.77 (m, 1H), 1.69-1.58 (m, 2H).
Compound 82-2 (0.014 g, 27%) was obtained in the same manner as step 3 of example 17, using compound 82-2.
1H NMR (400 MHz, CDCl3, δ): 7.46-7.30 (m, 5H), 7.12 (d, J=7.6 Hz, 1H), 6.88-6.85 (m, 1H), 6.58 (t, J=8.1 Hz, 1H), 6.32 (d, J=17.1 Hz, 1H), 6.13 (dd, J=17.1, 10.3 Hz, 1H), 5.69 (dd, J=10.3, 1.3 Hz, 1H), 5.19-5.11 (m, 3H), 4.40-4.32 (m, 1H), 4.28-4.18 (m, 1H), 2.26-2.17 (m, 1H), 2.12-2.03 (m, 1H);
ESIMS m/z: [M+H]+ 328.
The following compound was synthesized in accordance with the synthesis method of compound 31.
ESIMS m/z: [M+H]+ 332.
Compound 83-1 (0.30 g, 38%) was obtained in the same manner as step 1 of example 1, using 2-chlorobenzene-1,3-diol.
1H NMR (300 MHz, DMSO-d6, δ): 13.09 (s, 1H), 11.52 (s, 1H), 7.82 (d, J=9.0 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 3.92 (t, J=6.3 Hz, 2H), 3.54 (t, J=6.0 Hz, 2H).
Compound 83-2 (0.15 g, 60%) was obtained in the same manner as step 2 of example 1, using compound 83-1.
1H NMR (300 MHz, DMSO-d6, δ): 11.29 (s, 1H), 7.58 (d, J=9.0 Hz, 1H), 6.69 (d, J=8.7 Hz, 1H), 4.59 (t, J=6.6 Hz, 2H), 2.71 (t, J=6.6 Hz, 2H).
Compound 83-3 (0.35 g, 73%) was obtained in the same manner as step 1 of example 82, using compound 83-2.
1H NMR (300 MHz, DMSO-d6, δ): 7.71 (d, J=8.7 Hz, 1H), 7.39 (d, J=8.7 Hz, 2H), 7.03-6.95 (m, 3H), 5.22 (s, 2H), 4.62 (t, J=6.3 Hz, 2H), 3.75 (s, 3H), 2.77 (t, J=6.3 Hz, 2H).
Compound 83-4 (0.33 g, 94%) was obtained in the same manner as step 4 of example 1, using compound 83-3.
1H NMR (300 MHz, DMSO-d6, δ): 7.36 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.4 Hz, 1H), 5.23-5.01 (m, 3H), 4.35-4.18 (m, 2H), 3.74 (s, 3H), 2.08-1.92 (m, 1H), 1.85-1.69 (m, 1H).
Compound 83-4 (0.33 g, 1.03 mmol) was dissolved in dichloromethane (10 mL), and a 4 mol/L hydrochloric acid solution in 1,4-dioxane (1.81 mL, 7.24 mmol) was added to the solution. The mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure. The solid obtained was washed with dichloromethane to obtain compound 83-5 (0.20 g, 82%).
1H NMR (400 MHz, DMSO-d6, δ): 10.41 (br, 1H), 8.58 (br, 3H), 7.28 (d, J=8.8 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 4.41-4.31 (m, 3H), 2.26-2.15 (m, 2H).
Compound 83-6 (0.10 g, 93%) was obtained in the same manner as step 1 of example 76, using compound 83-5.
ESIMS m/z: [M+H]+ 254.
Compound 168 (0.13 g, 41%) was obtained in the same manner as step 1 of example 3, using compound 83-6.
1H NMR (400 MHz, DMSO-d6, δ): 8.64 (d, J=8.0 Hz, 1H), 8.54 (d, J=2.4 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.4, 2.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.29-6.19 (m, 2H), 5.66 (dd, J=9.6, 2.4 Hz, 1H), 5.17-5.14 (m, 1H), 4.44-4.32 (m, 2H), 2.16-2.12 (m, 1H), 1.99-1.96 (m, 1H);
ESIMS m/z: [M+H]+ 328.
Compound 84-1 (0.15 g, 21%) was obtained in the same manner as step 1 of example 1, using 2-bromobenzene-1,3-diol.
1H NMR (300 MHz, DMSO-d6, δ): 11.99 (br, 1H), 11.35 (br, 1H), 7.62 (d, J=8.7 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 4.59 (t, J=6.3 Hz, 2H), 2.72 (t, J=6.3 Hz, 2H).
Compound 84-2 (0.080 g, 62%) was obtained in the same manner as step 2 of example 1, using compound 84-1.
1H NMR (400 MHz, DMSO-d6, δ): 11.34 (s, 1H), 7.62 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 4.59 (t, J=6.4 Hz, 2H), 2.72 (t, J=6.4 Hz, 2H).
Compound 84-3 (0.55 g, 73%) was obtained in the same manner as step 1 of example 82, using compound 84-2.
1H NMR (300 MHz, CDCl3, δ): 7.85 (d, J=9.0 Hz, 1H), 7.37 (d, J=8.7 Hz, 2H), 6.93-6.88 (m, 3H), 5.17 (s, 2H), 4.63 (t, J=6.6 Hz, 2H), 3.81 (s, 3H), 2.79 (t, J=6.3 Hz, 2H).
Compound 84-4 (0.50 g, 90%) was obtained in the same manner as step 4 of example 1, using compound 84-3.
ESIMS m/z: [M+H]+ 364.
Compound 84-5 (0.25 g, 65%) was obtained in the same manner as step 5 of example 83, using compound 84-4.
ESIMS m/z: [M+H]+ 244.
Compound 84-6 (0.15 g, 61%) was obtained in the same manner as step 1 of example 76, using compound 84-5.
1H NMR (400 MHz, DMSO-d6, δ): 10.12 (s, 1H), 8.51 (d, J=8.0 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 6.26-6.11 (m, 2H), 5.61 (dd, J=9.6, 2.4 Hz, 1H), 5.01-4.96 (m, 1H), 4.34-4.29 (m, 1H), 4.22-4.00 (m, 1H), 2.07-1.98 (m, 1H), 1.87-1.83 (m, 1H).
Compound 169 (0.055 g, 23%) was obtained in the same manner as step 1 of example 3, using compound 84-6.
1H NMR (300 MHz, DMSO-d6, δ): 8.64 (d, J=8.1 Hz, 1H), 8.53 (d, J=2.4 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.38 (dd, J=8.7, 2.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.30-6.13 (m, 2H), 5.65 (dd, J=9.3, 2.7 Hz, 1H), 5.18-5.14 (m, 1H), 4.46-4.30 (m, 2H), 2.17-1.95 (m, 2H);
ESIMS m/z: [M+H]+ 443.
Compound 85-1 was obtained as a crude product in the same manner as step 6 of example 27, using compound 79-2.
ESIMS m/z: [M−16]+ 310.
Compound 170 (0.030 g, 16%) was obtained in the same manner as step 1 of example 76, using compound 85-1.
1H NMR (400 MHz, DMSO-d6, δ): 9.20 (s, 1H), 8.61 (d, J=8.0 Hz, 1H), 8.44 (d, J=2.8 Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 7.26 (dd, J=8.4, 2.4 Hz, 1H), 6.74-6.69 (m, 2H), 6.27 (dd, J=16.8, 7.2 Hz, 1H), 6.19-6.12 (m, 1H), 5.64 (dd, J=9.6, 2.4 Hz, 1H), 5.11-5.09 (m, 1H), 4.34-4.32 (m, 1H), 4.27-4.25 (m, 1H), 2.16-2.08 (m, 1H), 1.98-1.91 (m, 1H);
ESIMS m/z: [M+H]+ 381.
Compound 82-1 (1.33 g, 4.87 mmol) was dissolved in ethanol (100 mL), and the solution was subjected to a reaction using Pd/C CatCart(R) (manufactured by ThalesNano Technologies, Inc., 70 mm) in the full H2 mode of H-cube(R) at 35° C. The solvent was concentrated under reduced pressure to obtain compound 86-1 as a crude product, which was used as it is in the next reaction.
Compound 86-2 (0.35 g, 29% over two steps) was obtained in the same manner as step 3 of example 17, using compound 86-1.
1H NMR (400 MHz, CDCl3, δ): 6.83 (d, J=10.1 Hz, 1H), 6.55 (t, J=8.4 Hz, 1H), 6.34 (t, J=8.4 Hz, 1H), 6.13-6.07 (m, 2H), 5.70 (dd, J=10.1, 1.3 Hz, 1H), 5.17-5.13 (m, 1H), 4.38-4.32 (m, 1H), 4.23-4.16 (m, 1H), 2.28-2.18 (m, 1H), 2.15-2.07 (m, 1H);
ESIMS m/z: [M−H]+ 236.
Compound 171 (6.00 mg, 7%) was obtained in the same manner as step 3 of example 1, using compound 86-2.
1H NMR (400 MHz, CDCl3, δ): 8.54 (s, 2H), 7.10 (dd, J=8.8, 1.4 Hz, 1H), 6.75 (dd, J=8.8, 7.0 Hz, 1H), 6.40 (dd, J=17.0, 1.4 Hz, 1H), 6.13 (dd, J=17.0, 10.3 Hz, 1H), 5.80-5.75 (m, 2H), 5.34 (dd, J=13.5, 5.8 Hz, 1H), 4.48-4.40 (m, 1H), 4.36-4.27 (m, 1H), 2.37-2.27 (m, 1H), 2.22-2.13 (m, 1H);
ESIMS m/z: [M+H]+ 384.
Compound 170 (0.05 g, 0.131 mmol) was dissolved in DMF (2 mL), and potassium carbonate (0.037 g, 0.263 mmol) and iodoethane (0.050 mL, 0.657 mmol) were added to the solution. The mixture was stirred at 70° C. for one hour. The mixture was cooled to room temperature, and water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20−>40/60) to obtain compound 172 (0.030 g, 56%).
1H NMR (400 MHz, DMSO-d6, δ): 8.64 (d, J=8.0 Hz, 1H), 8.50 (d, J=2.7 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.30-6.15 (m, 2H), 5.66-5.63 (m, 1H), 5.12-5.10 (m, 1H), 4.34-4.22 (m, 2H), 3.93-3.86 (m, 2H), 2.13-2.09 (m, 1H), 1.95-1.92 (m, 1H), 1.03 (t, J=7.2 Hz, 3H);
ESIMS m/z: [M+H]+ 409.
2-Nitrobenzene-1,3-diol (12.0 g, 77.41 mmol) was dissolved in ethanol (100 mL), and 10% palladium carbon (2.0 g) was added to the solution. The mixture was stirred under hydrogen atmosphere at room temperature for 18 hours. The mixture was filtered with Celite(R), and the filtrate was concentrated under reduced pressure to obtain compound 88-1 (8.0 g, 83%).
1H NMR (400 MHz, DMSO-d6, δ): 8.83 (br, 2H), 6.25 (br, 2H), 6.23-6.20 (m, 3H).
Compound 88-1(3.0 g, 24.0 mmol) was dissolved in THF (40 mL), and the solution was cooled to 0° C. Formaldehyde (2.10 mL, 72.0 mmol) and sodium cyanoborohydride (2.20 g, 36.0 mmol) were added to the solution, and the mixture was stirred at room temperature for 18 hours. Water (50 mL) was added to the mixture. The organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10−>70/30) to obtain compound 88-2 (1.80 g, 38%).
1H NMR (300 MHz, DMSO-d6, δ): 9.44 (br, 2H), 6.82 (t, J=8.1 Hz, 1H), 6.29 (d, J=8.1 Hz, 2H), 2.77 (s, 6H).
Compound 88-3 (0.92 g, 33%) was obtained in the same manner as step 1 of example 1, using compound 88-2.
ESIMS m/z: [M+H]+ 244.
Compound 88-4 (0.35 g, 46%) was obtained in the same manner as step 2 of example 1, using compound 88-3.
1H NMR (400 MHz, DMSO-d6, δ): 9.49 (br, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.52 (d, J=8.4 Hz, 1H), 4.52 (t, J=6.0 Hz, 2H), 2.68-2.67 (m, 8H).
Compound 88-5 (0.30 g, 54%) was obtained in the same manner as step 1 of example 82, using compound 88-4.
1H NMR (300 MHz, DMSO-d6, δ): 7.51 (d, J=8.7 Hz, 1H), 7.39 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 6.83 (d, J=9.0 Hz, 1H), 5.10 (s, 2H), 4.49 (t, J=6.3 Hz, 2H), 3.75 (s, 3H), 2.70-2.67 (m, 8H).
Compound 88-6 (0.22 g, 73%) was obtained in the same manner as step 4 of example 1, using compound 88-5.
1H NMR (300 MHz, DMSO-d6, δ): 7.36 (d, J=8.4 Hz, 2H), 6.95-6.92 (m, 3H), 6.56 (d, J=8.4 Hz, 1H), 4.96 (s, 2H), 4.23-4.10 (m, 2H), 3.81-3.78 (m, 1H), 3.74 (s, 3H), 2.64 (s, 6H), 1.95-1.89 (m, 1H), 1.68-1.63 (m, 1H).
Compound 88-7 (0.10 g, 65%) was obtained in the same manner as step 5 of example 83, using compound 88-6.
ESIMS m/z: [M+H]+ 209.
Compound 88-8 (0.10 g, 65%) was obtained in the same manner as step 1 of example 76, using compound 88-7.
ESIMS m/z: [M+H]+ 317.
Compound 88-8 (0.12 g, 0.38 mmol) was dissolved in methanol (5 mL), and potassium carbonate (0.10 g, 0.75 mmol) were added to the solution. The mixture was stirred at 80° C. for one hour. The mixture was left to cool to room temperature. Water (20 mL) was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 88-9 (0.085 g, 85%).
1H NMR (300 MHz, DMSO-d5, δ): 8.52 (d, J=8.0 Hz, 1H), 8.35 (br, 1H), 7.22 (d, J=8.8 Hz, 1H), 6.76 (d, J=9.2 Hz, 1H), 6.25 (dd, J=17.2, 10.0 Hz, 1H), 6.13 (dd, J=17.2, 2.8 Hz, 1H), 5.59 (dd, J=9.6, 2.4 Hz, 1H), 4.95-4.91 (m, 1H), 4.28-4.11 (m, 2H), 2.65 (s, 6H), 2.08-1.96 (m, 1H), 1.87-1.81 (m, 1H).
Compound 173 (0.019 g, 15%) was obtained in the same manner as step 1 of example 3, using compound 88-9.
1H NMR (400 MHz, DMSO-d6, δ): 8.40 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.57 (d, J=8.4 Hz, 1H), 6.36 (dd, J=16.8, 1.2 Hz, 1H), 6.11 (dd, J=16.8, 10.0 Hz, 1H), 5.82 (d, J=7.2 Hz, 1H), 5.72 (dd, J=10.0, 0.8 Hz, 1H), 5.26-5.21 (m, 1H), 4.42-4.37 (m, 1H), 4.25-4.19 (m, 1H), 2.65 (s, 6H), 2.31-2.23 (m, 1H), 2.17-2.09 (m, 1H);
ESIMS m/z: [M+H]+ 408.
Compound 89-1 (0.50 g, 58%) was obtained in the same manner as step 2 of example 50, using commercially available 4-fluoro-3-methoxybenzonitrile.
1H NMR (400 MHz, DMSO-d6, δ): 7.67 (d, J=2.0 Hz, 1H), 7.46-7.41 (m, 3H), 7.11 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 3.83 (s, 3H).
Compound 89-2 (0.40 g, 85%) was obtained in the same manner as step 1 of example 19, using compound 89-1.
1H NMR (400 MHz, DMSO-d6, δ): 10.46 (s, 1H), 7.42 (d, J=9.2 Hz, 2H), 7.32-7.31 (m, 2H), 7.09 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H).
Compound 89-2 (1.00 g, 4.08 mmol) was dissolved in DMF (10 mL), and potassium carbonate (1.12 g, 8.16 mmol) and allyl chloride (0.40 mL, 4.89 mmol) were added to the solution. The mixture was stirred at 80° C. for one hour. The mixture was cooled to room temperature, and water was added to the mixture. The organic layer was extracted with tert-butyl methyl ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>80/20) to obtain compound 89-3 (1.00 g, 86%).
1H NMR (400 MHz, DMSO-d6, δ): 7.67 (d, J=1.8 Hz, 1H), 7.43-7.40 (m, 3H), 7.16 (d, J=8.4 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 5.97-5.84 (m, 1H), 5.25-5.17 (m, 2H), 4.65 (d, J=5.1 Hz, 2H).
Compound 89-3 (0.50 g, 1.75 mmol) was stirred using a microwave reactor at 180° C. for one hour. The mixture was cooled to room temperature, and ethyl acetate was added to the mixture. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 89-4 (0.45 g, 90%).
1H NMR (400 MHz, DMSO-d6, δ): 9.99 (s, 1H), 7.46 (d, J=9.2 Hz, 2H), 7.26 (d, J=8.4 Hz, 1H), 7.08 (d, J=9.2 Hz, 2H), 6.85 (d, J=8.4 Hz, 1H), 5.99-5.89 (m, 1H), 5.07-4.98 (m, 2H), 3.55 (d, J=6.4 Hz, 2H).
Compound 89-4 (0.50 g, 1.75 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.50 mL, 3.50 mmol) and acetic anhydride (0.35 mL, 3.50 mmol) were added to the solution. The mixture was stirred at room temperature for 2 hours. Dichloromethane was added to the mixture. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>90/10) to obtain compound 89-5 (0.45 g, 78%).
1H NMR (400 MHz, DMSO-d6, δ): 7.74 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 1H), 5.88-5.78 (m, 1H), 5.11-5.04 (m, 2H), 3.52 (d, J=6.4 Hz, 2H), 2.30 (s, 3H).
Compound 89-5 (0.40 g, 1.22 mmol) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (0.45 g, 1.83 mmol) was added to the solution. The mixture was stirred at room temperature for 24 hours. Dichloromethane was added to the mixture. The organic layer was washed with a 4 mol/L aqueous sodium hydroxide solution and a saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>80/20) to obtain compound 89-6 (0.35 g, 74%).
1H NMR (400 MHz, DMSO-d6, δ): 7.75 (d, J=8.8 Hz, 1H), 7.51 (d, J=9.2 Hz, 2H), 7.11 (d, J=9.2 Hz, 2H), 6.98 (d, J=8.4 Hz, 1H), 3.12-3.04 (m, 3H), 2.76-2.74 (m, 2H), 2.33 (s, 3H).
Compound 89-6 (6.00 g, 17.49 mmol) was dissolved in 1,4-dioxane (50 mL), and a 20% hydrochloric acid solution in 1,4-dioxane (15.96 mL, 87.46 mmol) was added to the solution. The mixture was stirred at room temperature for 72 hours. Water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10−>80/20) to obtain compound 89-7 (4.70 g, 70%).
1H NMR (300 MHz, DMSO-d6, δ): 10.19 (s, 1H), 7.45 (d, J=9.0 Hz, 2H), 7.24 (d, J=8.4 Hz, 1H), 7.05 (d, J=8.7 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 5.40-5.35 (m, 1H), 4.04-3.92 (m, 1H), 3.82-3.66 (m, 1H), 3.24-3.03 (m, 2H), 1.99 (s, 3H).
Compound 89-7 (0.24 g, 0.63 mmol) was dissolved in DMF (3.0 mL), and potassium carbonate (0.10 g, 0.76 mmol) was added to the solution. The mixture was stirred at room temperature for one hour. Water was added to the mixture. The organic layer was extracted with tert-butyl methyl ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>80/20) to obtain compound 89-8 (0.16 g, 75%).
1H NMR (400 MHz, DMSO-d6, δ): 7.45-7.42 (m, 3H), 7.03-6.97 (m, 3H), 5.32-5.30 (m, 1H), 4.32-4.16 (m, 2H), 3.38-3.33 (m, 1H), 2.99-2.94 (m, 1H), 2.02 (s, 3H).
Compound 89-9 (0.12 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 89-8.
ESIMS m/z: [M+H]+ 348.
Compound 174 (0.09 g, 71% over two steps) was obtained in the same manner as step 1 of example 76, using compound 89-9.
1H NMR (300 MHz, DMSO-d6, δ): 8.48 (t, J=5.4 Hz, 1H), 7.34 (d, J=9.0 Hz, 2H), 6.94 (d, J=8.4 Hz, 1H), 6.87-6.83 (m, 3H), 6.30 (dd, J=17.1, 10.2 Hz, 1H), 6.13 (dd, J=17.1, 2.1 Hz, 1H), 5.63 (dd, J=9.9, 2.1 Hz, 1H), 5.25 (br, 1H), 4.32-4.26 (m, 2H), 4.15-4.01 (m, 2H), 3.15-3.07 (m, 1H), 2.84-2.73 (m, 1H), 2.01 (s, 3H);
ESIMS m/z: [M+H]+ 402.
Compound 174 (0.27 g, 0.66 mmol) was dissolved in THF (2 mL), methanol (2 mL), and water (2 mL), and sodium hydroxide (0.04 g, 0.99 mmol) was added to the solution. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. Water and a 2 mol/L aqueous hydrochloric acid solution were added to the residue. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>80/20) to obtain compound 175 (0.12 g, 46%).
1H NMR (400 MHz, DMSO-d6, δ): 8.45 (t, J=5.6 Hz, 1H), 7.33 (d, J=9.2 Hz, 2H), 6.89 (d, J=8.0 Hz, 1H), 6.83-6.81 (m, 3H), 6.30 (dd, J=17.2, 10.4 Hz, 1H), 6.13 (dd, J=17.2, 2.4 Hz, 1H), 5.62 (dd, J=10.0, 2.0 Hz, 1H), 5.17 (d, J=4.0 Hz, 1H), 4.28 (d, J=5.6 Hz, 2H), 4.03-3.96 (m, 2H), 3.76-3.72 (m, 1H), 2.97-2.92 (m, 1H), 2.60-2.56 (m, 1H);
ESIMS m/z: [M+H]+ 360.
Compound 90-1 (0.30 g, 68%) was obtained in the same manner as step 11 of example 89, using compound 89-8.
1H NMR (400 MHz, DMSO-d6, δ): 7.41 (d, J=8.8 Hz, 2H), 7.37 (d, J=8.4 Hz, 1H), 6.99 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.4 Hz, 1H), 5.30 (d, J=3.6 Hz, 1H), 4.17-4.00 (m, 2H), 3.99-3.96 (m, 1H), 3.17-3.11 (m, 1H), 2.82-2.77 (m, 1H).
Compound 90-1 (0.25 g, 0.83 mmol) was dissolved in toluene (5.0 mL), and methyl N-(triethylammoniumsulfonyl)carbamate (0.39 g, 1.65 mmol) was added to the solution. The mixture was stirred at 100° C. for 3 hours. The mixture was cooled to 0° C., and sodium hydride (0.074 g, 1.63 mmol) was added to the mixture. The mixture was stirred at 100° C. for 3 hours. The mixture was cooled to 0° C., and water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20−>50/50) to obtain compound 90-2 (0.075 g, 32%).
1H NMR (300 MHz, DMSO-d6, δ): 7.43-7.36 (m, 3H), 7.04-6.99 (m, 6.66 (d, J=10.2 Hz, 1H), 6.27-6.22 (m, 1H), 4.87-4.86 (m, 2H).
Compound 90-3 (0.025 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 90-2.
ESIMS m/z: [M−16]+ 273.
Compound 176 (0.025 g, 31% over two steps) was obtained in the same manner as step 5 of example 1, using compound 90-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.44 (br, 1H), 7.32 (d, J=8.0 Hz, 2H), 6.89-6.80 (m, 4H), 6.30 (dd, J=17.6, 10.4 Hz, 1H), 6.15-6.11 (m, 1H), 5.63-5.61 (m, 1H), 4.29 (d, J=3.2 Hz, 2H), 4.03 (br, 2H), 2.72 (br, 2H), 1.92 (br, 2H);
ESIMS m/z: [M+H]+ 344.
The following compound was synthesized in accordance with the synthesis method of compound 152.
ESIMS m/z: [M+H]+ 344.
ESIMS m/z: [M+H]+ 397.
Compound 37-2 (0.20 g, 0.59 mmol) was dissolved in methanol (0.6 mL), and sodium methoxide (37.9 mg, 0.70 mmol) was added to the solution. The mixture was stirred at 60° C. overnight. A saturated aqueous sodium bicarbonate solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 91-1 (0.20 g) as a crude product, which was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 338.
Compound 91-2 (0.23 g) was obtained as a crude product in the same manner as step 2 of example 3, using compound 91-1, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 339.
Compound 179 (4.70 mg, 2.1% over three steps) was obtained in the same manner as step 1 of example 76, using compound 91-2.
1H NMR (400 MHz, CDCl3, δ): 7.56 (d, J=8.5 Hz, 3H), 7.28 (d, J=7.4 Hz, 2H), 6.71 (d, J=8.5 Hz, 1H), 6.38 (dd, J=16.9, 1.3 Hz, 1H), 6.13 (dd, J=16.9, 10.2 Hz, 1H), 5.75 (br, 1H), 5.74 (dd, J=10.2, 1.3 Hz, 1H), 5.38-5.32 (m, 2H), 3.80 (s, 3H), 2.36-2.29 (m, 1H), 2.17-2.09 (m, 3H).
ESIMS m/z: [M+H]+ 393.
Compound 37-2 (0.10 g, 0.29 mmol) was dissolved in DMF (1.5 mL), and N1,N1,N2-trimethylethane-1,2-diamine (44.9 mg, 0.44 mmol) was added to the solution. The mixture was stirred at 80° C. for 3 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by aminosilica gel column chromatography (hexane/ethyl acetate=70/30−>40/60) to obtain compound 92-1 (88.4 mg, 74%).
1H NMR (400 MHz, CDCl3, δ): 8.07 (d, J=9.0 Hz, 1H), 7.54 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 6.52 (d, J=9.0 Hz, 1H), 5.45 (dd, J=5.4, 3.6 Hz, 1H), 3.64-3.63 (m, 2H), 3.07 (s, 3H), 3.04-2.95 (m, 1H), 2.60 (ddd, J=17.4, 6.2, 5.0 Hz, 1H), 2.52-2.36 (m, 4H), 2.20 (s, 6H).
ESIMS m/z: [M+H]+ 408.
Compound 92-2 was obtained as a crude product in the same manner as step 2 of example 17, using compound 92-1 (88.4 mg, 0.22 mmol), and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 409.
Compound 180 (10.2 mg, 10% over two steps) was obtained in the same manner as step 3 of example 17, using compound 92-2.
1H NMR (400 MHz, CDCl3, δ): 7.54 (d, J=9.0 Hz, 2H), 7.41 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.47 (d, J=9.0 Hz, 1H), 6.35 (dd, J=17.0, 1.2 Hz, 1H), 6.11 (dd, J=17.0, 10.3 Hz, 1H), 5.72 (br, 1H), 5.71 (dd, J=10.3, 1.2 Hz, 1H), 5.30-5.24 (m, 2H), 3.62-3.59 (m, 1H), 3.54-3.47 (m, 1H), 2.97 (s, 3H), 2.37-2.03 (m, 6H), 2.18 (s, 6H).
ESIMS m/z: [M+H]+ 463.
Compound 93-1 (0.20 g) was obtained as a crude product in the same manner as step 4 of example 33, using compound 33-3 (0.10 g, 0.41 mmol) and 5,6-dichloropyridin-3-ol (70.0 mg, 0.41 mmol), and used as it is in the next reaction.
1H NMR (300 MHz, DMSO-d6, δ): 8.13 (d, J=2.7 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.67 (d, J=2.7 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 5.30 (t, J=3.6 Hz, 1H), 4.28-4.04 (m, 4H), 2.35-2.22 (m, 3H), 2.03-2.00 (m, 1H).
Compound 93-2 (0.18 g) was obtained as a crude product in the same manner as step 5 of example 33, using compound 93-1, and used as it is in the next reaction.
