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  • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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  • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

• the present invention relates to a macrocyclic compound having an activity of activating nuclear factor erythroid 2-related factor 2 (herein, may be abbreviated as "NRF2”) and is expected to be useful in treatment for diseases associated with oxidative stress.
• NRF2 nuclear factor erythroid 2-related factor 2
• Oxidative stress refers to a condition where oxidation and anti-oxidation is out of balance and excessive oxidation reaction adversely affects organisms, and it has been clear that oxidative stress is closely related to various pathogeneses.
• a living body provides a defense mechanism against oxidative stress, and NRF2 (nuclear factor erythroid 2-related factor 2) plays a central role in this mechanism.
• NRF2 nuclear factor erythroid 2-related factor 2
• NRF2 nuclear factor erythroid 2-related factor 2
• NRF2 when receiving some kind of oxidative stress, NRF2 dissociates from KEAPl, translocates to the inside of nucleus, and binds to a transcriptional region called ARE (anti-oxidant response element), thereby inducing gene expression of a variety of anti-oxidative substances (activation of NRF2).
• ARE anti-oxidant response element
• the NRF2-KEAP1 system is a biological defense mechanism for quickly responding to oxidative stress (Free Radical Biology and Medicine 2015 88: 362-372; Non Patent Literature 1). Accordingly, NRF2 activators are expected to provide a strong anti-oxidative activity by activating the NRF2-KEAP1 system.
• NRF2 activators there is one type that modifies a Cys residue of KEAP1, and there is another type that inhibits the protein-protein interaction of NRF2-KEAP1, but both have been known to activate NRF2 (Med Res Rev. 2016 36(5): 924-63; Non Patent Literature 2).
• NRF2 activators are believed to exhibit effectiveness in prevention or treatment for a variety of oxidative stress diseases.
• the diseases include hepatic disease (non-alcoholic steatohepatitis (NASH) or the like), bile duct disease (primary sclerosing cholangitis (PSC) or the like), lung disease (obstructive pulmonary disease (COPD) or the like), kidney disease (chronic kidney disease (CKD), acute kidney injury (AKI) or the like), heart disease (heart failure, pulmonary arterial hypertension or the like), central nervous system disease
• NASH non-alcoholic steatohepatitis
• PSC primary sclerosing cholangitis
• COPD obstructive pulmonary disease
• COPD chronic pulmonary disease
• kidney disease chronic kidney disease (CKD), acute kidney injury (AKI) or the like
• heart disease heart failure, pulmonary arterial hypertension or the like
• central nervous system disease heart failure, pulmonary arterial hypertension or the like
• An object of the present invention is to provide a compound having an NRF2 activating activity, having a novel structure, and being expected to be useful as a preventive or therapeutic agent for diseases associated with oxidative stress, in particular, hepatic disease (for example, non-alcoholic steatohepatitis (NASH)), bile duct disease (primary sclerosing cholangitis (PSC) or the like), cardiovascular disease (for example, heart failure or pulmonary arterial hypertension), lung disease (for example, chronic obstructive pulmonary disease (COPD)), kidney disease (for example, chronic kidney disease (CKD) or acute kidney injury (AKI)), central nervous system disease (for example, Parkinson's disease, Alzheimer's disease, cerebral stroke), mitochondrial disease (for example, Friedreich motor ataxia, mitochondrial myopathy), inflammatory disease (for example, multiple sclerosis (MS), inflammatory bowel disease (IBD)), sickle cell disease, cancer, or the like.
• hepatic disease for example, non-alcoholic steato
• a macrocyclic compound represented by the following formula (I) has an NRF2 activating activity, and therefore, is expected to be useful as a preventive or therapeutic agent for diseases associated with oxidative stress, in particular, hepatic disease (for example, non-alcoholic steatohepatitis (NASH)), bile duct disease (primary sclerosing cholangitis (PSC) or the like), cardiovascular disease (for example, heart failure or pulmonary arterial hypertension), lung disease (for example, chronic obstructive pulmonary disease (COPD)), kidney disease (for example, chronic kidney disease (CKD) or acute kidney injury (AKI)), central nervous system disease (for example, Parkinson's disease, Alzheimer's disease, cerebral stroke), mitochondrial disease (for example, Friedreich motor ataxia, mitochondrial myopathy), inflammatory disease (for example, multiple sclerosis (MS), inflammatory bowel disease (IBD)), sickle cell disease, cancer, or
• NASH non-alcoholic steatohepatitis
• PSC primary s
• the present invention is as follows:
• R 1 is OH, ORy or NHRy
• Ry is an optionally substituted Ci- 6 alkyl group or an optionally substituted cyclic group
• R 2 and R 3 which may be the same or different, are a hydrogen atom or an optionally substituted Ci- 6 alkyl group, or R 2 and R 3 are joined together to form a C3-6 cycloalkyl group;
• R xl and R x2 which may be the same or different, are a hydrogen atom or an optionally substituted Ci-6 alkyl group;
• ring A is a benzene ring which may have an additional substituent(s);
• ring B is a benzene ring which may have an additional substituent(s);
• ring C is an optionally substituted 5- or 6-membered aromatic ring which may contain a heteroatom(s) in the ring; and L is optionally substituted, saturated or unsaturated linear C4-8 alkylene optionally inserted by a heteroatom,
• L is -(CR 4 R 5 )n- Y 1 -(CR 6 R 7 )m- Y 2 - *
• n is an integer of 2 or more and 4 or less;
• n is an integer of 1 or more and 4 or less;
• R 4 and R 5 are the same as or different from each other, and are each a hydrogen atom, a halogen atom, OH, an optionally substituted Ci- 6 alkyl group or an optionally substituted Ci- 6 alkoxy group, or R 4 and R 5 are joined together to form an optionally substituted C3-6 cycloalkyl group, and a plurality of R 4 or a plurality of R 5 may be the same as or different from each other, and the adjacent R 4 or R 5 may be joined together to form a double bond;
• R 6 and R 7 are the same as or different from each other, and are each a hydrogen atom, a halogen atom, OH, an optionally substituted Ci- 6 alkyl group or an optionally substituted Ci- 6 alkoxy group, or R 6 and R 7 are joined together to form an optionally substituted C3-6 cycloalkyl group, and when m is 2 or more, a plurality of R 6 or a plurality of R 7 may be the same as or different from each other, and the adjacent R 6 or R 7 may be joined together to form a double bond;
• Y 1 and Y 2 which may be the same or different, are a bond, an oxygen atom, a sulfur atom, SO, SO2 or NR 8 , provided that when Y 1 is a bond, m is 1 or 4;
• R 8 is a hydrogen atom, an optionally substituted Ci- 6 alkyl group, or an optionally substituted Ci- 6 alkoxy group, provided that when a plurality of R 8 is present, the plurality of R 8 may be the same as or different from each other. ⁇ 3>
• L is selected from the group consisting of the following formulas:
• R 1 is OH or ORy
• Ry is an optionally substituted cyclic group
• R 2 and R 3 which may be the same or different, are a hydrogen atom or an optionally substituted Ci- 6 alkyl group;
• ring A is a benzene ring which may have an additional substituent(s);
• ring B is a benzene ring which may have an additional substituent(s); and ring C is an optionally substituted benzene ring.
• R 1 is OH or ORy
• Ry is a Ci-6 alkyl group
• ring A is a benzene ring which may have an additional substituent(s) of a fluorine atom, a chlorine atom, a C 1 -3 alkyl group optionally substituted with 1 to 3 substituents (selected from a halogen atom and a C1-3 alkoxy group), or a C 1 -3 alkoxy group optionally substituted with 1 to 3 substituents (selected from a halogen atom and a Ci-3 alkoxy group);
• ring B is a benzene ring which may have an additional substituent(s) of a fluorine atom, a chlorine atom, a cyano group, a C 1-3 alkyl group optionally substituted with 1 to 3 substituents (selected from a halogen atom and a C 1-3 alkoxy group), or a C1- 3 alkoxy group optionally substituted with 1 to 3 substituents (selected from a halogen atom and a C 1-3 alkoxy group); and
• ring C is a group represented by the following formula:
• Z 1 , Z 2 , Z 3 , Z 4 and Z 5 which may be the same or different, represent a carbon atom or a nitrogen atom;
• R c represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated Ci- 6 alkyl group, an optionally halogenated Ci- 6 alkoxy group, or a C3- 10 cycloalkyl group;
• R cl , R c2 , R° 3 and R c4 which may be the same or different, are a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated Ci- 6 alkyl group, an optionally halogenated Ci-6 alkoxy group, or a C3- 10 cycloalkyl group; or adjacent two of R cl , R c2 , R c3 and R c4 are joined together to form an optionally substituted ring, provided that when Z 1 , Z 2 , Z 3 , Z 4 or Z 5 is a nitrogen atom, R c , R cl , R c2 , R c3 or R c4 is not present.
• R 1 is OH
• R 2 and R 3 which may be the same or different, are a hydrogen atom or a C1-3 alkyl group
• ring A is a benzene ring which may have an additional substituent of a C 1 -3 alkyl group
• ring B is a benzene ring which does not have an additional substituent
• ring C is a group represented by the following formula:
• R cl and R c4 which may be the same or different, are a hydrogen atom, an optionally halogenated Ci- 6 alkyl group, an optionally halogenated Ci-6 alkoxy group, a chlorine atom, or a fluorine atom, and R c2 and R c3 are each a hydrogen atom; and
• L is -CH2-CH2-CH2-CH2-*, -CH 2 -CH 2 -CH 2 -CH 2 -O-*,
• R 1 is OH
• R 2 and R 3 which may be the same or different, are a hydrogen atom or a methyl group
• ring A is a substructure represented by the following formula:
• ring B is a benzene ring which does not have an additional substituent
• ring C is a group represented by the following formula:
• R cl and R c4 which may be the same or different, are a hydrogen atom, a chlorine atom, or a methyl group, and R c2 and R c3 are each a hydrogen atom; and L is -CH2-CH2-CH2-CH2-*,
• a medicament including the compound according to any of ⁇ 1> to ⁇ 7> above or a salt thereof.
