US20230287004A1 - Substituted polycyclic pyridone derivatives and prodrugs thereof - Google Patents

Substituted polycyclic pyridone derivatives and prodrugs thereof Download PDF

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US20230287004A1
US20230287004A1 US18/080,247 US202218080247A US2023287004A1 US 20230287004 A1 US20230287004 A1 US 20230287004A1 US 202218080247 A US202218080247 A US 202218080247A US 2023287004 A1 US2023287004 A1 US 2023287004A1
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compound
optionally substituted
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esi
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Makoto Kawai
Kenji Tomita
Toshiyuki Akiyama
Azusa OKANO
Masayoshi Miyagawa
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Priority claimed from PCT/JP2016/063139 external-priority patent/WO2016175224A1/en
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Priority to US18/080,247 priority Critical patent/US20230287004A1/en
Publication of US20230287004A1 publication Critical patent/US20230287004A1/en
Priority to US18/424,022 priority patent/US20240327424A1/en
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Definitions

  • This invention relates to substituted polycyclic pyridone derivatives having cap-dependent endonuclease inhibitory activity, prodrugs thereof, and pharmaceutical compositions including thereof.
  • Influenza is an acute respiratory infectious disease caused by infection with an influenza virus. In Japan, millions of influenza-like patients are reported every winter, and influenza is accompanied with high morbidity and mortality. Influenza is a particularly important disease in a high risk population such as baby and elderly, a complication rate with pneumonia is high in elderly, and death with influenza is occupied with elderly in many cases.
  • a cap-dependent endonuclease which is an influenza virus-derived enzyme is essential for virus proliferation, and has the virus-specific enzymatic activity which is not possessed by a host, it is believed that the endonuclease is suitable for a target of an anti-influenza drug.
  • the cap-dependent endonuclease of an influenza virus has a host mRNA precursor as a substrate, and has the endonuclease activity of producing a fragment of 9 to 13 bases including a cap structure (not including the number of bases of the cap structure). This fragment functions as a primer of a virus RNA polymerase, and is used in synthesizing mRNA encoding a virus protein. That is, it is believed that a substance which inhibits the cap-dependent endonuclease inhibits synthesis of a virus protein by inhibiting synthesis of virus mRNA and, as a result, inhibits virus proliferation.
  • Patent Document 1 and Non-Patent Documents 1 and 2 As the substance which inhibits the cap-dependent endonuclease, flutimide (Patent Document 1 and Non-Patent Documents 1 and 2), 4-substituted 2,4-dioxobutanoic acid (Patent Document 2 and Non-Patent Documents 3 and 4), the compounds described in Patent Documents 3 to 12 and the like have been reported, but they have not yet led to clinical use as anti-influenza drugs.
  • Patent Documents 9 and 12 describe compounds having a similar structure to that of this invention, but does not describe the compounds relating to the present invention.
  • Patent Documents 13 to 15 describe compounds having a similar structure to that of this invention as a compound having integrase inhibitory activity, however, the documents do not describe cap-dependent endonuclease.
  • Patent Document 16 and 17 describes an invention relating to compounds having a similar structure to that of this invention as a compound having cap-dependent endonuclease inhibitory activity, which has been filed by the applicants, but does not describe the compounds relating to the present invention.
  • An object of the present invention is to provide compounds having antiviral activities, especially inhibiting growth activity of influenza virus.
  • Another object of the present invention is to provide a prodrug prepared from compounds used for in vivo administration (for example, oral administration), being efficiently absorbed into the body after administration and showing high pharmacological effect.
  • the present invention provides inventions shown below.
  • R 2 , R 3 , R 4 and R 5 are each independently hydrogen or fluorine; the number of fluorine atoms of R 2 , R 3 , R 4 and R 5 is 1 or 2, or its pharmaceutically acceptable salt.
  • each definition has the same meaning as described in claim 1 , or its pharmaceutically acceptable salt.
  • P is hydrogen or a group P R to form a prodrug, or its pharmaceutically acceptable salt.
  • the present invention further provides a method for treating or preventing influenza infectious disease using the prodrug compound and the compound which exhibits anti influenza activity.
  • the present invention further provides a parent compound of the prodrug compound.
  • the parent compound is effective as an anti-influenza agent or an intermediate of the prodrug compound.
  • the compound according to the present invention has an inhibitory activity on cap-dependent endonuclease. More preferred compound is a prodrug, and the prodrug becomes a parent compound having an inhibitory activity on cap-dependent endonuclease in vivo after administration, thus is effective as a therapeutic agent and/or preventive agent for influenza infectious disease.
  • FIG. 1 is a result of measuring the plasma concentration of compound 111-2, after oral administration of prodrug Compound 11-6, the parent compound of which is Compound 111-2, to rat under non-fasting conditions.
  • FIG. 2 is a result of measuring the plasma concentration of compound 11-6, after oral administration of prodrug Compound 11-6, the parent compound of which is Compound 111-2, to rat under non-fasting conditions.
  • Optionally substituted by substituent group A means that an arbitrary position may be substituted by one, two or more same or different substituents selected from substituent group A.
  • Prodrug in the present description refers to a compound represented by formula (II) in the following reaction formula:
  • the prodrug more preferably means a compound in which bioavailability and/or AUC (area under the blood concentration curve) in in vivo administration is improved more than those of the compound represented by formula (III).
  • the prodrug is efficiently absorbed into the body in the stomach and/or intestines after in vivo administration (for example, oral administration), then converted into the compound represented by formula (III).
  • the prodrug preferably shows an effect of treating and/or preventing influenza higher than the compound represented by formula (III).
  • R 2 , R 3 , R 4 and R 5 are each independently hydrogen or fluorine; the number of fluorine atoms of R 2 , R 3 , R 4 and R 5 is 1 or 2.
  • Group P R to form a prodrug in the present description refers to a “P R ” group in the formula (II), in the following reaction formula:
  • the “group P R to form a prodrug” more preferably means a group that improves bioavailability and/or AUC (area under the blood concentration curve) of the compound represented by formula (III) by being added to the compound represented by formula (III).
  • Examples of the group P R to form a prodrug include the groups described in Prog. Med. 5: 2157-2161 (1985) and Supplied by The British Library—“The world's Knowledge”.
  • the “P R ” group in —OP R group in the formula (I) or (II) may be a group converted into —OH group in vivo, and examples preferably include a group selected from the following formulae a) to ac).
  • the group P R to form a prodrug is preferably a group selected from the followings.
  • Parenter compound in the present description means a compound to be a source before synthesizing the “prodrug” and/or a compound released from the “prodrug” by the reaction by enzymes, a gastric acid, and the like under physiological conditions in vivo, and specifically means a compound shown by the formula (III), or pharmaceutically acceptable salt thereof or a solvate thereof.
  • halogen includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a fluorine atom and a chlorine atom are especially preferable.
  • alkyl includes a C1 to C15, preferably C1 to C10, more preferably C1 to C6 and further preferably C1 to C4 linear or branched hydrocarbon group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like.
  • alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl.
  • a more preferred embodiment is methyl, ethyl, n-propyl, isopropyl or tert-butyl.
  • alkenyl includes a C2 to C15, preferably a C2 to C10, more preferably a C2 to C6 and further preferably a C2 to C4 linear or branched hydrocarbon group having one or more double bond(s) at any position(s).
  • Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and the like.
  • alkenyl is vinyl, allyl, propenyl, isopropenyl or butenyl.
  • alkylene includes a C1 to C15, preferably a C1 to C10, more preferably a C1 to C6 and further preferably a C1 to C4 liner or branched bivalent hydrocarbon group. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • alkenylene includes a C2 to C15, preferably a C2 to C10, more preferably a C2 to C6 and further preferably a C2 to C4 liner or branched bivalent hydrocarbon group having one or more double bond(s) at any position(s). Examples include vinylene, prenylene, butenylene, pentenylene and the like.
  • hydroxyalkyl means a group wherein one or more hydroxyl group(s) is replaced with hydrogen atom(s) attached to a carbon atom(s) of the above “alkyl”. Examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like.
  • hydroxyalkyl is hydroxymethyl
  • alkyloxy means a group wherein the above “alkyl” is bonded to an oxygen atom. Examples include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
  • alkyloxy is methyloxy, ethyloxy, n-propyloxy, isopropyloxy or tert-butyloxy.
  • haloalkyl means a group wherein one or more “halogen” described above is bonded to the above “alkyl”. Examples include monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
  • haloalkyl is trifluoromethyl or trichloromethyl.
  • alkylcarbonyl means a group wherein the above “alkyl” is bonded to a carbonyl group. Examples include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, penthylcarbonyl, isopenthylcarbonyl, hexylcarbonyl and the like.
  • alkylcarbonyl is methylcarbonyl, ethylcarbonyl or n-propylcarbonyl.
  • alkylamino means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is replaced with the above “alkyl”.
  • Two alkyl groups may be the same or different. Examples include methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, N,N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like.
  • alkylamino is methylamino, ethylamino, dimethylamino or diethylamino.
  • alkylaminoalkyl means a group wherein the above “alkylamino” is bonded to the above “alkyl”.
  • alkylaminocarbonyl means a group wherein the above “alkylamino” is bonded to a carbonyl group.
  • alkylaminocarbonyloxy means a group wherein the above “alkylaminocarbonyl” is bonded to an oxygen atom.
  • alkylcarbonylamino means a group wherein the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to a nitrogen atom of an amino group. Examples include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like.
  • alkylcarbonylamino is methylcarbonylamino or ethylcarbonylamino.
  • alkylcarbonyloxy means a group wherein the above “alkylcarbonyl” is bonded to an oxygen atom. Examples include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like.
  • alkylcarbonyloxy is methylcarbonyloxy or ethylcarbonyloxy.
  • alkylcarbonylaminoalkyl means a group wherein the above “alkylcarbonylamino” is bonded to the above “alkyl”.
  • alkyloxycarbonyl means a group wherein the above “alkyloxy” is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, penthyloxycarbonyl, isopenthyloxycarbonyl, hexyloxycarbonyl and the like.
  • alkyloxycarbonyl is methyloxycarbonyl, ethyloxycarbonyl or propyloxycarbonyl.
  • alkyloxycarbonylalkyl means a group wherein the above “alkyloxycarbonyl” is bonded to the above “alkyl”.
  • alkyloxycarbonyloxy means a group wherein the above “alkyloxycarbonyl” is bonded to an oxygen atom.
  • alkylsulfanyl means a group wherein the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like.
  • alkylsulfonyl means a group wherein the above “alkyl” is bonded to a sulfonyl group. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like.
  • alkylsulfonyl is methylsulfonyl or ethylsulfonyl.
  • titanium alkylsilyl means a group wherein three of the above “alkyl” are bonded to a silicon atom. Three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like.
  • Carbocyclyl group means C3 to C20 preferably C3 to C16, more preferably C4 to C12 cyclic hydrocarbon group and includes aromatic carbocyclyl and non-aromatic carbocyclyl.
  • aromatic carbocyclyl means a cyclic aromatic hydrocarbon group which is monocyclic or polycyclic having two or more rings. Examples include phenyl, naphthyl, anthryl, phenanthryl and the like.
  • aromatic carbocyclyl is phenyl, 1-naphthyl or 2-naphthyl. Another embodiment of “aromatic carbocyclyl” is phenyl,
  • non-aromatic carbocyclyl means a cyclic saturated hydrocarbon group or a cyclic unsaturated non-aromatic hydrocarbon group, which is monocyclic or polycyclic having two or more rings.
  • non-aromatic carbocyclyl which is polycyclic having two or more rings, include a fused ring group wherein a non-aromatic carbocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”.
  • non-aromatic carbocyclyl also include a group having a bridge or a group to form a spiro ring as follows:
  • the non-aromatic carbocyclyl which is monocyclic is preferably C3 to C16, more preferably C3 to C12 and further preferably C3 to C8 carbocyclyl.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.
  • non-aromatic carbocyclyl which is polycyclic having two or more rings, include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • carrier means C3 to C20 preferably C3 to C16, more preferably C4 to C12 cyclic hydrocarbon and includes aromatic carbocycle and non-aromatic carbocycle.
  • aromatic carbocycle means a cyclic aromatic hydrocarbon which is monocyclic or polycyclic having two or more rings. Examples include benzene ring, naphthalene ring, anthracene ring, phenanthrene ring and the like.
  • aromatic carbocycle A preferred embodiment of “aromatic carbocycle” is benzene ring and naphthalene ring are exemplified. Another embodiment of “aromatic carbocycle” is benzene ring.
  • non-aromatic carbocycle means a saturated carbocycle or an unsaturated non-aromatic carbocycle which is monocyclic or polycyclic having two or more rings.
  • non-aromatic carbocycle which is polycyclic having two or more rings, include a fused ring wherein a non-aromatic carbocycle, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocycle”.
  • non-aromatic carbocycle also include a cycle having a bridge or a cycle to form a spiro ring as follows:
  • the non-aromatic carbocycle which is monocyclic is preferably C3 to C16, more preferably C3 to C12 and further preferably C3 to C8 carbocycle.
  • Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene and the like.
  • non-aromatic carbocycle which is polycyclic having two or more rings
  • examples of non-aromatic carbocycle include indane, indene, acenaphthalene, tetrahydronaphthalene, fluorine and the like are exemplified.
  • heterocyclyl group includes an aromatic cyclyl and a non-aromatic heterocyclyl, which is containing one or more of heteroatom(s) selected independently from O, S and N.
  • aromatic heterocyclyl means an aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more of heteroatom(s) selected independently from O, S and N.
  • aromatic heterocyclyl which is polycyclic having two or more rings, include a fused ring group wherein an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”.
  • the aromatic heterocyclyl which is monocyclic, is preferably a 5- to 8-membered and more preferably 5- to 6-membered ring.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • aromatic heterocyclyl which is bicyclic, include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl and the like.
  • aromatic heterocyclyl which is polycyclic having three or more rings, include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like.
  • non-aromatic heterocyclyl means a non-aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more heteroatom(s) selected independently from O, S and N.
  • non-aromatic heterocyclyl which is polycyclic having two or more rings, include a fused ring group wherein a non-aromatic heterocycle, which is monocyclic or polycyclic having two or more ring(s), is fused with a ring of the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”.
  • non-aromatic heterocyclyl also include a group having a bridge or a group to form a Spiro ring as follows:
  • the non-aromatic heterocyclyl which is monocyclic, is preferably a 3- to 8-membered and more preferably 5- to 6-membered ring.
  • Examples include dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridinyl, tetrahydropyridinyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolinyl, tetrahydrothiazolinyl, t
  • non-aromatic heterocyclyl which is polycyclic having two or more rings
  • examples of non-aromatic heterocyclyl include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
  • heterocycle includes an aromatic cycle and a non-aromatic heterocycle, which is containing one or more of heteroatom(s) selected independently from O, S and N.
  • aromatic heterocycle means an aromatic cycle which is monocyclic or polycyclic having two or more rings, containing one or more of heteroatom(s) selected independently from O, S and N.
  • aromatic heterocycle which is polycyclic having two or more rings, include a fused ring wherein an aromatic heterocycle, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocycle”.
  • the aromatic heterocycle which is monocyclic, is preferably a 5- to 8-membered and more preferably 5- to 6-membered ring.
  • Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole and the like.
  • aromatic heterocycle which is bicyclic, include indoline, isoindoline, indazorin, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine and the like.
  • aromatic heterocycle which is polycyclic having three or more rings, include carbazole, acridine, xanthene, phenothiazine, phenoxathiin, phenoxazine, dibenzofuran and the like.
  • non-aromatic heterocycle means a non-aromatic cycle, which is monocyclic or polycyclic having two or more rings, containing one or more of heteroatom(s) selected independently from O, S and N.
  • non-aromatic heterocycle which is polycyclic having two or more rings, include a fused ling wherein a non-aromatic heterocycle, which is monocyclic or polycyclic having two or more ring(s), is fused with a ring of the above “aromatic carbocycle”, “non-aromatic carbocycle” and/or “aromatic heterocycle”.
  • non-aromatic heterocycle also include a cycle having a bridge or a cycle to form a spiro ring as follows:
  • the non-aromatic heterocycle which is monocyclic, is preferably a 3- to 8-membered and more preferably 5- to 6-membered ring.
  • Examples include dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydrofuran, tetrahydropyran, dihydrothiazoline, tetrahydrothiazoline, tetrahydroisothiazoline, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexa
  • non-aromatic heterocycle which is polycyclic having two or more rings
  • examples of non-aromatic heterocycle include indoline, isoindoline, chroman, isochroman and the like.
  • heterocycle part of “heterocyclylalkyl”, “heterocyclyloxy” or “heterocyclylamino” is same as the above “heterocycle”.
  • the present invention is characterized in that the compound isolated by optical resolution of tricyclic compounds substituted by the other tricyclic group improves cap-dependent endonuclease inhibitory activity.
  • the present invention is also characterized in that the present compound is efficiently absorbed into the body after administration (for example, oral administration), and showing high high efficacy by introducing a group P R to form a prodrug.
  • One or more hydrogen, carbon and/or other atoms in the compounds of the present invention may be replaced with isotopes of hydrogen, carbon and/or other atoms respectively.
  • isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl respectively.
  • the compounds of the present invention include compounds replaced with these isotopes.
  • the compounds replaced with the above isotopes are useful as medicines and include all of radiolabeled compounds of the compound of the present invention.
  • a “method of radiolabeling” in the manufacture of the “radiolabeled compounds” is encompassed by the present invention, and the “radiolabeled compounds” are useful for studies on metabolized drug pharmacokinetics, studies on binding assay and/or diagnostic tools.
  • a radiolabeled compound of the present invention can be prepared using well-known methods in this field of the invention.
  • a tritium-labeled compound of the present invention can be prepared by introducing a tritium to a certain compound of the present invention, through a catalytic dehalogenation reaction using a tritium. This method comprises reacting with an appropriately-halogenated precursor of the compound of the present invention with tritium gas in the presence of an appropriate catalyst, such as Pd/C, and in the presence or absent of a base.
  • an appropriate catalyst such as Pd/C
  • the other appropriate method of preparing a tritium-labeled compound can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”.
  • a 14 C-labeled compound can be prepared by using a raw material having 14 C.
  • the pharmaceutically acceptable salts of the compounds of the present invention include, for example, salts with alkaline metal (e.g., lithium, sodium, potassium or the like), alkaline earth metal (e.g., calcium, barium or the like), magnesium, transition metal (e.g., zinc, iron or the like), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline or the like) or amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid or the like) or organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, male
  • the compounds of the present invention or its pharmaceutically acceptable salts may form solvates (e.g., hydrates or the like) and/or crystal polymorphs.
  • the present invention encompasses those various solvates and crystal polymorphs.
  • “Solvates” may be those wherein any numbers of solvent molecules (e.g., water molecules or the like) are coordinated with the compounds of the present invention.
  • the compounds of the present invention or its pharmaceutically acceptable salts When the compounds of the present invention or its pharmaceutically acceptable salts are allowed to stand in the atmosphere, the compounds may absorb water, resulting in attachment of adsorbed water or formation of hydrates. Recrystallization of the compounds of the present invention or its pharmaceutically acceptable salts may produce crystal polymorphs.
  • Examples of more preferred embodiment of P R include a group selected from the following formulae a) to ac).
  • Examples of further preferred embodiment of P R include following groups.
  • Examples of another embodiment of a preferable substituent of P R include following groups.
  • a general method for producing the compound of the present invention will be exemplified below.
  • treatment which is performed in a normal experiment of organic chemistry may be conducted.
  • Synthesis of the compound of the present invention can be carried out referring to the procedures known in the art.
  • a salt of the compound of the present invention in the case where the compound of the present invention is obtained in a form of a salt, it may be purified as it is and, in the case where the compound of the present invention is obtained in a free form, a salt may be formed by a normal method by dissolving or suspending the compound in a suitable organic solvent, and adding an acid or a base.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof are present in a form of adducts with water or various solvents (hydrate or solvate) in some cases, and these adducts are included in the present invention.
  • P 1 is hydroxyl protective group
  • RP is acetal protective group
  • L is leaving group
  • Other each symbol is same as above.
  • Compound A3 can be obtained by adding Compound A2 to Compound A1 in the presence of a dehydration-condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimido-N-hydroxybenzotriazole, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, hexafluorophosphoric acid 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC ⁇ HCl, HATU, etc. in a solvent such as DMF, THF, dichloromethane, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at ⁇ 20° C. to 60° C., preferably ⁇ 10° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours.
  • Compound A3 can be obtained by adding an acylating reagent such as diphenylchlorophosphate, thionyl chloride, oxalyl chloride etc. to Compound A1 in the presence or absence of a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc. in the presence of a solvent such as THF, dioxane, dichloromethane, DMF etc., thereby, generating acid chloride, and adding Compound A2 having a substituent corresponding to an objective compound, and performing a reaction at ⁇ 20° C. to 60° C., preferably ⁇ 10° C. to 40° C. for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours.
  • an acylating reagent such as diphenylchlorophosphate, thionyl chloride, oxalyl chloride etc.
  • a base such as pyridine, triethyl
  • Compound A4 can be obtained by adding potassium carbonate, sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to Compound A3 in the presence of a solvent such as DMF, DMA, NMP, THF, etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
  • a solvent such as DMF, DMA, NMP, THF, etc.
  • a deprotecting reaction of an acetal protective group of Compound A4 can be performed by the general method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. Thereafter, a generated aldehyde group is subjected to an intramolecular reaction, thereby, Compound A5 can be obtained.
  • racemate of Compound A5 can be obtained by adding acetic acid and/or paratoluenesulfonic acid, metanesulfonic acid etc., to Compound A4 in the presence of a solvent such as DMF, toluene, THF, etc., and performing a reaction at 10° C. to 80° C., preferably 30° C. to 60° C. for 0.5 hours to 12 hours, preferably 1 hour to 6 hours.
  • Compound A5 can be obtained by optical resolution of the racemate of Compound A5 by SFC or HPLC (chiral column).
  • Compound A7 can be obtained by adding Compound A6, and a base such as sodium carbonate, potassium carbonate, cesium carbonate, etc. to Compound A5 in the presence of a solvent such as DMF, DMA, NMP, THF, etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
  • a solvent such as DMF, DMA, NMP, THF, etc.
  • Compound A7 can be obtained by adding Compound A6, and T3P, methane sulfonic acid or para-toluene sulfonic acid to Compound A5 in the presence of a solvent such as DMF, ethyl acetate, butyl acetate, 1,4-dioxane etc. or in a mixed solvent thereof, and performing a reaction at 40° C. to 150° C., preferably 60° C. to 120° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
  • a solvent such as DMF, ethyl acetate, butyl acetate, 1,4-dioxane etc. or in a mixed solvent thereof
  • a deprotecting reaction of hydroxyl protective group of Compound A7 can be performed by the general method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.
  • Compound (III) can be obtained by the general method including converting a hydroxyl group of Compound (II) into an ester group or ether group.
  • P 2 is NH protective group; L 1 and L 2 is leaving group; Other each symbol is same as above.
  • Compound B2 can be obtained by adding Compound A2 and halogenated alkyl such as methyl iodide to Compound B1 in the presence of a base such as diazabicycloundecene in a solvent such as DMF, THF, dichloromethane, acetonitrile, etc. or in a mixed solvent thereof, and performing a reaction at ⁇ 20° C. to 60° C., preferably ⁇ 10° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 24 hours.
  • a base such as diazabicycloundecene
  • a solvent such as DMF, THF, dichloromethane, acetonitrile, etc. or in a mixed solvent thereof
  • Compound B2 can be obtained by adding acylating reagent such as diphenylchlorophosphate, thionyl chloride, oxalyl chloride, etc. to Compound B1 in a solvent such as THF, dioxane, dichloromethane, DMF, etc. or in a mixed solvent thereof, and adding alcohol in the presence of a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc., and performing a reaction at ⁇ 20° C. to 60° C., preferably ⁇ 10° C. to 40° C. for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours.
  • acylating reagent such as diphenylchlorophosphate, thionyl chloride, oxalyl chloride, etc.
  • Compound B3 can be obtained by adding para-toluene sulfonic acid pyridinium and hydrazine protected by Roc etc. to Compound B2 in a solvent such as THF, dioxane, dichloromethane, DMF etc., or in a mixed solvent thereof, and performing a reaction at 10° C. to 150° C., preferably 40° C. to 100° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours.
  • a solvent such as THF, dioxane, dichloromethane, DMF etc.
  • a deprotecting reaction of amino protective group Compound B3 can be performed by the general method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.
  • Compound B6 can be obtained by adding a base such as n-butyl lithium, etc. to Compound B5 in a solvent such as THF, dioxane, dichloromethane, DMF etc., or in a mixed solvent thereof, and then adding haloformic acid alkyl and performing a reaction for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
  • a base such as n-butyl lithium, etc.
  • a solvent such as THF, dioxane, dichloromethane, DMF etc.
  • Compound B7 can be obtained by adding reducing agent such as Lithium diisobutylaluminum hydride, etc. to Compound B6 in a solvent such as THF, dioxane, dichloromethane, DMF etc., or in a mixed solvent thereof, and performing a reaction for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
  • reducing agent such as Lithium diisobutylaluminum hydride, etc.
  • Compound B8 can be obtained by adding para-toluene sulfonic acid or methane sulfonic acid to Compound B7 in alcohol, and performing a reaction at 0° C. to 100° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
  • Compound B10 can be obtained by adding haloformic acid alkyl to Compound B9 in the presence or absence of a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc., in a solvent such as THF, dioxane, dichloromethane, DMF etc., or in a mixed solvent thereof, and performing a reaction at ⁇ 40° C. to 40° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
  • a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc.
  • a solvent such as THF, dioxane, dichloromethane, DMF etc.
  • Compound B8 can be obtained by immersing carbon electrode (anode) and platinum electrode (cathode) to Compound B10 in a solvent such as alcohol in the presence of a base such as potassium carbonate and tetraethylaminium perchlorate, and flushing with a constant current of 0.1 ⁇ 1.0A with stirring for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
  • a base such as potassium carbonate and tetraethylaminium perchlorate
  • Compound (I) can be obtained from Compound B4 and B8 in the same manner as in the third to sixth steps in preparation 1.
  • the compound of the present invention has cap-dependent endonuclease inhibitory activity and is useful as a therapeutic or preventive agent for influenza.
  • the compounds of the present invention may be administered orally as a powder, a granule, tablets, capsules, pills, a liquid and the like or parenterally as an injection, suppositories, a percutaneous drug, an inhalant and the like.
  • the effective doses of the present compounds may be mixed with excipients suitable for the dosage form, such as fillers, binders, humectants, disintegrators, and lubricants, as appropriate, to form pharmaceutical preparations.
  • excipients suitable for the dosage form such as fillers, binders, humectants, disintegrators, and lubricants, as appropriate, to form pharmaceutical preparations.
  • sterilization is performed with a suitable carrier.
  • compositions according to the present invention can be administered either orally or parenterally.
  • oral administration commonly used dosage forms, such as tablets, granule, powder, and capsules, may be prepared according to conventional methods.
  • parenteral administration any commonly used dosage form, such as an injection, may be suitably used.
  • the compounds according to the present invention can be suitably used as oral preparations because of their high oral absorbability.
  • the effective doses of the compounds of the present invention can be mixed with various pharmaceutical excipients suitable for the dosage form, such as fillers, binders, disintegrators, and lubricants, as appropriate, to form pharmaceutical compositions.
  • various pharmaceutical excipients suitable for the dosage form such as fillers, binders, disintegrators, and lubricants, as appropriate, to form pharmaceutical compositions.
  • the dose depends on the condition of the disease, administration route, or age or weight of the patient.
  • the usual oral dose for adults is 0.1 to 100 mg/kg per day, preferably 1 to 20 mg/kg per day.
  • the dose of the pharmaceutical composition of the present invention is preferably determined on the basis of the age and weight of the patient, type and severity of the disease, administration route and the like.
  • the usual oral dose for adults is in the range of 0.05 to 100 mg/kg per day, preferably 0.1 to 10 mg/kg per day.
  • the parenteral dose for adults significantly varies depending on the administration route but is usually in the range of 0.005 to 10 mg/kg per day, preferably 0.01 to 1 mg/kg per day.
  • the dose may be administered once daily or may be divided into multiple daily doses.
  • the compound of the present invention can be used in combination with other drugs or the like (hereinafter referred to as combination drugs) to increase the activity of the compound, reduce the dose of the compound, or the like.
  • combination drugs e.g., Oseltamivir, Zanamivir, Peramivir, Inabiru and the like
  • RNA-dependent RNA polymerase inhibitor e.g., Favipiravir
  • M2 protein inhibitor e.g., Amantadine
  • PB2 Cap binding inhibitor e.g., VX-787
  • anti-HA antibody e.g., MHAA4549A
  • Immune agonists e.g., Nitazoxanide
  • the timing of administration for a compound of the present invention and the combination drug is not limited. They can be administered to the subjects to be treated, at a time or at different times. Furthermore, a compound of the present invention and the combination drug can be administered as two or more formulations independently comprising each active ingredient or a single formulation comprising each active ingredient.
  • the dose for combination drugs may be appropriately selected in reference to the clinical dose.
  • the compounding ratio of the compounds of the present invention and co-administered drugs may be appropriately selected depending on the subject to be treated, administration route, disease to be treated, symptoms, combination of the drugs and the like.
  • 1 part by weight of the compounds of the present invention may be used in combination with 0.01 to 100 parts by weight of co-administered drugs.
  • RT represents a retention time at LC/MS: liquid chromatography/mass spectrometry, and was measured under the following conditions.
  • Compound 16 was obtained in the same manner as in the seventh and eighth steps in reference example 1.
  • Compound 23 was obtained in the same manner as in the seventh step in reference example 1.
  • the obtained organic layer was washed with water and 8% aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was dissolved in THF (5.5 L) and potassium carbonate (790 g, 5713 mmol) was added thereto.
  • the mixture was warmed up to 50° C., benzyl bromide (240 ml, 2016 mmol) was added dropwise thereto, and the mixture was stirred at 60° C. for 8.5 hours.
  • To the mixture was added dropwise 2 mol/L aqueous solution of hydrochloric acid under ice-water bath, and the mixture was stirred at room temperature for 10 minutes and extracted with ethyl acetate.
  • Compound III-1 was obtained in the same manner as in the second step in example 1.
  • the compounds in connection with the present invention and/or the parent compounds of the compounds in connection with the present invention are useful for symptoms and/or diseases which are induced by influenza virus.
  • they are useful for treating and/or preventing, or improving symptoms of, cold-like symptoms accompanying fever, algor, headache, muscular pain, general malaise etc., airway inflammation symptoms such as pharyngalgia, nasal secretion, nasal congestion, cough, sputum etc., gastrointestinal symptoms such as abdominal pain, vomitus, diarrhea etc. and, further, complications accompanying secondary infection such as acute encephalopathy and pneumonia.