1H NMR (300 MHz, DMSO-d6, δ): 8.28 (d, J=8.4 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.76 (d, J=2.7 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H), 5.15 (t, J=3.6 Hz, 1H), 3.15-3.03 (m, 1H), 2.77-2.45 (m, 3H).
Compound 93-3 (50.0 mg, 35% over three steps) was obtained in the same manner as step 4 of example 1, using compound 93-2.
1H NMR (400 MHz, DMSO-d6, δ): 8.23-8.22 (m, 1H), 8.16 (d, J=8.4 Hz, 0.7H), 8.10-8.09 (m, 1H), 8.00 (d, J=8.4 Hz, 0.3H), 7.53-7.47 (m, 1H), 5.63-5.62 (m, 0.3H), 5.60-5.56 (m, 0.7H), 3.98-3.95 (m, 0.3H), 3.83-3.78 (m, 0.7H), 2.41-2.21 (m, 3H), 2.18-2.04 (m, 1H).
Compound 181 (0.22 g, 40%) was obtained in the same manner as step 5 of example 1, using compound 93-3 (0.48 mg, 0.14 mmol).
1H NMR (300 MHz, CDCl3, δ): 8.14 (d, J=3.0 Hz, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 6.41 (dd, J=16.8, 1.2 Hz, 1H), 6.16 (dd, J=17.1, 10.2 Hz, 1H), 5.82-5.76 (m, 2H), 5.43-5.31 (m, 2H), 2.42-2.37 (m, 1H), 2.31-2.13 (m, 3H).
ESIMS m/z: [M+H]+ 400.
Compound 94-1 (65.2 mg, 75%) was obtained in the same manner as step 1 of example 54, using compound 37-2 (90.0 mg, 0.26 mmol).
1H NMR (400 MHz, CDCl3, δ): 8.50 (d, J=7.7 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 2H), 5.70 (t, J=3.4 Hz, 1H), 3.21 (ddd, J=18.1, 13.1, 4.8 Hz, 1H), 2.80 (dt, J=18.1, 4.8 Hz, 1H), 2.72-2.65 (m, 1H), 2.49-2.40 (m, 1H).
ESIMS m/z: [M+H]+ 333.
Compound 94-2 was obtained as a crude product in the same manner as step 2 of example 3, using compound 94-1 (65.2 mg, 0.20 mmol), and used as it is in the next reaction.
Compound 182 (20.4 mg, 27% over two steps) was obtained in the same manner as step 1 of example 76, using compound 94-2.
1H NMR (400 MHz, CDCl3, δ): 7.90 (dd, J=8.1, 1.0 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 6.44 (dd, J=16.7, 1.0 Hz, 1H), 6.17 (dd, J=16.7, 10.3 Hz, 1H), 5.87 (d, J=9.0 Hz, 1H), 5.81 (dd, J=10.3, 1.0 Hz, 1H), 5.51-5.44 (m, 2H), 2.50-2.46 (m, 1H), 2.24-2.05 (m, 3H).
ESIMS m/z: [M+H]+ 388.
Compound 242 (30.0 mg, 0.076 mmol) was dissolved in toluene (1.0 mL), and added to the solution were palladium acetate (1.7 mg, 7.60 μmol), trimethylboroxine (38.0 mg, 0.30 mmol), dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphate (7.1 mg, 15.0 pmol), cesium carbonate (0.74 g, 0.23 mmol), and water (0.3 mL). The mixture was stirred at 100° C. overnight. The mixture was cooled to room temperature, and added to the mixture were palladium acetate (1.7 mg, 7.60 μmol), trimethylboroxine (19.0 mg, 0.15 mmol), dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphate (7.1 mg, 15.0 μmol), and cesium carbonate (0.74 g, 0.23 mmol). The mixture was again stirred at 100° C. for 1.5 hours. The mixture was cooled to room temperature and filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20−>40/60) to obtain compound 183 (30.0 mg, quantitatively).
1H NMR (400 MHz, CDCl3, δ): 7.60 (d, J=7.8 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.14 (d, J=7.8 Hz, 1H), 6.40 (dd, J=17.1, 1.3 Hz, 1H), 6.15 (dd, J=17.1, 10.3 Hz, 1H), 5.80 (br, 1H), 5.75 (dd, J=10.3, 1.3 Hz, 1H), 5.45 (t, J=2.5 Hz, 1H), 5.38 (dd, J=15.7, 9.0 Hz, 1H), 2.54 (s, 3H), 2.44-2.38 (m, 1H), 2.18-2.11 (m, 1H), 2.07-2.02 (m, 2H).
ESIMS m/z: [M+H]+ 377.
Compound 184 (18.2 mg, 64%) was obtained in the same manner as step 1 of example 95, using compound 76 (30.0 mg, 0.076 mmol).
1H NMR (400 MHz, CDCl3, δ): 7.60 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.40 (dd, J=17.0, 1.3 Hz, 1H), 6.15 (dd, J=17.0, 10.3 Hz, 1H), 5.79 (br, 1H), 5.75 (dd, J=10.3, 1.3 Hz, 1H), 5.45 (t, J=2.7 Hz, 1H), 5.38 (dd, J=16.2, 9.0 Hz, 1H), 2.54 (s, 3H), 2.44-2.39 (m, 1H), 2.16-2.14 (m, 1H), 2.08-2.01 (m, 2H),
ESIMS m/z: [M+H]+ 377.
Compound 185 (17.8 mg, 59%) was obtained in the same manner as step 1 of example 95, using compound 76 (30.0 mg, 0.076 mmol) and potassium cyclopropyltrifluoroborate (55.9 mg, 0.38 mmol).
1H NMR (400 MHz, CDCl3, δ): 7.56 (d, J=10.4 Hz, 2H), 7.53 (d, J=8.1 Hz, 1H), 7.27 (d, J=10.4 Hz, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.38 (dd, J=16.9, 1.3 Hz, 1H), 6.14 (dd, J=16.9, 10.3 Hz, 1H), 5.79 (br, 1H), 5.74 (dd, J=10.3, L3 Hz, 1H), 5.37-5.33 (m, 2H), 2.36-2.35 (m, 1H), 2.20-2.14 (m, 1H), 2.12-2.06 (m, 2H), 2.014.94 (m, 1H), 1.02-0.88 (m, 3H), 0.86-0.79 (m, 1H).
ESIMS m/z: [M+H]+ 403.
Compound 186 (7.5 mg, 25%) was obtained in the same manner as step 1 of example 95, using compound 76 (30.0 mg, 0.076 mmol) and ethylboronic acid (5.6 mg, 0.076 mmol).
1H NMR (400 MHz, CDCl3, δ): 7.63 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.1 Hz, 1H), 6.39 (dd, J=16.9, 1.3 Hz, 1H), 6.15 (dd, J=16.9, 10.1 Hz, 1H), 5.80 (d, J=9.4 Hz, 1H), 5.75 (dd, J=10.1, 1.3 Hz, 1H), 5.46 (t, J=2.5 Hz, 1H), 5.39 (dd, J=16.2, 9.9 Hz, 1H), 2.80 (q, J=7.6 Hz, 2H), 2.44-2.39 (m, 1H), 2.20-2.14 (m, 1H), 2.10-2.05 (m, 2H), 1.26 (t, J=7.6 Hz, 3H).
ESIMS m/z: [M+H]+ 391.
Compound 99-1 (0.13 g, 38%) was obtained in the same manner as step 4 of example 33, using compound 33-3 (0.20 g, 0.83 mmol) and 3-fluoro-4-(trifluoromethyl)phenol (0.18 g, 0.99 mmol).
1H NMR (400 MHz, CDCl3, δ): 7.84 (d, J=8.5 Hz, 1H), 7.51 (t, J=8.1 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 6.92 (d, J=10.3 Hz, 2H), 5.39 (t, J=3.4 Hz, 1H), 4.29-4.14 (m, 3H), 4.11-4.08 (m, 1H), 2.32-2.27 (m, 3H), 2.01-1.96 (m, 1H).
ESIMS m/z: [M+H]+ 404.
Compound 99-2 (0.11 g, quantitatively) was obtained in the same manner as step 5 of example 33, using compound 99-1 (0.13 g, 0.32 mmol).
1H NMR (400 MHz, CDCl3, δ): 8.31 (d, J=8.1 Hz, 1H), 7.54 (t, J=8.5 Hz, 1H), 7.49 (d, J=8.1 Hz, 1H), 7.04-7.01 (m, 2H), 5.59 (t, J=3.6 Hz, 1H), 3.11 (ddd, J=17.5, 12.1, 4.9 Hz, 1H), 2.74 (dt, J=17.5, 4.0 Hz, 1H), 2.64-2.60 (m, 1H), 2.48-2.39 (m, 1H).
ESIMS m/z: [M+H]+ 360.
Compound 99-3 (0.11 g) was obtained as a crude product in the same manner as step 2 of example 3, using compound 99-2 (0.11 g, 0.32 mmol), and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 361.
Compound 187 (33.3 mg, 25% over two steps) was obtained in the same manner as step 3 of example 17, using compound 99-3.
1H NMR (400 MHz, CDCl3, δ): 7.71 (d, J=8.1 Hz, 1H), 7.53 (t, J=8.3 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 6.96-6.93 (m, 2H), 6.42 (dd, J=16.9, 1.3 Hz, 1H), 6.16 (dd, J=16.9, 10.3 Hz, 1H), 5.79 (dd, J=10.3, 1.3 Hz, 1H), 5.77 (d, J=9.0 Hz, 1H), 5.42-5.38 (m, 2H), 2.42-2.41 (m, 1H), 2.19-2.17 (m, 1H), 2.08-2.02 (m, 2H).
ESIMS m/z: [M+H]+ 415.
Compound 37-1 (0.20 g, 0.52 mmol) was dissolved in ethanol (5 mL), and a 20% sodium ethoxide solution in ethanol (0.41 mL, 1.04 mmol) was added to the solution. The mixture was stirred at 80° C. for a week. Water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 100-1 (0.13 g) as a crude product, which was used as it is in the next reaction.
1H NMR (400 MHz, CDCl3, δ): 7.71 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.8 Hz, 2H), 6.70 (d, J=8.5 Hz, 1H), 5.37 (t, J=4.0 Hz, 1H), 4.27-4.05 (m, 6H), 2.35-2.28 (m, 3H), 2.02-1.98 (m, 1H), 1.23 (t, J=7.2 Hz, 3H).
ESIMS m/z: [M+H]+ 396.
Compound 100-2 (0.12 g) was obtained as a crude product in the same manner as step 5 of example 33, using compound 100-1 (0.13 g, 0.33 mmol), and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 352.
Compound 100-3 (71.0 mg) was obtained as a crude product in the same manner as step 4 of example 1, using compound 100-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 353.
Compound 188 (25.6 mg, 31% in four stages) was obtained in the same manner as step 3 of example 17, using compound 100-3.
1H NMR (400 MHz, CDCl3, δ): 7.57-7.54 (m, 3H), 7.26 (d, J=8.5 Hz, 2H), 6.68 (d, J=8.5 Hz, 1H), 6.38 (dd, J=17.1, 1.3 Hz, 1H), 6.13 (dd, J=17.1, 10.3 Hz, 1H), 5.74 (dd, J=10.3, 1.3 Hz, 1H), 5.73 (br, 1H), 5.36 (t, J=3.6 Hz, 1H), 5.30 (dd, J=8.8, 6.1 Hz, 1H), 4.22-4.16 (m, 2H), 2.34-2.26 (m, 1H), 2.15-2.07 (m, 3H), 1.27 (t, J=7.2 Hz, 3H).
ESIMS m/z: [M+H]+ 407.
Compound 101-1 (0.15 g, 47%) was obtained as a crude product in the same manner as step 4 of example 33, using compound 33-3 (0.20 g, 0.83 mmol) and 5-(trifluoromethyl)pyridin-2-ol (0.16 g, 0.99 mmol), and used as it is in the next reaction.
1H NMR (400 MHz, CDCl3, δ): 8.47 (s, 1H), 7.83 (d, J=8.1 Hz, 1H), 7.78 (dd, J=8.6, 2.5 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 6.30 (t, J=4.5 Hz, 1H), 4.28-4.09 (m, 4H), 2.41-2.36 (m, 2H), 2.24-2.19 (m, 1H), 2.01-1.97 (m, 1H).
ESIMS m/z: [M+H]+ 387.
Compound 101-2 (0.13 g, 97%) was obtained in the same manner as step 5 of example 33, using compound 101-1 (0.15 g, 0.39 mmol).
1H NMR (400 MHz, CDCl3, δ): 8.49 (dd, J=1.8, 0.9 Hz, 1H), 8.31 (d, J=8.3 Hz, 1H), 7.83 (dd, J=8.8, 1.8 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.54 (dd, J=4.9, 3.6 Hz, 1H), 3.01-2.97 (m, 1H), 2.77-2.62 (m, 2H), 2.53-2.45 (m, 1H).
ESIMS m/z: [M+H]+ 343.
Compound 101-3 (0.14 g) was obtained as a crude product in the same manner as step 2 of example 3, using compound 101-2 (0.13 g, 0.38 mmol), and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 344.
Compound 189 (25.7 mg, 17%) was obtained in the same manner as step 3 of example 17, using compound 101-3.
1H NMR (400 MHz, CDCl3, δ): 8.47 (s, 1H), 7.79 (dd, J=8.8, 2.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.8 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H), 6.41 (dd, J=16.9, 1.0 Hz, 1H), 6.25 (t, J=3.6 Hz, 1H), 6.15 (dd, J=16.9, 10.3 Hz, 1H), 5.82 (d, J=9.0 Hz, 1H), 5.77 (dd, J=10.3, 1.0 Hz, 1H), 5.39 (td, J=9.5, 5.5 Hz, 1H), 2.49-2.45 (m, 1H), 2.20-2.11 (m, 2H), 2.03-1.94 (m, 1H).
ESIMS m/z: [M+H]+ 398.
To a cyclohexane-1,3-dione (0.824 g, 7.35 mmol) solution in THF (20 mL), a 1 mol/L potassium tert-butoxide/tetrahydrofuran solution (8.00 mL, 8.00 mmol) was added dropwise at 0° C. After the mixture was stirred at room temperature for 30 minutes, 2-chloro-N,N-dimethylaminotrimethynium hexafluorophosphate (1.50 g, 4.89 mmol) was added to the mixture. The mixture was stirred at 50° C. for one hour. Next, ammonium acetate (1.70 g, 22.05 mmol) was added to the mixture, and the mixture was stirred at 100° C. for 1.5 hours. After the reaction liquid was concentrated under reduced pressure, ethyl acetate was added to the residue. The mixture was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>70/30) to obtain compound 102-1 (257.4 mg, 29%).
1H NMR (400 MHz, CDCl3, δ): 8.64 (d, J=2.7 Hz, 1H), 8.24 (d, J=2.7 Hz, 1H), 3.14 (t, J=6.3 Hz, 2H), 2.70 (dd, J=7.2, 5.9 Hz, 2H), 2.21 (m, 2H).
To a methanol solution (10 mL) of compound 102-1 (322.6 mg, 1.776 mmol), sodium borohydride (160.0 mg, 4.230 mmol) was added in small portions at 0° C. After the mixture was stirred at room temperature for 15 minutes, water was added to the mixture. The mixture was extracted with chloroform. After the extracted liquid was dried over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>50/50) to obtain compound 102-2 (296.7 mg, 91%).
1H NMR (400 MHz, CDCl3, δ): 8.25 (d, J=2.7 Hz, 1H), 7.80 (d, J=2.7 Hz, 1H), 4.74 (m, 1H), 4.62 (br d, J=6.3 Hz, 1H), 2.83 (m, 2H), 2.05 (m, 2H), 1.80 (m, 2H);
ESIMS m/z: [M+H]+ 184, 186.
Compound 102-2 (296.7 mg, 1.616 mmol) was dissolved in a toluene (8 mL)-tetra hyd rofu ran (2 mL) mixed solvent, and 1,8-diazabicyclo[5.4.0]-7-undecene (0.370 mL, 2.455 mmol) and diphenylphosphorylazide (0.530 mL, 2.459 mmol) were sequentially added to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The extracted liquid was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>80/20) to obtain compound 102-3 (337.0 mg, 100%).
1H NMR (400 MHz, CDCl3, δ): 8.43 (d, J=2.3 Hz, 1H), 7.64 (d, J=2.3 Hz, 1H), 4.54 (m, 1H), 2.91 (m, 2H), 2.07 (m, 2H), 2.00-1.83 (m, 2H);
ESIMS m/z: [M+H]+ 209, 211.
In ethyl acetate (15 mL), 10% palladium/carbon (140 mg) was suspended, and the suspension was stirred under hydrogen atmosphere for 15 minutes. Compound 102-3 (447.8 mg, 2.146 mmol) and an ethyl acetate solution (2 mL) of di-tert-butyl dicarbonate (937.0 mg, 4.290 mmol) were added to the suspension. The mixture was stirred at room temperature for 30 minutes. The reaction liquid was filtered using Celite(R). The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>50/50) to obtain compound 102-4 (296.1 mg, 49%).
1H NMR (400 MHz, CDCl3, δ): 8.37 (br, 1H), 7.66 (br, 1H), 4.87 (br, 1H), 4.77 (br, 1H), 2.89 (m, 2H), 2.10 (m, 1H), 1.94 (m, 2H), 1.71 (m, 1H), 1.50 (s, 9H);
ESIMS m/z: [M+H]+ 283, 285.
3-Chloroperoxybenzoic acid (300.0 mg, 1.738 mmol) was added to a methylene chloride solution (5 mL) of compound 102-4 (296.1 mg, 1.047 mmol). The mixture was stirred at room temperature for one hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction liquid, and the mixture was extracted with chloroform. The extracted liquid was washed with a saturated aqueous sodium thiosulfate solution and dried over anhydrous magnesium sulfate to obtain N-oxide (373.2 mg), N-Oxide obtained was dissolved in methylene chloride (3 mL). Trifluoroacetic anhydride (0.400 mL, 2.83 mmol) was added to the solution at 0° C. The mixture was stirred at 0° C. for 20 minutes, and then at room temperature for 16 hours. A 4 N aqueous sodium hydroxide solution (2 mL, 8 mmol) was added to the mixture at 0° C. The mixture was stirred at room temperature for 40 minutes. A 2 N aqueous hydrochloric acid solution was added dropwise to the mixture under cooling at 0° C. pH was adjusted to 2-3, and the mixture was extracted with chloroform. The extracted liquid was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0−>85/15) to obtain compound 102-5 (122.5 mg, 39%).
1H NMR (400 MHz, CDCl3, cis/trans-diastereo mixture, b): 8.10 (d, J=1.8 Hz, 1H), 7.68 (d, J=1.8 Hz, 1H), 7.65 (br, 1H), 7.31 (br, 1H), 5.54 (d, J=9.1 Hz, 1H), 5.38 (d, J=9,5 Hz, 1H), 4.89 (m, 1H), 4.82 (m, 2H), 4.65 (m, 3H), 2.85-2.65 (m, 2H), 2.32 (m, 1H), 2.11-1.95 (m, 3H), 1.81 (m, 1H), 1.68 (m, 1H), 1.49 (s, 18H);
ESIMS m/z: [M+H]+ 299, 301.
To a tetrahydrofuran solution (4 mL) of compound 102-5 (122.5 mg, 0.410 mmol), 4-(trifluoromethyl)phenol (140 mg, 0.864 mmol), triphenylphosphine (250 mg, 0.953 mmol), and a 2.2 mol/L diethyl azodicarboxylate/toluene solution (0.400 mL, 0.880 mmol) were sequentially added. The mixture was stirred at room temperature for 2 hours. After the reaction liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>70/30) to obtain compound 102-6 (182.0 mg, 100%).
1H NMR (400 MHz, CDCl3, cis/trans-diastereo mixture, δ): 8.51 (m, 2H), 7.80 (m, 2H), 7.52 (m, 4H), 7.10 (m, 4H), 5.47 (m, 2H), 5.01-4.85 (m, 3H), 3.75 (m, 1H), 2.38 (m, 2H), 2.21 (m, 2H), 2.12 (m, 1H), 1.99 (m, 2H), 1.85 (m, 1H), 1.52 (s, 9H), 1.50 (s, 9H);
ESIMS m/z: [M+H]+ 443, 445.
Trifluoroacetic acid (1.0 mL, 12.98 mmol) was added to a methylene chloride solution (2 mL) of compound 102-6 (191.5 mg, 0.432 mmol). The solution was stirred at room temperature for one hour. After the reaction liquid was concentrated under reduced pressure, the residue was dissolved in methylene chloride (2 mL). Triethylamine (0.150 mL, 1.076 mmol) and acryloyl chloride (0.100 mL, 1.231 mmol) were added dropwise to the solution. The mixture was stirred at room temperature for 30 minutes. The reaction liquid was poured onto a 1 N aqueous hydrochloric acid solution and the mixture was extracted with chloroform. The extracted liquid was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>55/45) to obtain compound 190 (cis isomer, 24.8 mg, 15%, and the trans isomer, 17.0 mg, 9.9%).
1H NMR (400 MHz, CDCl3, δ): 8.49 (d, J=1.8 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.15 (d, J=8.6 Hz, 2H), 6.42 (dd, J=16.8, 1.4 Hz, 1H), 6.19 (dd, J=16.8, 10.4 Hz, 1H), 6.08 (d, J=9.5 Hz, 1H), 5.78 (dd, J=10.4, 1.4 Hz, 1H), 5.47 (br t, J=2.3 Hz, 1H), 5.37 (m, 1H), 2.46-2.35 (m, 1H), 2.18-2.00 (m, 3H);
ESIMS m/z: [M+H]+ 397, 399.
Commercially available 2-chloro-7,8-dihydroquinolin-5(6H)-one (0.20 g, 1.10 mmol) was dissolved in DMF (5.5 mL), and cesium carbonate (0.72 g, 2.20 mmol) and 4-(trifluoromethyl)phenol (0.72 g, 1.65 mmol) were added to the solution. The mixture was subjected to a reaction at a temperature of 120° C. for 30 minutes using a microwave reactor manufactured by Biotage. Water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>60/40) to obtain compound 1034 (0.23 g, 68%).
1H NMR (400 MHz, CDCl3, δ): 8.32 (d, J=8.6 Hz, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.6 Hz, 1H), 2.96 (t, J=6.1 Hz, 2H), 2.65 (t, J=6.6 Hz, 2H), 2.15 (tt, J=6.6, 6.1 Hz, 2H).
ESIMS m/z: [M+H]+ 308.
Compound 103-2 was obtained as a crude product in the same manner as step 2 of example 3, using compound 103-1 (0.23 g, 0.75 mmol), and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 309.
Compound 191 (71.4 mg, 26%) was obtained in the same manner as step 3 of example 17, using compound 103-2.
1H NMR (400 MHz, CDCl3, δ): 7.65 (d, J=8.1 Hz, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H), 6.73 (d, J=8.1 Hz, 1H), 6.37 (dd, J=17.0, 1.1 Hz, 1H), 6.10 (dd, J=17.0, 10.3 Hz, 1H), 5.72 (dd, J=10.3, 1.1 Hz, 1H), 5.70 (d, J=8.5 Hz, 1H), 5.32 (dd, J=14.8, 6.3 Hz, 1H), 2.88-2.73 (m, 2H), 2.12-2.08 (m, 1H), 1.91-1.83 (m, 3H).
ESIMS m/z: [M+H]+ 363.
Compound 104-1 (78.0 mg, 44%) was obtained in the same manner as step 4 of example 33, using 4,4-difluorocyclohexanemethanol (110 mg, 0.733 mmol) and 3-amino-5-hydroxypiperidine (161 mg, 1.47 mmol).
1H NMR (400 MHz, CDCl3, δ): 7.73 (d, J=1.8 Hz, 2H), 6.52-6.48 (m, 1H), 3.82 (d, J=5.9 Hz, 2H), 3.67 (br, 2H), 2.22-2.08 (m, 2H), 1.99-1.66 (m, 5H), 1.50-1.35 (m, 2H).
ESIMS m/z: [M+H]+ 243.
Compound 192 (28.0 mg, yield 29%) was obtained in the same manner as in step 5 of example 1, using compound 104-1 (78.0 mg, 0.322 mmol) obtained in step 1.
1H NMR (400 MHz, CDCl3, δ): 8.09-8.05 (m, 3H), 7.38 (br, 1H), 6.48 (dd, J=16.8, 0.9 Hz, 1H), 6.26 (dd, J=16.8, 10.4 Hz, 1H), 5.85 (dd, J=10.2, 1.1 Hz, 1H), 3.88 (d, J=6.3 Hz, 2H), 2.22-2.09 (m, 2H), 2.01-1.67 (m, 5H), 1.52-1.36 (m, 2H).
ESIMS m/z: [M+H]+ 297.
The following compound was synthesized in accordance with the synthesis method of compound 95.
ESIMS m/z: [M+H]+ 311.
The following compound was synthesized in accordance with the synthesis method of compound 192.
ESIMS m/z: [M+H]+ 283.
The following compounds were synthesized in accordance with the synthesis method of compound 137.
ESIMS m/z: [M+H]+ 361.
ESIMS m/z: [M+H]+ 374.
ESIMS m/z: [M+H]+ 375.
Compound 105-1 (0.059 g, 66%) was obtained in the same manner as step 2 of example 50, using compound 54-1.
1H NMR (400 MHz, CDCl3, δ): 8.99 (dd, J=4.1, 1.8 Hz, 1H), 8.65 (dd, J=8.6, 1.8 Hz, 1H), 8.59 (s, 2H), 8.06 (d, J=8.2 Hz, 1H), 7.74 (dd, J=8.6, 4.1 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H);
ESIMS m/z: [M+H]+ 317.
Compound 105-2 (0.063 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 105-1.
ESIMS m/z: [M+H]+ 321.
Compound 196 (0.025 g, 36% over two steps) was obtained in the same manner as step 5 of example 1, using compound 105-2.
1H NMR (400 MHz, CDCl3, δ): 8.88 (dd, J=4.3, 1.5 Hz, 1H), 8.54 (dd, J=8.5, 1.5 Hz, 1H), 8.49 (s, 2H), 7.60-7.54 (m, 2H), 7,47 (d, J=7.6 Hz, 1H), 6.40 (dd, J=17.0, 1.2 Hz, 1H), 6.11 (dd, J=17.0, 10.3 Hz, 1H), 5.87 (br, 1H), 5.74 (dd, J=10.3, 1.2 Hz, 1H), 5.03 (d, J=5.8 Hz, 2H);
ESIMS m/z: [M+H]+ 375.
Compound 59-1 (0.10 g, 0.32 mmol) was dissolved in acetonitrile (5.0 mL), and iodine (0.12 g, 0.48 mmol) and tert-butyl hydroperoxide (0.44 mL, 3.18 mmol) were added to the solution. The mixture was stirred at 80° C. for five days. The mixture was cooled to room temperature, and sodium thiosulfate was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20−>50/50) to obtain compound 106-1 (0.051 g, 36%).
1H NMR (400 MHz, CDCl3, δ): 9.21 (d, J=1.8 Hz, 1H), 8.96 (d, J=1.8 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.27-7.26 (m, 2H), 7.07 (d, J=8.3 Hz, 1H).
Compound 106-1 (0.06 g, 0.14 mmol) was dissolved in toluene (1.0 mL) and water (0.25 mL), and added to the solution were cesium carbonate (0.22 g, 0.68 mmol), trimethylboroxine (0.095 mL, 0.68 mmol), 2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl (0.013 g, 0.027 mmol), and palladium acetate (0.003 g, 0.014 mmol). The mixture was stirred under argon atmosphere at 100° C. for 0.5 hours. The mixture was filtered with Presep ((R); diatomaceous earth, granular type M, 4.5 g/25 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20−>50/50) to obtain compound 106-2 (0.044 g, 98%).
1H NMR (400 MHz, CDCl3, δ): 8.93 (s, 1H), 8.34 (s, 1H), 7.86 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.27-7.26 (m, 2H), 7.00 (d, J=8.1 Hz, 1H), 2.65 (s, 3H).
