WO2018030550A1 - Heterocyclic compounds with an ror(gamma)t modulating activity - Google Patents

Heterocyclic compounds with an ror(gamma)t modulating activity Download PDF

Info

Publication number
WO2018030550A1
WO2018030550A1 PCT/JP2017/029695 JP2017029695W WO2018030550A1 WO 2018030550 A1 WO2018030550 A1 WO 2018030550A1 JP 2017029695 W JP2017029695 W JP 2017029695W WO 2018030550 A1 WO2018030550 A1 WO 2018030550A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
ring
salt
reaction
Prior art date
Application number
PCT/JP2017/029695
Other languages
French (fr)
Inventor
Satoshi Yamamoto
Junya Shirai
Mitsunori Kono
Zenyu Shiokawa
Tomoya Yukawa
Takashi Imada
Nobuyuki Negoro
Tsuneo Oda
Satoshi Sasaki
Yoshi Nara
Shinkichi Suzuki
Ayumu Sato
Naoki Ishii
Akito SHIBUYA
Yasuo Nakagawa
Derek Cole
Tony Gibson
Anthony IVETAC
Steve SWANN
John Tyhonas
Original Assignee
Takeda Pharmaceutical Company Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Publication of WO2018030550A1 publication Critical patent/WO2018030550A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—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 two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a heterocyclic compound which may have an RORyt modulating activity, a medicament containing the compound, and the like.
  • Thl7 cell and inflammatory cytokines produced thereby cause a decrease in QOL as a severe etiology cell and factor accompanying enhancement of a systemic new immune response, in various autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis and psoriasis.
  • IBD inflammatory bowel disease
  • rheumatoid arthritis multiple sclerosis
  • psoriasis a systemic new immune response
  • the existing therapeutic drugs show only limited effects, and therefore, the earliest possible development of a novel therapeutic drug has been desired.
  • Retinoid-related Orphan Receptor (ROR) yt which is one of the orphan nuclear receptors, plays an important role in the
  • Thl7 cells differentiated by Thl7 cells and production of IL-17A/IL-17F. That is, it has been reported that RORyt is mainly expressed in Thl7 cells and functions as a transcription factor of IL-17A and IL-17F, as well as a master modulator of Thl7 cell
  • a medicament that inhibits the action of RORyt is expected to show a treatment effect on various immune diseases by suppressing differentiation and activation of Thl7 cells.
  • Patent document 1 discloses the following compound having an NAMPT inhibitory action and useful as chemotherapy drugs (DNA damaging agent, .cell rescuing agent, cytotoxic agent) , a therapeutic drug for hyperproliferative disorder due to an abnormal cell proliferation action, or a prophylactic or therapeutic agent for malignant tumor, ovarian cancer, breast cancer, colorectal cancer, Hodgkin' s disease, inflammatory disease, IBS, IBD, rheumatoid arthritis and the like:
  • chemotherapy drugs DNA damaging agent, .cell rescuing agent, cytotoxic agent
  • a therapeutic drug for hyperproliferative disorder due to an abnormal cell proliferation action or a prophylactic or therapeutic agent for malignant tumor, ovarian cancer, breast cancer, colorectal cancer, Hodgkin' s disease, inflammatory disease, IBS, IBD, rheumatoid arthritis and the like:
  • Non-patent document 1 discloses the following compound having a p38 ⁇ MAP kinase inhibitory action, and useful as a prophylactic or therapeutic agent for inflammatory diseases such as rheumatoid arthritis, IBD and . the like:
  • Patent document 2 discloses the following compound having a ⁇ -38 ⁇ activity-inducing action, and useful as a prophylactic or therapeutic agent for inflammation-associated diseases (IBD, rheumatoid arthritis, Crohn's disease, Alzheimer's disease etc . ) :
  • Patent document 3 discloses the following compound having an NMDA NR2B antagonistic action, and useful as a prophylactic or therapeutic agent for migraine, depression, anxiety,
  • Non-patent document 2 discloses the following compound
  • Non-patent document 3 discloses the following compound:
  • Non-patent document 4 discloses the following compound:
  • Non-patent document 5 discloses the following compound
  • Non-patent document 6 discloses the following compound
  • Non-patent document 7 discloses the following compound: [0022]
  • Non-patent document 8 discloses the following compound:
  • Non-patent document 9 discloses the following compound:
  • Non-patent document 10 discloses the following compound
  • Non-patent document 11 discloses the following compound
  • Non-patent document 12 discloses the following compound [0032]
  • Non-patent document 13 discloses the following compound:
  • Non-patent document 14 discloses the following compound:
  • Non-patent document 15 discloses the following compound:
  • Non-patent document 16 discloses the following compound:
  • Non-patent document 17 discloses the following compound:
  • Non-patent document 18 discloses the following compound:
  • non-patent document 19 discloses the following compound
  • Non-patent document 20 discloses the following compound.
  • Non-patent document 21 discloses the following compound:
  • Non-patent document 22 discloses the following compound:
  • Patent document 4 discloses the following compound useful s a prophylactic or therapeutic agent for PPARG associated diseases (diabetes, insulin resistance, obesity, inflammation etc. ) :
  • Non-patent document 23 discloses the following compound useful as a PPARy antagonist:
  • Patent document 5 discloses the following compound:
  • Non-patent document 24 discloses the following compound useful as a selective cannabinoid receptor 2 agonist:
  • Patent document 6 discloses the following compound having a modulating action on glucocorticoid receptor, AP-1, NF-KB activity, and useful as a prophylactic or therapeutic agent for inflammation, immune system disease, cancer and the like:
  • Patent document 7 discloses the following compound having a cannabinoid receptor modulating action, and useful as a prophylactic or therapeutic agent for central nervous system pain, addiction, cancer (including melanoma) , inflammation and the like:
  • Patent document 8 discloses the following compound:
  • Non-patent document 25 discloses the following compound useful as a selective cannabinoid receptor 2 agonist:
  • Patent document 9 discloses the following compound having an RORy activity inhibitory action, and useful as a
  • inflammatory diseases e.g., rheumatoid arthritis, Crohn's disease, IBD etc.
  • inflammatory diseases e.g., rheumatoid arthritis, Crohn's disease, IBD etc.
  • Patent document 10 discloses the following compound useful as an SMYD protein inhibitor as an antitumor drug:
  • Non-patent document 26 discloses the following compound:
  • Non-patent document 27 discloses the following compound:
  • Non-patent document 28 discloses the following compound:
  • the present invention aims to provide a compound that may have an RORyt modulating action and may be useful as a
  • prophylactic or therapeutic agent for cancer and the like.
  • ⁇ ' represented by the following formula ( ⁇ ') or a salt thereof may have an RORyt modulating action based on its specific chemical structure, and may have efficacy as a prophylactic or
  • the present invention relates to the following.
  • ring A is an optionally further substituted ring
  • L 1 is a bond, optionally halogenated C 1 _ 2 alkylene, -NH- or -0-;
  • R 1 and R 2 are each independently a hydrogen atom or a substituent
  • R 1 and R 2 may be bonded together with an adjacent carbon atom to form an optionally further substituted ring, or R 1 and R 2 may be joined together to form an oxo group;
  • ring D is an optionally further substituted ring
  • R 4 is a hydrogen atom or a substituent
  • R 3 is a substituent
  • X is a carbon atom or a nitrogen atom
  • n is an integer of 1 or 2;
  • ring B is an optionally further substituted 6- or 7- membered oxygen-containing heterocycle
  • Y 1 , Y 2 and Y 3 are each independently a carbon atom or a nitrogen atom;
  • ring C is an optionally further substituted 6-membered aromatic ring
  • L 1 is a bond
  • R 1 is a hydrogen atom or a hydroxymethyl group
  • R 2 is a hydrogen atom
  • R 6 is a hydrogen atom, -C0 2 C 2 H 5 , -CH 2 OH, -C0 2 H, -CONH 2 or -
  • L is -S0 2 -
  • R is -CH 3 or -C 2 H 5 , or a salt thereof.
  • X is a carbon atom or a nitrogen atom
  • n is an integer of 1 or 2;
  • ring B is an optionally further substituted 6- or 7- membered oxygen-containing heterocycle
  • Y 1 , Y 2 and ⁇ 3 are each independently a carbon atom or a nitrogen atom
  • ring C is an optionally further substituted 6-membered aromatic ring, or a salt thereof (sometimes to be abbreviated as "compound (I)" in the present specification).
  • a medicament comprising the compound of [1] or a salt thereof .
  • a method of modulating RORyt in a mammal comprising administering an effective amount of the compound of [1] or a salt thereof to the mammal.
  • [12] A method for the prophylaxis or treatment of cancer in a mammal, comprising administering an effective amount of the compound of [1] or a salt thereof to the mammal.
  • the compound of the present invention may have an RORyt modulating action and may be useful as a prophylactic or therapeutic agent for cancer and the like.
  • each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following
  • halogen atom examples include fluorine, chlorine, bromine and iodine.
  • examples of the "C 1 _ 6 alkyl ' group” include methyl, ethyl, propyl, isopropyl, butyl,
  • examples of the "optionally halogenated C 1 _ 6 alkyl . group” include a C 1 _ 6 alkyl group
  • examples of the "C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-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.
  • examples of the "C 2 - 6 alkynyl group” 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 .
  • examples of the "C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl and adamantyl.
  • examples of the "optionally halogenated C 3-10 cycloalkyl group” include a C 3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2- difluorocyclopropyl, 2 , 3-difluorocyclopropyl , cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • examples of the "C 3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl , cyclopentenyl , cyclohexenyl, cycloheptenyl and cyclooctenyl .
  • examples of the "C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.
  • examples of the "C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl and phenylpropyl .
  • examples of the "C 1 _ 6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • examples of the "optionally halogenated C 1 _ 6 alkoxy group" include a C 1 _ 6 alkoxy group
  • examples of the "C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
  • examples of the "C 1 _ 6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
  • examples of the "optionally halogenated C 1 _ 6 alkylthio group” include a C 1 _ 6 alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylthio,
  • difluoromethylthio trifluoromethylthio, ethylthio,- propylthio, isopropylthio, butylthio, 4 , 4 , 4-trifluorobutylthio, pentylthio and hexylthio.
  • examples of the "C 1 _ 6 alkyl- carbonyl group” include acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 3-methylbutanoyl , 2-methylbutanoyl, 2 , 2-dimethylpropanoyl, hexanoyl and heptanoyl.
  • examples of the "optionally halogenated C 1 _ 6 alkyl-carbonyl group” include a C 1 _ 6 alkyl- carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl , trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
  • examples of the "C 1 _ 6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl , butoxycarbonyl ,
  • examples of the "C 6-14 aryl- carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
  • examples of the "C 7-16 aralkyl-carbonyl group” include phenylacetyl and
  • examples of the "5- to 14- membered aromatic heterocyclylcarbonyl group” include
  • examples of the "3- to 14- membered non-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and
  • examples of the "mono- or di-C 1 _ 6 alkyl-carbamoyl group” include methylcarbamoyl ,
  • examples of the "mono- or di-C 7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl .
  • examples of the "C 1 _ 6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl , isopropylsulfonyl , butylsulfonyl, sec- butylsulfonyl and tert-butylsulfonyl .
  • examples of the "optionally halogenated C 1 _ 6 alkylsulfonyl group” include a C 1 _ 6
  • alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include
  • methylsulfonyl difluoromethylsulfonyl , trifluoromethylsulfonyl, ethylsulfonyl , propylsulfonyl , isopropylsulfonyl , butylsulfonyl, 4 , 4 , 4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl .
  • examples of the "C 6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl .
  • substituted include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an
  • optionally substituted heterocyclic group an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally
  • “optionally substituted hydrocarbon group” include a C 1 _ 6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-10
  • cycloalkyl group a C 3-10 cycloalkenyl group, a C 6-14 aryl group and a C 7-16 aralkyl group.
  • examples of the "optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent ( s ) selected from the following substituent group A.
  • a C 6-14 aryloxy group e.g., phenoxy, naphthoxy
  • a C 7-16 aralkyloxy group e.g., benzyloxy
  • a C 1 _ 6 alkyl-carbonyloxy group e.g., acetoxy
  • a C 6-14 aryl-carbonyloxy group e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy
  • a C 6-14 aryl-carbonyloxy group e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy
  • a C 1 _ 6 alkoxy-carbonyloxy group e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy
  • a C 1 _ 6 alkoxy-carbonyloxy group e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy
  • a aryl-carbamoyloxy group e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy
  • a 5- to 14-membered aromatic heterocyclylcarbonyloxy group e.g., nicotinoyloxy
  • a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy
  • an optionally halogenated C 1 _ 6 alkylsulfonyloxy group e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy
  • a C 6-14 arylsulfonyloxy group optionally substituted by a C 1 _ 6 alkyl group e.g., phenylsulfonyloxy, toluenesulfonyloxy
  • a C 6-14 aryloxy-carbonyl group e.g., phenyloxycarbonyl , 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl ) ,
  • a C 7-16 aralkyloxy-carbonyl group e.g., benzyloxycarbonyl, phenethyloxycarbonyl ) , .
  • a 5- to 14-membered aromatic heterocyclylcarbamoyl group e.g., pyridylcarbamoyl, thienylcarbamoyl
  • a 5- to 14-membered aromatic heterocyclylsulfonyl group e.g., pyridylsulfonyl, thienylsulfonyl
  • an optionally halogenated C 1 _ 6 alkylsulfinyl group e.g., a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl )
  • an optionally halogenated C 1 _ 6 alkylsulfinyl group e.g., pyridylsulfonyl, thienylsulfonyl
  • a C 6-14 arylsulfinyl group e.g., phenylsulfinyl , 1- naphthylsulfinyl, 2-naphthylsulfinyl
  • arylsulfinyl group e.g., phenylsulfinyl , 1- naphthylsulfinyl, 2-naphthylsulfinyl
  • a 5- to 14-membered aromatic heterocyclylsulfinyl group e.g., pyridylsulfinyl, thienylsulfinyl
  • a mono- or di-C 1 _ 6 alkylamino group e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino,
  • a C 1 _ 6 alkyl-carbonylamino group e.g., acetylamino
  • a C 6-14 aryl-carbonylamino group e.g., phenylcarbonylamino, naphthylcarbonylamino
  • a C 1 _ 6 alkylsulfonylamino group e.g., methylsulfonylamino, ethylsulfonylamino
  • a C 6-14 arylsulfonylamino group optionally substituted by a C 1 _ 6 alkyl group e.g., phenylsulfonylamino
  • the number of the above-mentioned substituents in the "optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3.
  • the respective substituents may be the same or different .
  • heterocyclic group (including “heterocyclic group” of
  • optionally substituted heterocyclic group include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • examples of the "aromatic heterocyclic group” include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • aromatic heterocyclic group examples include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, 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, triazinyl and the like;
  • thiazolopyridinyl imidazopyrazinyl , imidazopyrimidinyl , thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2, 3-b] thienyl, phenoxathiinyl, indolyl, isoindolyl, lH-indazolyl , purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl , quinoxalinyl ,
  • phenanthridinyl acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.
  • non- aromatic heterocyclic group examples include a 3- to 14-membered
  • non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • non-aromatic heterocyclic group examples include 3- to 8-membered monocyclic non-aromatic
  • heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl,
  • examples of the "nitrogen- containing heterocyclic, group” include the “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom.
  • examples of the "optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent ( s ) selected from the
  • substituted heterocyclic group is, for example, 1 to 3.
  • the respective substituents may be the same or different.
  • examples of the "acyl group” include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having "1 or 2 substituents selected from a C 1 _ 6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C 1 - 6 alkoxy group, a hydroxy group, a a halogen
  • acyl group also include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group.
  • the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group
  • the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group
  • hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group.
  • acyl group examples include a formyl group, a carboxy group, a C 1 _ 6 alkyl-carbonyl group, a C 2-6 alkenyl-carbonyl group (e.g., crotonoyl) , a C 3-1 o cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl , cycloheptanecarbonyl) , a C 3-10
  • cycloalkenyl-carbonyl group e.g., 2-cyclohexenecarbonyl
  • C 6-14 aryl-carbonyl group e.g., 2-cyclohexenecarbonyl
  • C 7-16 aralkyl-carbonyl group e.g., 2-cyclohexenecarbonyl
  • 5- to 14-membered aromatic heterocyclylcarbonyl group e.g., 2-cyclohexenecarbonyl
  • 3- to 14- membered non-aromatic heterocyclylcarbonyl group e.g., 2-cyclohexenecarbonyl
  • a C 6-14 aryl-carbonyl group e.g., 2-cyclohexenecarbonyl
  • C 7-16 aralkyl-carbonyl group e.g., 2-cyclohexenecarbonyl
  • 5- to 14-membered aromatic heterocyclylcarbonyl group e.g., 2-cyclohexenecarbon
  • phenyloxycarbonyl, naphthyloxycarbonyl ) a C 7-16 aralkyloxy- carbonyl group (e.g., benzyloxycarbonyl , phenethyloxycarbonyl ) , a carbamoyl group, a mono- or di-C 1 _ 6 alkyl-carbamoyl group, a mono- or di-C 2-6 alkenyl-carbamoyl group (e.g.,
  • diallylcarbamoyl a mono- or di-C 3-10 cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl ) , a mono- or di-Cs-14 aryl- carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C 7 _ 16 aralkyl-carbamoyl group, a 5- to 14-membered aromatic
  • heterocyclylcarbamoyl group e.g., pyridylcarbamoyl
  • a heterocyclylcarbamoyl group e.g., pyridylcarbamoyl
  • thiocarbamoyl group a mono- or di-C 1 _ 6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl) , a mono- or di-C 2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl ) , a mono- or di-C 3-10
  • cycloalkyl-thiocarbamoyl group e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl
  • a mono- or di-C 6-14 aryl-thiocarbamoyl group e.g., phenylthiocarbamoyl
  • a mono- or di-C 7-16 aralkyl- thiocarbamoyl group e.g., benzylthiocarbamoyl
  • heterocyclylthiocarbamoyl group e.g., pyridylthiocarbamoyl
  • a sulfino group e.g., pyridylthiocarbamoyl
  • C 1 _ 6 alkylsulfinyl group e.g., methylsulfinyl, ethylsulfinyl
  • a sulfo group a C 1 _ 6 alkylsulfonyl group
  • C 6 - 14 arylsulfonyl group a phosphono group and a mono- or di-C 1 _ 6 alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) .
  • examples of the "optionally substituted amino group” include an amino group optionally having "1 or 2 substituents selected from a C 1 _ 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 C 1 _ 6 alkyl-carbonyl group, a C 6-14 aryl- carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C 1 _ 6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1 - 6 alkyl-carbamoyl group, a mono- or di-C 7-16
  • optionally substituted amino group examples include an amino group, a mono- or di- (optionally
  • halogenated C 1 _ 6 alkyl amino group (e.g., methylamino,
  • heterocyclylcarbonylamino group e.g., nicotinoylamino
  • isonicotinoylamino a mono- or di-3- to 14-membered non- aromatic heterocyclylcarbonylamino group (e.g.,
  • piperidinylcarbonylamino a mono- or di-C 1 _ 6 alkoxy- carbonylamino group (e.g., tert-butoxycarbonylamino) , a 5- to 14-membered aromatic heterocyclylamino group (e.g.,
  • pyridylamino a carbamoylamino group, a (mono- or di-C 1 - 6 alkyl-carbamoyl ) amino group (e.g., methylcarbamoylamino) , a (mono- or di-C 7-16 aralkyl-carbamoyl ) amino group (e.g.,
  • benzylcarbamoylamino a C 1 _ 6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) , a C 6-14
  • arylsulfonylamino group e.g., phenylsulfonylamino
  • a (C 1 _ 6 alkyl) (C 1 _ 6 alkyl-carbonyl ) amino group e.g., N-acetyl-N- methylamino
  • a (C 1 _ 6 alkyl) (C 6-14 aryl-carbonyl) amino group e.g., N-benzoyl-N-methylamino
  • examples of the "optionally substituted carbamoyl group” include a carbamoyl group
  • carbamoyl group include a carbamoyl group, a mono- or di-C 1 _ 6 alkyl-carbamoyl group, a mono- or di-C 2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C 3-10 cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,
  • cyclohexylcarbamoyl a mono- or di-C 6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C 7-16 aralkyl-carbamoyl group, a mono- or di-C 1 _ 6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl ) , a mono- or di-C 6-14 aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,
  • examples of the "optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a C 1 _ 6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a Ce- 14 aryl group, a C 7-16 aralkyl group, a C 1 _ 6 alkyl-carbonyl group, a C 6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C 1 _ 6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1 _ 6 alkyl-carbamo
  • thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C 1 _ 6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl , ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl) , a mono- or di-C 2-6 alkenyl- thiocarbamoyl group (e.g., diallylthiocarbamoyl ) , a mono- or di-C 3-10 cycloalkyl-thiocarbamoyl group (e.g.,
  • benzylthiocarbamoyl phenethylthiocarbamoyl ) , a mono- or di-C 1 _ 6 alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl , propionylthiocarbamoyl) , a mono- or di-C 6-14 aryl-carbonyl- thiocarbamoyl group (e.g., benzoylthiocarbamoyl ) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl ) .
  • a mono- or di-C 1 _ 6 alkyl-carbonyl-thiocarbamoyl group e.g., acetylthiocarbamoyl , propionylthiocarbamoy
  • examples of the "optionally substituted sulfamoyl group” include a sulfamoyl group
  • substituent group A optionally has 1 to 3 substituents selected from substituent group A" .
  • the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C 1 _ 6 alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl , dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl) , a mono- or di-C 2-6 alkenyl-sulfamoyl group (e.g.,
  • diallylsulfamoyl a mono- or di-C 3-10 cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl) , a mono- or di-C 6-14 aryl-sulfamoyl group (e.g., phenylsulfamoyl) , a mono- or di-C 7-16 aralkyl-sulfamoyl group (e.g.,
  • propionylsulfamoyl a mono- or di-C 6-14 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl ) and a 5- to 14-membered aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl) .
  • a mono- or di-C 6-14 aryl-carbonyl-sulfamoyl group e.g., benzoylsulfamoyl
  • a 5- to 14-membered aromatic heterocyclylsulfamoyl group e.g., pyridylsulfamoyl
  • examples of the "optionally substituted hydroxy group” include a hydroxyl group optionally having "a substituent selected from a C 1 _ 6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, a C 7 _ 16 aralkyl group, a C 1 _ 6 alkyl-carbonyl group, a C 6-14 aryl- carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C 1 _ 6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1 _ 6 alkyl-carbamoyl group, a mono- or di-C 7-16
  • the optionally substituted hydroxy group include a hydroxy group, a C 1 _ 6 alkoxy group, a C 2-6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) , a C 3-10 cycloalkyloxy group (e.g., cyclohexyloxy) , a C 6-14 aryloxy group (e.g., phenoxy, naphthyloxy) , a C 7-16 aralkyloxy group (e.g., benzyloxy, phenethyloxy) , a C 1 _ 6 alkyl- carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy) , a C 6-14 aryl-carbonyloxy group
  • heterocyclylcarbonyloxy group e.g., nicotinoyloxy
  • a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group e.g., piperidinylcarbonyloxy
  • a C 1 _ 6 alkoxy-carbonyloxy group e.g., tert-butoxycarbonyloxy
  • heterocyclyloxy group e.g., pyridyloxy
  • a carbamoyloxy group e.g., a C 1 _ 6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy) , a C 7-16 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy) , a C 1 _ 6 alkylsulfonyloxy group (e.g., methylsulfonyloxy,
  • a heterocyclyloxy group e.g., pyridyloxy
  • a carbamoyloxy group e.g., a C 1 _ 6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy)
  • a C 7-16 aralkyl-carbamoyloxy group e.g., benzylcarb
  • ethylsulfonyloxy ethylsulfonyloxy
  • a C 6-14 arylsulfonyloxy group e.g., phenylsulfonyloxy
  • examples of the "optionally substituted sulfanyl group” include a sulfanyl group optionally having "a substituent selected from a C 1 _ 6 alkyl group, a C 2 _ 6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, a C 7 _ i6 aralkyl group, a C 1 _ 6 alkyl-carbonyl group, a C 6-14 aryl- carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents
  • sulfanyl group include a sulfanyl (-SH) group, a C 1 _ 6 alkylthio group, a C 2 _ 6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C 3-10 cycloalkylthio group (e.g., cyclohexylthio) , a C 6-14 arylthio group (e.g., phenylthio, naphthylthio) , a C 7-16 aralkylthio group (e.g., benzylthio, phenethylthio) , a C 1 _ 6 alkyl-carbonylthio group (e.g.,
  • benzoylthio a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio) .
  • examples of the "optionally substituted silyl group” include a silyl group optionally having "1 to 3 substituents selected from a C 1 _ 6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group and a C 7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
  • the optionally substituted silyl group include a tri-C 1 _ 6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl (dimethyl) silyl) .
  • examples of the "C 1 _ 6 alkylene group” include -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, - (CH 2 ) 5 -, -(CH 2 ) 6 -/ -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH(C 2 H 5 )-, -CH(C 3 H 7 )-, - CH (CH (CH 3 ) 2 ) -/ -(CH(CH 3 )) 2 -/ -CH 2 -CH (CH 3 ) -, -CH (CH 3 ) -CH 2 -, -CH 2 - CH 2 -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -C (CH 3 ) 2 -, -C(CH 3
  • examples of the "C 2 _ 6 alkynylene group” include -C ⁇ C-, -CH 2 -C ⁇ C-, -C ⁇ C-CH 2 -, -
  • hydrocarbon ring include a C 6-14 aromatic hydrocarbon ring, C 3 _ 10 cycloalkane and C 3-10 cycloalkene.
  • examples of the "C 6-14 aromatic hydrocarbon ring” include benzene and naphthalene.
  • examples of the "C 3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
  • examples of the "C 3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
  • heterocycle include an aromatic heterocycle and a non- aromatic heterocycle, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • aromatic heterocycle examples include a 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocycle containing, as a ring- constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • aromatic heterocycle examples include 5- or 6-membered monocyclic aromatic heterocycles such as 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, triazine and the like; and 8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine
  • pyrrolopyrimidine pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2, 3-b] thiophene, phenoxathiin, indole, isoindole, 1H- indazole, purine, isoquinoline, quinoline, phthalazine,
  • non- aromatic heterocycle examples include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • non-aromatic heterocycle examples include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazdlidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine , tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridihe, dihydrothiopyran,
  • examples of the "nitrogen- containing heterocycle” include the “heterocycle” containing at least one nitrogen atom as a ring-constituting atom.
  • hydrocarbon ring also includes a nonaromatic hydrocarbon ring.
  • nonaromatic hydrocarbon ring include a C 6-14 nonaromatic
  • hydrocarbon ring e.g., tetrahydronaphthalene ring
  • hydrocarbon ring and “heterocycle” can be mentioned and, as the substituent thereof, the above-mentioned “substituent” can be mentioned.
  • a 6- or 7-membered monocyclic non-aromatic heterocycle e.g., a dihydropyran ring, a dihydrooxazine ring, tetrahydrooxepine ring, tetrahydrooxazepine ring
  • a 6- or 7-membered monocyclic non-aromatic heterocycle e.g., a dihydropyran ring, a dihydrooxazine ring, tetrahydrooxepine ring, tetrahydrooxazepine ring
  • C 1 _ 2 alkylene of the “optionally halogenated C 1 _ 2 alkylene”
  • C 1 _ 6 alkylene group having 1 or 2 carbon atoms
  • Ring A is an optionally further substituted ring.
  • ring of the "optionally further substituted ring” for ring A, the above-mentioned “hydrocarbon ring” and “heterocycle” can be mentioned. It is preferably C 3-10
  • cycloalkane e.g., cyclohexane
  • C 6-14 aromatic hydrocarbon ring e.g., benzene ring, naphthalene ring
  • C 6-14 nonaromatic hydrocarbon ring e.g., tetrahydronaphthalene ring
  • 5- to 14- membered aromatic heterocycle e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, guinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring
  • heterocycle e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring
  • a benzene ring a pyridine ring, an indazole ring or a pyrazolopyridine ring.
  • the "ring" of the "optionally further substituted ring” for ring A is optionally further substituted by 1 - 5
  • a halogen atom e.g., fluorine atom, chlorine atom
  • a cyano group e.g., methyl, ethyl, isopropyl, tert-butyl
  • an optionally substituted C 1 - 6 alkoxy group e.g., methoxy, ethoxy
  • an optionally substituted C 1 - 6 alkoxy group e.g., methoxy, ethoxy
  • substituted C 3-10 cycloalkyl group e.g., cyclopropyl
  • cyclobutyl cyclobutyl
  • C 3-10 cycloalkyloxy group e.g., cyclopropyloxy
  • an optionally substituted C 5 _ 14 aryl group e.g., phenyl
  • an optionally substituted C 6-14 aryloxy group e.g., phenoxy
  • an optionally substituted 3- to 14-membered nonaromatic heterocyclic group e.g.,
  • substituted 5- to 14-membered aromatic heterocyclic group e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl
  • an optionally substituted C 1 _ 6 alkyl-carbonyl group e.g., acetyl
  • heterocyclyloxy group e.g., pyrazinyloxy
  • C 1 - 6 alkoxy-carbonyl group e.g., tert- butoxycarbonyl
  • a halogen atom e.g., fluorine atom, chlorine atom
  • a cyano group e.g., a cyano group
  • an oxo group e.g., a C 1 _ 6 alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl)
  • halogen atom e.g., fluorine atom
  • C 1 _ 6 alkoxy group e.g., methoxy
  • Cx-g alkoxy group e.g., methoxy, ethoxy
  • 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, a C 3 _ 10 cycloalkyl group (e.g., cyclopropyl ) , a C 6-14 aryl group (e.g., phenyl) and a carbamoyl group, (6) a .C 3-10 cycloalkyl group
  • cyclopropyl, cyclobutyl optionally substituted by 1 - 3 substituents selected from a C 1 - 6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a cyano group and a hydroxy group, (7) a C 3-10 cycloalkyloxy group (e.g.,
  • a C 1 _ 6 alkyl group e.g., methyl
  • 1 - 3 halogen atoms e.g., fluorine atom
  • a C 1 _ 6 alkoxy group e.g., methoxy
  • 1 - 3 halogen atoms e.g., fluorine atom
  • a halogen atom e.g., chlorine atom
  • a cyano group cyano group
  • a Ce-14 aryloxy group e.g., phenoxy
  • 10 a 3- to 14-membered nonaromatic heterocyclic group (e.g.,
  • oxetanyl, morpholinyl, piperazinyl optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C 1 _ 6 alkyl group (e.g., methyl), (11) a 5- to 14- membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl) , (12) a C 1 _ 6 alkyl-carbonyl group (e.g., acetyl), (13) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) or (14) a C 1 _ 6 alkoxy-carbonyl group (e.g., tert-butoxycarbonyl) ,
  • a halogen atom e.g., fluorine atom
  • C 1 _ 6 alkyl group e
  • a halogen atom e.g., fluorine atom
  • a cyano group e.g., methyl, ethyl, isopropyl
  • a C 1 _ 6 alkyl group e.g., methyl, ethyl, isopropyl
  • a C 1 _ 6 alkoxy group e.g., methoxy
  • a C 1 _ 6 alkoxy group e.g., methoxy, ethoxy
  • 1 halogen atoms e.g., fluorine atom
  • a C 3-10 cycloalkyl group e.g., fluorine atom
  • cyclopropyl optionally substituted by 1 - 3 C 1 _ 6 alkyl groups (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom).