  • the compounds in connection with the present invention are a prodrug and thus have advantages that oral absorbability is high, good bioavailability is exhibited, good clearance is exhibited, and pulmonary transitivity is high, they can be excellent medicaments.
  • parent compounds of the compounds in connection with the present invention have the effects such as high inhibitory activity on cap structure-dependent endonuclease, and high selectivity due to a virus-specific enzyme, they can be medicaments having reduced side effects.
  • the compounds in connection with the present invention and/or the parent compounds of the compounds in connection with the present invention also have advantages that metabolism stability is high, solubility is high, oral absorbability is high, good bioavailability is exhibited, good clearance is exhibited, pulmonary transitivity is high, a half life is long, a non-protein binding rate is high, hERG channel inhibition is low, CYP inhibition is low, CPE (CytoPathic Effect) inhibiting effect is recognized, and/or negativity is exhibited in a phototoxicity test, an Ames test and a gene toxicity test, or toxicity such as liver damage is not caused. Therefore, the compounds in connection with the present invention can be excellent medicaments.
  • the compounds in connection with the present invention and/or the parent compounds of the compounds in connection with the present invention can be administered orally or parenterally.
  • the present compounds can be also used as a normal preparation, for example, as any dosage form of solid preparations such as tablets, powders, granules, capsules etc.; solutions; oleaginous suspensions; or liquid preparations such as syrups or elixirs etc.
  • the compounds in connection with the present invention can be used as aqueous or oleaginous suspension injectables, or nose drops.
  • the pharmaceutical composition of the present invention can be produced by combining (for example, mixing) a therapeutically effective amount of the present compound with pharmaceutically acceptable carriers or diluents.
  • a dose of the compounds in connection with the present invention is different depending on an administration method, an age, a weight and the state of a patient, and a kind of a disease and, usually, in the case of oral administration, about 0.05 mg to 3000 mg, preferably about 0.1 mg to 1000 mg for adult per day may be administered, if necessary, by division. In addition, in the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg for adult per day is administered.
  • Test Example 1 Measurement of Cap-Dependent Endonuclease (CEN) Inhibitory Activity
  • RNP was prepared from a virus particle using standard method (Reference Document: VIROLOGY(1976) 73, p327-338 OLGA M. ROCHOVANSKY). Specifically, A/WSN/33 virus (1 ⁇ 10 3 PFU/mL, 200 ⁇ L) was inoculated in a 10 days old embryonated chicken egg. After incubation at 37° C. for 2 days, the allantoic fluid of the chicken egg was recovered.
  • a virus particle was purified by ultracentrifugation using 20% sucrose, solubilized using TritonX-100 and lysolecithin, and an RNP fraction (50-70% glycerol fraction) was collected by ultracentrifugation using a 30-70% glycerol density gradient, and was used as an enzyme solution (containing approximately 1 nM PB1-PB2-PA complex).
  • An enzymatic reaction solution (2.5 ⁇ L) (composition: 53 mM Tris-hydrochloride (pH 7.8), 1 mM MgCl 2 , 1.25 mM dithiothreitol, 80 mM NaCl, 12.5% glycerol, enzyme solution 0.15 ⁇ L) was dispensed into a 384-well plate made of polypropylene. Then, 0.5 ⁇ L of a test compound solution which had been serially diluted with dimethyl sulfoxide (DMSO) was added to the plate. As a positive control (PC) or a negative control (NC), 0.5 ⁇ L of DMSO was added to the plate respectively. Each plate was mixed well.
  • DMSO dimethyl sulfoxide
  • PC positive control
  • NC negative control
  • a substrate solution (1.4 nM substrate RNA, 0.05% Tween20) was added to initiate a reaction. After room temperature incubation for 60 minutes, 1 ⁇ L, of the reaction solution was collected and added to 10 ⁇ L of a Hi-Di formamide solution (containing GeneScan 120 Liz Size Standard as a sizing marker: manufactured by Applied Biosystems (ABI)) in order to stop the reaction.
  • a Hi-Di formamide solution containing GeneScan 120 Liz Size Standard as a sizing marker: manufactured by Applied Biosystems (ABI)
  • the reaction was stopped in advance by adding EDTA (4.5 mM) before initiation of the reaction (all concentrations described above are final concentrations).
  • the solution for which the reaction was stopped was heated at 85° C. for 5 minutes, rapidly cooled on ice for 2 minutes, and analyzed with an ABI PRIZM 3730 genetic analyzer.
  • a peak of the cap-dependent endonuclease product was quantitated by analysis software ABI Genemapper, a CEN reaction inhibition ratio (%) of a test compound was obtained by setting fluorescent intensities of PC and NC to be 0% inhibition and 100% inhibition, respectively, an IC 50 value was obtained using curve fitting software (XLfit2.0: Model 205 (manufactured by IDBS) etc.).
  • the IC 50 values of test substances being a parent compound are shown in Table 39.
  • FCS E-MEM 2% FCS E-MEM was used at the use of MDBK cells, and 0.5% BSA E-MEM was used at the use of MDCK cells.
  • BSA E-MEM 0.5% BSA E-MEM was used at the use of MDCK cells.
  • test sample was diluted with a culture medium to an appropriate concentration in advance, and then 2 to 5-fold serial dilution on a 96 well plate (50 ⁇ L/well) was prepared. Two plates, one for measuring anti-Flu activity and the another for measuring cytotoxity, were prepared. Each assay was performed triplicate for each drug.
  • Trypsin was added to the cells to be a final concentration of 3 ⁇ g/mL only for measuring anti-Flu activity.
  • An influenza virus was diluted with a culture medium to an appropriate concentration in advance, and each 50 ⁇ L/well was dispensed on a 96-well plate containing a test substance. Each 50 ⁇ L/well of a culture medium was dispensed on a plate containing a test substance for measuring cytotoxity.
  • Each 100 ⁇ L/well of cells which had been adjusted to the appropriate cell number was dispensed on a 96 well plate containing a test sample.
  • the cells in the 96-well plate which had been incubated for 3 days was observed visually under a microscope, and appearance of the cells, the presence or absence of a crystal of test substance were checked. The supernatant was removed so that the cells were not absorbed from the plate.
  • WST-8 Kit was diluted 10-fold with a culture medium, and each 100 ⁇ L was dispensed into each well. After mixing with a plate mixer, cells were incubated in a CO2 incubator for 1 to 3 hours.
  • each 10 ⁇ L/well of a 10% SDS solution was dispensed in order to inactivate a virus.
  • the value was calculated using Microsoft Excel or a program having the equivalent calculation and processing ability, based on the following calculation equation.
  • test Example 1 For test substances (compounds of Reference examples) being a parent compound, measurement results of Test Example 1 and Test Example 2 are shown in Table 39.
  • the parent compounds exhibit high cap-dependent endonuclease (CEN) inhibitory activity and/or high CPE inhibitory effect and thus can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.
  • CEN cap-dependent endonuclease
  • CYP1A2 7-ethoxyresorufin O-deethylation
  • CYP2C9 mephenytoin 4′-hydroxylation
  • CYP2D6 dextromethorphan O-demethylation
  • CYP3A4 terfenedine hydroxylation
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol/L ethoxyresorufin (CYP1A2), 100 ⁇ mol/l, tolbutamide (CYP2C9), 50 ⁇ mol/L S-mephenytoinmephenitoin (CYP2C19), 5 ⁇ mol/L dextromethorphan (CYP2D6), 1 ⁇ mol/L terfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; concentration of a compound of the present invention, 1, 5, 10, 20 ⁇ mol/L (four points).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant was quantified by a fluorescent multilabel counter and toltributamide hydroxide (CYP2C9P metabolite), mephenytoin 4′ hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.
  • the prodrug had improved bioavailability other than the parent compound.
  • the compound of the present invention has excellent oral absorbability and can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.
  • a compound of the present invention was reacted for a constant time, and a remaining rate was calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver was assessed.
  • a reaction was performed (oxidative reaction) at 37° C. for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes.
  • the compound of the present invention in the supernatant was quantified by LC/MS/MS or Solid Phase Extraction (SPE)/MS, and a remaining amount of the compound of the present invention after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%.
  • Hydrolysis reaction was performed in the absence of NADPH and glucuronidation reaction was in the presence of 5 mM UDP-glucuronic acid in place of NADPH, followed by similar operations.
  • the CYP3A4 fluorescent MBI test is a test of investigating enhancement of CYP3A4 inhibition of a compound of the present invention by a metabolism reaction, and the test was performed using, as CYP3A4 enzyme expressed in Escherichia coli and employing, as an index, a reaction in which 7-benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme to produce a metabolite, 7-hydroxytrifluoromethylcoumarin (HFC) emitting fluorescent light.
  • 7-BFC 7-benzyloxytrifluoromethylcoumarin
  • reaction conditions were as follows: substrate, 5.6 ⁇ mol/L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25° C. (room temperature); CYP3A4 content (expressed in Escherichia coli ), at pre-reaction 62.5 ⁇ mol/mL, at reaction 6.25 ⁇ mol/mL (at 10-fold dilution); test drug concentration of a compound of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol/L (six points).
  • NADPH was added to a remaining preincubation solution to initiate a preincubation (with preincubation) and, after a predetermined time of a preincubation, a part was transferred to another plate so that it was 1/10 diluted with a substrate and a K-Pi buffer to initiate a reaction as an index.
  • rat typhoid bacillus Salmonella typhimurium TA98 strain, TA100 strain
  • a liquid nutrient medium (2.5% Oxoid nutrient broth No. 2)
  • 9 mL of a bacterial solution of the TA98 strain was centrifuged (2000 ⁇ g, 10 minutes) to remove a culturing solution.
  • DMSO solution of a compound of the present invention (several stage dilution from maximum dose 50 mg/mL at 2 to 3 fold ratio), DMSO as a negative control, and 50 ⁇ g/mL of 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain, 0.25 ⁇ g/mL of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain under the non-metabolism activating condition, 40 ⁇ g/mL of 2-aminoanthracene DMSO solution for the TA98 strain, 20 ⁇ g/mL of 2-aminoanthracene DMSO solution for the TA100 strain under the metabolism activating condition as a positive control, and 588 ⁇ L of the test bacterial solution (a mixed solution of 498 ⁇ l of the test bacterial solution and 90 ⁇ L of S9 mix under the metabolism activating condition) were mixed, and this was shaking-cultured at 37° C
  • 460 ⁇ L of the bacterial solution exposed to a compound of the present invention was mixed with 2300 ⁇ L of an Indicator medium (Micro F buffer containing biotin: 8 ⁇ g/mL, histidine: 0.2 ⁇ g/mL, glucose: 8 mg/mL, Bromo Cresol Purple: 37.5 ⁇ g/mL), each 50 ⁇ L was dispensed into microplate 48 wells/dose, and this was subjected to stationary culturing at 37° C. for 3 days.
  • an Indicator medium Micro F buffer containing biotin: 8 ⁇ g/mL, histidine: 0.2 ⁇ g/mL, glucose: 8 mg/mL, Bromo Cresol Purple: 37.5 ⁇ g/mL
  • the solubility of the compound of the present invention was determined under 1% DMSO addition conditions.
  • a 10 mmol/L solution of the compound was prepared with DMSO, and 2 ⁇ L of the solution of the compound of the present invention was added, respectively, to 198 ⁇ L of JP-1 solution (water were added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL) and, JP-2 solution (1 volume of water were added to 1 volume of the solution which 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate to reach 1000 mL).
  • the mixture was shaked for 1 hour at a room temperature, and the mixture was filtered.
  • JP-1st Fluid water was added to 2.0 g of sodium chloride in 7.0 mL of hydrochloride acid to reach 1000 mL
  • JP-2nd Fluid water was added to 500 mL of phosphate buffer solution with a pH of 6.8 and 20 mmol/L sodium taurocholate (TCA)/JP-2nd Fluid
  • TCA sodium taurocholate
  • JP-2nd Fluid was added to 1.08 g of TCA in JP-2nd Fluid to reach 100 mL
  • the mixture was filtered and 100 ⁇ L of methanol was added to 100 ⁇ L of each filtrate (double dilution). Dilution magnification was changed if necessary. After it was confirmed whether there were air bubbles and precipitates in the vials, the vials were shaken with tight stopper. The compound concentration was determined with HPLC by the absolute calibration method.
  • Test Example 11 Ames Test
  • Ames test was performed by using Salmonellas ( Salmonella typhimurium ) TA 98, TA100, TA1535 and TA1537 and Escherichia coli WP2uvrA as test strains with or without metabolic activation in the pre-incubation method to check the presence or absence of gene mutagenicity of compounds of the present invention.
  • the compound of the present invention was dissolved at target concentrations and was mixed with a 2.5 v/v % suspension of red blood cells prepared from a defibrinated blood of sheep on a microplate at concentrations of 0.0008 to 0.1 w/v %.
  • the mixtures were exposed to 10 J/cm 2 of UV-irradiation within a range of wavelength 290 to 400 nm, UVA and UVB using ultra violet fluorescent lamps, GL20SE and FL20S-BLB lamps manufactured by Sankyo Denki Co., Ltd. and Panasonic Corporation, respectively. After the completion of the irradiation, the mixtures were centrifuged, and a supernatant of the mixture was collected and was located on a microplate.
  • the phototoxicity was assessed by measuring an absorbance at wavelength of 540 nm and 630 nm in the supernatant.
  • the absorbance data at wavelength of 540 nm and 630 nm were used as indicators of biomembrane damage (photohemolysis %) and hyperoxidation of lipid membrane (methemoglobin formation), respectively.
  • the criteria of phototoxicity was as follows; It was judged to be non-phototoxic ( ⁇ ) when the photohemolysis % ⁇ 10 and the maximal change in the absorbance at 630 nm ( ⁇ OD) ⁇ 0.05 were observed. It was judged to be non-phototoxic (+) when the photohemolysis was more than 10% and the maximal change in the absorbance at 630 nm ( ⁇ OD) was more than 0.05.
  • FIGS. 1 and 2 show a result of measuring the plasma concentration of Compound 111-2 and Compound 11-6 after oral administration of prodrug Compound 11-6, the parent compound of which is Compound 111-2, to rat under non-fasting conditions.
  • prodrug Compound 11-6 the parent compound of which is Compound 111-2 is found to have changed promptly to Compound 111-2 in vivo after administration (see FIG. 2 ).
  • the compound converted into a prodrug was absorbed into the body after oral administration, and rapidly converted into a parent compound in the blood. Therefore, the compound of the present invention can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.
  • Compound 111-2 is a compound having a low total body clearance and a long half-life.
  • the compound of the present invention has excellent persistence and can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.
  • the compounds of the present invention, lactose and calcium stearate are mixed.
  • the mixture is crushed, granulated and dried to give a suitable size of granules.
  • calcium stearate is added to the granules, and the mixture is compressed and molded to give tablets.
  • the compounds of the present invention, lactose and calcium stearate are mixed uniformly to obtain powder medicines in the form of powders or fine granules.
  • the powder medicines are filled into capsule containers to give capsules.
  • lactose and calcium stearate are mixed uniformly and the mixture is compressed and molded. Then, it is crushed, granulated and sieved to give suitable sizes of granules.
  • the compounds of the present invention and crystalline cellulose are mixed, granulated and tablets are made to give orally disintegrated tablets.
  • the compounds of the present invention and lactose are mixed, crushed, granulated and sieved to give suitable sizes of dry syrups.
  • the compounds of the present invention and phosphate buffer are mixed to give injection.
  • the compounds of the present invention and phosphate buffer are mixed to give injection.
  • the compound of the present invention and lactose are mixed and crushed finely to give inhalations.
  • the compounds of the present invention and petrolatum are mixed to give ointments.
  • the compounds of the present invention and base such as adhesive plaster or the like are mixed to give patches.
  • the compound of the present invention has cap-dependent endonuclease (CEN) inhibitory activity after absorption into the body.
  • CEN cap-dependent endonuclease
  • the compound of the present invention can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.

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Abstract

The present invention provides the following compounds having anti-viral activity.A1 is CR1AR1B, S or O;A2 is CR2AR2B, S or O;A3 is CR3AR3B, S or O;A4 is CR4AR4B, S or O;the number of hetero atoms among atoms constituting the ring which consists of A1,A2, A3, A4, nitrogen atom adjacent to A1 and carbon atom adjacent to A1, is 1 or 2;R1A and R1B are each independently hydrogen, halogen, alkyl, or the like;R2A and R2B are each independently hydrogen, halogen, alkyl, or the like;R3A and R3B are each independently hydrogen, halogen, alkyl, or the like;R4A and R4B are each independently hydrogen, halogen, alkyl, or the like;R3A and R3B may be taken together to form non-aromatic carbocycle or non-aromatic heterocycle;X is CH2, S or O;R1 is each independently halogen, hydroxy, or the like;m is any integer of 0 to 2; andn is any integer of 1 to 2.

Description

    TECHNICAL FIELD
  • This invention relates to substituted polycyclic pyridone derivatives having cap-dependent endonuclease inhibitory activity, prodrugs thereof, and pharmaceutical compositions including thereof.
    • BACKGROUND ART
  • Influenza is an acute respiratory infectious disease caused by infection with an influenza virus. In Japan, millions of influenza-like patients are reported every winter, and influenza is accompanied with high morbidity and mortality. Influenza is a particularly important disease in a high risk population such as baby and elderly, a complication rate with pneumonia is high in elderly, and death with influenza is occupied with elderly in many cases.
  • As anti-influenza drugs, Symmetrel (trade name: Amantadine) and Flumadine (trade name: Rimantadine) which inhibit the denucleation process of a virus, and Oseltamivir (trade name: Tamiflu) and Zanamivir (trade name: Relenza) which are neuraminidase inhibitors suppressing virus budding and release from a cell are known. However, since problems of appearances of resistant strains and side effects, and worldwide epidemic of a new-type influenza virus having high pathogenicity and mortality are feared, development of an anti-influenza drug having a novel mechanism has been desired.
  • Since a cap-dependent endonuclease which is an influenza virus-derived enzyme is essential for virus proliferation, and has the virus-specific enzymatic activity which is not possessed by a host, it is believed that the endonuclease is suitable for a target of an anti-influenza drug. The cap-dependent endonuclease of an influenza virus has a host mRNA precursor as a substrate, and has the endonuclease activity of producing a fragment of 9 to 13 bases including a cap structure (not including the number of bases of the cap structure). This fragment functions as a primer of a virus RNA polymerase, and is used in synthesizing mRNA encoding a virus protein. That is, it is believed that a substance which inhibits the cap-dependent endonuclease inhibits synthesis of a virus protein by inhibiting synthesis of virus mRNA and, as a result, inhibits virus proliferation.
  • As the substance which inhibits the cap-dependent endonuclease, flutimide (Patent Document 1 and Non-Patent Documents 1 and 2), 4-substituted 2,4-dioxobutanoic acid (Patent Document 2 and Non-Patent Documents 3 and 4), the compounds described in Patent Documents 3 to 12 and the like have been reported, but they have not yet led to clinical use as anti-influenza drugs. Patent Documents 9 and 12 describe compounds having a similar structure to that of this invention, but does not describe the compounds relating to the present invention. Also, Patent Documents 13 to 15 describe compounds having a similar structure to that of this invention as a compound having integrase inhibitory activity, however, the documents do not describe cap-dependent endonuclease. In addition, Patent Document 16 and 17 describes an invention relating to compounds having a similar structure to that of this invention as a compound having cap-dependent endonuclease inhibitory activity, which has been filed by the applicants, but does not describe the compounds relating to the present invention.
    • PRIOR ART DOCUMENTS Patent Documents
    • Patent Document 1: GB2280435
    • Patent Document 2: U.S. Pat. No. 5,475,109
    • Patent Document 3: US20130090300
    • Patent Document 4: WO2013/057251
    • Patent Document 5: WO2013/174930
    • Patent Document 6: WO2014/023691
    • Patent Document 7: WO2014/043252
    • Patent Document 8: WO2014/074926
    • Patent Document 9: WO2014/108406
    • Patent Document 10: WO2014/108407
    • Patent Document 11: WO2014/108408
    • Patent Document 12: WO2015/038655
    • Patent Document 13: WO2005/016927
    • Patent Document 14: WO2006/066414
    • Patent Document 15: WO2007/049675
    • Patent Document 16: WO2010/147068
    • Patent Document 17: WO2012/039414
    Non-Patent Documents
    • Non-Patent Document 1: Tetrahedron Lett 1995, 36(12), 2005
    • Non-Patent Document 2: Tetrahedron Lett 1995, 36(12), 2009
    • Non-Patent Document 3: Antimicrobial Agents And Chemotherapy, Dec. 1994, p.2827-2837
    • Non-Patent Document 4: Antimicrobial Agents And Chemotherapy, May 1996, p.1304-1307
    SUMMARY OF THE INVENTION Problems to be Solved by the Invention
  • An object of the present invention is to provide compounds having antiviral activities, especially inhibiting growth activity of influenza virus. Another object of the present invention is to provide a prodrug prepared from compounds used for in vivo administration (for example, oral administration), being efficiently absorbed into the body after administration and showing high pharmacological effect.
    • Means for Solving the Problems
  • The present invention provides inventions shown below.
      • (1) A compound represented by formula (I):
  • Figure US20230287004A1-20230914-C00002
      • or its pharmaceutically acceptable salt:
      • wherein
      • P is hydrogen or a group PR to form a prodrug;
      • A1 is C1AR1B, S or O;
      • A2 is CR2AR2B, S or O;
      • A3 is CR3AR3B, S or O;
      • A4 is each independently CR4AR4B, S or 0;
      • the number of hetero atoms among atoms constituting the ring which consists of A1,
      • A2, A3, A4, nitrogen atom adjacent to A1 and carbon atom adjacent to A4, is 1 or 2;
      • R1A and R1B are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl;
      • R2A and R2B are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl;
      • R3A and R3B are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl;
      • R4A and R4B are each independently hydrogen, halogen, alkyl, haloalkyl, alkyloxy or phenyl;
      • R3A and R3B may be taken together with an adjacent carbon atom to form non-aromatic carbocycle or non-aromatic heterocycle;
      • X is CH2, S or O;
      • R1 is each independently halogen, hydroxy, alkyl, haloalkyl or alkyloxy;
      • m is any integer of 0 to 2; and
      • n is any integer of 1 to 2;
      • provided that the following compounds are excluded:
  • Figure US20230287004A1-20230914-C00003
      • wherein each definition has the same meaning as described above.
      • (2) The compound according to (1), wherein the group represented by formula:
  • Figure US20230287004A1-20230914-C00004
      • wherein each definition has the same meaning as described (1)
      • is a group represented by formula:
  • Figure US20230287004A1-20230914-C00005
  • wherein R2, R3, R4 and R5 are each independently hydrogen or fluorine; the number of fluorine atoms of R2, R3, R4 and R5 is 1 or 2, or its pharmaceutically acceptable salt.
      • (3) The compound according to (1), wherein the group represented by formula:
  • Figure US20230287004A1-20230914-C00006
  • wherein each definition has the same meaning as described (1)
      • is a group represented by formula:
  • Figure US20230287004A1-20230914-C00007
  • or its pharmaceutically acceptable salt.
      • (4) The compound according to any one of (1) to (3), wherein the group represented by formula:
  • Figure US20230287004A1-20230914-C00008
  • wherein each definition has the same meaning as described (1)
      • is represented by formula:
  • Figure US20230287004A1-20230914-C00009
  • wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt.
      • (5) The compound according to (1) represented by the following formula:
  • Figure US20230287004A1-20230914-C00010
    Figure US20230287004A1-20230914-C00011
    Figure US20230287004A1-20230914-C00012
    Figure US20230287004A1-20230914-C00013
    Figure US20230287004A1-20230914-C00014
    Figure US20230287004A1-20230914-C00015
    Figure US20230287004A1-20230914-C00016
  • wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt.
      • (6) The compound according to (1) represented by the following formula:
  • Figure US20230287004A1-20230914-C00017
  • wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt.
      • (7) The compound according to (1), represented by the following formula:
  • Figure US20230287004A1-20230914-C00018
  • wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt.
      • (8) The compound according to (1), represented by the following formula:
  • Figure US20230287004A1-20230914-C00019
  • wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt.
      • (9) The compound according to (1), represented by the following formula:
  • Figure US20230287004A1-20230914-C00020
  • wherein each definition has the same meaning as described (1), or its pharmaceutically acceptable salt.
      • (10) The compound according to (1), represented by the following formula:
  • Figure US20230287004A1-20230914-C00021
  • wherein each definition has the same meaning as described in claim 1, or its pharmaceutically acceptable salt.
      • (11) The compound represented by the following formula:
  • Figure US20230287004A1-20230914-C00022
  • wherein P is hydrogen or a group PR to form a prodrug, or its pharmaceutically acceptable salt.
      • (12) The compound according to any one of (1) to (11), or its pharmaceutically acceptable salt,
      • wherein PR is a group selected from the following formula a) to ac):
      • a) —C(═O)—PR0,
      • b) —C(═O)—PR1,
      • c) —C(═O)-L-PR1,
      • d) —C(═O)-L-O—PR1,
      • e) —C(═O)-L-O-L-O—PR1,
      • f) —C(═O)-L-O—C(═O)—PR1,
      • g) —C(═O)—O—PR2,
      • h) —C(═O)—N(—K)(PR2),
      • i) —C(═O)—O-L-O—PR2,
      • j) —C(PR3)2—O—PR4,
      • k) —C(PR3)2—O-L-O—PR4,
      • l) —C(PR3)2—O—C(═O)—PR4,
      • m) —C(PR3)2—O—C(═O)—O—PR4,
      • n) —C(PR3)2—O—C(═O)—N(—K)—PR4,
      • o) —C(PR3)2—O—C(═O)—O-L-O—PR4,
      • p) —C(PR3)2—O—C(═O)—O-L-N(PR4)2,
      • q) —C(PR3)2—O—C(═O)—N(—K)-L-O—PR4,
      • r) —C(PR3)2—O—C(═O)—N(K)-L-N(PR4)2,
      • s) —C(PR3)2—O—C(═O)—O-L-O-L-O—PR4,
      • t) —C(PR3)2—O—C(═O)—O-L-N(—K)—C(═O)—PR4,
      • u) —C(PR3)2—O—P(═O)(—PR5)2,
      • v) —C(PR3)2—PR6,
      • w) —C(═N+(PR7)2)(—N(PR7)2),
      • x) —C(PR3)2—C(PR3)2—C(═O)—O—PR2,
      • y) —C(PR3)2—N(—K)—C(═O)—O—PR2,
      • z) —P(═O)(—PR8)(—PR9),
      • aa) —S(═O)2—PR10,
      • ab) —PR11, and
      • ac) —C(PR3)2—C(PR3)2—O—PR2,
      • wherein L is straight or branched alkylene, or straight or branched alkenylene;
      • K is hydrogen, or alkyl optionally substituted by substituent group A;
      • PR0 is alkyl optionally substituted by substituent group A, or alkenyl optionally substituted by substituent group A;
      • PR1 is carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, or alkylsulfanyl optionally substituted by substituent group A;
      • PR2 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A or trialkylsilyl;
      • PR3 is each independently hydrogen or alkyl;
      • PR4 is each independently alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A, or trialkylsilyl;
      • PR5 is each independently hydroxy or OBn;
      • PR6 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR7 is each independently alkyl optionally substituted by substituent group A;
      • PR8 is alkyloxy optionally substituted by substituent group A;
      • PR9 is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A or heterocyclylamino optionally substituted by substituent group A;
      • PR8 and PR9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A;
      • PR10 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A or heterocyclylalkyl optionally substituted by substituent group A;
      • PR11 is alkyl optionally substituted by substituent group A, alkenyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • Substituent group A; oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl group, heterocyclyl group, carbocyclylalkyl, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkyloxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho.
      • (13) The compound according to (12), or its pharmaceutically acceptable salt,
      • wherein PR is a group selected from the following formula:
      • a) —C(═O)—PR0
      • b) —C(═O)—PR1,
      • g) —C(═O)—O—PR2,
      • h) —C(═O)—N(—K)(PR2)
      • i) —C(═O)—O-L-O—PR2
      • l) —C(PR3)2—O—C(═O)—PR4,
      • m) —C(PR3)2—O—C(═O)—O—PR4,
      • o) —C(PR3)2—O—C(═O)—O-L-O—PR4,
      • v) —C(PR3)2—PR6,
      • x) —C(PR3)2—C(PR3)2—C(═O)—O—PR2,
      • y) —C(PR3)2—N(—K)—C(═O)—O—PR2, and
      • z) —P(═O)(—PR8)(—PR9),
      • wherein L is straight or branched alkylene;
      • K is hydrogen or alkyl optionally substituted by substituent group A;
      • PR0 is alkyl optionally substituted by substituent group A;
      • PR1 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR2 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, or heterocyclylalkyl optionally substituted by substituent group A;
      • PR3 is each independently hydrogen or alkyl;
      • PR4 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR6 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR8 is alkyloxy optionally substituted by substituent group A;
      • PR9 is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A or heterocyclylamino optionally substituted by substituent group A; and
      • PR8 and PR9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A,
      • Substituent group A; oxo, alkyl, alkylamino, carbocyclyl group, heterocyclyl group, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, cyano, nitro, azido, alkylsulfonyl and trialkylsilyl.
      • (14) A compound represented by following formula:
  • Figure US20230287004A1-20230914-C00023
  • or its pharmaceutically acceptable salt.
      • (15) A compound represented by the following formula:
  • Figure US20230287004A1-20230914-C00024
  • or its pharmaceutically acceptable salt.
      • (16) A pharmaceutical composition comprising the compound of any one of (1) to (15), or its pharmaceutically acceptable salt.
      • (17) The pharmaceutical composition according to (16), which exhibits anti influenza activity.
      • (18) The pharmaceutical composition according to (16), which exhibits cap-dependent endonuclease inhibitory activity.
      • (19) A method for treating and/or preventing disease caused by a virus having cap-dependent endonuclease characterized in administering the compound of any one of (1) to (15), or its pharmaceutically acceptable salt.
      • (20) A compound according to any one of (1) to (15) or its pharmaceutically acceptable salt, for treating or preventing disease caused by a virus having cap-dependent endonuclease.
      • (21) A use of the compound according to any one of (1) to (15) or its pharmaceutically acceptable salt, for the production of a therapeutic or prophylactic agent for disease caused by a virus having cap-dependent endonuclease.
      • (22) A pharmaceutical composition comprising the compound of any one of (1) to (15), or its pharmaceutically acceptable salt, for oral administration.
      • (23) The pharmaceutical composition according to (22), which is a tablet, powder, granule, capsule, pill, film, suspension, emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract, decoction or tincture.