Compound 106-3 (0.039 g, 96%) was obtained in the same manner as step 2 of example 57, using compound 106-2.
1H NMR (400 MHz, CDCl3, δ): 8.80 (d, J=2.0 Hz, 1H), 8.26 (s, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.46 (d, J=7.8 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.09 (d, J=8.8 Hz, 2H), 4.31 (s, 2H), 2.57 (s, 3H).
Compound 199 (0.032 g, 80%) was obtained in the same manner as step 3 of example 17, using compound 106-3.
1H NMR (400 MHz, CDCl3, δ): 8.80 (d, J=2.0 Hz, 1H), 8.19 (s, 1H), 7.58 (d, J=9.3 Hz, 2H), 7.43 (d, J=7.8 Hz, 1H), 7.11-7.10 (m, 3H), 6.38 (dd, J=17.0, 1.1 Hz, 1H), 6.10 (dd, J=17.0, 10.2 Hz, 1H), 5.80 (br, 1H), 5.71 (dd, J=10.2, 1.1 Hz, 1H), 4.94 (d, J=5.4 Hz, 2H), 2.55 (s, 3H);
ESIMS m/z: [M+H]+ 387.
Compound 107-1 (0.22 g, 91%) was obtained in the same manner as step 1 of example 106, using compound 62-1.
1H NMR (400 MHz, CDCl3, δ): 9.16 (d, J=2.0 Hz, 1H), 8.98 (d, J=2.0 Hz, 1H), 8.57 (d, J=2.5 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.52 (dd, J=8.4, 2.5 Hz, 1H), 7.26-7.25 (m, 1H).
Compound 107-2 (0.040 g, 90%) was obtained in the same manner as step 2 of example 106, using compound 107-1.
1H NMR (400 MHz, CDCl3, δ): 8.89 (d, J=2.4 Hz, 1H), 8.57 (d, J=2.4 Hz, 1H), 8.36 (s, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H), 7.51 (dd, J=8.7, 2.7 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 2.65 (s, 3H).
Compound 107-3 (0.065 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 107-2.
ESIMS m/z: [M+H]+ 334.
Compound 200 (0.025 g, 54% over two steps) was obtained in the same manner as step 5 of example 1, using compound 107-3.
1H NMR (400 MHz, CDCl3, δ): 8.72 (s, 1H), 8.43 (d, J=2.7 Hz, 1H), 8.20 (s, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.30 (dd, J=8.5, 2.7 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 6.37 (dd, J=17.1, 1.3 Hz, 1H), 6.19 (br, 1H), 6.12 (dd, J=17.1, 10.3 Hz, 1H), 5.70 (d, J=10.3 Hz, 1H), 4.94 (d, J=5.4 Hz, 2H), 2.53 (s, 3H);
ESIMS m/z: [M+H]+ 388.
5-Bromo-2-fluoroaniline (0.20 g, 1.05 mmol) was dissolved in toluene (3.0 mL), and a 6 mol/L aqueous hydrochloric acid solution (0.53 mL, 3.16 mmol) and methyl vinyl ketone (0.17 mL, 2.11 mmol) were added to the solution. The mixture was stirred at 120° C. for 1.5 hours. The mixture was left to cool to room temperature, and water was added to the mixture. The aqueous layer was washed with ethyl acetate. A 2 mol/L aqueous sodium hydroxide solution was added to the aqueous layer, and the aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>80/20) to obtain compound 108-1 (0.040 g, 16%).
1H NMR (400 MHz, CDCl3, δ): 8.79 (d, J=4.2 Hz, 1H), 7.81 (dd, J=8.3, 5.4 Hz, 1H), 7.34 (d, J=4.2 Hz, 1H), 7.23 (t, J=9.0 Hz, 1H), 3.14 (s, 3H).
Compound 108-2 (0.047 g, 48%) was obtained in the same manner as step 1 of example 54, using compound 108-1.
1H NMR (400 MHz, CDCl3, δ): 8.90 (d, J=4.4 Hz, 1H), 8.01 (dd, J=8.1, 5.1 Hz, 1H), 7.49-7.42 (m, 2H), 3.12 (s, 3H).
Compound 108-3 (0.051 g, 66%) was obtained in the same manner as step 2 of example 50, using compound 108-2.
1H NMR (400 MHz, CDCl3, δ): 8.90 (d, J=4.4 Hz, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.70 (d, J=9.3 Hz, 2H), 7.44 (d, J=4.4 Hz, 1H), 7.26-7.22 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 3.14 (s, 3H).
Compound 108-4 (0.043 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 108-3.
Compound 201 (0.013 g, 22% over two steps) was obtained in the same manner as step 5 of example 1, using compound 108-4.
1H NMR (400 MHz, CDCl3, δ): 8.71 (d, J=4.4 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.47 (d, J=7.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.37 (d, J=17.1 Hz, 1H), 6.12 (dd, J=17.1, 10.2 Hz, 1H), 6.02 (br, 1H), 5.69 (d, J=10.2 Hz, 1H), 5.04 (d, J=4.9 Hz, 2H), 2.92 (s, 3H);
ESIMS m/z: [M+H]+ 387.
Compound 109-1 (0.40 g, 42%) was obtained in the same manner as step 2 of example 50, using compound 54-1.
ESIMS m/z: [M+H]+ 331.
Compound 109-2 (0.20 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 109-1.
ESIMS m/z: [M+H]+ 335.
Compound 202 (0.10 g, 34% over two steps) was obtained in the same manner as step 1 of example 76, using compound 109-2.
1H NMR (400 MHz, DMSO-d6, δ): 8.96 (dd, J=4.0, 1.6 Hz, 1H), 8.67 (t, J=5.6 Hz, 1H), 8.61 (dd, J=8.8, 1.6 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.70-7.67 (m, 1H), 7.58 (d, J=8.0 Hz, 2H), 7.47 (d, J=7.6 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 6.29-6.22 (m, 1H), 6.17-6.12 (m, 1H), 5.62 (dd, J=10.0, 2.4 Hz, 1H), 4.80 (d, J=5.6 Hz, 2H);
ESIMS m/z: [M+H]+ 389.
Compound 110-1 (0.25 g, 46%) was obtained in the same manner as step 2 of example 50, using compound 54-1.
ESIMS m/z: [M+H]+ 314.
Compound 110-2 (0.20 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 110-1.
ESIMS m/z: [M+H]+ 318.
Compound 203 (0.020 g, 8% over two steps) was obtained in the same manner as step 1 of example 76, using compound 110-2.
1H NMR (400 MHz, DMSO-d6, δ): 9.13 (s, 1H), 8.92 (d, J=3.9 Hz, 1H), 8.60-8.51 (m, 2H), 7.69-7.46 (m, 7H), 6.30-6.21 (m, 1H), 6.18-6.11 (m, 1H), 6.62 (dd, J=9.6, 2.4 Hz, 1H), 4.75 (d, J=5.4 Hz, 2H);
ESIMS m/z: [M+H]+ 372.
Compound 202 (0.050 g, 0.12 mmol) was dissolved in dichloroethane (10 mL), and Oxone (0.29 g, 1.93 mmol) was added to the solution. The mixture was stirred at 80° C. for 12 hours. The mixture was cooled to room temperature, and water (10 mL) was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20−>40/60) to obtain compound 204 (0.050 g, 85%).
1H NMR (300 MHz, DMSO-d6, δ): 8.91 (d, J=3.3 Hz, 1H), 8.80-7.79 (m, 1H), 8.69-8.64 (m, 2H), 8.27 (d, J=7.8 Hz, 2H), 7.93 (d, J=8.1 Hz, 2H), 7.78 (d, J=7.5 Hz, 1H), 7.66 (dd, J=8.4, 4.2 Hz, 1H), 6.33-6.24 (m, 1H), 6.19-6.13 (m, 1H), 5.68-5.64 (m, 1H), 4.90 (d, J=5.7 Hz, 2H);
ESIMS m/z: [M+H]+ 421.
Compound 112-1 (0.12 g, 21%) was obtained in the same manner as step 2 of example 50, using compound 54-1.
1H NMR (400 MHz, CDCl3, δ): 9.12 (dd, J=4.4, 1.6 Hz, 1H), 8.94 (dd, J=4.4 Hz, 2.0 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.74-7.71 (m, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 3.58 (s, 3H).
Compound 112-2 (0.10 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 112-1.
ESIMS m/z: [M+H]+ 332.
Compound 205 (0.030 g, 21% over two steps) was obtained in the same manner as step 1 of example 76, using compound 112-2.
1H NMR (400 MHz, CDCl3, δ): 8.91 (dd, J=4.4, 1.6 Hz, 1H), 8.48 (dd, J=8.8, 1.6 Hz, 1H), 7.59-7.47 (m, 3H), 7.35 (d, J=8.8 Hz, 2H), 6.68 (d, J=8.8 Hz, 2H), 6.39 (dd, J=17.2, 1.2 Hz, 1H), 6.10 (dd, J=16.8, 10.4 Hz, 1H), 5.83-5.82 (m, 1H), 5.72 (dd, J=10.4, 1.2 Hz, 1H), 5.01 (d, J=5.6 Hz, 2H), 3.48 (s, 3H);
ESIMS m/z: [M+H]+ 386.
Magnesium (turnings) (0.08 g, 3.41 mmol) was dissolved in THF (10 mL), and iodine (10 mg) was added to the solution. The mixture was stirred at room temperature for 5 minutes. 1-Bromo-4-(trifluoromethyl)benzene (0.38 g, 1.70 mmol) was added to the mixture. The mixture was stirred at room temperature for 45 minutes. Thereafter, the mixture was cooled to and a THF (5.0 mL) solution of 5-bromoquinoline-8-carboaldehyde (0.20 g, 0.85 mmol) was added to the mixture. The mixture was stirred at 0° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10−>70/30) to obtain compound 113-1 (0.15 g, 46%).
1H NMR (400 MHz, DMSO-d6, δ): 9.02 (dd, J=4.0, 1.6 Hz, 1H), 8.53 (dd, J=8.8, 1.6 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.89 (dd, J=8.0 Hz, 1H), 7.73-7.70 (m, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.00 (d, J=4.4 Hz, 1H), 6.26 (d, J=4.4 Hz, 1H).
Compound 113-2 (0.020 g, 58%) was obtained in the same manner as step 1 of example 54, using compound 113-1.
1H NMR (300 MHz, CDCl3, δ): 8.99 (d, J=3.9 Hz, 1H), 8.61 (d, J=8.4 Hz, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.70-7.65 (m, 1H), 7.63-7.57 (m, 5H), 6.55 (d, J=6.6 Hz, 1H), 6.04 (d, J=6.9 Hz, 1H).
Compound 113-3 (0.025 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 113-2.
1H NMR (300 MHz, DMSO-d6, δ): 8.93 (d, J=3.6 Hz, 1H), 8.59 (d, J=8.4 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.67-7.53 (m, 6H), 7.01 (br, 1H), 6.17 (br, 1H), 4.18 (s, 2H).
Compound 206 (0,13 g, 51%) was obtained in the same manner as step 1 of example 76, using compound 113-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.96 (dd, J=4.0, 1.2 Hz, 1H), 8.61 (t, J=5.6 Hz, 1H), 8.52 (dd, J=8.8, 1.6 Hz, 1H), 7.90 (d, J=7.2 Hz, 1H), 7.66 (d, J=8.0 Hz, 2H), 7.67-7.56 (m, 4H), 7.01 (d, J=4.4 Hz, 1H), 6.27-6.11 (m, 3H), 5.61 (dd, J=10.0, 2.4 Hz, 1H), 4.86-4.72 (m, 2H);
ESIMS m/z: [M+H]+ 387.
In toluene (10 mL), 1-(bromomethyl)-4-(trifluoromethyl)benzene (1.00 g, 4.18 mmol) was dissolved, and triphenylphosphine (1.64 g, 6.27 mmol) was added to the solution. The mixture was refluxed for 8 hours. The mixture was cooled to room temperature. The precipitated solid was filtered off and washed with hexane to obtain compound 114-1 (1.75 g, 99%).
ESIMS m/z: [M+H]+ 422.
Compound 114-1 (1.90 g, 4.51 mmol) was dissolved in THF (20 mL), and the mixture was cooled to -78° C. Potassium tert-butoxide (1.01 g, 9.02 mmol) was added to the mixture, and the mixture was stirred under argon atmosphere at -30° C. for 30 minutes. 5-Bromoquinoline-8-carboaldehyde (1.17 g, 4.96 mmol) was added to the mixture. The mixture was stirred at room temperature for one hour. Water (10 mL) was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20−>40/60) to obtain compound 114-2 (1.20 g, 70%).
ESIMS m/z: [M+H]+ 378.
Compound 114-3 (0.80 g, 78%) was obtained in the same manner as step 1 of example 54, using compound 114-2.
ESIMS m/z: [M+H]+ 325.
Compound 114-4 (0.10 g) was obtained as a crude product in the same manner as step 3 of example 54, using compound 114-3.
ESIMS m/z: [M+H]+ 329.
Compound 207 (0.040 g, 22% over two steps) was obtained in the same manner as step 1 of example 76, using compound 114-4.
1H NMR (400 MHz, DMSO-d6, δ): 8.97 (dd, J=4.0, 1.6 Hz, 1H), 8.65 (t, J=5.2 Hz, 1H), 8.57 (dd, J=8.4, 1.6 Hz, 1H), 7.66-7.63 (m, 1H), 7.58-7.52 (m, 3H), 7.46 (d, J=7.2 Hz, 1H), 7.38-7.35 (m, 3H), 6.90 (d, J=12.4 Hz, 1H), 6.30-6.23 (m, 1H), 6.17-6.12 (m, 1H), 5.62 (dd, J=10.0, 2.4 Hz, 1H), 4.81 (d, J=6.0 Hz, 2H);
ESIMS m/z: [M+H]+ 383.
Compound 206 (0.20 g, 0.52 mmol) was dissolved in dichloromethane (10 mL), and pyridinium chlorochromate (0.22 g, 1.03 mmol) was added to the solution. The mixture was stirred at room temperature for 3 hours. The mixture was filtered with Celite(R), and the filtrate was washed with dichloromethane (20 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20−>20/80) to obtain compound 208 (0.055 g, 24%).
1H NMR (400 MHz, DMSO-d6, δ): 8.79-8.77 (m, 2H), 8.66 (dd, J=8.4, 1.2 Hz, 1H), 7.88-7.81 (m, 5H), 7.68 (d, J=7.2 Hz, 1H), 7.64-7.61 (m, 1H), 6.31 (dd, J=16.8, 10.0 Hz, 1H), 6.18 (dd, J=17.2, 2.4 Hz, 1H), 5.66 (dd, J=10.0, 2.4 Hz, 1H), 4.92 (d, J=5.6 Hz, 2H);
ESIMS m/z: [M+H]+ 385.
Compound 114-4 (0.05 g, 1.15 mmol) was dissolved in ethanol (20 mL), and 10% palladium carbon (0.05 g) was added to the solution. The mixture was stirred under hydrogen atmosphere at room temperature for 2 hours. The mixture was filtered with Celite(R). The filtrate was concentrated under reduced pressure to obtain compound 116-1 (0.05 g) as a crude product.
ESIMS m/z: [M+H]+ 331.
Compound 209 (0.040 g, 7% over two steps) was obtained in the same manner as step 1 of example 76, using compound 116-1.
1H NMR (400 MHz, DMSO-d6, δ): 8.98 (dd, J=4.0, 1.6 Hz, 1H), 8.26 (t, J=5.6 Hz, 1H), 8.52 (dd, J=8.4, 1.6 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.61-7.56 (m, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.44 (d, J=7.2 Hz, 1H), 6.29-6.23 (m, 1H), 6.17-6.12 (m, 1H), 5.62 (dd, J=10.0, 2.4 Hz, 1H), 4.79 (d, J=5.6 Hz, 2H), 3.51 (t, J=8.4 Hz, 2H), 3.11 (t, J=8.4 Hz, 2H);
ESIMS m/z: [M+H]+ 385.
Quinolin-8-amine (0.20 g, 1.38 mmol) was dissolved in acetonitrile (20 mL), and N-bromosuccinimide (0.26 g, 1.43 mmol) was added to the solution. The mixture was stirred at room temperature for 30 minutes. Water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10−>70/30) to obtain compound 117-1 (0.15 g, 50%).
1H NMR (300 MHz, DMSO-d6, δ): 8.76 (d, J=3.3 Hz, 1H), 8.42 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.48 (dd, J=8.4, 4.2 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 5.04 (br, 2H).
Compound 117-1 (0.15 g, 1.20 mmol) was dissolved in DMF (5 mL), and added to the solution were O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.38 g, 1.45 mmol), diisopropylethylamine (0.45 mL, 2.41 mmol), and 4-(trifluoromethyl)benzoic acid (0.34 g, 1.81 mmol). The mixture was stirred at room temperature for 18 hours. Water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 117-2 (0.15 g, 57%).
1H NMR (300 MHz, CDCl3, δ): 10.76 (br, 1H), 8.88 (d, J=3.6 Hz, 1H), 8.82 (d, J=8.4 Hz, 1H), 8.58 (d, J=8.4 Hz, 1H), 8.18 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.64-7.60 (m, 1H).
Compound 117-3 (0.52 g, 72%) was obtained in the same manner as step 1 of example 54, using compound 117-2.
ESIMS m/z: [M+H]+ 342.
Compound 117-4 (0.09g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 117-3.
ESIMS m/z: [M+H]+ 346.
Compound 210 (0.15 g, 32% over two steps) was obtained in the same manner as step 1 of example 76, using compound 117-4.
1H NMR (300 MHz, DMSO-d6, δ): 10.79 (s, 1H), 9.00 (d, J=3.6 Hz, 1H), 8.67-8.62 (m, 3H), 8.24 (d, J=8.1 Hz, 2H), 8.00 (d, J=7.8 Hz, 2H), 7.76-7.72 (m, 1H), 7.62 (d, J=7.8 Hz, 1H), 6.32-6.13 (m, 2H), 5.63 (dd, J=9.6, 2.1 Hz, 1H), 4.82 (d, J=5.4 Hz, 2H);
ESIMS m/z: [M+H]+ 400.
Compound 113-2 (0.28 g, 0.85 mmol) was dissolved in toluene (5 mL), and thionyl chloride (0.53 g, 4.48 mmol) was added to the solution. The mixture was stirred at room temperature for 3 hours. The toluene in the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>85/15) to obtain compound 118-1 (0.17 g, 57%).
1H NMR (300 MHz, CDCl3, δ): 9.05 (d, J=3.9 Hz, 1H), 8.56 (d, J=8.4 Hz, 1H), 8.11-8.02 (m, 2H), 7.69-7.64 (m, 4H), 7.57 (d, J=8.1Hz, 2H).
Compound 118-2 (0.09 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 118-1.
1H NMR (400 MHz, DMSO-d6, δ): 8.94 (dd, J=4.4, 2.0 Hz, 1H), 8.59 (dd, J=8.4, 1.6 Hz, 1H), 7.63-7.55 (m, 5H), 7.49 (d, J=8.0 Hz, 2H), 4.65 (s, 2H), 4.21 (s, 2H).
Compound 211 (0.11 g, 6% over two steps) was obtained in the same manner as step 1 of example 76, using compound 118-2.
1H NMR (400 MHz, DMSO-d6, δ): 8.96 (dd, J=4.0, 1.6 Hz, 1H), 8.62 (br, 1H), 8.52 (dd, J=8.4, 1.6 Hz, 1H), 7.65-7.58 (m, 4H), 7.50-7.48 (m, 3H), 6.24 (dd, J=17.2, 10.0 Hz, 1H), 6.14 (dd, J=17.2, 2.8 Hz, 1H), 5.61 (dd, J=10.0, 2.8 Hz, 1H), 4.79 (d, J=5.60 Hz, 2H), 4.65 (s, 2H);
ESIMS m/z: [M+H]+ 371.
Compound 119-1 (0.050 g, 89%) was obtained in the same manner as step 2 of example 106, using compound 60-1.
1H NMR (400 MHz, CDCl3, δ): 8.45 (d, J=8.5 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.58 (d, J=8.5 Hz, 1H), 7.29-7.24 (m, 2H), 7.01 (d, J=8.3 Hz, 1H), 2.83 (s, 3H).
Compound 119-2 (0.051 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 119-1.
ESIMS m/z: [M+H]+ 333.
Compound 212 (0.029 g, 49% over two steps) was obtained in the same manner as step 5 of example 1, using compound 119-2.
1H NMR (400 MHz, CDCl3, δ): 8.33 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.38 (t, J=8.0 Hz, 2H), 7.11 (dd, J=8.0, 2.7 Hz, 3H), 6.37 (dd, J=16.9, 1.3 Hz, 1H), 6.09 (dd, J=16.9, 10.3 Hz, 1H), 5.85 (br, 1H), 5.70 (dd, J=10.3, 1.3 Hz, 1H), 4.94 (d, J=5.8 Hz, 2H), 2.71 (s, 3H);
ESIMS m/z: [M+H]+ 387.
Compound 60-2 (0.050 g, 0.14 mmol) was dissolved in DMSO (3 mL), and N-hydroxyacetamide (0.022 g, 0.29 mmol) and potassium carbonate (0.059 g, 0.43 mmol) were added to the solution. The mixture was stirred at 80° C. for 2 hours. The mixture was cooled to room o temperature, and water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=100/0−>50/50) to obtain compound 120-1 (0.043 g, 91%).
ESIMS m/z: [M+H]+ 331.
Compound 120-2 (0.045 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 120-1.
Compound 213 (7.0 mg, 13% over two steps) was obtained in the same manner as step 5 of example 1, using compound 120-2.
1H NMR (400 MHz, CDCl3, δ): 8.15 (d, J=9.9 Hz, 1H), 7.65 (d, J=8.5 Hz, 2H), 7.16 (dd, J=7.9, 6.1 Hz, 3H), 7.03 (d, J=8.1 Hz, 1H), 6.77 (d, J=9.9 Hz, 1H), 6.35 (dd, J=17.0, 1.3 Hz, 1H), 6.14 (dd, J=17.0, 10.2 Hz, 1H), 5.70 (dd, J=10.2, 1.3 Hz, 1H), 4.76 (s, 2H);
ESIMS m/z: [M+H]+ 389.
Compound 121-1 (0.15 g, 83%) was obtained in the same manner as step 1 of example 54, using 6-bromo-8-fluoroquinoline.
1H NMR (400 MHz, CDCl3, δ): 9.13 (dd, J=4.4, 1.6 Hz, 1H), 8.59-8.54 (m, 2H), 8.09 (dd, J=10.4, 1.6 Hz, 1H), 7.82 (dd, J=8.4, 4.0 Hz, 1H).
Compound 121-2 (0.16 g, 27%) was obtained in the same manner as step 2 of example 50, using compound 121-1.
ESIMS m/z: [M+H]+ 315.
Compound 121-3 (0.16 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 121-2.
ESIMS m/z: [M+H]+ 319.
Compound 214 (0.010 g, 6% over two steps) was obtained in the same manner as step 1 of example 76, using compound 121-3.
1H NMR (400 MHz, CDCl3, δ): 8.91(dd, J=4.0, 1.6 Hz, 1H), 8.18 (dd, J=8.4, 1.6 Hz, 1H), 7.59-7.57 (m, 3H), 7.49-7.46 (m, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.33 (dd, J=16.8, 1.2 Hz, 1H), 6.12 (dd, J=16.8, 10.0 Hz, 1H), 5.96 (bs, 1H), 5.72 (dd, J=10.4, 1.6 Hz, 1H), 4.66 (d, J=6.0 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
Compound 122-1 (0.030 g, 37%) was obtained in the same manner as step 1 of example 3, using 4-bromoquinolin-8-ol.
ESIMS m/z: [M+H]+ 369.
Compound 122-2 (0,018 g, 70%) was obtained in the same manner as step 1 of example 54, using compound 122-1.
ESIMS m/z: [M+H]+ 315.
Compound 122-3 (0.30 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 122-2.
ESIMS m/z: [M+H]+ 319.
Compound 215 (0.040 g, 11% over two steps) was obtained in the same manner as step 1 of example 76, using compound 122-3.
1H NMR (300 MHz, DMSO-d6, δ): 8.82 (t, J=5.4 Hz 1H), 8.77 (t, J=4.2 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.70-7.61 (m, 3H), 7.42 (d, J=4.2 Hz, 1H), 6.98 (d, J=8.4 Hz, 2H), 6.39-6.30 (m, 1H), 6.21-6.15 (m, 1H), 5.68 (dd, J=9.9, 1.8 Hz, 1H), 4.89 (d, J=5.7 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
Compound 123-1 (0.15 g, 65%) was obtained in the same manner as step 1 of example 54, using 8-bromo-5-fluoroquinoline.
1H NMR (300 MHz, CDCl3, δ): 9.17 (dd, J=4.2, 1.5 Hz, 1H), 8.51 (dd, J=8.4, 1.5 Hz, 1H), 8.11 (dd, J=8.1, 5.7 Hz, 1H), 7.63 (dd, J=8.4, 4.2 Hz, 1H), 7.31 (t, J=8.7 Hz, 1H).
Compound 123-2 (0.10 g, 36%) was obtained in the same manner as step 2 of example 50, using compound 123-1.
1H NMR (400 MHz, DMSO-d6, δ): 9.17 (dd, J=4.0, 1.6 Hz, 1H), 8.69 (dd, J=8.8, 2.0 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.61 (dd, J=8.4, 4.4 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H).
Compound 123-3 (0.060 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 123-2.
ESIMS m/z: [M+H]+ 319.
Compound 216 (0.010 g, 17% over two steps) was obtained in the same manner as step 1 of example 76, using compound 123-3.
1H NMR (300 MHz, CDCl3, δ): 8.97(dd, J=3.9, 1.5 Hz, 1H), 8.44 (dd, J=8.7, 1.5 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H), 7.47 (dd, J=8.4, 4.2 Hz, 1H), 7.10-7.01 (m, 4H), 6.28 (dd, J=16.8, 1.2 Hz, 1H), 6.09 (dd, J=16.8, 10.2 Hz, 1H), 5.61 (dd, J=9.9, 1.2 Hz, 1H), 5.05 (d, J=6.3 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
Phosphorus oxychloride (2.0 mL) was added to 8-bromoquinolin-4-ol (0.10 g, 0.44 mmol) at 0° C., and the solution was stirred at 120° C. for 2 hours. The mixture was cooled to room temperature and added dropwise to ice water (30 mL). The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 124-1 (0.070 g, 65%).
1H NMR (400 MHz, CDCl3, δ): 8.93 (d, J=4.8 Hz, 1H), 8.25 (dd, J=8.4, 1.2 Hz, 1H), 8.13 (dd, J=7.2, 1.2 Hz, 1H), 7.58 (d, J=4.8 Hz, 1H), 7.53-7.49 (m, 1H).
Compound 124-2 (0.050 g, 33%) was obtained in the same manner as step 2 of example 50, using compound 124-1.
1H NMR (300 MHz, CDCl3, δ): 8.87 (d, J=5.1 Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 7.48-7.42 (m, 1H), 7.29 (d, J=8.4 Hz, 2H), 6.70 (d, J=5.4 Hz, 1H).
Compound 124-3 (0.15 g, 58%) was obtained in the same manner as step 1 of example 54, using compound 124-2.
1H NMR (400 MHz, CDCl3, δ): 8.91 (d, J=5.2 Hz, 1H), 8.59 (dd, J=8.4, 1.2 Hz, 1H), 8.20 (dd, J=7.2, 1.6 Hz, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.69-7.65 (m, 1H), 7.32 (d, J=8.4 Hz, 2H), 6.72 (d, J=5.2 Hz, 1H).
Compound 124-4 (0.27 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 124-3.
ESIMS m/z: [M+H]+ 319.
Compound 217 (0.050 g, 31% over two steps) was obtained in the same manner as step 1 of example 76, using compound 124-4.