• the medicament is a preventive or therapeutic agent for hepatic and bile duct disease, cardiovascular disease, lung disease, kidney disease, central nervous system disease, cancer, sickle cell disease, mitochondrial disease, or inflammatory disease.
• a pharmaceutical composition comprising the compound according to any of ⁇ 1> to ⁇ 7> above or a pharmaceutically acceptable salt thereof for use in prevention or treatment for hepatic and bile duct disease, cardiovascular disease, lung disease, kidney disease, central nervous system disease, cancer, sickle cell disease, mitochondrial disease, or inflammatory disease.
• a method of activating NRF2 in a mammal comprising administering the compound according to any of ⁇ 1> to ⁇ 7> above or a salt thereof to the mammal in an effective amount.
• a method of preventing or treating hepatic and bile duct disease A method of preventing or treating hepatic and bile duct disease
• cardiovascular disease lung disease, kidney disease, central nervous system disease, cancer, sickle cell disease, mitochondrial disease, or inflammatory disease in a mammal, comprising administering the compound according to any of ⁇ 1> to ⁇ 7> or a salt thereof to the mammal.
• the present invention can provide a compound that has an excellent NRF2 activating activity, and is expected to be useful as a preventive or therapeutic agent for diseases associated with oxidative stress, in particular, hepatic and bile duct disease such as hepatic disease (for example, non-alcoholic steatohepatitis (NASH)) and bile duct disease (primary sclerosing cholangitis (PSC) or the like),
• hepatic disease for example, non-alcoholic steatohepatitis (NASH)
• NASH non-alcoholic steatohepatitis
• PSC primary sclerosing cholangitis
• cardiovascular disease for example, heart failure or pulmonary arterial pressure
• lung disease for example, chronic obstructive pulmonary disease (COPD)
• kidney disease for example, chronic kidney disease (CKD) or acute kidney injury (AKI)
• central nervous system disease for example, Parkinson's disease, Alzheimer's disease, cerebral stroke
• mitochondrial disease for example, Friedreich motor ataxia, mitochondrial myopathy
• inflammatory disease for example, multiple sclerosis (MS), inflammatory bowel disease (IBD)
• sickle cell disease cancer, or the like.
• halogen atom as used herein include fluorine, chlorine, bromine and iodine.
• Ci- 6 alkyl group as used herein include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, and 2-ethylbutyl.
• cyclic group in the “optionally substituted cyclic group” examples include a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a Ce-i4 aryl group, an aromatic heterocyclic group, and a non-aromatic heterocyclic group.
• optionally substituted ring means a ring that does not have a bonding hand of the cyclic group defined as the “optionally substituted cyclic group.”
• C3-10 cycloalkyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl.
• the C3-10 cycloalkyl group may be fused with a benzene ring, and examples of such a fused ring include tetrahydronaphthyl and dihydroindenyl.
• C3-10 cycloalkenyl group examples include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
• C6-14 aryl group examples include phenyl, 1 -naphthyl, 2-naphthyl, 1- anthryl, 2-anthryl, and 9-anthryl.
• the C6-14 aryl group described above may be fused with a C3-10 cycloalkane ring (preferably, a C5-6 cycloalkane ring (for example, cyclopentane and
• the aromatic heterocyclic group in the "cyclic group" of the "optionally substituted cyclic group” is preferably a 5- to 14-membered aromatic heterocyclic group, and more preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (for example, pyridyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl and thienyl), or a 8- to 14-membered fused polycyclic (preferably, bicyclic or tricyclic) aromatic heterocyclic group (for example, indazolyl, indolyl, benzimidazolyl, benzotriazolyl, benzothienyl and benzofuryl).
• non-aromatic heterocyclic group in the "cyclic group” of the "optionally substituted cyclic group” is preferably a 3- to 14-membered non-aromatic
• heterocyclic group and more preferably a 3- to 8-membered monocyclic nonaromatic heterocyclic group (for example, oxetanyl and tetrahydropyranyl) or a 9- to 14-membered fused polycyclic (preferably, bicyclic or tricyclic) non-aromatic heterocyclic group (for example, dihydrocumenyl, dihydrobenzofuryl,
• dihydrobenzodioxepinyl tetrahydroquinolyl, tetrahydroisoquinolyl, indolinyl, dihydrobenzodioxinyl, dihydrobenzoxazinyl and dihydrobenzoxazepinyl).
• the non-aromatic heterocyclic group may be a spiro ring, and examples of such a spiro ring include spiro[l-benzofuran-2,l'-cyclopropane]-yl, spiro[l-benzofuran-2,l'-cyclohexane]-yl, tetrahydro-3H-spiro[l-benzofuran-2,4'- pyrane]-yl, spiro[l-benzofuran-2,r-cyclopentane]-yl, and dihydrospiro[l,4- benzoxazine-2, 1 '-cyclobutane] -yl.
• C3-6 cycloalkyl group examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• Examples of the "Ci- 6 alkoxy group" as used herein include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
• Examples of the "5- or 6-membered aromatic ring which may contain a heteroatom(s) in the ring" as used herein include a 5- or 6-membered aromatic heterocyclic ring containing, other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as the constituent atoms of the ring, or a 6-membered aromatic carbocyclic ring not including heteroatoms.
• Z 1 , Z 2 , Z 3 , Z 4 and Z 5 which may be the same or different, are a carbon atom or a nitrogen atom;
• R c represents a hydrogen atom, or a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated Ci- 6 alkyl group, an optionally halogenated Ci- 6 alkoxy group, or a C3-10 cycloalkyl group;
• R cl , R c2 , R c3 and R 04 which may be the same or different, are a hydrogen atom, or a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated Ci- 6 alkyl group, an optionally halogenated Ci-6 alkoxy group, or a C3-10 cycloalkyl group; or adjacent two of R cl , R c2 , R c3 and R c4 , taken together, may form an optionally substituted ring, provided that when Z 1 , Z 2 , Z 3 , Z 4 or Z 5 is a nitrogen atom, R c , R cl , R c2 , R c3 or R c4 is not present.
• Optionally halogenated as used herein means, for example, optionally substituted with 1 to 7, preferably 1 to 5 halogen atoms.
• Suitable examples of such a 5- or 6-membered aromatic heterocyclic ring include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4- oxadiazole, 1 ,2,4-thiadiazole, 1 ,3,4-thiadiazole, triazole, tetrazole, and triazine, and a 6-membered aromatic carbocyclic ring not containing heteroatoms is a benzene ring.
• saturated or unsaturated linear C4-8 alkylene optionally inserted by a heteroatom means a saturated or unsaturated linear alkylene group in which one or two heteroatoms selected from a nitrogen atom or NR C (R c is a hydrogen atom or a Ci- 6 alkyl group optionally having a substituent), a sulfur atom, SO, SO2, and an oxygen atom are inserted to an arbitrary position of a C4-8 alkylene, thereby dividing that alkylene into two or more; a saturated or unsaturated linear alkylene group that is substituted with a heteroatom described above; or a saturated or unsaturated linear C4-8 alkylene group.
• n is an integer of 2 or more and 4 or less;
• n is an integer of 1 or more and 4 or less;
• R 4 and R 5 which may be the same as or different from each other, are a hydrogen atom, a halogen atom, OH, an optionally substituted Ci-6 alkyl group or an optionally substituted Ci- 6 alkoxy group, or R 4 and R 5 are joined together to form an optionally substituted C3-6 cycloalkyl group, and a plurality of R 4 or a plurality of R 5 may be the same as or different from each other, and the adjacent R 4 or R 5 may be joined together to form a double bond;
• R 6 and R 7 which may be the same as or different from each other, are each a hydrogen atom, a halogen atom, OH, an optionally substituted Ci-6 alkyl group or an optionally substituted Ci- 6 alkoxy group, or R 6 and R 7 are joined together to form an optionally substituted C 3-6 cycloalkyl group, and when m is 2 or more, a plurality of R 6 or a plurality of R 7 may be the same as or different from each other, and the adjacent R 6 or R 7 may be joined together to form a double bond;
• Y 1 and Y 2 which may be the same or different, are a bond, an oxygen atom, NR 8 , a sulfur atom, SO or SO2, provided that when Y 1 is a bond, m is 1 or 4;
• R 8 is a hydrogen atom or an optionally substituted Ci- 6 alkyl group, provided that when a plurality of R 8 is present, the plurality of R 8 may be the same as or different from each other.
• R 4 and R 5 are joined together to form an optionally substituted C 3-6 cycloalkyl group
• R 6 and R 7 are joined together to form an optionally substituted C 3-6 cycloalkyl group
• preferable groups represented by the formula: -(CR 4 R 5 )n-Y'- (CR 6 R 7 )m-Y 2 -* wherein the symbols in the formula are as defined above are the groups shown in Table 1 below.
• substituents in the "optionally substituted Ci-6 alkyl group", the “optionally substituted cyclic group", the " a benzene ring which may have an additional substituent(s)", the “optionally substituted 5- or 6-membered aromatic ring which may contain a heteroatom(s) in the ring", and the "optionally substituted, saturated or unsaturated linear C4-8 alkylene optionally inserted by a heteroatom” as used herein include substituents selected from Substituent Group A described below, and the number of the substituent is, for example, 1 to 5 (preferably 1 to 3). When the number of the substituent is two or more, those substituents may be the same as or different from each other.
• Examples of the "hydrocarbon group" of the "optionally substituted hydrocarbon group" in Substituent Group A include a Ci-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group, and a C7-16 aralkyl group.
• C2-6 alkenyl group examples include ethenyl, 1-propenyl, 2-propenyl, 2 -methyl- 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1- pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3- hexenyl, and 5-hexenyl.
• C2-6 alkynyl group examples include ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2- pentynyl.
• C7-16 aralkyl group examples include benzyl, phenethyl,
• Substituent Group A examples include a hydrocarbon group optionally having a substituent selected from Substituent Group B described below.