  • Ring A is preferably C 3-10 cycloalkane (e.g., cyclohexane) , a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a C 6-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring) , a 5- to 14-membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazol
  • a halogen atom e.g., fluorine atom, chlorine atom
  • a cyano group e.g., methyl, ethyl, isopropyl, tert-butyl
  • an optionally substituted C 1 _ 6 alkyl group e.g., methyl, ethyl, isopropyl, tert-butyl
  • an optionally substituted C 1 _ 6 alkoxy group e.g., methoxy, ethoxy
  • an optionally substituted C 3-10 cycloalkyl group e.g., cyclopropyl, cyclobutyl
  • cyclopropyloxy e.g., phenyl
  • C 6-14 aryl group e.g., phenyl
  • C 6-14 aryloxy group e.g., phenoxy
  • an optionally substituted 3- to 14- membered nonaromatic heterocyclic group e.g., oxetanyl
  • substituted C 1 _ 6 alkyl-carbonyl group e.g., acetyl
  • heterocyclyloxy group e.g., pyrazinyloxy
  • C 1 _ 6 alkoxy-carbonyl group e.g., tert- butoxycarbonyl
  • C 3-10 cycloalkane e.g., cyclohexane
  • a C 6-14 aromatic hydrocarbon ring e.g., benzene ring, naphthalene ring
  • a C 6-14 nonaromatic hydrocarbon ring e.g.,
  • a 5- to 14-membered aromatic heterocycle e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroind
  • a halogen atom e.g., fluorine atom, chlorine atom
  • a cyano group e.g., methyl, ethyl, isopropyl, tert-butyl
  • a C 1 _ 6 alkyl group e.g., methyl, ethyl, isopropyl, tert-butyl
  • substituents selected from a halogen atom (e.g., fluorine atom) and a C 1 _ 6 alkoxy group (e.g., methoxy)
  • a C 1 _ 6 alkoxy group e.g., methoxy, ethoxy
  • a C 1 _ 6 alkyl group e.g., methyl
  • 1 - 3 halogen atoms e.g., fluorine atom
  • a halogen atom e.g., fluorine atom
  • a cyano group and a hydroxy group (7) a C 3-10 cycloalkyloxy group (e.g., cyclopropyloxy)
  • a C 6-14 aryl group e.g., phenyl
  • substituents selected from a C 1 _ 6 alkyl group (e.g., methyl ) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a C 1 _ 6 alkoxy group (e.g., methoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a halogen
  • a benzene ring e.g., fluorine atom
  • a pyridine ring e.g., an indazole ring or a pyrazolopyridine ring
  • substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C 1 _ 6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C 1 _ 6 alkoxy groups (e.g., methoxy), (4) a C 1 _ 6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) and (5) a C 3-10 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 - 3 C 1
  • a halogen atom e
  • L 1 is a bond, optionally halogenated C 1 _ 2 alkylene, -NH- or -0- .
  • L 1 is preferably a bond, C 1 _ 2 alkylene (e.g., -CH 2 -, - (CH 2 ) 2 - / -CH(CH 3 )-), -NH- or -0-, more preferably a bond, C 1 _ 2 alkylene (e.g., -CH 2 -) or -NH- .
  • X is a carbon atom or a nitrogen atom
  • n is an integer of 1 or 2
  • ring B is an optionally further substituted 6- or 7-membered oxygen-containing heterocycle
  • Y 1 , Y 2 and Y 3 are each
  • ring C is an optionally further substituted 6-membered aromatic ring
  • the "6- or 7-membered oxygen-containing heterocycle" of the "optionally further substituted 6- or 7-membered oxygen- containing heterocycle" for ring B is preferably a dihydropyran ring (that is, X is a carbon atom, and n is 1) , a
  • dihydrooxazine ring that is, X is a nitrogen atom and n is 1
  • a tetrahydrooxazepine ring that is, X is a nitrogen atom and n is 2
  • the "6- or 7-membered oxygen-containing heterocycle" of the "optionally further substituted 6- or 7-membered oxygen- containing heterocycle" for ring B is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents other than ring A-L 1 - group at substitutable position (s ) .
  • substituents can be mentioned, which is preferably (1) an oxo group or (2) an optionally substituted C 1 _ 6 alkyl group (e.g., methyl), more preferably (1) an oxo group or (2) a C 1 - 6 alkyl group (e.g., methyl).
  • Ring B is preferably a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) an optionally substituted C 1 _ 6 alkyl group (e.g., methyl), more preferably, a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2),
  • ring B is preferably a 6- or 7-membered oxygen-containing heterocycle optionally further substituted by a methyl group, more
  • the "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring” for ring C is preferably a benzene ring (that is, Y 1 , Y 2 and Y 3 are carbon atoms) or a pyridine ring (that is, Y 1 is a nitrogen atom, Y 2 and Y 3 are carbon atoms or Y 1 and Y 2 are carbon atoms, Y 3 is a nitrogen atom) .
  • substituent thereof the above-mentioned "substituent" can be mentioned.
  • Ring C is preferably a benzene. ring (that is, Y 1 , Y 2 and Y 3 are carbon atoms) or a pyridine ring (preferably, Y 1 is a nitrogen atom, Y 2 and Y 3 are carbon atoms or Y 1 and Y 2 are carbon atoms, Y 3 is a nitrogen atom) .
  • ring A is preferably [0142]
  • L 1 is preferably a bond
  • R 1 is preferably a hydrogen atom or a hydroxymethyl group
  • R 2 is preferably a hydrogen atom
  • ring D is preferably
  • R 5 is a hydrogen atom, -C0 2 C 2 H 5 , -CH 2 OH, -C0 2 H, -CONH 2 or
  • L 2 is preferably -S0 2 -;
  • R 3 is preferably -CH 3 or -C 2 H 5 .
  • the partial structure in another embodiment of the present invention, the partial structure:
  • R 1 and R 2 are each independently a hydrogen atom or a substituent, R 1 and R z may be bonded together with an adjacent carbon atom to form an optionally further substituted ring, or R 1 and R 2 may be joined together to form an oxo group.
  • the above-mentioned “substituent” can be mentioned, preferably, (1) an optionally substituted C 1 _ 6 alkyl group (e.g., methyl, ethyl) or (2) an optionally substituted C 1 _ 6 alkoxy-carbonyl group (e.g., methoxycarbonyl) , more preferably, (1) a C 1 -g alkyl group (e.g., methyl, ethyl) optionally substituted by 1 - 3 substituents selected from a hydroxy group and a carboxy group or (2) a C 1 _ 6 alkoxy-carbonyl group (e.g., methoxycarbonyl).
  • cycloalkane e.g., cyclopropane ring
  • substituents As the substituent thereof, the above-mentioned "substituent" can be mentioned.
  • R 1 and R 2 are preferably each independently (1) a
  • Ring D is an optionally further substituted ring.
  • the above-mentioned “hydrocarbon ring” and “heterocycle” can be mentioned, preferably, a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring) , more preferably a benzene ring, a pyridine ring, a pyrimidine ring or a piperidine ring.
  • a C 6-14 aromatic hydrocarbon ring e.g., benzene ring
  • a 5- to 14-membered aromatic heterocycle e.g., pyridine ring, pyrimidine ring
  • a 3- to 14-membered non-aromatic heterocycle e.g., piperidine ring
  • substituents other than -N (H) -C (R 1 ) (R 2 ) - group and R 3 -L 2 - group at substitutable position (s).
  • substituents can be mentioned, preferably, a halogen atom (e.g., fluorine atom), a cyano group, an optionally substituted C 1 _ 6 alkyl group (e.g., methyl), a carboxyl group, an optionally substituted C 1 _ 6 alkoxy-carbonyl group (e.g., ethoxycarbonyl ) or an optionally substituted carbamoyl group, more preferably, (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C 1 _ 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carb
  • Ring D is preferably a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, an optionally substituted C 1 _ 6 alkyl group (e.g., methyl), a carboxyl group, an optionally substituted Cis alkoxy-carbonyl group (e.g., ethoxycarbonyl) and an optionally substituted carbamoyl group, more preferably, a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic
  • R 4 is a hydrogen atom or a substituent.
  • C 1 _ 6 alkyl group e.g., methyl
  • C 1 _ 6 alkyl group e.g., methyl
  • C 1 _ 6 alkyl group e.g., methyl
  • R 3 is a substituent.
  • R 3 is preferably an optionally substituted C 1 _ 6 alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group, more preferably a C 1 _ 6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C 1 _ 6 alkyl groups (e.g., methyl).
  • C 1 _ 6 alkyl group e.g., methyl, ethyl
  • R 3 is preferably an optionally substituted C 1 _ 6 alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group, more preferably a C 1 _ 6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C 1 _ 6 alkyl groups (e.g., methyl).
  • compound ( ⁇ ') are, for example, the following compounds.
  • ring A is C 3-10 cycloalkane (e.g., cyclohexane) , a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a C 6-14 nonaromatic hydrocarbon ring (e.g.,
  • a 5- to 14-membered aromatic heterocycle e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroind
  • a halogen atom e.g., fluorine atom, chlorine atom
  • a cyano group e.g., methyl, ethyl, isopropyl, tert-butyl
  • an optionally substituted C 1 _ 6 alkoxy group e.g., methoxy, ethoxy
  • an optionally substituted C 3-10 cycloalkyl group e.g., cyclopropyl, cyclobutyl
  • an optionally substituted C 3-10 cycloalkyloxy group e.g., cyclopropyl, cyclobutyl
  • an optionally substituted C 3-10 cycloalkyloxy group e.g.,
  • cyclopropyloxy , (8) an optionally substituted C 6-14 aryl group (e.g., phenyl), (9) an optionally substituted C 6-14 aryloxy group (e.g., phenoxy) , (10) an optionally substituted 3- to 14- membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl, piperazinyl) , (11) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl) , (12) an optionally
  • substituted C 1 _ 6 alkyl-carbonyl group e.g., acetyl
  • heterocyclyloxy group e.g., pyrazinyloxy
  • C 1 _ 6 alkoxy-carbonyl group e.g., tert- butoxycarbonyl
  • L 1 is a bond, C 1 _ 2 alkylene (e.g., -CH 2 -, - (CH 2 ) 2 - , ⁇
  • X is a carbon atom or a nitrogen atom
  • n is an integer of 1 or 2;
  • ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1) , a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) an
  • C 1 _ 6 alkyl group e.g., methyl
  • Y 1 , Y 2 and Y 3 are each independently a carbon atom or a nitrogen atom;
  • ring C is a benzene ring (that is, Y 1 , Y 2 and Y 3 are carbon atoms) or a pyridine ring (preferably, Y 1 is a nitrogen atom, Y 2 and Y 3 are carbon atoms or Y 1 and Y 2 is a carbon atom, Y 3 is a nitrogen atom) ;
  • R 1 and R 2 are each independently (1) a hydrogen atom, (2) an optionally substituted C 1 _ 6 alkyl group (e.g., methyl, ethyl) or (3) an optionally substituted C 1 _ 6 alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form optionally further substituted C 3 _ io cycloalkane (e.g., cyclopropane ring);
  • ring D is a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, an optionally substituted C 1 _ 6 alkyl group (e.g., methyl), a carboxyl group, an optionally substituted C 1 _ 6 alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and an optionally substituted carbamoyl group;
  • a halogen atom e.g., fluorine atom
  • a cyano group an optionally substituted C
  • R 3 is an optionally substituted C 1 _ 6 alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group.
  • ring A is C 3-10 cycloalkane (e.g., cyclohexane) , a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a Ce-14 nonaromatic hydrocarbon ring (e.g.,
  • a 5- to 14-membered aromatic heterocycle e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroind
  • a halogen atom e.g., fluorine atom, chlorine atom
  • a cyano group e.g., methyl, ethyl, isopropyl, tert-butyl
  • a C 1 _ 6 alkyl group e.g., methyl, ethyl, isopropyl, tert-butyl
  • substituents selected from a halogen atom (e.g., fluorine atom) and a C 1 _ 6 alkoxy group (e.g., methoxy)
  • a C 1 _ 6 alkoxy group e.g., methoxy, ethoxy
  • a C 1 _ 6 alkyl group e.g., methyl
  • 1 - 3 halogen atoms e.g., fluorine atom
  • a halogen atom e.g., fluorine atom
  • a cyano group and a hydroxy group (7) a C 3-10 cycloalkyloxy group (e.g., cyclopropyloxy)
  • a Ce-14 aryl group e.g., phenyl
  • substituents selected from a C 1 _ 6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a C 1 _ 6 alkoxy group (e.g., methoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a halogen atom (
  • pyrimidinyl (12) a C 1 _ 6 alkyl-carbonyl group (e.g., acetyl), (13) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) and (14) a C 1 - 6 alkoxy-carbonyl group (e.g., tert- butoxycarbonyl ) ;
  • L 1 is a bond, C 1 _ 2 alkylene (e.g., -CH 2 -, - ⁇ ⁇ 2 ) 2 ⁇ , ⁇
  • X is a carbon atom or a nitrogen atom
  • n is an integer of 1 or 2;
  • ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C 1 _ 6 alkyl group (e.g., methyl);
  • Y 1 , Y 2 and Y 3 are each independently a carbon atom or a nitrogen atom;
  • ring C is a benzene ring (that is, Y 1 , Y 2 and Y 3 are carbon atoms) or a pyridine ring (preferably, Y 1 is a nitrogen atom, Y 2 and Y 3 are carbon atoms or Y 1 and Y 2 is a carbon atom, Y 3 is a nitrogen atom) ;
  • R 1 and R 2 are each independently, (1) a hydrogen atom, (2) a C 1 _ 6 alkyl group (e.g., methyl, ethyl) optionally
  • ring D is a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is
  • 1 - 4 optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C 1 _ 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C 1 _ 6 alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and (6) a carbamoyl group;
  • substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C 1 _ 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C 1 _ 6 alkoxy-carbonyl group (e.g., ethoxycarbonyl )
  • R 3 is a C 1 _ 6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C 1 _ 6 alkyl groups (e.g., methyl) .
  • ring A is a benzene ring, a pyridine ring, an indazole ring or a pyrazolopyridine ring, each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C 1 _ 6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C 1 _ 6 alkoxy groups (e.g., methoxy) , (4) a C 1 _ 6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) and (5) a C 3-10 ' cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1
  • L 1 is a bond, C 1 - 2 alkylene (e.g., -CH 2 ⁇ ) or -NH-;
  • X is a carbon atom or a nitrogen atom
  • n is an integer of 1 or 2 ;
  • ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C 1 _ 6 alkyl group (e.g., methyl);
  • Y 1 , Y 2 and Y 3 are each independently a carbon atom or a nitrogen atom;
  • ring C is a benzene ring (that is, Y 1 , Y 2 and Y 3 are carbon atoms) or a pyridine ring (preferably, Y 1 is a nitrogen atom, Y 2 and Y 3 are carbon atoms or Y 1 and Y 2 are carbon atoms, Y 3 is a nitrogen atom) ;
  • Y 4 N-
  • R 1 and R 2 are (1) both hydrogen atoms or (2) one of them is a hydrogen atom and the other is a C 1 _ 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups;
  • ring D is a benzene ring, a pyridine ring, a pyrimidine ring or a piperidine ring, each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C 1 _ 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C 1 _ 6 alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and (6) a carbamoyl group;
  • a halogen atom
  • ring A is a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring) , a Ce-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring), a 5- to 14-membered
  • aromatic heterocycle e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring,
  • isobenzooxazole ring isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic
  • heterocycle e.g., tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring
  • heterocycle e.g., tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring
  • a halogen atom e.g., fluorine atom, chlorine atom
  • a cyano group e.g., methyl, ethyl, isopropyl, tert-butyl
  • an optionally substituted C 1 _ 6 alkyl group e.g., methyl, ethyl, isopropyl, tert-butyl
  • an optionally substituted C 1 _ 6 alkoxy group e.g., methoxy, ethoxy
  • an optionally substituted C 3-10 cycloalkyl group e.g., cyclopropyl, cyclobutyl
  • an optionally substituted C 3-10 cycloalkyloxy group e.g.,
  • cyclopropyloxy , (8) an optionally substituted Ce-14 aryl group (e.g., phenyl), (9) an optionally substituted C 6-14 aryloxy group (e.g., phenoxy) , (10) an optionally substituted 3- to 14- membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl) , (11) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl) and (12) an optionally substituted C 1 - 6 alkyl-carbonyl group (e.g., acetyl) ;
  • L 1 is a bond, C 1 _ 2 alkylene (e.g., -CH 2 -, - (CH 2 ) 2 - , ⁇
  • X is a carbon atom or a nitrogen atom
  • n is an integer of 1 or 2 ;
  • ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) an
  • C 1 _ 6 alkyl group e.g., methyl
  • Y 1 , Y 2 and Y 3 are each independently a carbon atom or a nitrogen atom;
  • ring C is a benzene ring (that is, Y 1 , Y 2 and Y 3 are carbon atoms) or a pyridine ring (preferably, Y 1 is a nitrogen atom, Y 2 and Y 3 are carbon atoms or Y 1 and Y 2 is a carbon atom, Y 3 is a nitrogen atom) ;
  • R 1 and R 2 are each independently (1) a hydrogen atom, (2) an optionally substituted C 1 _ 6 alkyl group (e.g., methyl, ethyl) or (3) an optionally substituted Cis alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form optionally further substituted C3- 10 cycloalkane (e.g., cyclopropane ring);
  • ring D is a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is
  • halogen atoms e.g., fluorine atom
  • R 3' is an optionally substituted C 1 _ 6 alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group.
  • ring A is a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring) , a C 6-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring), a 5- to 14-membered
  • aromatic heterocycle e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring,
  • isobenzooxazole ring isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic
  • heterocycle e.g., tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring
  • heterocycle e.g., tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring
  • a halogen atom e.g., fluorine atom,, chlorine atom
  • a cyano group e.g., methyl, ethyl, isopropyl, tert-butyl
  • a C 1 - 6 alkyl group e.g. methyl, ethyl, isopropyl, tert-butyl
  • substituents selected from a halogen atom (e.g., fluorine atom) and a C 1 _ 6 alkoxy group (e.g., methoxy)
  • a C 1 _ 6 alkoxy group e.g., methoxy, ethoxy
  • substituents selected from a C 1 _ 6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a cyano group and a hydroxy group, (7) a C 3-10 cycloalkyloxy group (e.g., cyclopropyloxy) , (8) a C 6-14 aryl group (e.g., phenyl) optionally substituted by 1 - 3
  • substituents selected from a C 1 _ 6 alkyl group e.g., methyl
  • substituents selected from a C 1 _ 6 alkyl group e.g., methyl
  • 1 - 3 halogen atoms e.g., fluorine atom
  • a C 1 _ 6 alkoxy group e.g., methoxy
  • halogen atoms e.g., fluorine atom
  • a halogen atom e.g., chlorine atom
  • a cyano group e.g., a C 6 _ 14 aryloxy group (e.g., phenoxy)
  • a 3- to 14-membered nonaromatic heterocyclic group e.g., oxetanyl, morpholinyl
  • 1 halogen atoms e.g., fluorine atom
  • (11) a 5- to 14 ⁇ membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl)
  • a C 1 _ 6 alkyl-carbonyl group e.g., acetyl
  • L 1 is a bond, C 1 _ 2 alkylene (e.g., -(CH 2 ) 2 -, - CH(CH 3 )-), -NH- or -0-;
  • X is a carbon atom or a nitrogen atom
  • n is an integer of 1 or 2;
  • ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1) , a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C 1 _ 6 alkyl group (e.g., methyl);
  • Y 1 , Y 2 and Y 3 are each independently a carbon atom or a nitrogen atom;
  • ring C is a benzene ring (that is, Y 1 , Y 2 and Y 3 are carbon atoms) or a pyridine ring (preferably, Y 1 is a nitrogen atom, Y 2 and Y 3 are carbon atoms or Y 1 and Y 2 is a carbon atom, Y 3 is a nitrogen atom) ;
  • R 1 and R 2 are each independently (1) a hydrogen atom, (2) a C 1 _ 6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 - 3 substituents selected from a hydroxy group and a carboxy group or (3) a C 1 _ 6 alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form C 3-10 cycloalkane (e.g., cyclopropane ring);
  • ring D is a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is
  • halogen atoms e.g., fluorine atom
  • R 3 is a C 1 _ 6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C 1 _ 6 alkyl groups (e.g., methyl) .
  • ring A is a benzene ring, a pyridine ring, an indazole ring or a pyrazolopyridine ring, each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C 1 - 6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C 1 _ 6 alkoxy groups (e.g., methoxy) , (4) a C 1 _ 6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) and (5) a C 3-10 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 -
  • L 1 is a bond, C 1 _ 2 alkylene (e.g., -CH 2 -) or -NH-; the partial structure:
  • X is a carbon atom or a nitrogen atom
  • n is an integer of 1 or 2;
  • ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C 1 - 6 alkyl group (e.g., methyl);
  • Y 1 , Y 2 and Y 3 are each independently a carbon atom or a nitrogen atom;
  • ring C is a benzene ring (that is, Y 1 , Y 2 and Y 3 are carbon atoms) or a pyridine ring (preferably, Y 1 is a nitrogen atom, Y 2 and Y 3 are carbon atoms or Y 1 and Y 2 is a carbon atom, Y 3 is a nitrogen atom) ;
  • R 1 and R 2 are (1) both hydrogen atoms or (2) one of them is a hydrogen atom and the other is a C 1 _ 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups;
  • ring D is a benzene ring, a pyridine ring, a pyrimidine ring or a piperidine ring, each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) halogen atoms, (e.g., fluorine atom) ;
  • ring A is C 3-10 cycloalkane (e.g., cyclohexane) , a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyrazole ring, pyridine ring, pyrimidine ring, benzoimidazole ring, indazole ring, quinoline ring, imidazopyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring) , each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2 ) substituents selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) an optionally substituted C 1 _ 6 alkyl group (e.g., methyl, e
  • cyclopropyl e.g., cyclopropyl
  • C 6-14 aryl group e.g., phenyl
  • an optionally substituted 3- to 14-membered nonaromatic heterocyclic group e.g., piperazinyl
  • an optionally substituted 5- to 14-membered aromatic heterocyclic group e.g., pyridyl, pyrimidinyl
  • substituted 5- to 14-membered aromatic heterocyclyloxy group e.g., pyrazinyloxy
  • an optionally substituted C 1 _ 6 alkoxy-carbonyl group e.g., tert-butoxycarbonyl
  • L 1 is a bond or C 1 _ 2 alkylene (e.g., -CH 2 -, -(CH 2 )2 _ ) ; the partial structure:
  • R 1 and R 2 are each independently a hydrogen atom or an optionally substituted C 1 _ 6 alkyl group (e.g., methyl);
  • ring D is a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., a pyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) an optionally substituted C 1 _ 6 alkyl group (e.g., methyl), (4) a carboxyl group, (5) an optionally substituted C 1 _ 6 alkoxy-carbonyl group (e.g.,
  • L 2 is -SO2-
  • R 3 is an optionally substituted C 1 _ 6 alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group.
  • ring A is C 3-10 cycloalkane cyclohexane) , a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyrazole ring, pyridine ring, pyrimidine ring, benzoimidazole ring, indazole ring, quinoline ring, imidazopyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring) , each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a C 1 _ 6 alkyl group (e.g., methyl, ethyl, isopropyl) optional
  • a C 3 _i 0 cycloalkyl group e.g., cyclopropyl
  • a C 6-14 aryl group e.g., phenyl
  • a 3- to 14-membered nonaromatic heterocyclic group e.g., piperazinyl
  • 1 - 3 C 1 _ 6 alkyl groups e.g., methyl
  • a 5- to 14-membered aromatic heterocyclic group e.g., pyridyl, pyrimidinyl
  • a 5- to 14-membered aromatic heterocyclyloxy group e.g., pyrazinyloxy
  • (9) a C 1 _ 6 alkoxy-carbonyl group e.g., tert-butoxycarbonyl
  • L 1 is a bond or C 1 _ 2 alkylene (e.g., -CH 2 -, -(CH 2 )2 ⁇ ) ;
  • R 1 and R 2 are each independently a hydrogen atom or a Cis alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups;
  • ring D is a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., a pyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C 1 - 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C 1 _ 6 alkoxy-carbonyl group (e.g., ethoxycarbonyl) and (6) a carbamoyl group;
  • 1 - 4 preferably 1 - 3, more preferably 1 or 2 substituents selected from (1) a hal
  • L 2 is -SO2-
  • R 3 is a C 1 _ 6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C 1 _ 6 alkyl groups (e.g., methyl) .
  • ring A is a pyridine ring optionally further substitut by 1 - 3 C 3-10 cycloalkyl groups (e.g., cyclopropyl) ;
  • L 1 is a bond
  • Y 4 N-
  • R 1 and R 2 are (1) both hydrogen atoms or (2) one of them is a hydrogen atom and the other is a C 1 - 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups;
  • ring D is a C 6-14 aromatic hydrocarbon ring (e.g., benzene ring) or a 5- to 14-membered aromatic heterocycle (e.g., a pyridine ring) , each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2)
  • L 2 is -SO2-
  • R 3 is a C1-6 alkyl group (e.g., methyl, ethyl).
  • compound ( ⁇ ') include the compounds of Examples 3 - 381, among which
  • salts with inorganic base examples include salts with inorganic base, ammonium salts, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acids, and the like.
  • the salt with inorganic base include alkaline 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 and the like.
  • salt with organic base examples include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,
  • salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salt with organic acid examples include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid,
  • salt with basic amino acid examples include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid examples include salt with aspartic acid, glutamic acid and the like.
  • a pharmaceutically acceptable salt is preferable.
  • the pharmaceutically acceptable preferable salt when the compound has a basic functional group therein,
  • examples of the salt thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric aid, succinic acid,
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid
  • organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric aid, succinic acid,
  • methanesulfonic acid methanesulfonic acid, p-toluenesulfonic acid and the like.
  • examples thereof include inorganic salts such as alkali metal salt (e.g., sodium salt, potassium salt etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt, and the like.
  • alkali metal salt e.g., sodium salt, potassium salt etc.
  • alkaline earth metal salt e.g., calcium salt, magnesium salt, barium salt etc.
  • ammonium salt e.g., sodium salt, potassium salt etc.
  • Compound ( ⁇ ') may be a crystal, and both a single crystal and crystal mixtures are encompassed in the compound (I' ) .
  • Compound ( ⁇ ') may be a pharmaceutically acceptable
  • cocrystal or cocrystal salt means a crystalline substance consisting of two or more particular substances which are solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of melting, hygroscopicity, solubility, stability etc.).
  • the cocrystal and cocrystal salt can be produced by cocrystallization method known per se.
  • Compound ( ⁇ ') encompasses solvates (e.g., hydrate etc.) and non-solvates (e.g., non-hydrate etc.) within the scope thereof.
  • a deuterium conversion form wherein 1 H is converted to 2 H(D) is also encompassed in compound (1') ⁇
  • Compound ( ⁇ ') may be a compound labeled or substituted with an isotope (e.g., 3 H, X1 C, 14 C, 18 F, 35 S, 125 I).
  • a compound labeled with or substituted by an isotope may be used, for example, as a tracer used for Positron Emission Tomography (PET) (PET tracer), and may be useful in the field of medical diagnosis and the like.
  • PET tracer Positron Emission Tomography
  • isomers such as enantiomer, diastereomer and the like may be present. Such isomers and a mixture thereof are all encompassed within the scope of the present invention. When an isomer is formed due to the conformation or tautomerism, such isomers and a mixture thereof are also encompassed in compound ( ⁇ ') of the present invention.
  • the starting materials and reagents used in each step in the following production method, and the obtained compounds each may form a salt.
  • the salt include those similar to the aforementioned salts of the compound of the present invention and the like.
  • the compound obtained in each step is a free compound, it can be converted to a desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted to a free form or a desired other kind of salt by a method known per se.
  • the compound obtained in each step can also be used for the next reaction as a reaction mixture thereof or after obtaining a crude product thereof.
  • the compound obtained in each step can be isolated and/or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like
  • the starting materials and reagent compounds of each step are commercially available, the commercially available products can be used as they are.
  • protection or deprotection reaction of a functional group is performed by the method known per se, for example, the methods described in "Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M. Wuts) Wiley-Interscience, 2007; “Protecting Groups 3rd Ed.” (P. J. Kocienski) Thieme, 2004 and the like, or the methods described in the Examples.
  • Examples of the protecting group of the hydroxyl group of alcohol and the like and a phenolic hydroxyl group include ether protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; carboxylate ester protecting groups such as acetate ester and the like; sulfonate ester protecting groups such as methanesulfonate ester and the like; carbonate ester protecting groups such as t-butylcarbonate and the like, and the like.
  • ether protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, tetrahydropyranyl ether and the like
  • carboxylate ester protecting groups such as acetate ester and the like
  • sulfonate ester protecting groups such as methanesulfonate ester and the like
  • carbonate ester protecting groups such as t
  • Examples of the protecting group of the carbonyl group of aldehyde include acetal protecting groups such as dimethyl acetal and the like; cyclic acetal protecting groups such as cyclic 1,3-dioxane and the like, and the like.
  • Examples of the protecting group of the carbonyl group of ketone include ketal protecting groups such as dimethyl ketal and the like; cyclic ketal protecting groups such as cyclic 1,3-dioxane and the like; oxime protecting groups such as 0- methyloxime and the like; hydrazone protecting groups such as N, N-dimethylhydrazone and the like, and the like.
  • carboxyl protecting group examples include ester protecting groups such as methyl ester and the like; amide protecting groups such as N, N-dimethylamide and the like, and the like.
  • thiol protecting group examples include ether protecting groups such as benzyl thioether and the like; ester protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like, and the like.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a compound that may have an ROR(gamma)t modulating activity and can thus be useful in the treatment of cancer.

Description

[DESCRIPTION]
[Title of Invention]
HETEROCYCLIC COMPOUNDS WITH AN ROR(GAM MA)T MODULATING ACTIVITY
[Technical Field]
[0001]
The present invention relates to a heterocyclic compound which may have an RORyt modulating activity, a medicament containing the compound, and the like.
[0002]
[Background Art]
Thl7 cell and inflammatory cytokines (IL-17A, IL-17F and the like) produced thereby cause a decrease in QOL as a severe etiology cell and factor accompanying enhancement of a systemic new immune response, in various autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis and psoriasis. However, the existing therapeutic drugs show only limited effects, and therefore, the earliest possible development of a novel therapeutic drug has been desired.
Involvement of T cells, inter alia, Thl7 cell and
inflammatory cytokines (IL-17A, IL-17F and the like) produced thereby, in the pathology of these immune diseases has been drawing attention in recent years.
Moreover, it has been recently clarified that a Retinoid- related Orphan Receptor (ROR) yt, which is one of the orphan nuclear receptors, plays an important role in the
differentiation of Thl7 cells and production of IL-17A/IL-17F. That is, it has been reported that RORyt is mainly expressed in Thl7 cells and functions as a transcription factor of IL-17A and IL-17F, as well as a master modulator of Thl7 cell
differentiation.
Therefore, a medicament that inhibits the action of RORyt is expected to show a treatment effect on various immune diseases by suppressing differentiation and activation of Thl7 cells. [0003]
Patent document 1 discloses the following compound having an NAMPT inhibitory action and useful as chemotherapy drugs (DNA damaging agent, .cell rescuing agent, cytotoxic agent) , a therapeutic drug for hyperproliferative disorder due to an abnormal cell proliferation action, or a prophylactic or therapeutic agent for malignant tumor, ovarian cancer, breast cancer, colorectal cancer, Hodgkin' s disease, inflammatory disease, IBS, IBD, rheumatoid arthritis and the like:
[0004]
[Chem. 1]
Figure imgf000004_0001
[0005]
wherein each symbol is as defined in the document.
Non-patent document 1 discloses the following compound having a p38α MAP kinase inhibitory action, and useful as a prophylactic or therapeutic agent for inflammatory diseases such as rheumatoid arthritis, IBD and . the like:
[0006]
[Chem. 2]
Figure imgf000004_0002
Patent document 2 discloses the following compound having a ρ-38α activity-inducing action, and useful as a prophylactic or therapeutic agent for inflammation-associated diseases (IBD, rheumatoid arthritis, Crohn's disease, Alzheimer's disease etc . ) :
[0008]
[Chem. 3]
Figure imgf000005_0001
[0009]
wherein each symbol is as defined in the document.