1H NMR (300 MHz, CDCl3, δ): 8.75(d, J=5.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 7.83 (d, J=6.9 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.56-7.51 (m, 1H), 7.30 (dd, J=8.7 Hz, 2H), 7.13 (br, 1H), 6.68 (d, J=5.1 Hz, 1H), 6.27 (d, J=16.5 Hz, 1H), 6.09 (dd, J=17.1, 10.2 Hz, 1H), 5.59 (d, J=10.2 Hz, 1H), 5.07 (d, J=6.3 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
Compound 125-1 (0.30 g, 60%) was obtained in the same manner as step 2 of example 50, using 4-chloroquinoline-2-carbonitrile.
1H NMR (400 MHz, CDCl3, δ): 8.38 (dd, J=8.4, 0.8 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.92-7.88 (m, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.77-7.73 (m, 1H), 7.32 (d, J=8.4 Hz, 2H), 6.85 (s, 1H).
Compound 125-2 (0.12 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 125-1.
ESIMS m/z: [M+H]+ 319.
Compound 218 (0.030 g, 13% over two steps) was obtained in the same manner as step 1 of example 76, using compound 125-2.
1H NMR (400 MHz, CDCl3, δ): 8.27 (dd, J=8.4, 0.8 Hz, 1H), 8.07 (d, J=8.4Hz, 1H), 7.81-7.73 (m, 3H), 7.61-7.57 (m, 1H), 7.28-7.23 (m, 3H), 6.57 (s, 1H), 6.36-6.24 (m, 2H), 5.69 (dd, J=9.6, 2.4 Hz, 1H), 4.66 (d, J=4.4 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
Compound 126-1 (0.20 g, 54%) was obtained in the same manner as step 2 of example 50, using compound 123-1.
ESIMS m/z: [M+H]+ 316.
Compound 126-2 (0.020 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 126-1.
ESIMS m/z: [M+H]+ 320.
Compound 219 (0.055 g, 20% over two steps) was obtained in the same manner as step 1 of example 76, using compound 126-2.
1H NMR (400 MHz, DMSO-d6, δ): 9.00 (dd, J=4.2 Hz, 1H), 8.57 (d, J=2.4 Hz, 1H), 8.42 (dd, J=8.4, 1.5 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.50 (dd, J=8.7, 4.2 Hz, 1H), 7.39-7.30 (m, 1H), 7.08-7.01 (m, 2H), 6.28 (dd, J=16.8, 1.5 Hz, 1H), 6.09 (dd, J=17.1, 10.2 Hz, 1H), 5.62 (dd, J=10.2, 1.5 Hz, 1H), 5.06 (d, J=6.3 Hz, 2H);
ESIMS m/z: [M+H]+ 374.
3-Bromo-5-fluoroaniline hydrochloride (4.00 g, 17.66 mmol) and glycerol (3.26 g, 35.50 mmol) were dissolved in nitrobenzene (2 mL). Iron(II) sulfate heptahydrate (0.24 g, 0.06 mmol) and concentrated sulfuric acid (4.8 mL) were added to the solution. The mixture was stirred at 80° C. for 12 hours. The mixture was cooled to room temperature and neutralized with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5−>90/10) to obtain a mixture (2.4 g) of compound 127-1-1 and compound 127-1-2.
ESIMS m/z: [M+H]+ 226.
The mixture (0.17 g) of compound 127-2-1 and compound 127-2-2 was obtained in the same manner as step 2 of example 50, using the mixture (0.27 g, 1.21 mmol) of compound 127-1-1 and compound 127-1-2.
ESIMS m/z: [M+H]30 173.
The mixture (1.2 g, 6.97 mmol) of compound 127-2-1 and compound 127-2-2 was dissolved in THF (10 mL), and a 25% methanol solution of sodium methoxide (0.73 mL, 13.94 mmol) was added to the solution. The mixture was stirred at 100° C. for 30 minutes. The mixture was left to cool to room temperature, and water (50 mL) was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20−>70/30) to obtain compound 127-3-1 (0.50 g, 38%) and compound 127-3-2 (0.40 g, 31%).
Compound 127-3-1: 1H NMR (300 MHz, CDCl3, δ): 8.95 (d, J=3.3 Hz, 1H), 8.45 (d, J=8.4 Hz, 1H), 7.65 (d, J=6.6 Hz, 2H), 7.49-7.45 (m, 1H), 3.99 (s, 3H).
Compound 127-3-2: 1H NMR (400 MHz, CDCl3, δ): 9.01 (d, J=2.4 Hz, 1H), 8.60 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.54-7.50 (m, 1H), 6.96 (s, 1H), 4.05 (s, 3H).
Compound 127-4 (0.45 g, 88%) was obtained in the same manner as step 2 of example 57, using compound 127-3-1.
ESIMS m/z: [M+H]+ 189.
Pyridine hydrochloride (0.15 g) was added to compound 127-4 (0.45 g, 2.39 mmol). The mixture was stirred at 180° C. for one hour using a microwave reactor. The mixture was left to cool to room temperature. A saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 127-5 (0.40 g, 54%).
ESIMS m/z: [M+H]+ 175.
Compound 127-6 (0.35 g, 54%) was obtained in the same manner as step 1 of example 76, using compound 127-5.
1H NMR (300 MHz, DMSO-d6, δ): 8.84 (dd, J=4.0, 1.2 Hz, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.26 (d, J=2.4 Hz, 1H), 6.60 (dd, J=17.2, 0.8 Hz, 1H), 6.34-6.26 (m, 2H), 6.08-5.99 (m, 3H), 5.61 (dd, J=10.4, 1.2 Hz, 1H), 4.88 (d, J=6.0 Hz, 2H).
Compound 127-6 (0.11 g, 0.38 mmol) was dissolved in methanol (5 mL), and potassium carbonate (0.10 g, 0.77 mmol) was added to the solution. The mixture was stirred at 80° C. for 30 minutes. The mixture was left to cool to room temperature, and water (20 mL) was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 127-7 (0.20 g, 70%).
1H NMR (400 MHz, DMSO-d6, δ): 10.15 (s, 1H), 8.75-8.73 (m, 1H), 8.67-8.66 (m, 1H), 8.35 (d, J=8.0 Hz, 1H), 7.31 (dd, J=8.4, 4.4 Hz, 1H), 7.16-7.10 (m, 2H), 6.29 (dd, J=16.8, 10.0 Hz, 1H), 6.15 (dd, J=16.8, 2.0 Hz, 1H), 5.64 (dd, J=10.0, 2.4 Hz, 1H), 4.75 (d, J=6.0 Hz, 2H).
Compound 220 (0.023 g, 14,/o) was obtained in the same manner as step 1 of example 3, using compound 127-7.
1H NMR (400 MHz, CDCl3, δ): 8.98 (s, 1H), 8.75-8.70 (m, 2H), 7.84 (d, J=7.6 Hz, 2H), 7.66 (bs, 1H), 7.43 (s, 2H), 7.35 (d, J=7.6 Hz, 2H), 6.30-6.12 (m, 2H), 5.64 (d, J=9.2 Hz, 1H), 4.87 (d, J=4.0 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
Compound 128-1 (0.25 g, 82%) was obtained in the same manner as step 2 of example 50, using 8-bromo-6-fluoroquinoline.
1H NMR (300 MHz, CDCl3, δ): 9.09 (d, J=3.0 Hz, 1H), 8.21 (dd, J=8.1, 1.2 Hz, 1H), 7.92 (dd, J=7.8, 2.7 Hz, 1H), 7.72 (dd, J=8.1, 2.7 Hz, 1H), 7.58 (dd, J=8.4, 4.2 Hz, 1H).
Compound 128-2 (0.75 g, 64%) was obtained in the same manner as step 3 of example 127, using compound 128-1.
1H NMR (400 MHz, CDCl3, δ): 8.95 (dd, J=4.4, 2.0 Hz, 1H), 8.12 (dd, J=8.4, 1.6 Hz, 1H), 7.79 (d, J=2.8 Hz, 1H), 7.51-7.49 (m, 1H), 7.32 (d, J=2.8 Hz, 1H), 3.97 (s, 3H).
Compound 128-3 (0.60 g, 90%) was obtained in the same manner as step 2 of example 57, using compound 128-2.
1H NMR (300 MHz, CDCl3, δ): 8.76 (dd, J=4.0, 1.6 Hz, 1H), 8.04 (dd, J=8.4, 1.6 Hz, 1H), 7.38-7.26 (m, 2H), 6.96 (d, J=2.8 Hz, 1H), 4.37 (s, 2H), 3.92 (s, 3H).
Compound 128-4 (0.20 g, 78%) was obtained in the same manner as step 5 of example 127, using compound 128-3.
ESIMS m/z: [M+H]+ 175.
Compound 128-5 (0.11 g, 27%) was obtained in the same manner as step 1 of example 76, using compound 128-4.
ESIMS m/z: [M+H]+ 283.
Compound 128-6 (0.070 g, 86%) was obtained in the same manner as step 7 of example 127, using compound 128-5.
ESIMS m/z: [M+H]+ 229.
Compound 221 (6.0 mg, 4%) was obtained in the same manner as step 1 of example 3, using compound 128-6.
1H NMR (400 MHz, CDCl3, δ): 8.90 (dd, J=4.4, 1.6 Hz, 1H), 8.11 (dd, J=8.4, 1.6 Hz, 1H),7.65-7.52 (m, 3H), 7.49-7.46 (m, 1H), 7.31-7.24 (m, 2H), 7.14(d, J=8.4 Hz, 2H), 6.26 (dd, J=16.8, 1.2 Hz, 1H), 6.10 (dd, J=16.8, 10.0 Hz, 1H), 5.61 (d, J=10.4, 1.6 Hz, 1H), 5.05 (d, J=6.0 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
Compound 129-1 (0.50 g) was obtained as a crude product in the same manner as step 2 of example 50, using 4-bromo-1-chloroisoquinoline.
ESIMS m/z: [M+H]+ 369.
Compound 129-2 (0.20 g, 43% over two steps) was obtained in the same manner as step 1 of example 54, using compound 129-1.
1H NMR (300 MHz, DMSO-d6, δ): 8.62 (s, 1H), 8.56 (d, J=8.1 Hz, 1H), 8.14-8.09 (m, 2H), 7.98-7.88 (m, 3H), 7.60 (d, J=8.7 Hz, 2H).
Compound 129-3 (0.15 g) was obtained as a crude product in the same manner as step 2 of example 57, using compound 129-2.
ESIMS m/z: [M+H]+ 319.
Compound 222 (0.070 g, 30% over two steps) was obtained in the same manner as step 1 of example 76, using compound 129-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.58 (t, J=5.6 Hz, 1H), 8.42 (d, J=7 Hz, 1H), 8.12 (d, J=8.4 Hz, 1H), 7.95-7.91 (m, 2H), 7.84 (d, J=8.4 Hz, 2H), 7.78 (t, J=8.0 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 6.25-6.11 (m, 2H), 5.61 (dd, J=9.6, 2.8 Hz, 1H), 4.71 (d, J=5.2 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
Compound 130-1 (0.30 g, 87%) was obtained in the same manner as step 1 of example 54, using 5-bromo-8-fluoroisoquinoline.
1H NMR (400 MHz, DMSO-d6, δ): 9.64 (d, J=0.8 Hz, 1H), 8.88 (d, J=6.0 Hz, 1H), 8.53 (dd, J=8.0, 5.2 Hz, 1H), 8.03-8.01 (m, 1H), 7.75-7.71 (m, 1H).
Compound 130-2 (0.35 g, 76%) was obtained in the same manner as step 2 of example 50, using compound 130-1.
1H NMR (400 MHz, DMSO-d6, δ): 9.83 (s, 1H).8.84 (d, J=6.0 Hz, 1H), 8.03 (dd, J=6.0 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.0 Hz, 1H).
Compound 130-3 (0.20 g, 66%) was obtained in the same manner as step 2 of example 57, using compound 130-2.
ESIMS m/z: [M+H]+ 319.
Compound 223 (0.028 g, 14%) was obtained in the same manner as step 1 of example 76, using compound 130-3.
1H NMR (300 MHz, DMSO-d6, δ): 9.43(d, J=0.8 Hz, 1H), 8.70-8.65 (m, 2H), 8.04 (dd, J=6.0, 1.2 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.27-7.25 (m, 3H), 6.27 (dd, J=16.8, 10.0 Hz, 1H), 6.16 (dd, J=17.2, 2.4 Hz, 1H), 5.64 (dd, J=9.6, 2.0 Hz, 1H), 4.80 (d, J=6.0 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
Compound 131-1 (0.45 g, 25%) was obtained in the same manner as step 1 of example 3, using 1-chloroisoquinolin-4-ol.
ESIMS m/z: [M+H]+ 324.
Compound 131-2 (0.32 g, 73%) was obtained in the same manner as step 1 of example 54, using compound 131-1.
1H NMR (300 MHz, DMSO-d6, δ): 8.39 (s, 1H), 8.35-8.25 (m, 2H), 8.05-8.02 (m, 2H), 7.83 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H);
ESIMS m/z: [M+H]+ 315.
Compound 131-2 (0.20 g, 0.63 mmol) was dissolved in ethanol (10 mL), and nickel chloride hexahydrate (0.010 g, 0.063 mmol) and sodium borohydride (0.070 g, 1.90 mmol) were added to the solution. The mixture was stirred at room temperature for 2 hours. The mixture was filtered with Celite(R). The filtrate was concentrated under reduced pressure to obtain compound 131-3 (0.20 g) as a crude product.
ESIMS m/z: [M+H]+ 319.
Compound 224 (0.050 g, 22% over two steps) was obtained in the same manner as step 1 of example 76, using compound 131-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.75-8.74 (m, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.33 (s, 1H), 7,94 (d, J=7.6 Hz, 1H), 7.86-7.77 (m, 2H), 7.74 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 6.39-6.32 (m, 1H), 6.19-6.14 (m, 1H), 5.63 (dd, J=10.0, 2.0 Hz, 1H), 5.03 (d, J=5.6 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
5-Methoxyisoquinoline (0.20 g, 1.25 mmol) was dissolved in acetic acid (5 mL), and bromine (0.20 g, 1.25 mmol) was added to the solution at 0° C. The mixture was stirred at room temperature for 16 hours. Water (50 mL) was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20−>70/30) to obtain compound 132-1 (0.10 g, 33%).
1H NMR (300 MHz, CDCl3, δ): 9.53 (5, 1H), 8.61 (d, J=5.7 Hz, 1H), 7.99 (d, J=5.7 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 4.00 (s, 3H).
Compound 132-2 (0.30 g, 77%) was obtained in the same manner as step 1 of example 54, using compound 132-1.
1H NMR (400 MHz, CDCl3, δ): 9.58 (s, 1H), 8.71 (d, J=6.0 Hz, 1H), 8.05 (d, J=5.6 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 4.10 (s, 3H).
Compound 132-3 (0.17 g, 66%) was obtained in the same manner as step 2 of example 57, using compound 132-2.
ESIMS m/z: [M+H]+ 189.
Compound 132-4 (0.20 g, 49%) was obtained in the same manner as step 6 of example 27, using compound 132-3.
ESIMS m/z: [M+H]+ 175.
Compound 132-4 (1.0 g, 3.93 mmol) was dissolved in dichloromethane (15 mL), and diisopropylethylamine (2.1 mL, 11.7 mmol) and di-tert-butyl dicarbonate (6.0 mL, 27.55 mmol) were added to the solution. The mixture was stirred at room temperature for 16 hours. Water (50 mL) was added to the mixture. The organic layer was extracted with tert-butyl methyl ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=60/40−>50/50) to obtain compound 132-5 (0.60 g, 41%).
1H NMR (400 MHz, DMSO-d6, δ): 9.61 (s, 1H), 8.62 (d, J=6.0 Hz, 1H), 7.69 (d, J=5.6 Hz, 1H 7.64-7.62 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 4.70 (d, J=6.0 Hz, 2H), 1.53 (s, 9H), 1.39 (s, 9H).
Compound 132-5 (0.60 g, 1.60 mmol) was dissolved in methanol (10 mL), and potassium carbonate (0.44 g, 3.20 mmol) was added to the solution. The mixture was stirred at 60° C. for 30 minutes. The mixture was left to cool to room temperature, and water (20 mL) was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 132-6 (0.50 g, 61%).
1H NMR (400 MHz, DMSO-d6, δ): 10.50 (bs, 1H), 9.42 (s, 1H), 8.48 (d, J=5.6 Hz, 1H), 7.94 (d, J=5.6 Hz, 1H), 7.45-7.44 (m, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 4.55 (d, J=5.6 Hz, 2H), 1.38 (s, 9H).
Compound 132-7 (0.28 g, 36%) was obtained in the same manner as step 1 of example 3, using compound 132-6.
ESIMS m/z: [M+H]+ 419.
Compound 132-7 (0.30 g, 0.71 mmol) was dissolved in dichloromethane (10 mL), and a 4 mol/L hydrochloric acid solution in 1,4-dioxane (0.04 mL, 1.43 mmol) was added to the solution at 0° C. The mixture was stirred for 16 hours. The mixture was concentrated under reduced pressure. The solid obtained was washed with tert-butyl methyl ether to obtain compound 132-8 (0.15 g, 59%).
ESIMS m/z: [M+H]+ 319.
Compound 132-8 (0.10 g, 0.28 mmol) was dissolved in DMF (5 mL), and added to the solution at 0° C. were diisopropylamine (0.10 mL, 0.56 mmmol), O-(7-azabenzotriazol-1-yl)-N,NN′,N′-tetramethyluronium hexafluorophosphate (0.12 g, 0.33 mmol), and acrylic acid (0.040 g, 0.56 mmol). The mixture was stirred at room temperature for 16 hours. Water (10 mL) was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a preparative HPLC to obtain compound 225 (6.0 mg, 6%).
1H NMR (400 MHz, CDCl3, δ): 9.47 (s, 1H), 8.55 (s, 1H), 7.86 (d, J=5.6 Hz, 1H), 7.55 (d, J=8.8 Hz, 2H), 7.45 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 6.30 (dd, J=16.8, 1.2 Hz, 1H), 6.05 (d, J=17.2, 10.4 Hz, 1H), 5.91 (bs, 1H), 5.64 (dd, J=10.0, 0.8 Hz, 1H), 5.04 (d, J=5.6 Hz, 2H);
ESIMS m/z: [M+H]+ 373.
Commercially available pyridine-2,3-diamine (2.0 g, 18.34 mmol) was dissolved in concentrated sulfuric acid (10 mL) and water (20 mL), and glycerol (6.69 mL, 91.74 mmol) and sodium 3-nitrobenzenesulfonate (8.25 g, 36.69 mmol) were added to the solution. The mixture was stirred at 135° C. for 36 hours. The mixture was cooled, and a 6 mol/L aqueous sodium hydroxide solution was added to the mixture to bring pH to 10. Thereafter, the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=100/0−>92/8) to obtain compound 133-1 (0.50 g, 20%).
1H NMR (400 MHz, DMSO-d6, δ): 8.78 (dd, J=4.0 Hz, 1.6 Hz, 1H), 8.16 (dd, J=6.8 Hz, 1.6 Hz, 1H), 7.85 (d, J=5.6 Hz, 1H), 7.66 (dd, J=8.4 Hz, 4.4 Hz, 1H), 6.94 (s, 2H), 6.91 (d, J=5.6 Hz, 1H).
Compound 133-1 (0.50 g, 3.44 mmol) was dissolved in acetic acid (5 mL), and bromine (1.18 mL) was added to the solution. The mixture was stirred at 90° C. for 3 hours. The mixture was cooled, and ammonia water was added to the mixture to bring pH to 7. Thereafter, the precipitated solid was filtered off and dried under reduced pressure to obtain compound 133-2 (0.45 g, 53%).
1H NMR (300 MHz, DMSO-d6, δ): 8.87-8.86 (m, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.05 (s, 1H), 7.84 (dd, J=7.8 Hz, 4.2 Hz, 1H), 7.23 (s, 2H).
Compound 133-2 (0.45 g, 3.10 mmol) was dissolved in concentrated hydrochloric acid (5 mL) and water (5 mL), and sodium nitrite (1.05 g, 15.51 mmol) dissolved in water (5 mL) was added dropwise to the solution at −10° C. The mixture was stirred at room temperature for one hour. The mixture was cooled, and a saturated aqueous sodium hydrogen carbonate solution was added to the mixture to bring pH to 8. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20−>60/40) to obtain compound 133-3 (0.15 g, 30%).
1H NMR (400 MHz, DMSO-d6, δ): 9.24 (dd, J=4.0 Hz, 1.2 Hz, 1H), 8.72 (s, 1H), 8.59 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.58 (dd, J=8.8 Hz, 4.4 Hz, 1H).
5-Bromo-8-(4-chlorophenoxy)-1,7-naphthyridine (Compound 133-4)
Compound 133-3 (0.50 g, 2.05 mmol) was dissolved in dimethylformamide (10 mL), and 4-chlorophenol (0.31 g, 2.46 mmol) and potassium carbonate (0.56 g, 4.11 mmol) were added to the solution. The mixture was stirred at 100° C. for one hour using a microwave reactor. The mixture was cooled, and water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10−>50/50) to obtain compound 133-4 (0.50 g, 72%).
1H NMR (400 MHz, DMSO-d6, δ): 9.15 (dd, J=4.4 Hz, 1.6 Hz, 1H), 8.50 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.30 (s, 1H), 8.02 (dd, J=8.8 Hz, 4.4 Hz, 1H), 7.53 (dd, J=6.8 Hz, 2.0 Hz, 2H), 7.33 (dd, J=6.8 Hz, 2.4 Hz, 2H).
Compound 133-4 (0.25 g, 0.75 mmol) was dissolved in dimethylacetamide (5 mL), and tert-butyl carbamate (0.175 g, 1.501 mmol), sodium tert-butoxide (0.144 g, 1.501 mmol), and X-phos (0.035 g, 0.075 mmol) were added to the solution. The mixture was purged with nitrogen. Tris(dibenzylideneacetone)dipalladium (0.034 g, 0.037 mmol) was added to the mixture. The mixture was stirred at 150° C. for one hour using a microwave reactor. The mixture was cooled, and water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10−>10/90) to obtain compound 133-5 (0.11 g, 40%).
1H NMR (400 MHz, DMSO-d6, δ): 9.31 (s, 1H), 9.06 (d, J=2.8 Hz, 1H), 8.40 (d, J=7.6 Hz, 1H), 8.01 (s, 1H), 7.88 (dd, J=8.8 Hz, 4.4 Hz, 1H), 7.50 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H), 1.47 (s, 9H).
Compound 133-5 (0.110 g, 0.296 mmol) was dissolved in dichloromethane (10 mL), and a 4 mol/L hydrochloric acid solution in 1,4-dioxane (2.0 mL) was added to the solution at The mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure, and the crystals obtained were washed with tert-butyl methyl ether to obtain compound 133-6 (0.05 g, 62%).
ESIMS m/z: [M+H]+ 272.
Compound 226 (15 mg, 25%) was obtained in the same manner as step 5 of example 1, using compound 133-6.
1H NMR (400 MHz, DMSO-d6, δ): 10.23 (s, 1H), 9.09 (d, J=2.4 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.20 (s, 1H), 7.92 (dd, J=8.4 Hz, 4.0 Hz, 1H), 7.52 (d, J=9.2 Hz, 2H), 7.31 (d, J=8.8 Hz, 2H), 6.62 (dd, J=17.2 Hz, 10.8 Hz, 1H), 6.30 (dd, J=17.2 Hz, 1.6 Hz, 1H), 5.86-5.84 (m, 1H).
ESIMS m/z: [M+H]+ 326.
Compound 133-4 (0.25 g, 0.75 mmol) was dissolved in dimethylformamide (5 mL), and zinc cyanide (0.113 g, 1.12 mmol) was added to the solution. The mixture was purged with nitrogen. Tetrakis(triphenylphosphine)palladium (0.043 g, 0.037 mmol) was added to the mixture, and the mixture was stirred at 150° C. for one hour using a microwave reactor. The mixture was cooled, and water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10−>30/70) to obtain compound 134-1 (0.10 g, 47%).
ESIMS m/z: [M+H]+ 282.
Compound 134-1 (0.10 g, 0.35 mmol) was dissolved in ethanol (10 mL), and ammonia water (1.0 mL) and Raney nickel (0.050 g) were added to the solution. The mixture was stirred under hydrogen atmosphere at room temperature for 2 hours. The mixture was filtered with Celite(R), and the filtrate was concentrated under reduced pressure to obtain compound 134-2 (0.08 g, 79%).
ESIMS m/z: [M+H]+ 286.
Compound 227 (18 mg, 19%) was obtained in the same manner as step 5 of example 1, using compound 134-2.
1H NMR (300 MHz, DMSO-d6, δ): 9.08-9.07 (m, 1H), 8.62 (t, J=5.1 Hz, 1H), 8.56-8.53 (m, 1H), 7.98 (s, 1H), 7.92 (dd, J=8.4 Hz, 4.2 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.27 (d, J=9.0 Hz, 2H), 6.25-6.15 (m, 2H), 5.63-5.94 (m, 1H), 4.70 (d, J=5.4 Hz, 2H).
ESIMS m/z: [M+H]+ 340.
Commercially available 5,6,7,8-tetrahydroisoquinoline (1.00 g, 7.51 mmol) was dissolved in water (33.4 mL) and acetic acid (0.56 mL), and potassium permanganate (2.67 g, 16.9 mmol) was added to the solution. The mixture was stirred at room temperature for 30 minutes. The mixture was filtered with Celite(R), and a saturated aqueous sodium bicarbonate solution was added to the filtrate. The organic layer was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=80/20−>50/50) to obtain compound 135-1 (0.17 g, 16%).
1H NMR (400 MHz, CDCl3, δ): 9.17 (s, 1H), 8.62 (d, J=5.1 Hz, 1H), 7.20 (dd, J=5.1, 0.7 Hz, 1H), 2.97 (t, J=6.1 Hz, 2H), 2.70 (t, J=6.5 Hz, 2H), 2.22-2.15 (m, 2H).
ESIMS m/z: [M+H]+ 148.
Compound 135-2 (0.17 g, 95%) was obtained in the same manner as step 1 of example 15, using compound 135-1 (0.17 g, 1.17 mmol).
1H NMR (400 MHz, CDCl3, δ): 8.63 (s, 1H), 8.35 (d, J=5.2 Hz, 1H), 7.01 (d, J=5.2 Hz, 1H), 4.87 (t, J=4.5 Hz, 1H), 2.85-2.78 (m, 1H), 2.72-2.68 (m, 1H), 2.17 (br, 1H), 2.07-1.90 (m, 3H), 1.85-1.76 (m, 1H).
ESIMS m/z: [M+H]+ 150.
Compound 135-3 (0.31 g, 95%) was obtained in the same manner as step 4 of example 33, using compound 135-2 (0.17 g, 1.11 mmol) and 4-(trifluoromethyl)phenol (0.22 g, 1.33 mmol).
1H NMR (400 MHz, CDCl3, δ): 8.55 (s, 1H), 8.43 (d, J=4.9 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.10 (d, J=4.9 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 5.49 (t, J=3.8 Hz, 1H), 2.91 (dt, J=17.7, 4.6 Hz, 1H), 2.79-2.74 (m, 1H), 2.26-2.20 (m, 1H), 2.09-1.98 (m, 2H), 1.87-1.82 (m, 1H).
ESIMS m/z: [M+H]+ 294.
Compound 135-3 (0.31 g, 1.05 mmol) was dissolved in dichloromethane (5.2 mL), and m-chloroperoxybenzoic acid (0.62 g, 2.32 mmol) was added to the solution. The mixture was stirred at room temperature for one hour. The mixture was basified by the addition of a 4 mol/L aqueous sodium hydroxide solution, and a saturated aqueous sodium thiosulfate solution was added to the mixture. The organic layer was extracted with chloroform/methanol, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain compound 135-4 as a crude product.
ESIMS m/z: [M+H]+ 310.