• Ci-6 alkoxy group optionally halogenated Ci-6 alkoxy group; (7) C6-i4 Aryloxy group (for example, phenoxy, naphthoxy);
• C6-14 Aryl-carbonyloxy group for example, benzoyloxy, 1-naphthoyloxy, 2- naphthoyloxy;
• Ci- 6 Alkoxy-carbonyloxy group for example, methoxycarbonyloxy,
• Mono- or di-Ci- 6 alkyl-carbamoyloxy group for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy;
• C6-14 Aryl-carbamoyloxy group (phenylcarbamoyloxy, naphthylcarbamoyloxy);
• Ci-6 alkylsulfonyloxy group for example,
• C6-14 Arylsulfonyloxy group optionally substituted with a Ci-6 alkyl group for example, phenylsulfonyloxy, toluenesulfonyloxy
• Ce-14 Aryloxy-carbonyl group for example, phenyloxycarbonyl, 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl;
• Ci - 6 Alkyl-carbonylamino group for example, acetylamino, propanoylamino, butanoylamino
• C6-14 Aryl-carbonylamino group (for example, phenylcarbonylamino, naphthylcarbonylamino) ;
• Ci- 6 Alkoxy-carbonylamino group for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert- butoxycarbonylamino
• Ci- 6 Alkylsulfonylamino group for example, methylsulfonylamino,
• the number of the substituent selected from Substituent B described above in the "optionally substituted hydrocarbon group" of Substituent Group A is, for example, 1 to 5, and preferably 1 to 3. When the number of the substituent is two or more, those substituents may be the same as or different from each other.
• Examples of the "aromatic heterocyclic group" in the “heterocyclic group” of Substituent Group A include a 5- to 14-membered (preferably, 5- to 10-membered) aromatic heterocyclic group containing, other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as the constituent atoms of the ring.
• Suitable examples of such an "aromatic heterocyclic group” include: a 5- to 6- membered monocyclic aromatic heterocyclic group such as thienyl, fiiryl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; and
• a 8- to 14-membered fused polycyclic preferably, bicyclic or tricyclic
• aromatic heterocyclic group such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl,
• non-aromatic heterocyclic group in the "heterocyclic group” of Substituent Group A (including the “3- to 14-membered non-aromatic heterocyclic group”) include a 3- to 14-membered (preferably, 4- to 10-membered) non-aromatic heterocyclic group containing, other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as the constituent atoms of the ring.
• non-aromatic heterocyclic group examples include: a 3- to 8-membered monocyclic non-aromatic heterocyclic group such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl,
• tetrahydropyrimidinyl tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetarhydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl;
• a 9- to 14-membered fused polycyclic preferably, bicyclic or tricyclic non-aromatic heterocyclic group such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl,
• tetrahydrobenzazepinyl tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl,
• Suitable examples of the "7- to 10-membered bridged heterocyclic group" in the "heterocyclic group" of Substituent Group A include quinuclidinyl and 7- azabicyclo [2.2.1 ]heptanyl .
• heterocyclic group examples include a heterocyclic group optionally having a substituent selected from
• the number of the substituent in the "optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of the substituent is two or more, those substituents may be the same as or different from each other.
• Substituent Group A examples include an amino group optionally having "1 or 2 substituents selected from a Ci-6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a Ci- 6 alkyl-carbonyl group, a Ce- aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclic ring carbonyl group, a 3- to 14-membered non-aromatic heterocyclic ring carbonyl group, a Ci-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci- 6 alkyl -carbamoyl group, a mono- or di-C7-i6 aralkyl
• Suitable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated Ci- 6 alkyl)amino group (for example, methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), a mono- or di-C2-6 alkenylamino group (for example, diallylamino), a mono- or di-C3-io cycloalkylamino group (for example,
• cyclopropylamino, cyclohexylamino a mono- or di-C6-i4 arylamino group (for example, phenylamino), a mono- or di-C7-i6 aralkylamino group (for example, benzylamino, dibenzylamino), a mono- or di-(optionally halogenated Ci- 6 alkyl)- carbonylamino group (for example, acetylamino, propionylamino), a mono- or di-C 6 - 14 aryl-carbonylamino group (for example, benzoylamino), a mono- or di-C7-i6 aralkyl-carbonylamino group (for example, benzylcarbonylamino), a mono- or di-5- to 14-membered aromatic heterocyclic ring carbonylamino group (for example, nicotinoylamino, isonicotinoylamino
• piperidinylcarbonylamino a mono- or di-Ci- 6 alkoxy-carbonylamino group (for example, tert-butoxycarbonylamino), a 5- to 14-membered aromatic heterocyclic ring amino group (for example, pyridylamino), a carbamoylamino group, a (mono- or di-Ci- 6 alkyl-carbamoyl)amino group (for example, methylcarbamoylamino), a (mono- or di-C7-i6 aralkyl-Carbamoyl)amino group (for example,
• Ci- 6 alkylsulfonylamino group for example,
• a C6-14 arylsulfonylamino group for example, phenylsulfonylamino
• a (Ci-6 alkyl)(Ci-6 alkyl-carbonyl)amino group for example, N-acetyl-N-methylamino
• Examples of the "optionally substituted carbamoyl group" of Substituent Group A include a carbamoyl group optionally having "1 or 2 substituents selected from a Ci- 6 alkyl group, a C 2-6 alkenyl group, a C3- 10 cycloalkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a Ci- 6 alkyl-carbonyl group, a C6- 14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclic ring carbonyl group, a 3- to 14-membered non-aromatic heterocyclic ring carbonyl group, a Ci- 6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci- 6 alkyl-carbamoyl group,
• Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-Ci- 6 alkyl-carbamoyl group, a mono- or di-C 2 -6 alkenyl-carbamoyl group (for example, diallylcarbamoyl), a mono- or di-C3-io cycloalkyl-carbamoyl group (for example, cyclopropylcarbamoyl,
• cyclohexylcarbamoyl a mono- or di-C 6 -i 4 aryl-carbamoyl group (for example, phenylcarbamoyl), a mono- or di-C 7 -i 6 aralkyl-carbamoyl group, a mono- or di-Ci- 6 alkyl-carbonyl-carbamoyl group (for example, acetylcarbamoyl,
• propionylcarbamoyl a mono- or di-C6-i 4 aryl-carbonyl-carbamoyl group (for example, benzoylcarbamoyl), and a 5- to 14-membered aromatic heterocyclic ring carbamoyl group (for example, pyridylcarbamoyl).
• Examples of the "optionally substituted thiocarbamoyl group" of Substituent Group A include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a Ci- 6 alkyl group, a C 2 -6 alkenyl group, a C3- 10 cycloalkyl group, a Ce- 14 aryl group, a C7- 16 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclic ring carbonyl group, a 3- to 14-membered non-aromatic heterocyclic ring carbonyl group, a Ci- 6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamo
• Suitable examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-Ci- 6 alkyl-thiocarbamoyl group (for example, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl,
• propionylthiocarbamoyl a mono- or di-C6-i4 aryl-carbonyl-thiocarbamoyl group (for example, benzoylthiocarbamoyl), and a 5- to 14-membered aromatic heterocyclic ring carbamoyl group (for example, pyridylthiocarbamoyl).
• Examples of the "optionally substituted sulfamoyl group" of Substituent Group A include a sulfamoyl group optionally having " 1 or 2 substituents selected from a Ci- 6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce-n aryl group, a C7-16 aralkyl group, a Ci- 6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclic ring carbonyl group, a 3- to 14-membered non-aromatic heterocyclic ring carbonyl group, a Ci - 6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci- 6 alkyl-carbamoyl
• Suitable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-Ci-6 alkyl-sulfamoyl group (for example,
• Examples of the "optionally substituted hydroxy group" of Substituent Group A include a hydroxy group optionally having "a substituent selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a Ci- 6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclic ring carbonyl group, a 3- to 14-membered non-aromatic heterocyclic ring carbonyl group, a Ci- 6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C7-i6 aralky
• Suitable examples of the optionally substituted hydroxy group include a hydroxy group, a Ci- 6 alkoxy group, a C2-6 alkenyloxy group (for example, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C3-10 cycloalkyloxy group (for example, cyclohexyloxy), a C6-14 aryloxy group (for example, phenoxy,
• a C7-16 aralkyloxy group for example, benzyloxy, phenethyloxy
• Ci - 6 alkyl-carbonyloxy group for example, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
• a C6-14 aryl-carbonyloxy group for example, benzoyloxy
• a C7-16 aralkyl-carbonyloxy group for example, benzylcarbonyloxy
• a 5- to 14-membered aromatic heterocyclic ring carbonyloxy group for example, nicotinoyloxy
• a 3- to 14-membered non-aromatic heterocyclic ring carbonyloxy group for example, piperidinylcarbonyloxy
• Ci- 6 alkoxy-carbonyloxy group for example, tert-butoxycarbonyloxy
• arylsulfonyloxy group for example, phenylsulfonyloxy.
• Examples of the "optionally substituted sulfanyl group" of Substituent Group A include a sulfanyl group optionally having "a substituent selected from a Ci- 6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a Ci- 6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, and a 5- to 14-membered aromatic heterocyclic group, all of which optionally have 1 to 3 substituents selected from Substituent Group B", and a halogenated sulfanyl group.
• Suitable examples of the optionally substituted sulfanyl group include a sulfanyl (-SH) group, a Ci- 6 alkylthio group, a C2-6 alkenylthio group (for example, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), a C3-10 cycloalkylthio group (for example, cyclohexylthio), a Ce-i4 arylthio group (for example, phenylthio, naphthylthio), a C7-16 aralkylthio group (for example, benzylthio, phenethylthio), a Ci- 6 alkyl-carbonylthio group (for example, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), a Ce-14 aryl-carbonylthio group (for
• C3-10 cycloalkyloxy group examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
• Ci- 6 alkylthio group examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.
• Examples of the "optionally substituted silyl group" of Substituent Group A include a silyl group optionally having " 1 to 3 substituents selected from a Ci- 6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, and a C7-16 aralkyl group, all of which optionally have 1 to 3 substituents selected from
• Suitable examples of the optionally substituted silyl group include a tri-Ci- 6 alkylsilyl group (for example, trimethylsilyl, tert-butyl(dimethyl)silyl).