      • (24) The pharmaceutical composition of according to (16), which is a sugar-coated tablet, film-coated tablet, enteric-coated tablet, sustained-release tablet, troche tablet, sublingual tablet, buccal tablet, chewable tablet, orally disintegrated tablet, dry syrup, soft capsule, micro capsule or sustained-release capsule.
      • (25) A pharmaceutical composition comprising the compound according to any one of (1) to (15), or its pharmaceutically acceptable salt, for parenteral administration.
      • (26) The pharmaceutical composition according to (25), for dermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, inner ear or vaginal administration.
      • (27) The pharmaceutical composition according to (25) or (26), which is injection, infusion, eye drop, nose drop, ear drop, aerosol, inhalation, lotion, impregnation, liniment, mouthwash, enema, ointment, plaster, jelly, cream, patch, cataplasm, external powder or suppository.
      • (28) A pharmaceutical composition comprising the compound according to any one of (1) to (15), or its pharmaceutically acceptable salt, for a pediatric or geriatric patient.
      • (29) A pharmaceutical composition consisting of a combination of the compound according to any one of (1) to (15) or its pharmaceutically acceptable salt and Neuraminidase inhibitor, RNA-dependent RNA polymerase inhibitor, M2 protein inhibitor, PB2 Cap binding inhibitor, an anti-HA antibody or immunological agent.
      • (30) A pharmaceutical composition comprising the compound according to any one of (1) to (15), or its pharmaceutically acceptable salt, for a combination therapy with Neuraminidase inhibitor, RNA-dependent RNA polymerase inhibitor, M2 protein inhibitor, PB2 Cap binding inhibitor, an anti-HA antibody or immunological agent.
  • The present invention further provides a method for treating or preventing influenza infectious disease using the prodrug compound and the compound which exhibits anti influenza activity. The present invention further provides a parent compound of the prodrug compound. The parent compound is effective as an anti-influenza agent or an intermediate of the prodrug compound.
    • Effect of the Invention
  • The compound according to the present invention has an inhibitory activity on cap-dependent endonuclease. More preferred compound is a prodrug, and the prodrug becomes a parent compound having an inhibitory activity on cap-dependent endonuclease in vivo after administration, thus is effective as a therapeutic agent and/or preventive agent for influenza infectious disease.
    • BRIEF DESCRIPTION OF DRAWINGS
  • FIG. 1 is a result of measuring the plasma concentration of compound 111-2, after oral administration of prodrug Compound 11-6, the parent compound of which is Compound 111-2, to rat under non-fasting conditions.
  • FIG. 2 is a result of measuring the plasma concentration of compound 11-6, after oral administration of prodrug Compound 11-6, the parent compound of which is Compound 111-2, to rat under non-fasting conditions.
    •  BEST MODE FOR CARRYING OUT THE INVENTION
  • The meaning of each term used in the present description is explained below. Each term is used in a unified sense, and is used in the same sense when used alone, or when used in combination of other term.
  • The term of “consisting of” means having only components.
  • The term of “comprising” means not restricting with components and not excluding undescribed factors.
  • “Optionally substituted by substituent group A” means that an arbitrary position may be substituted by one, two or more same or different substituents selected from substituent group A.
  • “Prodrug” in the present description refers to a compound represented by formula (II) in the following reaction formula:
  • Figure US20230287004A1-20230914-C00025
      • wherein each symbol is same as the above,
      • or its pharmaceutically acceptable salt, and means a compound showing cap-dependent endonuclease (CEN) inhibitory activity and/or CPE inhibitory effect by being converted into a compound represented by formula (III) by a decomposition reaction caused by drug-metabolizing enzymes, hydrolases, gastric acids, enterobacteria, etc. under physiological conditions in vivo.
  • The prodrug more preferably means a compound in which bioavailability and/or AUC (area under the blood concentration curve) in in vivo administration is improved more than those of the compound represented by formula (III).
  • Therefore, the prodrug is efficiently absorbed into the body in the stomach and/or intestines after in vivo administration (for example, oral administration), then converted into the compound represented by formula (III). Thus, the prodrug preferably shows an effect of treating and/or preventing influenza higher than the compound represented by formula (III).
  • One embodiment of the “group represented by
  • Figure US20230287004A1-20230914-C00026
      • “wherein each definition has the same meaning as described (1),
      • is a group represented by formula:
  • Figure US20230287004A1-20230914-C00027
  • wherein R2, R3, R4 and R5 are each independently hydrogen or fluorine; the number of fluorine atoms of R2, R3, R4 and R5 is 1 or 2.
  • Another embodiment is a group represented by formula:
  • Figure US20230287004A1-20230914-C00028
  • and a group represented by formula:
  • Figure US20230287004A1-20230914-C00029
  • is preferable, and a group represented by formula:
  • Figure US20230287004A1-20230914-C00030
  • is especially preferable.
  • “Group PR to form a prodrug” in the present description refers to a “PR” group in the formula (II), in the following reaction formula:
  • Figure US20230287004A1-20230914-C00031
      • wherein each symbol is same as the above,
      • and —OPR group is converted into —OH group in the formula (III) by a decomposition reaction caused by drug-metabolizing enzymes, hydrolases, gastric acids, enterobacteria, etc. under physiological conditions in vivo.
  • The “group PR to form a prodrug” more preferably means a group that improves bioavailability and/or AUC (area under the blood concentration curve) of the compound represented by formula (III) by being added to the compound represented by formula (III).
  • Examples of the group PR to form a prodrug include the groups described in Prog. Med. 5: 2157-2161 (1985) and Supplied by The British Library—“The world's Knowledge”.
  • The “PR” group in —OPR group in the formula (I) or (II) may be a group converted into —OH group in vivo, and examples preferably include a group selected from the following formulae a) to ac).
      • a) —C(═O)—PR0,
      • b) —C(═O)—PR1,
      • c) —C(═O)-L-PR1,
      • d) —C(═O)-L-O—PR1,
      • e) —C(═O)-L-O-L-O—PR1,
      • f) —C(═O)-L-O—C(═O)—PR1,
      • g) —C(═O)—O—PR2,
      • h) —C(═O)—N(—K)(PR2),
      • i) —C(═O)—O-L-O—PR2,
      • j) —C(PR3)2—O—PR4,
      • k) —C(PR3)2—O-L-O—PR4,
      • l) —C(PR3)2—O—C(═O)—PR4,
      • m) —C(PR3)2—O—C(═O)—O—PR4,
      • n) —C(PR3)2—O—C(═O)—N(—K)—PR4,
      • o) —C(PR3)2—O—C(═O)—O-L-O—PR4,
      • p) —C(PR3)2—O—C(═O)—O-L-N(PR4)2,
      • q) —C(PR3)2—O—C(═O)—N(—K)-L-O—PR4,
      • r) —C(PR3)2—O—C(═O)—N(K)-L-N(PR4)2,
      • s) —C(PR3)2—O—C(═O)—O-L-O-L-O—PR4,
      • t) —C(PR3)2—O—C(═O)—O-L-N(—K)—C(═O)—PR4,
      • u) —C(PR3)2—O—P(═O)(—PR5)2,
      • v) —C(PR3)2—PR6,
      • w) —C(═N+(PR7)2)(—N(PR7)2),
      • x) —C(PR3)2—C(PR3)2—C(═O)—O—PR2,
      • y) —C(PR3)2—N(—K)—C(═O)—O—PR2,
      • z) —P(═O)(—PR8)(—PR9),
      • aa) —S(═O)2—PR10,
      • ab) —PR11, and
      • ac) —C(PR3)2—C(PR3)2—O—PR2,
      • wherein L is straight or branched alkylene, or straight or branched alkenylene; K is hydrogen, or alkyl optionally substituted by substituent group A;
      • PR0 is alkyl optionally substituted by substituent group A, or alkenyl optionally substituted by substituent group A;
      • PR1 is carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, or alkylsulfanyl optionally substituted by substituent group A;
      • PR2 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A or trialkylsilyl;
      • PR3 is each independently hydrogen or alkyl;
      • PR4 is each independently alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyl alkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A, or trialkylsilyl;
      • PR5 is each independently hydroxy or OBn;
      • PR6 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR7 is each independently alkyl optionally substituted by substituent group A;
      • PR8 is alkyloxy optionally substituted by substituent group A;
      • PR9 is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A or heterocyclylamino optionally substituted by substituent group A;
      • PR8 and PR9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A;
      • PR10 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A or heterocyclylalkyl optionally substituted by substituent group A;
      • PR11 is alkyl optionally substituted by substituent group A, alkenyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A.
      • Substituent group A; oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl, heterocyclyl, carbocyclylalkyl, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkyloxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho.
  • The group PR to form a prodrug is preferably a group selected from the followings.
      • a) —C(═O)—PR0,
      • b) —C(═O)—PR1,
      • g) —C(═O)—O—PR2,
      • h) —C(═O)—N(—K)(PR2),
      • i) —C(═O)—O-L-O—PR2,
      • l) —C(PR3)2—O—C(═O)—PR4,
      • m) —C(PR3)2—O—C(═O)—O—PR4,
      • o) —C(PR3)2—O—C(═O)—O-L-O—PR4,
      • v) —C(PR3)2—PR6,
      • x) —C(PR3)2—C(PR3)2—C(═O)—O—PR2,
      • y) —C(PR3)2—N(—K)—C(═O)—O—PR2,
      • z) —P(═O)(—PR8)(—PR9),
      • wherein L is straight or branched alkylene;
      • K is hydrogen, or alkyl optionally substituted by substituent group A;
      • PR0 is alkyl optionally substituted by substituent group A;
      • PR1 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR2 is each independently alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, or heterocyclylalkyl optionally substituted by substituent group A;
      • PR3 is each independently hydrogen or alkyl;
      • PR4 is each independently alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR6 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR8 is alkyloxy optionally substituted by substituent group A;
      • PR9 is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A or heterocyclylamino optionally substituted by substituent group A; and
      • PR8 and PR9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A.
      • Substituent group A; oxo, alkyl, alkylamino, carbocyclyl, heterocyclyl, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, nitro, azido, alkylsulfonyl and trialkylsilyl.
  • “Converted into a prodrug” in the present description means that, as shown in the following reaction formula:
  • Figure US20230287004A1-20230914-C00032
      • wherein each symbol is same as the above,
      • a hydroxy group in the formula (III) or its pharmaceutically acceptable salt is converted into —OPR group.
  • “Parent compound” in the present description means a compound to be a source before synthesizing the “prodrug” and/or a compound released from the “prodrug” by the reaction by enzymes, a gastric acid, and the like under physiological conditions in vivo, and specifically means a compound shown by the formula (III), or pharmaceutically acceptable salt thereof or a solvate thereof.
  • The term “halogen” includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. A fluorine atom and a chlorine atom are especially preferable.
  • The term “alkyl” includes a C1 to C15, preferably C1 to C10, more preferably C1 to C6 and further preferably C1 to C4 linear or branched hydrocarbon group. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl and the like.
  • A preferred embodiment of “alkyl” is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or n-pentyl. A more preferred embodiment is methyl, ethyl, n-propyl, isopropyl or tert-butyl.
  • The term “alkenyl” includes a C2 to C15, preferably a C2 to C10, more preferably a C2 to C6 and further preferably a C2 to C4 linear or branched hydrocarbon group having one or more double bond(s) at any position(s). Examples include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl and the like.
  • A preferred embodiment of “alkenyl” is vinyl, allyl, propenyl, isopropenyl or butenyl.
  • The term “alkylene” includes a C1 to C15, preferably a C1 to C10, more preferably a C1 to C6 and further preferably a C1 to C4 liner or branched bivalent hydrocarbon group. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.
  • The term “alkenylene” includes a C2 to C15, preferably a C2 to C10, more preferably a C2 to C6 and further preferably a C2 to C4 liner or branched bivalent hydrocarbon group having one or more double bond(s) at any position(s). Examples include vinylene, prenylene, butenylene, pentenylene and the like.
  • The term “hydroxyalkyl” means a group wherein one or more hydroxyl group(s) is replaced with hydrogen atom(s) attached to a carbon atom(s) of the above “alkyl”. Examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like.
  • A preferred embodiment of “hydroxyalkyl” is hydroxymethyl.
  • The term “alkyloxy” means a group wherein the above “alkyl” is bonded to an oxygen atom. Examples include methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
  • A preferred embodiment of “alkyloxy” is methyloxy, ethyloxy, n-propyloxy, isopropyloxy or tert-butyloxy.
  • The term “haloalkyl” means a group wherein one or more “halogen” described above is bonded to the above “alkyl”. Examples include monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
  • A preferred embodiment of “haloalkyl” is trifluoromethyl or trichloromethyl.
  • The term “alkylcarbonyl” means a group wherein the above “alkyl” is bonded to a carbonyl group. Examples include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, penthylcarbonyl, isopenthylcarbonyl, hexylcarbonyl and the like.
  • A preferred embodiment of “alkylcarbonyl” is methylcarbonyl, ethylcarbonyl or n-propylcarbonyl.
  • The term “alkylamino” means a group wherein one or two hydrogen atom(s) attached to a nitrogen atom of an amino group is replaced with the above “alkyl”. Two alkyl groups may be the same or different. Examples include methylamino, ethylamino, isopropylamino, dimethylamino, diethylamino, N,N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like.
  • A preferred embodiment of “alkylamino” is methylamino, ethylamino, dimethylamino or diethylamino.
  • The term “alkylaminoalkyl” means a group wherein the above “alkylamino” is bonded to the above “alkyl”.
  • The term “alkylaminocarbonyl” means a group wherein the above “alkylamino” is bonded to a carbonyl group.
  • The term “alkylaminocarbonyloxy” means a group wherein the above “alkylaminocarbonyl” is bonded to an oxygen atom.
  • The term “alkylcarbonylamino” means a group wherein the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to a nitrogen atom of an amino group. Examples include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like.
  • A preferred embodiment of “alkylcarbonylamino” is methylcarbonylamino or ethylcarbonylamino.
  • The term “alkylcarbonyloxy” means a group wherein the above “alkylcarbonyl” is bonded to an oxygen atom. Examples include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like.
  • A preferred embodiment of “alkylcarbonyloxy” is methylcarbonyloxy or ethylcarbonyloxy.
  • The term “alkylcarbonylaminoalkyl” means a group wherein the above “alkylcarbonylamino” is bonded to the above “alkyl”.
  • The term “alkyloxycarbonyl” means a group wherein the above “alkyloxy” is bonded to a carbonyl group. Examples include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, penthyloxycarbonyl, isopenthyloxycarbonyl, hexyloxycarbonyl and the like.
  • A preferred embodiment of “alkyloxycarbonyl” is methyloxycarbonyl, ethyloxycarbonyl or propyloxycarbonyl.
  • The term “alkyloxycarbonylalkyl” means a group wherein the above “alkyloxycarbonyl” is bonded to the above “alkyl”.
  • The term “alkyloxycarbonyloxy” means a group wherein the above “alkyloxycarbonyl” is bonded to an oxygen atom.
  • The term “alkylsulfanyl” means a group wherein the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like.
  • The term “alkylsulfonyl” means a group wherein the above “alkyl” is bonded to a sulfonyl group. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like.
  • A preferred embodiment of “alkylsulfonyl” is methylsulfonyl or ethylsulfonyl.
  • The term “trialkylsilyl” means a group wherein three of the above “alkyl” are bonded to a silicon atom. Three alkyl groups may be the same or different. Examples include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like.
  • The term “carbocyclyl group” means C3 to C20 preferably C3 to C16, more preferably C4 to C12 cyclic hydrocarbon group and includes aromatic carbocyclyl and non-aromatic carbocyclyl.
  • The term “aromatic carbocyclyl” means a cyclic aromatic hydrocarbon group which is monocyclic or polycyclic having two or more rings. Examples include phenyl, naphthyl, anthryl, phenanthryl and the like.
  • A preferred embodiment of “aromatic carbocyclyl” is phenyl, 1-naphthyl or 2-naphthyl. Another embodiment of “aromatic carbocyclyl” is phenyl,
  • The term “non-aromatic carbocyclyl” means a cyclic saturated hydrocarbon group or a cyclic unsaturated non-aromatic hydrocarbon group, which is monocyclic or polycyclic having two or more rings. Examples of the “non-aromatic carbocyclyl”, which is polycyclic having two or more rings, include a fused ring group wherein a non-aromatic carbocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”.
  • In addition, examples of the “non-aromatic carbocyclyl” also include a group having a bridge or a group to form a spiro ring as follows:
  • Figure US20230287004A1-20230914-C00033
  • The non-aromatic carbocyclyl which is monocyclic is preferably C3 to C16, more preferably C3 to C12 and further preferably C3 to C8 carbocyclyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.
  • Examples of non-aromatic carbocyclyl, which is polycyclic having two or more rings, include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • The term “carbocycle” means C3 to C20 preferably C3 to C16, more preferably C4 to C12 cyclic hydrocarbon and includes aromatic carbocycle and non-aromatic carbocycle.
  • The term “aromatic carbocycle” means a cyclic aromatic hydrocarbon which is monocyclic or polycyclic having two or more rings. Examples include benzene ring, naphthalene ring, anthracene ring, phenanthrene ring and the like.
  • A preferred embodiment of “aromatic carbocycle” is benzene ring and naphthalene ring are exemplified. Another embodiment of “aromatic carbocycle” is benzene ring.
  • The term of “non-aromatic carbocycle” means a saturated carbocycle or an unsaturated non-aromatic carbocycle which is monocyclic or polycyclic having two or more rings. Examples of the “non-aromatic carbocycle” which is polycyclic having two or more rings, include a fused ring wherein a non-aromatic carbocycle, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocycle”.
  • In addition, examples of the “non-aromatic carbocycle” also include a cycle having a bridge or a cycle to form a spiro ring as follows:
  • Figure US20230287004A1-20230914-C00034
  • The non-aromatic carbocycle which is monocyclic is preferably C3 to C16, more preferably C3 to C12 and further preferably C3 to C8 carbocycle. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene and the like.
  • Examples of non-aromatic carbocycle, which is polycyclic having two or more rings, include indane, indene, acenaphthalene, tetrahydronaphthalene, fluorine and the like are exemplified.
  • The term “heterocyclyl group” includes an aromatic cyclyl and a non-aromatic heterocyclyl, which is containing one or more of heteroatom(s) selected independently from O, S and N.
  • The term “aromatic heterocyclyl” means an aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more of heteroatom(s) selected independently from O, S and N. Examples of “aromatic heterocyclyl”, which is polycyclic having two or more rings, include a fused ring group wherein an aromatic heterocyclyl, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocyclyl”.
  • The aromatic heterocyclyl, which is monocyclic, is preferably a 5- to 8-membered and more preferably 5- to 6-membered ring. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • Examples of aromatic heterocyclyl, which is bicyclic, include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl and the like.
  • Examples of aromatic heterocyclyl, which is polycyclic having three or more rings, include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl and the like.
  • The term “non-aromatic heterocyclyl” means a non-aromatic cyclyl, which is monocyclic or polycyclic having two or more rings, containing one or more heteroatom(s) selected independently from O, S and N. Examples of “non-aromatic heterocyclyl”, which is polycyclic having two or more rings, include a fused ring group wherein a non-aromatic heterocycle, which is monocyclic or polycyclic having two or more ring(s), is fused with a ring of the above “aromatic carbocyclyl”, “non-aromatic carbocyclyl” and/or “aromatic heterocyclyl”.
  • In addition, examples of the “non-aromatic heterocyclyl” also include a group having a bridge or a group to form a Spiro ring as follows:
  • Figure US20230287004A1-20230914-C00035
  • The non-aromatic heterocyclyl, which is monocyclic, is preferably a 3- to 8-membered and more preferably 5- to 6-membered ring. Examples include dioxanyl, thiiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridinyl, tetrahydropyridinyl, tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolinyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl, aziridinyl, dioxolinyl, oxepanyl, thiolanyl, thiinyl, thiazinyl and the like.
  • Examples of non-aromatic heterocyclyl, which is polycyclic having two or more rings, include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
  • The term “heterocycle” includes an aromatic cycle and a non-aromatic heterocycle, which is containing one or more of heteroatom(s) selected independently from O, S and N.
  • The term of “aromatic heterocycle” means an aromatic cycle which is monocyclic or polycyclic having two or more rings, containing one or more of heteroatom(s) selected independently from O, S and N. Examples of “aromatic heterocycle”, which is polycyclic having two or more rings, include a fused ring wherein an aromatic heterocycle, which is monocyclic or polycyclic having two or more rings, is fused with a ring of the above “aromatic carbocycle”.
  • The aromatic heterocycle, which is monocyclic, is preferably a 5- to 8-membered and more preferably 5- to 6-membered ring. Examples include pyrrole, imidazole, pyrazole, pyridine, pyridazine, pyrimidine, pyrazine, triazole, triazine, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole and the like.
  • Examples of aromatic heterocycle, which is bicyclic, include indoline, isoindoline, indazorin, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, oxazolopyridine, thiazolopyridine and the like.
  • Examples of aromatic heterocycle, which is polycyclic having three or more rings, include carbazole, acridine, xanthene, phenothiazine, phenoxathiin, phenoxazine, dibenzofuran and the like.
  • The term “non-aromatic heterocycle” means a non-aromatic cycle, which is monocyclic or polycyclic having two or more rings, containing one or more of heteroatom(s) selected independently from O, S and N. Examples of “non-aromatic heterocycle”, which is polycyclic having two or more rings, include a fused ling wherein a non-aromatic heterocycle, which is monocyclic or polycyclic having two or more ring(s), is fused with a ring of the above “aromatic carbocycle”, “non-aromatic carbocycle” and/or “aromatic heterocycle”.
  • In addition, examples of “non-aromatic heterocycle” also include a cycle having a bridge or a cycle to form a spiro ring as follows:
  • Figure US20230287004A1-20230914-C00036
  • The non-aromatic heterocycle, which is monocyclic, is preferably a 3- to 8-membered and more preferably 5- to 6-membered ring. Examples include dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane, thiazolidine, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydrofuran, tetrahydropyran, dihydrothiazoline, tetrahydrothiazoline, tetrahydroisothiazoline, dihydrooxazine, hexahydroazepine, tetrahydrodiazepine, tetrahydropyridazine, hexahydropyrimidine, dioxolane, dioxazine, aziridine, dioxoline, oxepane, thiolane, thiazine and the like.
  • Examples of non-aromatic heterocycle, which is polycyclic having two or more rings, include indoline, isoindoline, chroman, isochroman and the like.
  • The “carbocycle” part of “carbocyclylalkyl”, “carbocyclyloxy” or “carbocyclylamino” is same as the above “carbocycle”.
  • The “heterocycle” part of “heterocyclylalkyl”, “heterocyclyloxy” or “heterocyclylamino” is same as the above “heterocycle”.
  • The present invention is characterized in that the compound isolated by optical resolution of tricyclic compounds substituted by the other tricyclic group improves cap-dependent endonuclease inhibitory activity.
  • The present invention is also characterized in that the present compound is efficiently absorbed into the body after administration (for example, oral administration), and showing high high efficacy by introducing a group PR to form a prodrug.
  • One or more hydrogen, carbon and/or other atoms in the compounds of the present invention may be replaced with isotopes of hydrogen, carbon and/or other atoms respectively. Examples of isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, 123I and 36Cl respectively. The compounds of the present invention include compounds replaced with these isotopes. The compounds replaced with the above isotopes are useful as medicines and include all of radiolabeled compounds of the compound of the present invention. A “method of radiolabeling” in the manufacture of the “radiolabeled compounds” is encompassed by the present invention, and the “radiolabeled compounds” are useful for studies on metabolized drug pharmacokinetics, studies on binding assay and/or diagnostic tools.
  • A radiolabeled compound of the present invention can be prepared using well-known methods in this field of the invention. For example, a tritium-labeled compound of the present invention can be prepared by introducing a tritium to a certain compound of the present invention, through a catalytic dehalogenation reaction using a tritium. This method comprises reacting with an appropriately-halogenated precursor of the compound of the present invention with tritium gas in the presence of an appropriate catalyst, such as Pd/C, and in the presence or absent of a base. The other appropriate method of preparing a tritium-labeled compound can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”. A 14C-labeled compound can be prepared by using a raw material having 14C.
  • The pharmaceutically acceptable salts of the compounds of the present invention include, for example, salts with alkaline metal (e.g., lithium, sodium, potassium or the like), alkaline earth metal (e.g., calcium, barium or the like), magnesium, transition metal (e.g., zinc, iron or the like), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline or the like) or amino acids, or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid or the like) or organic acids (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or the like). Especially, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are included. These salts can be formed by the usual methods.
  • The compounds of the present invention or its pharmaceutically acceptable salts may form solvates (e.g., hydrates or the like) and/or crystal polymorphs. The present invention encompasses those various solvates and crystal polymorphs. “Solvates” may be those wherein any numbers of solvent molecules (e.g., water molecules or the like) are coordinated with the compounds of the present invention. When the compounds of the present invention or its pharmaceutically acceptable salts are allowed to stand in the atmosphere, the compounds may absorb water, resulting in attachment of adsorbed water or formation of hydrates. Recrystallization of the compounds of the present invention or its pharmaceutically acceptable salts may produce crystal polymorphs.
      • PR group is preferably a group converted into OH group by action of drug-metabolizing enzymes, hydrolases, gastric acids, and/or enterobacteria, after in vivo administration (for example, oral administration).
  • Examples of more preferred embodiment of PR include a group selected from the following formulae a) to ac).
      • a) —C(═O)—PR0,
      • b) —C(═O)—PR1,
      • c) —C(═O)-L-PR1,
      • d) —C(═O)-L-O—PR1,
      • e) —C(═O)-L-O-L-O—PR1,
      • f) —C(═O)-L-O—C(═O)—PR1,
      • g) —C(═O)—O—PR2,
      • h) —C(═O)—N(—K)(PR2),
      • i) —C(═O)—O-L-O—PR2,
      • j) —C(PR3)2—O—PR4,
      • k) —C(PR3)2—O-L-O—PR4,
      • l) —C(PR3)2—O—C(═O)—PR4,
      • m) —C(PR3)2—O—C(═O)—O—PR4,
      • n) —C(PR3)2—O—C(═O)—N(—K)—PR4,
      • o) —C(PR3)2—O—C(═O)—O-L-O—PR4,
      • p) —C(PR3)2—O—C(═O)—O-L-N(PR4)2,
      • q) —C(PR3)2—O—C(═O)—N(—K)-L-O—PR4,
      • r) —C(PR3)2—O—C(═O)—N(K)-L-N(PR4)2,
      • s) —C(PR3)2—O—C(═O)—O-L-O-L-O—PR4,
      • t) —C(PR3)2—O—C(═O)—O-L-N(—K)—C(═O)—PR4,
      • u) —C(PR3)2—O—P(═O)(—PR5)2,
      • v) —C(PR3)2—PR6,
      • w) —C(═N+(PR7)2)(—N(PR7)2),
      • x) —C(PR3)2—C(PR3)2—C(═O)—O—PR2,
      • y) —C(PR3)2—N(—K)—C(═O)—O—PR2,
      • z) —P(═O)(—PR8)(—PR9),
      • aa) —S(═O)2—PR10,
      • ab) —PR11, and
      • ac) —C(PR3)2—C(PR3)2—O—PR2,
      • wherein L is straight or branched alkylene, or straight or branched alkenylene;
      • K is hydrogen, or alkyl optionally substituted by substituent group A;
      • PR0 is alkyl optionally substituted by substituent group A, or alkenyl optionally substituted by substituent group A;
      • PR1 is carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, or alkylsulfanyl optionally substituted by substituent group A;
      • PR2 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A or trialkylsilyl optionally substituted by substituent group A;
      • PR3 is each independently hydrogen or alkyl;
      • PR4 is each independently alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, alkyl amino optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, heterocyclylalkyl optionally substituted by substituent group A, or trialkylsilyl;
      • PR5 is each independently hydroxy or OBn;
      • PR6 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR7 is each independently alkyl optionally substituted by substituent group A;
      • PR8 is alkyloxy optionally substituted by substituent group A;
      • PR9 is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A or heterocyclylamino optionally substituted by substituent group A;
      • PR8 and PR9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A;
      • PR10 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A or heterocyclylalkyl optionally substituted by substituent group A;
      • PR11 is alkyl optionally substituted by substituent group A, alkenyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A.
      • Substituent group A; oxo, alkyl, hydroxyalkyl, amino, alkylamino, carbocyclyl, heterocyclyl, carbocyclylalkyl, alkylcarbonyl, halogen, hydroxy, carboxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkyloxycarbonyloxy, alkylaminocarbonyloxy, alkylaminoalkyl, alkyloxy, cyano, nitro, azido, alkylsulfonyl, trialkylsilyl and phospho.
  • Examples of further preferred embodiment of PR include following groups.
      • a) —C(═O)—PR0,
      • b) —C(═O)—PR1,
      • g) —C(═O)—O—PR2,
      • h) —C(═O)—N(—K)(PR2),
      • i) —C(═O)—O-L-O—PR2,
      • l) —C(PR3)2—O—C(═O)—PR4,
      • m) —C(PR3)2—O—C(═O)—O—PR4,
      • o) —C(PR3)2—O—C(═O)—O-L-O—PR4,
      • v) —C(PR3)2—PR6 (except for a benzyl group)
      • x) —C(PR3)2—C(PR3)2—C(═O)—O—PR2,
      • y) —C(PR3)2—N(—K)—C(═O)—O—PR2, and
      • z) —P(═O)(—PR8)(—PR9),
      • wherein L is straight or branched alkylene;
      • K is hydrogen, or alkyl optionally substituted by substituent group A;
      • PR0 is alkyl optionally substituted by substituent group A;
      • PR1 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR2 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, heterocyclyl group optionally substituted by substituent group A, carbocyclylalkyl optionally substituted by substituent group A, or heterocyclylalkyl optionally substituted by substituent group A;
      • PR3 is each independently hydrogen or alkyl;
      • PR4 is alkyl optionally substituted by substituent group A, carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR6 is carbocyclyl group optionally substituted by substituent group A, or heterocyclyl group optionally substituted by substituent group A;
      • PR8 is alkyloxy optionally substituted by substituent group A;
      • PR9 is alkyloxy optionally substituted by substituent group A, alkylamino optionally substituted by substituent group A, carbocyclyloxy optionally substituted by substituent group A, heterocyclyloxy optionally substituted by substituent group A, carbocyclylamino optionally substituted by substituent group A or heterocyclylamino optionally substituted by substituent group A; and
      • PR8 and PR9 may be taken together with an adjacent phosphorus atom to form heterocycle optionally substituted by substituent group A.
      • Substituent group A; oxo, alkyl, alkylamino, carbocyclyl, heterocyclyl, alkylcarbonyl, halogen, hydroxy, alkylcarbonylamino, alkylcarbonyloxy, alkyloxycarbonyl, alkyloxycarbonylalkyl, alkylaminocarbonyloxy, alkyloxy, nitro, azido, alkylsulfonyl and trialkylsilyl.