Compound 135-4 as a crude product was dissolved in ethyl acetate (10.5 mL), and triethylamine (0.44 mL, 3.16 mmol) was added to the solution. Trifluoroacetic acid anhydride (0.30 mL, 2.11 mmol) was added to the mixture, and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure. Ethanol (5.0 mL) and a 2 mol/L aqueous sodium hydroxide solution (2.0 mL) were added to the residue, and the mixture was stirred at room temperature for one hour. Water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was aminosilica gel column chromatography (chloroform/methanol=100/0−>90/10−>85/15) to obtain compound 135-5 (145 mg) as a crude product.
ESIMS m/z: [M+H]+ 310.
Compound 135-5 was dissolved in dichloromethane (4.7 mL), and Dess-Martin Periodinane (0.24 mg, 0.57 mmol) was added to the solution. The mixture was stirred at room temperature for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the mixture. The organic layer was extracted with chloroform, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=90/10−>50/50) to obtain compound 135-6 (0.11 mg, 35% over three steps).
1H NMR (400 MHz, CDCl3, δ): 8.87 (s, 1H), 8.84 (d, J=5.0 Hz, 1H), 7.85 (d, J=5.0 Hz, 1H), 7.63 (d, J=9.1 Hz, 2H), 7.12 (d, J=9.1 Hz, 2H), 5.68 (dd, J=5.9, 3.6 Hz, 1H), 3.05 (ddd, J=17.7, 9.3, 5.2 Hz, 1H), 2.73 (ddd, J=17.7, 6.8, 5.2 Hz, 1H), 2.56-2.49 (m, 2H).
ESIMS m/z: [M+H]+ 308.
Compound 135-7 was obtained as a crude product in the same manner as step 2 of example 3, using compound 135-6 (40.0 mg, 0.13 mmol).
ESIMS m/z: [M+H]+ 309.
Compound 228 (1.00 mg, 2% over two steps) was obtained in the same manner as step 3 of example 17, using compound 135-7.
1H NMR (400 MHz, CDCl3, δ): 8.59 (s, 1H), 8.55 (d, J=5.4 Hz, 1H), 7.60 (d, J=8.8 Hz, 2H), 7.30 (d, J=5.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H), 6.42 (dd, J=16.7, 1.0 Hz, 1H), 6.18 (dd, J=16.7, 10.3 Hz, 1H), 5.85 (d, J=9.0 Hz, 1H), 5.79 (dd, J=10.3, 1.0 Hz, 1H), 5.48 (t, J=3.1 Hz, 1H), 5.34 (td, J=9.4, 5.4 Hz, 1H), 2.39-2.34 (m, 1H), 2.17-1.99 (m, 3H).
ESIMS m/z: [M+H]+ 363.
Compound 51 was optically resolved under the following chiral preparative conditions to obtain compound 229 (137 mg, 45%) having a retention time of 2.61 minutes and compound 230 (135 mg, 44%) having a retention time of 3.28 minutes.
Compound 229: ESIMS m/z: [M+H]+ 365.
Compound 230: ESIMS m/z: [M+H]+ 365.
Compound 153 was optically resolved under the following chiral preparative conditions to obtain compound 231 (7.6 mg, 36%) having a retention time of 2.44 minutes and compound 232 (8.1 mg, 39%) having a retention time of 3.24 minutes.
Compound 231: ESIMS m/z: [M+H]+ 443, 445.
Compound 232: ESIMS m/z: [M+H]+ 443, 445.
Compound 40 was optically resolved under the following chiral preparative conditions to obtain compound 233 (24 mg, 48%) having a retention time of 4.56 minutes and compound 234 (22 mg, 44%) having a retention time of 5.07 minutes.
Compound 233: ESIMS m/z: [M+H]+ 378.
Compound 234: ESIMS m/z: [M+H]+ 378.
Compound 153 was optically resolved under the following chiral preparative conditions to obtain compound 235 (13.5 mg, 45%) having a retention time of 3.67 minutes and compound 236 (12 mg, 40%) having a retention time of 4.35 minutes.
Compound 235: ESIMS m/z: [M+H]+ 345.
Compound 236: ESIMS m/z: [M+H]+ 345.
Compound 33 was optically resolved under the following chiral preparative conditions to obtain compound 237 having a retention time of 5.14 minutes and compound 238 having a retention time of 6.79 minutes.
Compound 237: ESIMS m/z: [M+H]+ 394.
Compound 238: ESIMS m/z: [M+H]+ 394.
Compound 31 was optically resolved under the following chiral preparative conditions to obtain compound 239 having a retention time of 6.19 minutes and compound 240 having a retention time of 7.43 minutes.
Compound 239: ESIMS m/z: [M+H]+ 382.
Compound 240: ESIMS m/z: [M+H]+ 382.
Compound 76 was optically resolved under the following chiral preparative conditions to obtain compound 241 having a retention time of 2.73 minutes and compound 242 having a retention time of 3.41 minutes.
Compound 241: ESIMS m/z: [M+H]+ 397.
Compound 242: ESIMS m/z: [M+H]+ 397.
2-Aminobenzene-1,3-diol was dissolved in acetonitrile (5 mL), and pentane-2,4-dione (0.24 g, 2.40 mmol), copper(I) iodide (0.030 g, 0.16 mmol) and p-toluenesulfonic acid monohydrate (0.030 g, 0.16 mmol) were added to the solution. The mixture was stirred at 80° C. for 18 hours in a sealed tube. The mixture was left to cool to room temperature, and water was added to the mixture. The organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>80/20) to obtain compound 143-1 (0.10 g, 42%).
1H NMR (400 MHz, CDCl3, δ): 9.79 (s, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.03 (dd, J=8.0, 0.4 Hz, 1H), 6.87 (dd, J=8.0, 0.8 Hz, 1H), 2.69 (s, 3H).
Compound 143-1 (0.10 g, 0.67 mmol) was dissolved in DMF (3 mL), and potassium carbonate (0.18 g, 1.34 mmol) and methyl iodide (0.21 mL, 3.35 mmol) were added to the solution. The mixture was stirred at room temperature for 18 hours. Water was added to the mixture, the organic layer was extracted with methyl tert-butyl ether, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 143-2 (0.070 g, 64%).
1H NMR (400 MHz, CDCl3, δ): 7.21 (t, J=8.4 Hz, 1H), 7.09 (dd, J=8.0, 0.4 Hz, 1H), 6.77-6.75 (m, 1H), 4.01 (s, 3H), 2.62 (s, 3H).
Compound 143-3 (0.060 g, 40%) was obtained in the same manner as step 1 of example 117, using compound 143-2.
1H NMR (400 MHz, DMSO-d6, δ): 7.33 (d, J=11.2 Hz, 1H), 6.68 (d, J=11.6 Hz, 1H), 4.00 (s, 3H), 2.65 (s, 3H).
Compound 143-4 (0.070 g, 74%) was obtained in the same manner as step 1 of example 19, using compound 143-3.
1H NMR (400 MHz, DMSO-d6, δ): 10.48 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 2.61 (s, 3H).
Compound 143-5 (0.065 g, 57%) was obtained in the same manner as step 1 of example 3, using compound 143-4.
1H NMR (400 MHz, DMSO-d6, δ): 7.59 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 1H), 2.67 (s, 3H).
Compound 143-6 (0.065 g, 57%) was obtained in the same manner as step 1 of example 54, using compound 143-5.
1H NMR (400 MHz, CDCl3, δ): 7.68 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.8 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 1H), 2.73 (s, 3H).
Compound 143-7 was obtained as a crude product in the same manner as step 3 of example 15, using compound 143-6, and used as it is in the next reaction.
1H NMR (300 MHz, DMSO-d6, δ): 7.70 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.13-7.06 (m, 3H), 3.99 (s, 2H), 2.58 (s, 3H).
Compound 243 (0.17 g, 65% over two steps) was obtained in the same manner as step 1 of example 76, using compound 143-7.
1H NMR (400 MHz, DMSO-d6, δ): 8.75 (br, 1H), 7.70 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.14-7.08 (m, 3H), 6.30 (dd, J=17.2, 10.4 Hz, 1H), 6.15 (dd, J=17.2, 2.0 Hz, 1H), 5.65 (dd, J=10.0, 2.0 Hz, 1H), 4.61 (d, J=5.6 Hz, 2H), 2.59 (s, 3H);
ESIMS m/z: [M+H]+ 377.
2-Amino-3-methoxyphenol (3.0 g, 21.58 mmol) was dissolved in toluene (80 mL), and propionic anhydride (3.3 mL, 25.90 mmol) was added to the solution. The mixture was stirred at room temperature for 2 hours. Ethyl acetate was added to the mixture, and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=90/10) to obtain compound 144-1 (4.0 g, 95%).
1H NMR (400 MHz, DMSO-d6, δ): 9.09 (br, 2H), 7.03 (t, J=8.3 Hz, 1H), 6.52-6.47 (m, 2H), 3.74 (s, 3H), 2.37 (q, J=7.5 Hz, 2H), 1.11-1.05 (m, 3H);
ESIMS m/z: [M+H]+ 196.
Compound 144-1 (4.0 g, 20.51 mmol) was dissolved in toluene (70 mL), and p-toluenesulfonic acid (0.388 g, 2.26 mmol) was added to the solution. The mixture was refluxed for 16 hours using a Dean-Stark apparatus. Ethyl acetate was added to the mixture, and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=95/5) to obtain compound 144-2 (2.8 g, 77%).
1H NMR (400 MHz, DMSO-d6, δ): 7.29-7.22 (m, 2H), 6.90 (dd, J=7.8, 1.2 Hz, 1H), 3.95 (s, 3H), 2.92 (q, J=7.6 Hz, 2H), 1.33 (t, I=7.6 Hz, 3H);
ESIMS m/z: [M+H]+ 178.
Compound 144-3 (2.2 g, 55%) was obtained in the same manner as step 1 of example 117, using compound 144-2.
1H NMR (500 MHz, DMSO-d6, δ): 7.48 (d, J=8.9 Hz, 1H), 6.90 (d, J=8.9 Hz, 1H), 3.95 (s, 3H), 2.97 (q, J=7.5 Hz, 2H), 1.34 (t, J=7.5 Hz, 3H);
ESIMS m/z: [M+H]+ 256.
Compound 144-3 (2.22 g, 8.70 mmol) was dissolved in toluene (40 mL), and aluminum chloride (2.32 g, 17.41 mmol) was added to the solution. The mixture was stirred at 80° C. for 1 hour. Water was added to the mixture, the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 144-4 (1.4 g, 67%). 1H NMR (500 MHz, CDCl3, 6): 7.46 (s, 1H), 7.31 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 3.00 (q, J=7.6 Hz, 2H), 1.45 (t, J=7.6 Hz, 3H);
ESIMS m/z: [M+H]+ 242.
Compound 144-5 (Li g, 49%) was obtained in the same manner as step 1 of example 3, using compound 144-4.
1H NMR (400 MHz, CDCl3, δ): 7.64-7.58 (m, 2H), 7.39 (d, J=8.6 Hz, 1H), 7.14-7.11 (m, 2H), 6.90-6.79 (m, 1H), 3.03-2.94 (m, 2H), 1.51-1.39 (m, 3H);
ESIMS m/z: [M+H]+ 386.
Compound 144-5 (1.0 g, 2.59 mmol) was dissolved in DMF (10 mL), and copper(I) cyanide (0.450 g, 5.18 mmol) was added to the solution. The mixture was stirred at 120° C. for 2 hours using a micro-wave reaction apparatus. After concentrated under reduced pressure, the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate=97/3) to obtain compound 144-6 (0.3 g, 35%).
1H NMR (400 MHz, CDCl3, δ): 7.69 (d, J=8.6 Hz, 2H), 7.54-7.50 (m, 1H), 7.23 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 1H), 3.07-3.01 (m, 2H), 1.50-1.46 (m, 3H);
ESIMS m/z: [M+H]+ 333.
Compound 144-7 (0.3 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 144-6, and used as it is in the next reaction.
1H NMR (400 MHz, DMSO-d6, δ): 7.71 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.3 Hz, 1H), 7.11-7.07 (m, 3H), 3.99 (br, 2H), 2.94 (q, J=7.6 Hz, 2H), 1.31-1.26 (m, 3H);
ESIMS m/z: [M+H]+ 337.
Compound 244 (0.080 g, 23% over two steps) was obtained in the same manner as step 5 of example 1, using compound 144-7.
1H NMR (400 MHz, DMSO-d6, δ): 8.72 (t, J=5.5 Hz, 1H), 7.72 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.3 Hz, 1H), 7.13-7.09 (m, 3H), 6.34-6.27 (m, 1H), 6.17-6.12 (m, 1H), 5.65 (dd, J=10.3, 2.2 Hz, 1H), 4.62 (d, J=5.9 Hz, 2H), 2.94 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.6 Hz, 3H);
ESIMS m/z: [M+H]+ 391.
Compound 145-1 (5.4 g) was obtained as a crude product in the same manner as step 1 of example 144, using 2-amino-3-methoxyphenol and isobutyric anhydride, and used as it is in the next reaction.
1H NMR (500 MHz, CDCl3, δ): 10.09 (br, 1H), 7.93 (br, 1H), 7.05-7.02 (m, 1H), 6.66-6.61 (m, 1H), 6.47-6.45 (m, 1H), 3.87 (s, 3H), 2.73-2.67 (m, 1H), 1.35 (d, J=7.5 Hz, 6H);
ESIMS m/z: [M+H]+ 210.
Compound 145-2 (4.1 g, 74% over two steps) was obtained in the same manner as step 2 of example 144, using compound 1454.
1H NMR (500 MHz, CDCl3, δ): 7.22 (t, J=8.3 Hz, 1H), 7.10 (dd, J=8.5, 1.0 Hz, 1H), 6.77-6.75 (m, 1H), 4.01 (s, 3H), 3.26-3.21 (m, 1H), 1.45 (d, J=7.0 Hz, 6H);
ESIMS m/z: [M+H]+ 192.
Compound 145-3 (4.1 g, 71%) was obtained in the same manner as step 1 of example 117, using compound 145-2.
1H NMR (400 MHz, CDCl3, δ): 7.34 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 4.00 (s, 3H), 3.31-3.24 (m, 1H), 1.48 (d, J=7.09 Hz, 6H);
ESIMS m/z: [M+H]+ 270.
Compound 145-4 (3.6 g, 92%) was obtained in the same manner as step 4 of example 144, using compound 145-3.
1H NMR (500 MHz, CDCl3, δ): 7.30 (d, J=8.5 Hz, 1H), 7.22 (s, 1H), 6.75 (d, J=8.9 Hz, 1H) 3.31-3.26 (m, 1H), 1.46 (d, J=7.0 Hz, 6H);
ESIMS m/z: [M+H]+ 256.
Compound 145-5 (4.0 g, 71%) was obtained in the same manner as step 1 of example 3, using compound 145-4.
ESIMS m/z: [M+H]+ 400.
Compound 145-6 (0.8 g, 62%) was obtained in the same manner as step 6 of example 144, using compound 145-5.
ESIMS m/z: [M+H]+ 347.
Compound 145-7 (0.5 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 145-6, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 351.
Compound 245 (0.130 g, 24% over two steps) was obtained in the same manner as step 5 of example 1, using compound 145-7.
1H NMR (400 MHz, DMSO-d6, δ): 8.71 (t, J=5.6 Hz, 1H,), 7.72 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.3 Hz, 1H), 7.15-7.06 (m, 3H), 6.34-6.27 (m, 1H), 6.15 (dd, J=17.2, 2.4 Hz, 1H), 5.64 (dd, J=10.0, 2.2 Hz, 1H), 4.63 (d, J=5.9 Hz, 2H), 3.29-3.21 (m, 1H), 1.34 (d, J=6.9 Hz, 6H);
ESIMS m/z: [M+H]+ 405.
Compound 146-1 (7.0 g) was obtained as a crude product in the same manner as step 1 of example 144, using 2-amino-3-methoxyphenol and benzoic anhydride, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 244.
Compound 146-2 (3.8 g, 78% over two steps) was obtained in the same manner as step 2 of example 144, using compound 146-1.
1H NMR (400 MHz, CDCl3, δ): 8.31-8.29 (m, 2H), 7.53-7.49 (m, 3H), 7.31-7.27 (m, 1H), 7.21 (dd, J=8.0, 0.8 Hz, 1H), 6.82 (dd, J=8.1, 0.7 Hz, 1H), 4.08 (s, 3H);
ESIMS m/z: [M+H]+ 226.
Compound 146-3 (3.5 g, 68%) was obtained in the same manner as step 1 of example 117, using compound 146-2.
1H NMR (500 MHz, CDCl3, δ): 8.32-8.30 (m, 2H), 7.54-7.50 (m, 3H), 7.39 (d, J=8.5 Hz, 1H), 6.73 (d, J=8.9 Hz, 1H), 4.06 (s, 3H);
ESIMS m/z: [M+H]+ 304.
Compound 146-4 (3.3 g, quantitatively) was obtained in the same manner as step 4 of example 144, using compound 146-3.
1H NMR (400 MHz, CDCl3, δ): 8.24 (d, J=8.1 Hz, 2H), 7.57-7.51 (m, 3H), 7.36 (d, J=8.6 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 2.78 (s, 1H);
ESIMS m/z: [M+H]+ 290.
Compound 146-5 (3.5 g, 14%) was obtained in the same manner as step 1 of example 3, using compound 146-4.
ESIMS m/z: [M+H]+ 434.
Compound 146-6 (0.7 g, 57%) was obtained in the same manner as step 6 of example 144, using compound 146-5.
1H NMR (500 MHz, CDCl3, δ): 8.32-8.30 (m, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.63-7.49 (m, 5H), 7.29 (d, J=8.5 Hz, 2H);
ESIMS m/z: [M+H]+ 381.
Compound 146-7 (0.5 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 146-6, and used as it is in the next reaction.
1H NMR (400 MHz, DMSO-d6, δ): 8.19-8.17 (m, 2H), 7.75-7.68 (m, 2H), 7.64-7.57 (m, 4H), 7.51-7.45 (m, 2H), 7.19-7.11 (m, 3H), 4.09 (s, 2H).
Compound 246 (0.115 g, 20% over two steps) was obtained in the same manner as step 5 of example 1, using compound 146-7.
1H NMR (400 MHz, CD3OD, δ): 8.24-8.22 (m, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.62-7.53 (m, 3H), 7.37 (d, J=7.8 Hz, 1H), 7.18 (d, I=8.8 Hz, 2H), 7.05 (d, J=8.3 Hz, 1H), 6.33-6.31 (m, 2H), 5.73-5.70 (m, 1H), 4.83 (s, 2H);
ESIMS m/z: [M+H]+ 439.
Ortho-methyl formate (5.24 mL, 48 mmol) was added to 2-aminobenzene-1,3-diol (4.0 g, 32.0 mmol), and the mixture was stirred at 130° C. for 2 hours. After concentrated under reduced pressure, the mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate=76/24) to obtain compound 147-1 (3.5 g, 81%).
1H NMR (400 MHz, DMSO-d6, δ): 10.33 (s, 1H), 8.56 (s, 1H), 7.23-7.14 (m, 2H), 6.77 (d, J=8.1 Hz, 1H);
ESIMS m/z: [M+H]+ 136.
Compound 147-1 (3.5 g, 25.92 mmol) was dissolved in acetonitrile (70 mL). Methyl iodide (1.64 mL, 25.92 mmol) and potassium carbonate (10.73 g, 77.78 mmol) were added to the solution, and the mixture was stirred at 80° C. for 16 hours. Water was added to the mixture and the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=90/10) to obtain compound 147-2 (2.8 g, 72%).
1H NMR (500 MHz, DMSO-d6, δ): 8.62 (s, 1H), 7.38-7.32 (m, 2H), 6.95 (dd, J=7.8, 1.1 Hz, 1H,), 3.98 (s, 3H);
ESIMS m/z: [M+H]+ 150.
Compound 147-3 (1.5 g, 35%) was obtained in the same manner as step 1 of example 117, using compound 147-2.
1H NMR (500 MHz, CDCl3, δ): 8.06 (s, 1H), 7.45 (d, J=8.9 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 4.05 (s, 3H);
ESIMS m/z: [M+H]+ 228.
Compound 147-4 (1.0 g, 71%) was obtained in the same manner as step 4 of example 144, using compound 147-3.
1H NMR (400 MHz, DMSO-d6, δ): 10.66 (s, 1H), 8.68 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H);
ESIMS m/z: [M+H]+ 214.
Compound 147-5 (0.3 g, 18%) was obtained in the same manner as step 1 of example 3, using compound 147-4.
1H NMR (400 MHz, CDCl3, δ): 8.11 (s, 1H), 7.61 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.3 Hz, 1H), 7.13 (d, J=8.3 Hz, 2H), 6.93 (d, J=8.8 Hz, 1H);
ESIMS m/z: [M+H]+ 358.
Compound 147-6 (0.2 g, 78%) was obtained in the same manner as step 6 of example 144, using compound 147-5.
1H NMR (400 MHz, CDCl3, δ): 8.19 (s, 1H), 7.68 (dd, J=15.9, 8.6 Hz, 3H), 7.24 (d, J=7.6 Hz, 2H), 6.93 (d, J=8.6 Hz, 1H).
Compound 147-6 (0.200 g, 0.65 mmol) was dissolved in methanol (5 mL), and nickel(II) chloride hexahydrate (0.015 g, 0.06 mmol) was added to the solution under ice cooling. The mixture was stirred at 0° C. for 10 minutes. Sodium borohydride (0.174 g, 4.60 mmol) was added to the mixture. The mixture was further stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain compound 147-7 (0.200 g) as a crude product, which was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 309.
Compound 247 (0.015 g, 6% over two steps) was obtained in the same manner as step 5 of example 1, using compound 147-7.
1H NMR (500 MHz, CDCl3, δ): 8.77 (s, 1H), 8.74 (t, J=5.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.2 Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.14 (d, J=8.5 Hz, 2H), 6.32-6.27 (m, 1H), 6.15 (dd, J=17.1, 2.1 Hz, 1H), 5.65 (dd, J=10.4, 2.1 Hz, 1H), 4.65 (d, J=5.8 Hz, 2H);
ESIMS m/z: [M+H]+ 363.
Compound 1484 (7.0 g) was obtained as a crude product in the same manner as step 1 of example 144, using 2-amino-3-methoxyphenol and anhydrous trifluoroacetic acid, and used as it is in the next reaction.
1H NMR (400 MHz, CDCl3, δ): 8.71 (br, 1H), 7.17 (t, J=8.4 Hz, 1H), 6.70 (d, J=8.6 Hz, 1H), 6.51 (d, J=8.1 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 1H);
ESIMS m/z: [M+H]+ 236.
Compound 148-2 (4.0 g, 51% over two steps) was obtained in the same manner as step 2 of example 144, using compound 148-1.
1H NMR (400 MHz, CDCl3, δ): 7.46 (t, J=8.3 Hz, 1H), 7.24 (s, 1H), 6.90 (d, J=8.3 Hz, 1H), 4.07 (s, 3H);
ESIMS m/z: [M+H]+ 218.
Compound 148-3 (3.5 g, 64%) was obtained in the same manner as step 1 of example 117, using compound 148-2.
1H NMR (500 MHz, CDCl3, δ): 7.58 (d, J=8.9 Hz, 1H,), 6.83 (d, J=8.9 Hz, 1H), 4.07 (s, 3H);
ESIMS m/z: [M+H]+ 296.
Compound 148-4 (2.3 g, 69%) was obtained in the same manner as step 4 of example 144, using compound 148-3.
1H NMR (400 MHz, CDCl3, δ): 7.54 (d, J=8.8 Hz, 1H), 6.91 (d, J=8.8 Hz, 1H), 6.58 (br, 1H);
ESIMS m/z: [M+H]+ 282.
Compound 148-5 (1.05 g, 30%) was obtained in the same manner as step 1 of example 3, using compound 148-4.
ESIMS m/z: [M+H]+ 426.
Compound 148-6 (0.200 g, 30%) was obtained in the same manner as step 6 of example 144, using compound 148-5.
1H NMR (400 MHz, DMSO-d6, δ): 8.19 (d, J=8.8 Hz, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.8 Hz, 1H).
Compound 148-6 (0.20 g, 0.54 mmol) was dissolved in THF (6 mL), and triethylamine (0.14 mL, 1.07 mmol) and Raney nickel (200 mg) were added to the solution. The mixture was stirred under hydrogen atmosphere at room temperature for 1 hour.
After completion of the reaction, the reaction vessel was substituted with Ar, THF (2 mL) solution of acryloyl chloride (0.034 mL, 0.43 mmol) was added to the mixture under ice cooling, and the mixture was stirred at 0° C. for 1 hour. Ethyl acetate was added to the mixture, and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a preparative HPLC (ammonium bicarbonate aqueous solution) to obtain compound 284 (0.040 g, 17%).
1H NMR (400 MHz, DMSO-d6, δ): 8.80 (t, J=5.7 Hz, 1H), 7.76 (d, J=8.9 Hz, 2H), 7.56 (d, J=8.2 Hz, 1H), 7.30-7. 23 (m, 3H), 6.32-6.27 (m, 1H), 6.17-6.13 (m, 1H), 5.66 (dd, J=10.4, 2.1 Hz, 1H),4.67 (d, J=5.5 Hz, 2H);
ESIMS m/z: [M+H]+ 431.
Compound 143-4 (1,0 g, 4.38 mmol) was dissolved in DMF (5 mL), and cesium carbonate (2.86 g, 8.77 mmol) and 5-bromo-2-(trifluoromethyl)pyridine (1.98 g, 8.77 mmol) were added to the solution. The mixture was stirred at 140° C. for 1.5 hours using a micro-wave reaction apparatus. The mixture was left to cool to room temperature, and water and ethyl acetate were added to the mixture. The mixture was filtered with Celite(R). The filtrate was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=90/10) to obtain compound 149-1 (0.45 g, 27%).
1H NMR (400 MHz, CDCl3, δ): 8.51 (d, J=2.7 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.38 (dd, J=8.6, 2.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 2.67 (s, 3H);
ESIMS m/z: [M+H]+ 373.
Compound 149-2 (0.14 g, 36%) was obtained in the same manner as step 6 of example 144, using compound 149-1.
1H NMR (400 MHz, CDCl3, δ): 8.56 (d, J=2.7 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.53 (dd, J=8.6, 2.9 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H), 2.71 (s, 3H);
ESIMS m/z: [M+H]+ 320.
Compound 249 (0.080 g, 24% over two steps) was obtained in the same manner as step 7 of example 148, using compound 149-2.
1H NMR (400 MHz, DMSO-d6, δ): 8.74-8.71 (m, 1H), 8.56 (d, J=2.9 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.48 (dd, J=8.8, 2.5 Hz, 1H), 7.31 (d, J=8.3 Hz, 1H), 7.22-7.20 (m, 1H), 6.34 -6.27 (m, 1H), 6.15 (dd, J=17.2, 2.4 Hz, 1H), 5.65 (dd, J=10.3, 2.0 Hz, 1H), 4.62 (d, J=5.9 Hz, 2H), 2.6 (s, 3H);
ESIMS m/z: [M+H]+ 378.
Compound 143-4 (0.95 g, 4.16 mmol) was dissolved in DMF (15 mL), and cesium carbonate (2.72 g, 8.33 mmol) and
2-chloro-5-(trifluoromethyl)pyridine (1.51 g, 8.33 mmol) were added to the solution. The mixture was stirred at 100° C. for 2 hours. The mixture was left to cool to room temperature, and water and ethyl acetate were added to the mixture. The mixture was filtered with Celite(R). The filtrate was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=90/10) to obtain compound 150-1 (1.1 g, 71%).
1H NMR (500 MHz, CDCl3, δ): 8.364-8.360 (m, 1H), 7.96-7.94 (m, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.19 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 2.64 (s, 3H); ESIMS m/z: [M+H]+ 373.
Compound 150-2 (0.26 g, 28%) was obtained in the same manner as step 6 of example 144, using compound 150-1.