• R 1 is preferably OH or ORy.
• Ry is preferably a Ci- 6 alkyl group.
• R 1 is more preferably OH.
• R 2 and R 3 are preferably the same or different, and are each a hydrogen atom or an optionally substituted Ci- 6 alkyl group (for example, methyl).
• R 2 and R 3 are more preferably the same or different, and are each a hydrogen atom or a C1-3 alkyl group (for example, methyl).
• R 2 and R 3 are each a hydrogen atom or a methyl group.
• the "benzene ring" of the "a benzene ring which may have an additional substituent(s)" indicated as ring A may be further substituted with, for example, a substituent(s) selected from Substituent Group A described above, and the number of the substituent is, for example, 1 to 3. When the number of the substituent is two or more, those substituents may be the same as or different from each other.
• That position of substitution preferably includes a position selected from positions a and b indicated by the following arrows:
• Ring A is preferably a benzene ring which may have an additional substituent(s) of a fluorine atom, a chlorine atom, a C1-3 alkyl group optionally substituted with 1 to 3 substituents (selected from a halogen atom and a C1-3 alkoxy group), or a C 1-3 alkoxy group optionally substituted with 1 to 3 substituents
• ring A is a benzene ring which may have an additional substituent(s) of 1 to 3 substituents selected from:
• Ci - 6 alkyl group for example, methyl
• Ci - 6 alkoxy group for example, methoxy
• ring A is a benzene ring which has an additional substituent(s) of one substituent selected from:
• Ci-3 alkyl group for example, methyl
• Ci-3 alkoxy group for example, methoxy
• the position of substitution on the benzene ring of ring A is preferably a position a or b indicated by the following arrows:
• ring A is more preferably a benzene ring which has an additional substituent(s) of 1 or 2 substituents selected from:
• Ci-3 alkyl group for example, methyl
• Ci-3 alkoxy group for example, methoxy
• the position(s) of substitution on the benzene ring of ring A is preferably a position selected from positions a and b indicated by the following arrows:
• ring A is further preferably a benzene ring which has an additional substituent of a C 1-3 alkyl group (for example, methyl).
• the position of substitution on the benzene ring of ring A is preferably position a indicated by the following arrow:
• R a represents a hydrogen atom or a Ci- 6 alkyl group
• R b represents a hydrogen atom or a Ci- 6 alkoxy group
• R a is preferably a C 1-3 alkyl group (for example, methyl), and more preferably methyl.
• R b is preferably a hydrogen atom or a C1-3 alkoxy group (for example, methoxy).
• ring A is a substructure represented by the following formula: [0047]
• the "benzene ring" of the "a benzene ring which may have an additional substituent(s)" indicated as ring B may have an additional substituent(s), for example, a substituent selected from Substituent Group A described above, and the number of the substituent is, for example, 1 to 3. When the number of the substituent is two or more, those substituents may be the same as or different from each other.
• Ring B is preferably a benzene ring which may have an additional substituent(s) of a fluorine atom, a chlorine atom, a cyano group, a C1-3 alkyl group optionally substituted with 1 to 3 substituents (selected from a halogen atom and a Ci-3 alkoxy group), or a C1-3 alkoxy group optionally substituted with 1 to 3 substituents (selected from a halogen atom and a C1-3 alkoxy group).
• Ring B is more preferably a benzene ring which does not have an additional substituent.
• "which does not have an additional substituent” indicates that ring B is the same as ring B described in formula I and does not have a substituent other than the substituents on ring B described in formula I.
• the "optionally substituted 5- or 6-membered aromatic ring which may contain a heteroatom(s) in the ring" indicated as ring C is preferably a ring represented by the following formula: [0049]
• Z 1 , Z 2 , Z 3 , Z 4 and Z 5 which may be the same or different, are a carbon atom or a nitrogen atom;
• R c represents H, a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated Ci- 6 alkyl group, an optionally halogenated Ci-6 alkoxy group, or a C3-10 cycloalkyl group;
• R cl , R c2 , R c3 and R° 4 which may be the same or different, are H, a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated Ci-6 alkyl group, an optionally halogenated Ci- 6 alkoxy group, or a C3-10 cycloalkyl group; or adjacent two of R cl , R c2 , R c3 and R c4 may be joined together to form an optionally substituted ring, provided that when Z 1 , Z 2 , Z 3 , Z 4 or Z 5 is a nitrogen atom, R c , R cl , R c2 , R c3 or R c4 is not present.
• formulas (C-l) to (C-5) are attached to X and L in formula (I) at certain bonding positions.
• ring C is any of groups represented by the following formulas:
• Z 1 , Z 2 , Z 3 , Z 4 and Z 5 which may be the same or different, are a carbon atom or a nitrogen atom.
• ring C is a group wherein Z 1 , Z 2 , Z 3 ,Z 4 and Z 5 are each a carbon atom; and R cl , R c2 , R c3 and R c4 , which may be the same or different, are H, or a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated Ci-6 alkyl group, an optionally halogenated Ci-6 alkoxy group, or a C 3-10 cycloalkyl group; or adjacent two of R cl , R c2 , R c3 and R c4 may be joined together to form an optionally substituted ring,
• ring C is a ring represented by formula (C-5), and is a group wherein adjacent two of R cl , R c2 , R c3 and R c4 may be joined together to form an optionally substituted saturated ring.
• saturated ring of the "optionally substituted saturated ring” means a C5-8 cycloalkyl ring or a saturated heterocyclic ring, and such a saturated heterocyclic ring means a 5- or 8-membered saturated heterocyclic ring containing, other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as the constituent atoms of the ring.
• a 5- to 6-membered saturated heterocyclic ring for example,
• tetrahydrofuran tetrahydropyran
• 1 ,3-dioxolane morpholine
• tetrahydrofuran tetrahydrofuran
• tetrahydropyran 1 ,3-dioxolane
• morpholine More preferably, it is optionally substituted tetrahydropyran or optionally substituted morpholine.
• the substituent in the "optionally substituted saturated ring” means 1 to 3 substituents that may be the same or different, and are selected from a halogen atom, a nitro group, a cyano group, a hydroxy group, an oxo group, an optionally halogenated Ci- 6 alkyl group, an optionally halogenated Ci- 6 alkoxy group, a C3-10 cycloalkyl group, and a C3-10 cycloalkyl-Ci-6 alkyl group.
• ring C is a ring represented by formula (C-5), wherein all of Z 1 , Z 2 , Z 4 and Z 5 are carbon atoms; and in one of combinations, R cl and R c2 or R c3 and R c4 , the two groups may be the same or different, and are H, or a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated Ci- 6 alkyl group, an optionally halogenated Ci- 6 alkoxy group, or a C3-10 cycloalkyl group; and in the other combination, adjacent two of R cl , R c2 , R c3 and R c4 are joined together to form a 5- or 6-membered heterocyclic ring containing, other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom as the constituent atoms of the ring.
• formula (C-5) wherein all
• the heterocyclic ring described above may be an aromatic heterocyclic ring or a non-aromatic heterocyclic ring.
• aromatic heterocyclic ring include, among those described as the monocyclic aromatic heterocyclic ring mentioned above, for example, pyridyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, and thienyl.
• non-aromatic heterocyclic ring examples include, among the monocyclic non-aromatic heterocyclic ring mentioned above, those that are 5- or 6- membered, such as tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl,
• tetrahydroisoxazolyl piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, and tetrahydropyridazinyl.
• it is tetrahydrofuran or morpholine.
• substituents that may be the same or different, and are selected from a halogen atom, a nitro group, a cyano group, a hydroxy group, an oxo group, an optionally halogenated Ci- 6 alkyl group, an optionally halogenated Ci-6 alkoxy group, a C3-10 cycloalkyl group, and a C3-10 cycloalkyl-Ci-6 alkyl group.
• ring C is preferably a group represented by the following formula:
• R cl and R c4 which may be the same or different, are a hydrogen atom, an optionally halogenated Ci- 6 alkyl group, a chlorine atom, an optionally halogenated Ci-6 alkoxy group, or a fluorine atom, and R c2 and R c3 are each a hydrogen atom.
• ring C is preferably a group represented by the following formula: wherein
• R cl and R c4 which may be the same or different, are a hydrogen atom, a methyl group, or a chlorine atom, and R c2 and R c3 are each a hydrogen atom.
• L is preferably -(CR 4 R 5 )n-Y 1 -(CR 6 R 7 )m-Y 2 -*
• n is an integer of 2 or more and 4 or less;
• n is an integer of 1 or more and 4 or less;
• R 4 and R 5 which may be the same as or different from each other, are each a hydrogen atom, a halogen atom, OH, an optionally substituted Ci- 6 alkyl group or an optionally substituted Ci- 6 alkoxy group, or R 4 and R 5 are joined together to form an optionally substituted C 3-6 cycloalkyl group, and a plurality of R 4 or a plurality of R 5 may be the same as or different from each other, and the adjacent R 4 or R 5 may be joined together to form a double bond;
• R 6 and R 7 which may be the same as or different from each other, are each a hydrogen atom, a halogen atom, OH, an optionally substituted Ci- 6 alkyl group or an optionally substituted Ci- 6 alkoxy group, or R 6 and R 7 are joined together to form an optionally substituted C 3-6 cycloalkyl group, and when m is 2 or more, a plurality of R 6 or a plurality of R 7 may be the same as or different from each other, and the adjacent R 6 or R 7 may be joined together to form a double bond; Y 1 and Y 2 , which may be the same or different, are a bond, an oxygen atom or NR 8 , provided that when Y 1 is a bond, m is 1 or 4; and
• R 8 is a hydrogen atom or an optionally substituted Ci- 6 alkyl group.
• L is any of groups represented by the following formulas: -CR 4 R 5 -CR 4 R 5 -CR 4 R 5 -CR 4 R 5 -CR 6 R 7 -*;
• L is
• Examples of the compound represented by formula (I) include the following Compounds A to D, or a salt thereof.