  • Examples of another embodiment of a preferable substituent of PR include following groups.
  • Figure US20230287004A1-20230914-C00037
    • (Method for Producing Compound of the Present Invention)
  • A general method for producing the compound of the present invention will be exemplified below. As to the extraction and purification, treatment which is performed in a normal experiment of organic chemistry may be conducted.
  • Synthesis of the compound of the present invention can be carried out referring to the procedures known in the art.
  • As a raw material compound, commercially available compounds, compounds described in the present description, compounds described in the references cited in the present description, and other known compounds can be utilized.
  • When one wants to obtain a salt of the compound of the present invention, in the case where the compound of the present invention is obtained in a form of a salt, it may be purified as it is and, in the case where the compound of the present invention is obtained in a free form, a salt may be formed by a normal method by dissolving or suspending the compound in a suitable organic solvent, and adding an acid or a base.
  • In addition, the compound of the present invention and a pharmaceutically acceptable salt thereof are present in a form of adducts with water or various solvents (hydrate or solvate) in some cases, and these adducts are included in the present invention.
  • In a general synthesis method as well as Reference examples, Examples, and Intermediate Synthesis Examples, the meaning of each abbreviation is as follows.
      • Boc: tert-butoxycarbonyl
      • DBU: diazabicycloundecene
      • DMA: N,N-dimethylacetamide
      • DMF: N,N-dimethylformamide
      • HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′N-tetramethyluronium hexafluorophosphate
      • NMP: N-methylpyrrolidone
      • OBn: benzyloxy
      • THF: tetrahydrofuran
      • T3P: propyl phoshonic anhydride
      • WSC·HCl: N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • The up and down of the “wedge” and “broken line wedge” indicates the absolute configuration.
    • Preparation 1
  • Figure US20230287004A1-20230914-C00038
  • wherein P1 is hydroxyl protective group; RP is acetal protective group; L is leaving group; Other each symbol is same as above.
    • First Step
  • Compound A3 can be obtained by adding Compound A2 to Compound A1 in the presence of a dehydration-condensation agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimido-N-hydroxybenzotriazole, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, hexafluorophosphoric acid 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium, WSC·HCl, HATU, etc. in a solvent such as DMF, THF, dichloromethane, acetonitrile etc. or in a mixed solvent thereof, and performing a reaction at −20° C. to 60° C., preferably −10° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 12 hours.
  • Alternatively, Compound A3 can be obtained by adding an acylating reagent such as diphenylchlorophosphate, thionyl chloride, oxalyl chloride etc. to Compound A1 in the presence or absence of a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc. in the presence of a solvent such as THF, dioxane, dichloromethane, DMF etc., thereby, generating acid chloride, and adding Compound A2 having a substituent corresponding to an objective compound, and performing a reaction at −20° C. to 60° C., preferably −10° C. to 40° C. for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours.
    • Second Step
  • Compound A4 can be obtained by adding potassium carbonate, sodium carbonate, and O-(2,4-dinitrophenyl)hydroxylamine to Compound A3 in the presence of a solvent such as DMF, DMA, NMP, THF, etc., and performing a reaction at 10° C. to 60° C., preferably 20° C. to 40° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
    • Third Step
  • A deprotecting reaction of an acetal protective group of Compound A4 can be performed by the general method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc. Thereafter, a generated aldehyde group is subjected to an intramolecular reaction, thereby, Compound A5 can be obtained.
  • For example, racemate of Compound A5 can be obtained by adding acetic acid and/or paratoluenesulfonic acid, metanesulfonic acid etc., to Compound A4 in the presence of a solvent such as DMF, toluene, THF, etc., and performing a reaction at 10° C. to 80° C., preferably 30° C. to 60° C. for 0.5 hours to 12 hours, preferably 1 hour to 6 hours. Compound A5 can be obtained by optical resolution of the racemate of Compound A5 by SFC or HPLC (chiral column).
    • Fourth Step
  • Compound A7 can be obtained by adding Compound A6, and a base such as sodium carbonate, potassium carbonate, cesium carbonate, etc. to Compound A5 in the presence of a solvent such as DMF, DMA, NMP, THF, etc. or in a mixed solvent thereof, and performing a reaction at 0° C. to 60° C., preferably 10° C. to 40° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
  • Alternatively, Compound A7 can be obtained by adding Compound A6, and T3P, methane sulfonic acid or para-toluene sulfonic acid to Compound A5 in the presence of a solvent such as DMF, ethyl acetate, butyl acetate, 1,4-dioxane etc. or in a mixed solvent thereof, and performing a reaction at 40° C. to 150° C., preferably 60° C. to 120° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
    • Fifth Step
  • A deprotecting reaction of hydroxyl protective group of Compound A7 can be performed by the general method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.
    • Sixth Step
  • Compound (III) can be obtained by the general method including converting a hydroxyl group of Compound (II) into an ester group or ether group.
  • For example, the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), Prog. Med. 5: 2157-2161 (1985), and Supplied by The British Library—“The world's Knowledge”, etc. can be utilized.
    • Preparation 2
  • Figure US20230287004A1-20230914-C00039
  • wherein P2 is NH protective group; L1 and L2 is leaving group; Other each symbol is same as above.
    • First Step
  • Compound B2 can be obtained by adding Compound A2 and halogenated alkyl such as methyl iodide to Compound B1 in the presence of a base such as diazabicycloundecene in a solvent such as DMF, THF, dichloromethane, acetonitrile, etc. or in a mixed solvent thereof, and performing a reaction at −20° C. to 60° C., preferably −10° C. to 40° C. for 0.1 hours to 24 hours, preferably 1 hour to 24 hours.
  • Alternatively, Compound B2 can be obtained by adding acylating reagent such as diphenylchlorophosphate, thionyl chloride, oxalyl chloride, etc. to Compound B1 in a solvent such as THF, dioxane, dichloromethane, DMF, etc. or in a mixed solvent thereof, and adding alcohol in the presence of a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc., and performing a reaction at −20° C. to 60° C., preferably −10° C. to 40° C. for 0.1 hours to 24 hours, preferably 0.5 hours to 12 hours.
    • Second Step
  • Compound B3 can be obtained by adding para-toluene sulfonic acid pyridinium and hydrazine protected by Roc etc. to Compound B2 in a solvent such as THF, dioxane, dichloromethane, DMF etc., or in a mixed solvent thereof, and performing a reaction at 10° C. to 150° C., preferably 40° C. to 100° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours.
    • Third Step
  • A deprotecting reaction of amino protective group Compound B3 can be performed by the general method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons) etc.
    • Fourth Step
  • Compound B6 can be obtained by adding a base such as n-butyl lithium, etc. to Compound B5 in a solvent such as THF, dioxane, dichloromethane, DMF etc., or in a mixed solvent thereof, and then adding haloformic acid alkyl and performing a reaction for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
    • Fifth Step
  • Compound B7 can be obtained by adding reducing agent such as Lithium diisobutylaluminum hydride, etc. to Compound B6 in a solvent such as THF, dioxane, dichloromethane, DMF etc., or in a mixed solvent thereof, and performing a reaction for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
    • Sixth Step
  • Compound B8 can be obtained by adding para-toluene sulfonic acid or methane sulfonic acid to Compound B7 in alcohol, and performing a reaction at 0° C. to 100° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
    • Seventh Step
  • Compound B10 can be obtained by adding haloformic acid alkyl to Compound B9 in the presence or absence of a base such as pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, etc., in a solvent such as THF, dioxane, dichloromethane, DMF etc., or in a mixed solvent thereof, and performing a reaction at −40° C. to 40° C. for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
    • Eighth Step
  • Compound B8 can be obtained by immersing carbon electrode (anode) and platinum electrode (cathode) to Compound B10 in a solvent such as alcohol in the presence of a base such as potassium carbonate and tetraethylaminium perchlorate, and flushing with a constant current of 0.1 ˜1.0A with stirring for 0.1 hours to 48 hours, preferably 1 hour to 24 hours.
    • Ninth to Tenth Step
  • Compound (I) can be obtained from Compound B4 and B8 in the same manner as in the third to sixth steps in preparation 1.
  • The compound of the present invention has cap-dependent endonuclease inhibitory activity and is useful as a therapeutic or preventive agent for influenza.
  • The compound of the present invention not only has cap-dependent endonuclease inhibitory activity but also is useful as a medicine and has any or all of the following excellent characteristics:
      • a) The compound is a weak inhibitor of CYP enzymes (e.g., CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and the like).
      • b) The compound demonstrates good pharmacokinetics, such as a high bioavailability, moderate clearance and the like.
      • c) The compound has a high metabolic stability.
      • d) The compound has no irreversible inhibitory action against CYP enzymes (e.g., CYP3A4) when the concentration is within the range described in the present description as the measurement conditions.
      • e) The compound has no mutagenicity.
      • f) The compound is associated with a low cardiovascular risk.
      • g) The compound has a high solubility.
      • h) The compound has no phototoxicity.
  • For the purpose of treating the above-mentioned diseases in humans, the compounds of the present invention may be administered orally as a powder, a granule, tablets, capsules, pills, a liquid and the like or parenterally as an injection, suppositories, a percutaneous drug, an inhalant and the like. The effective doses of the present compounds may be mixed with excipients suitable for the dosage form, such as fillers, binders, humectants, disintegrators, and lubricants, as appropriate, to form pharmaceutical preparations. For preparing an injection, sterilization is performed with a suitable carrier.
  • The pharmaceutical compositions according to the present invention can be administered either orally or parenterally. For oral administration, commonly used dosage forms, such as tablets, granule, powder, and capsules, may be prepared according to conventional methods. For parenteral administration, any commonly used dosage form, such as an injection, may be suitably used. The compounds according to the present invention can be suitably used as oral preparations because of their high oral absorbability.
  • The effective doses of the compounds of the present invention can be mixed with various pharmaceutical excipients suitable for the dosage form, such as fillers, binders, disintegrators, and lubricants, as appropriate, to form pharmaceutical compositions.
  • The dose depends on the condition of the disease, administration route, or age or weight of the patient. The usual oral dose for adults is 0.1 to 100 mg/kg per day, preferably 1 to 20 mg/kg per day.
  • The dose of the pharmaceutical composition of the present invention is preferably determined on the basis of the age and weight of the patient, type and severity of the disease, administration route and the like. The usual oral dose for adults is in the range of 0.05 to 100 mg/kg per day, preferably 0.1 to 10 mg/kg per day. The parenteral dose for adults significantly varies depending on the administration route but is usually in the range of 0.005 to 10 mg/kg per day, preferably 0.01 to 1 mg/kg per day. The dose may be administered once daily or may be divided into multiple daily doses.
  • The compound of the present invention can be used in combination with other drugs or the like (hereinafter referred to as combination drugs) to increase the activity of the compound, reduce the dose of the compound, or the like. In the case of treating influenza, the compound can be used combined with or in a coupled formulation with neuraminidase inhibitor (e.g., Oseltamivir, Zanamivir, Peramivir, Inabiru and the like); RNA-dependent RNA polymerase inhibitor (e.g., Favipiravir); M2 protein inhibitor (e.g., Amantadine); PB2 Cap binding inhibitor (e.g., VX-787); anti-HA antibody (e.g., MHAA4549A); Immune agonists (e.g., Nitazoxanide) are also possible. In this case, the timing of administration for a compound of the present invention and the combination drug is not limited. They can be administered to the subjects to be treated, at a time or at different times. Furthermore, a compound of the present invention and the combination drug can be administered as two or more formulations independently comprising each active ingredient or a single formulation comprising each active ingredient.
  • The dose for combination drugs may be appropriately selected in reference to the clinical dose. The compounding ratio of the compounds of the present invention and co-administered drugs may be appropriately selected depending on the subject to be treated, administration route, disease to be treated, symptoms, combination of the drugs and the like. For administration in humans, for example, 1 part by weight of the compounds of the present invention may be used in combination with 0.01 to 100 parts by weight of co-administered drugs.
  • The present invention will be explained in more detail below by way of Examples, Reference examples, Intermediate Synthesis Examples, as well as Test Examples of the present invention, but the present invention is not limited by them.
  • The NMR analysis obtained in each reference example and example was carried out in 300 MHz, and was measured using DMSO-d6, CDCl3.
  • The term RT represents a retention time at LC/MS: liquid chromatography/mass spectrometry, and was measured under the following conditions.
    • (Measurement Conditions)
      • (1) Column: ACQUITY UPLC (Registered trademark) BEH C18 (1.7 μm i.d.2.1×50 mm) (Waters)
        • Flow rate: 0.8 mL/min
        • UV detection wavelength: 254 nm
        • Mobile phase: [A]: a 0.1% formic acid-containing aqueous solution, [B]: a 0.1% formic acid-containing acetonitrile solution
        • Gradient: a linear gradient of 5% to 100% solvent [B] was carried out in 3.5 minutes, and 100% solvent 1131 was kept for 0.5 minutes.
      • (2) Column: Shim-pack XR-ODS (2.2 μm, i.d.50×3.0 mm) (Shimadzu)
        • Flow rate: 1.6 mL/min
        • UV detection wavelength: 254 nm
        • Mobile phase: [A]: a 0.1% formic acid-containing aqueous solution, [B]: a 0.1% formic acid-containing acetonitrile solution
        • Gradient: a linear gradient of 10% to 100% solvent [B] was carried out in 3 minutes, and 100% solvent [B] was kept for 0.5 minutes.
    Reference Example 1
  • Figure US20230287004A1-20230914-C00040
    • First Step
  • To a solution of Compound 1 (5.0 g, 49.5 mmol) in TIIF (100 mL) was added dropwise 1.62 mol/L n-butyllithium in hexane (30.5 mL, 49.5 mmol) at −78° C. under a nitrogen atmosphere, and the mixture was stirred at −78° C. for 2 hours. A solution of chloroformate allyl (5.96 g, 49.5 mmol) in THF (20 mL) was added dropwise thereto, and the mixture was stirred at −78° C. for 2 hours. The mixture was quenched with a saturated aqueous solution of ammonium chloride, warmed up to room temperature, and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain Compound 2 (5.66 g, 62%).
      • 1H-NMR(CDCl3)δ:3.83 (t, J=8.0 Hz, 2H), 3.92 (t, J=8.0 Hz, 2H), 4.26 (s, 2H), 4.78 (d, J=8.0 Hz, 2H), 5.30 (d, J=12.0 Hz, 1H), 5.44 (d, J=16.0 Hz, 1H), 5.93-6.03 (m, 1H),
    Second Step
  • To a solution of Compound 2 (6.6 g, 35.6 mmol) in THF (66 mL) was added dropwise 1.03 mol/L DIBAL-H in hexane (45.0 mL, 46.3 mmol), and the mixture was stirred at −78° C. for 1 hour. The mixture was quenched with acetone, an aqueous solution of Rochelle salt was added thereto. The mixture was stirred, and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magunesium sulfate, and concentrated under reduced pressure to obtain Compound 3 (6.21 g, 93%).
  • 1H-NMR (CDCl3)δ:3.44 (br, 1H), 3.50-3.64 (m, 2H), 3.71 (br, 1H), 3.95 (d, J=8.0 Hz, 2H), 4.64 (d, J=8.0 Hz, 2H), 5.24 (d, J=12.0 Hz, 1H), 5.40 (d, J=16.0 Hz, 1H), 5.47 (d, J=4 Hz, 1H), 5.87-6.00 (m, 1H)
    • Third Step
  • To a solution of Compound 3 (6.2 g, 33.1 mmol) in methanol (65 mL) was added p-Toluenesulfonic acid monohydrate (0.63 g, 3.31 mmol), and the mixture was stirred at room temperature over night. The mixture was quenched with an aqueous solution of sodium hydrogen carbonate, concentrated, and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magunesium sulfate, and concentrated under reduced pressure to obtain Compound 4 (5.77 g, 87%).
  • 1H-NMR (CDCl3)δ:3.34 (s, 3H), 3.55 (br, 2H), 3.73-3.99 (m, 3H), 4.64 (d, J=8.0 Hz, 2H), 5.10-5.20 (m, 1H), 5.25 (d, J=8.0 Hz, 1H), 5.33 (d, J=16 Hz, 1H), 5.88-6.05 (in, 1H)
    • Fourth Step
  • To a solution of Compound 5 (20.0 g, 81 mmol) in DMF (100 mL) were added ethyl iodide (22.8 g, 146 mmol) and diazabicycloundecene (18.4 mL, 122 mmol), and the mixture was stirred at room temperature over night. The mixture was poured into 10% aqueous solution of ammonium chloride, and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magunesium sulfate, and concentrated under reduced pressure to obtain Compound 6 (22.3 g, 100%).
  • 1H-NMR (CDCl3)δ:1.23 (t, J=8.0 Hz, 3H), 4.28 (q, J=8.0 Hz, 2H), 5.16 (s, 2H), 6.57 (d, J=4.0 Hz, 1H), 7.28-7.48 (m, 5H), 8.21 (d, J=4.0 Hz, 1H).
    • Fifth Step
  • To a solution of Compound 6 (500 mg, 1.82 mmol) in DMA (5.0 mL) were added pyridinium p-toluenesulfonate (1.37 g, 5.47 mmol) and Boc-hydrazine (361 mg, 2.74 mmol), and the mixture was stirred at 60° C. for 14 hours. To the mixture was added water and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magunesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 7 (519 mg, 73%).
  • 1H-NMR (CDCl3)δ:1.24 (t, J=8.0 Hz, 3H), 1.46 (s, 9H), 4.26 (q, J=8.0 Hz, 2H), 5.28 (s, 2H), 6.40 (d, J=8.0 Hz, 1H), 7.27-7.38 (m, 4H), 7.40-7.45 (m, 2H).
    • Sixth Step
  • Compound 7 (500 mg, 1.29 mmol) was dissolved in 4 mol/L hydrogen chloride in ethyl acetate (5 mL), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. To the obtained residue was added a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with brine, dried over anhydrous magunesium sulfate, and concentrated under reduced pressure to obtain Compound 8 (369 mg, 99%).
  • 1H-NMR (CDCl3)δ:1.26 (t, J=8.0 Hz, 3H), 4.31 (q, J=8.0 Hz, 2H), 5.24 (s, 2H), 6.47 (d, J=8.0, 1H), 7.28-7.44 (m, 5H), 7.64 (d, J=8.0, 1H).
    • Seventh Step
  • To a solution of Compound 8 (365 mg, 1.27 mmol) and Compound 4 (306 mg, 1.52 mmol) in acetonitrile (8 mL) was added dropwise tin chloride (0.223 mL, 1.90 mmol) at −25° C. under a nitrogen atmosphere, and the mixture was stirred at −25° C. for 45 minutes. The mixture was quenched with a saturated aqueous solution of sodium hydrogen carbonate, and dichloromethane was added thereto. The mixture was stirred at room temperature and filtered through Celite, and filtrate was extracted with dichloromethane. The obtained organic layer was washed with brine, dried over anhydrous magunesium sulfate, and concentrated under reduced pressure to obtain crude Compound 9. The obtained Compound 9 was dissolved in THF (8 mL), morpholine (1.10 mL, 12.7 mmol) and tetrakis(triphenylphosphine)palladium (146 mg, 0.127 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. To the mixture was added diethyl ether (16 mL), and the precipitated solid was filtered and dried to obtain Compound 10 (418 mg, 100%).
  • 1H-NMR (CDCl3)δ:2.90-2.99 (m, 1H), 3.13 (t, J=12.0 Hz, 1H), 3.40-3.46 (m, 1H), 4.00-4.08 (m, 1H), 4.14 (d, J=12.0 Hz, 1H), 5.07 (s, 2H), 6.22 (d, J=8.0 Hz, 1H), 7.29-7.40 (m, 3H), 7.56 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 1H)
    • Eighth Step
  • To a suspension of (R)-2-Tetrahydrofurioic Acid (855 mg, 7.36 mmol) and Compound 10 (2.00 g, 6.11 mmol) in ethyl acetate (9 ml) were added pyridine (4.00 ml, 49.6 mmol) and T3P (50% in ethyl acetate, 11.0 ml, 18.5 mmol) at room temperature, and the mixture was stirred over night. The presipitated solid was filtered and washed with ethyl acetate (4 ml) and ethanol (4 ml). The obtained solid was suspended in ethanol (6 ml) and the suspention was stirred at room temperature for 6.5 hours. The suspention was filtered and the obtained solid was washed with ethanol (2 ml) twise to obtain Compound 11 (1.18 g, 45.4%).
  • 1H-NMR (DMSO)δ: 1.80-1.94 (m, 2H), 1.95-2.14 (m, 2H), 3.21-3.35-(m, 2H), 3.50-3.60 (m, 1H), 3.70-3.82 (m, 3H), 4.00-4.05 (m, 1H), 4.32-4.38 (m, 1H), 5.14(dd, J=10.8 Hz, 21.6 Hz, 2H), 5.76-5.81 (m, 1H), 6.29(d; J=4.8 Hz, 1H), 7.28-7.39 (m, 3H), 7.48-7.54 (m, 2H), 7.64-7.75 (m, 1H)
    • Ninth Step
  • To a suspension of Compound 11 (500 mg, 1.18 mmol) in ethanol (3.5 ml) was added DBU (0.0035 ml, 0.023 mmol) at room temperature, and the mixture was stirred for 30 minutes. To the obtained suspension was added diisopropylether (6.5 ml), and the mixture was stirred at room temperature for 30 minutes. The presipitated solid was filtered and washed with ethyl acetate (1.5 ml) twise to obtain Compound it (346 mg, 89.9%).
  • 1H-NMR (DMSO)δ: 2.80-3.00 (m, 1H), 3.10-3.18 (m, 1H), 3.38-3.50 (m, 1H), 3.98-4.08 (m, 2H), 4.10-4.20 (m, 1H), 4.76-4.84 (m, 1H), 5.04-5.14 (m, 2H), 6.22 (m, J=7.6 Hz, 1H), 7.27-7.40 (m, 4H), 7.56-7.60 (m, 2H), 7.70 (d, J=7.6 Hz, 1H)
    • Reference Example 2
  • Figure US20230287004A1-20230914-C00041
    • First Step
  • To a suspension of Compound 13 (8.0 g, 50.8 mmol) in dichloromethane (120 mL) was added triethylamine (17.6 mL, 127 mmol) under ice-water bath, and allyl chloroformate (6.44 mL, 60.9 mmol) was added dropwise thereto, and the mixture was stirred at 0° C. for 1 hour. To the mixture was added water, and the mixture was extracted with dichloromethane. The obtained organic layer was washed with 5% aqueous solution of citric acid and a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magunesium sulfate, and concentrated under reduced pressure to obtain Compound 14 (10.1 g, 97%).
  • 1H-NMR (CDCl3)δ:1.96 (br, 4H), 3.62 (s, 4H), 4.60 (s, 2H), 5.22 (d, J=12.0 Hz, 1H), 5.30 (d, J=16.0 Hz, 1H), 5.86-5.99 (m, 1H)
    • Second Step
  • To a solution of Compound 14 (0.9 g, 4.39 mmol), potassium carbonate (60 mg, 0.44 mmol) and tetraethylaminium perchlorate (50 mg, 0.22 mmol) in methanol (30 mL) were immersed carbon electrode (anode) and platinum electrode (cathode), and the mixture was flushed with a constant current of 0.1A with stirring at room temperature for 6 hours. To the mixture were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magunesium sulfate, and concentrated under reduced pressure to obtain Compound 15 (992 mg, 96%).
  • 1H-NMR (CDCl3)δ:1.81-2.15 (m, 3H), 2.39 (t, J=12.0 Hz, 1H), 3.27 (s, 3H), 3.61 (s, 1H), 4.11 (br, 1H), 4.61 (br, 2H), 5.20-5.36 (m, 2H), 5.57 (br, 1H), 5.88-5.99 (m, 1H)
    • Third Step
  • Compound 16 was obtained in the same manner as in the seventh and eighth steps in reference example 1.
    • Fourth Step
  • The optical resolution of Compound 16 (870 mg, 2.41 mmol) by Waters SFC30 System (Daicel CHIRALPAK 1B, liquefied carbon dioxide-methanol) gave Compound i2 (270 mg, 31%).
    • Analysis Condition
      • <Waters SFC30 System (SPRC4·5N406)>
        • Column: CHIRALPAK IB/SFC (5 μm, i.d.250×4.6 mm) (DAICEL)
        • Flow rate: 8.0 mL/min; UV detection wavelength: 254 nm
        • Back pressure: 100 bar
        • Mobile phase: [A]: liquefied carbon dioxide, [B]: methanol
        • Gradient: 5% solvent [B] was kept for 1 minute, a linear gradient of 5% to 40% solvent [B] was carried out in 6 minutes, 40% solvent [B] was kept for 2 minutes, and 5% solvent [B] was kept for 1 minute.
        • Elution time: 7.3 minutes
    Reference Example 3
  • Figure US20230287004A1-20230914-C00042
    • First Step
  • To a solution of Compound 17 (4.00 g, 16.3 mmol) in dichloromethane (40 mL) were added oxalyl dichloride (1.56 mL, 17.9 mmol) and DMF (0.013 mL, 0.162 mmol) under iced-bath, and the mixture was warmed up to room temperature and stirred for 5 hours. The mixture was concentrated under reduced pressure, and the obtained residue was dissolved in dichloromethane (40 mL), 2,2,2-trifluoroethanol (2.44 g, 24.4 mmol), triethylamine (4.50 mL, 32.5 mmol) and 4-(dimethylamino)pyridine (99.0 mg, 0.812 mmol) were added thereto under iced-bath, and the mixture was warmed up to room temperature and stirred for 1 hour. The mixture was concentrated under reduced pressure and to the obtained residue was added 1 mol/L aqueous solution of hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with 1 mol/L aqueous solution of hydrochloric acid and brine, dried over anhydrous magunesium sulfate to obtain Compound 18 (5.33 g, 100%).
  • 1H-NMR (CDCl3)δ: 4.64 (q, d=8.2 Hz, 2H), 5.38 (s, 2H), 6.49 (d, J=5.6 Hz, 1H), 7.30-7.38 (m, 311), 7.43-7.49 (m, 211), 7.75 (d, J=5.6 Hz, iii).
    • Second and Third Steps
  • Compound 20 was obtained in the same manner as in the fifth and sixth steps in reference example 1.
  • 1H-NMR (CDCl3)δ: 4.55 (q, d=8.3 Hz, 2H), 5.18 (s, 2H), 5.29 (s, 2H), 6.37 (d, d=7.8 Hz, 1H), 7.30-7.42 (m, 6H).
    • Fourth and Fifth Steps
  • Compound 23 was obtained in the same manner as in the seventh step in reference example 1.
      • LC/MS (ESI):m/z=342.1[M+H]+, RT=1.00,1.09 min, method (1)
    Sixth Step
  • To a solution of Compound 23 (820 mg, 2.40 mmol) in dichloromethane (16.5 mL) were added Boc2O (0.837 mL, 3.60 mmol), triethylamine (0.499 mL, 3.60 mmol) and 4-(dimethylamino)pyridine (44.0 mg, 0.360 mmol), and the mixture was stirred at room temperature for 3.5 hours. To the mixture was added 1 mol/L aqueous solution of hydrochloric acid and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with 1 mol/L aqueous solution of hydrochloric acid and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 24 (593 mg, 56%) and Compound i3 (170 mg, 16%).
      • Compound 24:LC/MS (ESI):m/z=441.9 [M+H]+, RT=1.67 min, method (1)
    Seventh Step
  • Compound 24 (547 mg, 1.24 mmol) was dissolved in acetic acid (5.5 mL) and the mixture was stirred at 80° C. for 5 hours. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound i3 (454 mg, 100%).
  • 1H-NMR (CDCl3)δ: 1.46 (d, J=6.4 Hz, 3H), 3.45 (dd, J=10.5, 10.5 Hz, 1H), 3.55 (dd, J=11.7, 4.3 Hz, 1H), 3.92 (dd, J=11.7, 3.6 Hz, 1H), 3.95-4.01 (m, 2H), 4.76 (dq, J=13.9, 4.3 Hz, 1H), 5.19 (d, J=10.2 Hz, 1H), 5.22 (d, J=10.2 Hz, 1H), 5.36 (d, J=12.9 Hz, 1H), 6.28 (d, d=7.8 Hz, 1H), 7.25 (d, d=7.8 Hz, 1H), 7.28-7.36 (m, 3H), 7.56-7.61 (m, 2H).
    • Example 1
  • Figure US20230287004A1-20230914-C00043
    • First Step
  • Compound i1 (1100 g, 3360 mmol) and 7,8-difluoro-6,11-dihydrodibenzothiepine-11-ol (977 g, 3697 mmol) were suspended in 50 wt % T3P in ethyl acetate (3208 g, 5041 mmol) and ethyl acetate (1.1 L). To the mixture was added methanesulfonic acid (436 ml, 6721 mmol) at room temperature and the mixture was stirred at 70° C. for 5.5 hours. To the mixture was added water under ice-water bath and the mixture was stirred at room temperature for 1 hour. THF was added thereto and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and 8% aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in THF (5.5 L) and potassium carbonate (790 g, 5713 mmol) was added thereto. The mixture was warmed up to 50° C., benzyl bromide (240 ml, 2016 mmol) was added dropwise thereto, and the mixture was stirred at 60° C. for 8.5 hours. To the mixture was added dropwise 2 mol/L aqueous solution of hydrochloric acid under ice-water bath, and the mixture was stirred at room temperature for 10 minutes and extracted with ethyl acetate. The obtained organic layer was washed with water and 8% aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. An activated carbon (Norit SX-2, 240 g) was added thereto, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure To the obtained residue was added ethyl acetate and hexane and the precipitated solid was filtered to obtain Compound 25 (1019 g, 1776 mmol, 53%).
  • 1H-NMR (CDCl3)δ: 2.88 (1H, t, J=11.2 Hz), 3.28-3.39 (2H, m), 3.72 (1H, d, J=12.6 Hz), 3.86 (1H, d, J=9.6 Hz), 4.03 (1H, d, J=13.9 Hz), 4.45 (1H, d, J=8.6 Hz), 4.67 (1H, d, d=13.1 Hz), 5.19-5.26 (2H, m), 5.45 (1H, d, J=10.9 Hz), 5.63 (1H, d, J=10.9 Hz), 5.77 (1H, d, J=7.6 Hz), 6.40 (1H, d, J=7.8 Hz), 6.68 (1H, t, J=6.9 Hz), 6.94-7.01 (2H, m), 7.03-7.12 (3H, m), 7.29-7.38 (3H, m), 7.61 (2H, d, J=7.1 Hz).