1H NMR (400 MHz, CDCl3, δ): 8.37 (s, 1H), 8.00 (dd, J=8.8, 2.5 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 2H), 2.67 (s, 3H);
ESIMS m/z: [M+H]+ 320.
Compound 250 (0.080 g, 32% over two steps) was obtained in the same manner as step 7 of example 148, using compound 150-2.
1H NMR (400 MHz, DMSO-d6, δ): 8.8 (m, 1H), 8.5 (s, 1H), 8.26 (dd, J=8.8, 2.5 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.34-6.27 (m, 1H), 6.15 (dd, J=17.2, 2.0 Hz, 1H), 5.64 (dd, J=10.0, 2.2 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.57 (s, 3H);
ESIMS m/z: [M+H]+ 378.
Compound 151-1 (0.65 g, 41%) was obtained in the same manner as step 1 of example 150, using compound 144-4 and 5-bromo-2-(trifluoromethyl)pyridine.
ESIMS m/z: [M+H]+ 387.
Compound 151-2 (0.20 g, 39%) was obtained in the same manner as step 6 of example 144, using compound 151-1.
ESIMS m/z: [M+H]+ 334.
Compound 251 (0.040 g, 14% over two steps) was obtained in the same manner as step 7 of example 148, using compound 151-2.
1H NMR (500 MHz, DMSO-d6, δ): 8.73 (t, J=5.5 Hz, 1H), 8.59 (d, J=3.1 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.50 (dd, J=8.5, 2.8 Hz, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.19-7.16 (m, 1H), 6.33-6.28 (m, 1H), 6.15 (dd, J=17.1, 2.1 Hz, 1H), 5.65 (dd, J=10.2, 2.0 Hz, 1H), 4.62 (d, J=5.4 Hz, 2H), 2.94 (q, J=7.5 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H);
ESIMS m/z: [M+H] 392.
Compound 152-1 (3.0 g, 63%) was obtained in the same manner as step 1 of example 150, using compound 144-4 and 2-chloro-5-(trifluoromethyl)pyridine.
1H NMR (500 MHz, CDCl3, δ): 8.367-8.365 (m, 1H), 7.96-7.93 (m, 1H), 7.47 (d, J=8.8 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.05 (d, J=8.4 Hz, 1H), 2.96 (q, J=7.6 Hz, 2H),1.41 (t, J=7.6 Hz, 3H);
ESIMS m/z: [M+H]+ 387.
Compound 152-2 (0.55 g, 43%) was obtained in the same manner as step 6 of example 144, using compound 152-1.
1H NMR (400 MHz, CDCl3, δ): 8.379-8.374 (m, 1H), 8.01(dd, J=8.75, 2.25 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.26-7.23 (m, 2H), 2.99 (q, J=7.5 Hz, 2H), 1.42 (t, J=7.5 Hz, 3H);
ESIMS m/z: [M+H]+ 334.
Compound 252 (0.11 g, 17% over two steps) was obtained in the same manner as step 7 of example 148, using compound 152-2.
1H NMR (400 MHz, DMSO-d6, δ): 8.74 (t, J=5.6 Hz, 1H), 8.50 (d, J=1.0 Hz, 1H), 8.26 (dd, J=8.8, 2.5 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.34-6.27 (m, 1H), 6.15 (dd, J=17.6, 2.0 Hz, 1H), 5.64 (dd, J=10.2, 2.0 Hz, 1H), 4.61 (d, J=5.4 Hz, 2H), 2.91 (q, J=7.34 Hz, 2H), 1.27 (t, J=7.4 Hz, 3H);
ESIMS m/z: [M+H]+ 392.
Compound 153-1 (1.4 g) was obtained as a crude product in the same manner as step 1 of example 147, using 3-aminobenzene-1,2-diol, and used as it is in the next reaction.
1H NMR (400 MHz, CDCl3, δ): 7.24 (d, J=8.1 Hz, 1H), 7.16 (t, J=8.0 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 5.67 (br, 1H), 2.65 (s, 3H);
ESIMS m/z: [M+H]+ 150.
Compound 153-2 (1.0 g, 77% over two steps) was obtained in the same manner as step 2 of example 147, using compound 153-1.
1H NMR (400 MHz, CDCl3, δ): 7.27 (br, 1H), 7.24-7.20 (m, 1H), 6.83 (dd, J=7.8, 1.2 Hz, 1H), 4.02 (s, 3H), 2.65 (s, 3H);
ESIMS m/z: [M+H]+ 164.
Compound 153-3 (1.2 g, 81%) was obtained in the same manner as step 1 of example 117, using compound 153-2.
1H NMR (400 MHz, CDCl3, δ): 7.38 (d, J=8.8 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 4.00 (s, 3H), 2.68 (s, 3H);
ESIMS m/z: [M+H]+ 242.
Compound 153-4 (1.0 g, 88%) was obtained in the same manner as step 4 of example 144, using compound 153-3.
1H NMR (400 MHz, CDCl3, δ): 8.77 (s, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.8 Hz, 1H), 2.71 (s, 3H);
ESIMS m/z: [M+H]+ 228.
Compound 153-5 (1.0 g, 61%) was obtained in the same manner as step 1 of example 3, using compound 153-4.
1H NMR (400 MHz, CDCl3, δ): 7.61 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.6 Hz, 1H), 7.08 (d, J=8.3 Hz, 2H), 6.91 (d, J=8.6 Hz, 1H), 2.66 (s, 3H);
ESIMS m/z: [M+H]+ 372.
Compound 153-6 (0.5 g) was obtained as a crude product in the same manner as step 6 of example 144, using compound 153-5, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 319.
Compound 153-7 (0.5 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 153-6, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 323.
Compound 253 (0.080 g, 8% over three steps) was obtained in the same manner as step 5 of example 1, using compound 153-7.
1H NMR (500 MHz, DMSO-d6, δ): 8.69 (t, J=5.7 Hz, 1H), 7.74 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.16 (dd, J=8.4, 2.6 Hz, 3H), 6.34-6.29 (m, 1H), 6.14 (dd, J=17.1, 2.1 Hz, 1H), 5.63 (dd, J=10.5, 2.5 Hz, 1H), 4.65 (d, J=5.8 Hz, 2H), 2.61 (s, 3H);
ESIMS m/z: [M+H]+ 377.
2-Aminobenzene-1,3-diol (0.50 g, 4.00 mmol) was dissolved in the mixed solvent of dichloromethane (5 mL) and THF (5 mL), and ethyl 2-chloroacetimidate hydrochloride (0.74 g, 4.00 mmol) was added to the solution under ice cooling. The mixture was stirred at room temperature for 16 hours. Water was added to the mixture, and the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 154-1 (0.40 g, 54%).
1H NMR (400 MHz, CDCl3, δ): 8.16 (s, 1H), 7.30 (t, J=16.4 Hz, 1H), 7.12 (dd, J=8.4, 0.8 Hz, 1H), 6.91 (dd, J=8.4, 0.8 Hz, 1H), 4.82 (s, 2H),
Compound 154-2 (0.060 g, 34%) was obtained in the same manner as step 1 of example 3, using compound 154-1.
1H NMR (400 MHz, CDCl3, δ): 7.61 (d, J=8.4 Hz, 2H), 7.38 (m, 2H), 7.14 (d, J=8.4 Hz, 2H), 6.95 (dd, J=7.6, 1.2 Hz,1H), 4.74 (s, 2H).
Compound 154-2 (0.30 g, 0.91 mmol) was dissolved in DMF (5 mL), and potassium carbonate (0.37 g, 2.75 mmol) and phthalimide potassium salt (0.20 g, 1.10 mmol) were added to the solution. The mixture was stirred at 100° C. for 30 minutes using a micro-wave reaction apparatus. The mixture was left to cool to room temperature and water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30−>50/50) to obtain compound 154-3 (0.40 g, 91%).
1H NMR (300 MHz, DMSO-d6, δ): 7.95-7.91 (m, 4H), 7.69 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.1 Hz, 1H), 5.13 (s, 2H).
Compound 154-3 (0.40 g, 0.91 mmol) was dissolved in methanol (10 mL), and hydrazine monohydrate (0.040 g, 0.91 mmol) was added to the solution. The mixture was stirred at room temperature for 30 minutes. After concentrated under reduced pressure, the mixture was purified by silica gel column chromatography (hexane/ethyl acetate=50/50−>30/70) to obtain compound 154-4 (0.25 g, 89%).
ESIMS m/z: [M+H]+ 309.
Compound 254 (0.045 g, 19%) was obtained in the same manner as step 1 of example 76, using compound 154-4.
1H NMR (300 MHz, DMSO-d6, δ): 8.91 (br, 1H), 7.72 (d, J=8.7 Hz, 2H), 7.65 (d, J=7.8 Hz, 1H), 7.45 (t, J=8.1 Hz, 1H), 7.16-7.13 (m, 3H), 6.29 (dd, J=17.4, 10.2 Hz, 1H), 6.13 (d, J=17.7 Hz, 1H), 5.66 (d, J=9.3 Hz, 1H), 4.63 (d, J=6.0 Hz, 2H);
ESIMS m/z: [M+H]+ 363.
Compound 155-1 (0.11 g, 93%) was obtained in the same manner as step 1 of example 154, using 2-aminobenzene-1,4-diol.
1H NMR (300 MHz, CDCl3, δ): 7.40 (d, J=8.7 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.92 (dd, J=8.7, 2.4 Hz, 1H), 5.24 (s, 1H), 4.72 (s, 2H).
Compound 155-2 (0.050 g, 35%) was obtained in the same manner as step 1 of example 3, using compound 155-1.
1H NMR (400 MHz, CDCl3, δ): 7.58-7.55 (m, 3H), 7.42 (d, J=2.4 Hz, 1H), 7.13 (dd, J=8.8, 2.4 Hz, 1H), 7.03 (d, J=8.8 Hz, 2H), 4.76 (s, 2H).
Compound 155-3 (0.80 g, 51%) was obtained in the same manner as step 3 of example 154, using compound 155-2.
ESIMS m/z: [M+H]+ 439.
Compound 155-4 (0.50 g, 89%) was obtained in the same manner as step 4 of example 154, using compound 155-3.
ESIMS m/z: [M+H]+ 309.
Compound 255 (0.10 g, 21%) was obtained in the same manner as step 1 of example 76, using compound 155-4.
1H NMR (400 MHz, CDCl3, δ): 7.58-7.51 (m, 3H), 7.37 (d, J=2.4 Hz, 1H), 7.08 (dd, J=8.8, 2.4 Hz, 1H), 7.02 (d, J=8.4 Hz, 2H), 6.42-6.38 (m, 2H), 6.23 (dd, J=17.2, 10.4 Hz, 1H), 5.76 (dd, J=10.4, 1.2 Hz, 1H), 4.83 (d, J=5.2 Hz, 2H);
ESIMS m/z: [M+H]+ 363.
N-(2-Methoxyphenyl)acetamide (10.0 g, 60.60 mmol) was dissolved in chlorobenzene (40 mL), and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (12.24 g, 30.30 mmol) was added to the solution. The mixture was stirred at 120° C. for 4 hours. The mixture was left to cool to room temperature, and was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>90/10) to obtain compound 156-1 (8.0 g, 72%).
1H NMR (500 MHz, CDCl3, δ): 9.12 (br, 1H), 7.21-7.17 (m, 1H), 7.03-6.93 (m, 3H), 3.91 (s, 3H), 2.77 (s, 3H).
Compound 156-1 (8.0 g, 44.19 mmol) was dissolved in water (480 mL). Potassium hydroxide (11.38 g, 203.27 mmol) and potassium ferricyanide (33.40 g, 101.65 mmol) were added to the solution, and the mixture was stirred at 100° C. for 4 hours. The mixture was left to cool to room temperature and water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0−>80/20) to obtain compound 156-2 (2.0 g, 25%).
1H NMR (400 MHz, CDCl3, δ): 7.40 (dd, J=8.0, 0.8 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 6.88 (dd, J=8.0, 0.4 Hz, 1H), 4.03 (s, 3H), 2.84 (s, 3H).
Compound 156-3 (1.20 g, 42%) was obtained in the same manner as step 1 of example 117, using compound 156-2.
1H NMR (400 MHz, CDCl3, δ): 7.40 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 4.02 (s, 3H), 2.84 (s, 3H).
Compound 156-4 (0.065 g, 69%) was obtained in the same manner as step 1 of example 19, using compound 156-3.
1H NMR (400 MHz, DMSO-d6, δ): 10.42 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 2.79 (s, 3H).
Compound 156-5 (0.050 g, 49%) was obtained in the same manner as step 1 of example 3, using compound 156-4.
1H NMR (400 MHz, DMSO-d6, δ): 7.60 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.8 Hz, 1H), 2.84 (s, 3H).
Compound 156-6 (0.220 g, 46%) was obtained in the same manner as step 1 of example 54, using compound 156-5.
1H NMR (400 MHz, CDCl3, δ): 7.69 (d, J=8.8 Hz, 2H), 7.62 (d, J=8.4 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 2.93 (s, 3H).
Compound 156-7 (0.03 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 156-6, and used as it is in the next reaction.
1H NMR (300 MHz, DMSO-d6, δ): 7.68 (d, J=7.8 Hz, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 3.97 (s, 2H), 2.72 (s, 3H).
Compound 256 (0.075 g, 37% over two steps) was obtained in the same manner as step 1 of example 76, using compound 156-7.
1H NMR (400 MHz, DMSO-d5, δ): 8.76 (br, 1H), 7.69 (d, J=8.4 Hz, 2H ), 7.39 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.4 Hz, 2H), 6.30 (dd, J=17.2, 10.0 Hz, 1H), 6.19-6.15 (m, 1H), 5.67 (dd, J=10.0, 1.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.75 (s, 3H);
ESIMS m/z: [M+]+ 393.
Step 1
N-(2-Bromo-5-methoxyphenyl)acetamide (6.0 g, 24.69 mmol) was dissolved in 1,4-dioxane (50 mL), and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (9.98 g, 24.69 mmol) was added to the solution. The mixture was stirred at 100° C. for 5 hours. The mixture was left to cool to room temperature and water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=90/10) to obtain compound 157-1 (4.0 g, 63%).
1H NMR (500 MHz, CDCl3, δ): 9.03-8.83 (m, 1H), 8.42 (d, J=3.1 Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 6.72 (dd, J=8.9, 3.1 Hz, 1H), 3.81 (s, 3H), 2.79 (s, 3H); ESIMS m/z: [M+]+ 260.
Compound 157-1 (4.0 g, 15.44 mmol) was dissolved in water (80 mL), and sodium hydroxide (12.35 g, 308.88 mmol) was added to the solution. The mixture was stirred at room temperature for 15 minutes. An aqueous solution (80 mL) of potassium ferricyanide (20.34 g, 61.77 mmol) was added dropwise to the mixture under ice cooling. The mixture was sirred at 0° C. for 2 hours. The mixture was filtered, and the residue obtained was washed with iced water, and dried under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase column chromatography [REVELERIS (R) C18 column, 40 μm silica, acetonitrile/water (65/35)] to obtain compound 157-2 (2.0 g, 50%).
1H NMR (400 MHz, CDCl3, δ): 7.56 (dd, J=8.6, 0.7 Hz, 1H), 6.69 (d, J=8.3 Hz, 1H), 3.96 (s, 3H), 2.88 (d, J=0.7 Hz, 3H);
ESIMS m/z: [M+H]+ 258.
Compound 157-3 (1.1 g, 58%) was obtained in the same manner as step 4 of example 144, using compound 157-2.
1H NMR (500 MHz, CDCl3, δ): 7.48 (d, J=8.2 Hz, 1H), 6.67 (d, J=8.5 Hz, 1H), 3.96 (s, 1H), 2.88 (d, J=6.0 Hz, 3H); ESIMS m/z: [M+H]+ 244.
Compound 157-4 (0.550 g, 32%) was obtained in the same manner as step 1 of example 3, using compound 157-3.
1H NMR (400 MHz, CDCl3, 6): 7.64-7.60 (m, 3H), 7.12-7.08 (m, 2H), 6.87 (d, J=8.0 Hz, 1H), 2.88 (d, J=6.0 Hz, 3H);
ESIMS m/z: [M+H]+ 388.
Compound 157-5 (0.220 g, 46%) was obtained in the same manner as step 6 of example 144, using compound 157-4.
1H NMR (400 MHz, CDCl3, δ): 7.73 (d, J=8.3 Hz, 1H), 7.70 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.3 Hz, 1H), 2.93 (s, 3H);
ESIMS m/z: [M+H]+ 335.
Compound 157-6 (0.200 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 157-5, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 339.
Compound 257 (0.064 g, 28% over two steps) was obtained in the same manner as step 5 of example 1, using compound 157-6.
1H NMR (500 MHz, DMSO-d6, δ): 8.67 (t, J=5.8 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.2 Hz, 1H), 7.18 (dd, J=11.9, 8.2 Hz, 3H), 6.34 (dd, J=17.1, 10.4 Hz, 1H), 6.14 (dd, J=17.2, 2.3 Hz, 1H), 5.63 (dd, J=10.2, 2.3 Hz, 1H), 4.81 (d, J=5.8 Hz, 2H), 2.83 (s, 3H);
ESIMS m/z: [M+H]+ 393.
To a methanol solution (4.9 mL) of 6-bromobenzo[b]thiophene-3(2H)-on-1,1-dioxide (128 mg, 0.49 mmol) obtained by a well-known method (WO2014/146493), sodium acetate (201 mg, 2.45 mmol) and hydroxylamine hydrochloride (170 mg, 2.45 mmol) were added at room temperature, and the mixture was refluxed for 1 hour. The mixture was left to cool to room temperature and water was added to the mixture. The organic layer was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 158-1 as a crude product, which was used as it is in the next reaction.
ESIMS m/z: [M−H]− 274, 276.
To a methanol solution (2.5 mL) of compound 158-1 (135 mg, 0.49 mmol), zinc powder (160 mg, 2.45 mmol) and an aqueous hydrochloric acid solution (6 mol/L, 1 mL) were added at room temperature, and the mixture was stirred at 60° C. for 2 hours. The mixture was cooled in ice bath, and then neutralized with an aqueous sodium hydrogen carbonate solution. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 158-2 as a crude product, which was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 262, 264.
Compound 158-3 (99 mg, 91% over three steps) was obtained in the same manner as step 3 of example 17, using compound 158-2.
1H-NMR (400 MHz, DMSO-d6, δ): 8.95 (d, J=7.7 Hz, 1H), 8.13 (d, J=1.8 Hz, 1H), 7.94 (dd, J=8.4, 2.0 Hz, 1H), 7.51 (d, J=8.2 Hz, 1H), 6.27 (dd, J=17.2, 9.5 Hz, 1H), 6.19 (dd, J=17.2, 2.7 Hz, 1H), 5.71 (dd, J=9.3, 2.9 Hz, 1H), 5.65 (q, J=6.9 Hz, 1H), 4.09 (dd, J=13.6, 7.7 Hz, 1H), 3.50 (dd, J=13.8, 5.7 Hz, 1H);
ESIMS m/z: [M−H]− 314, 316.
Compound 158-3 (34.0 mg, 0.108 mmol) was dissolved in 1,4-dioxane (1.0 mL), and 4-(trifluoromethyl)phenol (34.9 mg, 0.215 mmol), cesium carbonate (123 mg, 0.376 mmol), dimethylglycine (5.5 mg, 0.054 mmol) and copper(I) iodide (5.1 mg, 0.027 mmol) were added to the solution. The mixture was refluxed for 1 hour. The mixture was left to cool to room temperature, and a saturated ammonium chloride aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>50/50) to obtain a crude product. The crude product obtained was purified using a preparative HPLC [Waters Xbridge Prep C18 OBD column, 5 μm silica, diameter 19 mm, length 100 mm; acetonitrile/0.05% aqueous TFA solution (30/70−>40/60)] to obtain compound 258 (11 mg, 26%).
1H-NMR (400 MHz, CDCl3, δ): 7.65 (d, J=8,2 Hz, 2H), 7.57 (d, J=7.7 Hz, 1H), 7.32-7.29 (m, 2H), 7.12 (d, J=8.2 Hz, 2H), 6.37 (d, J=16.8 Hz, 1H), 6.25-6.22 (m, 1H), 6.07 (dd, J=17.0, 10.6 Hz, 1H), 5.92-5.90 (m, 1H), 5.75 (d, J=10.0 Hz, 1H), 3.85 (dd, J=14.3, 7.5 Hz, 1H), 3.44 (dd, J=14.0, 2.7 Hz, 1H);
ESIMS m/z: [M−H]− 396.
7-Chloro-2,3-dihydro-4H-pyrano[2,3-b]pyridin-4-one (130 mg, 0.708 mmol) obtained by a well-known method (Bioorganic & Medicinal Chemistry Letters, 2011, 21, 1402.) was dissolved in DMF (0.7 mL), and 4-(trifluoromethyl)phenol (115 mg, 0.708 mmol), triethylamine (0.148 mL, 1.06 mmol) and 1,4-diazabicyclo[2,2,2]octane (15.9 mg, 0.142 mmol) were added to the solution at room temperature. The mixture was stirred for 3 hours. Saturated saline was added to the mixture. The organic layer was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=95/5−>65/35) to obtain compound 159-1 (150 mg, 69%).
1H-NMR (400 MHz, CDCl3, δ) 8.29 (d, J=8.6 Hz, 1H), 7.69 (d, J=9.1 Hz, 2H), 7.28 (d, J=8.2 Hz, 2H), 6.72 (d, J=8.2 Hz, 1H), 4.60 (t, J=6.6 Hz, 2H), 2.80 (t, J=6.3 Hz, 2H);
ESIMS m/z: [M+H]+ 310.
Compound 159-1 (126 mg, 0.407 mmol) was dissolved in methanol (8.0 mL), and ammonium acetate (314 mg, 4.07 mmol) and sodium cyanoborohydride (51.2 mg, 0.814 mmol) were added to the solution at room temperature. The mixture was refluxed overnight. The mixture was left to cool to room temperature and a saturated sodium bicarbonate aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 159-2 as a crude product, which was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 311.
Compound 259 (51 mg, 36% over two steps) was obtained in the same manner as step 3 of example 17, using compound 159-2.
1H-NMR (400 MHz, CDCl3, δ): 7.66-7.61 (m, 3H), 7.22 (d, J=8.6 Hz, 2H), 6.60 (d, J=7.7 Hz, 1H), 6.38 (d, J=16.8 Hz, 1H), 6.10 (dd, J=16.8, 9.5 Hz, 1H), 5.78-5.72 (m, 2H), 5.29-5.24 (m, 1H), 4.42-4.36 (m, 1H), 4.32-4.26 (m, 1H), 2.28-2.20 (m, 1H), 2.13-2.05 (m, 1H);
ESIMS m/z: [M+H]+ 365.
Commercially available 6-bromo-2-hydroxy-3-methoxybenzaldehyde (0.50 g, 2.16 mmol) was dissolved in methanol (21.6 mL), and 2-(methylamino)ethan-1-ol (0.24 g, 3.25 mmol) and acetic acid (0.012 mL, 0.22 mmol) were added to the solution. The mixture was stirred at 50° C. for 1.5 hours. The mixture was cooled to room temperature, and sodium borohydride (0.25 g, 6.49 mmol) was added to the mixture. The mixture was stirred for 30 minutes. The mixture was concentrated under reduced pressure, and a saturated sodium bicarbonate aqueous solution was added to the residue. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 160-1 (0.62 g) as a crude product, which was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 290.
Compound 160-1 and triphenylphosphine (0.85 g, 3.25 mmol) were dissolved in THF (21 mL), and the solution was cooled to 0° C. Diisopropyl azodicarboxylate (0.63 mL, 3.25 mmol) was added to the solution, and the solution was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, and a 2 mol/L aqueous hydrochloric acid solution was added to the residue. The mixture was washed with ethyl acetate. A 4 mol/L aqueous sodium hydroxide solution was added to the aqueous layer, and the organic layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain compound 160-2 (93.0 mg, 98% over two steps).
1H-NMR (400 MHz, CDCl3, δ): 7.23 (d, J=9.0 Hz, 1H), 6.70 (d, J=9.0 Hz, 1H), 4.14-4.13 (m, 2H), 4.07 (s, 2H), 3.84 (s, 3H), 3.04-3.03 (m, 2H), 2.44 (s, 3H); ESIMS m/z: [M+H]30 272.
Compound 160-3 (285 mg) was obtained as a crude product in the same manner as step 1 of example 19, using compound 160-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 258.
Compound 160-3 (50.0 mg, 0.15 mmol) was dissolved in DMA (1 mL), and cesium carbonate (144 mg, 0.44 mmol) and 1-fluoro-4-(trifluoromethyl)benzene were added to the solution. The mixture was stirred at 120° C. overnight. Water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0−>95/5) to obtain compound 160-4 (31.1 mg, 21% over two steps).
1H-NMR (400 MHz, CDCl3, δ): 7.54 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5 Hz, 1H), 4.08 (s, 2H), 3.93-3.92 (m, 2H), 2.96-2.95 (m, 2H), 2.46 (s, 3H);
ESIMS m/z: [M+H]+ 402.
Compound 160-5 (16.3 mg, 61%) was obtained in the same manner as step 1 of example 54, using compound 160-4.
1H-NMR (400 MHz, CDCl3, δ): 7.60 (d, J=8.5 Hz, 2H), 7.39 (d, J=8.1 Hz, 1H), 7.02 (d, J=8.1 Hz, 3H), 4.05 (s, 2H), 3.96-3.94 (m, 2H), 3.01-2.99 (m, 2H), 2.49 (s, 3H);
ESIMS m/z: [M+H]+ 349.
Compound 160-6 was obtained as a crude product in the same manner as step 1 of example 86, using compound 160-5, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 353.
Compound 260 (2.2 mg, 12% over two steps) was obtained in the same manner as step 1 of example 76, using compound 160-6.
1H-NMR (400 MHz, CDCl3, δ): 7.54 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.1 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 6.96 (d, J=8.5 Hz, 2H), 6.37 (dd, J=16.8, 1.6 Hz, 1H), 6.15 (dd, J=16.6, 10.3 Hz, 1H), 6.09 (br, 1H), 5.70 (dd, J=10.3, 1.3 Hz, 1H), 4.57 (d, J=4.9 Hz, 2H), 3.90-3.89 (m, 2H), 3.71 (s, 2H), 2.90-2.88 (m, 2H), 2.44 (s, 3H);
ESIMS m/z: [M+H]+ 407.
3-{4-(trifluoromethyl)phenoxy}phenol (300 mg, 1.18 mmol) obtained by a well-known method (Bioorganic & Medicinal Chemistry Letters, 2015, 23, 3322.) was dissolved in acetone (8.0 mL), and potassium carbonate (489 mg, 3.54 mmol) and ethyl 4-bromobutyrate (0.20 mL, 1.42 mmol) were added to the solution at room temperature. The mixture was refluxed for 2 hours. The reaction mixture was left to cool to room temperature and water was added to the mixture. The organic layer was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=95/5−>80/20) to obtain compound 161-1 (320 mg, 74%).
1H-NMR (400 MHz, CDCl3, δ): 7.57 (d, J=9.1 Hz, 2H), 7.26 (t, J=8.4 Hz, 1H), 7.06 (d, J=8.6 Hz, 2H), 6.71 (dd, J=7.9, 2.0 Hz, 1H), 6.63 (dd, J=7.9, 2.0 Hz, 1H), 6.58-6.58 (m, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.98 (t, J=5.9 Hz, 2H), 2.51 (t, J=7.2 Hz, 2H), 2.14-2.07 (m, 2H), 1.25 (t, J=7.2 Hz, 3H).
Compound 161-1 (320 mg, 0.869 mmol) was dissolved in a mixed solvent of tetrahydrofuran (0.87 mL), distilled water (0.43 mL) and ethanol (0.87 mL). Lithium hydroxide monohydrate (72.9 mg, 1.74 mmol) was added to the solution at room temperature. The mixture was stirred for 2 hours. The mixture was concentrated under reduced pressure. A 2 mol/L hydrochloric acid aqueous solution was added to the residue obtained while the residue was cooled in ice bath. The solid was filtered off, washed with water, and dried under reduced pressure to obtain compound 161-2 (254 mg, 86%).