• R 1 is OH
• R 2 and R 3 which may be the same or different, are a hydrogen atom or an optionally substituted Ci- 6 alkyl group;
• ring A is a benzene ring which may have an additional substituent(s);
• ring B is a benzene ring which may have an additional substituent(s);
• ring C is an optionally substituted benzene ring
• L is -CR 4 R 5 -CR 4 R 5 -CR 6 R 7 -CR 6 R 7 -CR 6 R 7 -CR 6 R 7 -*;
• R 1 is NHRy
• Ry is an optionally substituted cyclic group
• R 2 and R 3 which may be the same or different, are a hydrogen atom or an optionally substituted Ci- 6 alkyl group;
• ring A is a benzene ring which may have an additional substituent(s);
• ring B is a benzene ring which may have an additional substituent(s);
• ring C is an optionally substituted benzene ring
• L is -CR 4 R 5 -CR 4 R 5 -CR 6 R 7 -CR 6 R 7 -CR 6 R 7 -CR 6 R 7 -*;
• R 1 is OH
• R 2 and R 3 which may be the same or different, are a hydrogen atom or an optionally substituted Ci- 6 alkyl group;
• ring A is a benzene ring which may have an additional substituent(s);
• ring B is a benzene ring which may have an additional substituent(s);
• ring C is a group represented by the following formula:
• Z 1 , Z 2 , Z 4 and Z 5 are carbon atoms; and in one of combinations, R cl and R c2 or R c3 and R c4 , the two groups which may be the same or different, are a hydrogen atom, or a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally halogenated Ci-6 alkyl group, an optionally halogenated Ci- 6 alkoxy group, or a C3-10 cycloalkyl group; and in the other combination, adjacent two of R cl , R c2 ,
• R c3 and R c4 are joined together to form an optionally substituted ring
• L is -CR 4 R 5 -CR 4 R 5 -CR 6 R 7 -CR 6 R 7 -CR 6 R 7 -CR 6 R 7 -*;
• R 1 is ORy
• Ry is an optionally substituted Ci- 6 alkyl group
• R 2 and R 3 which may be the same or different, are a hydrogen atom or an optionally substituted Ci- 6 alkyl group
• ring A is a benzene ring which may have an additional substituent(s);
• ring B is a benzene ring which may have an additional substituent(s);
• ring C is an optionally substituted benzene ring
• L is -CR 4 R 5 -CR 4 R 5 -CR 6 R 7 -CR 6 R 7 -CR 6 R 7 -CR 6 R 7 -*;
• compound (I) is Compound A or a salt thereof.
• compound (I) examples include compounds of Examples 1 to 68 and salts thereof.
• examples of such a salt include metal salts, ammonium salt, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids.
• Suitable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; and aluminum salt.
• Suitable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, and N,N'- dibenzylethylenediamine.
• Suitable examples of the metal with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid.
• Suitable examples of the salt with an organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and />-toluenesulfonic acid.
• Suitable examples of the salt with a basic amino acid include salts with arginine, lysine and ornithine, and suitable examples of the salt with an acidic amino acid include salts with aspartic acid and glutamic acid. Among them, preferable are pharmaceutically acceptable salts.
• examples thereof include inorganic salts such as alkali metal salts (for example, sodium salt, potassium salt) and alkaline earth metal salts (for example, calcium salt, magnesium salt, barium salt), ammonium salt and the like
• examples thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, or salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, and -toluenesulfonic acid.
• Compound (I) may be a crystal, and whether it has only one crystal form or a mixture of crystal forms, it is encompassed in compound (I).
• Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
• the cocrystal or cocrystal salt means a crystalline material composed of two or more unique solids at room temperature, each solid having different physical properties (for example, structure, melting point, heat of fusion, hygroscopicity, solubility and stability).
• the cocrystal or cocrystal salt can be produced by cocrystallization methods known per se.
• Compound (I) may be a solvate (for example, hydrate) or a non-solvate (for example, non-hydrate), and either is encompassed in compound (I).
• compounds labeled or substituted with an isotope for example, 3 H, H C, 14 C, 18 F, 35 S, 125 I
• compounds labeled or substituted with an isotope can be used as a tracer for use in positron emission tomography (PET) (PET tracer), and can be useful in fields such as medical diagnosis.
• PET positron emission tomography
• Ingredients and reagents used in each step of the following production method, and obtained compounds may be in their salt forms.
• Examples of such salts include salts or the like that are the same as salts of the inventive compound mentioned above.
• a compound obtained in each step When a compound obtained in each step is a free compound, it can be transformed into a salt of interest by a method known per se. On the other hand, when a compound obtained in each step is a salt, it can be transformed into a free form or another salt of interest by a method known per se.
• a compound obtained in each step can remain a reaction solution or be used for next reaction after being obtained as a crude product.
• a compound obtained in each step can be, in accordance with a normal method, isolated and/or purified from a reaction mixture by separating means such as concentration, crystallization, distillation, solvent extraction, fractional distillation, and chromatography.
• a racemic compound can be separated into chiral compounds using a chiral column for purification.
• ingredients and reagent compounds for each step are commercially available, commercial products can be used as they are.
• reaction time may be different depending on reagents and solvents to be used, but it is normally 1 minute to 7 days, and preferably 10 minutes to 8 hours if there is no particular description.
• reaction temperature may be different depending on reagents and solvents to be used, but it is normally -78°C to 300°C, and preferably - 78°C to 150°C if there is no particular description.
• pressure may be different depending on reagents and solvents to be used, but it is normally 1 atm to 20 atm, and preferably 1 atm to 3 atm if there is no particular description.
• a microwave synthesis apparatus such as Initiator manufactured by Biotage.
• Reaction temperature may be different depending on reagents and solvents to be used, but it is normally room temperature to 300°C, and preferably 50°C to 250°C if there is no particular description.
• Reaction time may be different depending on reagents and solvents to be used, but it is normally 1 minute to 48 hours, and preferably 1 minute to 8 hours if there is no particular description.
• a reagent is used in an amount of 0.5 equivalent to 20 equivalent, and preferably 0.8 equivalent to 5 equivalent relative to a substrate if there is no particular description.
• the reagent is used in an amount of 0.001 equivalent to 1 equivalent, and preferably 0.01 equivalent to 0.2 equivalent relative to a substrate.
• the reagent is used in a solvent amount.
• reaction of each step that reaction is carried out with no solvent, or in a dissolved or suspended state in an appropriate solvent if there is no particular description.
• Specific examples of the solvent include solvents described in Examples, or the following:
• alcohols methanol, ethanol, tert- butyl alcohol, 2-methoxyethanol and the like; ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1 ,2-dimethoxyethane and the like, cyclopentyl methyl ether;
• aromatic hydrocarbons chlorobenzene, toluene, xylene and the like;
• amides iV,iV-dimethylformamide, JV-methylpyrrolidone and the like;
• halogenated hydrocarbons dichloromethane, dichloroethane, carbon tetrachloride and the like;
• nitriles acetonitrile and the like
• sulfoxides dimethylsulfoxide and the like
• aromatic organic bases pyridine and the like;
• organic acids formic acid, acetic acid, trifluoroacetic acid and the like;
• inorganic acids hydrochloric acid, sulfuric acid and the like;
• esters ethyl acetate and the like
• ketones acetone, methyl ethyl ketone and the like.
• Two or more of the solvents described above may be mixed in an appropriate proportion for use.
• bases shown below or bases described in Examples are used: inorganic bases: sodium hydroxide, potassium phosphate, sodium phosphate, potassium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate,
• organic bases triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N- dimethylaniline, 1 ,4-diazabicyclo[2.2.2]octane, 1 ,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, potassium trimethylsilanolate and the like;
• metal alkoxides sodium ethoxide, potassium ter/-butoxide and the like;
• alkali metal hydrides sodium hydride and the like
• metal amides sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide and the like;
• organic lithiums n-butyllithium and the like.
• acids or acidic catalysts shown below, or acids or acidic catalysts described in Examples are used:
• inorganic acids hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like;
• organic acids acetic acid, trifluoroacetic acid, citric acid, 7-toluenesulfonic acid, 10- camphorsulfonic acid and the like;
• Lewis acids boron trifluoride-diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, titanium chloride, anhydrous iron chloride and the like.
• Reaction of each step is carried out in accordance with a method known per se, for example, methods described in The Fifth Series of Experimental Chemistry, vol. 13 to 19 (edited by The Chemical Society of Japan); The New Experimental Chemistry, vol. 14 to 15 (edited by The Chemical Society of Japan); Fine Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions; The Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I to VII (John Wiley & Sons Inc.); Modem Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (written by Jie Jack Li, published by OXFORD
• hydrolysis reaction When hydrolysis reaction is carried out in each step, an acid or a base is used as a reagent.
• an acid or a base is used as a reagent.
• formic acid, triethylsilane or the like may be added in order to reductively trap a secondarily produced tert- butyl cation.
• examples of the reagent to be used include acyl halide forms such as acid chlorides and acid bromides; and activated carboxylic acids in the form of acid anhydride, active ester, sulfuric ester or the like.
• Examples of the activator for a carboxylic acid include carbodiimide-based condensing agents such as 1-ethyl- 3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4- methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate ester-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPP A); benzotriazol-l-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-l-methyl-pyridinium iodide (Mukaiyama reagent); thionyl chloride; lower alkyl haloformates such as ethyl chloroformate; ⁇ 9-(7-aza
• additives such as 1-hydroxybenzotriazole (HOBt), N- hydroxysuccinimide (HOSu) and dimethylaminopyridine (DMAP) may be further added to the reaction.
• HOBt 1-hydroxybenzotriazole
• HOSu N- hydroxysuccinimide
• DMAP dimethylaminopyridine
• an electrophile such as a halogenated alkyl or an optionally substituted sulfonyloxy group (for example, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy and the like), and a nucleophile (for example, amine, alcohol, active methylene compound adjacent to an electroattracting group and the like) and a base (for example, organic base, metal alkoxide, inorganic base and the like) as reagents.