    • Second Step
  • To a solution of Compound 25 (1200 g, 2092 mmol) in DMA (3.6 L) was added lithium chloride (443 g, 10.5 mol) at room temperature, and the mixture was stirred at 80° C. for 3 hours. To the mixture were added acetone (1.2 L), 0.5 mol/L aqueous solution of hydrochloric acid (6.0 L) and water (2.4 L) under ice-water bath, and the mixture was stirred for 1 hour. The presipitated solid was filtered. The obtained solid was dissolved in chloroform, isopropyl ether was added thereto, and the presipitated solid was filtered to obtain Compound 111-2 (950 g, 1965 mmol, 94%).
  • 1H-NMR (CDCl3)δ: 2.99 (111, dt, J=17.5, 6.8 Hz), 3.47 (111, td, J=11.9, 2.5 Hz), 3.60 (1H, t, J=10.6 Hz), 3.81 (1H, dd, J=11.9, 3.3 Hz), 3.96 (1H, dd, J=11.0, 2.9 Hz), 4.07 (1H, d, J=13.8 Hz), 4.58 (1H, dd, J=10.0, 2.9 Hz), 4.67 (1H, dd, J=13.5, 1.9 Hz), 5.26-5.30 (2H, m), 5.75 (1H, d, J=7.8 Hz), 6.69 (1H, d, J=7.7 Hz), 6.83-6.87 (1H, m), 6.99-7.04 (2H, m), 7.07-7.15 (3H, m).
    • Example 2
  • Figure US20230287004A1-20230914-C00044
    • First Step
  • Compound i1(400 mg, 1.22 mmol) and 6,11-dihydrodibenzothiepine-11-ol (418 mg, 1.83 mmol) were dissolved in 50% T3P in ethyl acetate (7.27 mL, 12.2 mmol) and the mixture was stirred in a sealed tube at 110° C. for 1.5 hours. To the mixture was added water and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol and ethyl acetate-methanol) to obtain Compound 26 (316 mg, 47%).
  • 1H-NMR (CDCl3)δ: 2.86 (dd, J=11.4, 11.4 Hz, 1H), 3.26-3.40 (m, 2H), 3.55 (d, J=13.4 Hz, 1H), 3.70 (d, J=10.4 Hz, 1H), 3.86 (d, J=10.4 Hz, 1H), 4.48 (d, J=9.5 Hz, 1H), 4.66 (d, J=13.4 Hz, 1H), 5.20 (s, 1H), 5.43-5.50 (m, 2H), 5.63 (d, J=10.9 Hz, 1H), 5.79 (d, J=7.8 Hz, 1H), 6.40 (d, J=7.7 Hz, 1H), 6.62-6.69 (m, 1H), 7.02-7.07 (m, 3H), 7.18 (d, J=7.4 Hz, 1H), 7.27-7.44 (m, 6H), 7.60-7.66 (m, 2H).
    • Second Step
  • Compound III-1 was obtained in the same manner as in the second step in example 1.
  • 1H-NMR (CDCl3)δ: 2.98 (dd, J=13.0, 12.3 Hz, 1H), 3.46 (dd, J=13.1, 10.0 Hz, 1H), 3.55-3.63 (m, 2H), 3.79 (d, J=11.4 Hz, 1H), 3.96 (d, J=11.0 Hz, 1H), 4.62-4.66 (m, 2H), 5.26 (s, 1H), 5.52 (d, J=13.4 Hz, 1H), 5.75 (d, J=7.7 Hz, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.79-6.85 (m, 1H), 7.05-7.12 (m, 3H), 7.23 (d, J=7.4 Hz, 1H), 7.30 (t, J=7.3 Hz, 1H), 7.36 (d, J=7.4 Hz, 1H), 7.44 (t, J=7.4 Hz, 1H).
    • Example 3
  • Figure US20230287004A1-20230914-C00045
    • First Step
  • Compound 27 (290 mg, 0.880 mmol) and Compound i1 (240 mg, 0.733 mmol) were dissolved in 50% T3P in ethyl acetate (2.4 mL) and the mixture was stirred in a sealed tube at 100° C. for 1.5 hours. To the mixture was added water and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-ethyl acetate-methanol) to obtain Compound 28 (106 mg, 24%).
  • 1H-NMR (CDCl3)δ:2.37 (s, 3H), 2.94-3.03 (m, 1H), 3.15-3.23 (m, 1H), 3.28 (t, J=10.4 Hz, 1H), 3.58 (d, J=13.2 Hz, 1H), 3.66 (dd, J=3.2 Hz, 11.6 Hz, 1H), 3.84 (dd, J=2.8 Hz, 10.8 Hz, 1H), 4.40-4.52 (m, 2H), 5.49 (t, J=13.6 Hz, 2H), 5.60 (d, J=10.4 Hz, 2H), 5.78 (d, J=7.6 Hz, 1H), 6.41 (d, J=7.2 Hz, 1H), 6.66-6.71 (m, 1H), 6.98-7.12 (m, 4H), 7.21 (d, J=7.6 Hz, 1H), 7.30-7.42 (m, 4H), 7.56-7.61 (m, 2H).
    • Second Step
  • To a solution of Compound 28 (100 mg, 0.168 mmol) in methanol (1 mL) was added 2 mol/L aqueous solution of sodium hydroxide (252 μL, 0.504 mmol) and the mixture was stirred at room temperature for 1 hour. To the mixture was added 2 mol/L aqueous solution of hydrochloric acid (0.3 mL) and the mixture was extracted with chloroform. The obtained organic layer was concentrated under reduced pressure. The obtained residue was dissolved in DMA (1.0 mL), lithium chloride (35.6 mg, 0.839 mmol) was added thereto, and the mixture was stirred at, 100° C. for 15 hours. The mixture was purified by reversed phase silica gel column chromatography (acetonitrile-water) to obtain Compound 111-24 (20 mg, 26%).
  • 1H-NMR (CDCl3)δ:3.09 (t, J=11.2 Hz, 1H), 3.40-3.58 (m, 3H), 3.76 (d, J=10.8 Hz, 1H), 3.91 (d, J=10.8 Hz, 1H), 4.66 (d, J=13.2 Hz, 1H), 4.73 (d, J=9.6 Hz, 1H), 5.50 (d, J=13.6 Hz, 1H), 5.79 (d, J=6.8 Hz, 1H), 6.25 (s, 1H), 6.61-6.70 (m, 2H), 6.79 (d, J=6.8 Hz, 1H), 6.93-7.08 (m, 3H), 7.10-7.19 (m, 2H).
  • The following example compounds were synthesized from commercially available compounds or intermediates described in reference example according to the above examples.
  • TABLE 1
    No. Structure H-NMR or LC/MS
    III-3
    Figure US20230287004A1-20230914-C00046
         		1H-NMR (CDCl3) δ: 2.99 (t, J = 12.4 Hz, 1H), 3.43-3.61 (m, 3H), 3.81 (d, J = 12.0 Hz, 1H), 3.96 (d, J = 11.0 Hz, 1H), 4.59 (d, J = 9.8 Hz, 1H), 4.66 (d, J = 13.2 Hz, 1H), 5.26 (s, 1H), 5.54 (d, J = 13.4 Hz, 1H), 5.75 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 6.84 (t, J = 7.0 Hz, 1H), 6.98-7.05 (m, 2H), 7.07-7.12 (m, 3H), 7.22 (t, J = 7.0 Hz, 1H).
    III-4
    Figure US20230287004A1-20230914-C00047
         		1H-NMR (CDCl3) δ: 3.09 (t, J = 12.7 Hz, 1H), 3.48 (t, J = 11.9 Hz, 1H), 3.59 (t, J = 11.2 Hz, 2H), 3.82 (d, J = 11.7 Hz, 1H), 3.94 (d, J = 10.9 Hz, 1H), 4.53 (d, J = 10.2 Hz, 1H), 4.71 (d, J = 13.6 Hz, 1H), 5.68 (d, J = 13.2 Hz, 1H), 5.77 (d, J = 7.5 Hz, 1H), 6.26 (s, 1H), 6.81-6.88 (m, 2H), 7.07-7.16 (m, 3H), 7.26-7.28 (m, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H).
    III-5
    Figure US20230287004A1-20230914-C00048
         		1H-NMR (CDCl3) δ: 2.34 (d, J = 13.2 Hz, 1H), 2.57 (d, J = 12.4 Hz, 1H), 2.79-2.87 (m, 1H), 2.90-3.01 (m, 2H), 3.58 (d, J = 13.6 Hz, 1H), 4.67 (dd, J = 2.4 Hz, 10.8 Hz, 1H), 5.03-5.08 (m, 1H), 5.12 (s, 1H), 5.53 (d, J = 13.6 Hz, 1H), 5.79 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.78-6.84 (m, 1H), 7.05-7.10 (m, 3H), 7.20 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.37 (d, J = 6.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H)
    III-7
    Figure US20230287004A1-20230914-C00049
         		1H-NMR (CDCl3) δ: 1.64-1.69 (m, 2H), 1.88-1.96 (m, 2H), 2.60- 2.70 (m, 1H), 3.58 (d, J = 13.2 Hz, 1H), 3.80-3.96 (m, 4H), 4.52-4.67 (m, 2H), 5.21 (s, 1H), 5.53 (d, J = 13.2 Hz, 1H), 5.78 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.78-6.85 (m, 1H), 7.00-7.09 (m, 3H), 7.20 (d, J = 7.6 Hz, 1H), 7.29 (t, J = 7.2 Hz, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H).
    III-8
    Figure US20230287004A1-20230914-C00050
         		1H-NMR (CDCl3) δ: 1.90-1.99 (m, 1H), 2.26-2.32 (m, 1H), 2.60- 2.68 (m, 1H), 3.38-3.43 (m, 1H), 3.55-3.64 (m, 2H), 3.90 (dd, J = 3.6 Hz, 12.8 Hz, 1H), 4.00-4.06 (m, 1H), 4.63 (dd, J = 2.4 Hz, 14.2 Hz, 1H), 4.70-4.75 (m, 1H), 5.06 (s, 1H), 5.52 (d, J = 13.2 Hz, 1H), 5.84 (d, J = 7.6 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.80-6.85 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.10 (d, J = 4.0 Hz, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.36 (d, J = 6.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H)
    III-9
    Figure US20230287004A1-20230914-C00051
         		1H-NMR (CDCl3) δ: 2.37 (d, J = 13.2 Hz, 1H), 2.57 (d, J = 12.4 Hz, 1H), 2.79-2.87 (m, 1H), 2.90-3.03 (m, 2H), 4.08 (d, J = 13.6 Hz, 1H), 4.64 (d, J = 10.8 Hz, 1H), 5.05 (d, J = 12.0 Hz, 1H), 5.19 (s, 1H), 5.25-5.32 (m, 1H), 5.78 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.90-7.20 (m, 5H).
  • TABLE 2
    No. Structure H-NMR or LC/MS
    III-10
    Figure US20230287004A1-20230914-C00052
         		1H-NMR (CDCl3) δ: 3.06 (t, J = 11.6 Hz, 1H), 3.47 (t, J = 11.2 Hz, 1H), 3.50-3.63 (m, 2H), 3.80 (d, J = 11.6 Hz, 1H), 3.94 (d, J = 11.2 Hz, 1H), 4.58 (d, J = 9.6 Hz, 1H), 4.69 (d, J = 13.6 Hz, 1H), 5.57 (d, J = 13.6 Hz, 1H), 5.75 (d, J = 7.6 Hz, 1H), 5.90 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 7.04-7.17 (m, 5H), 7.35-7.42 (m, 1H).
    III-11
    Figure US20230287004A1-20230914-C00053
         		1H-NMR (CDCl3) δ: 3.04 (t, J = 12.0 Hz, 1H), 3.47 (t, J = 11.6 Hz, 1H), 3.59 (t, J = 11,2 Hz, 1H), 3.82 (d, J = 12.0 Hz, 1H), 3.97 (d, J = 10.8 Hz, 1H), 4.03 (d, J = 14.0 Hz, 1H), 4.56 (d, J = 11.6 Hz, 1H), 4.68 (d, J = 13.6 Hz, 1H), 5.17 (d, J = 14.0 Hz, 1H), 5.24 (s, 1H), 5.75 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 7.6 Hz, 1H), 6.80-6.88 (m, 2H), 6.98 (t J = 8.8 Hz, 1H), 7.04-7.16 (m, 3H).
    III-12
    Figure US20230287004A1-20230914-C00054
         		1H-NMR (CDCl3) δ: 3.04 (t, J = 12.8 Hz, 1H), 3.40-3.62 (m, 3H), 3.82 (d, J = 12.0 Hz, 1H), 3.96 (d, J = 11.2 Hz, 1H), 4.58 (d, J = 9.6 Hz, 1H), 4.68 (d, J = 13.6 Hz, 1H), 5.19 (s, 1H), 5.49 (d, J = 13.6 Hz, 1H), 5.74 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.06-7.16 (m, 3H), 7.21 (t, J = 8.8 Hz, 1H).
    III-13
    Figure US20230287004A1-20230914-C00055
         		1H-NMR (CDCl3) δ: 3.04 (t, J = 12.0 Hz, 1H), 3.47 (t, J = 12.0 Hz, 1H), 3.58 (t, J = 10.8 Hz, 1H), 3.69 (d, J = 13.6 Hz, 1H), 3.81 (d, J = 12.0 Hz, 1H), 3.94 (d, J = 11.2 Hz, 1H), 4.57 (d, J = 13.6 Hz, 1H), 4.69 (d, J = 14.0 Hz, 1H), 5.59 (d, J = 13.6 Hz, 1H), 5.79 (d, J = 7.6 Hz, 1H), 5.96 (s, 1H), 6.63 (d, J = 7.6 Hz, 1H), 6.81-6.88 (m, 1H), 6.96 (t, J = 9.6 Hz, 1H), 7.04-7.13 (m, 2H), 7.17 (d, J = 7.6 Hz, 1H), 7.38- 7.45 (m, 1H).
    III-14
    Figure US20230287004A1-20230914-C00056
         		1H-NMR (CDCl3) δ: 3.00-3.07 (m, 1H), 3.47 (td, J = 12.0, 2.6 Hz, 1H), 3.57-3.62 (m, 2H), 3.82 (dd, J = 11.9, 3.3 Hz, 1H), 3.97 (dd, J = 11.1, 2.9 Hz, 1H), 4.60 (dd, J = 10.0, 3.0 Hz, 1H), 4.68 (dd, J = 13.6, 2.0 Hz, 1H), 5.20 (s, 1H), 5.47 (d, J = 13.4 Hz, 1H), 5.76 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.82-6.86 (m, 1H), 6.98 (dd, J = 8.7, 2.5 Hz, 1H), 7.07-7.16 (m, 4H), 7.35 (dd, J = 8.3, 5.5 Hz, 1H).
    III-15
    Figure US20230287004A1-20230914-C00057
         		1H-NMR (CDCl3) δ: 3.02-3.09 (m, 1H), 3.47 (td, J = 11.9, 2.6 Hz, 1H), 3.56-3.62 (m, 2H), 3.82 (dd, J = 11.9, 3.3 Hz, 1H), 3.96 (dd, J = 11.2, 3.0 Hz, 1H), 4.59 (dd, J = 10.0, 3.1 Hz, 2H), 4.69 (dd, J = 13.6, 2.3 Hz, 2H), 5.20 (s, 1H), 5.47 (d, J = 13.4 Hz, 1H), 5.75 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.82-6.87 (m, 1H), 7.05- 7.14 (m, 3H), 7.25 (d, J = 2.1 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.41 (dd, J = 8.2, 2.1 Hz, 1H).
  • TABLE 3
    No. Structure H-NMR or LC/MS
    III-16
    Figure US20230287004A1-20230914-C00058
         		1H-NMR (CDCl3) δ: 3.01-3.09 (m, 1H), 3.47 (td, J = 11.9, 2.6 Hz, 1H), 3.59 (t, J = 10.5 Hz, 1H), 3.72 (dd, J = 13.6, 0.9 Hz, 1H), 3.82 (dd, J = 12.0, 3.2 Hz, 1H), 3.95 (dd, J = 11.0, 3.0 Hz, 1H), 4.58 (dd, J = 10.0, 3.1 Hz, 1H), 4.70 (dd, J = 13.6, 2.3 Hz, 1H), 5.63 (d, J = 13.6 Hz, 1H), 5.80 (d, J = 7.8 Hz, 1H), 5.95 (s, 1H), 6.76 (dd, J = 7.8, 1.4 Hz, 1H), 6.82 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 7.10 (t, J = 9.1 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.29 (dd, J = 7.9, 1.5 Hz, 1H), 7.42 (td, J = 8.0, 5.6 Hz, 1H).
    III-17
    Figure US20230287004A1-20230914-C00059
         		1H-NMR (CDCl3) δ: 2.97-3.04 (m, 1H), 3.47 (td, J = 11.9, 2.7 Hz, 1H), 3.60 (t, J = 10.7 Hz, 1H), 3.82 (dd, J = 12.0, 3.1 Hz, 1H), 3.94- 4.00 (m, 2H), 4.58 (dd, J = 10.0, 3.0 Hz, 1H), 4.68 (dd, J = 13.7, 2.1 Hz, 1H), 5.39 (s, 1H), 5.73 (d, J = 14.6 Hz, 1H), 5.77 (d, J = 7.8 Hz, 1H), 6.70 (d, J = 7.4 Hz, 1H), 6.82-6.86 (m, 1H), 7.01 (d, J = 7.7 Hz, 1H), 7.08-7.15 (m, 2H), 7.40-7.45 (m, 2H), 7.80-7.83 (m, 1H).
    III-18
    Figure US20230287004A1-20230914-C00060
         		1H-NMR (CDCl3) δ: 2.39 (s, 3H), 3.00 (t, J = 11.6 Hz, 1H), 3.47 (t, J = 13.2 Hz, 1H), 3.50-3.61 (m, 2H), 3.80 (d, J = 12.0 Hz, 1H), 3.95 (d, J = 11.2 Hz, 1H), 4.60 (d, J = 10.0 Hz, 1H), 4.68 (d, J = 13.6 Hz, 1H), 5.62 (d, J = 13.2 Hz, 1H), 5.73 (s, 1H), 5.77 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.82 (t, J = 6.0 Hz, 1H), 7.07-7.20 (m, 6H).
    III-19
    Figure US20230287004A1-20230914-C00061
         		1H-NMR (CDCl3) δ: 2.95-3.03 (m, 1H), 3.43-3.49 (m, 2H), 3.59 (t, J = 10.6 Hz, 1H), 3.81 (dd, J = 12.0, 3.2 Hz, 1H), 3.97 (dd, J = 11.2, 3.0 Hz, 1H), 4.08 (d, J = 13.7 Hz, 1H), 4.60 (dd, J = 10.0, 3.0 Hz, 1H), 4.67 (dd, J = 13.6, 2.3 Hz, 1H), 5.23 (dd, J = 13.7, 2.1 Hz, 1H), 5.31 (s, 1H), 5.76 (d, J = 7.7 Hz, 1H), 6.70 (d, J = 7.5 Hz, 1H), 6.81- 6.86 (m, 1H), 7.02-7.14 (m, 4H), 7.20-7.30 (m, 1H).
    III-20
    Figure US20230287004A1-20230914-C00062
         		1H-NMR (CDCl3) δ: 3.09 (t, J = 12.8 Hz, 1H), 3.48 (t, J = 11.6 Hz, 1H), 3.55-3.62 (m, 2H), 3.81 (d, J = 11.6 Hz, 1H), 3.93 (d, J = 10.8 Hz, 1H), 4.53 (d, J = 9.6 Hz, 1H), 4.69 (d, J = 13.2 Hz, 1H), 5.68 (d, J = 12.8 Hz, 1H), 5.76 (d, J = 6.8 Hz, 1H), 6.26 (s, 1H), 6.80-6.88 (m, 2H), 7.05-7.15 (m, 3H), 7.24-7.28 (m, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H).
    III-21
    Figure US20230287004A1-20230914-C00063
         		1H-NMR (CDCl3) δ: 1.85-1.98 (m, 1H), 2.10-2.23 (m, 2H), 2.31- 2.43 (m, 1H), 2.69 (t, J = 10.8 Hz, 1H), 4.09 (d, J = 13.2 Hz, 1H), 4.51 (d, J = 12.4 Hz, 1H), 4.77 (d, J = 13.6 Hz, 1H), 5.20-5.30 (m, 1H), 5.78 (d, J = 7.2 Hz, 1H), 5.77 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 6.81-6.88 (m, 1H), 6.96-7.02 (m, 1H), 7.05-7.17 (m, 4H).
  • TABLE 4
    No. Structure H-NMR or LC/MS
    III-22
    Figure US20230287004A1-20230914-C00064
         		1H-NMR (CDCl3) δ: 1.22 (d, J = 7.2 Hz, 3H), 3.49-3.58 (m, 4H), 3.95 (dd, J = 10.8, 2.8 Hz, 1H), 4.08 (d, J = 13.8 Hz, 1H), 4.74 (dd, J = 10.0, 2.8 Hz, 1H), 4.99-5.05 (m, 1H), 5.22 (s, 1H), 5.30 (dd, J = 13.8, 2.3 Hz, 1H), 5.75 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 7.7 Hz, 1H), 6.84 (t, J = 7.0 Hz, 1H), 6.97-7.02 (m, 2H), 7.08-7.14 (m, 3H).
    III-23
    Figure US20230287004A1-20230914-C00065
         		1H-NMR (CDCl3) δ: 1.29-1.87 (m, 8H), 2.67 (td, J = 13.5, 2.6 Hz, 1H), 3.54-3.66 (m, 5H), 4.08 (d, J = 13.7 Hz, 1H), 4.47 (dd, J = 12.0, 2.3 Hz, 1H), 4.61 (dd, J = 13.8, 3.1 Hz, 1H), 5.24-5.33 (m, 2H), 5.79 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 6.83-6.87 (m, 1H), 6.98-7.15 (m, 5H).
    III-25
    Figure US20230287004A1-20230914-C00066
         		1H-NMR (CDCl3) δ: 1.47-1.75 (4H, m), 1.80-2.02 (2H, m), 2.53 (1H, t, J = 12.1 Hz), 3.57 (1H, d, J = 13.1 Hz), 4.30 (1H, d, J = 11.1 Hz), 4.70 (1H, d, J = 13.1 Hz), 5.21 (1H, s), 5.59 (1H, d, J = 13.4 Hz), 5.80 (1H, d, J = 7.3 Hz), 6.69 (1H, d, J = 7.6 Hz), 6.81 (1H, s), 7.08-7.11 (3H, m), 7.20-7.44 (4H, m)
    III-26
    Figure US20230287004A1-20230914-C00067
         		1H-NMR (CDCl3) δ: 1.82-2.17 (5H, m), 2.59-2.76 (1H, m), 2.84 (1H, t, J = 11.5 Hz) 4.09 (1H, d, J = 13.8 Hz), 4.63-4.69 (2H, m), 5.22 (1H, s), 5.27 (1H, dd, J = 13.9, 2.4 Hz), 5.79 (1H, d, J = 7.7 Hz), 6.68 (1H, d, J = 7.7 Hz), 6.83-6.87 (1H, m), 7.15-6.96 (5H, m).
    III-27
    Figure US20230287004A1-20230914-C00068
         		1H-NMR (CDCl3) δ: 1.49-1.79 (m, 4H), 1.89 (d, J = 10.4 Hz, 1H), 1.99 (d, J = 11.8 Hz, 1H), 2.54 (td, J = 12.7, 2.4 Hz, 1H), 3.93 (d, J = 14.4 Hz, 1H), 4.27 (dd, J = 11.4, 2.6 Hz, 1H), 4.73 (d, J = 14.7 Hz, 1H), 5.35 (s, 1H), 5.78-5.82 (m, 2H), 6.69 (d, J = 7.8 Hz, 1H), 6.81-6.85 (m, 1H), 7.03 (d, J = 7.7 Hz, 1H), 7.07-7.14 (m, 2H), 7.38-7.44 (m, 2H), 7.78-7.81 (m, 1H).
    III-28
    Figure US20230287004A1-20230914-C00069
         		1H-NMR (CDCl3) δ: 1.79 (d, J = 7.2 Hz, 3H), 3.33-3.40 (m, 1H), 3.46-3.75 (m, 5H), 3.94 (dd, J = 11.0, 2.9 Hz, 1H), 4.43 (dd, J = 9.7, 2.7 Hz, 1H), 5.58 (d, J = 13.6 Hz, 1H), 5.81 (d, J = 7.7 Hz, 1H), 6.00 (s, 1H), 6.65 (d, J = 7.7 Hz, 1H), 6.82-6.88 (m, 1H), 6.94-7.01 (m, 2H), 7.11 (t, J = 9.2 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.39-7.44 (m, 1H).
  • TABLE 5
    No. Structure H-NMR or LC/MS
    III-29
    Figure US20230287004A1-20230914-C00070
         		1H-NMR (CDCl3) δ: 1.62-1.69 (m, 1H), 1.90 (t, J = 12.4 Hz, 1H), 2.13 (d, J = 13.7 Hz, 1H), 2.38-2.46 (m, 2H), 4.09-4.20 (m, 3H), 4.32 (d, J = 6.3 Hz, 1H), 4.37-4.41 (m, 2H), 4.71 (dd, J = 13.7, 3.4 Hz, 1H), 5.23 (s, 1H), 5.36 (dd, J = 13.7, 2.6 Hz, 1H), 5.79 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.82-6.87 (m, 1H), 6.94-6.99 (m, 1H), 7.05-7.15 (m, 4H).
    III-30
    Figure US20230287004A1-20230914-C00071
         		1H-NMR (CDCl3) δ: 1.78 (d, J = 7.2 Hz, 3H), 3.26-3.32 (m, 1H), 3.44-3.60 (m, 3H), 3.72 (dd, J = 11.7, 2.6 Hz, 1H), 3.94 (dd, J = 11.2, 2.9 Hz, 1H), 4.42 (dd, J = 9.9, 2.8 Hz, 1H), 5.29 (s, 1H), 5.54 (d, J = 13.6 Hz, 1H), 5.76 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 7.7 Hz, 1H), 6.81-6.86 (m, 1H), 6.96-7.04 (m, 2H), 7.07-7.11 (m, 3H), 7.23- 7.25 (m, 1H).
    III-31
    Figure US20230287004A1-20230914-C00072
         		LC/MS (ESI): m/z = 480 [M + H]+, RT = 1.81 min, method (1)
    III-32
    Figure US20230287004A1-20230914-C00073
         		1H-NMR (CDCl3) δ: 1.78 (d, J = 7.2 Hz, 3H), 3.25-3.30 (m, 1H), 3.44-3.51 (m, 2H), 3.54-3.59 (m, 2H), 3.71 (dd, J = 11.5, 2.6 Hz, 1H), 3.94 (dd, J = 11.2, 2.8 Hz, 1H), 4.45 (dd, J = 10.0, 2.8 Hz, 1H), 5.28 (s, 1H), 5.51 (d, J = 13.4 Hz, 1H), 5.77 (d, J = 7.7 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 6.80-6.84 (m, 1H), 7.01 (d, J = 7.7 Hz, 1H), 7.08-7.10 (m, 2H), 7.26-7.45 (m, 3H).
    III-33
    Figure US20230287004A1-20230914-C00074
         		1H-NMR (CDCl3) δ: 0.85 (s, 3H), 0.97 (s, 3H), 1.34-2.00 (m, 4H), 2.62-2.66 (m, 1H), 4.05 (d, J = 13.6 Hz, 1H), 4.40-4.48 (m, 1H), 4.56- 4.63 (m, 1H), 5.24 (s, 1H), 5.30-5.35 (s, 1H), 5.80 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.78-6.90 (m, 1H), 6.95-7.15 (m, 4H), 7.16- 7.22 (m, 1H)
    III-34
    Figure US20230287004A1-20230914-C00075
         		1H-NMR (CDCl3) δ: 1.86-2.18 (4H, m), 2.30-2.46 (1H, m), 2.90 (1H, dd, J = 30.0, 13.9 Hz), 4.07 (1H, d, J = 13.7 Hz), 4.41-4.48 (1H, m), 4.99-5.06 (1H, m), 5.20 (1H, s), 5.30 (1H, dd, J = 13.7, 2.4 Hz), 5.78 (1H, d, J = 7.8 Hz), 6.68 (1H, d, J = 7.8 Hz), 6.83-6.87 (1H, m), 7.00 (1H, dd, J = 8.3, 4.1 Hz), 7.06-7.17 (4H, m).
    III-35
    Figure US20230287004A1-20230914-C00076
         		1H-NMR (CDCl3) δ: 0.89 (s, 3H), 0.95 (s, 3H), 1.25-2.20 (m, 4H), 2.39 (d, J = 12.4 Hz, 1H), 4.05 (d, J = 12.4 Hz, 1H), 4.20-4.28 (m, 1H), 4.39-4.44 (m, 1H), 5.20 (m, 1H), 5.33-5.38 (m, 1H), 5.78 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.80-6.83 (m, 1H), 6.88-7.18 (m, 5H)
  • TABLE 6
    No. Structure H-NMR or LC/MS
    III-36
    Figure US20230287004A1-20230914-C00077
         		1H-NMR (CDCl3) δ: 0.18-0.25 (m, 1H), 0.26-0.35 (m, 1H), 0.36-0.50 (m, 2H), 0.76-0.83 (m, 1H), 0.98-1,40 (m, 1H), 1.60-2.24 (m, 4H), 2.60-2.70 (m, 1H), 4.04 (d, J = 13.6 Hz, 1H), 4.32-4.48 (m, 1H), 4.69-4.75 (m, 1H), 5.26 (s, 1H), 5.77 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.80-6.90 (m, 1H), 7.00-7.18 (m, 5H)
    III-37
    Figure US20230287004A1-20230914-C00078
         		1H-NMR (CDCl3) δ: 3.26 (dd, J = 14.6, 5.7 Hz, 1H), 3.85-4.11 (m, 4H), 4.68 (dd, J = 10.4, 3.6 Hz, 1H), 5.07 (d, J = 14.7 Hz, 1H), 5.22- 5.27 (m, 2H), 5.74 (d, J = 7.7 Hz, 1H), 6.69 (d, J = 7.5 Hz, 1H), 6.85 (t, J = 6.9 Hz, 1H), 6.97-7.15 (m, 5H).
    III-38
    Figure US20230287004A1-20230914-C00079
         		1H-NMR (CDCl3) δ: 1.49-1.79 (m, 2H), 1.91 (d, J = 11.9 Hz, 1H), 2.08-2.13 (m, 1H), 2.47-2.62 (m, 2H), 4.07-4.10 (m, 1H), 4.35 (dd, J = 11.9, 2.3 Hz, 1H), 4.84 (dd, J = 13.4, 4.0 Hz, 1H), 5.25 (s, 1H), 5.31 (dd, J = 13.9, 2.4 Hz, 1H), 5.79 (d, J = 7.7 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.83-6.87 (m, 1H), 6.97-7.00 (m, 1H), 7.06-7.15 (m, 4H).