Patent document 3 discloses the following compound having an NMDA NR2B antagonistic action, and useful as a prophylactic or therapeutic agent for migraine, depression, anxiety,
schizophrenia, Parkinson' s disease, cerebral apoplexy and the like:
[0010]
[Chem. 4]
Figure imgf000005_0002
[0011]
wherein each symbol is as defined in the document.
Non-patent document 2 discloses the following compound
[0012]
[Chem. 5]
Figure imgf000005_0003
[0013]
Non-patent document 3 discloses the following compound:
[0014]
[Chem. 6]
Figure imgf000006_0001
[0015]
Non-patent document 4 discloses the following compound:
[0016]
[Chem. 7]
Figure imgf000006_0004
[0017]
Non-patent document 5 discloses the following compound
[0018]
[Chem. 8]
Figure imgf000006_0002
[0019]
Non-patent document 6 discloses the following compound
[0020]
[Chem. 9]
Figure imgf000006_0003
[0021]
Non-patent document 7 discloses the following compound: [0022]
[Chem. 10]
Figure imgf000007_0001
[0023]
Non-patent document 8 discloses the following compound:
[0024]
[Chem. 11]
Figure imgf000007_0002
[0025]
Non-patent document 9 discloses the following compound:
[0026]
[Chem. 12]
Figure imgf000007_0003
[0027]
Non-patent document 10 discloses the following compound
[0028]
[Chem. 13]
Figure imgf000007_0004
[0029]
Non-patent document 11 discloses the following compound
[0030] [Chem. 14]
Figure imgf000008_0001
[0031]
Non-patent document 12 discloses the following compound [0032]
[Chem. 15]
Figure imgf000008_0002
[0033]
Non-patent document 13 discloses the following compound:
[0034]
[Chem. 16]
Figure imgf000008_0003
[0035]
Non-patent document 14 discloses the following compound:
[0036]
[Chem. 17]
Figure imgf000008_0004
[0037]
Non-patent document 15 discloses the following compound:
[0038]
[Chem. 18]
Figure imgf000009_0001
[0039]
Non-patent document 16 discloses the following compound:
[0040]
[Chem. 19]
Figure imgf000009_0002
[0041]
Non-patent document 17 discloses the following compound:
[0042]
[Chem. 20]
Figure imgf000009_0003
[0043]
Non-patent document 18 discloses the following compound:
[0044]
[Chem. 21]
Figure imgf000009_0004
[0045]
non-patent document 19 discloses the following compound
[0046]
[Chem. 22]
Figure imgf000010_0001
[0047]
Non-patent document 20 discloses the following compound.
[0048]
[Chem. 23]
Figure imgf000010_0002
[0049]
Non-patent document 21 discloses the following compound:
[0050]
[Chem. 24]
Figure imgf000010_0003
[0051]
Non-patent document 22 discloses the following compound:
[0052]
[Chem. 25]
Figure imgf000010_0004
[0053]
Patent document 4 discloses the following compound useful s a prophylactic or therapeutic agent for PPARG associated diseases (diabetes, insulin resistance, obesity, inflammation etc. ) :
[0054]
[Chem. 26]
Figure imgf000011_0001
[0055]
wherein each symbol is as defined in the document.
Non-patent document 23 discloses the following compound useful as a PPARy antagonist:
[0056]
[Chem. 27]
Figure imgf000011_0002
[0057]
Patent document 5 discloses the following compound:
[0058]
[Chem. 28]
Figure imgf000011_0003
[0059]
wherein each symbol is as defined in the document. Non-patent document 24 discloses the following compound useful as a selective cannabinoid receptor 2 agonist:
[0060]
[Chem. 29]
Figure imgf000012_0001
[0061]
Patent document 6 discloses the following compound having a modulating action on glucocorticoid receptor, AP-1, NF-KB activity, and useful as a prophylactic or therapeutic agent for inflammation, immune system disease, cancer and the like:
[0062]
[Chem. 30]
Figure imgf000012_0002
[0063]
wherein each symbol is as defined in the document.
Patent document 7 discloses the following compound having a cannabinoid receptor modulating action, and useful as a prophylactic or therapeutic agent for central nervous system pain, addiction, cancer (including melanoma) , inflammation and the like:
[0064]
[Chem. 31]
Figure imgf000013_0001
[0065]
wherein each symbol is as defined in the document.
Patent document 8 discloses the following compound:
[0066]
[Chem. 32]
Figure imgf000013_0002
[0067]
wherein each symbol is as defined in the document.
Non-patent document 25 discloses the following compound useful as a selective cannabinoid receptor 2 agonist:
[0068]
[Chem. 33]
Figure imgf000013_0003
[0069]
Patent document 9 discloses the following compound having an RORy activity inhibitory action, and useful as a
prophylactic or therapeutic agent for immune disease,
inflammatory diseases (e.g., rheumatoid arthritis, Crohn's disease, IBD etc.) and the like:
[0070]
[Chem. 34]
Figure imgf000014_0001
[0071]
wherein each symbol is as defined in the document.
Patent document 10 discloses the following compound useful as an SMYD protein inhibitor as an antitumor drug:
[0072]
[Chem. 35]
Figure imgf000014_0002
[0073]
wherein each symbol is as defined in the document.
Non-patent document 26 discloses the following compound:
[0074]
[Chem. 36]
Figure imgf000014_0003
[0075]
Non-patent document 27 discloses the following compound:
[0076]
[Chem. 37]
Figure imgf000014_0004
[0077] Non-patent document 28 discloses the following compound:
[0078]
[Chem. 38]
O
Figure imgf000015_0001
[Citation List]
[Patent Literature]
[0079]
[PTL 1] WO 2012/031197
[PTL 2] WO 2005/033072A2
[PTL 3] WO 2002/080928
[PTL 4] KR 2015110901
[PTL 5] WO 2011/073276
[PTL 6] US 2009/0075995
[PTL 7] WO 2009/012221
[PTL 8] WO 2008/021926
[PTL 9] WO 2015/083130
[PTL 10] WC 1 2016/040505
[Non Patent . Literature]
[0080]
[NPL 1] Bioorganic & Medicinal Ch
2560- -2563
[NPL 2] RN 1808757-09-6 REGISTRY
[NPL 3] RN 1808600-79-4 REGISTRY
[NPL 4] RN 1808584-22-6 REGISTRY
[NPL 5] RN 1808382-90-2 REGISTRY
[NPL 6] RN 1791070-99-9 REGISTRY
[NPL 7] RN 1790978-50-5 REGISTRY
[NPL 8] RN 1626839-07-3 REGISTRY
[NPL 9] RN 1626420-44-7 REGISTRY
[NPL 10] RN 1414842-31-1 REGISTRY
[NPL 11] RN 1414839-85-2 REGISTRY [NPL 12 RN 1320956-59-9 REGISTRY
[NPL 13 RN 1302037-83-7 REGISTRY
[NPL 14 RN 1240829-86-0 REGISTRY
[NPL 15 RN 1223212-11-0 REGISTRY
[NPL 16 RN 1197718-13-0 REGISTRY
[NPL 17 RN 1197529-23-9 REGISTRY
[NPL 18 RN 1197525-10-2 REGISTRY
[NPL 19 RN 1197511-74-2 REGISTRY
[NPL 20 RN 1147378-16-2 REGISTRY
[NPL 21 RN 1026269-51-1 REGISTRY
[NPL 22 RN 950026-22-9 REGISTRY
[NPL 23 ACS Medicinal Chemistry Letters (2015), 6(9), 998-1003 [NPL 24 ChemMedChem (2009), 4(10), 1615-1629
[NPL 25 RN 958772-68-4 REGISTRY
[NPL 26 RN 1240904-56-6 REGISTRY
[NPL 27 RN 1009913-68-1 REGISTRY
[NPL 28 RN 941202-67-1 REGISTRY
[Summary of Invention]
[Technical Problem]
[0081]
The present invention aims to provide a compound that may have an RORyt modulating action and may be useful as a
prophylactic or therapeutic agent for cancer and the like.
[Solution to Problem]
[0082]
The present inventors have found that a compound
represented by the following formula (Ι') or a salt thereof may have an RORyt modulating action based on its specific chemical structure, and may have efficacy as a prophylactic or
therapeutic agent for cancer and the like. Based on this finding, the present inventors have conducted intensive studies and completed the present invention.
[0083]
Therefore, the present invention relates to the following.
[1] A compound represented by the formula (I' ) : [0084]
Chem. 39]
Figure imgf000017_0001
[0085]
wherein
ring A is an optionally further substituted ring;
L1 is a bond, optionally halogenated C1_2 alkylene, -NH- or -0-;
R1 and R2 are each independently a hydrogen atom or a substituent;
R1 and R2 may be bonded together with an adjacent carbon atom to form an optionally further substituted ring, or R1 and R2 may be joined together to form an oxo group;
ring D is an optionally further substituted ring;
L2 is -SO2-, -S(=0)- or -S(=0) (=NR4) - ;
R4 is a hydrogen atom or a substituent;
R3 is a substituent;
a partial structure:
[0086]
[Chem. 40]
Figure imgf000017_0002
[0087]
is
[0088]
[Chem.
Figure imgf000018_0001
[0089]
X is a carbon atom or a nitrogen atom;
n is an integer of 1 or 2;
ring B is an optionally further substituted 6- or 7- membered oxygen-containing heterocycle;
Y1, Y2 and Y3 are each independently a carbon atom or a nitrogen atom;
ring C is an optionally further substituted 6-membered aromatic ring; and
Y4 is =CH- or =N-, or a salt thereof (sometimes to be abbreviated as "compound (I')" in the present specification).
[2] The compound of [1] , wherein the ring A is
[0090]
[Chem. 42]
Figure imgf000018_0002
[0091]
L1 is a bond;
R1 is a hydrogen atom or a hydroxymethyl group
R2 is a hydrogen atom;
ring D is
[0092]
[Chem. 43]
Figure imgf000019_0001
[0093]
wherein
W is =CR - or =N-;
R6 is a hydrogen atom, -C02C2H5, -CH2OH, -C02H, -CONH2 or -
CN;
L is -S02-; and
R is -CH3 or -C2H5, or a salt thereof.
[3] The compound of [1], wherein the partial structure:
[0094]
[Chem. 44]
Figure imgf000019_0002
[0095]
is
[0096]
[Chem.
Figure imgf000019_0003
[0097]
wherein
X is a carbon atom or a nitrogen atom;
n is an integer of 1 or 2;
ring B is an optionally further substituted 6- or 7- membered oxygen-containing heterocycle; Y1, Y2 and Υ3 are each independently a carbon atom or a nitrogen atom; and
ring C is an optionally further substituted 6-membered aromatic ring, or a salt thereof (sometimes to be abbreviated as "compound (I)" in the present specification).
[4] 1- (2, 6-Dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide or a salt thereof.
[5] 4- (2, 6-Dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl) pyridin-2-yl ) methyl) chromane-7-carboxamide or a salt thereof.
[6] 5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (4-
(methylsulfonyl) benzyl) -5,6,7, 8-tetrahydro-l , 5-naphthyridine-2- carboxamide or a salt thereof.
[7] Ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin-4-yl) -5, 6, 7, 8- tetrahydro-1 , 5-naphthyridin-2-yl) carbonyl) amino) methyl) -5- (methylsulfonyl ) benzoate or a salt thereof.
[8] A medicament comprising the compound of [1] or a salt thereof .
[9] The medicament of [8], which is a RORyt modulator.
[10] The medicament of [8], which is a prophylactic or
therapeutic agent for cancer.
[11] A method of modulating RORyt in a mammal, comprising administering an effective amount of the compound of [1] or a salt thereof to the mammal.
[12] A method for the prophylaxis or treatment of cancer in a mammal, comprising administering an effective amount of the compound of [1] or a salt thereof to the mammal.
[13] The compound of [1] or a salt thereof for use in the prophylaxis or treatment of cancer.
[14] Use of the compound of [1] or a salt thereof in the production of an agent for the prophylaxis or treatment of cancer .
[Advantageous Effects of Invention]
[0098] The compound of the present invention may have an RORyt modulating action and may be useful as a prophylactic or therapeutic agent for cancer and the like.
[0099]
[Description of Embodiments]
The definition of each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following
definition .
In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.
In the present specification, examples of the "C1_6 alkyl ' group" 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 .
In the present specification, examples of the "optionally halogenated C1_6 alkyl . group" include a C1_6 alkyl group
optionally having 1 to 7, preferably 1 to 5, halogen atoms.
Specific examples thereof include methyl, chloromethyl,
difluoromethyl, trichloromethyl, trifluoromethyl , ethyl, 2- bromoethyl, 2, 2, 2-trifluoroethyl, tetrafluoroethyl,
pentafluoroethyl, propyl, 2 , 2-difluoropropyl , 3,3,3- trifluoropropyl, isopropyl, butyl, 4 , 4 , 4-trifluorobutyl , isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl, hexyl and 6, 6, 6-trifluorohexyl .
In the present specification, examples of the "C2-6 alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-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.
In the present specification, examples of the "C2- 6 alkynyl group" 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 .
In the present specification, examples of the "C3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl and adamantyl.
In the present specification, examples of the "optionally halogenated C3-10 cycloalkyl group" include a C3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2- difluorocyclopropyl, 2 , 3-difluorocyclopropyl , cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the present specification, examples of the "C3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl , cyclopentenyl , cyclohexenyl, cycloheptenyl and cyclooctenyl .
In the present specification, examples of the "C6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.
In the present specification, examples of the "C7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl .
[0100]
In the present specification, examples of the "C1_6 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
In the present specification, examples of the "optionally halogenated C1_6 alkoxy group" include a C1_6 alkoxy group
optionally having 1 to 7, preferably 1 to 5, halogen atoms.
Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2 , 2 , 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4 , 4 , 4-trifluorobutoxy, isobutoxy, sec- butoxy, pentyloxy and hexyloxy.
In the present specification, examples of the "C3-10 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy. In the present specification, examples of the "C1_6 alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
In the present specification, examples of the "optionally halogenated C1_6 alkylthio group" include a C1_6 alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio,- propylthio, isopropylthio, butylthio, 4 , 4 , 4-trifluorobutylthio, pentylthio and hexylthio.
In the present specification, examples of the "C1_6 alkyl- carbonyl group" include acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 3-methylbutanoyl , 2-methylbutanoyl, 2 , 2-dimethylpropanoyl, hexanoyl and heptanoyl.
In the present specification, examples of the "optionally halogenated C1_6 alkyl-carbonyl group" include a C1_6 alkyl- carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl , trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
In the present specification, examples of the "C1_6 alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl , butoxycarbonyl ,
isobutoxycarbonyl , sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl .
In the present specification, examples of the "C6-14 aryl- carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.
In the present specification, examples of the "C7-16 aralkyl-carbonyl group" include phenylacetyl and
phenylpropionyl .
In the present specification, examples of the "5- to 14- membered aromatic heterocyclylcarbonyl group" include
nicotinoyl, isonicotinoyl , thenoyl and furoyl.
In the present specification, examples of the "3- to 14- membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and
pyrrolidinylcarbonyl .
[0101]
In the present specification, examples of the "mono- or di-C1_6 alkyl-carbamoyl group" include methylcarbamoyl ,
ethylcarbamoyl , dimethylcarbamoyl , diethylcarbamoyl and N- ethyl-N-methylcarbamoyl .
In the present specification, examples of the "mono- or di-C7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl .
In the present specification, examples of the "C1_6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl , isopropylsulfonyl , butylsulfonyl, sec- butylsulfonyl and tert-butylsulfonyl .
In the present specification, examples of the "optionally halogenated C1_6 alkylsulfonyl group" include a C1_6
alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include
methylsulfonyl , difluoromethylsulfonyl , trifluoromethylsulfonyl, ethylsulfonyl , propylsulfonyl , isopropylsulfonyl , butylsulfonyl, 4 , 4 , 4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl .
In the present specification, examples of the "C6-14 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl .
[0102]
In the present specification, examples of the
"substituent" include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an
optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally
substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group. In the present specification, examples of the "hydrocarbon group" (including "hydrocarbon group" of
"optionally substituted hydrocarbon group") include a C1_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.
[0103]
In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group optionally having substituent ( s ) selected from the following substituent group A.
[substituent group A]
(1) a halogen atom,
(2) a nitro group,
(3) a cyano group,
(4) an oxo group,
(5) a hydroxy group,
(6) an optionally halogenated C1_6 alkoxy group,
(7) a C6-14 aryloxy group (e.g., phenoxy, naphthoxy) ,
(8) a C7-16 aralkyloxy group (e.g., benzyloxy) , .
(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy) ,
(10) a 3- to 14-membered non-aromatic heterocyclyloxy group
(e.g . , morpholinyloxy, piperidinyloxy) ,
(11) a C1_6 alkyl-carbonyloxy group (e.g., acetoxy,
propanoyloxy) ,
(12) a C6-14 aryl-carbonyloxy group (e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy) ,
(13) a C1_6 alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) ,
(14) a mono- or di-C1_6 alkyl-carbamoyloxy group (e.g.,
methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy) ,
(15) a aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy) , (16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy) ,
(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy) , (18) an optionally halogenated C1_6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy) ,
(19) a C6-14 arylsulfonyloxy group optionally substituted by a C1_6 alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy) ,
(20) an optionally halogenated C1-6 alkylthio group,
(21) a 5- to 14-membered aromatic heterocyclic group,
(22) a 3- to 14-membered non-aromatic heterocyclic group,
(23) a formyl group,
(24) a carboxy group,
(25) an optionally halogenated C1_6 alkyl-carbonyl group,
(26) a C6-14 aryl-carbonyl group,
(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,
(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,
(29) a C1_6 alkoxy-carbonyl group,
(30) a C6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl , 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl ) ,
(31) a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl ) , .
(32) a carbamoyl group,
(33) a thiocarbamoyl group,
(34) a mono- or di-C1_6 alkyl-carbamoyl group,
(35) a C6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl ) ,
(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl) ,
(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl , piperidinylcarbamoyl ) ,
(38) an optionally halogenated C1_6 alkylsulfonyl group,
(39) a C6-14 arylsulfonyl group,
(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl ) , (41) an optionally halogenated C1_6 alkylsulfinyl group,
(42) a C6-14 arylsulfinyl group (e.g., phenylsulfinyl , 1- naphthylsulfinyl, 2-naphthylsulfinyl) ,
(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl) ,
(44) an amino group,
(45) a mono- or di-C1_6 alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino,
dimethylamino, diethylamino, dipropylamino, dibutylamino, N- ethyl-N-methylamino) ,
(46) a mono- or di-C6-14 arylamino group (e.g., phenylamino) ,
(47) a 5-: to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino) ,
(48) a C7-16 aralkylamino group (e.g., benzylamino) ,
(49) a formylamino group,
(50) a C1_6 alkyl-carbonylamino group (e.g., acetylamino,
propanoylamino, butanoylamino) ,
(51) a (C1_6 alkyl) (C1_6 alkyl-carbonyl ) amino group (e.g., N- acetyl-N-methylamino) ,
(52) a C6-14 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino) ,
(53) a C1_6 alkoxy-carbonylamino group (e.g.,
methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino) ,
(54) a C7-16 aralkyloxy-carbonylamino group (e.g.,
benzyloxycarbonylamino) ,
(55) a C1_6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) ,
(56) a C6-14 arylsulfonylamino group optionally substituted by a C1_6 alkyl group (e.g., phenylsulfonylamino,
toluenesulfonylamino) ,
(57) an optionally halogenated C1_6 alkyl group,
(58) a C2-6 alkenyl group,
(59) a C2-6 alkynyl group,
(60) a C3-10 cycloalkyl group, (61) a C3-10 cycloalkenyl group and
(62) a C6-14 aryl group.
[0104]
The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different .
In the present specification, examples of the
"heterocyclic group" (including "heterocyclic group" of
"optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
[0105]
In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the "aromatic heterocyclic group" include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, 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, triazinyl and the like; and
8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromatic heterocyclic groups such as benzothiophenyl ,
benzofuranyl, benzimidazolyl, benzoxazolyl , benzisoxazolyl , benzothiazolyl, benzisothiazolyl, benzotriazolyl ,
imidazopyridinyl, thienopyridinyl , furopyridinyl , pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl ,
thiazolopyridinyl, imidazopyrazinyl , imidazopyrimidinyl , thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2, 3-b] thienyl, phenoxathiinyl, indolyl, isoindolyl, lH-indazolyl , purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl , quinoxalinyl ,
quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl,
phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.
[0106]
In the present specification, examples of the "non- aromatic heterocyclic group" (including "3- to 14-membered non- aromatic heterocyclic group") include a 3- to 14-membered
(preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the "non-aromatic heterocyclic group" include 3- to 8-membered monocyclic non-aromatic
heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl,
tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl , imidazolinyl , imidazolidinyl , oxazolinyl, oxazolidinyl , pyrazolinyl,
pyrazolidinyl, thiazolinyl, thiazolidinyl,
tetrahydroisothiazolyl, tetrahydrooxazolyl ,
tetrahydroisooxazolyl , piperidinyl, piperazinyl,
tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl , tetrahydropyrimidinyl, tetrahydropyridazinyl , dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl , morpholinyl,
thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and
9- to 14-membered fused polycyclic (preferably bi or tricyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl , dihydrobenzothiazolyl , dihydrobenzisothiazolyl,
dihydronaphtho [2, 3-b] thienyl, tetrahydroisoquinolyl ,
tetrahydroquinolyl, 4H-quinolizinyl , indolinyl, isoindolinyl, tetrahydrothieno [2 , 3-c] pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl,
hexahydrophenothiazinyl, hexahydrophenoxazinyl ,
tetrahydrophthalazinyl, tetrahydronaphthyridinyl,
tetrahydroquinazolinyl, tetrahydrocinnolinyl,
tetrahydrocarbazolyl, tetrahydro-β-carbolinyl,
tetrahydroacrydinyl, tetrahydrophenazinyl,
tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.
[0107]
In the present specification, preferable examples of the "7- to 10-membered bridged heterocyclic group" include
quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl .
In the present specification, examples of the "nitrogen- containing heterocyclic, group" include the "heterocyclic group" containing at least one nitrogen atom as a ring-constituting atom.
In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group optionally having substituent ( s ) selected from the
aforementioned substituent group A.
The number of the substituents in the "optionally
substituted heterocyclic group" is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
[0108]
In the present specification, examples of the "acyl group" include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having "1 or 2 substituents selected from a C1_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group, a C7-16 aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group".
Examples of the "acyl group" also include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group.
Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the
hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group.
Preferable examples of the "acyl group" include a formyl group, a carboxy group, a C1_6 alkyl-carbonyl group, a C2-6 alkenyl-carbonyl group (e.g., crotonoyl) , a C3-1o cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl , cycloheptanecarbonyl) , a C3-10
cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl ) , a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C1_6 alkoxy- carbonyl group, a C6-14 aryloxy-carbonyl group (e.g.,
phenyloxycarbonyl, naphthyloxycarbonyl ) , a C7-16 aralkyloxy- carbonyl group (e.g., benzyloxycarbonyl , phenethyloxycarbonyl ) , a carbamoyl group, a mono- or di-C1_6 alkyl-carbamoyl group, a mono- or di-C2-6 alkenyl-carbamoyl group (e.g.,
diallylcarbamoyl ) , a mono- or di-C3-10 cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl ) , a mono- or di-Cs-14 aryl- carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C7_16 aralkyl-carbamoyl group, a 5- to 14-membered aromatic
heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl) , a
thiocarbamoyl group, a mono- or di-C1_6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl) , a mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl ) , a mono- or di-C3-10
cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl) , a mono- or di-C6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C7-16 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl ,
phenethylthiocarbamoyl) , a 5- to 14-membered aromatic
heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) , a sulfino group, a C1_6 alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl ) , a sulfo group, a C1_6 alkylsulfonyl group, a C6- 14 arylsulfonyl group, a phosphono group and a mono- or di-C1_6 alkylphosphono group (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) .
[0109]
In the present specification, examples of the "optionally substituted amino group" include an amino group optionally having "1 or 2 substituents selected from a C1_6 alkyl group, a C2-6 alkenyl group, a C3-.10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1_6 alkyl-carbonyl group, a C6-14 aryl- carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C1_6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group, a mono- or di-C7-16 aralkyl-carbamoyl group, a C1_6 alkylsulfonyl group and a C6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
Preferable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally
halogenated C1_6 alkyl) amino group (e.g., methylamino,
trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino) , a mono- or di-C2-6 alkenylamino group (e.g., diallylamino) , a mono- or di-C3-io cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino) , a mono- or di- C6-14 arylamino group (e.g., phenylamino) , a mono- or di-C7-16 aralkylamino group (e.g., benzylamino, dibenzylamino) , a mono- or di- (optionally halogenated C1_6 alkyl ) -carbonylamino group (e.g., acetylamino, propionylamino) , a mono- or di-C6-14 aryl- carbonylamino group (e.g., benzoylamino) , a mono- or di-C7-16 aralkyl-carbonylamino group (e.g., benzylcarbonylamino) , a mono- or di-5- to 14-membered aromatic
heterocyclylcarbonylamino group (e.g., nicotinoylamino,
isonicotinoylamino) , a mono- or di-3- to 14-membered non- aromatic heterocyclylcarbonylamino group (e.g.,
piperidinylcarbonylamino) , a mono- or di-C1_6 alkoxy- carbonylamino group (e.g., tert-butoxycarbonylamino) , a 5- to 14-membered aromatic heterocyclylamino group (e.g.,
pyridylamino) , a carbamoylamino group, a (mono- or di-C1-6 alkyl-carbamoyl ) amino group (e.g., methylcarbamoylamino) , a (mono- or di-C7-16 aralkyl-carbamoyl ) amino group (e.g.,
benzylcarbamoylamino) , a C1_6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) , a C6-14
arylsulfonylamino group (e.g., phenylsulfonylamino) , a (C1_6 alkyl) (C1_6 alkyl-carbonyl ) amino group (e.g., N-acetyl-N- methylamino) and a (C1_6 alkyl) (C6-14 aryl-carbonyl) amino group (e.g., N-benzoyl-N-methylamino) .
[0110]
In the present specification, examples of the "optionally substituted carbamoyl group" include a carbamoyl group
optionally having "1 or .2 substituents selected from a C1_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce- 14 aryl group, a C7_16 aralkyl group, a C1_6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C1_6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1_6 alkyl-carbamoyl group and a mono- or di-C7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A" . Preferable examples of the optionally substituted
carbamoyl group include a carbamoyl group, a mono- or di-C1_6 alkyl-carbamoyl group, a mono- or di-C2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C3-10 cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,
cyclohexylcarbamoyl ) , a mono- or di-C6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C7-16 aralkyl-carbamoyl group, a mono- or di-C1_6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl ) , a mono- or di-C6-14 aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,
pyridylcarbamoyl ) .
[0111]
In the present specification, examples of the "optionally substituted thiocarbamoyl group" include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a C1_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a Ce- 14 aryl group, a C7-16 aralkyl group, a C1_6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C1_6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1_6 alkyl-carbamoyl group and a mono- or di-C7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A" .
Preferable examples of the optionally substituted
thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C1_6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl , ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl) , a mono- or di-C2-6 alkenyl- thiocarbamoyl group (e.g., diallylthiocarbamoyl ) , a mono- or di-C3-10 cycloalkyl-thiocarbamoyl group (e.g.,
cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl) , a mono- or di-C6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl ) , a mono- or di-C7-16 aralkyl-thiocarbamoyl group (e.g.,
benzylthiocarbamoyl , phenethylthiocarbamoyl ) , a mono- or di-C1_6 alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl , propionylthiocarbamoyl) , a mono- or di-C6-14 aryl-carbonyl- thiocarbamoyl group (e.g., benzoylthiocarbamoyl ) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl ) .
[0112]
In the present specification, examples of the "optionally substituted sulfamoyl group" include a sulfamoyl group
optionally having "1 or 2 substituents selected from a C^g alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6- 14 aryl group, a C7-16 aralkyl group, a C1_6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C1_6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1_6 alkyl-carbamoyl group and " a mono- or di-C7-16 aralkyl-carbamoyl group, each of which
optionally has 1 to 3 substituents selected from substituent group A" .
Preferable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di-C1_6 alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl , dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl) , a mono- or di-C2-6 alkenyl-sulfamoyl group (e.g.,
diallylsulfamoyl ) , a mono- or di-C3-10 cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl) , a mono- or di-C6-14 aryl-sulfamoyl group (e.g., phenylsulfamoyl) , a mono- or di-C7-16 aralkyl-sulfamoyl group (e.g.,
benzylsulfamoyl, phenethylsulfamoyl ) , a mono- or di-C1_6 alkyl- carbonyl-sulfamoyl group (e.g., acetylsulfamoyl,
propionylsulfamoyl) , a mono- or di-C6-14 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl ) and a 5- to 14-membered aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl) . [0113]
In the present specification, examples of the "optionally substituted hydroxy group" include a hydroxyl group optionally having "a substituent selected from a C1_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7_ 16 aralkyl group, a C1_6 alkyl-carbonyl group, a C6-14 aryl- carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C1_6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1_6 alkyl-carbamoyl group, a mono- or di-C7-16 aralkyl-carbamoyl group, a C1_6 alkylsulfonyl group and a C6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a C1_6 alkoxy group, a C2-6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) , a C3-10 cycloalkyloxy group (e.g., cyclohexyloxy) , a C6-14 aryloxy group (e.g., phenoxy, naphthyloxy) , a C7-16 aralkyloxy group (e.g., benzyloxy, phenethyloxy) , a C1_6 alkyl- carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy) , a C6-14 aryl-carbonyloxy group
(e.g., benzoyloxy) , a C7-16 aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy) , a 5- to 14-membered aromatic
heterocyclylcarbonyloxy group (e.g., nicotinoyloxy) , a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy) , a C1_6 alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy) , a 5- to 14-membered aromatic
heterocyclyloxy group (e.g., pyridyloxy) , a carbamoyloxy group, a C1_6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy) , a C7-16 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy) , a C1_6 alkylsulfonyloxy group (e.g., methylsulfonyloxy,
ethylsulfonyloxy) and a C6-14 arylsulfonyloxy group (e.g., phenylsulfonyloxy) .
[0114] In the present . specification, examples of the "optionally substituted sulfanyl group" include a sulfanyl group optionally having "a substituent selected from a C1_6 alkyl group, a C2_6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7_ i6 aralkyl group, a C1_6 alkyl-carbonyl group, a C6-14 aryl- carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents
selected from substituent group A" and a halogenated sulfanyl group .
Preferable examples of the optionally substituted
sulfanyl group include a sulfanyl (-SH) group, a C1_6 alkylthio group, a C2_6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C3-10 cycloalkylthio group (e.g., cyclohexylthio) , a C6-14 arylthio group (e.g., phenylthio, naphthylthio) , a C7-16 aralkylthio group (e.g., benzylthio, phenethylthio) , a C1_6 alkyl-carbonylthio group (e.g.,
acetylthio, propionylthio, butyrylthio, isobutyrylthio,
pivaloylthio) , a C6-14 aryl-carbonylthio group (e.g.,
benzoylthio) , a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio) .
[0115]
In the present specification, examples of the "optionally substituted silyl group" include a silyl group optionally having "1 to 3 substituents selected from a C1_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group and a C7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
Preferable examples of the optionally substituted silyl group include a tri-C1_6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl (dimethyl) silyl) .
[0116]
In the present specification, examples of the "C1_6 alkylene group" include -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, - (CH2)5-, -(CH2)6-/ -CH(CH3)-, -C(CH3)2-, -CH(C2H5)-, -CH(C3H7)-, - CH (CH (CH3)2) -/ -(CH(CH3))2-/ -CH2-CH (CH3) -, -CH (CH3) -CH2-, -CH2- CH2-C(CH3)2-, -C(CH3)2-CH2-CH2-, -CH2-CH2-CH2-C (CH3) 2- and - C(CH3)2-CH2-CH2-CH2-.