• the alkylation can also be carried out, after transforming an alcohol into an active ester, in the presence of a silyl enol ether and an acid such as 1,1,1 -trifluoro-A-
• [(trifluoromethyl)sulfonyl]methanesulfonamide can also be carried out in the presence of an alcohol, a silyl enol ether and a Lewis acid.
• protection or deprotection reaction of a functional group is carried out in accordance with a method known per se, for example, methods described in "Protective Groups in Organic Synthesis, 4th Ed.” (written by Theodora W. Greene, Peter G. M. Wuts), Wiley-Interscience, issued in 2007; “Protecting Groups 3rd Ed.” (written by P. J. Kocienski), Thieme, issued in 2004; and the like, or methods described in Examples.
• Examples of the protecting group of a hydroxy group of alcohol and the like and a phenolic hydroxy group include ether protecting groups such as methoxymethyl ether, benzyl ether, /er/-butyldimethylsilyl ether and
• tetrahydropyranyl ether tetrahydropyranyl ether
• carboxylate ester protecting groups such as acetate ester
• sulfonate ester protecting groups such as methanesulfonate ester
• carbonate ester protecting groups such as te -butylcarbonate.
• Examples of the protecting group of a carbonyl group of aldehyde include acetal protecting groups such as dimethyl acetal; and cyclic acetal protecting groups such as 1,3-dioxane.
• Examples of the protecting group of a carbonyl group of ketone include ketal protecting groups such as dimethyl ketal; cyclic ketal protecting groups such as 1,3- dioxane; oxime protecting groups such as O-methyloxime; and hydrazone protecting groups such as iV,/V-dimethylhydrazone.
• Examples of the protecting group of a carboxyl group include ester protecting groups such as methyl ester; and amide protecting groups such as N,N- dimethylamide.
• protecting group of thiol examples include ether protecting groups such as benzyl thioether; and ester protecting groups such as thioacetate ester,
• Examples of the protecting group of an amino group and an aromatic heterocycle such as imidazole, pyrrole and indole include carbamate protecting groups such as benzyl carbamate and tert- butylcarbamate; amide protecting groups such as acetamide; alkylamine protecting groups such as V-triphenylmethyl amine ; and sulfonamide protecting groups such as methanesulfonamide.
• the protecting group can be removed by a method known per se, for example, a method using acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N- methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or trialkylsilyl halide (for example, trimethylsilyl iodide, trimethylsilyl bromide), a reduction method, and the like.
• a strong base potassium trimethylsilanolate
• hydrogen-palladium catalyst or zerovalent palladium catalyst.
• examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),
• a phosphine ligand may be added to the reaction, and examples of such a phosphine include triphenylphosphine, 1,1'- bis(diphenylphosphino)ferrocene, and tri-o-tolylphosphine.
• a base may be added to the reaction, and examples of such a base include organic bases, inorganic bases and the like.
• examples of the metal catalyst to be used include palladium compounds such as
• a base may be added to the reaction, and examples of such a base include organic bases, inorganic bases and the like.
• examples of the boron source include pinacol diborane.
• a borate ester group can be transformed into a boric acid group using ammonium acetate and sodium periodate as reagents.
• examples of the metal catalyst to be used include palladium compounds such as palladium acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0) and l,r-bis(diphenylphosphino)ferrocene palladium(II) chloride; and cyanides such as sodium cyanide, zinc cyanide and copper cyanide.
• a phosphine ligand such as l,l'-bis(diphenylphosphino)ferrocene or zinc powder may be added to the reaction.
• Compound (I) can be produced by, for example, the following method.
• Compound (la), compound (lb) and compound (Ic), in which R 1 of compound (I) is a hydroxy group, ORy and NHRy, respectively, can be produced by the following method.
• Re represents an optionally substituted Ci- 6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, tert- butyl), allyl group or benzyl group, and the other symbols are as defined above.
• Rd represents an optionally substituted Ci- 6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, tert- butyl), allyl group or benzyl group; Rf represents a fert-butoxy group or benzyloxy group; and the other symbols are as defined above.
• Compound (Ii), in which R 2 and R 3 of compound (If) are hydrogen, can be produced by the following method.
• XI represents a chlorine atom, a bromine atom, a iodine atom, an optionally substituted sulfonyloxy group (for example, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy and the like);
• B1 represents a boron group (for example, potassium trifluoroborate (-BF3K), boronic acid group (-B(OH)2), borate ester group (-B(OR')2, wherein R' represents a Ci-6 alkyl group) or cyclic group thereof (for example, 4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl and the like); and the other symbols are
• Compound (II) can be produced by the following method.
• Compound (If) can be produced by the following method. wherein the symbols in the formula are as defined above.
• compound (I) in a step of producing compound (I) from ingredient compounds and/or production intermediates of compound (I), compound (I) can be synthesized, if desired, by singly carrying out reduction reaction, oxidation reaction, Wittig reaction, Homer-Emmons reaction, protection reaction, nucleophilic aromatic substitution reaction, nucleophilic addition reaction with carbanion, Grignard reaction, azidation reaction, reductive animation reaction, Claisen rearrangement reaction, Mitsunobu reaction, Wohl-Ziegler reaction, sulfonate esterification reaction, Staudinger reaction, halogenation reaction of hydroxy group, dehydration reaction, cyclization reaction or ring-closing metathesis reaction, or by carrying out two or more of them in combination, depending on various substituents that compound (I) may have.
• examples of the reducing agent to be used include iron; metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminium hydride (DIBAL-H), sodium borohydride and tetramethylammonium
• the reduction reaction may be carried out by a method using a catalyst such as palladium-carbon, Lindlar catalyst and the like.
• a catalyst such as palladium-carbon, Lindlar catalyst and the like.
• the reduction reaction may also be carried out by using iron and ammonium chloride.
• the reduction reaction may also be carried out by using the reducing agents described above and sodium phosphinate.
• the reduction reaction may also be carried out by, after making a mixed acid anhydride with isobutyl chloroformate or the like, using sodium borohydride. This step can be carried out by using only one of the reagents, or by using two or more of them in combination.
• examples of the oxidizing agent to be used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide and fe/7-butyl hydroperoxide; perchlorates such as
• chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high valent iodine reagents such as iodosylbenzene; reagents having manganese such as manganese dioxide and potassium permanganate; leads such as lead tetraacetate; reagents having chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC) and Jones reagent; halogen compounds such as iV-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complex; oxalyl chloride-dimethylsulfoxide; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ).
• DDQ 2,3-dichloro-5,6-dicyano-l,4-benzoquinone
• Examples of the Wittig reagent to be used include alkylidene phosphoranes.
• Alkylidene phosphoranes can be prepared by a method known per se, for example, by allowing a phosphonium salt to react with a strong base.
• examples of the reagent to be used include phosphonoacetate esters such as methyl
• dimethylphosphonoacetate and ethyl diethylphosphonoacetate dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides and organic lithiums.
• nucleophilic aromatic substitution reaction is carried out in each step, for the reagent, a nucleophile (for example, an amine) and a base (for example, an inorganic base, an organic base and the like) are used.
• a nucleophile for example, an amine
• a base for example, an inorganic base, an organic base and the like
• examples of the base to be used for generating carbanion include organic lithiums, metal alkoxides, inorganic bases, and organic bases.
• examples of the Grignard reagent include aryl magnesium halides such as phenyl magnesium bromide; and alkyl magnesium halides such as methyl magnesium bromide.
• the Grignard reagent can be prepared by a method known per se, for example, by allowing an alkyl halide or an aryl halide to react with a metal magnesium in ether or
• azidation agent examples include diphenylphosphoryl azide (DPPA), trimethylsilyl azide and sodium azide.
• DPPA diphenylphosphoryl azide
• the azidation reaction may be carried out by a method using diphenylphosphoryl azide and l,8-diazabicyclo[5,4,0]undec-7-ene (DBU), a method using trimethylsilyl azide and a Lewis acid, or the like.
• examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium
• cyanoborohydride hydrogen and formic acid.
• the substrate is an amine compound
• examples of the carbonyl compound to be used include, in addition to paraformaldehyde, aldehydes such as acetaldehyde and ketones such as
• examples of the amine to be used include ammonia; primary amines such as methylamine; and secondary amines such as dimethylamine.
• azodicarboxylate esters for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) and the like
• triphenylphosphine triphenylphosphine
• halogenating agent examples include iV-iodosuccinimide, iV-bromosuccinimide (NBS), A-chlorosuccinimide (NCS), bromine and sulfuryl chloride.
• NBS iV-iodosuccinimide
• NCS A-chlorosuccinimide
• bromine sulfuryl chloride.
• the reaction can be accelerated by adding heat, light, radical initiators such as benzoyl peroxide and azobisisobutyronitrile to the reaction.
• examples of the halogenating agent to be used include a hydrohalic acid and an acid halide of an inorganic acid; specifically, hydrochloric acid, thionyl chloride and phosphorus oxychloride for chlorination, and 48% hydrobromic acid for
• a method of obtaining an alkyl halide form from an alcohol through the action between triphenylphosphine and carbon tetrachloride, carbon tetrabromide or the like may be used.
• a method of synthesizing an alkyl halide form over the course of two-step reaction including converting an alcohol into a sulfonate ester, and allowing it to react with lithium bromide, lithium chloride or sodium iodide may also be used.
• examples of the sulfonylating agent to be used include methanesulfonyl chloride, p- toluenesulfonyl chloride, methanesulfonic anhydride and i-toluenesulfonic anhydride.
• examples of the dehydrating agent to be used include sulfuric acid, phosphorus pentaoxide, phosphorus oxychloride, 7V,/V-dicyclohexylcarbodiimide, alumina and
• sodium nitrite is used as a reagent, and an acidic solvent such as acetic acid and hydrochloric acid is used as a solvent.
• examples of the reagent include phosphines such as triphenylphosphine and water.
• a ruthenium compound such as Grubbs 1 st-generation catalyst, Grubbs 2nd-generation catalyst and Grubbs-Hoveyda 2nd-generation catalyst is used.
• reaction can be carried out by heating a reaction solution formed of the ingredients and solvent.