1H-NMR (400MHz, DMSO-d6, δ): 7.74 (d, J=9.1 Hz, 2H), 7.35 (t, J=8.4 Hz, 1H), 7.15 (d, J=9.1 Hz, 2H), 6.82 (dd, J=8.2, 2.3 Hz, 1H), 6.71 (t, J=2.3 Hz, 1H), 6.67 (dd, J=7.7, 2.3 Hz, 1H), 3.98 (t, J=6.6 Hz, 2H), 2.37 (t, J=7.2 Hz, 2H), 1.95-1.88 (m, 2H);
ESIMS m/z: [M−H]− 339.
To compound 161-2 (120 mg, 0.353 mmol), Eaton's reagent (phosphorus pentoxide/methanesulfonic acid, CAS No: 39394-84-8) (0.3 mL) was added dropwise at room temperature. The mixture was stirred at 80° C. for 1 hour. The mixture was left to cool to room temperature and added dropwise in iced water. The organic layer was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=95/5−>70/30) to obtain compound 161-3 (85 mg, 75%).
1H-NMR (400 MHz, CDCl3, δ): 7.81 (d, J=9.1 Hz, 1H), 7.65 (d, J=9.5 Hz, 2H), 7.15 (d, J=8.6 Hz, 2H), 6.75 (dd, J=8.6, 2.3 Hz, 1H), 6.66 (d, J=2.3 Hz, 1H), 4.25 (t, J=6.6 Hz, 2H), 2.90 (t, J=7.0 Hz, 2H), 2.26-2.19 (m, 2H).
Compound 161-4 was obtained as a crude product in the same manner as step 2 of example 159, using compound 161-3, and used as it is in the next reaction.
ESIMS m/z: [M−H]− 322.
Compound 261 (11 mg, 12% over two steps) was obtained in the same manner as step 3 of example 17, using compound 161-4.
1H-NMR (400 MHz, CDCl3, δ): 7.59 (d, J=7.7 Hz, 2H), 7.28-7.25 (m, 1H), 7.07 (d, J=8.6 Hz, 2H), 6.74-6.71 (m, 2H), 6.32 (dd, J=17.4, 1.6 Hz, 1H), 6.25 (br, 1H), 6.12 (dd, J=16.5, 10.2 Hz, 1H), 5.67 (dd, J=10.2, 1.6 Hz, 1H), 5.35-5.31 (m, 1H), 4.41-4.36 (m, 1H), 3.75 (m, 1H), 2.28-2.23 (m, 2H), 1.91-1.74 (m, 2H);
ESIMS m/z: [M+H]+ 378.
Compound 162-1 was obtained as a crude product in the same manner as step 1 of example 158, using commercially available 5-bromobenzofuran-3(2H)-one (200 mg, 0.94 mmol), and was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 228, 230.
Compound 162-2 was obtained as a crude product in the same manner as step 2 of example 158, using compound 162-1, and used as it is in the next reaction.
Compound 162-3 (75 mg, 30% over three steps) was obtained in the same manner as step 3 of example 17, using compound 162-2.
1H-NMR (400 MHz, CDCl3, δ): 7.45 (d, J=2.3 Hz, 1H), 7.35 (dd, J=8.4, 2.0 Hz, 1H), 6.76 (d, J=8.2 Hz, 1H), 6.35 (d, J=17.0 Hz, 1H), 6.07 (dd, J=16.8, 10.0 Hz, 1H), 5.82 (br, 1H), 5.73 (d, J=10.2 Hz, 1H), 5.69-5.67 (m, 1H), 4.76 (dd, J=10.2, 7.9 Hz, 1H), 4.39 (dd, J=10.2, 4.3 Hz, 1H);
ESIMS m/z: [M−H]− 266, 268.
Compound 162-3 (75 mg, 0.280 mmol) was dissolved in DMF (1.1 mL), and potassium acetate (96 mg, 0.979 mmol), bis(pinacolato)diboron (213 mg, 0.839 mmol) and {1,1′-bis(diphenylphosphino)ferrocene}palladium(II)dichloride dichloromethane adduct (22.8 mg, 0.028 mmol) were added to the solution at room temperature. The mixture was stirred under Ar atmosphere at 80° C. for 2 hours. The mixture was left to cool to room temperature and water was added to the mixture. The organic layer was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>30/70) to obtain compound 162-4 as a crude product, which was used as it is in the next reaction.
ESIMS m/z: [M+H]+ 316.
Compound 162-4 was dissolved in THF (0.300 mL), and an aqueous hydrogen peroxide solution (30%, 0.113 mL) was added dropwise to the solution at 0° C. The temperature of the mixture was raised to room temperature, and the mixture was stirred for 1 hour. After the mixture was cooled in ice bath, a saturated sodium thiosulfate aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>50/50) to obtain compound 162-5 (8 mg, 14% over two steps).
1H-NMR (400 MHz, CD3OD, δ): 6.77-6.76 (m, 1H), 6.65-6.63 (m, 2H), 6.26-6.23 (m, 2H), 5.68 (dd, J=8.8, 3.4 Hz, 1H), 5.55 (dd, J=8.4, 3.9 Hz, 1H), 4.63 (dd, J=9.5, 8.2 Hz, 1H), 4.23 (dd, J=10.0, 4.5 Hz, 1H);
ESIMS m/z: [M−H]− 204
Compound 262 (11 mg, 92%) was obtained in the same manner as step 3 of example 1, using compound 162-5 (7 mg, 0.034 mmol).
1H-NMR (400 MHz, CDCl3, δ): 7.55 (d, J=8.2 Hz, 2H), 7.07 (d, J=2.7 Hz, 1H), 6.99-6.96 (m, 3H), 6.88 (d, J=9.1 Hz, 1H), 6.34 (d, J=16.8 Hz, 1H), 6.07 (dd, J=17.0, 10.2 Hz, 1H), 5.90-5.87 (br m, 1H), 5.72-5.68 (m, 2H), 4.80 (dd, J=9.7, 7.9 Hz, 1H), 4.42 (dd, J=10.4, 4.1 Hz, 1H);
ESIMS m/z: [M+H]+ 350.
1-(3-Bromo-2-hydroxy-5-methoxyphenyl)ethan-1-one (0.545 g, 2.22 mmol) obtained by a well-known method (Tetrahedron, 2008, 64, 3471.) was dissolved in a mixed solvent of dichloroethane (31.8 mL) and methanol (12.7 mL), and benzyltrimethylammonium dichloroiodate (1.55 g, 4.45 mmol) was added to the solution at room temperature. The mixture was stirred at 80° C. for 3 hours. The mixture was left to cool to room temperature and a 5% sodium hydrogensulfite aqueous solution was added to the mixture. The organic layer was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 163-1 as a crude product, which was used as it is in the next reaction.
ESIMS m/z: [M−H]− 277, 279.
Compound 163-1 was dissolved in dichloromethane (4.0 mL), and a 1 mol/L boron tribromide dichloromethane solution (2.5 mL, 2.50 mmol) was added dropwise to the solution at -78° C. The mixture was stirred for 30 minutes at −78° C. The temperature of the mixture was raised to room temperature, and the mixture was stirred for 1 hour. The mixture was added dropwise to iced water, and then stirred for 10 minutes. The organic layer was extracted with chloroform. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 163-2 as a crude product, which was used as it is in the next reaction.
ESIMS m/z: [M−H]− 263, 265.
Compound 163-2 was dissolved in ethanol (6.7 mL), and sodium acetate (116 mg, 1.41 mmol) was added to the solution at room temperature. The solution was refluxed for 1 hour. The mixture was left to cool to room temperature and water was added to the mixture. The organic layer was extracted with ethyl acetate. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>50/50) to obtain compound 163-3 (85 mg, 17% over three steps).
1H-NMR (400 MHz, DMSO-d6, δ): 7.42 (d, J=2.3 Hz, 1H), 6.90 (d, J=1.8 Hz, 1H), 4.87 (s, 2H);
ESIMS m/z: [M−H]− 227, 229.
Compound 163-4 was obtained as a crude product in the same manner as step 1 of example 158, using compound 163-3 (55 mg, 0.24 mmol), and used as it is in the next reaction.
ESIMS m/z: [M−H]− 242, 244.
Compound 163-5 was obtained as a crude product in the same manner as step 2 of example 158, using compound 163-4, and used as it is in the next reaction.
To a solution of compound 163-5 in DMA (2.0 mL), triethylamine (0.100 mL) and acryloyl chloride (0.058 mL, 0.72 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 hour. After confirmation of vanishment of the raw materials, potassium carbonate (166 mg, 1.2 mmol) and methanol (1.00 mL) were added to the reaction mixture. The mixture was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature and water was added to the mixture. The organic layer was extracted with ethyl acetate, and washed with saturated saline. The organic layer obtained was dried over anhydrous sodium sulfate, insolubles were filtered out, and the organic layer was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (heptane/ethyl acetate=90/10−>50/50) to obtain a crude product 163-6, which was used as it is in the next reaction.
ESIMS m/z: [M−H]− 282, 284.
Compound 263 (27 mg, 26% over four steps) was obtained in the same manner as step 3 of example 1, using compound 163-6.
1H-NMR (400 MHz, CDCl3, δ): 7.58 (d, J=8.2 Hz, 2H), 7.18 (d, J=1.8 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 6.99 (d, J=9.1 Hz, 2H), 6.35 (d, J=17.2 Hz, 1H), 6.06 (dd, J=17.0, 10.6 Hz, 1H), 5.89-5.86 (br, 1H), 5.85-5.79 (m, 1H), 5.74 (d, J=9.1 Hz, 1H), 4.89 (dd, J=10.2, 7.9 Hz, 1H), 4.50 (dd, J=10.4, 4.1 Hz, 1H);
ESIMS m/z: [M−H]− 426, 428.
Compound 164-1 was obtained as a crude product in the same manner as step 1 of example 158, using commercially available 7-bromobenzofuran-3(2H)-one (300 mg, 1.41 mmol), and was used as it is in the next reaction.
ESIMS m/z: [M−H]− 226, 228.
Compound 164-2 was obtained as a crude product in the same manner as step 2 of example 158, using compound 164-1, and used as it is in the next reaction.
Compound 164-3 (160 mg, 46% over three steps) was obtained in the same manner as step 3 of example 17, using compound 164-2.
1H-NMR (400 MHz, CDCl3, δ): 7.43 (d, J=7.2 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 6.84 (t, J=7.9 Hz, 1H), 6.34 (d, J=17.1 Hz, 1H), 6.07 (dd, J=17.3, 10.5 Hz, 1H), 5.92-5.86 (m, 1H), 5.81-5.75 (m, 1H), 5.73 (dd, J=10.3, 1.3 Hz, 1H), 4.83 (dd, J=10.3, 8.1 Hz, 1H), 4.48 (dd, J=10.3, 3.6 Hz, 1H);
ESIMS m/z: [M−H]− 266, 268.
Compound 164-4 was obtained as a crude product in the same manner as step 4 of example 162, using compound 164-3, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 316.
Compound 164-5 (10 mg, 9% over two steps) was obtained in the same manner as step 5 of example 162, using compound 164-4.
1H-NMR (400 MHz, CDCl3, δ): 6.91-6.82 (m, 3H), 6.34 (dd, J=16.8, 1.4 Hz, 1H), 6.07 (dd, J=17.0, 10.2 Hz, 1H), 5.70-5.67 (m, 3H), 4.77 (dd, J=10.0, 7.7 Hz, 1H), 4.44 (dd, J=10.4, 3.6 Hz, 1H);
ESIMS m/z: [M−H]− 204.
Compound 264 (11 mg, 65%) was obtained in the same manner as step 3 of example 1, using compound 164-5 (10 mg, 0.049 mmol).
1H-NMR (400 MHz, CDCl3, δ): 7.57 (d, J=8.2 Hz, 2H), 7.22 (d, J=7.2 Hz, 1H), 7.04-7.00 (m, 3H), 6.96 (t, J=7.5 Hz, 1H), 6.36 (dd, J=16.5, 1.1 Hz, 1H), 6.09 (dd, J=16.8, 10.4 Hz, 1H), 5.92 (br, 1H), 5.79-5.70 (m, 2H), 4.78 (dd, J=10.2, 7.9 Hz, 1H), 4.42 (dd, J=10.4, 4.1 Hz, 1H);
ESIMS m/z: [M+H]+ 350.
Compound 165-1 was obtained as a crude product in the same manner as step 1 of example 158, using commercially available 7-bromobenzofuran-3(2H)-one (300 mg, 1.41 mmol), and was used as it is in the next reaction.
ESIMS m/z: [M−H]− 226, 228.
Compound 165-2 was obtained as a crude product in the same manner as step 2 of example 158, using compound 165-1, and used as it is in the next reaction.
Compound 165-3 (110 mg, 33% over three steps) was obtained in the same manner as step 3 of example 17, using compound 165-2.
1H-NMR (400 MHz, CDCl3, δ): 7.20 (d, J=8.2 Hz, 1H), 7.09-7.00 (m, 2H), 6.38-6.34 (m, 1H), 6.07-6.03 (m, 1H), 5.84-5.80 (m, 1H), 5.75-5.72 (m, 1H), 5.64 (m, 1H), 4.76 (dd, J=10.0, 7.7 Hz, 1H), 4.40 (dd, J=10.2, 3.9 Hz, 1H);
ESIMS m/z: [M−H]− 266, 268.
Compound 165-4 was obtained as a crude product in the same manner as step 4 of example 162, using compound 165-3, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 316.
Compound 165-5 (13 mg, 21% over two steps) was obtained in the same manner as step 5 of example 162, using compound 165-4.
1H-NMR (400 MHz, CD3OD, δ): 7.11 (d, J=7.7 Hz, 1H), 6.35 (dd, J=8.2, 2.3 Hz, 1H), 6.26-6.20 (m, 3H), 5.66 (dd, J=8.6, 3.2 Hz, 1H), 5.47 (dd, J=7.9, 3.9 Hz, 1H), 4.65 (dd, J=10.0, 7.7 Hz, 1H), 4.28 (dd, J=10.0, 4.1 Hz, 1H);
ESIMS m/z: [M−H]− 204
Compound 265 (10 mg, 47%) was obtained in the same manner as step 3 of example 1, using compound 165-5 (13 mg, 0.063 mmol).
1H-NMR (400 MHz, CDCl3, δ): 7.59 (d, J=8.6 Hz, 2H), 7.31 (d, J=8.6 Hz, 1H), 7.07 (d, J=8.6 Hz, 2H), 6.62 (dd, J=8.2, 2.3 Hz, 1H), 6.56 (d, J=2.3 Hz, 1H), 6.35 (dd, J=16.8, 1.4 Hz, 1H), 6.08 (dd, J=16.8, 10.4 Hz, 1H), 5.92-5.84 (br, 1H), 5.73(dd, J=10.4, 0.9 Hz, 1H), 5.67-5.65 (m, 1H), 4.79 (dd, J=10.0, 7.7 Hz, 1H), 4.44 (dd, J=10.2, 3.4 Hz, 1H).
ESIMS m/z: [M+H]+ 350.
Compound 166-1 was obtained as a crude product in the same manner as step 1 of example 163, using commercially available 1-(5-bromo-2-hydroxy-4-methylphenyl)ethan-1-one (1.00 g, 4.37 mmol), and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 263, 265.
Compound 166-2 (0.750 g, 76%) was obtained in the same manner as step 3 of example 163, using compound 166-1.
1H-NMR (400 MHz, CDCl3, δ): 7.83 (s, 1H), 7.06 (s, 1H), 4.64 (s, 2H), 2.48 (s, 3H),
ESIMS m/z: [M+H]+ 227, 229.
Compound 166-3 was obtained as a crude product in the same manner as step 1 of example 158, using compound 166-2 (200 mg, 0.881 mmol), and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 242, 244.
Compound 166-4 was obtained as a crude product in the same manner as step 2 of example 158, using compound 166-3, and used as it is in the next reaction.
Compound 166-5 (110 mg, 44% over three steps) was obtained in the same manner as step 3 of example 17, using compound 166-4.
1H-NMR (400 MHz, CDCl3, δ): 7.47 (s, 1H), 6.77 (s, 1H), 6.34 (dd, J=16.8, 1.4 Hz, 1H), 6.06 (dd, J=17.2, 10.4 Hz, 1H), 5.90-5.84 (br, 1H), 5.72 (dd, J=10.4, 1.4 Hz, 1H), 5.63-5.61 (m, 1H), 4.73 (dd, J=10.2, 7.9 Hz, 1H), 4.37 (dd, J=10.2, 3.9 Hz, 1H), 2.36 (s, 3H);
ESIMS m/z: [M−H]− 280, 282.
Compound 166-6 was obtained as a crude product in the same manner as step 4 of example 162, using compound 166-5, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 330.
Compound 166-7 (8 mg, 16% over two steps) was obtained in the same manner as step 5 of example 162, using compound 166-6.
1H-NMR (400 MHz, CD3OD, δ): 6.73 (s, 1H), 6.56 (s, 1H), 6.24-6.23 (m, 2H), 5.66 (dd, J=8.6, 3.6 Hz, 1H), 5.52 (dd, J=7.9, 4.3 Hz, 1H), 4.60 (dd, J=10.0, 8.2 Hz, 1H), 4.21 (dd, J=9.7, 4.3 Hz, 1H), 2.15 (s, 3H);
ESIMS m/z: [M+H]+ 220.
Compound 266 (5.5 mg, 62%) was obtained in the same manner as step 3 of example 1, using compound 166-7 (5.4 mg, 0.025 mmol),
1H-NMR (400 MHz, CDCl3, δ): 7.53 (d, J=10.0 Hz, 2H), 6.99 (s, 1H), 6.89 (d, J=8.6 Hz, 2H), 6.79 (s, 1H), 6.33 (dd, J=16.8, 1.4 Hz, 1H), 6.05 (dd, J=17.0, 10.2 Hz, 1H), 5.83 (br, 1H), 5.70 (dd, J=10.4, 1.4 Hz, 1H), 5.67-5.65 (m, 1H), 4.78 (dd, J=10.2, 7.9 Hz, 1H), 4.40 (dd, J=10.2, 3.9 Hz, 1H), 2.15 (s, 3H);
ESIMS m/z: [M−H]− 362.
Compound 167-1 (0.30 g, 43%) was obtained in the same manner as step 6 of example 144, using compound 143-3.
1H NMR (400 MHz, CDCl3, δ): 7.56 (d, J=8.6 Hz, 1H), 6.83 (d, J=8.6 Hz), 4.10 (s, 3H), 2.69 (s, 3H);
ESIMS m/z: [M+H]+ 189.
Compound 167-2 (0.85 g, 63%) was obtained in the same manner as step 4 of example 144, using compound 167-1.
1H NMR (400 MHz, DMSO-d6, δ): 11.54 (brs, 1H), 7.64 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 2.64 (s, 3H);
ESIMS m/z: [M+H]+ 175.
Compound 167-2 (0.3 g, 1.72 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.72 mL, 5.17 mmol) and trifluoromethanesulfonic anhydride (0.43 mL, 2.58 mmol) were added to the solution at 0° C. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to obtain compound 167-3 as a crude product, which was used as it is in the next reaction.
ESIMS m/z: [M−H]− 305.
Compound 167-3 (0.9 g, 2.94 mmol) was dissolved in THF (10 mL), and 1-(trifluoromethyl)-4-vinylbenzene (0.26 mL, 1.76 mmol), palladium acetate (0.066 g, 0.29 mmol), 2,2-bis(diphenylphosphino)-1,1′binaphthyl (0.366 g, 0.59 mmol) and N,N-diisopropylamine (2.56 mL, 14.7 mmol) were added to the solution. The solution was deaerated in Ar atmosphere for 5 minutes, and then stirred at 70° C. in a sealed tube for 16 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=95/5) to obtain compound 167-4 (0.17 g, 18% over two steps).
1H NMR (500 MHz, CDCl3, δ): 7.94 (d, J=16.5 Hz, 1H), 7.73 (d, J=8.2 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.58-7.50 (m, 3H), 2.77 (s, 3H,);
ESIMS m/z: [M+H]+ 329.
Compound 167-5 (0.14 g) was obtained as a crude product in the same manner as step 1 of example 116, using compound 167-4, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 331.
Compound 167-6 (0.16 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 167-5, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 335.
Compound 267 (0.012 g, 7% over three steps) was obtained in the same manner as step 5 of example 1, using compound 167-6.
1H NMR (500 MHz, DMSO-d6, δ): 8.63 (t, J=5.2 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.14-7.10 (m, 2H), 6.28 (dd, J=17.0, 10.0 Hz, 1H), 6.14 (dd, J=17.0, 2.0 Hz, 1H), 5.62 (dd, J=10.0, 2.0 Hz, 1H), 4.55 (d, J=6.0 Hz, 2H), 3.20-3.17 (m, 2H), 3.11-3.08 (m, 2H), 2.63 (s, 3H);
ESIMS m/z: [M+H]+ 389.
Commercially available methyl 3-hydroxy-2-nitrobenzoate (5.0 g, 25.38 mmol) was dissolved in chloroform (60 mL), and bromine (2.6 mL, 50.76 mmol) was added to the solution at room temperature. The mixture was stirred at 60° C. for 20 hours. The mixture was cooled to room temperature and sodium pyrosulfite was added to the mixture. The organic layer was extracted with dichloromethane. The organic layer obtained was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=90/10) to obtain compound 168-1 (1.25 g, 18%).
1H NMR (400 MHz, CDCl3, δ): 10.66 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 4.02 (s, 3H);
ESIMS m/z: [M−H]− 274.
Compound 168-1 (3.5 g, 12.72 mmol) was dissolved in THF (80 mL), and an aqueous solution (80 mL) of sodium hydrosulfite (11.07 g, 63.64 mmol) was added to the solution at room temperature. The mixture was stirred at 60° C. for 1 hour. Water was added to the mixture, and the organic layer was extracted with ethyl acetate. After pH of the water layer was adjusted to 3, the organic layer was further extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized with n-pentane, and compound 168-2 (3.0 g, 96%) was obtained by filtering the crystals obtained.
1H NMR (500 MHz, CDCl3, δ): 6.82 (d, J=8.5 Hz, 1H), 6.61 (d, J=8.2 Hz, 1H), 3.94 (s, 3H);
ESIMS m/z: [M+H]+ 246.
Compound 168-3 (2.0 g, 62%) was obtained in the same manner as step 1 of example 147, using compound 168-2.
1H NMR (500 MHz, CDCl3, δ): 7.52 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 4.06 (s, 3H), 2.67 (s, 3H);
ESIMS m/z: [M+H] 270.
Compound 168-3 (2.0 g, 7.43 mmol) was dissolved in THF (20 mL), and diisobutylaluminum hydride (22 mL, 22.3 mmol, 1.0 mol/L in THF) was added to the solution at 0° C. The mixture was stirred at room temperature for 1 hour. A saturated ammonium chloride aqueous solution was added to the mixture, and the organic layer was extracted with ethyl acetate. The organic layer obtained was washed with a potassium sodium tertrate aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=85/15) to obtain compound 168-4 (1.5 g, 84%).
1H NMR (500 MHz, CDCl3, δ): 7.47 (d, J=8.5 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H), 5.12 (d, J=4.3 Hz, 2H), 4.06 (brs, 1H), 2.65 (s, 3H);
ESIMS m/z: [M+H]+ 242.
Compound 168-4 (1.5 g, 6.22 mmol) was dissolved in dichloromethane (70 mL), and manganese oxide (15.70 g, 180.50 nmol) was added to the solution at 0° C. The mixture was stirred at room temperature for 1 hour. The mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue was crystallized with n-pentane, and compound 168-5 (1.1 g, 74%) was obtained by filtering the crystals obtained.
1H NMR (400 MHz, DMSO-d6, δ): 10.51 (s, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 2.70 (s, 3H);
ESIMS m/z: [M+H]+ 240.
1-Bromo-4-(trifluoromethyl)benzene (1.69 g, 7.53 mmol) was dissolved in THF (5 mL), and isopropylmagnesium chloride lithium chloride complex (5.21 mL, 6.78 mmol, 1.3 mol/L in THF) was added to the solution. The mixture was stirred at 40° C. for 1 hour. Then, the mixture was cooled to 0° C., and a solution of compound 168-5 (0.9 g, 3.76 mmol) in THF (5 mL) was added to the mixture. The resultant mixture was stirred at room temperature for 30 minutes. A saturated ammonium chloride aqueous solution was added to the mixture and the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10) to obtain compound 168-6 (0.55 g, 38%).
ESIMS m/z: [M+H]+ 386.
Compound 168-7 (0.28 g, 59%) was obtained in the same manner as step 6 of example 144, using compound 168-6.
ESIMS m/z: [M−H]− 331.
Compound 168-8 (0.27 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 168-7, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 337.
Compound 268 (0.028 g, 9% over two steps) was obtained in the same manner as step 1 of example 76, using compound 167-8.
1H NMR (400 MHz, DMSO-d5, δ): 8.61 (t, J=5.5 Hz, 1H), 7.64 (s, 4H), 7.38 (d, J=7.9 Hz, 1H), 7.21 (d, J=7.9 Hz, 1H), 6.32 (d, J=4.4 Hz, 1H), 6.26 (dd, J=17.2, 10.0 Hz, 1H), 6.18 (d, J=4.4 Hz, 1H), 6.11 (dd, J=16.8, 2.0 Hz, 1H), 5.61 (dd, J=10.2, 2.3 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H), 2.64 (s, 3H);
ESIMS m/z: [M+H]+ 391.
Compound 167-3 (0.32 g, 1.04 mmol) was dissolved in toluene (5 mL), and 4-(trifluoromethyl)aniline (0.09 mL, 0.73 mmol), bis(dibenzylideneacetone)palladium(0) (0.12 g, 0.21 mmol), 1,1-bis(diphenylphosphino)ferrocene (0.057 g, 0.104 mmol) and sodium tert-butoxide (0.150 g, 1.57 mmol) were added to the solution. The mixture was deaerated in Ar atmosphere for 5 minutes, and then stirred at 80° C. for 6 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=80/20) to is obtain compound 169-1 (0.080 g, 24%).
1H NMR (400 MHz, CDCl3, δ): 7.63 (d, J=8.6 Hz, 2H), 7.47 (d, J=8.6 Hz, 1H), 7.35 (d, J=8.3 Hz, 2H), 7.17 (d, J=8.8 Hz, 1H), 7.13 (br s, 1H), 2.71 (s, 3H);
ESIMS m/z: [M+H]+ 318.
Compound 169-1 (0.150 g, 0.47 mmol) was dissolved in THF (3 mL), and sodium hydride (60%, 0.037 g, 0.95 mmol) was added to the solution at 0° C. The mixture was stirred for 15 minutes. Then, Methyl iodide (0.058 mL, 0.95 mmol) was added to the mixture, and the resultant mixture was stirred at room temperature for 3 hours. Iced water was added to the mixture and the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=95/5) to obtain compound 169-2 (0.080 g, 51%).
1H NMR (500 MHz, CDCl3, δ): 7.56 (d, J=8.5 Hz, 2H), 7.40 (d, J=9.0 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 6.89 (d, J=8.5 Hz, 1H), 3.74 (s, 3H), 2.66 (s, 3H);
ESIMS m/z: [M+H]+ 332.
Compound 169-3 (0.080 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 169-2, and used as it is in the next reaction.
ESIMS m/z: [M−NH2]− 319.
Compound 269 (0.016 g, 17% over two steps) was obtained in the same manner as step 5 of example 1, using compound 169-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.70 (t, J=5.5 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 7.28-7.20 (m, 2H), 6.81 (d, J=8.8 Hz, 2H), 6.31 (dd, J=16.8, 10.0 Hz, 1H), 6.15 (dd, J=17.2, 2.0 Hz, 1H), 5.64 (dd, J=10.1, 2.2 Hz, 1H), 4.61 (d, J=5.7 Hz, 2H), 3.41 (s, 3H), 2.60 (s, 3H);
ESIMS m/z: [M+H]+ 390.