In the present specification, examples of the "C2_6 alkenylene group" include -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, - C (CH3) 2-CH=CH-, -CH=CH-C (CH3) 2-, -CH2-CH=CH-CH2- , -CH2-CH2-CH=CH-, -CH=CH-CH2-CH2-, -CH=CH-CH=CH-, -CH=CH-CH2-CH2-CH2- and -CH2-CH2- CH2-CH=CH-.
In the present specification, examples of the "C2_6 alkynylene group" include -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -
C (CH3)2-C≡C-, -C≡C-C(CH3)2-, -CH2-C≡C-CH2-, -CH2-CH2-C≡C-, -C≡ C-CH2-CH2-, -C≡OC≡C-, -C≡C-CH2-CH2-CH2- and -CH2-CH2-CH2-C≡C- .
[0117]
In the present specification, examples of the
"hydrocarbon ring" include a C6-14 aromatic hydrocarbon ring, C3_ 10 cycloalkane and C3-10 cycloalkene.
In the present specification, examples of the "C6-14 aromatic hydrocarbon ring" include benzene and naphthalene.
In the present specification, examples of the "C3-10 cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
In the present specification, examples of the "C3-10 cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
In the present specification, examples of the
"heterocycle" include an aromatic heterocycle and a non- aromatic heterocycle, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
[0118]
In the present specification, examples of the "aromatic heterocycle" include a 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocycle containing, as a ring- constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "aromatic heterocycle" include 5- or 6-membered monocyclic aromatic heterocycles such as 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, triazine and the like; and 8- to 14-membered fused polycyclic (preferably bi or tricyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine,
oxazolopyridine, thiazolopyridine, imidazopyrazine,
imidazopyrimidine, thienopyrimidine, furopyrimidine,
pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2, 3-b] thiophene, phenoxathiin, indole, isoindole, 1H- indazole, purine, isoquinoline, quinoline, phthalazine,
naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine and the like.
[0119]
In the present specification, examples of the "non- aromatic heterocycle" include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazdlidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine , tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridihe, dihydrothiopyran,
tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine,
thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, oxepane and the like; and
9- to 14-membered fused polycyclic (preferably bi or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran,
dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho [2 , 3-b] thiophene,
tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno [2 , 3-c] pyridine,
tetrahydrobenzazepine, tetrahydroquinoxaline,
tetrahydrophenanthridine, hexahydrophenothiazine,
hexahydrophenoxazine, tetrahydrophthalazine,
tetrahydronaphthyridine, tetrahydroquinazoline,
tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β- carboline, tetrahydroacridine, tetrahydrophenazine,
tetrahydrothioxanthene, octahydroisoquinoline and the like.
In the present specification, examples of the "nitrogen- containing heterocycle" include the "heterocycle" containing at least one nitrogen atom as a ring-constituting atom.
[0120]
In the present specification, the "hydrocarbon ring" also includes a nonaromatic hydrocarbon ring. Examples of the nonaromatic hydrocarbon ring include a C6-14 nonaromatic
hydrocarbon ring (e.g., tetrahydronaphthalene ring).
In the present specification, as the "ring" of the
"optionally further substituted ring", the above-mentioned
"hydrocarbon ring" and "heterocycle" can be mentioned and, as the substituent thereof, the above-mentioned "substituent" can be mentioned.
In the present specification, as the "6- or 7-membered oxygen-containing heterocycle" of the "optionally further substituted 6- or 7-membered. oxygen-containing heterocycle", a 6- or 7-membered monocyclic non-aromatic heterocycle (e.g., a dihydropyran ring, a dihydrooxazine ring, tetrahydrooxepine ring, tetrahydrooxazepine ring) containing, as a ring- constituting atom, one oxygen atom besides carbon atom, and optionally containing one more nitrogen atom can be mentioned, and as the substituent thereof, the above-mentioned
"substituent" can be mentioned.
In the present specification, as the "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring", a benzene ring and the above-mentioned 6- membered "aromatic heterocycle" can be mentioned, and as the substituent thereof, the above-mentioned "substituent" can be mentioned.
In the present specification, as the "C1_2 alkylene" of the "optionally halogenated C1_2 alkylene", the above-mentioned "C1_6 alkylene group" having 1 or 2 carbon atoms can be
mentioned, which may have 1 to 4 "halogen atoms" mentioned above.
[0121]
The definition of each symbol in the formula (Ι') is described in detail below.
Ring A is an optionally further substituted ring.
As the "ring" of the "optionally further substituted ring" for ring A, the above-mentioned "hydrocarbon ring" and "heterocycle" can be mentioned. It is preferably C3-10
cycloalkane (e.g., cyclohexane) , C6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), C6-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring), 5- to 14- membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, guinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic
heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , more preferably a benzene ring, a pyridine ring, an indazole ring or a pyrazolopyridine ring.
[0122]
The "ring" of the "optionally further substituted ring" for ring A is optionally further substituted by 1 - 5
(preferably 1 - 3, more preferably 1 or 2) substituents other than -L1- (ring B' ) (ring C ) - group at substitutable position (s). As the substituent thereof, the above-mentioned "substituent" can be mentioned, and
preferred is (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) , (5) an optionally substituted C1-6 alkoxy group (e.g., methoxy, ethoxy) , (6) an optionally
substituted C3-10 cycloalkyl group (e.g., cyclopropyl,
cyclobutyl) , (7) an optionally substituted C3-10 cycloalkyloxy group (e.g., cyclopropyloxy) , (8) an optionally substituted C5_ 14 aryl group (e.g., phenyl), (9) an optionally substituted C6-14 aryloxy group (e.g., phenoxy) , (10) an optionally substituted 3- to 14-membered nonaromatic heterocyclic group (e.g.,
oxetanyl, morpholinyl, piperazinyl) , (11) an optionally
substituted 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl ) , (12) an optionally substituted C1_6 alkyl-carbonyl group (e.g., acetyl), (13) an optionally substituted 5- to 14-membered aromatic
heterocyclyloxy group (e.g., pyrazinyloxy) or (14) an
optionally substituted C1-6 alkoxy-carbonyl group (e.g., tert- butoxycarbonyl) ,
more preferred is (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) a C1_6 alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl)
optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C1_6 alkoxy group (e.g., methoxy), (5) a Cx-g alkoxy group (e.g., methoxy, ethoxy)
optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, a C3_10 cycloalkyl group (e.g., cyclopropyl ) , a C6-14 aryl group (e.g., phenyl) and a carbamoyl group, (6) a .C3-10 cycloalkyl group
(e.g., cyclopropyl, cyclobutyl) optionally substituted by 1 - 3 substituents selected from a C1-6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a cyano group and a hydroxy group, (7) a C3-10 cycloalkyloxy group (e.g.,
cyclopropyloxy) , (8) a C6-14 aryl group (e.g., phenyl)
optionally substituted by 1 - 3 substituents selected from a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a C1_6 alkoxy group (e.g., methoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., chlorine atom) and a cyano group, (9) a Ce-14 aryloxy group (e.g., phenoxy) , (10) a 3- to 14-membered nonaromatic heterocyclic group (e.g.,
oxetanyl, morpholinyl, piperazinyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C1_6 alkyl group (e.g., methyl), (11) a 5- to 14- membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl) , (12) a C1_6 alkyl-carbonyl group (e.g., acetyl), (13) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) or (14) a C1_6 alkoxy-carbonyl group (e.g., tert-butoxycarbonyl) ,
further preferred is (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C1_6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C1_6 alkoxy groups (e.g., methoxy), (4) a C1_6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) or (5) a C3-10 cycloalkyl group (e.g.,
cyclopropyl) optionally substituted by 1 - 3 C1_6 alkyl groups (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom).
[0123]
Ring A is preferably C3-10 cycloalkane (e.g., cyclohexane) , a C6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a C6-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring) , a 5- to 14-membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5
(preferably 1 - 3, more preferably 1 or 2) substituents
selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) , (5) an optionally substituted C1_6 alkoxy group (e.g., methoxy, ethoxy) , (6) an optionally substituted C3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) , (7) an
optionally substituted C3-10 cycloalkyloxy group (e.g.,
cyclopropyloxy) , (8) an optionally substituted C6-14 aryl group (e.g., phenyl), (9) an optionally substituted C6-14 aryloxy group (e.g., phenoxy) , (10) an optionally substituted 3- to 14- membered nonaromatic heterocyclic group (e.g., oxetanyl,
morpholinyl, piperazinyl) , (11) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl,
pyrazolyl, pyridyl, pyrimidinyl ) , (12) an optionally
substituted C1_6 alkyl-carbonyl group (e.g., acetyl), (13) an optionally substituted 5- to 14-membered aromatic
heterocyclyloxy group (e.g., pyrazinyloxy) and (14) an
optionally substituted C1_6 alkoxy-carbonyl group (e.g., tert- butoxycarbonyl ) ,
more preferably, C3-10 cycloalkane (e.g., cyclohexane) , a C6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a C6-14 nonaromatic hydrocarbon ring (e.g.,
tetrahydronaphthalene ring) , a 5- to 14-membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran - ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5
(preferably 1 - 3, more preferably 1 or 2) substituents
selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) a C1_6 alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C1_6 alkoxy group (e.g., methoxy) , (5) a C1_6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, a C3-10 cycloalkyl group (e.g., cyclopropyl) , a C6-14 aryl group (e.g., phenyl) and a carbamoyl group, (6) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionally substituted by 1 - 3 substituents
selected from a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a cyano group and a hydroxy group, (7) a C3-10 cycloalkyloxy group (e.g., cyclopropyloxy) , (8) a C6-14 aryl group (e.g., phenyl) optionally substituted by 1 - 3 substituents selected from a C1_6 alkyl group (e.g., methyl ) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a C1_6 alkoxy group (e.g., methoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., chlorine atom) and a cyano group, (9) a C6_ 14 aryloxy group (e.g., phenoxy) , (10) a 3- to 14-membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl, piperazinyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C1-6 alkyl group (e.g., methyl), (11) a 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl) , (12) a C1_6 alkyl-carbonyl group (e.g., acetyl), (13) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) and (14) a C1_6 alkoxy-carbonyl group (e.g., tert- butoxycarbonyl ) ,
further preferably, a benzene ring, a pyridine ring, an indazole ring or a pyrazolopyridine ring, each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C1_6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C1_6 alkoxy groups (e.g., methoxy), (4) a C1_6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) and (5) a C3-10 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 - 3 C1_6 alkyl groups (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom).
[0124]
L1 is a bond, optionally halogenated C1_2 alkylene, -NH- or -0- .
L1 is preferably a bond, C1_2 alkylene (e.g., -CH2-, - (CH2)2-/ -CH(CH3)-), -NH- or -0-, more preferably a bond, C1_2 alkylene (e.g., -CH2-) or -NH- .
[0125]
The partial structure:
[0126]
[Chem. 46]
Figure imgf000047_0001
[0127]
is
[0128]
[Chem.
Figure imgf000047_0002
[0129]
X is a carbon atom or a nitrogen atom, n is an integer of 1 or 2, ring B is an optionally further substituted 6- or 7-membered oxygen-containing heterocycle, Y1, Y2 and Y3 are each
independently a carbon atom or a nitrogen atom, ring C is an optionally further substituted 6-membered aromatic ring, and Y4 is =CH- or =N-.
The "6- or 7-membered oxygen-containing heterocycle" of the "optionally further substituted 6- or 7-membered oxygen- containing heterocycle" for ring B is preferably a dihydropyran ring (that is, X is a carbon atom, and n is 1) , a
dihydrooxazine ring (that is, X is a nitrogen atom and n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom and n is 2 ) .
[0130]
The "6- or 7-membered oxygen-containing heterocycle" of the "optionally further substituted 6- or 7-membered oxygen- containing heterocycle" for ring B is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents other than ring A-L1- group at substitutable position (s ) . As the substituent thereof, the above-mentioned "substituent" can be mentioned, which is preferably (1) an oxo group or (2) an optionally substituted C1_6 alkyl group (e.g., methyl), more preferably (1) an oxo group or (2) a C1- 6 alkyl group (e.g., methyl).
[0131]
Ring B is preferably a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) an optionally substituted C1_ 6 alkyl group (e.g., methyl), more preferably, a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2)
substituents selected from (1) an oxo group and (2) a C1-6 alkyl group (e.g., methyl).
[0132]
In one embodiment of the present invention, ring B is preferably a 6- or 7-membered oxygen-containing heterocycle optionally further substituted by a methyl group, more
preferably a 6- or 7-membered oxygen-containing heterocycle not further substituted.
[0133]
The "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring" for ring C is preferably a benzene ring (that is, Y1, Y2 and Y3 are carbon atoms) or a pyridine ring (that is, Y1 is a nitrogen atom, Y2 and Y3 are carbon atoms or Y1 and Y2 are carbon atoms, Y3 is a nitrogen atom) .
[0134]
The "6-membered aromatic ring" of the "optionally further substituted 6-membered aromatic ring" for ring C is optionally further substituted by 1 - 3 (preferably 1 - 2, more preferably 1) substituents other than -C (=0) N (H) - group at substitutable position(s). As the substituent thereof, the above-mentioned "substituent" can be mentioned.
[0135]
Ring C is preferably a benzene. ring (that is, Y1, Y2 and Y3 are carbon atoms) or a pyridine ring (preferably, Y1 is a nitrogen atom, Y2 and Y3 are carbon atoms or Y1 and Y2 are carbon atoms, Y3 is a nitrogen atom) .
[0136]
Y4 is preferably =N- . That is, in one embodiment of the present invention, the partial structure:
[0137]
[Chem. 48]
Figure imgf000049_0001
[0138]
is preferably
[0139]
[Chem. 49]
Figure imgf000049_0002
[0140]
wherein each symbol is as defined above.
[0141]
In one embodiment of the present invention, ring A is preferably [0142]
[Chem. 50]
Figure imgf000050_0001
[0143]
L1 is preferably a bond;
R1 is preferably a hydrogen atom or a hydroxymethyl group;
R2 is preferably a hydrogen atom;
ring D is preferably
[0144]
[Chem. 51]
Figure imgf000050_0002
[0145]
wherein
W is =CR5- or =N-;
R5 is a hydrogen atom, -C02C2H5, -CH2OH, -C02H, -CONH2 or
CN;
L2 is preferably -S02-; and
R3 is preferably -CH3 or -C2H5.
[0146]
In another embodiment of the present invention, the partial structure:
[0147]
[Chem. 52]
Figure imgf000051_0001
[0148]
is preferably
[0149]
[Chem. 53]
Figure imgf000051_0002
[0150]
wherein each symbol is as defined above.
[0151]
R1 and R2 are each independently a hydrogen atom or a substituent, R1 and Rz may be bonded together with an adjacent carbon atom to form an optionally further substituted ring, or R1 and R2 may be joined together to form an oxo group.
As the "substituent" for R1 or R2, the above-mentioned "substituent" can be mentioned, preferably, (1) an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl) or (2) an optionally substituted C1_6 alkoxy-carbonyl group (e.g., methoxycarbonyl) , more preferably, (1) a C1-g alkyl group (e.g., methyl, ethyl) optionally substituted by 1 - 3 substituents selected from a hydroxy group and a carboxy group or (2) a C1_6 alkoxy-carbonyl group (e.g., methoxycarbonyl).
As the "ring" of the "optionally further substituted ring" optionally formed by R1 and R2 bonded together with the adjacent carbon atom, the above-mentioned "hydrocarbon ring" and "heterocycle" can be mentioned, preferably, C3-1o
cycloalkane (e.g., cyclopropane ring). The "ring" is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents other than -C(=0)N(H)- group and R3-L2-ring D- group at substitutable position (s) . As the substituent thereof, the above-mentioned "substituent" can be mentioned.
[0152]
R1 and R2 are preferably each independently (1) a
hydrogen atom, (2) an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl) or (3) an optionally substituted C1_6 alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form an optionally further substituted C3-10 cycloalkane (e.g., cyclopropane ring), more preferably (1) a hydrogen atom, (2) a C1_6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 - 3
substituents selected from a hydroxy group and a carboxy group or (3) a C1_6 alkoxy-carbonyl group (e.g., methoxycarbonyl), or (4) bonded together with the adjacent carbon atom to form C3-10 cycloalkane (e.g., cyclopropane ring), further preferably, (1) both hydrogen atoms or (2) one is a hydrogen atom and the other is a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 hydroxy groups .
[0153]
Ring D is an optionally further substituted ring.
As the "ring" of the "optionally further substituted ring" for ring D, the above-mentioned "hydrocarbon ring" and "heterocycle" can be mentioned, preferably, a C6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring) , more preferably a benzene ring, a pyridine ring, a pyrimidine ring or a piperidine ring.
[0154]
The "ring" of the "optionally further substituted ring" for ring D is optionally further substituted by 1 - 4
(preferably 1 - 3, more preferably 1 or 2) substituents other than -N (H) -C (R1) (R2) - group and R3-L2- group at substitutable position (s). As the substituent thereof, the above-mentioned "substituent" can be mentioned, preferably, a halogen atom (e.g., fluorine atom), a cyano group, an optionally substituted C1_6 alkyl group (e.g., methyl), a carboxyl group, an optionally substituted C1_6 alkoxy-carbonyl group (e.g., ethoxycarbonyl ) or an optionally substituted carbamoyl group, more preferably, (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C1_6 alkoxy-carbonyl group (e.g., ethoxycarbonyl) or (6) a carbamoyl group.
[0155]
Ring D is preferably a C6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, an optionally substituted C1_6 alkyl group (e.g., methyl), a carboxyl group, an optionally substituted Cis alkoxy-carbonyl group (e.g., ethoxycarbonyl) and an optionally substituted carbamoyl group, more preferably, a C6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non- aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C1_6 alkoxy-carbonyl group (e.g., ethoxycarbonyl) and (6) a carbamoyl group.
[0156]
L2 is -SO2-, -S(=0)- or -S(=0) (=NR4) -, R4 is a hydrogen atom or a substituent. As the "substituent" for R4, the above-mentioned
"substituent" can be mentioned, which is preferably an
optionally substituted C1_6 alkyl group (e.g., methyl), more preferably a C1_6 alkyl group (e.g., methyl).
L2 is preferably -S02- or -S (=0) (=NR4)- (R4 is a hydrogen atom or an optionally substituted C1-6 alkyl group (e.g., methyl)), more preferably, -S02- or -S (=0) (=NR4) - (R4 is a hydrogen atom or a C1_6 alkyl group (e.g., methyl)), further preferably, -S02- or -S (=0) (=NR4) - (R4 is a hydrogen atom).
[0157]
R3 is a substituent.
As the "substituent" for R3, the above-mentioned
"substituent" can be mentioned.
R3 is preferably an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group, more preferably a C1_6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C1_6 alkyl groups (e.g., methyl).
[0158]
Preferable examples of compound (Ι') are, for example, the following compounds.
[Compound A-l]
Compound (Ι') wherein
ring A is C3-10 cycloalkane (e.g., cyclohexane) , a C6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a C6-14 nonaromatic hydrocarbon ring (e.g.,
tetrahydronaphthalene ring) , a 5- to 14-membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5
(preferably 1 - 3, more preferably 1 or 2) substituents
selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4)- an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) , (5) an optionally substituted C1_6 alkoxy group (e.g., methoxy, ethoxy) , (6) an optionally substituted C3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) , (7) an optionally substituted C3-10 cycloalkyloxy group (e.g.,
cyclopropyloxy) , (8) an optionally substituted C6-14 aryl group (e.g., phenyl), (9) an optionally substituted C6-14 aryloxy group (e.g., phenoxy) , (10) an optionally substituted 3- to 14- membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl, piperazinyl) , (11) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl, pyrimidinyl) , (12) an optionally
substituted C1_6 alkyl-carbonyl group (e.g., acetyl), (13) an optionally substituted 5- to 14-membered aromatic
heterocyclyloxy group (e.g., pyrazinyloxy) and (14) an
optionally substituted C1_6 alkoxy-carbonyl group (e.g., tert- butoxycarbonyl ) ;
L1 is a bond, C1_2 alkylene (e.g., -CH2-, - (CH2) 2 - , ~
CH(CH3)-), -NH- or -0-;
the partial structure :
[0159]
[Chem. 54]
Figure imgf000055_0001
[0160]
is [0161]
[Chem. 55]
Figure imgf000056_0001
X is a carbon atom or a nitrogen atom;
n is an integer of 1 or 2;
ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1) , a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) an
optionally substituted C1_6 alkyl group (e.g., methyl);
Y1, Y2 and Y3 are each independently a carbon atom or a nitrogen atom;
ring C is a benzene ring (that is, Y1, Y2 and Y3 are carbon atoms) or a pyridine ring (preferably, Y1 is a nitrogen atom, Y2 and Y3 are carbon atoms or Y1 and Y2 is a carbon atom, Y3 is a nitrogen atom) ;
Y4 is =CH- or =N-;
R1 and R2 are each independently (1) a hydrogen atom, (2) an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl) or (3) an optionally substituted C1_6 alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form optionally further substituted C3_ io cycloalkane (e.g., cyclopropane ring);
ring D is a C6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, an optionally substituted C1_6 alkyl group (e.g., methyl), a carboxyl group, an optionally substituted C1_6 alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and an optionally substituted carbamoyl group;
L2 is -S02- or -S(=0) (=NR4) - (R4 is a hydrogen atom or an optionally substituted C1_6 alkyl group (e.g., methyl)); and
R3 is an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group.
[0163]
[Compound B-l]
Compound (Ι') wherein
ring A is C3-10 cycloalkane (e.g., cyclohexane) , a C6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a Ce-14 nonaromatic hydrocarbon ring (e.g.,
tetrahydronaphthalene ring) , a 5- to 14-membered aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring, isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5
(preferably 1 - 3, more preferably 1 or 2) substituents
selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) a C1_6 alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C1_6 alkoxy group (e.g., methoxy) , (5) a C1_6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a cyano group, a C3-10 cycloalkyl group (e.g., cyclopropyl) , a C6-14 aryl group (e.g., phenyl) and a carbamoyl group, (6) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) optionally substituted by 1 - 3 substituents
selected from a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a cyano group and a hydroxy group, (7) a C3-10 cycloalkyloxy group (e.g., cyclopropyloxy) , (8) a Ce-14 aryl group (e.g., phenyl) optionally substituted by 1 - 3 substituents selected from a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a C1_6 alkoxy group (e.g., methoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., chlorine atom) and a cyano group, (9) a Ce- 14 aryloxy group (e.g., phenoxy) , (10) a 3- to 14-membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl, piperazinyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C1_6 alkyl group (e.g., methyl), (11) a 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl, pyridyl,
pyrimidinyl) , (12) a C1_6 alkyl-carbonyl group (e.g., acetyl), (13) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) and (14) a C1-6 alkoxy-carbonyl group (e.g., tert- butoxycarbonyl ) ;
L1 is a bond, C1_2 alkylene (e.g., -CH2-, - { Οϊ2 ) 2 ~ , ~
CH(CH3)-), -NH- or -0-;
the partial structure:
[0164]
[Chem. 56]
Figure imgf000058_0001
[0165]
is
[0166]
[Chem. 57]
Figure imgf000059_0001
[0167]
X is a carbon atom or a nitrogen atom;
n is an integer of 1 or 2;
ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C1_6 alkyl group (e.g., methyl);
Y1, Y2 and Y3 are each independently a carbon atom or a nitrogen atom;
ring C is a benzene ring (that is, Y1, Y2 and Y3 are carbon atoms) or a pyridine ring (preferably, Y1 is a nitrogen atom, Y2 and Y3 are carbon atoms or Y1 and Y2 is a carbon atom, Y3 is a nitrogen atom) ;
Y4 is =CH- or =N-;
R1 and R2 are each independently, (1) a hydrogen atom, (2) a C1_6 alkyl group (e.g., methyl, ethyl) optionally
substituted by 1 - 3 substituents selected from a hydroxy group and a carboxy group or (3) a C1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form C3-10 cycloalkane (e.g., cyclopropane ring); ring D is a C6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is
optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C1_6 alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and (6) a carbamoyl group;
L2 is -S02- or -S(=0) (=NR4)- (R4 is a hydrogen atom or a C1_6 alkyl group (e.g., methyl)); and
R3 is a C1_6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C1_6 alkyl groups (e.g., methyl) .
[0168]
[Compound C-l]
Compound (Ι') wherein
ring A is a benzene ring, a pyridine ring, an indazole ring or a pyrazolopyridine ring, each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C1_6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C1_6 alkoxy groups (e.g., methoxy) , (4) a C1_6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) and (5) a C3-10 ' cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 - 3 C1_6 alkyl groups (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom);
L1 is a bond, C1-2 alkylene (e.g., -CH2~) or -NH-;
the partial structure:
[0169]
[Chem. 58]
Figure imgf000061_0001
[0170]
is
[0171]
[Chem.
Figure imgf000061_0002
[0172]
X is a carbon atom or a nitrogen atom;
n is an integer of 1 or 2 ;
ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C1_6 alkyl group (e.g., methyl);
Y1, Y2 and Y3 are each independently a carbon atom or a nitrogen atom;
ring C is a benzene ring (that is, Y1, Y2 and Y3 are carbon atoms) or a pyridine ring (preferably, Y1 is a nitrogen atom, Y2 and Y3 are carbon atoms or Y1 and Y2 are carbon atoms, Y3 is a nitrogen atom) ;
Y4 is =N-;
R1 and R2 are (1) both hydrogen atoms or (2) one of them is a hydrogen atom and the other is a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups; ring D is a benzene ring, a pyridine ring, a pyrimidine ring or a piperidine ring, each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C1_6 alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and (6) a carbamoyl group;
L2 is -S02- or -S(=0) (=NR4)- (R4 is a hydrogen atom); and R3 is a C1_6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C1_6 alkyl groups (e.g., methyl) .
[0173]
[Compound A-2]
Compound (Ι') wherein
ring A is a C6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring) , a Ce-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring), a 5- to 14-membered
aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring,
isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic
heterocycle (e.g., tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5
(preferably 1 - 3, more preferably 1 or 2) substituents
selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a cyano group, (3) an oxo group, (4) an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl, isopropyl, tert-butyl) , (5) an optionally substituted C1_6 alkoxy group (e.g., methoxy, ethoxy) , (6) an optionally substituted C3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl) , (7) an optionally substituted C3-10 cycloalkyloxy group (e.g.,
cyclopropyloxy) , (8) an optionally substituted Ce-14 aryl group (e.g., phenyl), (9) an optionally substituted C6-14 aryloxy group (e.g., phenoxy) , (10) an optionally substituted 3- to 14- membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl) , (11) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl) and (12) an optionally substituted C1-6 alkyl-carbonyl group (e.g., acetyl) ;
L1 is a bond, C1_2 alkylene (e.g., -CH2-, - (CH2) 2 - , ~
CH(CH3)-), -NH- or -0-;
the partial structure:
[0174]
[Chem. 60]
Figure imgf000063_0001
[0177]
X is a carbon atom or a nitrogen atom;
n is an integer of 1 or 2 ;
ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) an
optionally substituted C1_6 alkyl group (e.g., methyl);
Y1, Y2 and Y3 are each independently a carbon atom or a nitrogen atom;
ring C is a benzene ring (that is, Y1, Y2 and Y3 are carbon atoms) or a pyridine ring (preferably, Y1 is a nitrogen atom, Y2 and Y3 are carbon atoms or Y1 and Y2 is a carbon atom, Y3 is a nitrogen atom) ;
R1 and R2 are each independently (1) a hydrogen atom, (2) an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl) or (3) an optionally substituted Cis alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form optionally further substituted C3- 10 cycloalkane (e.g., cyclopropane ring);
ring D is a C6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is
optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) halogen atoms (e.g., fluorine atom);
L2 is -SO2- or -S(=0) (=NR4 ) - (R4 is a hydrogen atom or an optionally substituted C1_6 alkyl group (e.g., methyl)); and
R3' is an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group.
[0178]
[Compound B-2]
Compound (Ι') wherein
ring A is a C6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring) , a C6-14 nonaromatic hydrocarbon ring (e.g., tetrahydronaphthalene ring), a 5- to 14-membered
aromatic heterocycle (e.g., thiophene ring, oxazole ring, thiazole ring, pyrazole ring, pyridine ring, pyrimidine ring, quinoxaline ring, quinazoline ring, benzooxazole ring,
isobenzooxazole ring, benzofuran ring, benzoimidazole ring, benzothiazole ring, indazole ring, indole ring, quinoline ring, isoquinoline ring, imidazopyridine ring, pyrazolopyridine ring, naphthyridine ring) or a 3- to 14-membered non-aromatic
heterocycle (e.g., tetrahydropyran ring, tetrahydroquinazoline ring, dihydroindene ring, dihydroindole ring, dihydrobenzofuran ring, dihydrocyclopentapyridine ring, dihydrobenzodioxin ring) , each of which is optionally further substituted by 1 - 5
(preferably 1 - 3, more preferably 1 or 2) substituents
selected from (1) a halogen atom (e.g., fluorine atom,, chlorine atom), (2) a cyano group, (3) an oxo group, (4) a C1-6 alkyl group (e.g. methyl, ethyl, isopropyl, tert-butyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C1_6 alkoxy group (e.g., methoxy) , (5) a C1_6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a cyano group and a carbamoyl group, (6) a C3-10 cycloalkyl group (e.g., cyclopropyl, cyclobutyl)
optionally substituted by 1 - 3 substituents selected from a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., fluorine atom), a cyano group and a hydroxy group, (7) a C3-10 cycloalkyloxy group (e.g., cyclopropyloxy) , (8) a C6-14 aryl group (e.g., phenyl) optionally substituted by 1 - 3
substituents selected from a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a C1_6 alkoxy group (e.g., methoxy) optionally
substituted by 1 - 3 halogen atoms (e.g., fluorine atom), a halogen atom (e.g., chlorine atom) and a cyano group, (9) a C6_ 14 aryloxy group (e.g., phenoxy) , (10) a 3- to 14-membered nonaromatic heterocyclic group (e.g., oxetanyl, morpholinyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom), (11) a 5- to 14^membered aromatic heterocyclic group (e.g., oxazolyl, pyrazolyl) and (12) a C1_6 alkyl-carbonyl group (e.g., acetyl) ;
L1 is a bond, C1_2 alkylene (e.g., -(CH2)2-, - CH(CH3)-), -NH- or -0-;
the partial structure:
[0179]
[Chem. 62]
Figure imgf000066_0001
[0180]
is
[0181]
[Chem.
Figure imgf000066_0002
[0182]
X is a carbon atom or a nitrogen atom;
n is an integer of 1 or 2;
ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1) , a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C1_6 alkyl group (e.g., methyl);
Y1, Y2 and Y3 are each independently a carbon atom or a nitrogen atom;
ring C is a benzene ring (that is, Y1, Y2 and Y3 are carbon atoms) or a pyridine ring (preferably, Y1 is a nitrogen atom, Y2 and Y3 are carbon atoms or Y1 and Y2 is a carbon atom, Y3 is a nitrogen atom) ;
R1 and R2 are each independently (1) a hydrogen atom, (2) a C1_6 alkyl group (e.g., methyl, ethyl) optionally substituted by 1 - 3 substituents selected from a hydroxy group and a carboxy group or (3) a C1_6 alkoxy-carbonyl group (e.g., methoxycarbonyl) , or (4) bonded together with the adjacent carbon atom to form C3-10 cycloalkane (e.g., cyclopropane ring); ring D is a C6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyridine ring, pyrimidine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is
optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) halogen atoms (e.g., fluorine atom);
L2 is -SO2- or -S(=0) (=NR4 ) - (R4 is a hydrogen atom or a C1_6 alkyl group (e.g., methyl)); and
R3 is a C1_6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C1_6 alkyl groups (e.g., methyl) .