• examples of the base to be used for generating carbanion include organic lithiums, metal alkoxides, inorganic bases, and organic bases.
• Ingredient compounds and/or production intermediates of compound (I) may be in the salt forms, and although they are not particularly limited as long as the reaction is achieved, for example, salts and the like are used that are the same as salts that compound (I) and the like may form.
• configurational isomers (E, Z forms) may be generated, and at the time point where configurational isomers (E, Z forms) are generated, they can be isolated and purified by normal separating means such as extraction, recrystallization, distillation and chromatography to produce a pure compound.
• isomerization of the double bond can be advanced through heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical species catalyst, photoirradiation, a strong base catalyst or the like to obtain a corresponding pure isomer in accordance with the methods described in The New Experimental Chemistry, vol. 14 (edited by The Chemical Society of Japan), pp.251 to 253; The Fourth Series of Experimental Chemistry, vol.
• a target compound is obtained in the free form through the reactions described above, it may be transformed into a salt in accordance with a normal method, and when a target compound is obtained in the form of salt, it can be transformed into a free form or another salt in accordance with a normal method.
• Compound (I) obtained as such can be isolated or purified from the reaction solution by any known means, for example, solvent transition, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography or the like.
• reaction intermediates and ingredient compounds thereof can be isolated or purified from the reaction mixture in accordance with a method known per se, for example, by using a means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC) and moderate pressure preparative liquid chromatography (moderate pressure preparative LC).
• a means such as extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC) and moderate pressure preparative liquid chromatography (moderate pressure preparative LC).
• Compound (I) may be in the form of salt, and a salt of compound (I) can be produced according to a method known per se.
• compound (I) when compound (I) is a basic compound, it can be produced by adding an inorganic acid or organic acid, or when compound (I) is an acidic compound, it can be produced by adding an organic base or inorganic base.
• compound (I) When compound (I) is a solvate (for example, hydrate), a solvate of the target compound can be isolated from the reaction mixture by various methods such as distillation and crystallization after allowing the ingredient compounds to react in an appropriate solvent. A non-solvate can be produced by desolvation transition of a solvate through temperature rising, drying or the like.
• compound (I) may have enantiomers, individual enantiomers and a mixture thereof are of course all encompassed in the scope of the present invention, and these isomers may be subjected to optical resolution or may be produced individually, in accordance with a method known per se, if desired.
• compound (I) When compound (I) is present as configurational isomers, diastereomers, conformers or the like, they can be isolated in accordance with the separation or purification means described above, if desired. In addition, when compound (I) is a racemate, it can be isolated into S-form and R-form in accordance with a normal optical resolution means.
• the present invention encompasses a single stereoisomer and a mixture thereof.
• Compound (I) may be a prodrug.
• the prodrug refers to a compound that is converted into compound (I) as a result of reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, a compound that undergoes enzymatic oxidation, reduction, hydrolysis or the like to be converted into compound (I) and a compound that undergoes hydrolysis or the like by gastric acid or the like to be converted into compound (I).
• prodrug for compound (I) examples include compounds with an amino group in compound (I) acylated, alkylated and phosphorylated (for example, compounds with an amino group in compound (I) eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-l,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated and the like); compounds with a hydroxyl group in compound (I) acylated, alkylated, phosphorylated and borated (for example, compounds with a hydroxy group in compound (I) acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated and the like);
• cyclohexyloxycarbonylethyl esterified, methylamidated and the like can be produced from compound (I) according to a known method.
• a prodrug of compound (I) may also be one that is converted into compound (I) under physiological conditions as described in "Pharmaceutical Research and Development", vol. 7, Design of Molecules, pp.163-198, issued in 1990 by HIROKAWA SHOTEN.
• Compound (I) or a prodrug thereof (hereinafter, may be simply abbreviated as the inventive compound) can have an excellent NRF2 activating activity in vivo, and can be useful as a preventive or therapeutic agent for diseases associated with oxidative stress.
• the inventive compound is expected to be excellent in pharmacokinetics (for example, oral absorbability, drug half-life in blood, intracerebral transferability, metabolic stability) and have low toxicity (for example, acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity), and can be safely administered orally or parenterally to a mammal (for example, human, monkey, cattle, horse, pig, mouse, rat, hamster, rabbit, cat, dog, sheep, goat) as a medicament with no change or as a pharmaceutical
• pharmacokinetics for example, oral absorbability, drug half-life in blood, intracerebral transferability, metabolic stability
• low toxicity for example, acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity
• a mammal for example, human, monkey, cattle, horse, pig, mouse, rat, hamster, rabbit, cat, dog, sheep, goat
• composition formed by mixing the inventive compound with a pharmaceutically acceptable carrier or the like examples include sublingual, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal and intratumor administrations, administration to the vicinity of tumor and the like, and direct administration to the lesion.
• the inventive compound has a fixed conformation because it has a macrocyclic structure, and has an excellent NRF2 activating activity, and therefore, it can exhibit effectiveness in prevention or treatment for diseases associated with oxidative stress and caused by oxidative stress, such as hepatic disease (for example, hepatitis (for example, non-alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, hepatitis B, hepatitis C, hepatic veno-occlusive disease), hepatic cirrhosis, bile duct disease (for example, primary sclerosing cholangitis (PSC)), cardiovascular disease (for example, heart failure, pulmonary arterial hypertension, myocardial infarction, arteriosclerosis, angina pectoris, brain infarction, cerebral hemorrhage, aortic aneurysm, aortic dissection, nephrosclerosis (for example, hypertensive nephrosclerosis), peripheral arterial disease
• osteoporosis systemic bone disease, bone fracture
• viral infection for example,
• HIV virus HIV virus, cytomegalovirus, respiratory syncytial virus, influenza vims
• heavy metal poisoning for example, lead poisoning, mercury poisoning
• pesticide poisoning for example, paraquat poisoning, organophosphorus poisoning
• drug- induced disorder for example, drug-induced renal disorder, drug-induced hepatic disorder (for example, hepatic disorder due to acetaminophen), drug-induced lung disorder, orthopedic disease (for example, low back pain, sciatic neuralgia, intervertebral disk displacement, neck ache, stiff shoulder), pain (for example, fibromyalgia, neuropathic pain), ischemia-reperfusion injury and shock upon organ transplantation and surgery, aging, progeria, hyperanakinesia (for example, sarcopenia), urologic disease (for example, urination disorder), dental disease (for example, periodontal disease), otolaryngologic disease (for example, hearing difficulty), altitude sickness, chronic fatigue syndrome, and thinning
• the inventive compound can exhibit enhancement of the effect of cancer treatment and the effect of improving survival rate by a combined use with an immunity anticancer agent (for example, immune checkpoint inhibiting antibody). Further, it can exhibit a regeneration promoting activity (for example, hepatic regeneration promoting agent after hepatectomy).
• an immunity anticancer agent for example, immune checkpoint inhibiting antibody
• a regeneration promoting activity for example, hepatic regeneration promoting agent after hepatectomy.
• the inventive compound can be, based on its NRF2 activating activity, useful as a preventive or therapeutic agent for hepatic disease (for example, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, drug-induced hepatic disorder), bile duct disease (for example, primary sclerosing cholangitis (PSC)), cardiovascular disease (for example, heart failure or pulmonary arterial
• hepatic disease for example, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, drug-induced hepatic disorder
• bile duct disease for example, primary sclerosing cholangitis (PSC)
• cardiovascular disease for example, heart failure or pulmonary arterial
• lung disease for example, chronic obstructive pulmonary disease (COPD)
• kidney disease for example, chronic kidney disease (CKD) or acute kidney injury (AKI)
• acetaminophen poisoning central nervous system disease (for example, Parkinson's disease, Alzheimer's disease, cerebral stroke), mitochondrial disease (for example, Friedreich motor ataxia, mitochondrial myopathy), inflammatory disease (for example, multiple sclerosis, inflammatory bowel disease (IBD)), sickle cell disease, or the like.
• COPD chronic obstructive pulmonary disease
• kidney disease for example, chronic kidney disease (CKD) or acute kidney injury (AKI)
• acetaminophen poisoning for example, central nervous system disease (for example, Parkinson's disease, Alzheimer's disease, cerebral stroke)
• mitochondrial disease for example, Friedreich motor ataxia, mitochondrial myopathy
• inflammatory disease for example, multiple sclerosis, inflammatory bowel disease (IBD)
• sickle cell disease or the like.
• the dosage of the inventive compound varies depending on an administration route, symptom and the like.
• the dosage is, for example, 0.001 to 1000 mg/kg body weight/day, preferably 0.01 to 100 mg/kg body weight/day, and further preferably 0.1 to 10 mg/kg body weight/day. This amount can be administered in one to three portions per day.
• a medicament containing the inventive compound may be used as the inventive compound solely or as a pharmaceutical composition formed by mixing the inventive compound with a pharmaceutically acceptable carrier in accordance with a method (for example, the methods described in The Pharmacopoeia of Japan) that is known per se as a method of producing a pharmaceutical formulation.
• the medicament containing the inventive compound can be safely administered orally or parenterally (for example, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal and intraperitoneal administrations, and administration to the lesion) in the form of, for example, tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal or the like), pill, powder, granule, capsule
• release control formulation for example, immediate-release formulation, sustained- release formulation, sustained-release microcapsule
• aerosol for example, film (for example, orally disintegrating film, oral mucosa-adhesive film), injection (for example, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip infusion, transdermal absorption type formulation, ointment, lotion, patch, suppository (for example, rectal suppository, vaginal suppository), pellet, nasal formulation, pulmonary formulation (inhalant), eye drop or the like.
• formulation materials for the "pharmaceutically acceptable carrier" described above, a variety of organic or inorganic carriers that have been conventionally used as formulation materials (starting materials) are used.
• an excipient, a lubricant, a binder, a disintegrant and the like are used for a solid formulation, and a solvent, a dissolving aid, a suspending agent, an isotonizing agent, a buffering agent, a soothing agent and the like are used for a liquid formulation.
• formulation additives such as a preservative, an antioxidant, a colorant and a sweetening agent can also be used.