Compound 170-1 (0.110 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 169-1, and used as it is in the next reaction.
ESIMS m/z: [M−NH2]− 305.
Compound 270 (0.020 g, 14% over two steps) was obtained in the same manner as step 5 of example 1, using compound 170-1.
1H NMR (400 MHz, DMSO-d6, δ): 8.88 (s, 1H), 8.61 (t, J=5.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.19-7.17 (m, 4H), 6.29 (dd, J=17.2, 10.0 Hz, 1H), 6.14 (dd, J=17.2, 2.0 Hz, 1H), 5.63 (dd, J=10.0, 2.0 Hz, 1H), 4.55 (d, J=6.0 Hz, 2H), 2.62 (s, 3H);
ESIMS m/z: [M+H]+ 376.
Compound 167-3 (0.5 g, 1.63 mmol) was dissolved in DMF (5 mL), and 4-(trifluoromethyl)benzenethiol (0.156 mL, 1.14 mmol), palladium acetate (0.110 g, 0.16 mmol), 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene (0.094 g, 0.16 mmol) and N,N-diisopropylamine (1.42 mL, 8.17 mmol) were added to the solution. The solution was deaerated in Ar atmosphere for 5 minutes, and then stirred at 100° C. in a sealed tube for 4 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=95/5) to obtain compound 171-1 (0.12 g, 21% over two steps).
1H NMR (500 MHz, CDCl3, δ): 7.67 (d, J=8.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7,43 (d, J=8.2 Hz, 1H), 6.92 (d, J=8.2 Hz, 1H), 2.74 (s, 3H);
ESIMS m/z: [M+H]+ 335.
Compound 171-2 (0.120 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 171-1, and used as it is in the next reaction.
ESIMS m/z: [M−NH7]− 322.
Compound 272 (0.025 g, 18% over two steps) was obtained in the same manner as step 5 of example 1, using compound 171-2.
1H NMR (400 MHz, DMSO-d6, δ): 8.75 (t, J=5.7 Hz, 1H), 7.63 (d, J=8.3 Hz, 2H), 7.44 (d, J=7.9 Hz, 1H), 7.30-7.28 (m, 3H), 6.30 (dd, J=17.2, 10.0 Hz, 1H), 6.15 (dd, J=17.2, 2.4 Hz, 1H), 5.65 (dd, J=10.3, 2.0 Hz, 1H), 4.64 (d, J=6.1 Hz, 2H), 2.63 (s, 3H);
ESIMS m/z: [M+H]+ 393.
Compound 272 (0.150 g, 0.38 mmol) was dissolved in dichloromethane (4 mL), and m-chloroperoxybenzoic acid (0.198 g, 1.15 mmol) was added to the solution at 0° C. The mixture was stirred at room temperature for 2 hours. Dichloromethane was added to the mixture, and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a preparative HPLC to obtain compound 271 (0.023 g, 14%).
1H NMR (400 MHz, DMSO-d6, δ): 8.77 (t, J=5.7 Hz, 1H), 8.30 (d, J=8.3 Hz, 2H), 8.00 (d, J=7.9 Hz, 3H), 7.45 (d, J=8.1 Hz, 1H), 6.28 (dd, J=17.2, 10.0 Hz, 1H), 6.12 (dd, J=17.2, 2.4 Hz, 1H), 5.65 (dd, J=10.1, 2.2 Hz, 1H),4.63(d,J=5.9Hz,2H),2.69(s,3H),
ESIMS m/z: [M+H]+ 425.
Compound 172-1 (0.13 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 167-4, and used as it is in the next reaction.
ESIMS m/z: [M−NH2]− 316.
Compound 273 (0.021 g, 15% over two steps) was obtained in the same manner as step 5 of example 1, using compound 172-1.
1H NMR (400 MHz, DMSO-d6, δ): 8.70-8.68 (m, 1H), 7.92 (d, J=16.4 Hz, 1H), 7.85 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.63 (d, J=16.4 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.25 (d, J=7.9 Hz, 1H), 6.31 (dd, J=17.2, 10.0 Hz, 1H), 6.15 (dd, J=17.2, 2.0 Hz, 1H), 5.64 (dd, J=10.2, 2.1 Hz, 1H), 4.62 (d, J=5.5 Hz, 2H), 2.70 (s, 3H),
ESIMS m/z: [M+H]+ 387.
Compound 173-1 (11.0 g, 95%) was obtained in the same manner as step 1 of example 147, using commercially available 2-amino-3-nitrophenol.
1H NMR (400 MHz, CDCl3, δ): 8.18 (dd, J=8.3, 0.8 Hz, 1H), 7.83 (dd, J=8.2, 0.8 Hz, 1H), 7.46 (t, J=8.2 Hz, 1H), 2.79 (s, 3H);
ESIMS m/z: [M+H]+ 179.
Compound 173-1 (11.0 g, 61.79 mmol) was dissolved in THF (50 mL), ethanol (50 mL), and water (50 mL), and iron powder (17.30 g, 308.99 mmol) and ammonium chloride (4.91 g, 92.70 mmol) were added to the solution at room temperature. The mixture was stirred at 70° C. for 2 hours. The mixture was cooled to room temperature, and concentrated under reduced pressure. The residue/organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized with n-pentane, and compound 173-2 (9.2 g, quantitatively) was obtained by filtering the crystals obtained.
1H NMR (400 MHz, CDCl3, δ): 7.51 (d, J=8.4 Hz, 1H), 6.62 (d, J=8.4 Hz, 1H), 5.99 (s, 1H), 4.31 (brs, 2H), 3.86 (s, 3H);
ESIMS m/z: [M+H]+ 149.
Compound 173-3 (0.55 g, 51%) was obtained in the same manner as step 1 of example 117, using compound 173-2.
1H NMR (500 MHz, CDCl3, δ): 7.18 (d, J=8.5 Hz, 1H), 6.48 (d, J=8.5 Hz, 1H), 2.64 (s, 3H);
ESIMS m/z: [M+H]+ 227.
Commercially available 4-(trifluoromethyl)benzoic acid (0.34 g, 1.77 mmol) was dissolved in DMF (15 mL), and (1-cyano-2-ethoxy-2-oxoethylidenaminoxy)dimethylamino-morpholino-car benium hexafluorophosphate (1.13 g, 2.65 mmol) and N,N-diisopropylamine (0.92 mL, 5.31 mmol) were added to the solution. The mixture was stirred at room temperature for 15 minutes. Then, compound 173-3 (0.4 g, 1.77 mmol) was added to the mixture. The mixture was further stirred at room temperature for 16 hours. Water was added to the mixture and the organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=95/5) to obtain compound 173-4 (0.13 g, 18%).
1H NMR (500 MHz, CDCl3, δ): 8.71 (brs, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.48 (d, J=9.0 Hz, 1H), 2.70 (s, 3H);
ESIMS m/z: [M+H]+ 399.
Compound 173-5 (0.17 g, 56%) was obtained in the same manner as step 6 of example 144, using compound 173-4.
1H NMR (400 MHz, CDCl3, δ): 8.91 (brs, 1H), 8.55 (d, J=8.5 Hz, 1H), 8.10 (d, J=7.9 Hz, 2H), 7.82 (d, J=7.9 Hz, 2H), 7.65 (d, J=8.5 Hz, 1H), 2.74 (s, 3H);
ESIMS m/z: [M+H]+ 346.
Compound 173-6 (0.18 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 173-5, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 350.
Compound 274 (0.050 g, 25% over two steps) was obtained in the same manner as step 5 of example 1, using compound 173-6.
1H NMR (500 MHz, DMSO-d6, δ): 10.58 (s, 1H), 8.70 (t, J=5.8 Hz, 1H), 8.21 (d, J=7.9 Hz, 2H), 7.93 (d, J=8.2 Hz, 2H), 7.66 (d, J=7.9 Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 6.30 (dd, J=17.5, 10.5 Hz, 1H), 6.15 (dd, J=17.2, 2.3 Hz, 1H), 5.64 (dd, J=10.0, 2.0 Hz, 1H), 4.60 (d, J=5.8 Hz, 2H), 2.65 (s, 3H);
ESIMS m/z: [M+H]+ 404.
4-Hydroxy-2-methylbenzo[d]oxazole-7-carbonitrile (Compound 174-1) Compound 174-1 (0.19 g, 25%) was obtained in the same manner as step 6 of example 144, using compound 143-4.
1H NMR (400 MHz, DMSO-d6, δ): 11.57 (brs, 1H), 7.64 (d, J=8.6 Hz, 1H), 6.84 (d, J=8.6 Hz, 1H), 2.64 (s, 3H);
ESIMS m/z: [M+H]+ 175.
Compound 174-2 (0.18 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 174-1, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 179.
Compound 174-2 (0.18 g, 1.01 mmol) was dissolved in THF (2 mL) and water (1 mL), and sodium hydrogen carbonate (0.17 g, 2.02 mmol) and acryloyl chloride (0.065 mL, 0.81 mmol) were added to the solution at 0° C. The mixture was stirred at room temperature for 1 hour. Then, lithium hydroxide monohydrate (0.085 g, 2.02 mmol) was added to the mixture. The mixture was further stirred for 1 hour. Water was added to the mixture. The organic layer was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=30/70) to obtain compound 174-3 (0.13 g) as a crude product.
ESIMS m/z: [M+H]+ 233.
Compound 174-3 (0.17 g, 0.73 mmol) was dissolved in dichloromethane (5 mL), and {4-(dimethylamino)phenyl}boronic acid (0.423 g, 2.56 mmol), pyridine (0.29 mL, 3.66 mmol), copper(II) acetate (0.265 g, 1.46 mmol) and molecular sieve 4 angstrom (200 mg) were added to the solution. The mixture was stirred in oxygen atmosphere at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified using a preparative HPLC to obtain compound 275 (0.034 g, 13% over three steps).
1H NMR (400 MHz, DMSO-d6, δ): 8.60 (brs, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.92 (d, J=9.0 Hz, 2H), 6.75 (d, J=9.0 Hz, 2H), 6.64 (d, J=8.3 Hz, 1H), 6.27 (dd, J=17.0, 10.0 Hz, 1H), 6.11 (dd, J=17.2, 2.0 Hz, 1H), 5.61 (dd, J=10.0, 2.0 Hz, 1H), 4.53 (d, J=5.6 Hz, 2H), 2.87 (s, 6H),2.61 (s, 3H);
ESIMS m/z: [M+H]+ 352.
Compound 143-4 (1.0 g, 4.38 mmol) was dissolved in acetonitrile (20 mL), and bromocyclohexane (2.84 g, 17.54 mmol) and potassium carbonate (1.21 g, 8.77 mmol) were added to the solution. The mixture was stirred at 70° C. for 72 hours. The mixture was filtered with Celite(R), and washed with acetonitrile. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=85/15−>80/20) to obtain compound 175-1 (0.30 g, 22%).
1H NMR (500 MHz, CDCl3, δ): 7.29 (d, J=8.8 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 4.59-4.55 (m, 1H), 2.66 (s, 3H), 2.08-2.05 (m, 2H), 1.85-1.78 (m, 3H), 1.31-1.42 (m, 5H);
ESIMS m/z: [M+H]+ 310.
Compound 175-2 (0.15 g, 73%) was obtained in the same manner as step 6 of example 144, using compound 175-1.
ESIMS m/z: [M+H]+ 257.
Compound 175-3 (0.16 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 175-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 261.
Compound 276 (0.030 g, 16% over two steps) was obtained in the same manner as step 5 of example 1, using compound 175-3.
1H NMR (500 MHz, DMSO-d6, δ): 8.57 (t, J=5.0 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H),6.86(d,J=8.5Hz,1H),6.26(dd,J=17.0,10.0Hz,1H),6.13(dd, J=17.0, 2.0 Hz, 1H), 5.61 (dd, J=10.0, 2.0 Hz, 1H), 4.74-4.70 (m, 1H), 4.50 (d, J=5.5 Hz, 2H), 2.59 (s, 3H), 1.92 (brs, 2H), 1.74-1.72 (m, 2H), 1.54-1.44 (m, 3H), 1.40-1.36 (m, 3H);
ESIMS m/z: [M+H]+ 315.
Compound 176-1 (0.55 g, 64%) was obtained in the same manner as step 1 of example 3, using compound 143-4 and 3-fluoro-4-(trifluoromethyl)phenylboronic acid.
1H NMR (500 MHz, CDCl3, δ): 7.54 (t, J=8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 6.84 (d, J=9.0 Hz, 1H), 6.79 (d, J=12.0 Hz, 1H), 2.67 (s, 3H);
ESIMS m/z: [M+H]hu + 390.
Compound 176-2 (0.23 g, 48%) was obtained in the same manner as step 6 of example 144, using compound 176-1.
1H NMR (500 MHz, CDCl3, δ): 7.64-7.59 (m, 2H), 6.99-6.90 (m, 3H), 2.72 (s, 3H);
ESIMS m/z: [M+H]+ 337.
Compound 176-3 (0.20 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 176-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 341.
Compound 277 (0.078 g, 29% over two steps) was obtained in the same manner as step 5 of example 1, using compound 176-3.
1H NMR (500 MHz, DMSO-d6, δ): 8.73 (t, J=4.5 Hz, 1H), 7.73 (t, J=8.7 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 7.14 (d, J=12.5 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 6.31 (dd, J=17.0, 10.0 Hz, 1H), 6.15 (d, J=17.0 Hz, 1H), 5.65 (d, J=10.0 Hz, 1H), 4.62 (d, J=5.5 Hz, 2H), 2.64 (s, 3H);
ESIMS m/z: [M+H]+ 395.
Compound 278 (0.032 g, 17%) was obtained in the same manner as step 4 of example 174, using compound 174-3 and 4-cyano phenylboronic acid.
1H NMR (500 MHz, DMSO-d6, δ): 8.72 (brs, 1H), 7.81 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.30 (dd, J=17.0, 10.0 Hz, 1H), 6.15 (dd, J=17.0, 1.8 Hz, 1H), 5.65 (dd, J=10.3, 1.8 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.59 (s, 3H);
ESIMS m/z: [M+H]+ 334.
Compound 178-1 (0.55 g) was obtained as a crude product in the same manner as step 4 of example 174, using compound 143-4 and 3-(trifluoromethyl)phenylboronic acid, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 372.
Compound 178-2 (0.28 g, 40% over two steps) was obtained in the same manner as step 6 of example 144, using compound 178-1.
1H NMR (400 MHz, CDCl3, δ): 7.57-7.50 (m, 3H), 7.39 (s, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 2.73 (s, 3H);
ESIMS m/z: [M+H]+ 319.
Compound 178-3 (0.25 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 178-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 323.
Compound 279 (0.046 g, 14% over two steps) was obtained in the same manner as step 5 of example 1, using compound 178-3.
1H NMR (500 MHz, DMSO-d6, δ): 8.71 (t, J=5.5 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.30-7.21 (m, 3H), 7.08 (d, J=8.0 Hz, 1H), 6.33-6.27 (dd, J=10.0, 17.0 Hz, 1H), 6.15 (dd, J=17.0, 2.0 Hz, 1H), 5.64 (dd, J=10.2, 2.0 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 2.60 (s, 3H);
ESIMS m/z: [M+H]+ 377.
Compound 179-1 (0.55 g, 75%) was obtained in the same manner as step 4 of example 174, using compound 143-4 and 4-methoxyphenyl boronic acid.
1H NMR (500 MHz, DMSO-d6, δ): 7.48 (d, J=8.5 Hz, 1H), 7.06-7.03 (m, 2H), 6.99-6.96 (m, 2H), 6.68 (d, J=9.0 Hz, 1H), 3.76 (s, 3H), 2.64 (s, 3H);
ESIMS m/z: [M+H]+ 334.
Compound 179-2 (0.28 g, 60%) was obtained in the same manner as step 6 of example 144, using compound 179-1.
1H NMR (500 MHz, CDCl3, δ): 7.44 (d, J=8.5 Hz, 1H), 7.10-7.08 (m, 2H), 6.96-6.94 (m, 2H), 6.62 (d, J=8.5 Hz, 1H), 3.84 (s, 3H), 2.73 (s, 3H);
ESIMS m/z: [M+H]+ 281.
Compound 280 (0.030 g, 19%) was obtained in the same manner as step 7 of example 148, using compound 179-2.
1H NMR (500 MHz, DMSO-d6, δ): 8.64 (t, J=5.3 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.99-6.92 (m, 4H), 6.74 (d, J=8.5 Hz, 1H), 6.28 (dd, J=17.0, 10.5 Hz, 1H), 6.13 (dd, J=17.5, 2.5 Hz, 1H), 5.62 (dd, J=10.2, 2.0 Hz, 1H), 4.55 (d, J=5.5 Hz, 2H), 3.74 (s, 3H), 2.61 (s, 3H);
ESIMS m/z: [M+H]+ 339.
Compound 281 (0.022 g, 15%) was obtained in the same manner as step 4 of example 174, using compound 174-3 and 4-chiorophenyl boronic add.
1H NMR (500 MHz, DMSO-d6, δ): 8.69 (t, J=5.3 Hz, 1H), 7.40 (d, J=8.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 1H), 6.99-6.97 (m, 3H), 6.29 (dd, J=17.0, 10.0 Hz, 1H), 6.14 (dd, J=17.0, 2.0 Hz, 1H), 5.64 (dd, J=10.0, 2.0 Hz, 1H), 4.59 (d, J=6.0 Hz, 2H), 2.60 (s, 3H);
ESIMS m/z: [M+H]+ 343.
Compound 181-1 (0.50 g, 89%) was obtained in the same manner as step 1 of example 175, using compound 143-4 and benzyl bromide.
1H NMR (400 MHz, DMSO-d6, δ): 7.49-7.47 (m, 3H), 7.45-7.39 (m, 2H), 7.37-7.35 (m, 1H), 6.98 (d, J=8.8 Hz, 1H), 5.34 (s, 2H), 2.63 (a, 3H);
ESIMS m/z: [M+H]+ 318.
Compound 181-2 (0.20 g, 53%) was obtained in the same manner as step 6 of example 144, using compound 181-1.
1H NMR (400 MHz, DMSO-d6, δ): 7.82 (d, J=8.8 Hz, 1H), 7.51-7.49 (m, 2H), 7.45-7.37 (m, 3H), 7.18 (d, J=8.8 Hz, 1H), 5.45 (s, 2H), 2.66 (s, 3H);
ESIMS m/z: [M+H]+ 265.
Compound 282 (0.035 g, 14%) was obtained in the same manner as step 7 of example 148, using compound 181-2.
1H NMR (500 MHz, DMSO-d5, δ): 8.58 (t, J=5.5 Hz, 1H), 7.48-7.47 (m, 2H), 7.41-7.38 (m, 2H), 7.35-7.32 (m, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.27 (dd, J=17.0, 10.5 Hz, 1H), 6.12 (dd, J=17.5, 2.5 Hz, 1H), 5.61 (dd, J=10.0, 2.0 Hz, 1H), 5.33 (s, 2H), 4.50 (d, J=5.5 Hz, 2H), 2.60 (s, 3H);
ESIMS m/z: [M+H]+ 323.
Compound 153-4 (1.0 g, 4.38 mmol) was dissolved in DMF (10 mL), and 5-bromo-2-(trifluoromethyl)pyridine (1.98 g, 8.77 mmol) and cesium carbonate (2.86 g, 8.77 mmol) were added to the solution. The mixture was stirred at 145° C. for 1 hour using a micro-wave reaction apparatus Biotage(R) Initiator. The mixture was cooled to room temperature, and water was added to the mixture. The organic layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=95/5) to obtain compound 182-1 (0.40 g, 24%).
1H NMR (500 MHz, CDCl3, δ): 8.52 (d, J=2.8 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.36 (dd, J=8.0, 2.8 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 2.71 (s, 3H);
ESIMS m/z: [M+H]+ 373.
Compound 182-2 (0.18 g, 52%) was obtained in the same manner as step 6 of example 144, using compound 182-1.
1H NMR (500 MHz, CDCl3, δ): 8.58 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 2.71 (s, 3H);
ESIMS m/z: [M+H]+ 320.
Compound 182-3 (0.14 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 182-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 324.
Compound 283 (0.031 g, 14% over two steps) was obtained in the same manner as step 5 of example 1, using compound 182-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.68 (t, J=5.6 Hz, 1H), 8.64 (d, J=2.4 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.58 (dd, J=8.6, 2.7 Hz, 1H), 7.29-7.21 (m, 2H), 6.33 (dd, J=17.2, 10.4 Hz, 1H), 6.14 (dd, J=17.2, 2.0 Hz, 1H), 5.63 (dd, J=10.4, 2.0 Hz, 1H), 4.64 (d, J=5.6 Hz, 2H), 2.61 (s, 3H);
ESIMS m/z: [M+H]+ 378.
Compound 183-1 (0.45 g, 55%) was obtained in the same manner as step 1 of example 182, using compound 153-4 and 2-chloro-5-(trifluoromethyl)pyridine.
1H NMR (400 MHz, CDCl3, δ): 8.37 (s, 1H), 7.99 (dd, J=8.8, 2.4 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 2.63 (s, 3H);
ESIMS m/z: [M+H]+ 373.
Compound 183-2 (0.12 g, 46%) was obtained in the same manner as step 6 of example 144, using compound 183-1.
1H NMR (400 MHz, CDCl3, δ): 8.37 (s, 1H), 8.03 (dd, J=8.8, 2.4 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.26-7.23 (m, 2H), 2.67 (s, 3H);
ESIMS m/z: [M+H]+ 320.
Compound 183-3 (0.14 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 183-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 324.
Compound 284 (0.018 g, 13% over two steps) was obtained in the same manner as step 5 of example 1, using compound 183-3.
1H NMR (500 MHz, DMSO-d6, δ): 8.70 (s, 1H), 8.54 (s, 1H), 8.30 (d, J=8.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.27-7.22 (m, 2H), 6.32 (dd, J=17.0, 10.0 Hz, 1H), 6.14 (d, J=17.0 Hz, 1H), 5.63 (d, J=10.0 Hz, 1H), 4.65 (d, J=5.5 Hz, 2H), 2.58 (s, 3H);
ESIMS m/z: [M+H]+ 378.
Compound 184-1 (0.60 g, 54%) was obtained in the same manner as step 1 of example 182, using compound 156-4.
1H NMR (500 MHz, CDCl3, δ): 8.52 (d, J=2.5 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.38-7.35 (m, 1H), 7.00 (d, J=8.5 Hz, 1H), 2.82 (s, 3H);
ESIMS m/z: [M+H]+ 389.
Compound 184-2 (0.20 g, 39%) was obtained in the same manner as step 6 of example 144, using compound 184-1.
1H NMR (400 MHz, CDCl3, δ): 8.58 (d, J=2.8 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.53 (dd, J=8.0, 2.0 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 2.90 (s, 3H);
ESIMS m/z: [M+H]+ 336.
Compound 184-3 (0.22 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 184-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 340.
Compound 285 (0.018 g, 13% over two steps) was obtained in the same manner as step 5 of example 1, using compound 184-3.
1H NMR (500 MHz, DMSO-d6, δ): 8.76 (s, 1H), 8.56 (s, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.42-7.35 (m, 3H), 6.31 (dd, J=17.0, 10.0 Hz, 1H), 6.18 (d, J=17.0 Hz, 1H), 5.67 (d, J=10.0 Hz, 1H), 4.60 (d, J=5.5 Hz, 2H), 2.75 (s, 3H);
ESIMS m/z: [M+H]+ 394.
Compound 185-1 (0.35 g, 55%) was obtained in the same manner as step 1 of example 183, using compound 156-4.
1H NMR (500 MHz, CDCl3, δ): 8.36 (s, 1H), 7.95 (d, J=8.5 Hz, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 2.78 (s, 3H);
ESIMS m/z: [M+H]+ 389.
Compound 185-2 (0.18 g, 60%) was obtained in the same manner as step 6 of example 144, using compound 185-1.
1H NMR (400 MHz, CDCl3, δ): 8.35 (d, J=2.4 Hz, 1H), 8.01 (dd, J=8.4, 2.4 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 2H), 2.83 (s, 3H);
ESIMS m/z: [M+H]+ 336.
Compound 185-3 (0.17 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 185-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 340.
Compound 286 (0.018 g, 13% over two steps) was obtained in the same manner as step 5 of example 1, using compound 185-3.
1H NMR (400 MHz, DMSO-d6, δ): 8.73 (t, J=5.6 Hz, 1H), 8.47 (s, 1H), 8.23 (dd, J=8.8, 2.4 Hz, 1H), 7.39-7.31 (m, 3H), 6.31 (dd, J=17.0, 10.0 Hz, 1H), 6.16 (dd, J=17.0, 2.0 Hz, 1H), 5.65 (dd, J=10.0, 2.4 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 2.71 (s, 3H);
ESIMS m/z: [M+H]+ 394.
Compound 186-1 (0.45 g, 36%) was obtained in the same manner as step 1 of example 182, using compound 157-3.
1H NMR (400 MHz, CDCl3, δ): 8.53 (d, J=2.4 Hz, 1H), 7.68-7.65 (m, 2H), 7.37 (dd, J=8.8, 2.8 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 2.89 (s, 3H);
ESIMS m/z: [M+H]+ 389.
Compound 186-2 (0.19 g, 55%) was obtained in the same manner as step 6 of example 144, using compound 186-1.
1H NMR (400 MHz, CDCl3, δ): 8.60 (d, J=2.8 Hz, 1H), 7.79-7.75 (m, 2H), 7.54 (dd, J=8.8, 2.8 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 2.95 (s, 3H);
ESIMS m/z: [M+H]+ 336.
Compound 287 (0.050 g, 22%) was obtained in the same manner as step 7 of example 148, using compound 186-2.
1H NMR (500 MHz, DMSO-d6, δ): 8.70 (t, J=5.8 Hz, 1H), 8.64 (d, J=3.0 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.58 (dd, J=8.5, 2.5 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.34 (dd, J=17.0, 10.0 Hz, 1H), 6.15 (dd, J=17.0, 2.0 Hz, 1H), 5.64 (dd, J=10.0, 2.0 Hz, 1H), 4.82 (d, J=5.8 Hz, 2H), 2.84 (s, 3H);
ESIMS m/z: [M+H]+ 394.
Compound 187-1 (0.33 g, 52%) was obtained in the same manner as step 1 of example 183, using compound 157-3.
1H NMR (400 MHz, CDCl3, δ): 8.40 (s, 1H), 7.96 (dd, J=8.4, 2.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.15-7.09 (m, 2H), 2.87 (s, 3H);
ESIMS m/z: [M+H]+ 389.
Compound 187-2 (0.19 g, 73%) was obtained in the same manner as step 6 of example 144, using compound 187-1.
1H NMR (400 MHz, CDCl3, δ): 8.42 (s, 1H), 8.03 (dd, J=8.4, 2.4 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 2.91 (s, 3H);
ESIMS m/z: [M+H]+ 336.
Compound 187-3 (0.15 g) was obtained as a crude product in the same manner as step 3 of example 15, using compound 187-2, and used as it is in the next reaction.
ESIMS m/z: [M+H]+ 340.
Compound 288 (0.045 g, 20% over two steps) was obtained in the same manner as step 5 of example 1, using compound 187-3.
1H NMR (500 MHz, DMSO-d6, δ): 8.72 (t, J=5.8 Hz, 1H), 8.54 (s, 1H), 8.30 (dd, J=8.8, 2.3 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 6.34 (dd, J=17.0, 10.0 Hz, 1H), 6.15 (dd, J=17.0, 2.0 Hz, 1H),5.63 (dd, J=10.0, 2.0 Hz, 1H), 4.82 (d, J=5.8 Hz, 2H), 2.82 (s, 3H);
ESIMS m/z: [M+H]+ 394.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2017-123231 | Jun 2017 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2018/023723 | 6/22/2018 | WO | 00 |