[0183]
[Compound C-2]
Compound (Ι') wherein
ring A is a benzene ring, a pyridine ring, an indazole ring or a pyrazolopyridine ring, each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C1-6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 C1_6 alkoxy groups (e.g., methoxy) , (4) a C1_6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) and (5) a C3-10 cycloalkyl group (e.g., cyclopropyl) optionally substituted by 1 - 3 C1_6 alkyl groups (e.g., methyl) optionally substituted by 1 - 3 halogen atoms (e.g., fluorine atom) ;
L1 is a bond, C1_2 alkylene (e.g., -CH2-) or -NH-; the partial structure:
[0184]
[Chem. 64]
Figure imgf000068_0001
[0185]
is
[0186]
[Chem.
Figure imgf000068_0002
[0187]
X is a carbon atom or a nitrogen atom;
n is an integer of 1 or 2;
ring B is a dihydropyran ring (that is, X is a carbon atom, n is 1), a dihydrooxazine ring (that is, X is a nitrogen atom, n is 1) or a tetrahydrooxazepine ring (that is, X is a nitrogen atom, n is 2), each of which is optionally further substituted by 1 - 6 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) an oxo group and (2) a C1-6 alkyl group (e.g., methyl);
Y1, Y2 and Y3 are each independently a carbon atom or a nitrogen atom;
ring C is a benzene ring (that is, Y1, Y2 and Y3 are carbon atoms) or a pyridine ring (preferably, Y1 is a nitrogen atom, Y2 and Y3 are carbon atoms or Y1 and Y2 is a carbon atom, Y3 is a nitrogen atom) ;
R1 and R2 are (1) both hydrogen atoms or (2) one of them is a hydrogen atom and the other is a C1_6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups;
ring D is a benzene ring, a pyridine ring, a pyrimidine ring or a piperidine ring, each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) halogen atoms, (e.g., fluorine atom) ;
L2 is -S02- or -S(=0) (=NR4 ) - (R4 is a hydrogen atom); and R3 is a C1_6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C1_6 alkyl groups (e.g., methyl) .
[0188]
[Compound A-3]
Compound (Ι') wherein
ring A is C3-10 cycloalkane (e.g., cyclohexane) , a C6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyrazole ring, pyridine ring, pyrimidine ring, benzoimidazole ring, indazole ring, quinoline ring, imidazopyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring) , each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2 ) substituents selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl, isopropyl) , (3) an optionally substituted C1_6 alkoxy group (e.g., methoxy, ethoxy) , (4) an optionally substituted C3-1o cycloalkyl group (e.g.,
cyclopropyl) , (5) optionally substituted C6-14 aryl group (e.g., phenyl), (6) an optionally substituted 3- to 14-membered nonaromatic heterocyclic group (e.g., piperazinyl) , (7) an optionally substituted 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) , (8) an optionally
substituted 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) and (9) an optionally substituted C1_6 alkoxy-carbonyl group (e.g., tert-butoxycarbonyl) ;
L1 is a bond or C1_2 alkylene (e.g., -CH2-, -(CH2)2_) ; the partial structure:
[0189]
[Chem. 66]
Figure imgf000070_0001
[0190]
is
[0191]
[Chem.
Figure imgf000070_0002
[0192]
Y4 is =CH- or =N- ;
R1 and R2 are each independently a hydrogen atom or an optionally substituted C1_6 alkyl group (e.g., methyl);
ring D is a C6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., a pyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) an optionally substituted C1_6 alkyl group (e.g., methyl), (4) a carboxyl group, (5) an optionally substituted C1_6 alkoxy-carbonyl group (e.g.,
ethoxycarbonyl) and (6) an optionally substituted carbamoyl group;
L2 is -SO2-; and
R3 is an optionally substituted C1_6 alkyl group (e.g., methyl, ethyl) or an optionally substituted amino group.
[0193]
[Compound B-3]
Compound (Ι') wherein
ring A is C3-10 cycloalkane cyclohexane) , a C6-14 aromatic hydrocarbon ring (e.g., benzene ring, naphthalene ring), a 5- to 14-membered aromatic heterocycle (e.g., pyrazole ring, pyridine ring, pyrimidine ring, benzoimidazole ring, indazole ring, quinoline ring, imidazopyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring, tetrahydropyran ring) , each of which is optionally further substituted by 1 - 5 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom, chlorine atom), (2) a C1_6 alkyl group (e.g., methyl, ethyl, isopropyl) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom) and a C1_6 alkoxy group (e.g., methoxy) , (3) a C1_6 alkoxy group (e.g., methoxy, ethoxy) optionally substituted by 1 - 3 substituents selected from a halogen atom (e.g., fluorine atom), a C3-10 cycloalkyl group (e.g., cyclopropyl) and a C6-14 aryl group
(e.g., phenyl), (4) a C3_i0 cycloalkyl group (e.g., cyclopropyl), (5) a C6-14 aryl group (e.g., phenyl), (6) a 3- to 14-membered nonaromatic heterocyclic group (e.g., piperazinyl) optionally substituted by 1 - 3 C1_6 alkyl groups (e.g., methyl), (7) a 5- to 14-membered aromatic heterocyclic group (e.g., pyridyl, pyrimidinyl) , (8) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyrazinyloxy) and (9) a C1_6 alkoxy-carbonyl group (e.g., tert-butoxycarbonyl) ;
L1 is a bond or C1_2 alkylene (e.g., -CH2-, -(CH2)2~) ;
the partial structure:
[0194]
[Chem. 68]
Figure imgf000072_0001
[0195]
is
[0196]
[Chem.
Figure imgf000072_0002
[0197]
Y4 is =CH- or =N-;
R1 and R2 are each independently a hydrogen atom or a Cis alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups;
ring D is a C6-14 aromatic hydrocarbon ring (e.g., benzene ring), a 5- to 14-membered aromatic heterocycle (e.g., a pyridine ring) or a 3- to 14-membered non-aromatic heterocycle (e.g., piperidine ring), each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2) substituents selected from (1) a halogen atom (e.g., fluorine atom), (2) a cyano group, (3) a C1-6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (4) a carboxyl group, (5) a C1_6 alkoxy-carbonyl group (e.g., ethoxycarbonyl) and (6) a carbamoyl group;
L2 is -SO2-; and
R3 is a C1_6 alkyl group (e.g., methyl, ethyl) or an amino group optionally substituted by 1 or 2 C1_6 alkyl groups (e.g., methyl) .
[0198] [Compound C-3]
Compound (Ι') wherein
ring A is a pyridine ring optionally further substitut by 1 - 3 C3-10 cycloalkyl groups (e.g., cyclopropyl) ;
L1 is a bond;
the partial structure:
[0199]
[Chem. 70]
Figure imgf000073_0001
[0200]
is
[0201]
[Chem.
Figure imgf000073_0002
[0202]
Y4 is =N-;
R1 and R2 are (1) both hydrogen atoms or (2) one of them is a hydrogen atom and the other is a C1- 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups;
ring D is a C6-14 aromatic hydrocarbon ring (e.g., benzene ring) or a 5- to 14-membered aromatic heterocycle (e.g., a pyridine ring) , each of which is optionally further substituted by 1 - 4 (preferably 1 - 3, more preferably 1 or 2)
substituents selected from (1) a cyano group, (2) a C1- 6 alkyl group (e.g., methyl) optionally substituted by 1 -3 hydroxy groups, (3) a carboxyl group, (4) a C1_6 alkoxy-carbonyl group (e.g., ethoxycarbonyl ) and (5) a carbamoyl group;
L2 is -SO2-; and
R3 is a C1-6 alkyl group (e.g., methyl, ethyl).
[0203]
Specific examples of compound (Ι') include the compounds of Examples 3 - 381, among which
1- (2, 6-dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [1, 4 ] oxazine-6-carboxamide (Example 249),
4- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5-
(methylsulfonyl) pyridin-2-yl) methyl) chromane-7-carboxamide (Example 290) ,
5- (2, 6-dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl ) benzyl) -5,6,7, 8-tetrahydro-l , 5-naphthyridine-2- carboxamide (Example 292) and
ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin-4-yl ) -5, 6,7,8- tetrahydro-1 , 5-naphthyridin-2-yl) carbonyl) amino) methyl) -5- (methylsulfonyl) benzoate (Example 295)
are preferable.
[0204]
When compound (Ι') is a salt, examples of such salt include salts with inorganic base, ammonium salts, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acids, and the like.
[0205]
Preferable examples of the salt with inorganic base include alkaline 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 and the like.
[0206]
Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,
dicyclohexylamine, N, N' -dibenzylethylenediamine and the like.
[0207] Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
[0208]
Preferable examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid and the like.
[0209]
Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
[0210]
Preferable examples of the salt with acidic amino acid include salt with aspartic acid, glutamic acid and the like.
[0211]
Of these salts, a pharmaceutically acceptable salt is preferable. As the pharmaceutically acceptable preferable salt, when the compound has a basic functional group therein,
examples of the salt thereof include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid, and salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric aid, succinic acid,
methanesulfonic acid, p-toluenesulfonic acid and the like.
When an acidic functional group is contained in the compound, examples thereof include inorganic salts such as alkali metal salt (e.g., sodium salt, potassium salt etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt, and the like.
[0212]
Compound (Ι') may be a crystal, and both a single crystal and crystal mixtures are encompassed in the compound (I' ) .
Compound (Ι') may be a pharmaceutically acceptable
cocrystal or cocrystal salt. Here, the cocrystal or cocrystal salt means a crystalline substance consisting of two or more particular substances which are solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of melting, hygroscopicity, solubility, stability etc.). The cocrystal and cocrystal salt can be produced by cocrystallization method known per se.
Compound (Ι') encompasses solvates (e.g., hydrate etc.) and non-solvates (e.g., non-hydrate etc.) within the scope thereof. A deuterium conversion form wherein 1H is converted to 2H(D) is also encompassed in compound (1')·
Compound (Ι') may be a compound labeled or substituted with an isotope (e.g., 3H, X1C, 14C, 18F, 35S, 125I). A compound labeled with or substituted by an isotope may be used, for example, as a tracer used for Positron Emission Tomography (PET) (PET tracer), and may be useful in the field of medical diagnosis and the like.
[0213]
When compound (Ι') of the present invention has an
asymmetric center, isomers such as enantiomer, diastereomer and the like may be present. Such isomers and a mixture thereof are all encompassed within the scope of the present invention. When an isomer is formed due to the conformation or tautomerism, such isomers and a mixture thereof are also encompassed in compound (Ι') of the present invention.
[0214]
The production method of the compound of the present invention is explained in the following.
[0215]
The starting materials and reagents used in each step in the following production method, and the obtained compounds each may form a salt. Examples of the salt include those similar to the aforementioned salts of the compound of the present invention and the like.
[0216]
When the compound obtained in each step is a free compound, it can be converted to a desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted to a free form or a desired other kind of salt by a method known per se.
[0217]
The compound obtained in each step can also be used for the next reaction as a reaction mixture thereof or after obtaining a crude product thereof. Alternatively, the compound obtained in each step can be isolated and/or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractionation, chromatography and the like
according to a conventional method.
[0218]
When the starting materials and reagent compounds of each step are commercially available, the commercially available products can be used as they are.
[0219]
In each step, protection or deprotection reaction of a functional group is performed by the method known per se, for example, the methods described in "Protective Groups in Organic Synthesis, 4th Ed." (Theodora W. Greene, Peter G. M. Wuts) Wiley-Interscience, 2007; "Protecting Groups 3rd Ed." (P. J. Kocienski) Thieme, 2004 and the like, or the methods described in the Examples.
Examples of the protecting group of the hydroxyl group of alcohol and the like and a phenolic hydroxyl group include ether protecting groups such as methoxymethyl ether, benzyl ether, t-butyldimethylsilyl ether, tetrahydropyranyl ether and the like; carboxylate ester protecting groups such as acetate ester and the like; sulfonate ester protecting groups such as methanesulfonate ester and the like; carbonate ester protecting groups such as t-butylcarbonate and the like, and the like.
Examples of the protecting group of the carbonyl group of aldehyde include acetal protecting groups such as dimethyl acetal and the like; cyclic acetal protecting groups such as cyclic 1,3-dioxane and the like, and the like.
Examples of the protecting group of the carbonyl group of ketone include ketal protecting groups such as dimethyl ketal and the like; cyclic ketal protecting groups such as cyclic 1,3-dioxane and the like; oxime protecting groups such as 0- methyloxime and the like; hydrazone protecting groups such as N, N-dimethylhydrazone and the like, and the like.
Examples of the carboxyl protecting group include ester protecting groups such as methyl ester and the like; amide protecting groups such as N, N-dimethylamide and the like, and the like.
Examples of the thiol protecting group include ether protecting groups such as benzyl thioether and the like; ester protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like, and the like.
Examples of the protecting group of an amino group and an aromatic heterocycle such as imidazole, pyrrole, indole and the like include carbamate protecting groups such as benzyl
carbamate and the like; amide protecting groups such as
acetamide and the like; alkylamine protecting groups such as N- triphenylmethylamine and the like, sulfonamide protecting groups such as methanesulfonamide and the like, and the like.
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, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), a reduction method and the like.
[0220]
The compounds and a salt thereof encompassed in the compound (Ι') of the present invention can be produced by the following Method A, Method B-l, Method B2-2, Method C, Method D, Method E, Method F-l, Method F-2, Method G, Method H, Method I, Method J, Method K, Method L, Method M, Method N, Method 0, Method P, Method U, Method V, Method W, Method X or Method
Compound (la) which is the compound of the present invention (Ι') wherein the partial structure:
[0221],
[Chem. 72]
Figure imgf000079_0001
[0222]
is
[0223]
[Chem.
Figure imgf000079_0002
[0224]
L1 is a bond, and X is a carbon atom can be produced by the following Method A.
[Method A]
[0225]
[Chem. 74]
Figure imgf000080_0001
Figure imgf000080_0002
(la)
[0226]
wherein Hal is a halogen atom, LG is a leaving group, R5 is an optionally substituted hydrocarbon group, and other symbols are as defined above.
Examples of the halogen atom for Hal include chlorine atom, bromine atom and iodine atom.
As the leaving group for LG, a halogen atom (chlorine atom, bromine atom, iodine atom and the like) , a substituted sulfonyloxy group (C1_6 alkylsulfonyloxy group such as
methanesulfonyloxy, trifluoromethylsulfonyloxy,
ethanesulfonyloxy and the like; a C6-14 arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy and the like; a C7-16 aralkylsulfonyloxy group such as benzylsulfonyloxy group and the like, and the like) , an acyloxy group (acetoxy, benzoyloxy and the like) , an oxy group substituted by a
heterocyclic group or an aryl group (2, 5-dioxo-l-pyrrolidinyl, benzotriazolyl, quinolyl, 4-nitrophenyl and the like) , a heterocyclic group (imidazolyl and the like) and the like are used.
Examples of the optionally substituted hydrocarbon group for R5 include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like.
[0227]
(Step 1)
In this step, compound (II) or a salt thereof is
subjected to dehydration condensation with p- toluenesulfonylhydrazide to produce compound (III) .
Compound (II) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
The amount of p-toluenesulfonylhydrazide to be used is generally about 1 - 10 molar equivalents, preferably 1.1 molar equivalents, per 1 mol of compound (II).
This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene and the like) , halogenated
hydrocarbons (chloroform, 1 , 2-dichloroethane and the like), nitriles (acetonitrile and the like) , ethers (cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran) , alcohols
(methanol, ethanol and the like), aprotic polar solvents (N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide and the like), and a mixture thereof.
This step can also be performed in the presence of an acid. Examples of the acid to be used in this step include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , Lewis acid (aluminum chloride, tin chloride, zinc bromide and the like) , organic sulfonic acid (tosylic acid, camphorsulfonic acid) and the like. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 0.001 - not less than 2 mol equivalents per 1 mol of compound (II) .
The reaction temperature is generally about 0 - 120°C, preferably about 60 - 100°C, and the reaction time is generally about 0.5 - 48 hr, preferably about 0.5 - about 24 hr.
[0228]
(Step 2)
In this step, compound (III) or a salt thereof is coupled with compound (IV) in the presence of a Pd catalyst and a base to produce compound (V) .
Compound (IV) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
Examples of the Pd catalyst to be used for the reaction include palladium acetate, palladium chloride,
tetrakis (triphenylphosphine ) palladium ( 0 ) ,
tris (dibenzylideneacetone) dipalladium ( 0 ) , XPHOS Pd G2 and the like, and a ligand (Xphos, triphenylphosphine, tri-t- butylphosphine, S-Phos, BINAP, 2' - (di-tert-butylphosphino) -N,N- dimethyl- [1, 1' -biphenyl] -2-amine, XANTPHOS and the like) is added as necessary. The amount of the catalyst to be used is generally about 0.0001 - 1 molar equivalent, preferably about 0.01 - 0.5 molar equivalent, per 1 mol of compound (III) . The amount of the ligand to be used is generally about 0.0001 - 4 molar equivalents, preferably about 0.01 - 2 molar equivalents, per 1 mol of compound (III) .
As the base, an alkali metal salt (sodium hydrogen
carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium acetate and the like) , metal hydride (potassium hydride, sodium hydride and the like) , alkali metal alkoxide (lithium t- butoxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like) , or alkali disilazide (lithium disilazide, sodium disilazide, potassium disilazide and the like) ) is added. The amount of the base to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents per 1.mol of compound (III).
This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene and the like) , halogenated
hydrocarbons (chloroform, 1 , 2-dichloroethane and the like), nitriles (acetonitrile and the like) , ethers (cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran) , alcohols
(methanol, ethanol and the like), aprotic polar solvents (N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide and the like), and a mixture thereof.
The reaction temperature is generally about 0 - 150°C, preferably about 60 - 100°C, and the reaction time is generally about 0.5 — 48 hr, preferably about 0.5 - about 24 hr. The reaction may be performed under microwave irradiation as necessary.
[0229]
(Step 3)
In this step, compound (V) or a salt thereof was
subjected to a catalytic hydrogenation reaction to produce compound (VI) or a salt thereof.
The catalytic hydrogenation reaction can be performed in hydrogen atmosphere in the presence of a catalyst. Examples of the catalyst include palladiums (palladium carbon, palladium carbon-ethylenediamine complex, palladium-activated carbon
Evonik Degussa type E, palladium hydroxide carbon, palladium oxide and the like), nickels (sponge nickel catalyst and the like) , platinums (platinum oxide, platinum carbon and the like) , rhodiums (rhodium carbon and the like) and the like. The amount thereof to be used is generally about 0.001 - about 1 molar equivalent, preferably about 0.01 - about 0.5 molar equivalent, per 1 mol of compound (V) . The catalytic hydrogenation reaction is generally performed in a solvent inert to the reaction. Examples of the solvent include alcohols (methanol, ethanol, propanol, butanol and the like) , hydrocarbons (benzene, toluene, xylene and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , esters (ethyl acetate and the like) , amides (N, N-dimethylformamide and the like), carboxylic acids (acetic acid and the like), water and a mixture thereof.
The reaction is performed at a hydrogen pressure of generally about 1 - about 50 atm, preferably about 1 - about 10 atm. The reaction temperature is generally about 0°C - about 150°C, preferably about 20°C - about 100°C, and the reaction time is generally about 5 min - about 72 hr, preferably about 0.5 hr - about 40 hr.
[0230]
(Step 4)
In this step, compound (VI) or a salt thereof is
subjected to a cyanation reaction to produce compound (VII) .
This reaction can be performed in the presence of a transition metal catalyst by using a cyanation reagent in a solvent that does not adversely influence the reaction.
Examples of the transition metal catalyst to be used in this reaction include palladium catalyst (palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium ( 0 ) and the like) , nickel catalyst (nickel chloride and the like) and the like, and a ligand (triphenylphosphine, tri-t- butylphosphine, S-Phos, BINAP and the like) may also be used as necessary. While the amount of the transition metal catalyst to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 0.001 - 1 mol equivalents, preferably about 0.1 - 0.5 molar equivalents, per 1 mol of compound (VI), and the amount of the ligand to be used is generally about 0.001 - 1 mol equivalents per 1 mol of compound (VI) . Examples of the cyanation reagent to be used in this reaction include zinc cyanide, copper cyanide and the like. While the amount thereof to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 0.5 - 10 molar equivalents, preferably about 0.5 - 2 molar equivalents, per 1 mol of compound (VI) .
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl . methyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and the like) , nitriles (acetonitrile and the like), esters (ethyl acetate and the like), amides (N,N- dimethylformamide and the like) , sulfoxides (dimethyl sulfoxide and the like) and the like. Two or more kinds of these
solvents may be used in a mixture in an appropriate ratio.
The reaction temperature is, for example, about -10 - 200°C. The reaction time varies depending on the kind of compound (VI), reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr. The reaction may be performed under microwave irradiation as necessary.
[0231]
(Step 5)
In this step, compound (VI) or a salt thereof is
alkoxycarbonylated under a carbon monoxide atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CIX) :
R5OH (CIX)
(R5 is as defined above) ,
to produce compound (VIII) or a salt thereof.
Examples of the transition metal catalyst include
palladium catalyst (palladium acetate, palladium chloride, tetrakis (triphenylphosphine ) palladium ( 0) and the like), nickel catalyst (nickel chloride and the like) and the like, and an organic phosphorus reagent such as triphenylphosphine, 1,1'- bis (diphenylphosphino) ferrocene (dppf) and the like can be used as necessary. The amount of the catalyst to be used varies depending on the kind of the catalyst, and is generally about 0.0001 - 1 mol, preferably about 0.01 - 0.5 mol, per 1 mol of compound (VI) , and the amount of the organic phosphorus reagent to be used is preferably about 0.01 - 2 mols.
The alcohol represented by the formula (CIX) is
preferably methanol or ethanol. The above-mentioned alcohol in this step is used in an excess amount.
This reaction can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), aprotic polar solvents (N, N-dimethylformamide, dimethyl sulfoxide and the like) and the like can be mentioned. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
In addition, this step can also be performed in the presence of a base or a salt. Examples of the base or salt include inorganic base (alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate,
potassium hydrogen carbonate and the like, alkali metal
carbonates such as lithium carbonate, sodium carbonate,
potassium carbonate, cesium carbonate and the like, or organic base (amines such as trimethylamine, triethylamine,
diisopropylethylamine and the like, cyclic amine such as pyridine and the like, and the like) and the like. The amount of the base or salt to be used is generally about 1 - 100 molar equivalents, preferably about 1 - 10 molar equivalents, per 1 mol of compound (VI) .
The reaction is generally performed under normal pressure, carbon monoxide atmosphere and can be performed under
pressurization (e.g., about 3 - 10 atm) where necessary.
The reaction temperature varies depending on the kind of the solvent, and is, for example, about -50 - 200°C, preferably about 20 - 150°C. The reaction time varies depending on the kind of compound (VI) or a salt thereof, the reaction
temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[0232]
(Step 6)
In this step, compound (VII) or a salt thereof is
subjected to hydrolysis to convert same to compound (IX) or a salt thereof. This reaction can be performed by a method known per se, and generally performed, in the presence of an acid or a base and, where necessary, in a solvent that does not
adversely influence the reaction.
Examples of the acid include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid and the like) , sulfonic acids (methanesulfonic acid, p- toluenesulfonic acid and the like) , Lewis acid (aluminum chloride, tin chloride, zinc bromide and the like) or a mixture of two or more kinds thereof can be mentioned. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction conditions, it is generally not less than about 0.1 mol equivalent per 1 mol of compound (VII), and it can also be used as a solvent.
As the base, for example, inorganic bases (alkali metal hydroxides such as lithium hydroxide, sodium hydroxide,
potassium hydroxide and the like, alkali metal hydrogen
carbonates such as sodium hydrogen carbonate, potassium
hydrogen carbonate and the like, alkali metal carbonates such as sodium carbonate, potassium carbonate and the like, alkoxides such as sodium methoxide, sodium ethoxide and the like, and the like) , organic bases (amines such as
trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine 5 and the like, and the like) and the like are used. Of these, sodium hydroxide is preferable. While the amount of the base to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 0.1 - 10 molar eguivalents, preferably about 1 - 5 molar equivalents, per 1
10 mol of compound (VII) .
Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) ,
hydrocarbons (benzene, toluene, xylene, hexane, heptane and the
15 like) , halogenated hydrocarbons (dichloromethane, chloroform
and the like) , ethers (diethyl ether, diisopropyl ether, t- butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , carboxylic acids (acetic acid and the like), amides (N, -dimethylformamide,
20 N, N-dimethylacetamide and the like), sulfoxides (dimethyl
sulfoxide and the like), water and the like. Of these, ethanol, tetrahydrofuran or water is preferable. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
The reaction temperature is, for example, about -50 -
25 200°C, preferably about 0 - 100°C. While the reaction time
varies depending on the kind of compound (VII) or a salt
thereof, reaction temperature and the like, it is, for example, about 0.5 min - 100 hr, preferably about 0.5 - 24 hr.
[0233]
30 (Step 7)
In this step, compound (VIII) or a salt thereof is subjected to hydrolysis to convert same to compound (IX) or a salt thereof. This step can be performed by a method according to that of Method A, Step 6.
35 [0234] (Step 8)
In this step, compound (IX) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (la) or a salt thereof.
Compound (X) or a salt thereof is commercially available or can be produced according to a method known per se or a method analogous thereto or the below-mentioned method.
The condensation reaction can be performed by a method known per se, for example, the method described in The Chemical Society of Japan, 1991, "4th ed. Jikken Kagaku Kouza 22,
Organic Synthesis IV" and the like, or a method analogous thereto. Examples of the method include (A) a method using a condensing agent, (B) a method via a reactive derivative and the like.
[0235]
Examples of the condensing agent to be used in (A) Ma method using a condensing agent" include (dimethylamino) -N, N- dimethyl (3H-[l,2,3]triazolo[4,5-b] pyridin-3-yloxy) methaniminium hexafluorophosphate (HATU) , 1- [ (1- (cyano-2-ethoxy-2- oxoethylideneaminooxy) -dimethylamino-morpholino) ] carbenium hexafluorophosphate (COMU) , 2 , 4 , 6-tripropyl-l , 3 , 5 , 2 , 4 , 6- trioxatriphosphorinane-2 , 4, 6-trioxide (T3P) ,
dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC), N-ethyl-N' -3-dimethylaminopropylcarbodiimide and hydrochlorides thereof (WSC, WSC-HC1, EDCI), benzotriazol-l-yl- tris (dimethylamino) phosphonium hexafluorophosphate (BOP), diphenylphosphoryl azide (DPPA) , ( 4-oxobenzo [d] [1, 2, 3] triazin- 3 (4H) -yl) diethyl phosphate (DETBT) , ( 3-hydroxy-3H-l , 2 , 3- triazolo [4, 5-b] pyridinato-O) tri-l-pyrrolidinyl-phosphorus hexafluorophosphate (PyAOP), Ν,Ν,Ν' ,Ν' -tetramethyl-O- (3, 4- dihydro-4-oxo-l, 2, 3-benzotriazin-3-yl ) uronium tetrafluoroborate (TDBTU) , 4- (4, 6-dimethoxy-l, 3, 5-triazin-2-yl) -4- methylmorpholinium chloride (DMT-MM) and hydrate thereof and the like. These may be used singly, or can also be used in combination with additive (e.g., N-hydroxysuccinimide, 1- hydroxybenzotriazole, 3-hydroxy-4-oxo-3, 4-dihydro-l, 2, 3- benzotriazine and the like) . The amount of the condensing agent to be used is generally about 1 - 10 molar equivalents, preferably about 1 .- 2 molar equivalents, per 1 mol of compound (IX) . The amount of the additive to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar
equivalents, per 1 mol of compound (IX) .
The above-mentioned reaction can be generally performed in a solvent that does not adversely influence the reaction, or can also be performed in the presence of a base. Examples of the solvent include hydrocarbons (benzene, toluene and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , esters (ethyl acetate and the like) , halogenated
hydrocarbons (chloroform, dichloromethane and the like) , amides (N, N-dimethylformamide and the like), aromatic amines (pyridine and the like), water and a mixture of these. Examples of the base include alkali metal hydroxides (sodium hydroxide,
potassium hydroxide and the like) , hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate and the like) , carbonates (sodium carbonate, potassium carbonate and the like) , acetates (sodium acetate and the like) , tertiary amines
(trimethylamine, triethylamine, N-methylmorpholine,
diisopropylamine and the like) , aromatic amines (pyridine, picoline, N, N-dimethylaniline, 4-dimethylaminopyridine and the like) and the like. The amount of the base to be used is generally about 1 - 100 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (IX) .
The reaction temperature is generally about -80 - 150°C, preferably about 0 - 50°C. The reaction time is generally about 0.5 - 48 hr, preferably 0.5 - 16 hr.
[0236]
As the reactive derivative shown in (B) "a method via a reactive derivative", a compound represented by the formula:
[0237]
[Chem. 75]
Figure imgf000091_0001
(IXa)
[0238]
wherein LG1 is a leaving group, and other symbols are as defined above,
(hereinafter to be referred to as compound (IXa)) or a salt thereof (e.g., acid halide, acid anhydride, mixed acid
anhydride, active ester and the like) and the like can be mentioned. Examples of the leaving group for LG1 include those similar to LG.
Compound (IX) can be converted to a reactive derivative
(compound (IXa)) according to a method known per se. For example, for conversion to acid halide, a method using acid halide (e.g., thionyl chloride, oxalyl chloride and the like), a method using phosphorus or phosphoric acid halide (e.g., phosphorus trichloride, phosphorus pentachloride and the like) and the like can be mentioned. The above-mentioned reaction via a reactive derivative can be performed, depending on the kind of compound (IX) , generally in a solvent that does not adversely influence the reaction, and the reaction can also be performed in the presence of a base. The kind and the amount of the solvent and base to be used in the reaction, reaction temperature and the reaction time are similar to those
described in the above-mentioned "method using a condensing agent".
[0239]
Compound (Ib-I) which is the compound of the present invention (Ι'), wherein the partial structure:
[0240]
[Chem. 76]
Figure imgf000092_0001
[0241]
is
[0242]
[Chem.
Figure imgf000092_0002
L1 is optionally halogenated C1 alkylene and X is a carbon atom, can be produced by the following Method B-1.
[Method B-1]
[0244]
[Chem. 78]
Figure imgf000093_0001
[0245]
wherein R5a, R5b and R5c are each independently an optionally substituted hydrocarbon group, and other symbols are as defined above .
Examples of the optionally substituted hydrocarbon group for R5a, R5b or R5c include those similar to R5 mentioned above.
[0246]
(Step 1)
In this step, compound (II) or a salt thereof is alkoxycarbonylated under a carbon monoxide atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CIXa) :
R5a0H (CIXa)
wherein the symbol is as defined above,
to produce compound (XI) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 5.
[0247]
(Step 2)
In this step, compound (XI) or a salt thereof and
compound (XII) or a salt thereof are subjected to a Horner- Wadsworth-Emmons reaction to produce compound (XIII) or a salt thereof .
Compound (XII) or a salt thereof to be used in this reaction may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
This reaction can be performed in the presence of a base, in a solvent that does not adversely influence the reaction.
As the base to be used in this reaction, sodium hydride, sodium methoxide, potassium carbonate, 1,8- diazabicyclo [ 5.4.0 ] undec-7-ene (DBU) , triethylamine and the like can be mentioned. A salt such as lithium chloride and the like may also be co-present. The amount of the base to be used is generally about 0.1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (XII) .
Examples of the solvent to be used in this reaction include alcohols (methanol, ethanol and the like) , ethers
(diethyl ether, dioxane, tetrahydrofuran, 1 , 2-dimethoxyethane and the like), dimethyl sulfoxide and the like, and they may also be appropriately used in a mixture.
The reaction temperature is generally about -78°C - about 150°C, preferably about 0°C - about 100°C, and the reaction time is generally about 5 min - about 72 hr, preferably about 0.5 hr - about 40 hr.
[0248]
(Step 3)
In this step, compound (XIII) or a salt thereof is subjected to a catalytic hydrogenation reaction to produce compound (XIV) or a salt thereof.