    III-39
    Figure US20230287004A1-20230914-C00080
         		1H-NMR (CDCl3) δ: 1.31-1.44 (m, 1H), 1.58 (q, J = 11.6 Hz, 1H), 2.05 (d, J = 10.8 Hz, 1H), 2.26 (d, J = 11.6 Hz, 1H), 2.47 (t, J = 11.2 Hz, 1H), 3.31 (s, 3H), 3.40-3.48 (m, 1H), 4.06 (d, J = 13.6 Hz, 1H), 4.24 (d, J = 10.0 Hz, 1H), 4.68-4.76 (m, 1H), 5.23 (s, 1H), 5.34 (d, J = 13.6 Hz, 1H), 5.78 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.95-7.00 (m, 1H), 7.03-7.15 (m, 4H).
    III-40
    Figure US20230287004A1-20230914-C00081
         		1H-NMR (CDCl3) δ: 0.94 (3H, d, J = 7.2 Hz), 1.45-1.86 (5H, m), 1.86-2.12 (1H. m), 2.79 (1H, dd, J = 13.3, 3.5 Hz), 4.05 (1H, d, J = 13.7 Hz), 4.27 (1H, dd, J = 11.6, 2.4 Hz), 4.56 (1H, d, J = 13.2 Hz), 5.36 (1H, dd, J = 13.6, 2.4 Hz), 5.20 (1H, s), 5.79 (1H, d, J = 7.7 Hz), 6.69 (1H, d, J = 7.4 Hz), 6.81-6.87 (1H, m), 6.95-7.01 (1H, m), 7.05-7.14 (4H, m).
    III-41
    Figure US20230287004A1-20230914-C00082
         		1H-NMR (CDCl3) δ: 0.96 (3H, d, J = 6.5 Hz), 1.16-1.20 (1H, m), 1.34-1.40 (1H, m), 1.64-1.79 (3H, m), 1.85-1.89 (1H, m), 2.52 (1H, td, J = 13.1, 2.6 Hz), 4.05 (1H, d, J = 13.8 Hz), 4.28 (1H, dd, J = 11.5, 2.2 Hz), 4.70 (1H, dd, J = 13.3, 3.6 Hz), 5.23 (1H, s), 5.36 (1H, dd, J = 13.7, 2.4 Hz), 5.79 (1H, d, J = 7.8 Hz), 6.68 (1H, d, J = 7.5 Hz), 6.82-6.86 (1H, m), 6.98 (1H, dd, J = 8.3, 5.3 Hz), 7.02-7.15 (4H, m).
  • TABLE 7
    No. Structure H-NMR or LC/MS
    III-42
    Figure US20230287004A1-20230914-C00083
         		1H-NMR (CDCl3) δ: 0.91 (3H, d, J = 6.6 Hz), 1.22-1.29 (2H, m), 1.57-1.87 (5H, m), 1.96 (1H, d, J = 13.6 Hz), 2.18 (1H, t, J = 12.4 Hz), 4.05 (1H, d, J = 13.9 Hz), 4.25 (1H, dd, J = 11.4, 2.5 Hz), 4.57- 4.65 (1H, m), 5.22 (1H, s), 5.35 (1H, dd, J = 13.8, 2.4 Hz), 5.78 (1H, d, J = 7.6 Hz), 6.68 (1H, d, J = 7.8 Hz), 6.82-6.86 (1H, m), 6.94- 7.01 (1H, m), 7.03-7.15 (4H, m).
    III-43
    Figure US20230287004A1-20230914-C00084
         		1H-NMR (CDCl3) δ: 1.55 (1H, ddd, J = 26.3, 13.0, 4.6 Hz), 1.74 (1H, q, J = 12.3 Hz), 1.89 (1H. d, J = 13.1 Hz), 2.09 (1H, d, J = 12.7 Hz), 2.58 (1H, td, J = 13.2, 2.6 Hz), 2.40-2.52 (1H, m), 3.54 (1H, d, J = 13.4 Hz), 4.35 (1H, dd, J = 11.7, 2.3 Hz), 4.84 (1H, dd, J = 13.4, 3.8 Hz), 5.23 (1H, s), 5.57 (1H, d, J = 13.4 Hz), 5.80 (1H, d, J = 7.7 Hz), 6.69 (1H, d, J = 7.7 Hz), 6.82-6.86 (1H. m), 6.98 (1H, td, J = 8.2, 2.6 Hz), 7.07-7.14 (4H, m), 7.20 (1H, dd, J = 8.3, 5.5 Hz).
    III-44
    Figure US20230287004A1-20230914-C00085
         		1H-NMR (CDCl3) δ: 1.83-2.00 (m, 1H), 2.08-2.23 (m, 2H), 2.37 (t, J = 13.6 Hz, 1H), 2.74 (t, J = 13.2 Hz, 1H), 3.63 (d, J = 13.6 Hz, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.76-4.84 (m, 1H), 5.54 (d, J = 13.2 Hz, 1H), 5.79 (d, J = 8.0 Hz, 1H), 5.87 (s, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 7.04-7.18 (m, 5H), 7.35-7.43 (m, 1H).
    III-45
    Figure US20230287004A1-20230914-C00086
         		1H-NMR (CDCl3) δ: 0.82 (s, 3H), 0.96 (s, 3H), 1.30-1.61 (m, 4H), 2.71 (t, J = 13.2 Hz, 1H), 1.99 (d, J = 12.8 Hz, 1H), 2.54 (t, J = 12.8 Hz, 1H), 4.04 (d, J = 13.6 Hz, 1H), 4.27 (dd, J = 2.0 Hz, 11.2 Hz, 1H), 4.69-4.74 (m, 1H), 5.23 (s, 1H), 5.35 (dd, J = 2.4 Hz, 13.6 Hz, 1H), 5.77 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.80-6.86 (m, 1H), 6.95-7.00 (m, 1H), 7.03-7.14 (m, 4H).
    III-46
    Figure US20230287004A1-20230914-C00087
         		1H-NMR (CDCl3) δ: 1.83-2.00 (m, 1H), 2.07-2.27 (m, 2H), 2.37 (t, J = 13.2 Hz, 1H), 2.67 (t, J = 13.2 Hz, 1H), 3.54 (d, J = 13.2 Hz, 1H), 4.51 (d, J = 11.2 Hz, 1H), 4.75-4.82 (m, 1H), 5.24 (s, 1H), 5.50 (d, J = 13.2 Hz, 1H), 5.77 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.80-6.86 (m, 1H), 6.95-7.02 (m, 1H), 7.05-7.14 (m, 4H), 7.16-7.23 (m, 1H)
    III-47
    Figure US20230287004A1-20230914-C00088
         		1H-NMR (CDCl3) δ: 0.82 (s, 3H), 0.97 (s, 3H), 1.24-1.44 (m, 2H), 1.46-1.60 (m, 2H), 2.58-2.68 (m, 1H), 3.50 (d, J = 13.2 Hz, 1H), 4.44 (dd, J = 2.8 Hz, 11.6 Hz, 1H), 4.57 (dd, J = 2.8 Hz, 13.2 Hz, 1H), 5.23 (s, 1H), 5.58 (d, J = 13.6 Hz, 1H), 5.78 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.80-6.86 (m, 1H), 6.95-7.03 (m, 2H), 7.05-7.13 (m, 3H), 7.18-7.24 (m, 1H).
    III-48
    Figure US20230287004A1-20230914-C00089
         		1H-NMR (CDCl3) δ: 0.10-0.16 (m, 1H), 0.25-0.31 (m, 1H), 0.36- 0.49 (m, 2H), 0.79 (d, J = 14.0 Hz, 1H), 0.99 (d, J = 12.8 Hz, 1H), 1.92-2.03 (m, 1H), 2.18 (t, J = 12.0 Hz, 1H), 2.65-2.77 (m, 1H), 3.58 (d, J = 13.6 Hz, 1H), 4.45 (dd, J = 2.4 Hz, 11.6 Hz, 1H), 4.73 (dd, J = 3.6 Hz, 13.2 Hz, 1H), 5.58 (d, J = 13.6 Hz, 1H), 5.81 (d, J = 7.6 Hz, 1H), 5.88 (s, 1H), 6.78 (d, J = 7.2 Hz, 1H), 6.81-6.88 (m, 1H), 7.05- 7.16 (m, 5H), 7.34-7.43 (m, 1H).
  • TABLE 8
    No. Structure H-NMR or LC/MS
    III-49
    Figure US20230287004A1-20230914-C00090
         		1H-NMR (CDCl3) δ: 0.95 (d, J = 6.5 Hz, 3H), 1.12-1.24 (m, 1H), 1.36 (dd, J = 24.1, 11.7 Hz, 1H), 1.48-1.75 (m, 2H), 1.86 (d, J = 12.7 Hz, 1H), 2.59 (td, J = 13.1, 2.8 Hz, 1H), 3.59 (d, J = 13.3 Hz, 1H), 4.28 (dd, J = 11.5, 2.4 Hz, 1H), 4.73 (dd, J = 13.6, 3.0 Hz, 1H), 5.66 (d, J = 13.3 Hz, 1H), 5.79 (d, J = 7.7 Hz, 1H), 5.85 (s, 1H), 6.77-6.79 (m, 1H), 6.82-6.86 (m, 1H), 7.03-7.11 (m, 3H), 7.14 (d, J = 7.7 Hz, 2H), 7.36 (td, J = 8.0, 5.5 Hz, 1H).
    III-50
    Figure US20230287004A1-20230914-C00091
         		1H-NMR (CDCl3) δ: 0.95 (d, J = 6.5 Hz, 3H), 1.12-1.28 (m, 1H), 1.36 (q, J = 12.0 Hz, 1H), 1.63-1.78 (m, 3H), 1.86 (d, J = 12.8 Hz, 1H), 2.52 (td, J = 13.1, 2.8 Hz, 1H), 3.51 (d, J = 13.4 Hz, 1H), 4.28 (dd, J = 11.6, 2.3 Hz, 1H), 4.69 (dd, J = 13.5, 3.3 Hz, 1H), 5.22 (s, 1H), 5.62 (d, J = 13.4 Hz, 1H), 5.78 (d, J = 7.7 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 6.81-6.85 (m, 1H), 6.97 (td, J = 8.3, 2.6 Hz, 1H), 7.05- 110 (m, 4H), 7.20 (dd, J = 8.4, 5.4 Hz, 1H).
    III-51
    Figure US20230287004A1-20230914-C00092
         		1H-NMR (CDCl3) δ: 1.17 (d, J = 6.1 Hz, 3H), 2.61 (dd, J = 13.3, 10.7 Hz, 1H), 3.54-3.59 (m, 1H), 3.64 (t, J = 10.6 Hz, 1H), 3.96 (dd, J = 11.1, 2.9 Hz, 1H), 4.07 (d, J = 13.8 Hz, 1H), 4.54 (dd, J = 10.0, 2.9 Hz, 1H), 4.64 (dd, J = 13.4, 2.3 Hz, 1H), 5.26-5.30 (m, 2H), 5.75 (d, J = 7.7 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 6.85 (t, J = 7.2 Hz, 1H), 6.98-7.03 (m, 2H), 7.07-7.15 (m, 3H).
    III-52
    Figure US20230287004A1-20230914-C00093
         		1H-NMR(CDCl3) δ: 1.16 (d, J = 6.0 Hz, 3H), 2.55-2.65 (m, 1H), 3.48-3.60 (m, 2H), 3.64 (t, J = 10.4 Hz, 1H), 3.94 (dd, J = 2.8 Hz, 11.2 Hz, 1H), 4.54 (dd, J = 2.8 Hz, 10.0 Hz, 1H), 4.62 (dd, J = 2.0 Hz, 13.6 Hz, 1H), 5.25 (s, 1H), 5.54 (d, J = 13.2 Hz, 1H), 5.74 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 6.79-6.86 (m, 1H), 6.96-7.05 (m, 2H), 7.05-7.15 (m, 3H), 7.17-7.24 (m, 1H).
  • TABLE 9
    No. Structure H-NMR or LC/MS
    III-53
    Figure US20230287004A1-20230914-C00094
         		1H-NMR (CDCl3) δ: 1.45-1.74 (m, 4H), 1.85 (d, J = 12.0 Hz, 1H), 1.95-2.02 (m, 1H), 2.61 (t, J = 12.4 Hz, 1H), 3.58 (d, J = 14.0 Hz, 1H), 4.27 (d, J = 10.8 Hz, 1H), 4.74 (d, J = 12.4 Hz, 1H), 5.65 (d, J = 14.0 Hz, 1H), 5.78 (d, J = 6.8 Hz, 1H), 5.85 (s, 1H), 6.75-6.88 (m, 2H), 7.02-7.15 (m, 5H), 7.34-7.40 (m, 1H),
    III-54
    Figure US20230287004A1-20230914-C00095
         		1H-NMR (CDCl3) δ: 1.47-2.05 (m, 6H), 2.50-2.58 (m, 1H), 3.51 (d, J = 12.0 Hz, 1H), 4.26-4.31 (m, 1H), 4.68-4.74 (m, 1H), 5.22 (s, 1H), 5.62 (d, J = 13.6 Hz, 1H), 5.77 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.80-6.82 (m, 1H), 6.88-7.02 (m, 1H), 7.03- 7.15 (m, 5H)
    III-55
    Figure US20230287004A1-20230914-C00096
         		1H-NMR (CDCl3) δ: 0.12-0.18 (m, 1H), 0.25-0.31 (m, 1H), 0.36-0.49 (m, 2H), 0.78 (d, J = 14.0 Hz, 1H), 0.99 (d, J = 12.4 Hz, 1H), 1.92-2.00 (m, 1H), 2.18 (t, J = 11.6 Hz, 1H), 2.58- 2.68 (m, 1H), 3.48 (d, J = 13.2 Hz, 1H), 4.44 (dd, J = 2.0 Hz, 11.6 Hz, 1H), 4.70 (dd, J = 3.2 Hz, 12.8 Hz, 1H), 5.24 (s, 1H), 5.53 (d, J = 13.6 Hz, 1H), 5.77 (d, J = 8.0 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 6.80-6.87 (m, 1H), 6.95-7.02 (m, 2H), 7.03-7.14 (m, 3H), 7.20-7.26 (m, 1H).
    III-56
    Figure US20230287004A1-20230914-C00097
         		(CDCl3) δ: 7.36 (1H, t, J = 6.9 Hz), 7.29-7.19 (4H, m ), 7.16 (1H, d, J = 7.8 Hz), 6.95 (1H, t, J = 7.2 Hz), 6.68 (1H, d, J = 7.5 Hz), 6.54 (1H, d, J = 7.7 Hz), 5.69 (1H, d, J = 7.4 Hz), 5.15 (1H, s), 4.63 (1H, d, J = 13.1 Hz), 4.48 (1H, d, J = 9.7 Hz), 3.94-3.85 (2H, m ), 3.79-3.69 (2H, m ), 3.50-3.39 (2H, m), 3.02 (1H, t, J = 13.7 Hz), 2.92 (2H, t, J = 11.7 Hz).
    III-57
    Figure US20230287004A1-20230914-C00098
         		1H-NMR: 7.20 (dd, J = 8.6, 5.5 Hz, 1H), 7.14-7.08 (m, 3H), 7.03-6.97 (m, 2H), 6.85-6.82 (m, 1H), 6.68 (d, J = 7.7 Hz, 1H), 5.81 (d, J = 7.5 Hz, 1H), 5.53 (d, J = 13.6 Hz, 1H), 5.21 (s, 1H), 4.69-4.63 (m, 1H), 3.54 (d, J = 13.6 Hz, 1H), 2.85-2.80 (m, 1H), 2.66 (brs, 1H), 2 15-2.00 (m, 2H), 1.95-1.80 (m, 2H)
    III-58
    Figure US20230287004A1-20230914-C00099
         		1H-NMR (CDCl3) δ: 0.90 (d, J = 6.5 Hz, 3H), 1.23 (ddd, J = 25.6, 12.8, 4.1 Hz, 1H), 1.63-1.86 (m, 3H), 1.95 (d, J = 13.7 Hz, 1H), 2.17 (t, J = 12.3 Hz, 1H), 3.51 (d, J = 13.4 Hz, 1H), 4.25 (d, J = 11.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 5.21 (s, 1 H), 5.61 (d, J = 13.3 Hz, 1H), 5.78 (d, J = 7.7 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 6.7 Hz, 1H), 6.99 (t, J = 8.2 Hz, 1H), 7.05-7.09 (m, 4H), 7.20 (dd, J = 8.1, 5.7 Hz, 1H).
    III-59
    Figure US20230287004A1-20230914-C00100
         		1H-NMR (CDCl3) δ: 1.45-1.79 (m, 4H), 1.87 (d, J = 10.8 Hz, 1H), 1.99 (d, J = 12.8 Hz, 1H), 2.54 (t, J = 12.8 Hz, 1H), 4.04 (d, J = 13.6 Hz, 1H), 4.27 (dd, J = 2.0 Hz, 11.2 Hz, 1H), 4.69-4.74 (m, 1H), 5.23 (s, 1H), 5.35 (dd, J = 2.4 Hz, 13.6 Hz, 1H), 5.77 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.80-6.86 (m, 1H), 6.95-7.00 (m, 1H), 7.03-7.14 (m, 4H).
    • Example 4
  • Figure US20230287004A1-20230914-C00101
  • To a suspention of Compound 111-2 (1.00 g, 2.07 mmol) in DMA (5 ml) were added chloromethyl methyl carbonate (0.483 g, 3.10 mmol), potassium carbonate (0.572 g, 4.14 mmol) and potassium iodide (0.343 g, 2.07 mmol) and the mixture was stirred at 50° C. for 6 hours. To the mixture was added DMA (1 ml) and the mixture was stirred for 6 hours. The mixture was cooled to room temperature, DMA (6 ml) was added thereto, and the mixture was stirred at 50° C. for 5 minutes. The mixture was filtered. To the obtained filtrate were added 1 mol/L aqueous solution of hydrochloric acid (10 ml) and water (4 ml) and the mixture was stirred for 1 hour. The presipitated solid was filtered and dried under reduced pressure at 60° C. for 3 hours to obtain Compound 11-6 (1.10 g, 1.93 mmol, 93%).
  • 1H-NMR (DMSO-D6)δ: 2.91-2.98 (1H, m), 3.24-3.31 (1H, m), 3.44 (1H, t, J=10.4 Hz), 3.69 (1H, dd, J=11.5, 2.8 Hz), 3.73 (3H, s), 4.00 (1H, dd, J=10.8, 2.9 Hz), 4.06 (1H, d, J=14.3 Hz), 4.40 (1H, d, J=11.8 Hz), 4.45 (1H, dd, J=9.9, 2.9 Hz), 5.42 (1H, dd, J=14.4, 1.8 Hz), 5.67 (1H, d, J=6.5 Hz), 5.72-5.75 (3H, m), 6.83-6.87 (1H, m), 7.01 (1H, d, J=6.9 Hz), 7.09 (1H, dd, J=8.0, 1.1 Hz), 7.14-7.18 (1H, m), 7.23 (1H, d, J=7.8 Hz), 7.37-7.44 (2H, in).
    • Example 5
  • Figure US20230287004A1-20230914-C00102
    • First Step
  • To a solution of chloromethyl chloroformate (300 mg, 2.33 mmol) and Compound 30 (330 mg, 2.79 mmol) in dichloromethane (6.0 mL) was added pyridine (207 μL, 2.56 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred at 0° C. for 30 minutes, was warmed up to room temperature and was stirred for 1 hour. To the mixture was added 2 mol/L aqueous solution of hydrochloric acid and the mixture was extracted with dichloromethane. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain Compound 31 (440 mg, 90%).
  • 1H-NMR (CDCl3)δ:1.65 (s, 6H), 3.77 (s, 3H), 5.71 (s, 2H).
    • Second Step
  • Compound 111-2 (300 mg, 0.62 mmol), potassium carbonate (172 mg, 1.24 mmol), potassium iodide (103 mg, 0.62 mmol) and Compound 31 (261 mg, 1.24 mmol) were dissolved in DMA (3.0 mL) and the mixture was stirred at 80° C. for 3 hours. To the mixture was added 2 mol/L aqueous solution of hydrochloric acid and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 11-61 (350 mg, 86%).
  • 1H-NMR (CDCl3)δ:1.63 (s, 3H), 1.67 (s, 3H), 2.86-2.93 (m, 1H), 3.38-3.61 (m, 2H), 3.68-3.78 (m, 4H), 3.90-3.96 (m, 1H), 4.06 (d, d=14.0 Hz, 1H), 4.51 (dd, d=2.0 Hz, 9.6 Hz, 1H), 4.65 (d, J=12.4 Hz, 1H), 5.21 (d, J=14.4 Hz, 1H), 5.36 (s, 1H), 5.80-5.95 (m, 311), 6.85-6.92 (m, 211), 7.03-7.22 (m, 511).
    • Example 6
  • Figure US20230287004A1-20230914-C00103
  • To a solution of Compound 111-2 (90 mg, 0.186 mmol) in dichloromethane (2 mL) were added acetic anhydride (0.053 mL, 0.558 mmol), triethylamine (0.077 mL, 0.558 mmol) and a catalytic amount of DMAP, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-methanol). To the obtained solution was added ether and the presipitated solid was filtered to obtain Compound 11-4 (71 mg, 73%).
  • 1H-NMR (CDCl3)δ:2.46 (s, 3H), 2.88-2.99 (m, 1H), 3.35-3.50 (m, 1H), 3.60-3.65 (m, 1H), 3.75-3.83 (m, 1H), 3.90-4.00 (m, 1H), 4.05 (d, J=14.0 Hz, 1H), 4.52-4.57 (m, 1H), 4.60-4.70 (m, 1H), 5.24-5.34 (m, 1H), 5.35 (s, 1H), 5.88 (d, J=7.6 Hz, 1H), 6.85-6.82 (m, 1H), 6.90-7.05(m, 211), 7.06-7.20(m, 411)
      • LC/MS (ESI):m/z=526.2 [M+H]+, RT=1.87 min, method (1)
    Example 7
  • Figure US20230287004A1-20230914-C00104
    • First Step
  • To a solution of triphosgene (300 mg, 2.54 mmol) in dichloromethane (6.0 mL) was added pyridine (257 μL, 3.17 mmol) at 0° C. under nitrogen atmosphere and the mixture was stirred for 15 minutes. To the mixture was added a solution of Compound 30 (377 mg, 1.27 mmol) in dichloromethane (1.0 mL), and the mixture was stirred at 0° C. for 15 minutes, warmed up to room temperature and stirred for 15 minutes. The mixture was concentrated under reduced pressure, ethyl acetate (4.0 mL) was added thereto, and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain Compound 32 (380 mg).
    • Second Step
  • To a solution of Compound 111-2 (350 mg, 0.724 mmol) in dichloromethane (3.5 mL) were added Compound 32 (196 mg, 1.09 mmol) and triethylamine (301 μL, 2.17 mmol) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. To the mixture was added 2 mol/L aqueous solution of hydrochloric acid and the mixture was extracted with dichloromethane. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 11-65 (380 mg, 84%).
  • 1H-NMR (CDCl3)δ:1.73 (s, 3H), 1.77 (s, 3H), 2.90-2.99 (m, 1H), 3.37-3.43 (m, 1H), 3.57 (t, J=8.8 Hz, 1H), 3.76 (dd, J=2.8 Hz, 12.0 Hz, 1H), 3.81 (s, 3H), 3.94 (dd, J=2.8 Hz, 10.8 Hz, 1H), 4.05 (d, J=14.0 Hz, 1H), 4.55 (dd, J=2.8 Hz, 9.6 Hz, HD, 4.65 (d, J=12.0 Hz, 1H), 5.28 (d, J=12.0 Hz, 1H), 5.34 (s, 1H), 5.89 (d, d=8.0 Hz, 1H), 6.86-6.95 (m, 2H), 7.03-7.15 (m, 5H).
    • Example 8
  • Figure US20230287004A1-20230914-C00105
  • To a solution of Compound 33 (276 mg, 0.402 mmol) in THF (1 mL) were added acetic acid (121 mg, 2.01 mmol) and 1 mol/L TBAF in THF (1.21 mL, 1.21 mmol) under ice-water bath and the mixture was stirred at room temperature for 4 hours. The mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound II-129 (179 mg, 78%).
      • LC/MS (ESI):m/z=572.0 [M+H]+, RT=1.74 min, method (2)
    Example 9
  • Figure US20230287004A1-20230914-C00106
  • To a solution of Compound 111-2 (300 mg, 0.62 mmol) in DMF (4 mL) were added potassium carbonate (258 mg, 1.87 mmol),4-(chloromethyl)phenyl acetate (344 mg, 1.87 mmol) and sodium iodide (139 mg, 1.87 mmol) at room temperature and the mixture was stirred at 65° C. for 1 hour. To the mixture was added water and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound 11-115 (120 mg, 31%).

  • LC/MS (ESI):m/z=631.95 [M+H] + , RT=2.07 min, method  (2)
    • Example 10
  • Figure US20230287004A1-20230914-C00107
  • To a solution of Compound 111-2 (150 mg, 0.31 mmol) in dichloromethane (2 mL) 3 mmol/g triphenylphosphine supported on polymer (310 mg, 0.93 mmol), pyridin-4-ylmethanol (68 mg, 0.62 mmol) and 40% DEAD in toluene (270 mg, 0.62 mmol) at room temperature and the mixture was stirred at room temperature for 30 minutes. The mixture was purified by amino column chromatography (ethyl acetate-methanol) to obtain Compound 11-143 (63 mg, 35%).
      • LC/MS (ESI):m/z=575.00 [M+H]+, RT=1.43 min, method (2)
    Example 11
  • Figure US20230287004A1-20230914-C00108
  • To a solution of Compound 111-2 (65 mg, 0.134 mmol) in pyridine (0.8 mL) was added dimethylcarbamoyl chloride (21.7 mg, 0.202 mmol) and the mixture was stirred at 80° C. over night. To the mixture was added 1 mol/L aqueous solution of hydrochloric acid and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was solidified with ethyl acetate-hexane to obtain Compound 11-27 (65 mg, 87%).
  • 1H-NMR (CDCl3)δ:2.89 (t, J=11.2 Hz, 1H), 2.99 (s, 1H), 3.01 (s, 3H), 3.18-3.26 (m, 4H), 3.45 (t, J=10.8 Hz, 1H), 3.59 (t, J=10.8 Hz, 1H), 3.70-3.80 (m, 1H), 3.90-3.98 (m, 1H), 4.03 (d, J=13.6 Hz, 1H), 4.50-4.70 (m, 2H), 5.21-5.35 (m, 2H), 5.82 (d, J=7.6 Hz, 1H), 6.91 (t, J=7.6 Hz, 1H), 7.00-7.20 (m, 6H).
    • Example 12
  • Figure US20230287004A1-20230914-C00109
  • To a solution of ethyl phosphorodichloridate (135 mg, 0.829 mmol) in dichloromethane (3 mL) was added L-valine methyl ester hydrochloride (139 mg, 0.829 mmol) and then added dropwise a solution of triethylamine (168 mg, 1.66 mmol) in dichloromethane (2 mL) at, −78° C. The mixture was stirred at, room temperature for 1 hour. Compound 111-2 (200 mg, 0.414 mmol) and triethylamine (126 mg, 1.25 mmol) were added thereto, and the mixture was stirred at same temperature for 6 hours. The mixture was concentrated and the obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound 11-55 (112 mg, 38%).
      • LC/MS (ESI):m/z=705.05 [M+H]+, RT=2.18 min, method (2)
    Example 13
  • Figure US20230287004A1-20230914-C00110
  • To a solution of ethyl phosphorodichloridate (202 mg, 1.24 mmol) in dichloromethane (3 mL) was added dropwise a mixture of triethylamine (126 mg, 1.24 mmol) and methyl glycolate (112 mg, 1.24 mmol in dichloromethane (2 mL). The mixture was stirred at room temperature for 2 hours. Compound 111-2 (200 mg, 0.414 mmol) and triethylamine (126 mg, 1.25 mmol) were added thereto and the mixture was stirred at same temperature for 1 hour. The mixture was concentrated and the obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound 11-57 (143 mg, 52%).
      • LC/MS (ESI):m/z=664.00 [M+H]+, RT=1.93 min, method (2)
    Example 14
  • Figure US20230287004A1-20230914-C00111
  • To a solution of phosphoryl chloride (1.53 g, 10 mmol) in dichloromethane (10 mL) was added dropwise the mixture of triethylamine (2.12 g, 20.95 mmol) and methyl glycolate (1.89 mg, 21 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 hours. To the mixture (2 mL) were added Compound 111-2 (200 mg, 0.414 mmol) and triethylamine (126 mg, 1.25 mmol) and the mixture was stirred at same temperature for 1 hour. The mixture was concentrated and the obtained residue was purified by silica gel column chromatography (ethyl acetate-methanol) to obtain Compound 11-58 (166 mg, 57%).
      • LC/MS (ESI):m/z=707.90 [M+H]+, RT=1.93 min, method (2)
  • The following example compounds were synthesized from commercially available compounds according to the above examples.
  • TABLE 10
    No. Structure NMR or LC/MS
    II-1
    Figure US20230287004A1-20230914-C00112
         		LC/MS (ESI): m/z = 534.2 [M + H]+, RT = 2.22 min, method (1)
    II-2
    Figure US20230287004A1-20230914-C00113
         		LC/MS (ESI): m/z = 534.2 [M + H]+, RT = 2.24 min, method (2)
    II-3
    Figure US20230287004A1-20230914-C00114
         		1H-NMR (CDCl3) δ: 2.86 (dd, J = 11.4, 11.4 Hz, 1H), 3.26- 3.40 (m, 2H), 3.55 (d, J = 13.4 Hz, 1H), 3.70 (d, J = 10.4 Hz, 1H), 3.86 (d, J = 10.4 Hz, 1H), 4.48 (d, J = 9.5 Hz, 1H), 4.66 (d, J = 13.4 Hz, 1H), 5.20 (s, 1H), 5.43-5.50 (m, 2H), 5.63 (d, J = 10.9 Hz, 1H), 5.79 (d, J = 7.8 Hz, 1H), 6.40 (d, J = 7.7 Hz, 1H), 6.62-6.69 (m, 1H), 7.02-7.07 (m, 3H), 7.18 (d, J = 7.4 Hz, 1H), 7.27-7.44 (m, 6H), 7.60-7.66 (m, 2H).