• excipient examples include lactose, white sugar, D-mannitol, starch, com starch, crystalline cellulose and light anhydrous silicic acid.
• lubricant examples include magnesium stearate, calcium stearate, talc and colloidal silica.
• binder examples include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
• polyvinylpyrrolidone starch, sucrose, gelatin, methyl cellulose and sodium carboxymethyl cellulose.
• disintegrant examples include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch and L-hydroxypropyl cellulose.
• solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, com oil and olive oil.
• dissolving aid examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol,
• suspending agent examples include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
• surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride and glycerin monostearate
• hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
• Examples of the isotonizing agent include glucose, D-sorbitol, sodium chloride, glycerin and D-mannitol.
• Examples of the buffering agent include buffering solutions of phosphate salt, acetate salt, carbonate salt and citrate salt.
• Examples of the soothing agent include benzyl alcohol.
• preservative examples include para-oxybenzoate esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid and sorbic acid.
• antioxidant examples include sulfite salt, ascorbic acid, a-tocopherol.
• the pharmaceutical composition can be produced in accordance with a normal method by adding the inventive compound in a proportion of normally 0.01 to 100% (w/w) and preferably 0.1 to 95% (w/w) relative to the whole amount of the formulation although the proportion varies depending on the dosage from, administration method, carrier and the like.
• the inventive compound may be used in combination with another active ingredient (hereinafter, abbreviated as a concomitant drug).
• a compound that may have a preventive and/or therapeutic effect against oxidative stress diseases or a salt thereof can be any compound that may have a preventive and/or therapeutic effect against oxidative stress diseases or a salt thereof.
• Examples of the compound that may have a preventive and/or therapeutic effect against oxidative stress diseases or a salt thereof include cardiotonic agents such as digoxin, b agonists such as dobutamine, b inhibitors such as carvedilol, vasodilator drugs such as nitroglycerin, prostacyclin and riociguat, angiotensin converting enzyme inhibitors such as ramipril, angiotensin II receptor antagonists such as candesartan, diuretic drugs such as hydrochlorothiazide and furosemide, calcium receptor antagonists such as amlodipine, mineralocorticoid receptor antagonists such as eplerenone, endothelin receptor antagonists such as bosentan, anticoagulant drugs such as rivaroxaban, antiplatelet drugs such as clopidogrel, antidiabetic drugs such as metformin, alogliptin, pioglitazone and ipragliflozin, dyslipidemia improving
• the dosage can be reduced as compared to single administration of the inventive compound or a concomitant drug
• the drug to be combined with the inventive compound can be selected depending on symptoms of the patient (mild symptom, severe symptom and the like);
• the treatment duration can be set long by selecting a concomitant drug having an action mechanism different from that of the inventive compound
• a sustained treatment effect can be designed by selecting a concomitant drug having an action mechanism different from the inventive compound.
• administration time of the inventive compound and the concomitant drug is not limited, and the inventive compound or a pharmaceutical composition thereof and the concomitant drug or a pharmaceutical composition thereof may he administered to an administration subject simultaneously, or may be administered with time difference.
• the dosage of the concomitant drug may be determined in accordance with a dosage that is clinically used, and can be appropriately selected depending on an administration subject, administration route, disease, combination and the like.
• the administration mode of the combination agent according to the present invention is not particularly limited, and it is sufficient that the inventive compound and the concomitant drug are combined upon administration.
• Examples of such an administration mode include (1) administration of a single formulation obtained by simultaneously formulating the inventive compound and the concomitant drug, (2) simultaneous administration of two kinds of formulations obtained by separately formulating the inventive compound and the concomitant drug through the same administration route, (3) administration of two kinds of formulations obtained by separately formulating the inventive compound and the concomitant drug through the same administration route but with time difference, (4) simultaneous administration of two kinds of formulations obtained by separately formulating the inventive compound and the concomitant drug through different administration routes, (5) administration of two kinds of formulations obtained by separately formulating the inventive compound and the concomitant drug through different administration routes with time difference (for example, administration of the inventive compound and the concomitant drug in the order described, or in the reverse order) and the like.
• the combination agent according to the present invention has low toxicity.
• inventive compound or(and) the concomitant drug described above can be combined with a pharmacologically acceptable carrier according to a known method to prepare a pharmaceutical composition such as a tablet (including sugar- coated tablet and film-coated tablet), powder, granule, capsule (including soft capsule), liquid, injection, suppository, sustained-release agent and the like.
• a pharmaceutical composition such as a tablet (including sugar- coated tablet and film-coated tablet), powder, granule, capsule (including soft capsule), liquid, injection, suppository, sustained-release agent and the like.
• a pharmaceutical composition such as a tablet (including sugar- coated tablet and film-coated tablet), powder, granule, capsule (including soft capsule), liquid, injection, suppository, sustained-release agent and the like.
• a pharmaceutical composition such as a tablet (including sugar- coated tablet and film-coated tablet), powder, granule, capsule (including soft capsule), liquid, injection, suppository, sustained-release agent and the like.
• Examples of the pharmacologically acceptable carrier that may be used for production of the combination agent according to the present invention include a variety of organic or inorganic carrier substances that are conventionally used as formulation materials.
• an excipient, a lubricant, a binder and a disintegrant can be used for a solid formulation.
• a solvent, a dissolving aid, a suspending agent, an isotonizing agent, a buffering agent, a soothing agent and the like can be used.
• normal additives such as a preservative, an antioxidant, a colorant, a sweetening agent, an adsorbent, and a wetting agent can be appropriately used in an appropriate amount.
• excipient examples include lactose, white sugar, D-mannitol, starch, com starch, crystalline cellulose and light anhydrous silicic acid.
• lubricant examples include magnesium stearate, calcium stearate, talc and colloidal silica.
• binder examples include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
• polyvinylpyrrolidone starch, sucrose, gelatin, methyl cellulose and sodium carboxymethyl cellulose.
• disintegrant examples include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch and L-hydroxypropyl cellulose.
• solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil, com oil and olive oil.
• dissolving aid examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, tris-aminomethane, cholesterol,
• suspending agent examples include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride and glycerin monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
• surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride and glycerin monostearate
• hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose.
• isotonizing agent examples include glucose, D-sorbitol, sodium chloride, glycerin and D-mannitol.
• buffering agent examples include buffering solutions of phosphate salt, acetate salt, carbonate salt and citrate salt.
• Examples of the soothing agent include benzyl alcohol.
• preservative examples include para-oxybenzoate esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid and sorbic acid.
• antioxidant examples include sulfite salt, ascorbic acid, a-tocopherol.
• the mixing ratio of the inventive compound and the concomitant drug in the combination agent according to the present invention can be appropriately selected depending on an administration subject, administration route, disease and the like.
• the content of the inventive compound in the combination agent according to the present invention varies depending on the form of the formulation, but is normally from about 0.01 to 100% by weight, preferably from about 0.1 to 50% by weight, and further preferably approximately from about 0.5 to 20% by weight relative to the entire formulation.
• the content of the concomitant drug in the combination agent according to the present invention varies depending on the form of the formulation, but is normally from about 0.01 to 100% by weight, preferably from about 0.1 to 50% by weight, and further preferably approximately from about 0.5 to 20% by weight relative to the entire formulation.
• the content of additives such as a carrier in the combination agent according to the present invention varies depending on the form of the formulation, but is normally from about 1 to 99.99% by weight, and preferably approximately from about 10 to 90% by weight relative to the entire formulation.
• inventive compound and the concomitant drug are separately formulated, the contents thereof may be the same as above.
• room temperature normally indicates about 10°C to about 35°C.
• Ratios shown in mixed solvents indicate volume ratios unless otherwise noted. % indicates % by weight unless otherwise noted.
• CDCh deuterated chloroform
• DM AP N, A-dimethylamino-4-aminopyridine
• HATU 2-(7-azabenzotriazol- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium hexafluorophosphate
• KHMDS potassium hexamethyl disilazide
• DIPEA diisopropylethylamine
• NBS A-bromosuccinimide
• Preparative HPLC was done on Waters auto purification instrument. Column name: YMC Triart C18 (100 x 30 mm, 5pm) operating at ambient temperature and flow rate of 30 mL/min.
• Preparative HPLC was done on Waters auto purification instrument. Column name: REFLECT I CELLULOSE C (250 x 21.2 mm, 5pm) operating at ambient temperature and flow rate of 16 mL/min.
• Preparative HPLC was done on Agilent Prep-HPLC.
• Chiral HPLC was carried out on Waters Manual purification system with 2545 Quaternary Gradient Pump and 2489 UV Detector.
• Isocratic Profile: A : B 30% : 70%, same composition was held up for the total runtime of 35 min.
• Detector was programmed at compound's wavelength i.e. 293 nm and sample preparation was done by using Methanol and DCM.
• MS was measured by LC/MS.
• ESI method or APCI method was used for ionization method.
• measured values are described.
• molecular ion peaks such as [M+H] + and [M-H] ) are observed, but for example, in the case of a compound having a tert-butoxycarbonyl group, a peak for which a terl- butoxycarbonyl group or tert- butyl group is desorbed may be observed as a fragment ion, and in the case of a compound having a hydroxy group, a peak for which FbO is desorbed may be observed as a fragment ion.
• the molecular ion peak of the free form or a fragment ion peak is normally observed.
• the unit of sample concentration (c) in optical rotation ([(X]D) is g/100 mL.
• the powder X-ray diffraction pattern was measured by using Cu-Ka characteristic X-ray of Rigaku Ultima IV, and characteristic peaks are described.
• toluenesulfonyl chloride (19.4 g) and triethylamine (8.6 g) were added thereto, and the reaction mixture was further stirred at 60°C for 3 hours.
• triethylamine (8.6 g) and /Mxtluenesulfonyl chloride (19.4 g) were further added, and the reaction solution was stirred at 50°C for 5 hours.
• ethyl acetate was added to the mixture was added ethyl acetate at room temperature, and the reaction mixture was washed with water and saturated brine, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure.
• the extract solution was washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure.
• the residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column

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