This step can be performed by a method according to . that of Method A, Step 3.
[0249]
(Step 4)
In this step, compound (XIV) or a salt thereof is subjected to hydrolysis to convert same to compound (XV) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 6.
[0250]
(Step 5)
In this step, compound (XV) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ib-I) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 8.
[0251]
Compound (Ib-II) which is the compound of the present invention (I' ) , wherein the partial ,structure :
[0252]
[Chem. 79]
Figure imgf000095_0001
[0253]
is
[0254]
[Chem. 80]
Figure imgf000095_0002
[0255]
L1 is optionally halogenated C2 alkylene, and X is a carbon atom can be produced the following Method B-2.
[Method B-2]
[0256]
[Chem. 81]
Figure imgf000096_0001
Figure imgf000096_0002
(XX) (lb-ll)
[0257]
wherein R5d is an optionally substituted hydrocarbon group, and other symbols are as defined above.
As the optionally substituted hydrocarbon group for R5d, those similar to the above-mentioned R5 can be mentioned.
[0258]
(Step 1) In this step, compound (II) or a salt thereof is
subjected to a one-carbon homologation reaction to produce compound (XVI) or a salt thereof.
In this reaction, compound (II) or a salt thereof is reacted with (methoxymethylene) triphenylphosphorane in a solvent that does not adversely influence the reaction, and post-treated with water to produce compound (XVI) or a salt thereof .
Examples of the solvent to be used in this reaction include alcohols (methanol, ethanol and the like), ethers
(diethyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane and the like) , dimethyl sulfoxide and the like, which may also be used in a mixture as appropriate.
The amount of (methoxymethylene) triphenylphosphorane to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (II) .
The reaction temperature is generally about -78°C - about 150°C, preferably about 0°C - about 100°C, and the reaction time is generally about 5 min - about 72 hr, preferably about 0.5 hr - about 40 hr.
[0259]
(Step 2)
In this step, compound (XVI) or a salt thereof is
subjected to alkoxycarbonylation under a carbon monoxide atmosphere, by using a transition metal catalyst and alcohol represented by the following formula (CIXd) :
R5dOH (CIXd)
wherein the symbol is as defined above,
to produce compound (XVII) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 5.
[0260]
(Step 3)
In this step, compound (XVII) or a salt thereof and compound (XII) or a salt thereof is subjected to a Horner- Wadsworth-Emmons reaction to produce compound (XVIII) or a salt thereof .
This step can be performed by a method according to that of Method B-l, Step 2.
[0261]
(Step 4)
In this step, compound (XVIII) or a salt thereof is subjected to a catalytic hydrogenation reaction to produce compound (XIX) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 3.
[0262]
(Step 5)
In this step, compound (XIX) or a salt thereof is
subjected to hydrolysis to convert same to compound (XX) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 6.
[0263]
(Step 6)
In this step, compound (XX) or a salt thereof and
compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ib-.II) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 8.
[0264]
Compound (Ic), which is the compound of the present invention (I' ) wherein the partial structure:
[0265]
[Chem. 82]
Figure imgf000098_0001
[0266]
is
[0267] ,
[Chem. 83]
Figure imgf000099_0001
[0268]
L1 is -NH-, and X is a carbon atom can be produced by the following Method C.
[Method C]
[0269]
[Chem. 84]
Figure imgf000099_0002
[0270]
wherein each symbol is as defined above.
[0271]
(Step 1)
In this step, compound (XI) or a salt thereof and compound (XXI) or a salt thereof are subjected to reductive amination reaction to produce compound (XXII) or a salt thereof.
Compound (XXI) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
The reductive amination reaction in this step can be performed by a method known per se. For example, it can be performed by reacting compound (XI) or a salt thereof and compound . (XXI ) or a salt thereof, and subjecting the resulting imine or iminium ion to a reduction reaction.
The amount of compound (XXI) to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 3 molar equivalents, per 1 mol of compound (XI) .
The solvent in the reaction to produce imine or iminium ion is not particularly limited as long as the reaction
proceeds. Examples of the solvent to be used in this step include hydrocarbons (heptane, hexane, toluene, xylene and the like) , halogenated hydrocarbons (chloroform, dichloromethane, 1 , 2-dichloroethane and the like), ethers (diethyl ether,
tetrahydrofuran, dioxane and the like) , esters (ethyl acetate, t-butyl acetate and the like) , alcohols (methanol, ethanol, 2- propanol and the like) , nitriles (acetonitrile, butyronitrile and the like), amides (N, N-dimethylformamide, N,N- dimethylacetamide and the, like) , sulfoxides (dimethyl sulfoxide and the like) and the like, and a mixed solvent thereof.
In this step, a catalyst may be added as necessary. As such catalyst, mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like) , sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, zinc
chloride, zinc bromide, boron trifluoride, titanium chloride and the like) , acetate (sodium acetate, potassium acetate and the like) , molecular sieves (molecular sieves 3A, 4A, 5A and the like) , dehydrating agent (magnesium sulfate and the like) and the like can be mentioned. The amount of the catalyst to be used is generally about 0.01 - 50 molar equivalents,
preferably about 0.1 - about 10 mol, per 1 mol of compound (XI) .
The reaction temperature is generally about 0°C - about 200°C, preferably about 20°C - about 150°C, and the reaction time is generally about 0.5 hr - about 48 hr, preferably about 0.5 hr - about 24 hr.
Imine or iminium ion can be converted to compound (XXII) by various reduction reactions in a solvent inert to the
reaction. Such reduction reaction can be performed by a method known per se and, for example, a method using a metal hydride and a method by a catalytic hydrogenation reaction can be mentioned.
Examples of the metal hydride include sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride,
dibutylaluminum hydride, aluminum hydride, lithium aluminum hydride, borane complex (borane-THF complex, catecholborane etc.) and the like, and sodium borohydride, sodium
cyanoborohydride, sodium triacetoxyborohydride and the like are preferable. The amount of the metal hydride to be used is, for example, generally about 1 - about 50 mol, preferably about 1 - about ,10 mol, per 1 mol of imine.
A reduction reaction using metal hydride can be performed in a solvent inert to the reaction. Examples of such solvent include aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbons such as heptane, hexane and the like; halogenated hydrocarbons such as chloroform,
dichloromethane and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; alcohols such as
methanol, ethanol, 2-propanol, butanol, benzyl alcohol and the like; nitriles such as acetonitrile and the like; N,N- dimethylformamide; dimethyl sulfoxide and the like. These solvents may be used in a mixture in an appropriate ratio.
The reaction temperature is generally about -80°C - about 80°C, preferably about -40°C - about 40°C, and the reaction time is generally about 5 min - about 48 hr, preferably about 1 hr - about 24 hr.
A catalytic hydrogenation reaction can be performed in hydrogen atmosphere in the presence of a catalyst. As the catalyst, palladiums such as palladium carbon, palladium
hydroxide carbon, palladium oxide and the like; nickels such as sponge nickel catalyst and the like; platinums such as platinum oxide, platinum carbon and the like; rhodiums such as rhodium carbon and the like; and the like can be mentioned. The amount thereof to be used is generally about 0.001 - about 1 mol, preferably about 0.01 - about 0.5 mol, per 1 mol of imine or oxime .
A catalytic hydrogenation reaction can be generally performed in a solvent inert to the reaction. Examples of the solvent include alcohols such as methanol, ethanol, propanol, butanol and the like; hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as
dichloromethane, chloroform and the like; ethers such as
diethyl ether, dioxane, tetrahydrofuran and the like; esters such as ethyl acetate and the like; amides such as N,N- dimethylformamide and the like; carboxylic acids such as acetic acid and the like; water and a mixture thereof.
The reaction is performed at a hydrogen pressure of generally about 1 - about 50 atm, preferably about 1 - about 10 atm. The reaction temperature is generally about 0°C - about 150°C, preferably about 20°C - about 100°C, and the reaction time is generally about 5 min - about 72 hr, preferably about 0.5 hr - about 40 hr.
In this step, the next reduction reaction may be
performed without isolating imine or oxime as an intermediate, and compound (XXII) may be directly obtained from compound (XI) . In this case, the pH of the reaction mixture is preferably about 4 to about 5.
[0272] (Step 2)
In this step, compound (XXII) or a salt thereof is subjected to hydrolysis to convert same to compound (XXIII) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 6.
[0273]
(Step 3)
In this step, compound (XXIII) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ic) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 8.
[0274]
Compound ( Id) , which is the compound of the present invention (I' ) wherein the partial structure:
[0275]
[Chem. 85]
Figure imgf000103_0001
[0276]
is
[0277]
[Chem.
Figure imgf000103_0002
[0278]
L1 is -0-, and X is a carbon atom, can be produced by the following Method D.
[Method D]
[0279]
[Chem. 87]
Figure imgf000104_0001
(XXVI) (Id)
[0280]
wherein each symbol is as defined above.
[0281]
(Step 1)
In this step, compound (XI) is treated with a reducing agent to produce compound (CVI) .
Examples of the reducing agent to be used in this
reaction include metal hydride (e.g., sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride) and the like. The amount of the metal hydride to be used is generally about 1 - 50 molar equivalents, per 1 mol of compound (XI) .
This reaction can be performed in a solvent inert to the reaction. Examples of such solvent include alcohols such as methanol, ethanol, propanol, butanol and the like; hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like; ethers such as diethyl ether, dioxane, tetrahydrofuran and the like; esters such as ethyl acetate and the like; amides such as N, N-dimethylformamide and the like; carboxylic acids such as acetic acid and the like; water and a mixture thereof.
The reaction temperature is, for example, about -50 -
200°C, preferably about 0 - 50°C. While the reaction time varies depending on the kind of compound (XI) , reaction
temperature and the like, it is, for example, about 0.1 - 100 hr, preferably about 0.1 - 6 hr.
[0282]
(Step 2)
In this step, compound (CVI) or a salt thereof is reacted with compound (XXIV) or a salt thereof in the presence of
Mitsunobu reagent and organic phosphorus reagent to produce compound (XXV) or a salt thereof.
Compound (XXIV) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
While the amount of compound (XXIV) to be used varies depending on the kind of the solvent and other reaction
conditions, it is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CVI) .
As the Mitsunobu reagent, azodicarboxylate such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like, and the like are used, of which diisopropyl
azodicarboxylate is preferable. While the amount of the
Mitsunobu reagent to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CVI) .
As the organic phosphorus reagent, organic phosphorus compounds such as tributylphosphine, triphenylphosphine and the like are used, of which triphenylphosphine is preferable.
While the amount of the organic phosphorus reagent to be used varies depending on the kind of the solvent and other reaction conditions, it is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CVI) .
This reaction can be performed in a solvent that does not adversely influence the reaction. Examples of such solvent include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like) and the like. Of these, toluene or tetrahydrofuran is preferable. Two or more kinds of these solvents may be used in a mixture in an
appropriate ratio.
The reaction temperature varies depending on the kind of the solvent, and is, for example, about 0 - 200°C, preferably about 50 - 100°C. While the reaction time varies depending on the kind of compound (CVI) or a salt thereof, reaction
temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[0283]
(Step 3)
In this step, compound (XXV) or a salt thereof is
subjected to hydrolysis to convert same to compound (XXVI) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 6.
[0284]
(Step 4)
In this step, compound (XXVI) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Id) or a salt thereof. This step can be performed by a method according to that of Method A, Step 8.
[0285]
Compound (Ie), which is the compound of the present invention (I' ) wherein the partial structure:
[0286]
[Chem. 88]
Figure imgf000107_0001
[0287]
is
[0288]
[Chem. 89
Figure imgf000107_0002
[0289]
L1 is a bond, and X is a nitrogen atom can be produced by the following Method E.
[Method E]
[0290]
[Chem. 90]
Figure imgf000108_0001
[0291]
wherein R5e is an optionally substituted hydrocarbon group, LG2 is a leaving group, Boc is t-butoxycarbonyl, and other symbols are as defined above.
Examples of the optionally substituted hydrocarbon group for R5e include those similar to the above-mentioned R5.
Examples of the leaving group for LG2 include those similar to the above-mentioned LG.
[0292]
(Step 1)
In this step, compound (XXVII) or a salt thereof is subjected to deprotection reaction to produce compound (XXVIII) or a salt thereof.
Such deprotection reaction can be performed according to a known method (e.g., "Protective Groups in Organic Synthesis, 3rd Ed." (Theodora W. Greene, Peter G. M. Wuts), Wiley- Interscience, 1999) . For example, while subject to variation depending on the kind of compound (XXVII), it can be generally performed in the presence of an acid and in a solvent as necessary that does not adversely influence the reaction.
Examples of the acid include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride and the like) , carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid and the like) , sulfonic acids
(methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, tin chloride, zinc bromide and the like) and the like, and two or more kinds thereof may be used in a mixture as necessary. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction conditions, it is generally not less than about 0.1 mol equivalent per 1 mol of compound (XXVII), and it can also be used as a solvent.
Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) ,
aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) ,
halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , carboxylic acids (acetic acid and the like) , amides (N, N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like) , water and the like, and a mixed solvent thereof can be mentioned.
The reaction temperature varies depending on the kind of the solvent, and it is, for example, about -50 - 200°C,
preferably about 0 - 100°C. While the reaction time varies depending on the kind of compound (XXVII), reaction temperature and the like, it is, for example, about 0.5 - 100 hr,
preferably about 0.5 - 24 hr. [0293]
(Step 2)
In this step, compound (XXVIII) or a salt thereof is subjected to a coupling reaction with compound (CX) or a salt thereof in the presence of a transition metal catalyst and a base to produce compound (XXIX) or a salt thereof.
Compound (CX) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
Examples of the transition metal catalyst to be used in this reaction include palladium catalysts (palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium (0) , tris (dibenzylideneacetone ) dipalladium ( 0 ) and the like), nickel catalysts (nickel chloride and the like) and the like and, where necessary, a ligand (triphenylphosphine, tri-t- butylphosphine, S-Phos, XPhos, BINAP, 2'-(di-tert- butylphosphino) -N, N-dimethyl- [ 1 , 1 ' -biphenyl] -2-amine and the like), a base (e.g., organic amines (trimethylamine,
triethylamine, diisopropylamine , N-methylmorpholine, 1,8- diazabicyclo [5, 4 , 0] undec-7-ene, pyridine, N, N-dimethylaniline and the like), an alkali metal salt (sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium acetate and the like) , metal hydride (potassium hydride, sodium hydride and the like), alkali metal alkoxide (sodium methoxide, sodium ethoxide, sodium-t-butoxide, potassium-t-butoxide and the like) , alkali disilazide (lithium disilazide, sodium disilazide, potassium disilazide and the like) ) may be added, or metal oxide (copper oxide, silver oxide and the like) and the like may be used as a cocatalyst. The amount of the catalyst to be used is generally about 0.0001 - 1 mol
equivalents, preferably about 0.01 - 0.5 molar equivalents, per 1 mol of compound (XXVIII) . The amount of the ligand to be used is generally about 0.0001 - 4 molar equivalents, preferably about 0.01 - 2 molar equivalents, per 1 mol of compound (XXVIII) . The amount of the base to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (XXVIII) . The amount of the cocatalyst to be used is generally about 0.0001 - 4 molar equivalents, preferably about 0.01 - 2 molar
equivalents, per 1 mol of compound (XXVIII).
The solvent to be used may be any as long as it does not adversely influence the reaction and, for example, hydrocarbons (benzene, toluene, xylene and the like) , halogenated
hydrocarbons (chloroform, 1 , 2-dichloroethane and the like), nitriles (acetonitrile and the like) , ethers (dimethoxyethane, tetrahydrofuran) , alcohols (methanol, ethanol and the like) , aprotic polar solvents (N, N-dimethylformamide, dimethyl
sulfoxide, hexamethylphosphoramide and the like) , water and a mixture thereof can be used.
The reaction temperature is generally about -100 - 200°C, preferably about -80 - 150°C, and the reaction time is
generally about 0.5 - 48 hr, preferably about 0.5 - 24 hr. The reaction may be performed under microwave irradiation as necessary .
[0294]
(Step 3)
In this step, compound (XXVII) or a salt thereof is subjected to hydrolysis to convert same to compound (XXX) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 6.
[0295]
(Step 4)
In this step, compound (XXVIII) or a salt thereof is subjected to hydrolysis to convert same to compound (XXXI) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 6. [0296]
(Step 5)
In this step, compound (XXIX) or a salt thereof is
subjected to hydrolysis to convert same to compound (XXXII) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 6.
[0297]
(Step 6)
In this step, compound (XXX) or a salt thereof and
compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (XXXIII) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 8.
[0298]
(Step 7)
In this step, compound (XXXI) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (XXXIV) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 8.
[0299]
(Step 8)
In this step, compound (XXXII) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ie) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 8.
[0300]
(Step 9)
In this step, compound (XXXIII) or a salt thereof is subjected to deprotection reaction to produce compound (XXXIV) or a salt thereof.
This step can be performed by a method according to that of Method E, Step 1. [0301]
(Step 10)
In this step, compound (XXXIV) or a salt thereof is subjected to a coupling reaction with compound (CX) or a salt thereof in the presence of a transition metal catalyst and a base to produce compound (Ie) or a salt thereof.
This step can be performed by a method according to that of Method E, Step 2.
[0302]
Compound (If-I), which is the compound of the present invention (Ι') wherein the partial structure:
[0303]
[Chem. 91]
Figure imgf000113_0001
[0304]
IS
[0305]
[Chem. 92]
Figure imgf000113_0002
[0306]
L1 is optionally halogenated C1 alkylene, and X is a nitrogen atom can be produced by the following Method F-1.
[Method F-1]
[0307]
[Chem. 93]
Figure imgf000114_0001
[0308]
wherein LG3 is a leaving group, Hal2 is a halogen atom, and other symbols are as defined above.
Examples of the leaving group for LG3 include those similar to the above-mentioned LG.
Examples of the halogen atom for Hal2 include those similar to the above-mentioned Hal.
[0309]
(Step 1)
In this step, compound (XXXVI) or a salt thereof is reacted with compound (XXXVII) or a salt thereof in the presence of a base to produce compound (XXXIX) or a salt thereof (alkylation) , or compound (XXXVI) or a salt thereof is reacted with compound (XXXVIII) or a salt thereof in the presence of a reducing agent to produce compound (XXXIX) or a salt thereof (reductive alkylation) .
Compound (XXXVI), compound (XXXVII) and compound
(XXXVIII) may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.
As the base to be used in "alkylation" reaction, for example, inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium
hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like) , organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine, etc. and the like) and the like are used and, of these, sodium hydride is preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (XXXVI) .
This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like),
sulfoxides (dimethyl sulfoxide and the like) and the like. Of these, dimethylformamide is preferable. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
The reaction temperature is, for example, about 0 - 200°C, preferably about 25 - 100°C. While the reaction time varies depending on the kind of compound (XXXVI) or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - about 24 hr.
The "reductive alkylation" reaction can be performed according to Method C, Step 1.
[0310]
(Step 2)
In this step, compound (XXXIX) or a salt thereof is subjected to alkoxycarbonylation under carbon monoxide
atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CIXe) :
R5eOH (CIXe)
wherein the symbol is as defined above,
to produce compound (CXI) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 5.
[0311]
(Step 3)
In this step, in compound (XXXVI) or a salt thereof, a free amino group is protected, and the obtained compound or a salt thereof is subjected to alkoxycarbonylation under carbon monoxide atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CIXe) :
R5eOH (CIXe)
wherein the symbol is as defined above,
and then the amino group is deprotected to produce compound (XXVIII) or a salt thereof.
The protecting group used for protecting a free amino group includes, for example, t-butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz or Z) group, benzyl (Bn) group, 4- methoxybenzyl (PMB) group, trifluoroacetyl (CF3CO) group and the like, of which Boc group is preferable.
When amino group is protected with Boc group, compound (XXXVI) or a salt thereof is reacted with di-t-butyl
dicarbonate (BOC2O) in the presence of a base and in a solvent that does not adversely influence the reaction.
As the base to be used in this step, for example,
inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride, lithium hexamethyldisilazide, sodium
hexamethyldisilazide and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium
ethoxide, etc. and the like) , organic base (amines such as trimethylamine, triethylamine , diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine, etc. and the like) and the like are used and, of these, sodium hydride, trimethylamine and sodium hexamethyldisilazide are preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (XXXVI) .
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like), ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and the like) , nitriles (acetonitrile and the like), esters (ethyl acetate and the like), amides (N,N- ■ dimethylformamide and the like) , sulfoxides (dimethyl sulfoxide and the like), and water and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio. Boc20 to be used in this step is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (XXXVI) .
The reaction temperature is, for example, about -10 - 100°C. The reaction time varies depending on the kind of compound (XXXVI) or a salt thereof, the reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
When amino group is protected with Cbz (Z) group, compound (XXXVI) or a salt thereof is reacted with benzyl chloroformate in the presence of a base and in a solvent that does not adversely influence the reaction. The base, solvent, reagent amount, reaction temperature, reaction time used in this step can be the same as those used for the above-mentioned protection of amino group with Boc group.
When amino group is protected with Bn group, compound (XXXVI) or a salt thereof is reacted with benzaldehyde in a solvent that does not adversely influence the reaction, and then treated with a reducing agent, or compound (XXXVI) or a salt thereof is reacted with benzyl bromide or benzyl chloride in the presence of a base and in a solvent that does not adversely influence the reaction.
When reacted with benzaldehyde, examples of the solvent that does not adversely influence the reaction include
hydrocarbons (heptane, hexane, toluene, xylene and the like) , halogenated hydrocarbons (chloroform, dichloromethane, 1,2- dichloroethane and the like) , ethers (diethyl ether,
tetrahydrofuran, dioxane and the like) , esters (ethyl acetate, t-butyl acetate and the like) , alcohols (methanol, ethanol, 2- propanol and the like), nitriles (acetonitrile, butyronitrile and the like), amides (N, N-dimethylformamide, N,N- dimethylacetamide and the like) , sulfoxides (dimethyl sulfoxide and the like) and the like, and a mixed solvent thereof.
Examples of the reducing agent to be used in this
reaction include metal hydrides (sodium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium cyanoborohydride, diisobutyl aluminum hydride, aluminum hydride, lithium aluminum hydride and the like) , borane complex (borane-THF complex, catechol borane etc.) and the like. The amount of the metal hydride to be used is generally about 1 - about 50 molar equivalents, per 1 mol of compound (XXXVI) .
In this reaction, a catalyst may be added as necessary to advantageous perform the reaction. As such catalyst, mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like), carboxylic acids (formic acid, acetic acid,
propionic acid, trifluoroacetic acid and the like) , sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, zinc chloride, zinc bromide, boron trifluoride, titanium chloride and the like) , acetate (sodium acetate, potassium acetate and the like) , molecular sieves (molecular sieves 3A, 4A, 5A and the like) , dehydrating agent (magnesium sulfate and the like) and the like can be mentioned. The amount of the catalyst to be used is generally about 0.01 - 50 molar equivalents, preferably about 0.1 - 10 mol, per 1 mol of compound (XXXVI).
The amount of benzaldehyde to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar
equivalents, per 1 mol of compound (XXXVI) .
The reaction temperature is generally about 0°C - 200°C, preferably about 20°C - 150°C, and the reaction time is
generally about 0.5 hr - 48 hr, preferably about 0.5 hr - 24 hr.
When reacted with benzyl bromide or benzyl chloride, examples of the base to be used in this reaction include
inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like), organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine, etc. and the like) and the like are used and, of these, potassium carbonate is preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (XXXVI) .
The amount of benzyl bromide and benzyl chloride to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (XXXVI) .
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and the like) , nitriles (acetonitrile and the like), esters (ethyl acetate and the like), amides (N,N- dimethylformamide and the like) , sulfoxides (dimethyl sulfoxide and the like) and the like. Of these, acetonitrile is
preferable. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
The reaction temperature is, for example, about 0 - 200°C, preferably about 25 - 100°C. While the reaction time varies depending on the kind of compound (XXXVI) or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - about 24 hr.
When amino group is protected with PMB group, compound (XXXVI) or a salt thereof is reacted with 4-methoxybenzaldehyde in a solvent that does not adversely influence the reaction, and treated with a reducing agent. The solvent, reducing agent, reagent amount, additive, reaction temperature, reaction time used in this step can be the same as those used for the above-mentioned protection of amino group with Bn group.
When amino group is protected with CF3CO group, in the presence of a base, compound (XXXVI) or a salt thereof is reacted with trifluoroacetic anhydride in a solvent that does not adversely influence the reaction. The base, solvent, reagent amount, reaction temperature, reaction -time used in this step can be the same as those used for the above-mentioned protection of amino group with Boc group.
The compound or a salt thereof obtained by protecting a free amino group is subjected to alkoxycarbonylation under carbon monoxide atmosphere by using a transition metal catalyst and alcohol represented by the formula (CIXe) , and this step can be performed according to Method A, Step 5.
The step of producing compound (XXVIII) or a salt thereof by deprotecting the amino group (deprotection) can be performed according to a known method (e.g., "Protective Groups in
Organic Synthesis, 3rd Ed." (Theodora W. Greene, Peter G. M. Wuts) Wiley-Interscience, 1999) ) .
When the protecting group is Boc group, deprotection reaction can be performed in the presence of an acid, in a solvent that does not adversely influence the reaction.
Examples of the acid include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid and the like) , sulfonic acids (methanesulfonic acid, p- toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, tin chloride, zinc bromide and the like) and the like, and two or more kinds thereof may be used in a mixture as necessary. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction
conditions, it is generally not less than about 0.1 mol
equivalent per 1 mol of the substrate, and it can also be used as a solvent.
Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) ,
aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) ,
halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , carboxylic acids (acetic acid and the like) , amides (N, -dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like) , water and the like, and a mixed
solvent thereof.
The reaction temperature is, for example, about -50 -
200°C, preferably about 0 - 100°C. While the reaction time varies depending on the kind of the substrate or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
When the protecting group is Bn group, Cbz(Z) group or
PMB group, deprotection reaction can be performed by catalytic hydrogenation reaction, oxidation reaction or acid
decomposition.
The catalytic hydrogenation reaction can be performed in a hydrogen atmosphere, in the presence of a catalyst. Examples of the catalyst include palladiums such as palladium carbon, palladium hydroxide carbon, palladium oxide and the like;
nickels such as sponge nickel catalyst and the like; platinums such as platinum oxide, platinum carbon and the like; rhodiums such as rhodium carbon and the like; and the like. The amount thereof to be used is generally about 0.001 - 1 molar
equivalents, preferably about 0.01 - 0.5 molar equivalents, per 1 mol of the substrate.
The catalytic hydrogenation reaction can be generally performed in a solvent inert to the reaction. Examples of such solvent include alcohols such as methanol, ethanol, propanol, butanol and the like; hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as
dichloromethane, chloroform and the like; ethers such as diethyl ether, dioxane, tetrahydrofuran and the like; esters such as ethyl acetate and the like; amides such as N,N- dimethylformamide and the like; carboxylic acids such as acetic acid and the like; water and a mixture thereof.
The reaction is performed at a hydrogen pressure of generally about 1 - 50 atm, preferably about 1 - 10 atm. The reaction temperature is generally about 0°C - 150°C, preferably about 20°C - 100°C, and the reaction time is generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.
Examples of the oxidant to be used for the oxidation reaction include cerium (IV) ammonium nitrate. The amount thereof to be used is generally about 1 - about 50 molar equivalents per 1 mol of the substrate.
The oxidation reaction can be performed in a solvent that does not adversely influence the reaction. Examples of such solvent include nitriles (e.g., acetonitrile) , hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers (e.g., diethyl ether, dioxane, tetrahydrofuran) , amides (e.g., N,N- dimethylformamide) , water and a mixture thereof.
The reaction temperature is generally about 0°C - 150°C, preferably about 20°C - 100°C, and the reaction time is
generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.
As the acid to be used for acid decomposition,
trifluoroacetic acid can be mentioned, and it can be utilized as a solvent. The reaction temperature is generally about 0°C - 150°C, preferably about 0°C - 30°C, and the reaction time is generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.
When the protecting group is CF3CO group, deprotection reaction can be performed in the presence of a base, in a solvent that does not adversely influence the reaction. Examples of the base include inorganic base (alkali metal hydroxides such as lithium hydroxide, sodium hydroxide,
potassium hydroxide and the like, alkali metal hydrogen
carbonates such as sodium hydrogen carbonate, potassium
hydrogen carbonate and the like, alkali metal carbonates such as sodium carbonate, potassium carbonate and the like, and the like, alkoxide such as sodium methoxide, sodium ethoxide and the like, and the like) . The amount of the base to be used is generally about 1 - 100 molar equivalents, preferably about 1 - 20 molar equivalents, per 1 mol of the substrate.
Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene, hexane, heptane and the like) , halogenated hydrocarbons
(dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like), amides (N, N-dimethylformamide, N,N- dimethylacetamide and the like) , sulfoxides (dimethyl sulfoxide and the like) water, and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
The reaction temperature is, for example, about -50 - 200°C, preferably about 0 - 100°C. While the reaction time varies depending on the kind of the substrate or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 24 hr, preferably about 0.5 - 2 hr.
[0312]
(Step 4)
In this step, compound (XXVIII) or a salt thereof is reacted with compound (XXXVII) or a salt thereof in the
presence of a base to produce compound (CXI) or a salt thereof (alkylation) , or compound (XXVIII) or a salt thereof is reacted with compound (XXXVIII) or a salt thereof in the presence of a reducing agent to produce compound (CXI) or a salt thereof
(reductive alkylation) .
This step can be performed by a method according to that of Method F-l, Step 1.
[0313]
(Step 5)
In this step, compound (CXI) or a salt thereof is subjected to hydrolysis to be converted to compound (XL) or a salt thereof .
This step can be performed by a method according to that of Method A, Step 6.
[0314]
(Step 6)
In this step, compound (XL) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (If-I) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 8.
[0315]
Compound (If-II), which is the compound of the present invention (Ι') wherein the partial structure:
[0316]
[Chem. 94]
Figure imgf000125_0001
[0317]
is
[0318]
[Chem. 95]
Figure imgf000125_0002
[0319]
L1 is optionally halogenated C2 alkylene, and X is a nitrogen atom can be produced by the following Method F-2.
[Method F-2]
[0320]
[Chem. 96]
Figure imgf000126_0001
(lf-ll)
[0321]
wherein LG4 is a leaving group, Hal3 is a halogen atom, and other symbols are as defined above.
Examples of the leaving group for LG4 include those similar to the above-mentioned LG.
Examples of the halogen atom for Hal3 include those similar to the above-mentioned Hal.
[0322]
(Step 1) In this step, compound (XXXV) or a salt thereof is reacted with compound (XLI) or a salt thereof in the presence of a base to produce compound (XLIII) or a salt thereof
(alkylation) , or compound (XXXV) or a salt thereof is reacted with compound (XLII) or a salt thereof in the presence of a reducing agent to produce compound (XLIII) or a salt thereof (reductive alkylation) .
Compound (XXXV), compound (XLI), compound (XLII) may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto .
This step can be performed by a method according to that of Method F-l, Step 1.
[0323]
(Step 2)
In this step, compound (XLIII) or a salt thereof is subjected to alkoxycarbonylation under carbon monoxide
atmosphere, by using a transition metal catalyst and alcohol represented by the following formula (CIXe) :
R5eOH (CIXe)
wherein the symbol is as defined above,
to produce compound (XLIVI) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 5.
[0324]
(Step 3)
In this step, compound (XXVIII) or a salt thereof is reacted with compound (XLI) or a salt thereof in the presence of a base to produce compound (XLIVI) or a salt thereof
(alkylation), or compound (XXVIII) or a salt thereof is reacted with compound (XLII) or a salt thereof in the presence of a reducing agent to produce compound (XLIVI) or a salt thereof (reductive alkylation) .
Compound (XXVIII), compound (XLI), compound (XLII) may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto .
This step can be performed by a method according to that of Method F-l, Step 1.