    II-5
    Figure US20230287004A1-20230914-C00115
         		1H-NMR (DMSO-d6)δ: 2.04 (s, 3H), 2.90-3.00 (m, 1H), 3.44-3.50(m, 2H), 3.64-3.72(m, 1H), 3.95-4.00(m, 1H), 4.11-4.10(m, 1H), 4.20-4.30(m, 2H), 5.40-5.5.46(m, 1H), 6.62-5.75(m, 4H), 6.80-6.90(m, 1H), 6.98-7.10(m, 1H), 7.11-7.20(m, 2H), 7.21-7.30(m, 1H), 7.45-7.50(m, 2H)
    II-7
    Figure US20230287004A1-20230914-C00116
         		1H-NMR (CDCl3) δ: 2.85-2.97 (m, 1H), 3.38 (s, 3H), 3.39- 3.48 (m, 1H) 3.54 (t, J = 10.4 Hz, 1H), 3.68 (t, J = 4.4 Hz, 2H), 3.74 (dd, J = 2.8 Hz, 12.0 Hz, 1H), 3.92 (dd, J = 2.8 Hz, 10.8 Hz, 1H), 4.05 (d, J = 13.6 Hz, 1H), 4.36 (q, J = 4.4 Hz, 2H). 4.51 (dd, J = 2.8 Hz, 9.6 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 5.27 (dd, J = 2.0 Hz, 13.6 Hz, 1H), 5.34 (s, 1H), 5.86 (d, J = 8.0 Hz, 1H), 5.93 (s, 2H), 6.81-6.89 (m, 2H), 6.98-7.15 (m, 5H).
  • TABLE 11
    No. Structure NMR or LC/MS
    II-8
    Figure US20230287004A1-20230914-C00117
         		LC/MS (ESI): m/z = 508 [M + H]+, RT = 1.76 min, method (2)
    II-9
    Figure US20230287004A1-20230914-C00118
         		1H-NMR(CDCl3)δ: 2.05(s, 3H), 2.92-3.02(m, 1H), 3.40- 3.48(m, 1H), 3.51-3.62(m, 2H), 3.72-3.80(m, 1H), 3.88- 3.92(m, 1H), 4.50-4.56(m, 1H), 4.64-4.72(m, 1H), 5.55(d, J = 13.6 Hz, 1H), 5.78-5.82(m, 1H), 5.84-5.88(m, 1H), 5.90- 5.98(m, 2H), 6.82-7.00(m, 2H), 7.00-7.20(m, 5H), 7.35- 7.42(m, 1H)
    II-10
    Figure US20230287004A1-20230914-C00119
         		LC/MS (ESI): m/z = 554 [M + H]+, RT = 1.76 min, method (1)
    II-11
    Figure US20230287004A1-20230914-C00120
         		LC/MS (ESI): m/z = 598 [M + H]+, RT = 1.80 min, method (2)
    II-12
    Figure US20230287004A1-20230914-C00121
         		LC/MS (ESI): m/z = 558 [M + H]+, RT = 1.97 min, method (2)
  • TABLE 12
    No. Structure NMR or LC/MS
    II-13
    Figure US20230287004A1-20230914-C00122
         		LC/MS (ESI): m/z = 588 [M + H]+, RT = 2.00 min, method (2)
    II-14
    Figure US20230287004A1-20230914-C00123
         		LC/MS (ESI): m/z = 604 [M + H]+, RT = 2.02 min, method (2)
    II-15
    Figure US20230287004A1-20230914-C00124
         		LC/MS (ESI): m/z = 648 [M + H]+, RT = 2.06 min, method (2)
    II-16
    Figure US20230287004A1-20230914-C00125
         		LC/MS (ESI): m/z = 508 [M + H]+, RT = 1.76 min, method (2)
    II-17
    Figure US20230287004A1-20230914-C00126
         		LC/MS (ESI): m/z = 538 [M + H]+, RT = 1.78 min, method (2)
  • TABLE 13
    No. Structure NMR or LC/MS
    II-18
    Figure US20230287004A1-20230914-C00127
         		LC/MS (ESI): m/z = 554 [M + H]+, RT = 1.81 min, method (2)
    II-19
    Figure US20230287004A1-20230914-C00128
         		LC/MS (ESI): m/z = 598 [M + H]+, RT = 1.85 min, method (2)
    II-20
    Figure US20230287004A1-20230914-C00129
         		LC/MS (ESI): m/z = 524 [M + H]+, RT = 1.91 min, method (2)
    II-21
    Figure US20230287004A1-20230914-C00130
         		LC/MS (ESI): m/z = 554 [M + H]+, RT = 1.94 min, method (2)
    II-22
    Figure US20230287004A1-20230914-C00131
         		LC/MS (ESI): m/z = 570 [M + H]+, RT = 1.97 min, method (2)
    II-23
    Figure US20230287004A1-20230914-C00132
         		LC/MS (ESI): m/z = 614 [M + H]+, RT = 2.00 min, method (2)
  • TABLE 14
    No. Structure NMR or LC/MS
    II-24
    Figure US20230287004A1-20230914-C00133
         		1H-NMR (CDCl3) δ: 1.33 (3H, t, J = 7.0 Hz), 2.82 (2H, d, J = 6.1 Hz), 2.93 (1H, t, J = 11.2 Hz), 3.42 (1H, t, J = 11.4 Hz), 3.59 (1H, t, J = 10.2 Hz), 3.78 (1H, d, J = 11.2 Hz), 3.96 (1H, d, J = 10.3 Hz), 4.06 (1H, d, J = 13.8 Hz), 4.55 (1H, d, J = 8.9 Hz), 4.63 (1H, d, J = 13.6 Hz), 5.29 (1H, d, J = 13.9 Hz), 5.36 (1H, s), 5.88 (1H, d, J = 7.4 Hz), 6.90 (1H, s), 7.03-7.12 (6H, m).
    II-25
    Figure US20230287004A1-20230914-C00134
         		1H-NMR (CDCl3) δ: 1.42 (d, J = 6.8 Hz, 6H), 2.85-3.05 (m, 2H), 3.40-3.49 (m, 1H), 3.59 (t, J = 10.4 Hz, 1H), 3.76 (d, J = 11.4 Hz, 1H), 3.94 (d, J = 10.4 Hz, 1H), 4.06 (d, J = 14.1 Hz, 1H), 4.51-4.57 (m, 1H), 4.59-4.70 (m, 1H), 5.25- 5.32 (m, 1H), 5.35-5.39 (m, 1H), 5.80-5.89 (m, 1H), 6.85- 7.15 (m, 7H).
    II-26
    Figure US20230287004A1-20230914-C00135
         		LC/MS (ESI): m/z = 542 [M + H]+, RT = 1.92 min, method (1)
    II-28
    Figure US20230287004A1-20230914-C00136
         		LC/MS (ESI): m/z = 610 [M + H]+, RT = 1.57 min, method (1)
    II-29
    Figure US20230287004A1-20230914-C00137
         		LC/MS (ESI): m/z = 554 [M + H]+, RT = 2.10 min, method (1)
  • TABLE 15
    No. Structure NMR or LC/MS
    II-30
    Figure US20230287004A1-20230914-C00138
         		LC/MS (ESI): m/z = 568 [M + H]+, RT = 1.91 min, method (1)
    II-31
    Figure US20230287004A1-20230914-C00139
         		1H-NMR (CDCl3) δ: 1.42 (d, J = 6.8 Hz, 6H), 2.90-3.07 (m, 2H), 3.44 (t, J = 10.8 Hz, 1H), 3.60 (d, J = 12.8 Hz, 2H), 3.77 (d, J = 10.8 Hz, 1H), 3.93 (dd, J = 10.8, 2.8 Hz, 1H), 4.56 (dd, J = 9.6, 2.8 Hz, 1H), 4.67 (m, 1H), 5.59 (m, 1H), 5.87 (m, 1H), 5.59 (s, 1H), 6.91-7.21 (m, 7H), 7.38 (m, 1H).
    II-32
    Figure US20230287004A1-20230914-C00140
         		1H-NMR (CDCl3) δ: 2.88 (1H, t, J = 11.2 Hz), 3.28-3.39 (2H, m), 3.72 (1H, d, J = 12.6 Hz), 3.86 (1H, d, J = 9.6 Hz), 4.03 (1H, d, J = 13.9 Hz), 4.45 (1H, d, J = 8.6 Hz), 4.67 (1H, d, J = 13.1 Hz), 5.19-5.26 (2H, m), 5.45 (1H, d, J = 10.9 Hz), 5.63 (1H, d, J = 10.9 Hz), 5.77 (1H, d, J = 7.6 Hz), 6.40 (1H, d, J = 7.8 Hz), 6.68 (1H, t, J = 6.9 Hz), 6.94-7.01 (2H, m), 7.03-7.12 (3H, m), 7.29-7.38 (3H, m), 7.61 (2H, d, J = 7.1 Hz).
    II-33
    Figure US20230287004A1-20230914-C00141
         		1H-NMR (CDCl3) δ: 1.46 (t, J = 7.2 Hz, 3H), 2.95 (m, 1H), 3.42 (td, J = 12.0, 2.4 Hz, 1H), 3.58 (t, J = 10.4 Hz, 1H), 3.78 (dd, J = 12.0, 2.8 Hz, 1H), 3.95 (dd, J = 11.2, 2.8 Hz, 1H), 4.07 (d, J = 13.6 Hz, 1H), 4.41 (m, 2H), 4.56 (dd, J = 10.0, 2.8 Hz, 1H), 4.67 (dd, J = 10.0, 2.4 Hz, 1H), 5.29 (dd, J = 13.6, 2.0 Hz, 1H), 5.36 (s, 1H), 5.91 (d, J = 8.0 Hz, 1H), 6.88-7.15 (m, 7H).
    II-34
    Figure US20230287004A1-20230914-C00142
         		1H-NMR (CDCl3) δ: 1.46 (m, 6H), 2.95 (m, 1H), 3.41 (td, J = 12.0, 2.0 Hz, 1H), 3.58 (t, J = 10.8 Hz, 1H), 3.77 (dd, J = 12.0, 3.2 Hz, 1H), 3.95 (dd, J = 10.8, 2.4 Hz, 1H), 4.06 (d, J = 14.0 Hz, 1H), 4.55 (dd, J = 9.6, 2.8 Hz, 1H), 4.67 (d, J = 13.6 Hz, 1H), 5.04 (m, 1H), 5.29 (d, J = 13.6 Hz, 1H), 5.36 (s, 1H), 5.90 (d, J = 8.0 Hz, 1H), 6.90-7.13 (m, 7H).
  • TABLE 16
    No. Structure NMR or LC/MS
    II-35
    Figure US20230287004A1-20230914-C00143
         		LC/MS (ESI): m/z = 594 [M + H]+, RT = 2.13 min, method (1)
    II-36
    Figure US20230287004A1-20230914-C00144
         		LC/MS (ESI): m/z = 663 [M + H]+, RT = 2.29 min, method (1)
    II-37
    Figure US20230287004A1-20230914-C00145
         		LC/MS (ESI): m/z = 626 [M + H]+, RT = 2.18 min, method (1)
    II-38
    Figure US20230287004A1-20230914-C00146
         		LC/MS (ESI): m/z = 570 [M + H]+, RT = 1.85 min, method (2)
    II-39
    Figure US20230287004A1-20230914-C00147
         		LC/MS (ESI): m/z = 606 [M + H]+, RT = 2.12 min, method (2)
  • TABLE 17
    No. Structure NMR or LC/MS
    II-40
    Figure US20230287004A1-20230914-C00148
         		LC/MS (ESI): m/z = 568 [M + H]+, RT = 1.92 min, method (2)
    II-41
    Figure US20230287004A1-20230914-C00149
         		LC/MS (ESI): m/z = 598 [M + H]+, RT = 2.27 min, method (2)
    II-42
    Figure US20230287004A1-20230914-C00150
         		LC/MS (ESI): m/z = 638 [M + H]+, RT = 2.17 min, method (2)
    II-43
    Figure US20230287004A1-20230914-C00151
         		LC/MS (ESI): m/z = 584 [M + H]+, RT = 2.18 min, method (2)
    II-44
    Figure US20230287004A1-20230914-C00152
         		LC/MS (ESI): m/z = 588 [M + H]+, RT = 2.00 min, method (2)
  • TABLE 18
    No. Structure NMR or LC/MS
    II-45
    Figure US20230287004A1-20230914-C00153
         		LC/MS (ESI): m/z = 580 [M + H]+, RT = 2.14 min, method (2)
    II-46
    Figure US20230287004A1-20230914-C00154
         		LC/MS (ESI): m/z = 588 [M + H]+, RT = 2.04 min, method (2)
    II-47
    Figure US20230287004A1-20230914-C00155
         		LC/MS (ESI): m/z = 580 [M + H]+, RT = 2.17 min, method (2)
    II-48
    Figure US20230287004A1-20230914-C00156
         		LC/MS (ESI): m/z = 586 [M + H]+, RT = 2.03 min, method (2)
    II-49
    Figure US20230287004A1-20230914-C00157
         		LC/MS (ESI): m/z = 596 [M + H]+, RT = 2.18 min, method (2)
  • TABLE 19
    No. Structure NMR or LC/MS
    II-50
    Figure US20230287004A1-20230914-C00158
         		LC/MS (ESI): m/z = 566 [M + H]+, RT = 2.02 min, method (2)
    II-51
    Figure US20230287004A1-20230914-C00159
         		LC/MS (ESI): m/z = 566 [M + H]+, RT = 2.08 min, method (2)
    II-52
    Figure US20230287004A1-20230914-C00160
         		LC/MS (ESI): m/z = 568 [M + H]+, RT = 1.93 min, method (2)
    II-53
    Figure US20230287004A1-20230914-C00161
         		LC/MS (ESI): m/z = 598.1 [M + H]+, RT = 1.96 min, method (2)
    II-54
    Figure US20230287004A1-20230914-C00162
         		1H-NMR (CDCl3) δ: 2.89-2.98 (m, 1H), 3.30-3.43 (m, 2H), 3.57 (d, J = 13.4 Hz, 1H), 3.73 (dd, J = 11.6, 2.8 Hz, 1H), 3.87 (dd, J = 10.7, 2.4 Hz, 1H), 4.49 (dd, J = 9.9, 2.5 Hz, 1H), 4.72 (d, J = 12.9 Hz, 1H), 5.43 (d, J = 10.8 Hz, 1H), 5.51 (d, J = 13.4 Hz. 1H), 5.64 (d, J = 10.9 Hz, 1H), 5.78 (d, J = 7.7 Hz, 1H), 5.84 (s, 1H), 6.44 (d, J = 7.8 Hz, 1H), 6.67 (t, J = 7.0 Hz, 1H), 7.02-7.13 (m, 5H), 7.29-7.40 (m, 4H), 7.64 (d, J = 7.7 Hz, 2H).
  • TABLE 20
    No. Structure NMR or LC/MS
    II-56
    Figure US20230287004A1-20230914-C00163
         		LC/MS (ESI): m/z = 595.90 [M + H]+, RT = 1.93 min, method (2)
    II-59
    Figure US20230287004A1-20230914-C00164
         		LC/MS (ESI): m/z = 705.05 [M + H]+, RT = 2.16 min, method (2)
    II-60
    Figure US20230287004A1-20230914-C00165
         		LC/MS (ESI): m/z = 691.00 [M + H]+, RT = 2.08 min, method (2)
    II-62
    Figure US20230287004A1-20230914-C00166
         		LC/MS (ESI): m/z = 615.95 [M + H]+, RT = 2.07 min, method (2)
  • TABLE 21
    No. Structure NMR or LC/MS
    II-63
    Figure US20230287004A1-20230914-C00167
         		LC/MS (ESI): m/z = 579.95 [M + H]+, RT = 1.92 min, method (2)
    II-64
    Figure US20230287004A1-20230914-C00168
         		LC/MS (ESI): m/z = 642.35 [M + H]+, RT = 2.05 min, method (2)
    II-66
    Figure US20230287004A1-20230914-C00169
         		LC/MS (ESI): m/z = 654.05 [M + H]+, RT = 2.43, 2.51 min, method (2)
    II-67
    Figure US20230287004A1-20230914-C00170
         		LC/MS (ESI): m/z = 600.00 [M + H]+, RT = 2.05, 2.11 min, method (2)
    II-68
    Figure US20230287004A1-20230914-C00171
         		LC/MS (ESI): m/z = 569.95 [M + H]+, RT = 1.84 min, method (2)
  • TABLE 22
    No. Structure NMR or LC/MS
    II-69
    Figure US20230287004A1-20230914-C00172
         		LC/MS (ESI): m/z = 568.00 [M + H]+, RT = 2.17 min, method (2)
    II-70
    Figure US20230287004A1-20230914-C00173
         		LC/MS (ESI): m/z = 598.00 [M + H]+, RT = 2.23 min, method (2)
    II-71
    Figure US20230287004A1-20230914-C00174
         		LC/MS (ESI): m/z = 599.05 [M + H]+, RT = 1.99 min, method (2)
    II-72
    Figure US20230287004A1-20230914-C00175
         		LC/MS (ESI): m/z = 656.00 [M + H]+, RT = 2.13 min, method (2)
    II-73
    Figure US20230287004A1-20230914-C00176
         		LC/MS (ESI): m/z = 719.05 [M + H]+, RT = 2.28 min, method (2)
  • TABLE 23
    No. Structure NMR or LC/MS
    II-74
    Figure US20230287004A1-20230914-C00177
         		LC/MS (ESI): m/z = 638.95 [M + H]+, RT = 1.89 min, method (2)
    II-75
    Figure US20230287004A1-20230914-C00178
         		LC/MS (ESI): m/z = 668.95 [M + H]+, RT = 1.97 min, method (2)
    II-76
    Figure US20230287004A1-20230914-C00179
         		LC/MS (ESI): m/z = 671.00 [M + H]+, RT = 2.24 min, method (2)
    II-77
    Figure US20230287004A1-20230914-C00180
         		LC/MS (ESI): m/z = 612.10 [M + H]+, RT = 2.45 min, method (2)
    II-78
    Figure US20230287004A1-20230914-C00181
         		LC/MS (ESI): m/z = 598.00 [M + H]+, RT = 2.29 min, method (2)
  • TABLE 24
    No. Structure NMR or LC/MS
    II-79
    Figure US20230287004A1-20230914-C00182
         		LC/MS (ESI): m/z = 672 [M + H]+, RT = 2.27 min, method (1)
    II-80
    Figure US20230287004A1-20230914-C00183
         		LC/MS (ESI): m/z = 706 [M + H]+, RT = 2.39 min, method (1)
    II-81
    Figure US20230287004A1-20230914-C00184
         		LC/MS (ESI): m/z = 644 [M + H]+, RT = 2.13 min, method (1)
    II-82
    Figure US20230287004A1-20230914-C00185
         		LC/MS (ESI): m/z = 630 [M + H]+, RT = 2.03 min, method (1)
  • TABLE 25
    No. Structure NMR or LC/MS
    II-83
    Figure US20230287004A1-20230914-C00186
         		LC/MS (ESI): m/z = 644 [M + H]+, RT = 2.06 min, method (1)
    II-84
    Figure US20230287004A1-20230914-C00187
         		LC/MS (ESI): m/z = 644 [M + H]+, RT = 2.15 min, method (1)
    II-85
    Figure US20230287004A1-20230914-C00188
         		LC/MS (ESI): m/z = 692 [M + H]+, RT = 2.31 min, method (1)
    II-86
    Figure US20230287004A1-20230914-C00189
         		LC/MS (ESI): m/z = 670 [M + H]+, RT = 2.20 min, method (1)
  • TABLE 26
    No. Structure NMR or LC/MS
    II-87
    Figure US20230287004A1-20230914-C00190
         		LC/MS (ESI): m/z = 700 [M + H]+, RT = 2.45 min, method (1)
    II-88
    Figure US20230287004A1-20230914-C00191
         		LC/MS (ESI): m/z = 672 [M + H]+, RT = 2.31 min, method (1)
    II-89
    Figure US20230287004A1-20230914-C00192
         		LC/MS (ESI): m/z = 706 [M + H]+, RT = 2.37 min, method (1)
    II-90
    Figure US20230287004A1-20230914-C00193
         		LC/MS (ESI): m/z = 644 [M + H]+, RT = 2.13 min, method (1)
  • TABLE 27
    No. Structure NMR or LC/MS
    II-91
    Figure US20230287004A1-20230914-C00194
         		LC/MS (ESI): m/z = 670 [M + H]+, RT = 2.16 min, method (1)
    II-92
    Figure US20230287004A1-20230914-C00195
         		LC/MS (ESI): m/z = 617.00 [M + H]+, RT = 2.09 min, method (2)
    II-93
    Figure US20230287004A1-20230914-C00196
         		LC/MS (ESI): m/z = 586.00 [M + H]+, RT = 1.91 min, method (2)
    II-94
    Figure US20230287004A1-20230914-C00197
         		LC/MS (ESI): m/z = 598.00 [M + H]+, RT = 1.89 min, method (2)
    II-95
    Figure US20230287004A1-20230914-C00198
         		LC/MS (ESI): m/z = 598.00 [M + H]+, RT = 1.89 min, method (2)
  • TABLE 28
    No. Structure NMR or LC/MS
    II-96
    Figure US20230287004A1-20230914-C00199
         		LC/MS (ESI): m/z = 600.00 [M + H]+, RT = 2.01 min, method (2)
    II-97
    Figure US20230287004A1-20230914-C00200
         		LC/MS (ESI): m/z = 626.00 [M + H]+, RT = 1.98 min, method (2)
    II-98
    Figure US20230287004A1-20230914-C00201
         		LC/MS (ESI): m/z = 611.95 [M + H]+, RT = 1.93 min, method (2)
    II-99
    Figure US20230287004A1-20230914-C00202
         		LC/MS (ESI): m/z = 626.05 [M + H]+, RT = 2.46 min, method (2)
  • TABLE 29
    No. Structure NMR or LC/MS
    II-100
    Figure US20230287004A1-20230914-C00203
         		LC/MS (ESI): m/z = 682.05 [M + H]+, RT = 2.27 min, method (2)
    II-101
    Figure US20230287004A1-20230914-C00204
         		LC/MS (ESI): m/z = 719.05 [M + H]+, RT = 2.26 min, method (2)
    II1-102
    Figure US20230287004A1-20230914-C00205
         		LC/MS (ESI): m/z = 731.15 [M + H]+, RT = 2.29 min, method (2)
    II-103
    Figure US20230287004A1-20230914-C00206
         		LC/MS (ESI): m/z = 691.10 [M + H]+, RT = 2.05 min, method (2)
  • TABLE 30
    No. Structure NMR or LC/MS
    II-104
    Figure US20230287004A1-20230914-C00207
         		LC/MS (ESI): m/z = 688.95 [M + H]+, RT = 1.98 min, method (2)
    II-105
    Figure US20230287004A1-20230914-C00208
         		LC/MS (ESI): m/z = 759.05 [M + H]+, RT = 2.53 min, method (2)
    II-106
    Figure US20230287004A1-20230914-C00209
         		LC/MS (ESI): m/z = 639.95 [M + H]+, RT = 2.01 min, method (2)
    II-107
    Figure US20230287004A1-20230914-C00210
         		LC/MS (ESI): m/z = 683.95 [M + H]+, RT = 1.87 min, method (2)
  • TABLE 31
    No. Structure NMR or LC/MS
    II-108
    Figure US20230287004A1-20230914-C00211
         		LC/MS (ESI): m/z = 625.00 [M + H]+, RT = 1.75 min, method (2)
    II-109
    Figure US20230287004A1-20230914-C00212
         		LC/MS (ESI): m/z = 640.00 [M + H]+, RT = 1.90 min, method (2)
    II-110
    Figure US20230287004A1-20230914-C00213
         		LC/MS (ESI): m/z = 633.90 [M + H]+, RT = 1.82 min, method (2)
    II-111
    Figure US20230287004A1-20230914-C00214
         		LC/MS (ESI): m/z = 661.00 [M + H]+, RT = 1.90 min, method (2)
  • TABLE 32
    No. Structure NMR or LC/MS
    II-112
    Figure US20230287004A1-20230914-C00215
         		LC/MS (ESI): m/z = 624.95 [M + H]+, RT = 1.38 min, method (2)
    II-113
    Figure US20230287004A1-20230914-C00216
         		LC/MS (ESI): m/z = 691.95 [M + H]+, RT = 2.00 min, method (2)
    II-114
    Figure US20230287004A1-20230914-C00217
         		LC/MS (ESI): m/z = 604.00 [M + H]+, RT = 2.09 min, method (2)
    II-116
    Figure US20230287004A1-20230914-C00218
         		LC/MS (ESI): m/z = 631.00 [M + H]+, RT = 2.18 min, method (2)
  • TABLE 33
    No. Structure NMR or LC/MS
    II-117
    Figure US20230287004A1-20230914-C00219
         		LC/MS (ESI): m/z = 620.00 [M + H]+, RT = 1.93 min, method (2)
    II-118
    Figure US20230287004A1-20230914-C00220
         		LC/MS (ESI): m/z = 620.00 [M + H]+, RT = 1.93 min, method (2)
    II-119
    Figure US20230287004A1-20230914-C00221
         		LC/MS (ESI): m/z = 614 [M + H]+, RT = 2.31 min, method (1)
    II-120
    Figure US20230287004A1-20230914-C00222
         		LC/MS (ESI): m/z = 614 [M + H]+, RT = 2.24 min, method (1)
  • TABLE 34
    No. Structure NMR or LC/MS
    II-121
    Figure US20230287004A1-20230914-C00223
         		LC/MS (ESI): m/z = 686 [M + H]+, RT = 2.27 min, method (1)
    II-122
    Figure US20230287004A1-20230914-C00224
         		LC/MS (ESI): m/z = 642 [M + H]+, RT = 2.19 min, method (1)
    II-123
    Figure US20230287004A1-20230914-C00225
         		LC/MS (ESI): m/z = 642 [M + H]+, RT = 2.17 min, method (1)
    II-124
    Figure US20230287004A1-20230914-C00226
         		LC/MS (ESI): m/z = 662 [M + H]+, RT = 2.22 min, method (1)
  • TABLE 35
    No. Structure NMR or LC/MS
    II-125
    Figure US20230287004A1-20230914-C00227
         		LC/MS (ESI): m/z = 668 [M + H]+, RT = 2.32 min, method (1)
    II-126
    Figure US20230287004A1-20230914-C00228
         		LC/MS (ESI): m/z = 587.95 [M + H]+, RT = 2.24 min, method (2)
    II-127
    Figure US20230287004A1-20230914-C00229
         		LC/MS (ESI): m/z = 588.05 [M + H]+, RT = 2.17 min, method (2)
    II-128
    Figure US20230287004A1-20230914-C00230
         		LC/MS (ESI): m/z = 686.00 [M + H]+, RT = 2.67 min, method (2)
  • TABLE 36
    No. Structure NMR or LC/MS
    II-130
    Figure US20230287004A1-20230914-C00231
         		LC/MS (ESI): m/z = 645.95 [M + H]+, RT = 2.12 min, method (2)
    II-131
    Figure US20230287004A1-20230914-C00232
         		LC/MS (ESI): m/z = 615.00 [M + H]+, RT = 2.24 min, method (2)
    II-132
    Figure US20230287004A1-20230914-C00233
         		LC/MS (ESI): m/z = 658.95 [M + H]+, RT = 2.31 min, method (2)
    II-133
    Figure US20230287004A1-20230914-C00234
         		LC/MS (ESI): m/z = 661.00 [M + H]+, RT = 2.06 min, method (2)
  • TABLE 37
    No. Structure NMR or LC/MS
    II-134
    Figure US20230287004A1-20230914-C00235
         		LC/MS (ESI): m/z = 656 [M + H]+, RT = 2.24 min, method (1)
    II-135
    Figure US20230287004A1-20230914-C00236
         		1H-NMR (CDCl3) δ: 1.24 (s, 3H), 1.38 (s, 3H), 2.94 (td, J = 11.8, 3.5 Hz, 1H), 3.44 (dd, J = 12.0, 10.9 Hz, 1H), 3.57 (t, J = 10.9 Hz, 1H), 3.78 (dd, J = 12.0, 3.5 Hz, 1H), 3.96 (dd, J = 10.9, 2.9 Hz, 1H), 4.05-4.12 (m, 3H), 4.58 (dd, J = 10.0, 2.9 Hz, 1H), 4.66 (d, J = 13.5 Hz, 1H), 5.24 (d, J = 13.5 Hz, 1H), 5.32 (s, 1H), 5.58 (s, 1H), 5.91 (d, J = 7.8 Hz, 1H), 6.81 (s, 2H), 7.06-7.20 (m, 5H).
    II-136
    Figure US20230287004A1-20230914-C00237
         		1H-NMR (CDCl3) δ: 1.26 (s, 3H), 1.33 (s, 3H), 2.96 (t, J = 11.9 Hz, 1H), 3.46 (t, J = 10.6 Hz, 1H), 3.59 (t, J = 10.6 Hz, 1H), 3.77 (dd, J = 11.9, 2.9 Hz, 1H), 3.95 (dd, J = 11.0, 2.9 Hz, 1H), 4.04-4.13 (m, 3H), 4.56 (dd, J = 10.0, 2.9 Hz, 1H), 4.72 (d, J = 13.4 Hz, 1H), 5.27-5.31 (m, 2H), 5.37 (s, 1H), 5.91 (d, J = 8.0 Hz, 1H), 6.87-6.91 (m, 2H), 7.00-7.05 (m, 1H), 7.07-7.15 (m, 4H).
    II-137
    Figure US20230287004A1-20230914-C00238
         		1H-NMR (CDCl3) δ: 2.92 (t, J = 11.0 Hz, 1H), 3.38 (t, J = 11.0 Hz, 1H), 3.56 (t, J = 10.4 Hz, 1H), 3.75 (d, J = 9.3 Hz, 1H), 3.81 (s, 3H), 3.95 (d, J = 9.3 Hz, 1H), 4.06 (d, J = 13.9 Hz, 1H), 4.55 (d, J = 8.1 Hz, 1H), 4.63 (d, J = 13.0 Hz, 1H), 5.27 (d, J = 13.9 Hz, 1H), 5.43 (br s, 1H), 5.91 (d, J = 8.1 Hz, 1H), 6.09 (s, 1H), 6.82-6.86 (m, 1H), 6.93 (d, J = 8.1 Hz, 1H), 7.04-7.13 (m, 5H), 7.39-7.43 (m, 3H), 7.56-7.59 (m, 2H).