[0325]
(Step 4)
In this step, compound (XLIVI) or a salt thereof is subjected to hydrolysis to convert same to compound (XLV) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 6.
[0326]
(Step 5)
In this step, compound (XLV) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (If-II) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 8.
[0327]
Compound (Ig), which is the compound of the present invention (Ι') wherein the partial structure:
[0328]
[Chem. 97]
Figure imgf000128_0001
[0329]
is
[0330]
[Chem.
Figure imgf000129_0001
[0331]
L1 is -NH-, and X is a nitrogen atom can be produced by the following Method G.
[Method G]
[0332]
[Chem. 99]
Figure imgf000129_0002
(XXVIII)
Figure imgf000129_0003
[0333]
wherein each symbol is as defined above.
[0334]
(Step 1)
In this step, compound (XXVIII) or a salt thereof is subjected to a nitrosation reaction to produce compound (XLVI) or a salt thereof. The nitrosation reaction can be performed by a method known per se, for example, the method described in The Chemical Society of Japan, 1991, "4th ed. Jikken Kagaku Kouza 20,
Organic Synthesis II" and the like, or a method analogous thereto. Examples of the method include a method using, for example, tert-butyl nitrite or sodium nitrite and the amount thereof to be used is generally 1 - 20 equivalents per 1 mol of compound (XXVIII) .
This step can be performed in a solvent that does not adversely influence the reaction. This step can also be performed in the presence of an acid. Examples of such solvent include hydrocarbons (benzene, toluene, xylene and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , carboxylic acids (acetic acid and the like) , water or a mixture thereof. Examples of the acid include hydrochloric acid and nitric acid. The reaction temperature is generally about 0 - 150°C, preferably about 0 - 100°C, and the reaction time is generally, 5 min - 72 hr.
[0335]
(Step 2)
In this step, compound (XLVI) or a salt thereof is subjected to a reduction reaction to produce compound (XLVII) or a salt thereof.
The reduction reaction can be generally performed by using a reducing agent such as metal and metal salt, metal hydride and the like. Preferable examples of the metal and metal salt to be used include alkali metal (lithium, sodium, potassium and the like) , alkaline earth metal (magnesium, calcium and the like) , other metals (zinc, chrome, titanium, iron, samarium, selenium and the like), and metal salt (zinc- amalgam, zinc-copper alloy, aluminum-amalgam, sodium
hydrosulfite and the like) and the like. Examples of the metal hydride include lithium aluminum hydride. The amount of the reducing agent to be used is, for example, generally 1 - 50 molar equivalents per 1 mol of compound (XLVI) .
Examples of the solvent to be used for the reaction include alcohols (methanol, ethanol, 2-propanol, t-butanol, benzyl alcohol and the like) , amines (liquid ammonia,
methylamine, ethylamine, ethylenediamine and the like) , ethers (diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (acetic acid and the like) , amides (hexamethylphosphoramide) , water and the like, and these solvents can be used alone or in a mixture.
The reaction temperature is generally about -80 - 150°C, preferably about -80 - 100°C, and the reaction time is
generally, 5 min - 48 hr, preferably 1 - 24 hr.
[0336]
(Step 3)
In this step, compound (XLVII) or a salt thereof is subjected to a coupling reaction with compound (CX) or a salt thereof in the presence of a transition metal catalyst and a base to produce compound (XLVIII) or a salt thereof.
This step can be performed by a method according to that of Method E, Step 2.
[0337]
(Step 4)
In this step, compound (XLVIII) or a salt thereof is subjected to hydrolysis to convert same to compound (XLIX) or a salt thereof.
This step can be performed by a method according to that of Method A,. Step 6.
[0338]
(Step 5)
In this step, compound (XLIX) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ig) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 8. [0339]
Compound (In), which is the compound of the present invention (I' ) wherein the partial structure:
[0340]
[Chem. 100]
Figure imgf000132_0001
[0341]
is
[0342]
[Chem. 101]
Figure imgf000132_0002
[0343]
L1 is -0-, and X is a nitrogen atom can be produced by the following Method H.
[Method H]
[0344]
[Chem. 102]
Figure imgf000133_0001
Figure imgf000133_0002
[0345]
wherein R5f and R5g are each independently an optionally
substituted hydrocarbon group, LG5 is a leaving group, Hal4 is a halogen atom, and other symbols are as defined above.
Examples of the optionally substituted hydrocarbon group for R5f or R5g include those similar to the above-mentioned R5.
Examples of the halogen atom for Hal4 include those similar to the above-mentioned Hal.
Examples of the leaving group for LG5 include those similar to the above-mentioned LG.
[0346]
(Step 1)
In this step, compound (L) or a salt thereof is reacted with compound (LI) or a salt thereof in the presence of a base to produce compound (LII) or a salt thereof.
Compound (L) , compound (LI) may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.
This step can be performed according to the method by an
"alkylation" reaction described in Method F-l, Step 1. [0347]
(Step 2)
In this step, compound (LII) is subjected to a reduction reaction using a transition metal catalyst to produce compound (LIII) or a salt thereof.
Examples of the transition metal catalyst to be used in this reaction include palladiums (palladium carbon, palladium hydroxide, palladium oxide and the like) , nickels (Raney-nickel and the like) , platinums (platinum oxide, platinum carbon and the like) , rhodiums (rhodium acetate, rhodium carbon and the like) and the like. The amount thereof to be used is, for example, about 0.001 - 1 molar equivalents, preferably about 0.01 - 0.5 molar equivalents, per 1 mol of compound (LII) .
The catalytic hydrogenation reaction can be generally performed in a solvent inert to the reaction. Examples of such solvent include alcohols (methanol, ethanol, propanol, butanol and the like), hydrocarbons (benzene, toluene, xylene and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , esters (ethyl acetate and the like) , amides
(N, N-dimethylformamide and the like), carboxylic acids (acetic acid and the like), water or a mixture thereof. The hydrogen pressure at which the reaction is performed is generally about 1 - 50 atm, preferably about 1 - 10 atm.
The reaction temperature is generally about 0 - 150°C, preferably about 20 - 100°C, and the reaction time is generally about 5 min - 72 hr, preferably about 0.5 - 40 hr.
[0348]
(Step 3)
In this step, compound (LIII) or a salt thereof is reacted with compound (XXIV) or a salt thereof in the presence of a Mitsunobu reagent and an organic phosphorus reagent to produce compound (LIV) or a salt thereof.
This step can be performed by a method according to that described in Method D, Step 2. [0349]
(Step 4)
In this step, compound (LIV) or a salt thereof is
subjected to a reduction reaction to produce compound (LV) or a salt thereof.
The reduction reaction can be performed by reduction with a metal hydride in a solvent that does not adversely influence the reaction.
Examples of the metal hydride include diisobutylaluminum hydride, aluminum hydride, lithium aluminum hydride, borane complex (borane-THF complex, catechol borane etc.) and the like. The amount of metal hydride to be used is, for example, about 1 - 50 molar equivalents per 1 mol of compound (LIV) .
The reduction reaction with metal hydride can be
generally performed in a solvent inert to the reaction.
Examples of such solvent include aromatic hydrocarbons (toluene, xylene etc.), aliphatic hydrocarbons (heptane, hexane etc.), halogenated hydrocarbons (chloroform, dichloromethane etc.), ethers (diethyl ether, tetrahydrofuran, dioxane etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N, N-dimethylformamide , dimethyl sulfoxide and the like. These solvent may be used in a mixture at an appropriate ratio.
While the reaction temperature varies depending on the kind of the solvent, it is generally about -80 - 80°C,
preferably about -40 - 40°C. The reaction time is generally about 5 min - 48 hr, preferably about 1 = 24 hr.
[0350]
(Step 5)
In this step, compound (LV) or a salt thereof is
subjected to alkoxycarbonylation under carbon monoxide
atmosphere, by using a transition metal catalyst and alcohol represented by the following formula (CIXf) :
R5fOH (CIXf)
wherein the symbol is as defined above, to produce compound (LVI) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 5.
[0351]
(Step 6)
In this step, compound (LVI) or a salt thereof is subjected to hydrolysis to convert same to compound (LVII) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 6.
[0352]
(Step 7)
In this step, compound (LVII) or a salt thereof and compound (X) or a salt thereof are subjected to a condensation reaction to convert same to compound (Ih) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 8.
[0353]
Compound (XXVIII) or a salt thereof used in Method E, Method F-l, Method F-2, Method G can be produced by the
following Method I.
[Method I]
[0354]
[Chem. 103]
Figure imgf000137_0001
[0355]
wherein each symbol is as defined above.
[0356]
(Step 1)
In this step, compound (LVIII) or a salt thereof is subjected to a brominating reaction in the presence of a base to produce compound (LIX) or a salt thereof.
Compound (LVIII) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
Examples of the brominating agent to be used for the brominating reaction include bromine, perbromides (pyridinium bromide perbromide, 4-dimethylaminopyridinium bromide
perbromide and the like) , bromoimides (N-bromosuccinimide, N- bromophthalimide, N-bromosaccharin, dibromoisocyanuric acid and the like) , boron tribromide, phosphorus tribromide,
bromodimethylsulfonium bromide, 5 , 5-dibromomeldrum' s acid, 2, 4, 4, 6-tetrabromo-2, 5-cyclohexadienone and the like. The amount of the brominating agent to be used is, for example, about 1 - 10 molar equivalents, per 1 mol of compound (LVIII) .
The brominating reaction can be generally performed in a solvent inert to the reaction. Examples of such solvent include aromatic hydrocarbons (toluene, xylene etc. ) , aliphatic hydrocarbon (heptane, hexane etc. ) , halogenated hydrocarbons (chloroform, dichloromethane etc. ) , ethers (diethyl ether, tetrahydrofuran, dioxane etc. ) , alcohols (methanol, ethanol, 2- propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N, N-dimethylformamide, dimethyl sulfoxide, water and the like. These solvents may be used in a mixture in an
appropriate ratio.
The reaction temperature varies depending on the kind of the solvent, and is generally about -80 - 80°C, preferably about -40 - 40°C, and the reaction time is generally about 5 min - 48 hr, preferably about 1 - 24 hr.
[0357]
(Step 2)
In this step, compound (LIX) or a salt thereof is
subjected to a demethylation reaction to produce compound (LX) or a salt there.
The demethylation reaction can be performed by a method known per se or a method analogous thereto. For example, a method using bromide or a method using Lewis acid in the presence of thiol can be mentioned.
In the method using bromide, boron tribromide, hydrogen bromide are preferably used. The amount thereof to be used is, for example, about 1 - 100 molar equivalents, per 1 mol of compound (LIX) .
The method using bromide can be generally performed in a solvent inert to the reaction. Examples of such solvent include aromatic hydrocarbons (toluene, xylene etc.), aliphatic hydrocarbon (heptane, hexane etc.), halogenated hydrocarbons (chloroform, dichloromethane etc.), ethers (diethyl ether, tetrahydrofuran, dioxane etc.), alcohols (methanol, ethanol, 2- propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N, N-dimethylformamide, dimethyl sulfoxide, water and the like. These solvents may be used in a mixture in an
appropriate ratio.
The reaction temperature varies depending on the kind of the solvent, and it is generally about -80 - 100°C, and the reaction time is generally about 5 min - 48 hr.
In the method using Lewis acid in the presence of thiol, dodecylmercaptan is preferably used as. thiol and the amount thereof to be used is, for example, about 1 - 10 molar
equivalents, per 1 mol of compound (LIX) .
As Lewis acid, aluminum chloride is preferably used. The amount thereof to be used is, for example, about 1 - 10 molar equivalents, per 1 mol of compound (LIX) .
The method using Lewis acid in the presence of thiol is generally performed in a solvent inert to the reaction.
Examples of such solvent include aromatic hydrocarbons (toluene, xylene etc.), aliphatic hydrocarbon (heptane, hexane etc.), halogenated hydrocarbons (chloroform, dichloromethane etc.), ethers (diethyl ether, tetrahydrofuran, dioxane etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N, N-dimethylformamide, dimethyl sulfoxide and the like. These solvents may be used in a
mixture in an appropriate ratio.
The reaction temperature varies depending on the kind of the solvent, and it is generally about -80 - 100°C, and the reaction time is generally about 5 min - 48 hr.
[0358]
(Step 3)
In this step, compound (LX) or a salt thereof is reacted with compound (LI) or a salt thereof in the presence of a base to produce compound (LXI) or a salt thereof.
This step can be performed by a method by "alkylation" reaction described in Method F-l, Step 1. [0359]
(Step 4)
In this step, compound (LXI) or a salt thereof is subjected to reduction reaction to produce compound (XXXVI) or a salt thereof.
This step can be performed by a method according to that of Method H, Step 4.
[0360]
(Step 5)
In this step, compound (XXXVI) or a salt thereof is reacted with Boc20 in the presence of a base to produce
compound (LXII) or a salt thereof.
This step can be performed according to the method described in the method of protection with Boc group in Method F-l, Step 3.
[0361]
(Step 6)
In this step, compound (LXII) or a salt thereof is subjected to alkoxycarbonylation under carbon monoxide
atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CIX) :
R5OH (CIX)
wherein the symbol is as defined above,
to produce compound (XXVII) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 5.
[0362]
(Step 7)
In this step, compound (XXVII) or a salt thereof is subjected to deprotection reaction to produce compound (XXVIII) or a salt thereof.
This step can be performed by a method according to that of Method E, Step 1.
[0363]
(Step 8) In this step, compound (LXIII) or a salt thereof is reacted with compound (LI) or a salt thereof in the presence of a base to produce compound (LXIV) or a salt thereof.
This step can be performed according to the method by an "alkylation" reaction described in Method F-l, Step 1.
[0364]
(Step 9)
In this step, compound (LXIV) or a salt thereof is subjected to a reduction reaction to produce compound (XXVIII) or a salt thereof.
This step can be performed by a method according to the method described in Method H, Step 4.
Compound (LXII) or a salt thereof to be used in Method I can also be produced by the following Method J.
[Method J]
[0365]
[Chem. 104]
Figure imgf000141_0001
[0366]
wherein Hal5 is a halogen atom, and other symbols are as defined above.
As the examples of the halogen atom for Hal5, those similar to the above-mentioned Hal can be mentioned.
[0367]
(Step 1) In this step, compound (LXV) or a salt thereof is reacted with compound (LXVI) or a salt thereof in the presence of a Mitsunobu reagent and an organic phosphorus reagent to produce compound (LXVII) or a salt thereof.
Compound (LXV) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
This step can be performed by a method according to the method described in Method D, Step 2.
[0368]
(Step 2)
In this step, compound (LXVII) or a salt thereof is subjected to deprotection reaction to produce compound (LXVIII) or a salt thereof.
This step can be performed by a method according to that of Method E, Step 1.
[0369]
(Step 3)
In this step, compound (LXVIII) or a salt thereof is subjected to a cyclization reaction in the presence of a base to produce compound (LXIX) or a salt thereof.
As the base to be used in the cyclization reaction, for example, inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium
hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like), organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine, etc. and the like) and the like are used and, of these, sodium hydride is preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound ( LXVI I I ) .
This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated
hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and the like) ,
nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like),
sulfoxides (dimethyl sulfoxide and the like) and the like. Of these, dimethylformamide is preferable. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
The reaction temperature is, for example, about 0 - 200°C, preferably about 25 - 100°C. The reaction time varies
depending on the kind of compound (LXVIII) or a salt thereof, reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[0370]
(Step 4)
In this step, compound (LXIX) or a salt thereof is
subjected to a brominating reaction in the presence of a base to produce compound ( XXXVI ) or a salt thereof.
This step can be performed by a method according to that of Method I, Step 1.
[0371]
(Step 5)
In this step, compound (XXXVI) or a salt thereof is reacted with Boc20 in the presence of a base to produce
compound (LXII) or a salt thereof.
This step can be performed according to the method described in the method of protection with Boc group in Method
F-l, Step 3.
[0372]
Compound (LXXVI) , which is the compound of the present invention (Ι') wherein the partial structure:
[0373]
[Chem. 105]
Figure imgf000144_0001
[0374]
is
[0375]
[Chem. 106]
Figure imgf000144_0002
[0376]
R is a hydroxymethyl group, D is a piperidine ring, and
-SO2- can be produced by the following Method K.
[Method K]
[0377]
[Chem. 107]
Figure imgf000145_0001
[0378]
wherein R5h is an optionally substituted hydrocarbon group, LG6 is a leaving group, and other symbols are as defined above.
Examples of the optionally substituted hydrocarbon group for R5h include those similar to the above-mentioned R5.
Examples of the leaving group for LG6 include those similar to the above-mentioned LG.
[0379]
(Step 1)
In this step, compound (LXX) or a salt thereof and compound (LXXI) or a salt thereof are subjected to a
condensation reaction to convert same to compound (LXXII) or a salt thereof.
Compound (LXX) and compound (LXXI) may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.
This step can be performed by a method according to that of Method A, Step 8.
[0380]
(Step 2)
In this step, compound (LXXII) or a salt thereof is subjected to deprotection reaction to produce compound (LXXIII) or a salt thereof.
This step can be performed by a method according to that of Method E, Step 1.
[0381]
(Step 3)
In this step, compound (LXXIII) or a salt thereof is reacted with sulfonylating agent (LXXIV) or a salt thereof in the presence of a base to produce compound (LXXV) or a salt thereof .
The sulfonylating agent (LXXIV) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
As the base to be used in this step, for example,
inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride, lithium hexamethyldisilazide, sodium
hexamethyldisilazide, and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium
hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like), organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine , etc. and the like) and the like are used and, of these, sodium hydride, triethylamine and sodium hexamethyldisilazide are preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (LXXIII) .
Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and the like) , nitriles (acetonitrile and the like), esters (ethyl acetate and the like), amides (N,N- dimethylformamide and the like) , sulfoxides (dimethyl sulfoxide and the like), and water and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
The sulfonylating agent (LXXIV) is used in this step generally at about 1 - 10 molar equivalents, preferably about 1- 2 molar equivalents, per 1 mol of compound (LXXIII) .
The reaction temperature is, for example, about -10 - 100°C. The reaction time varies depending on the kind of compound (LXXIII) or a salt thereof, the reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[0382]
(Step 4)
In this step, compound (LXXV) or a salt thereof is
treated with a reducing agent to produce compound (LXXVI) or a salt thereof.
This step can be performed by a method according to that of Method D, Step 1.
[0383]
Compound (LXXX) or a salt thereof, compound (LXXXV) or a salt thereof, compound (XC) or a salt thereof, compound (XCII) or a salt thereof used as intermediates in Method A, Method B-l, Method B2-2, Method C, Method D, Method E, Method F-l, Method F-2, Method G, Method H can be produced by the following Method L.
[Method L] [0384]
[Chem. 108;
Figure imgf000148_0001
[0385]
wherein R3a and R3b are each independently a hydrogen atom or a substituent of an amino group, Hal6 is a halogen atom, and other symbols are as defined above.
When R3a and R3b are substituents of the amino group, they are exemplified by those similar to the substituents of the above-mentioned "optionally substituted amino group".
Examples of the halogen atom for Hal6 include those similar to the above-mentioned Hal.
[0386]
(Step 1)
In this step, compound (LXXVII) or a salt thereof is reacted with compound (LXXVIII) or a salt thereof to convert same to compound (LXXIX) or a salt thereof.
Compound (LXXVII) and compound (LXXVIII) may be
commercially available products, or can also be produced
according to a method known per se or a method analogous thereto .
This step can be performed in a solvent inert to the reaction. Examples of such solvent include aromatic
hydrocarbons (toluene, xylene etc.), aliphatic hydrocarbons (heptane, hexane etc. ) , halogenated hydrocarbons (chloroform, dichloromethane etc.), ethers (diethyl ether, tetrahydrofuran, dioxane etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N,N- dimethylformamide, dimethyl sulfoxide and the like. These solvent may be used in a mixture at an appropriate ratio.
Compound (LXXVIII) is used in this step at generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (LXXVII).
The reaction temperature varies depending on the kind of the solvent, and is generally about -80 - 200°C, and the
reaction time is generally about 5 min - 48 hr.
[0387]
(Step 2)
In this step, compound (LXXIX) or a salt thereof is subjected to a catalytic hydrogenation reaction to produce compound (LXXX) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 3.
[0388]
(Step 3)
In this step, compound (LXXVII) or a salt thereof is reacted with phenylmethanethiol in the presence of a Pd
catalyst and a base to convert same to compound (LXXXI) or a salt thereof.
Phenylmethanethiol may be a "commercially available product .
Examples of the Pd catalyst to be used for the reaction include palladium acetate, palladium chloride,
tetrakis (triphenylphosphine) palladium ( 0 ) ,
tris (dibenzylideneacetone ) dipalladium ( 0 ) , XPHOS Pd G2 and the like. Where necessary, a ligand (Xphos, triphenylphosphine, tri-t-butylphosphine, S-Phos, BINAP, 2 ' - (di-tert- butylphosphino) -N, N-dimethyl- [1, 1' -biphenyl] -2-amine, XANTPHOS and the like) is added. The amount of the catalyst to be used is generally about 0.0001 - 1 molar equivalents, preferably about 0.01 - 0.5 molar equivalents, per 1 mol of compound
(LXXVII) . The amount of the ligand to be used is generally about 0.0001 - 4 molar equivalents, preferably about 0.01 - 2 molar equivalents, per 1 mol of compound (LXXVII).
As the base, an organic base (triethylamine,
diisopropylethylamine and the like) , an alkali metal salt
(sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium acetate and the like) , metal hydride
(potassium hydride, sodium hydride and the like) , alkali metal alkoxide (lithium t-butoxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like) , alkali disilazide (lithium disilazide, sodium disilazide, potassium disilazide and the like) ) may be added. The amount of the base to be used is generally about 1 - 10 molar equivalents,
preferably about 1 - 2 molar equivalents, per 1 mol of compound (LXXVII) .
This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene and the like) , halogenated
hydrocarbons (chloroform, 1 , 2-dichloroethane and the like), nitriles (acetonitrile and the like) , ethers (cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran) , alcohols (methanol, ethanol and the like), aprotic polar solvents (N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide and the like), and a mixture thereof.
The reaction temperature is generally about 0 - 150°C, preferably about 60 - 100°C, and the reaction time is generally about 0.5 - 48 hr, preferably about 0.5 - 24 hr. The reaction may be performed under microwave irradiation as necessary.
[0389]
(Step 4)
In this step, compound (LXXXI) or a salt thereof is treated with N-chlorosuccinimide to convert same to compound (LXXXII) or a salt thereof.
The amount of N-chlorosuccinimide to be used is generally about 1 - about 50 molar equivalents relative to compound
(LXXXI) .
This reaction can be performed in a solvent that does not adversely influence the reaction. Examples of such solvent include nitriles (e.g., acetonitrile) , hydrocarbons (e.g., benzene, toluene, xylene), halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers (e.g., diethyl ether, dioxane, tetrahydrofuran) , amides (e.g., N, N-dimethylformamide) , acid (e.g., hydrochloric acid, acetic acid), water and a
mixture thereof.
The reaction temperature is generally about -80°C - 100°C, preferably about -5°C - 30°C, and the reaction time is
generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.
[0390]
(Step 5)
In this step, compound (LXXXII) or a salt thereof is reacted with compound (LXXXIII) or a salt thereof in the
presence of a base to convert same to compound (LXXXIV) or a salt thereof.
Compound (LXXXIII) may be a commercially available
product, or can also be produced according to a method known per se or a method analogous thereto. The amount of compound (LXXXIII) to be used is generally about 1 - about 50 molar equivalents relative to compound
(LXXXII) .
As the base to be used in this step, for example,
inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium
ethoxide, etc. and the like) , organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine, etc. and the like) and the like are used. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (LXXXII) . In addition, compound
(LXXXIII) itself may be used as a base.
This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated
hydrocarbons (dichloromethane, chloroform and the like) , alcohol (methanol, ethanol and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , amides
(N, N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like), and water and the like. Two or more kinds of these solvents may be used in a mixture in an
appropriate ratio. The reaction temperature is, for example, about -80 -
200°C, preferably about -5 - 100°C. The reaction time varies depending on . the kind of compound (LXXXII) or a salt thereof, reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[0391]
(Step 6)
In this step, compound (LXXXIV) or a salt thereof is subjected to a catalytic hydrogenation reaction to produce compound (LXXXV) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 3.
[0392]
(Step 7)
In this step, compound (LXXXVI) or a salt thereof is treated with N-bromosuccinimide in the presence of potassium-t- butoxide and cyanamide to convert same to compound (LXXXVII) or a salt thereof.
The amount of potassium-t-butoxide to be used is
generally about 1 - about 10 molar equivalents relative to compound (LXXXVI) .
The amount of cyanamide to be used is generally about 1 - about 10 molar equivalents relative to compound (LXXXVI) .
The amount of N-bromosuccinimide to be used is generally about 1 - about 10 molar equivalents relative to compound
(LXXXVI) .
This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated
hydrocarbons (dichloromethane, chloroform and the like) , alcohol (methanol, ethanol and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , amides (N, N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like), water and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
The reaction temperature is, for example, about -80 -
100°C, preferably about -5 - 50°C. The reaction time varies depending on the kind of compound (LXXXVI) or the salt, reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[0393]
(Step 8)
In this step, compound (LXXXVII) or a salt thereof is treated with an oxidant to convert same to compound (LXXXVIII) or a salt thereof.
Examples of the oxidant to be used in this reaction include m-chloroperbenzoic acid. The amount thereof to be used is generally about 1 - about 50 molar equivalents, per 1 mol of compound (LXXXVII) .
The oxidation reaction can be performed in a solvent that does not adversely influence the reaction. Examples of such solvent include nitriles (e.g., acetonitrile) , hydrocarbons (e.g., benzene, toluene, xylene), alcohol (e.g., methanol, ethanol) , halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers (e.g., diethyl ether, dioxane,
tetrahydrofuran) , amides (e.g., N, N-dimethylformamide ) , water and a mixture thereof.
The reaction temperature is generally about -50°C - 100°C, preferably about -5°C - 50°C, and the reaction time is
generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.
[0394]
(Step 9)
In this step, compound (LXXXVIII) or a salt thereof is treated with trifluoroacetic anhydride and subsequently treated with potassium carbonate to convert same to compound (LXXXIX) or a salt thereof.
The amount of trifluoroacetic anhydride to be used is generally about 1 - about 50 molar equivalents, per 1 mol of compound (LXXXVIII) .
5 This step can be performed in a solvent that does not
adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated
10 hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
15 The reaction temperature is, for example, about -80 -
100°C, preferably about -5 - 50°C. The reaction time varies depending on the kind of compound (LXXXVIII) or a salt thereof, reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
20 The amount of potassium carbonate to be used is generally about 1 - about 50 molar equivalents, per 1 mol of compound (LXXXVIII) .
This step can be performed in a solvent that does not adversely influence the reaction. Examples of the solvent that
25 does not adversely influence the reaction include aromatic
hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , alcohol (methanol, ethanol and the like) , halogenated hydrocarbons
(dichloromethane, chloroform and the like) , ethers (diethyl
30 ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like), water and the like.
Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
The reaction temperature is, for example, about -80 -
35 100°C, preferably about -5 - 50°C. The reaction time varies depending on the kind of compound (LXXXVIII) or a salt thereof, reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[0395]
(Step 10)
In this step, compound (LXXXIX) or a salt thereof is subjected to a catalytic hydrogenation reaction to produce compound (XC) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 3.
[0396]
(Step 11)
In this step, compound (LXXXIX) or a salt thereof is subjected to an alkylation reaction or a reductive alkylation reaction to produce compound (XCI) or a salt thereof.
This step can be performed by a method according to that of Method F-l, Step 1.
[0397]
(Step 12)
In this step, compound (XCI) or a salt thereof is
subjected to a catalytic hydrogenation reaction to produce compound (XCII) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 3.
[0398]
Compound (XCIV) or a salt thereof to be used as an intermediate for Method A, Method B-l, Method B2-2, Method C, Method D, Method E, Method F-l, Method F-2, Method G, and
Method H can be produced by the following Method M.
Of the compounds (I) of the present invention, compound
(CI) or a salt thereof and compound (CIV) or a salt thereof can be produced by the following Method M.
[Method M]
[0399]
[Chem. 109]
(XCIII) (XCIV)
Figure imgf000157_0002
[0400]
wherein R51 is an optionally substituted hydrocarbon group, Hal7 is a halogen atom, and other symbols are as defined above. Examples of the optionally substituted hydrocarbon group for R51 include those similar to the above-mentioned R5.
Examples of the halogen atom for Hal7 include those similar to the above-mentioned Hal.
[0401]
(Step 1)
In this step, compound (XCIII) or a salt thereof is reacted with hydroxylamine or a salt thereof and the obtained oxime intermediate is subjected to a reduction reaction to produce compound (XCIV) or a salt thereof.
Compound (XCIII) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
The amount of hydroxylamine to be used is generally about 1 - about 10 molar equivalents, per 1 mol of compound (XCIII) .
This step can be performed by a method according to that of Method C, Step 1.
[0402]
(Step 2)
In this step, compound (XCV) or a salt thereof is reacted with glyoxylic acid ester (XCVI) and diallylamine to produce compound (XCVII) or a salt thereof.
Compound (XCV) to be used in this reaction may be a commercially available product, or can also be produced
according to a method known per se or a method analogous thereto .
The amount of glyoxylic acid ester (XCVI) to be used is generally about 1 - 10 molar equivalents, per 1 mol of compound (XCV) .
The amount of diallylamine to be used is generally about
1 - 10 molar equivalents, per 1 mol of compound (XCV) .
The above-mentioned reaction can be generally performed in a solvent that does not adversely influence the reaction. Examples of the solvent to be used include nitriles
(acetonitrile and the like) , hydrocarbons (benzene, toluene and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , esters (ethyl acetate and the like) , halogenated hydrocarbons (chloroform, dichloromethane and the like) , amides (N, N-dimethylformamide and the like) and the like, and they may be mixed as appropriate. The reaction temperature is generally about -80 - 150°C, preferably about 0 - 10°C, and the reaction time is generally about 0.5 - 100 hr, preferably about 0.5 - 60 hr .
[0403]
(Step 3)
In this step, compound (XCVII) or a salt thereof is treated with an oxidant to convert same to compound (XCVIII) or a salt thereof.
Examples of the oxidant to be used in this reaction include m-chloroperbenzoic acid, oxone and the like. The amount thereof to be used is generally about 1 - about 50 molar equivalents, per 1 mol of compound (XCVII) .
The oxidation reaction can be performed in a solvent that does not adversely influence the reaction. Examples of such solvent include nitriles (e.g., acetonitrile) , hydrocarbons (e.g., benzene, toluene, xylene), alcohol (e.g., methanol, ethanol) , halogenated hydrocarbons (e.g., dichloromethane, chloroform), ethers (e.g., diethyl ether, dioxane,
tetrahydrofuran) , amides (e.g., N, N-dimethylformamide ) , water and a mixture thereof.
The reaction temperature is generally about -50°C - 100°C, preferably about -5°C - 50°C, and the reaction time is
generally about 5 min - 72 hr, preferably about 0.5 hr - 40 hr.
[0404]
(Step 4)
In this step, compound (XCVIII) or a salt thereof is reacted with hydroxylamine or a salt thereof and the obtained oxime intermediate is subjected to a reduction reaction to produce compound (XCIX) or a salt thereof.
The amount of hydroxylamine to be used is generally about 1 - about 10 molar equivalents, per 1 mol of compound (XCVIII) .
This step can be performed by a method according to that of Method C, Step 1.
[0405]
(Step 5)
In this step, compound (XCIX) or a salt thereof and compound (LXX) or a salt thereof are subjected to a
condensation reaction to convert same to compound (C) or a salt thereof.
Compound (LXX) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
This step can be performed by a method according to that of Method A, Step 8.
[0406]
(Step 6)
In this step, compound (C) or a salt thereof is treated with a reducing agent to produce compound (CI) or a salt thereof .