  • TABLE 38
    No. Structure NMR or LC/MS
    II-138
    Figure US20230287004A1-20230914-C00239
         		1H-NMR (CDCl3) δ: 2.94 (t, J = 11.3 Hz, 1H), 3.41 (t, J = 11.3 Hz, 1H), 3.57 (t, J = 10.5 Hz, 1H), 3.76 (d, J = 11.0 Hz, 1H), 3.83 (s, 3H), 3.94 (dd, J = 10.5, 2.7 Hz, 1H), 4.06 (d, J = 14.0 Hz, 1H), 4.55 (dd, J = 9.5, 2.7 Hz, 1H), 4.68 (d, J = 12.6 Hz, 1H), 5.28 (d, J = 14.0 Hz, 1H), 5.35 (s, 1H), 5.90 (d, J = 8.0 Hz, 1H), 6.05 (s, 1H), 6.84-6.90 (m, 2H), 7.00-7.15 (m, 5H), 7.38-7.42 (m, 3H), 7.56-7.60 (m, 2H).
    II-139
    Figure US20230287004A1-20230914-C00240
         		LC/MS (ESI): m/z = 614 [M + H]+, RT = 2.10 min, method (1)
    II-140
    Figure US20230287004A1-20230914-C00241
         		LC/MS (ESI): m/z = 614 [M + H]+, RT = 2.04 min, method (1)
    II-141
    Figure US20230287004A1-20230914-C00242
         		LC/MS (ESI): m/z = 614 [M + H]+, RT = 2.02 min, method (1)
  • TABLE 39
    No. Structure NMR or LC/MS
    II-142
    Figure US20230287004A1-20230914-C00243
         		LC/MS (ESI): m/z = 670 [M + H]+, RT = 2.41 min, method (1)
    II-144
    Figure US20230287004A1-20230914-C00244
         		LC/MS (ESI): m/z = 575.20 [M + H]+, RT = 1.49 min, method (2)
    II-145
    Figure US20230287004A1-20230914-C00245
         		LC/MS (ESI): m/z = 575.00 [M + H]+, RT = 1.52 min, method (2)
    II-146
    Figure US20230287004A1-20230914-C00246
         		LC/MS (ESI): m/z = 657.90 [M + H]+, RT = 2.23 min, method (2)
  • The compounds in connection with the present invention and/or the parent compounds of the compounds in connection with the present invention are useful for symptoms and/or diseases which are induced by influenza virus. For example, they are useful for treating and/or preventing, or improving symptoms of, cold-like symptoms accompanying fever, algor, headache, muscular pain, general malaise etc., airway inflammation symptoms such as pharyngalgia, nasal secretion, nasal congestion, cough, sputum etc., gastrointestinal symptoms such as abdominal pain, vomitus, diarrhea etc. and, further, complications accompanying secondary infection such as acute encephalopathy and pneumonia.
  • Since the compounds in connection with the present invention are a prodrug and thus have advantages that oral absorbability is high, good bioavailability is exhibited, good clearance is exhibited, and pulmonary transitivity is high, they can be excellent medicaments.
  • Since the parent compounds of the compounds in connection with the present invention have the effects such as high inhibitory activity on cap structure-dependent endonuclease, and high selectivity due to a virus-specific enzyme, they can be medicaments having reduced side effects.
  • Further, since the compounds in connection with the present invention and/or the parent compounds of the compounds in connection with the present invention also have advantages that metabolism stability is high, solubility is high, oral absorbability is high, good bioavailability is exhibited, good clearance is exhibited, pulmonary transitivity is high, a half life is long, a non-protein binding rate is high, hERG channel inhibition is low, CYP inhibition is low, CPE (CytoPathic Effect) inhibiting effect is recognized, and/or negativity is exhibited in a phototoxicity test, an Ames test and a gene toxicity test, or toxicity such as liver damage is not caused. Therefore, the compounds in connection with the present invention can be excellent medicaments.
  • The compounds in connection with the present invention and/or the parent compounds of the compounds in connection with the present invention can be administered orally or parenterally. In the case of oral administration, the present compounds can be also used as a normal preparation, for example, as any dosage form of solid preparations such as tablets, powders, granules, capsules etc.; solutions; oleaginous suspensions; or liquid preparations such as syrups or elixirs etc. In the case of parenteral administration, the compounds in connection with the present invention can be used as aqueous or oleaginous suspension injectables, or nose drops. Upon preparation of them, conventional excipients, binders, lubricants, aqueous solvents, oleaginous solvents, emulsifiers, suspending agents, preservatives, stabilizers etc. can be arbitrarily used. The pharmaceutical composition of the present invention can be produced by combining (for example, mixing) a therapeutically effective amount of the present compound with pharmaceutically acceptable carriers or diluents.
  • A dose of the compounds in connection with the present invention is different depending on an administration method, an age, a weight and the state of a patient, and a kind of a disease and, usually, in the case of oral administration, about 0.05 mg to 3000 mg, preferably about 0.1 mg to 1000 mg for adult per day may be administered, if necessary, by division. In addition, in the case of parenteral administration, about 0.01 mg to 1000 mg, preferably about 0.05 mg to 500 mg for adult per day is administered.
    • Test Example 1: Measurement of Cap-Dependent Endonuclease (CEN) Inhibitory Activity 1) Preparation of Substrate
  • 30merRNA(5′-pp-[m2′-O]GAA UAU(—Cy3) GCA UCA CUA GUA AGC UUU GCU CUA-BHQ2-3′: manufactured by Japan Bio Services Co., LTD.) in which G at a 5′ end is diphosphate-modified, a hydroxy group at 2′ position is methoxylation-modified, U sixth from a 5′ end is labelled with Cy3, and a 3′ end is labelled with BHQ2 was purchased, and a cap structure was added using ScriptCap system manufactured by EPICENTRE (a product was m7G [5′]-ppp-[5′][m2′-0]GAA UAU(—Cy3) GCA UCA CUA GUA AGC UUU GCU CUA(-BHQ2)-3′). This was separated and purified by denatured polyacrylamide gel electrophoresis, and used as a substrate.
    • 2) Preparation of Enzyme
  • RNP was prepared from a virus particle using standard method (Reference Document: VIROLOGY(1976) 73, p327-338 OLGA M. ROCHOVANSKY). Specifically, A/WSN/33 virus (1×103 PFU/mL, 200 μL) was inoculated in a 10 days old embryonated chicken egg. After incubation at 37° C. for 2 days, the allantoic fluid of the chicken egg was recovered. A virus particle was purified by ultracentrifugation using 20% sucrose, solubilized using TritonX-100 and lysolecithin, and an RNP fraction (50-70% glycerol fraction) was collected by ultracentrifugation using a 30-70% glycerol density gradient, and was used as an enzyme solution (containing approximately 1 nM PB1-PB2-PA complex).
    • 3) Enzymatic Reaction
  • An enzymatic reaction solution (2.5 μL) (composition: 53 mM Tris-hydrochloride (pH 7.8), 1 mM MgCl2, 1.25 mM dithiothreitol, 80 mM NaCl, 12.5% glycerol, enzyme solution 0.15 μL) was dispensed into a 384-well plate made of polypropylene. Then, 0.5 μL of a test compound solution which had been serially diluted with dimethyl sulfoxide (DMSO) was added to the plate. As a positive control (PC) or a negative control (NC), 0.5 μL of DMSO was added to the plate respectively. Each plate was mixed well. Then, 2 μL of a substrate solution (1.4 nM substrate RNA, 0.05% Tween20) was added to initiate a reaction. After room temperature incubation for 60 minutes, 1 μL, of the reaction solution was collected and added to 10 μL of a Hi-Di formamide solution (containing GeneScan 120 Liz Size Standard as a sizing marker: manufactured by Applied Biosystems (ABI)) in order to stop the reaction. For NC, the reaction was stopped in advance by adding EDTA (4.5 mM) before initiation of the reaction (all concentrations described above are final concentrations).
    • 3) Measurement of Inhibition Ratio (IC50 Value)
  • The solution for which the reaction was stopped was heated at 85° C. for 5 minutes, rapidly cooled on ice for 2 minutes, and analyzed with an ABI PRIZM 3730 genetic analyzer. A peak of the cap-dependent endonuclease product was quantitated by analysis software ABI Genemapper, a CEN reaction inhibition ratio (%) of a test compound was obtained by setting fluorescent intensities of PC and NC to be 0% inhibition and 100% inhibition, respectively, an IC50 value was obtained using curve fitting software (XLfit2.0: Model 205 (manufactured by IDBS) etc.). The IC50 values of test substances being a parent compound, are shown in Table 39.
    • Test Example 2: CPE Inhibitory Effect Confirming Assay <Material>
      • 2% FCS E-MEM (prepared by adding kanamycin and FCS to MEM (Minimum Essential Medium) (Invitrogen))
      • 0.5% BSA E-MEM (prepared by adding kanamycin and BSA to MEM (Minimum Essential Medium) (Invitrogen))
      • HBSS (Hanks' Balanced Salt Solution)
      • MDBK cell
      • Cells were adjusted to the appropriate cell number (3×105/mL) with 2% FCS E-MEM.
      • MDCK cell
      • After washing with HBSS two times, cells were adjusted to the appropriate cell number (5×105/mL) with 0.5% BSA E-MEM.
      • Trypsin Solution
      • Trypsin from porcine pancreas (SIGMA) was dissolved in PBS(−), and filtrated with a 0.45 μm filter.
      • EnVision (PerkinElmer)
      • WST-8 Kit (Kishida Chemical Co., Ltd.)
      • 10% SDS solution
    <Operation Procedure>
      • Dilution and dispensation of test sample
  • As a culture medium, 2% FCS E-MEM was used at the use of MDBK cells, and 0.5% BSA E-MEM was used at the use of MDCK cells. Hereinafter, for diluting virus, cells and a test sample, the same culture medium was used.
  • A test sample was diluted with a culture medium to an appropriate concentration in advance, and then 2 to 5-fold serial dilution on a 96 well plate (50 μL/well) was prepared. Two plates, one for measuring anti-Flu activity and the another for measuring cytotoxity, were prepared. Each assay was performed triplicate for each drug.
  • At the use of MDCK cells, Trypsin was added to the cells to be a final concentration of 3 μg/mL only for measuring anti-Flu activity.
  • Dilution and Dispensation of Influenza Virus
  • An influenza virus was diluted with a culture medium to an appropriate concentration in advance, and each 50 μL/well was dispensed on a 96-well plate containing a test substance. Each 50 μL/well of a culture medium was dispensed on a plate containing a test substance for measuring cytotoxity.
    • Dilution and Dispensation of Cell
  • Each 100 μL/well of cells which had been adjusted to the appropriate cell number was dispensed on a 96 well plate containing a test sample.
  • This was mixed with a plate mixer, and incubated in a CO2 incubator for 3 days for measuring anti-Flu activity and measuring cytotoxity.
    • Dispensation of WST-8
  • The cells in the 96-well plate which had been incubated for 3 days was observed visually under a microscope, and appearance of the cells, the presence or absence of a crystal of test substance were checked. The supernatant was removed so that the cells were not absorbed from the plate.
  • WST-8 Kit was diluted 10-fold with a culture medium, and each 100 μL was dispensed into each well. After mixing with a plate mixer, cells were incubated in a CO2 incubator for 1 to 3 hours.
  • After incubation, regarding the plate for measuring anti-Flu activity, each 10 μL/well of a 10% SDS solution was dispensed in order to inactivate a virus.
    • Measurement of Absorbance
  • After the 96-well plate was mixed, absorbance was measured with EnVision at two wavelengths of 450 nm/620 nm.
    • <Calculation of Each Measurement Item Value>
  • The value was calculated using Microsoft Excel or a program having the equivalent calculation and processing ability, based on the following calculation equation.
      • Calculation of effective inhibition concentration to achieve 50% influenza infected cell death (EC50)

  • EC50=10Z

  • Z=(50%−High %)/(High %−Low %)×{log(High conc.)−log(Low conc.)}+log(High conc.)
  • For test substances (compounds of Reference examples) being a parent compound, measurement results of Test Example 1 and Test Example 2 are shown in Table 39.
  • TABLE 40
    CEN_IC50 CPE_EC50
    No. nM nM
    III-1 10.90 2.10
    III-2 1.93 1.13
    III-3 2.22 3.39
    III-4 2.81 2.08
    III-5 10.80 4.28
    III-7 8.09 11.50
    III-8 2.81 7.18
    III-9 2.17 10.90
    III-10 4.05 3.46
    III-11 13.10 9.98
    III-12 2.18 3.38
    III-13 3.94 4.00
    III-14 15.00 15.70
    III-15 37.30 16.90
    III-16 4.33 10.20
    III-17 3.89 8.14
    III-18 2.37 3.28
    III-19 2.37 1.43
    III-20 3.24 4.00
    III-21 4.06 2.70
    III-22 3.46 3.07
    III-23 1.48 0.86
    III-24 13.30 24.10
    III-25 2.96 2.35
    III-26 1.63 3.00
    III-27 4.19 3.61
    III-28 10.70 5.67
    III-29 0.87 0.66
    III-30 5.68 3.01
    III-31 18.50 3.17
    III-32 27.60 7.23
    III-33 2.08 2.36
    III-34 4.69 2.85
    III-35 3.86 3.00
    III-36 2.37 2.45
    III-37 4.24 3.43
    III-38 8.26 4.04
    III-39 2.75 2.81
    III-40 2.99 2.95
    III-41 2.10 2.17
    III-42 3.93 2.64
    III-43 3.90 3.18
    III-44 3.81 3.68
    III-45 1.63 3.07
    III-46 2.91 3.18
    III-47 2.25 2.53
    III-48 3.49 3.57
    III-49 6.79 4.17
    III-50 2.55 4.36
    III-51 2.22 2.58
    III-52 3.62 3.28
  • TABLE 41
    CEN_IC50 CPE_EC50
    No. nM nM
    III-53 2.46 3
    III-54 1.27 1.18
    III-55 2.13 3.45
    III-56 6.64 4.99
    III-57 4.27 3.47
    III-58 2.65 3.13
    III-59 0.57 3.11
  • Based on the above results, the parent compounds exhibit high cap-dependent endonuclease (CEN) inhibitory activity and/or high CPE inhibitory effect and thus can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.
  • Biological test examples for compounds of the present invention were described below.
    • Test Example 3: CYP Inhibition Test
  • Using commercially available pooled human hepatic microsome, and employing, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenedine hydroxylation (CYP3A4) as typical substrate metabolism reactions of human main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), an inhibitory degree of each metabolite production amount by a compound of the present invention was assessed.
  • The reaction conditions were as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/l, tolbutamide (CYP2C9), 50 μmol/L S-mephenytoinmephenitoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/L terfenedine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; concentration of a compound of the present invention, 1, 5, 10, 20 μmol/L (four points).
  • Each five kinds of substrates, human hepatic microsome, or a compound of the present invention in 50 mmol/L Hepes buffer as a reaction solution was added to a 96-well plate at the composition as described above, NADPH, as a cofactor was added to initiate metabolism reactions as markers and, after the incubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction. After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multilabel counter and toltributamide hydroxide (CYP2C9P metabolite), mephenytoin 4′ hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.
  • Addition of only DMSO being a solvent dissolving a compound of the present invention to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a compound of the present invention added as the solution and IC50 was calculated by reverse presumption by a logistic model using a concentration and an inhibition rate.
    • (Result)
      • Compound 111-2: five kinds>20 μmol/L
    Test Example 4: BA Test
  • Materials and methods for experiments to evaluate oral absorption
      • (1) Experimental animals: mice or SD rats were used.
      • (2) Rearing condition: mice or SD rats were allowed free access to solid feed and sterilized tap water.
      • (3) Setting of dosage and grouping: Oral administration and intravenous administration were performed with the predetermined dosage. Grouping was set as below. (Dosage was changed per compound)
        • Oral administration 1 to 30 mg/kg (n=2 to 3)
        • Intravenous administration 0.5 to 10 mg/kg (n=2 to 3)
      • (4) Preparation of administration solutions: Oral administration was performed as solution or suspension. Intravenous administration was performed after solubilization.
      • (5) Routes of administration: Oral administration was performed mandatory into the stomach by oral sonde. Intravenous administration was performed from caudal vein by syringes with needle.
      • (6) Evaluation items: Blood was collected serially and concentration of a compound of the present invention in plasma was measured by LC/MS/MS.
      • (7) Statistical analysis: About transition of concentration of a compound of the present invention in plasma, the area under the plasma concentration versus time curve (AUC) was calculated by non-linear least-squares method program, WinNonlin (a registered trademark), and bioavailability (BA) of a compound of the present invention was calculated from AUCs of the oral administration group and the intravenous administration group.
    (Result)
      • Compound 11-6: 14.9%
      • Compound 111-2: 4.2%
  • Based on the above results, the prodrug had improved bioavailability other than the parent compound.
  • Therefore, the compound of the present invention has excellent oral absorbability and can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.
    • Test Example 5: Metabolism Stability Test
  • Using commercially available pooled human hepatic microsomes, a compound of the present invention was reacted for a constant time, and a remaining rate was calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver was assessed.
  • A reaction was performed (oxidative reaction) at 37° C. for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes. After the reaction, 50 μL, of the reaction solution was added to 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC/MS/MS or Solid Phase Extraction (SPE)/MS, and a remaining amount of the compound of the present invention after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%. Hydrolysis reaction was performed in the absence of NADPH and glucuronidation reaction was in the presence of 5 mM UDP-glucuronic acid in place of NADPH, followed by similar operations.
      • (Result) % inhibition was shown at 2 μmol/T, of test compound.
      • Compound 111-2: 90.1%
    Test Example 6: CYP3A4 Fluorescent MBI Test
  • The CYP3A4 fluorescent MBI test is a test of investigating enhancement of CYP3A4 inhibition of a compound of the present invention by a metabolism reaction, and the test was performed using, as CYP3A4 enzyme expressed in Escherichia coli and employing, as an index, a reaction in which 7-benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme to produce a metabolite, 7-hydroxytrifluoromethylcoumarin (HFC) emitting fluorescent light.
  • The reaction conditions were as follows: substrate, 5.6 μmol/L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25° C. (room temperature); CYP3A4 content (expressed in Escherichia coli), at pre-reaction 62.5 μmol/mL, at reaction 6.25 μmol/mL (at 10-fold dilution); test drug concentration of a compound of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol/L (six points).
  • An enzyme in a K-Pi buffer (pH 7.4) and a solution of a compound of the present invention as a pre-reaction solution were added to a 96-well plate at the above composition of the pre-reaction, a part of it was transferred to another 96-well plate so that it was 1/10 diluted with a substrate and a K-Pi buffer, NADPH as a co-factor was added to initiate a reaction as an index (without preincubation) and, after a predetermined time of a reaction, acetonitrile/0.5 mol/L Tris (trishydroxyaminomethane)=4/1 (V/V) was added to stop the reaction. In addition, NADPH was added to a remaining preincubation solution to initiate a preincubation (with preincubation) and, after a predetermined time of a preincubation, a part was transferred to another plate so that it was 1/10 diluted with a substrate and a K-Pi buffer to initiate a reaction as an index. After a predetermined time of a reaction, acetonitrile/0.5 mol/L Tris (trishydroxyaminomethane)=4/1 (V/V) was added to stop the reaction. For the plate on which each index reaction had been performed, a fluorescent value of 7-HFC which is a metabolite was measured with a fluorescent plate reader. (Ex=420 nm, Em=535 nm).
  • Addition of only DMSO which is a solvent dissolving a compound of the present invention to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a compound of the present invention added as the solution, and IC50 was calculated by reverse-presumption by a logistic model using a concentration and an inhibition rate. When a difference between IC50 values is 5 μmol/L or more, this was defined as (+) and, when the difference is 3 μmol/L or less, this was defined as (−).
    • (Result)
      • Compound 111-2: (−)
    Test Example 7: Fluctuation Ames Test
  • Mutagenicity of compounds of the present invention was evaluated.
  • 20 μL of freezing-stored rat typhoid bacillus (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated on 10 mL of a liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and this was cultured before shaking at 37° C. for 10 hours. 9 mL of a bacterial solution of the TA98 strain was centrifuged (2000×g, 10 minutes) to remove a culturing solution. The bacteria was suspended in 9 mL of a Micro F buffer (K2IIPO4: 3.5 g/L, KH2PO4: 1 g/L, (NH4)2SO4: 1 g/L, trisodium citrate dehydrate: 0.25 g/L, MgSO4 7H2O: 0.1 g/L), the suspension was added to 110 mL of an Exposure medium (Micro F buffer containing Biotin: 8 μg/mL, histidine 0.2 μg/mL, glucose: 8 mg/mL). The TA100 strain was added to 120 mL of the Exposure medium relative to 3.16 mL of the bacterial solution to prepare a test bacterial solution. Each 12 μL of DMSO solution of a compound of the present invention (several stage dilution from maximum dose 50 mg/mL at 2 to 3 fold ratio), DMSO as a negative control, and 50 μg/mL of 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain, 0.25 μg/mL of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain under the non-metabolism activating condition, 40 μg/mL of 2-aminoanthracene DMSO solution for the TA98 strain, 20 μg/mL of 2-aminoanthracene DMSO solution for the TA100 strain under the metabolism activating condition as a positive control, and 588 μL of the test bacterial solution (a mixed solution of 498 μl of the test bacterial solution and 90 μL of S9 mix under the metabolism activating condition) were mixed, and this was shaking-cultured at 37° C. for 90 minutes. 460 μL of the bacterial solution exposed to a compound of the present invention was mixed with 2300 μL of an Indicator medium (Micro F buffer containing biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, Bromo Cresol Purple: 37.5 μg/mL), each 50 μL was dispensed into microplate 48 wells/dose, and this was subjected to stationary culturing at 37° C. for 3 days. Since a well containing a bacterium which has obtained the proliferation ability by mutation of an amino acid (histidine) synthesizing enzyme gene turns from purple to yellow due to a pH change, the bacterium proliferation well which has turned to yellow in 48 wells per dose is counted, and was assessed by comparing with a negative control group. (−) means that mutagenicity is negative and (+) is positive.
    • (Result)
      • Compound 111-2: (−)
    Test Example 8: hERG Test
  • For the purpose of assessing risk of an electrocardiogram QT interval prolongation of the compound of the present invention, effects of the compound of the present invention on delayed rectifier K+ current (1Kr), which plays an important role in the ventricular repolarization process, was studied using HEK293 cells expressing human ether-a-go-go related gene (hERG) channel.
  • After a cell was retained at a membrane potential of −80 mV by whole cell patch clamp method using an automated patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), Ix, induced by depolarization pulse stimulation at +40 mV for 2 seconds and, further, repolarization pulse stimulation at −50 mV for 2 seconds, was recorded. After the generated current was stabilized, extracellular solution (NaCl: 135 mmol/L, KCl: 5.4 mmol/L, NaH2PO4: 0.3 mmol/L, CaCl2·2H2O: 1.8 mmol/L, MgCl2·6H2O: 1 mmol/L, glucose: 10 mmol/L, REYES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4), in which the compound of the present invention had been dissolved at an objective concentration, was applied to the cell at room temperature for 10 minutes. From the recording IKr, an absolute value of the tail peak current was measured based on the current value at the resting membrane potential using analysis software (DataXpress ver.1, Molecular Devices Corporation). Further, the % inhibition relative to the tail peak current before application of the compound of the present invention was calculated, and compared with the vehicle-applied group (0.1% dimethyl sulfoxide solution) to assess influence of the compound of the present invention on IKr.
  • (Result) % inhibition was shown at 0.3 to 10 μM of test compound.
      • Compound 111-2: 7.9%
    Test Example 9: Solubility Test
  • The solubility of the compound of the present invention was determined under 1% DMSO addition conditions. A 10 mmol/L solution of the compound was prepared with DMSO, and 2 μL of the solution of the compound of the present invention was added, respectively, to 198 μL of JP-1 solution (water were added to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to reach 1000 mL) and, JP-2 solution (1 volume of water were added to 1 volume of the solution which 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate to reach 1000 mL). The mixture was shaked for 1 hour at a room temperature, and the mixture was filtered. The filtrate was ten-fold diluted with methanol/water=1/1(v/v), and the compound concentration in the filtrate was measured with LC/MS or SPE/MS by the absolute calibration method.
    • (Result)
      • Compound 111-2: 42.2 μmol/L
    Test Example 10: Powder Solubility Test
  • Appropriate amounts of the compound of the present invention was put into vials and 200 μL of JP-1st Fluid (water was added to 2.0 g of sodium chloride in 7.0 mL of hydrochloride acid to reach 1000 mL), JP-2nd Fluid (water was added to 500 mL of phosphate buffer solution with a pH of 6.8) and 20 mmol/L sodium taurocholate (TCA)/JP-2nd Fluid (JP-2nd Fluid was added to 1.08 g of TCA in JP-2nd Fluid to reach 100 mL) was added to each vial. When the compound was completely dissolved, appropriate amount of compound was added. After shaken for 1 hour at 37° C., the mixture was filtered and 100 μL of methanol was added to 100 μL of each filtrate (double dilution). Dilution magnification was changed if necessary. After it was confirmed whether there were air bubbles and precipitates in the vials, the vials were shaken with tight stopper. The compound concentration was determined with HPLC by the absolute calibration method.
    • (Result)
      • Compound 111-2: JP-1 solution; 7.1 μg/mL, JP-2 solution; 4.4 μg/mL, 20 mmol/L
      • TCA/JP-2 solution; 16.1 μg/mL
    Test Example 11: Ames Test
  • Ames test was performed by using Salmonellas (Salmonella typhimurium) TA 98, TA100, TA1535 and TA1537 and Escherichia coli WP2uvrA as test strains with or without metabolic activation in the pre-incubation method to check the presence or absence of gene mutagenicity of compounds of the present invention.
    • (Result)
      • Compound 111-2: (−)
    Test Example 12: Light Hemolysis Test
  • The compound of the present invention was dissolved at target concentrations and was mixed with a 2.5 v/v % suspension of red blood cells prepared from a defibrinated blood of sheep on a microplate at concentrations of 0.0008 to 0.1 w/v %. The mixtures were exposed to 10 J/cm2 of UV-irradiation within a range of wavelength 290 to 400 nm, UVA and UVB using ultra violet fluorescent lamps, GL20SE and FL20S-BLB lamps manufactured by Sankyo Denki Co., Ltd. and Panasonic Corporation, respectively. After the completion of the irradiation, the mixtures were centrifuged, and a supernatant of the mixture was collected and was located on a microplate. The phototoxicity was assessed by measuring an absorbance at wavelength of 540 nm and 630 nm in the supernatant. The absorbance data at wavelength of 540 nm and 630 nm were used as indicators of biomembrane damage (photohemolysis %) and hyperoxidation of lipid membrane (methemoglobin formation), respectively. The criteria of phototoxicity was as follows; It was judged to be non-phototoxic (−) when the photohemolysis %<10 and the maximal change in the absorbance at 630 nm (ΛOD)<0.05 were observed. It was judged to be non-phototoxic (+) when the photohemolysis was more than 10% and the maximal change in the absorbance at 630 nm (ΔOD) was more than 0.05.
    • (Result)
      • Compound 111-2: (−)
  • FIGS. 1 and 2 show a result of measuring the plasma concentration of Compound 111-2 and Compound 11-6 after oral administration of prodrug Compound 11-6, the parent compound of which is Compound 111-2, to rat under non-fasting conditions.
  • In addition, the concentration of Compound 11-6 in all plasma samples was a determination limit or less. Therefore, prodrug Compound 11-6, the parent compound of which is Compound 111-2 is found to have changed promptly to Compound 111-2 in vivo after administration (see FIG. 2 ).
  • Based on the above test results, it was revealed that the compound converted into a prodrug was absorbed into the body after oral administration, and rapidly converted into a parent compound in the blood. Therefore, the compound of the present invention can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.
    • Test Example 13: Intravenous Administration Test
  • Examined experimental materials and method of intravenous administration test
      • (1) Animals used: SD rats were used.
      • (2) Rearing conditions: Pellets and sterilized tap water were fed to SD rats ad libitum.
      • (3) Dosage and grouping: A predetermined dosage was intravenously administered. Groups were set as follows. (Dosage varied for each compound)
        • Intravenous administration 0.5-1 mg/kg (n=2-3)
      • (4) Preparation of administration solution: Intravenous administration was performed after solubilization.
      • (5) Administration method: Intravenous administration was performed with a needle-equipped syringe on the caudal vein.
      • (6) End point: Blood was collected over time, and the plasma concentration of the compound of the present invention was measured using LC/MS/MS.
      • (7) Statistical analysis: As for the transition of the plasma concentration of the compound of the present invention, the total body clearance (CLtot) and the elimination half-life (t1/2, z) were calculated using nonlinear least-squares program WinNonlin (R).
    (Results)
      • Compound No. 111-2:
      • CLtot: 16.4 mL/min/kg
      • t1/2, z: 3.4 hours
  • From the above results, it was found that Compound 111-2 is a compound having a low total body clearance and a long half-life.
  • Therefore, the compound of the present invention has excellent persistence and can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.
    • Formulation Example
  • The following Formulation Examples are only exemplified and not intended to limit the scope of the invention.
    • Formulation Example 1: Tablets
  • The compounds of the present invention, lactose and calcium stearate are mixed. The mixture is crushed, granulated and dried to give a suitable size of granules. Next, calcium stearate is added to the granules, and the mixture is compressed and molded to give tablets.
    • Formulation Example 2: Capsules
  • The compounds of the present invention, lactose and calcium stearate are mixed uniformly to obtain powder medicines in the form of powders or fine granules. The powder medicines are filled into capsule containers to give capsules.
    • Formulation Example 3: Granules
  • The compounds of the present invention, lactose and calcium stearate are mixed uniformly and the mixture is compressed and molded. Then, it is crushed, granulated and sieved to give suitable sizes of granules.
    • Formulation Example 4: Orally Disintegrated Tablets
  • The compounds of the present invention and crystalline cellulose are mixed, granulated and tablets are made to give orally disintegrated tablets.
    • Formulation Example 5: Dry Syrups
  • The compounds of the present invention and lactose are mixed, crushed, granulated and sieved to give suitable sizes of dry syrups.
    • Formulation Example 6: Injections
  • The compounds of the present invention and phosphate buffer are mixed to give injection.
    • Formulation Example 7: Infusions
  • The compounds of the present invention and phosphate buffer are mixed to give injection.
    • Formulation Example 8: Inhalations
  • The compound of the present invention and lactose are mixed and crushed finely to give inhalations.
    • Formulation Example 9: Ointments
  • The compounds of the present invention and petrolatum are mixed to give ointments.
    • Formulation Example 10: Patches
  • The compounds of the present invention and base such as adhesive plaster or the like are mixed to give patches.
    • INDUSTRIAL APPLICABILITY
  • The compound of the present invention has cap-dependent endonuclease (CEN) inhibitory activity after absorption into the body. The compound of the present invention can be a useful agent for treatment and/or prevention of symptom and/or disease induced by infection with influenza virus.

Claims (2)

1-20. (canceled)
21. A compound of formula II-58:
Figure US20230287004A1-20230914-C00247
or a pharmaceutically acceptable salt thereof.
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