This step can be performed by a method according to that of Method D, Step 1.
[0407]
(Step 7)
In this step, compound (CII) or a salt thereof and compound (LXX) or a salt thereof are subjected to a
condensation reaction to convert same to compound (CIII) or a salt thereof.
Compound (CII) and compound (LXX) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
This step can be performed by a method according to that of Method A, Step 8.
[0408]
(Step 8)
In this step, compound (CIII) or a salt thereof is reacted with sodium methanesulfinate to convert same to compound (CIV) or a salt thereof.
The amount of methanesulfonic acid to be used is
generally about 1 - about 10 molar equivalents, per 1 mol of compound (CIII).
This step can be performed by a method according to that of Method L, Step 1.
[0409]
Of compounds (XXVII) used in Method E and Method I, compound (CVIII) wherein any of Y1, Y2 and Y3 is a carbon atom, or a salt thereof can be produced by the following Method N. [Method N]
[0410]
[Chem. 110]
Figure imgf000161_0001
(CV) (CVI) (CVIII)
[0411]
wherein R5j is an optionally substituted hydrocarbon group, and other symbols are as defined above.
Examples of the optionally substituted hydrocarbon group for R5j include those similar to the above-mentioned R5.
[0412]
(Step 1)
In this step, compound (CV) or a salt thereof is reacted with B0C2O in the presence of a base to produce compound (CVI) or a salt thereof.
This step can be performed according to the method described in the method of protection with Boc group in Method F-l, Step 3.
[0413]
(Step 2) In this step, compound (CVI) or a salt thereof is treated with potassium carbonate and reacted with compound (CVII) or a salt thereof to produce compound (CVIII) or a salt thereof.
Compound (CVII) may be a commercially available product, or can also be produced according to a method known per se or a method analogous thereto.
The amount of potassium carbonate to be used is generally about 1 - about 10 molar equivalents, per 1 mol of compound (CVI).
This reaction can be generally performed in a solvent that does not adversely influence the reaction. Examples of the solvent include alcohols (methanol, ethanol and the like), nitriles (acetonitrile and the like) , hydrocarbons (benzene, toluene and the like) , ethers (diethyl ether, dioxane,
tetrahydrofuran and the like) , esters (ethyl acetate and the like) , halogenated hydrocarbons (chloroform, dichloromethane and the like), amides (N, N-dimethylformamide and the like), water and the like, and they may be mixed as appropriate. The reaction temperature is generally about -80 - 150°C, preferably about 0 - 10°C, and the reaction time is generally about 0.5 - 100 hr, preferably about 0.5 - 60 hr.
[0414]
Compound (Ij), which is the compound of the present invention (I' ) wherein the partial structure:
[0415]
[Chem. Ill]
Figure imgf000162_0001
[0416]
is
[0417]
[Chem. 112]
Figure imgf000163_0001
[0418]
ring A is
[0419]
[Chem. 113]
Figure imgf000163_0002
[0420]
L1 is a bond, R1 and R2 are each a hydrogen atom, ring
[0421]
[Chem. 114]
Figure imgf000163_0003
[0422]
(wherein W is as defined in the DESCRIPTION) , L2 is -S02-, and R3 is a methyl group or an ethyl group can be produced by the following Method 0.
[Method 0]
[0423]
[Chem. 115]
Figure imgf000164_0001
Figure imgf000164_0002
(CXV) (Ij)
[0424]
wherein R7 is an optionally substituted hydrocarbon group, and other symbols are as defined above.
[0425]
(Step 1)
In this step, compound (CXII) or a salt thereof is coupled with compound (CXIII) or a salt thereof in the presence of a Pd catalyst and a base to produce compound (CXIV) .
Compound (CXII) or a salt thereof can be produced
according to the below-mentioned Method Q or a method analogous thereto.
Examples of the Pd catalyst to be used for the reaction include palladium acetate, palladium chloride,
tetrakis (triphenylphosphine) palladium,
tris (dibenzylideneacetone) dipalladium (0) , XPHOS Pd G2 and the like and, where necessary, a ligand (XPHOS, triphenylphosphine, tri-t-butylphosphine, tricyclohexylphosphine , S-Phos, BINAP, 2' - (di-tert-butylphosphino) -N, N-dimethyl- [1, 1' -biphenyl] -2- amine, XANTPHOS and the like) is added. The amount of the catalyst to be used is about 0.0001 - 1 molar equivalents, preferably about 0.01 - 0.5 molar equivalents, per 1 mol of compound (CXII) , and the amount of the ligand to be used is about 0.0001 - 4 molar equivalents, preferably about 0.01 - 2 molar equivalents, per 1 mol of compound (CXII) .
As the base, an alkali metal salt (sodium hydrogen
carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium acetate and the like) , metal hydride (potassium hydride, sodium hydride and the like) , alkali metal alkoxide (lithium t- butoxide, sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide and the like) , alkali disilazide (lithium disilazide, sodium disilazide, potassium disilazide and the like) ) are added. The amount of the base to be used is about 1
- 10 molar equivalents, preferably about 1 - 2 molar
equivalents, per 1 mol of compound (CXII).
This step is performed in a solvent that does not
adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include hydrocarbons (benzene, toluene, xylene and the like) , halogenated
hydrocarbons (chloroform, 1 , 2-dichloroethane and the like), nitriles (acetonitrile and the like) , ethers (cyclopentyl methyl ether, dimethoxyethane, tetrahydrofuran) , alcohols
(methanol, ethanol and the like), aprotic polar solvents (N,N- dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide and the like), water and a mixture thereof.
Compound (CXIII) or a salt thereof can be produced
according to the below-mentioned Method R or a method analogous thereto. The amount of compound (CXIII) to be used is about 1
- 2 molar equivalents per 1 mol of compound (CXII) .
The reaction temperature is generally about 0 - 200°C, preferably about 60 - 150°C, and the reaction time is generally about 0.5 - 48 hr, preferably about 0.5 - 24 hr. The reaction may be performed under microwave irradiation as necessary. [0426]
(Step 2)
In this step, compound (CXIV) or a salt thereof is subjected to hydrolysis to convert same to compound (CXV) or a salt thereof. This reaction can be performed by a method known per se, generally in the presence of an acid or a base, and where necessary, in a solvent that does not adversely influence the reaction.
Examples of the acid to be used include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid and the like) , sulfonic acids
(methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acid (aluminum chloride, tin chloride, zinc bromide and the like) and the like. Where necessary, two or more kinds thereof may be used in a mixture. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction conditions, it is generally not less than about 0.1 molar equivalent, per 1 mol of compound (CXIV), and it can also be used as a solvent.
As the base, for example, inorganic bases (alkali metal hydroxides such as lithium hydroxide, sodium hydroxide,
potassium hydroxide and the like, alkali metal hydrogen
carbonates such as sodium hydrogen carbonate, potassium
hydrogen carbonate and the like, alkali metal carbonates such as sodium carbonate, potassium carbonate and the like,
alkoxides such as sodium methoxide, sodium ethoxide and the like, and the like) , organic bases (amines such as
trimethylamine, triethylamine , diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine and the like, and the like) and the like are used. Of these, sodium hydroxide is preferable. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 0.1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXIV) .
Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) ,
hydrocarbons (benzene, toluene, xylene, hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t^ butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , carboxylic acids (acetic acid and the like) , amides (dimethylformamide, dimethylacetamide and the like) , sulfoxides (dimethyl sulfoxide and the like), water and the like. Of these, ethanol,
tetrahydrofuran or water is preferable. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
The reaction temperature is, for example, about -50 -
200°C, preferably about 0 - 100°C. While the reaction time varies depending on the kind of compound (CXIV) or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 min - 100 hr, preferably about 0.5 - 24 hr.
[0427]
(Step 3)
In this step, compound (CXV) or a salt thereof and
compound (CXVI) or a salt thereof are subjected to a
condensation reaction to convert same to compound (Ij) or a salt thereof.
Compound (CXVI) or a salt thereof can be produced
according to the below-mentioned Method S or a method analogous thereto. The amount of compound (CXVI) to be used is about 1 - 2 molar equivalents, per 1 mol of compound (CXV) .
The condensation reaction can be performed by a method known per se, for example, the method described in The Chemical Society of Japan, 1991, "4th ed. Jikken Kagaku Kouza 22,
Organic Synthesis IV" and the like, or a method analogous thereto. Examples of the method include a method using a condensing agent, a method via a reactive derivative and the like.
Examples of the condensing agent to be used in "a method using a condensing agent" include (dimethylamino) -N, N- dimethyl ( 3H- [1,2,3] triazolo [ 4 , 5-b] pyridin-3-yloxy) methaniminium hexafluorophosphate (HATU) , 1- [ (1- (cyano-2-ethoxy-2- oxoethylideneaminooxy) -dimethylamino-morpholino) ] carbenium hexafluorophosphate (COMU) , 2,4, 6-tripropyl-l , 3,5,2,4,6- trioxatriphosphorinane-2 , 4 , 6-trioxide (T3P) ,
dicyclohexylcarbodiimide (DCC) , diisopropylcarbodiimide (DIC) , N-ethyl-N' -3-dimethylaminoprop.ylcarbodiimide and hydrochlorides thereof (WSC, WSC-HC1, EDCI) , benzotriazol-l-yl- tris (dimethylamino) phosphonium hexafluorophosphate (BOP), diphenylphosphoryl azide (DPPA) , (4-oxobenzo [d] [1, 2, 3] triazin- 3 (4H) -yl) diethyl phosphate (DETBT) , ( 3-hydroxy-3H-l , 2 , 3- triazolo [4 , 5-b] pyridinato-O) tri-l-pyrrolidinyl-phosphorus hexafluorophosphate (PyAOP) , N, N, N' , N' -tetramethyl-O- ( 3 , 4- dihydro-4-oxo-l, 2, 3-benzotriazin-3-yl ) uronium tetrafluoroborate (TDBTU) , 4- (4, 6-dimethoxy-l, 3, 5-triazin-2-yl) - 4 - methylmorpholinium chloride (DMT-MM) and hydrate thereof and the like. These may be used singly, or can also be used in combination with additive (e.g., N-hydroxysuccinimide, 1- hydroxybenzotriazole, 3-hydroxy-4-oxo-3, 4-dihydro-l, 2, 3- benzotriazine and the like) . The amount of the condensing agent to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (CXV) . The amount of the additive to be used is generally about 1 - 10 molar equivalents, preferably about 1 - 2 molar equivalents, per 1 mol of compound (CXV) .
The above reaction is generally performed in a solvent that does not adversely influence the reaction, and a
convenient base may be added to promote the reaction. Examples of the solvent include hydrocarbons (benzene, toluene and the like) , ethers (diethyl ether, dioxane, tetrahydrofuran and the like) , esters (ethyl acetate and the like) , halogenated
hydrocarbons (chloroform, dichloromethane and the like) , amides (N, N-dimethylformamide and the like), aromatic amines (pyridine and the like) , alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) , water and the like, which may be mixed as appropriate. Examples of the base include alkali metal hydroxides (sodium hydroxide, potassium hydroxide and the like) , hydrogen carbonates (sodium hydrogen carbonate, potassium hydrogen carbonate and the like) , carbonates (sodium carbonate, potassium carbonate and the like) , acetates (sodium acetate and the like), tertiary amines
(trimethylamine, triethylamine, N-methylmorpholine,
diisopropylethylamine and the like) , aromatic amines (pyridine, picoline, N, N-dimethylaniline , 4-dimethylaminopyridine and the like) and the like. The amount of the base to be used is generally about 1 - 100 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXV) .
The reaction temperature is generally about -80 - 150°C, preferably about 0 - 50°C. The reaction time is generally about 0.5 - 48 hr, preferably 0.5 - 16 hr.
As the reactive derivative in "the method via a reactive derivative", a compound represented by the formula:
[0428]
Chem. 116]
Figure imgf000169_0001
(CXVa)
[0429]
wherein LG7 is a leaving group,
(hereinafter to be referred to as compound (CXVa) ) or a salt thereof (e.g., acid halide, acid anhydride, mixed acid
anhydride, active ester and the like) and the like can be mentioned . As the leaving group for LG7, for example, halogen atom (chlorine atom, bromine atom, iodine atom and the like) , substituted sulfonyloxy group (C1_5 alkylsulfonyloxy group such as methanesulfonyloxy, trifluoromethylsulfonyloxy,
ethanesulfonyloxy and the like; C6-14 arylsulfonyloxy group such as benzenesulfonyloxy, p-toluenesulfonyloxy and the like; C7-16 aralkylsulfonyloxy group such as "benzylsulfonyloxy group and the like, and the like) , acyloxy group (acetoxy, benzoyloxy and the like) , oxy group substituted by heterocyclic group or aryl group (2 , 5-dioxo-l-pyrrolidinyl, benzotriazolyl, quinolyl, 4- nitrophenyl and the like) , heterocyclic group (imidazolyl and the like) and the like are used.
Compound (CXV) can be converted to a reactive derivative (compound (CXVa) ) according to a method known per se. For example, for conversion to acid halide, a method using acid halide (e.g., thionyl chloride, oxalyl chloride and the like), a method using halide of phosphorus and phosphoric acid (e.g., phosphorus trichloride, phosphorus pentachloride and the like) and the like can be mentioned. The above-mentioned reaction via a reactive derivative is generally performed in a solvent that does not adversely influence the reaction, though subject to change depending on the kind of compound (CXV) , and a convenient base may be added to promote the reaction. The kind and amount of solvent and base to be used in the reaction, reaction temperature and reaction time are similar to those described in the above-mentioned "method using a condensing agent".
[0430]
Compound (Ik), which is the compound of the present invention (Ι') wherein the partial structure:
[0431]
[Chem. 117]
Figure imgf000171_0001
[0432]
is
[0433]
[Chem. 118]
Figure imgf000171_0002
[0434]
ring A is
[0435]
[Chem. 119]
Figure imgf000171_0003
[0436]
L1 is a bond, ring D is [0437]
[Chem. 120]
Figure imgf000171_0004
[0438] (wherein W is as defined in the DESCRIPTION) , L2 is -S02-, R3 is a methyl group or an ethyl group, R1 is a -CH2OH group, R2 is a hydrogen atom can be produced by the following Method P.
[Method P]
[0439]
[Chem. 121]
Figure imgf000172_0001
[0440]
wherein each symbol is as defined above.
[0441]
(Step 1)
In this step, compound (CXV) or a salt thereof and compound (CXVII) or a salt thereof are subjected to a
condensation reaction to convert same to compound (Ik) or a salt thereof.
Compound (CXV) or a salt thereof can be produced
according to Method 0.
Compound (CXVII) or a salt thereof can be produced according to the below-mentioned Method T or a method analogous thereto. The amount of compound (CXVII) to be used is about 1 - 2 molar equivalents per 1 mol of compound (CXV) .
This step can be performed by a method according to that of Method 0, Step 3.
[Method Q]
[0442]
[Chem. 122]
Figure imgf000173_0001
de
Figure imgf000173_0002
(CXI I)
[0443]
wherein Hal1 is a halogen atom (chlorine atom, bromine atom, iodine atom), and other symbol is as defined above.
[0444]
(Step 1)
In this step, compound (CXVIII) or a salt thereof is reacted with di-t-butyl dicarbonate (Boc20) in the presence of a base to convert same to compound (CXIX) or a salt thereof.
Compound (CXVIII) or a salt thereof may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.
As the base to be used in this step, for example, inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, etc. and the like) , organic base (alkali disilazides such as lithium hexamethyldisilazide , sodium
hexamethyldisilazide and the like, amines such as
trimethylamine, triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine , etc. and the like) and the like are used. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXVIII) .
The amount of Boc20 to be used in this step is about 1 - 10 molar equivalents, preferably, about 1 - 5 molar equivalents, per 1 mol of compound (CXVIII) .
The solvent to be used in this step includes aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether/ t-butyl methyl ether, tetrahydrofuran, dioxane, dimethoxyethane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , amides (dimethylformamide and the like) , sulfoxides (dimethyl sulfoxide and the like), and the like. Two or more kinds of these solvents may be used in a mixture in an
appropriate ratio.
The reaction temperature is, for example, about -80 -
100°C. While the reaction time varies depending on the kind of compound (CXVIII) or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[0445]
(Step 2)
In this step, compound (CXIX) or a salt thereof is subjected to carbonylation under carbon monoxide atmosphere by using a transition metal catalyst and alcohol represented by the following formula (CXX) :
R7OH (CXX)
wherein R7 is as defined above
to produce compound (CXXI) or a salt thereof.
Examples of the transition metal catalyst include
palladium catalyst (palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium and the like), nickel catalyst (nickel chloride and the like) and the like and, where necessary, an organophosphorus reagent such as
triphenylphosphine, 1, 1' -bis (diphenylphosphino) ferrocene (dppf) and the like can be used. The amount of the catalyst to be used varies depending on the kind of the catalyst, and is generally about 0.0001 ^ 1 mol, preferably about 0.01 - 0.5 mol, per 1 mol of compound (CXIX) , and the amount of the
organophosphorus reagent to be used is preferably about 0.01 - 2 mol.
The alcohol represented by the formula (CXX) is generally used in excess, and particularly, methanol or ethanol is used.
This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and the like) ,
nitriles (acetonitrile and the like) , esters (ethyl acetate and the like) , aprotic polar solvent (dimethylformamide, dimethyl sulfoxide and the like) and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio.
In addition, the reaction can be advantageously performed by adding a base or a salt. Examples of such base or salt include inorganic bases (alkali metal hydroxides such as sodium hydroxide, potassium , hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate,
potassium hydrogen carbonate and the like, alkali metal
carbonates such as lithium carbonate, sodium carbonate,
potassium carbonate, cesium carbonate and the like, and the like) or organic bases (amines such as trimethylamine,
triethylamine, diisopropylethylamine and the like, cyclic amines such as pyridine and the like and the like) and the like. The amount of the base or salt to be used is about 1 - 100 molar equivalents, preferably about 1 - 10 molar equivalents, per 1 mol of compound (CXIX) .
While the reaction is generally performed under a carbon monoxide atmosphere at normal pressure, where necessary, it can be performed under pressurization (e.g., about 3 - 10 atm) .
The reaction temperature varies depending on the kind of the solvent and it is, for example, about -50 - 200°C,
preferably about 20 - 150°C. The reaction time varies
depending on the kind of compound (CXIX) or a salt thereof, the reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[0446]
(Step 3)
In this step, compound (CXXI) or a salt thereof is subjected to deprotection reaction to produce compound (CXII) or a salt thereof.
Such deprotection reaction can be performed according to a known method (e.g., "Protective Groups in Organic Synthesis, 3rd Ed." (Theodora W. Greene, Peter G. M. Wuts) , Wiley- Interscience, 1999)). For example, while subject to variation depending on the kind of compound (CXXI), it is generally performed in the presence of an acid and in a solvent as necessary that does not adversely influence the reaction.
Examples of the acid include mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride and the like) , carboxylic acids (acetic acid, trifluoroacetic acid, trichloroacetic acid and the like) , sulfonic acids
(methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, tin chloride, zinc bromide and the like) and the like, and two or more kinds thereof may be used in a mixture as necessary. While the amount of the acid to be used varies depending on the kind of the solvent and other reaction conditions, it is generally not less than about 0.1 mol equivalent per 1 mol of compound (CXXI), and it can also be used as a solvent.
Examples of the solvent that does not adversely influence the reaction include alcohols (methanol, ethanol, propanol, 2- propanol, butanol, isobutanol, t-butanol and the like) , aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) ,
halogenated hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, t-butyl methyl .ether.,, t.etrahydrofuran, dioxane, dimethox.y.e_thane and the like) , nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), carboxylic acids (acetic acid and the like), amides (N, N-dimethylformamide and the like), sulfoxides (dimethyl sulfoxide and the like) , water and the like, and a mixed solvent thereof can be mentioned.
The reaction temperature varies depending on the kind of the solvent, and it is, for example, about -50 - 200°C,
preferably about 0 - 100°C. While the reaction time varies depending on the kind of compound (CXXI), reaction temperature and the like, it is, for example, about 0.5 - 100 hr,
preferably about 0.5 - 24 hr.
[Method R]
[0447]
[Chem. 123]
Figure imgf000177_0001
(CXXI I) (CXXI 11) (CXI11)
[0448]
wherein the symbol is as defined above.
[0449]
(Step 1)
In this step, compound (CXXII) or a salt thereof is coupled with cyclopropylboronic acid in the presence of a Pd catalyst and a base to produce compound (CXXIII) .
Compound (CXXII) or a salt thereof may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.
The amount of cyclopropylboronic acid to be used is about 1 - 10 molar equivalents, preferably about 1 - 5 molar
equivalents, per 1 mol of compound (CXXII) .
This step can be performed by a method according to that of Method 0, Step 1.
[0450]
(Step 2)
In this step, compound (CXXIII) or a salt thereof is subjected to a triflating reaction to produce compound (CXIII) or a salt thereof.
This reaction can be performed in the presence of a base and a triflating agent.
Examples of the base to be used in this reaction include inorganic base (alkali metal hydride such as sodium hydride, lithium hydride and the like, alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, and the like) or organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, 1,8- diazabicyclo [ 5 , 4 , 0 ] undec-7-ene and the like, cyclic amines such as pyridine, 4-dimethylaminopyridine and the like, and the like) and the like. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXIII). Pyridine is sometimes used as a solvent.
As the triflating agent to be used in this reaction, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) , N-(5- chloro-2-pyridyl ) triflimide and the like can be mentioned.
While the amount of the triflating agent to be used varies depending on the kind of the solvent and other reaction
conditions, it is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXIII) .
This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated
hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1 , 2-dimethoxyethane and the like), nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like),
sulfoxides (dimethyl sulfoxide and the like) and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio, or the base to be used in this reaction may be used as a solvent.
The reaction temperature is, for example, about -10 - 100°C. While the reaction time varies depending on the kind of compound (CXXIII) or a salt thereof, reaction temperature and the like, it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[Method S]
[0451]
Chem. 124]
Figure imgf000179_0001
(CXXIV) (CXXV) (CXVI)
[0452]
wherein Hal8 is a halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom) , and other symbols are as defined above .
[0453] (Step 1)
In this step, compound (CXXIV) or a salt thereof is treated with sodium sulfinate represented by the following formula (LXXVIII) :
R3S02Na (LXXVIII)
wherein the symbol is as defined above,
to produce compound (CXXV) or a salt, thereof.
Compound (CXXIV) or a salt thereof may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.
Sodium sulfinate (LXXVIII) may be a commercially
available product, or can also be produced according to a method known per se or a method analogous thereto. The amount of use thereof is about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXIV) .
This step is performed in a solvent that does not
adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated
hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1 , 2-dimethoxyethane and the like), nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like),
sulfoxides (dimethyl sulfoxide and the like) , and water and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio or a base to be used in this reaction may be used as a solvent.
The reaction temperature is, for example, about -10 -
200°C. The reaction time varies depending on the kind of compound (CXXIV) or a salt thereof, reaction temperature and the like and is, for example, about 0.5 - 100 hr, preferably about 0.5 - about 24 hr .
[0454] (Step 2)
In this step, compound (CXXV) is subjected to reduction reaction by using a transition metal catalyst to produce compound (CXVI) .
Examples of the transition metal catalyst to be used in this reaction include palladiums (palladium carbon, palladium hydroxide, palladium oxide and the like), nickels. (Raney-nickel and the like) , platinums (platinum oxide, platinum carbon and the like) , rhodiums (rhodium acetate, rhodium carbon and the like) and the like. The amount thereof to be used is, for example, about 0.001 - 1 molar equivalent, preferably about 0.01 - 0.5 molar equivalent, per 1 mol of compound (CXXV) . The catalytic hydrogenation reaction is generally performed in a solvent inert to the reaction. Examples of the solvent include alcohols (methanol, ethanol, propanol, butanol and the like) , hydrocarbons (benzene, toluene, xylene and the like) ,
halogenated hydrocarbons (dichloromethane, chloroform and the like), ethers (diethyl ether, 1,4-dioxane, tetrahydrofuran and the like), esters (ethyl acetate and the like), amides (N,N- dimethylformamide and the like) , carboxylic acids (acetic acid and the like), water and a mixture thereof. The reaction is performed at a hydrogen pressure of generally about 1 - 50 atm, preferably about 1 - 10 atm. The reaction temperature is generally about 0 - 150°C, preferably about 20 - 100°C, and the reaction time is generally about 5 min - 72 hr, preferably about 0.5 - 40 hr.
To accelerate the reaction, an acid (hydrochloric acid and the like) may also be added. The amount thereof to be used is about 0.01 - 10 molar equivalents per 1 mol of compound (CXXV) .
[Method T]
[0455]
[Chem. 125]
Figure imgf000182_0001
Figure imgf000182_0002
[0456]
wherein each symbol is as defined above.
[0457]
(Step 1)
In this step, compound (CXXVI) or a salt thereof is reacted with acetic acid in the presence of a base to produce compound (CXXVII) or a salt thereof.
Compound (CXXVI) or a salt thereof may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto.
As the base to be used in this reaction, for example, inorganic bases (alkali metal hydrides such as sodium hydride, lithium hydride and the like, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, alkali metal hydrogen carbonates such as sodiumhydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, and the like) , organic base (amines such as trimethylamine, triethylamine, diisopropylethylamine, 1,8- diazabicyclo [5, 4, 0 ] undec-7-ene and the like, and the like) and the like are used. The amount of the base to be used varies depending on the kind of the solvent, and other reaction conditions, and is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXVI) .
The amount of acetic acid to be used in this reaction is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXVI) .
This step is performed in a solvent that does not
adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include aromatic hydrocarbons (benzene, toluene, xylene and the like) , aliphatic hydrocarbons (hexane, heptane and the like) , halogenated
hydrocarbons (dichloromethane, chloroform and the like) , ethers (diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, l,4^dioxane, 1 , 2-dimethoxyethane and the like), nitriles (acetonitrile and the like) , esters (ethyl acetate and the like), amides (N, N-dimethylformamide and the like),
sulfoxides (dimethyl sulfoxide . and the like), and water and the like. Two or more kinds of these solvents may be used in a mixture in an appropriate ratio or a base to be used in this reaction may be used as a solvent.
The reaction temperature is, for example, about -10 - 100°C. The reaction time varies depending on the kind of compound (CXXVI) or a salt thereof, the reaction temperature and the like, and it is, for example, about 0.5 - 100 hr, preferably about 0.5 - 24 hr.
[0458]
(Step 2)
In this step, compound (CXXVII) or a salt thereof is reacted with hydroxylamine or a salt thereof to produce
compound (CXXVIII) or a salt thereof.
The amount of hydroxylamine or a salt thereof to be used in this reaction is generally about 1 - 10 molar equivalents, preferably about 1 - 5 molar equivalents, per 1 mol of compound (CXXVII) .
In this step, the reaction can be advantageously carried out by adding a catalyst as necessary. As such catalyst, mineral acids (hydrochloric acid, hydrobromic acid, sulfuric acid and the like) , carboxylic acids (formic acid, acetic acid, propionic acid, trifluoroacetic acid and the like) , sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid and the like) , Lewis acids (aluminum chloride, zinc chloride, zinc bromide, boron trifluoride, titanium chloride and the like) , acetate (sodium acetate, potassium acetate and the like) , molecular sieves (molecular sieves 3A, 4A, 5A and the like) , dehydrating agents (magnesium sulfate and the like) and the like can be mentioned, and these may be combined. The amount of the catalyst to be used is generally 0.01 - 50 molar
equivalents, preferably about 0.1 - about 10 mol, per 1 mol of compound (CXXVII) .
This step is performed in a solvent that does not
adversely influence the reaction. Examples of the solvent that does not adversely influence the reaction include hydrocarbons (heptane, hexane, toluene, xylene and the like) , halogenated hydrocarbons (chloroform, dichloromethane, 1 , 2-dichloroethane and the like), ethers (diethyl ether, tetrahydrofuran, 1,4- dioxane and the like) , esters (ethyl acetate, tert-butyl acetate and the like) , alcohols (methanol, ethanol, 2-propanol and the like) , nitriles (acetonitrile, butyronitrile and the like), amides (N, N-dimethylformamide, N, N-dimethylacetamide and the like) , sulfoxides (dimethyl sulfoxide and the like) and the like, and a mixed solvent thereof.
The reaction temperature is generally about 0°C - about 200°C, preferably about 20°C - about 150°C, and the reaction time is generally about 0.5 hr - about 48 hr, preferably about 0.5 hr - about 24 hr.
[0459]
(Step 3)
In this step, compound (CXXVIII) or a salt thereof is subjected to a reduction reaction and deprotection reaction to produce compound (CXVII) or a salt thereof. The reduction reaction can be performed by various
reduction reactions in a solvent inert to the reaction. Such reduction reaction can be performed by a method known per se, which includes, for example, a method using metal hydride, and a method by a catalytic hydrogenation reaction.
Examples of the metal hydride include sodium borohydride, lithium borohydride, zinc borohydride, sodium cyan.oboro.hydri.de, sodium triacetoxyborohydride, lithium cyanoborohydride,
dibutylaluminum hydride, aluminum hydride, lithium aluminum hydride, borane complex (borane-THF complex, catecholborane etc.) and the like, and sodium borohydride, sodium,
cyanoborohydride, sodium triacetoxyborohydride and the like are preferable. The amount of metal hydride to be used is, for example, about 1 - about 50 molar equivalents, preferably about 1 - about 10 molar equivalents, per 1 mol of compound (CXXVIII) .
The reduction reaction with metal hydride is generally performed in a solvent inert to the reaction. Examples of such solvent include aromatic hydrocarbons (toluene, xylene etc. ) , aliphatic hydrocarbons (heptane, hexane etc. ) , halogenated hydrocarbons (chloroform, dichloromethane etc. ) , ethers
(diethyl ether, tetrahydrofuran, 1,4-dioxane etc.), alcohols (methanol, ethanol, 2-propanol, butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), N, N-dimethylformamide, dimethyl sulfoxide and the like. These solvents may be used in a
mixture in an appropriate ratio.
The reaction temperature is generally about -80°C - about 80°C, preferably about -40°C - about 40°C. The reaction time is generally about 5 min - about 48 hr, preferably about 1 - about 24 hr.
The catalytic hydrogenation reaction can be performed in hydrogen atmosphere in the presence of a catalyst. Examples of the catalyst include palladiums such as palladium carbon, palladium hydroxide carbon, palladium oxide and the like; .
nickels such. as sponge nickel catalyst and the like; platinums such as platinum oxide, platinum carbon and the like; rhodiums such as rhodium carbon and the like, and the like. The amount thereof to be used is generally about 0.001 - about 1 molar equivalent, preferably about 0.01 - about 0.5 molar equivalent, per 1 mol of (CXXVIII) .
The catalytic hydrogenation reaction is generally performed in a solvent inert to the reaction. Examples of such so.lvent include alcohols (methanol, ethano.1., propanol, butanol etc.), hydrocarbons (benzene, toluene, xylene etc.),
halogenated hydrocarbons (dichloromethane, chloroform etc.), ethers (diethyl ether, 1,4-dioxane, tetrahydrofuran etc.), esters (ethyl acetate etc.), amides (N, N-dimethylformamide etc.), carboxylic acids (acetic acid etc.), water and a mixture thereof .
The reaction is performed at a hydrogen pressure of generally about 1 - about 50 atm, preferably about 1 - about 10 atm. The reaction temperature is generally about 0°C - about 150°C, preferably about 20°C - about 100°C, and the reaction time is generally about 5 min - about 72 hr, preferably about 0.5 hr - about 40 hr.
The deprotection reaction can be performed by the method described in Method Q, Step 3, or a method analogous thereto.
[0460]
Compound (II), (Im), (In), (Io) or (Ip), which is the compound of the present invention (Ι') wherein the partial structure:
[0461]
[Chem. 126]
Figure imgf000186_0001
[0463] [Chem. 127]
Figure imgf000187_0001
[0464]
ring A is
[0465]
[Chem. 128]
Figure imgf000187_0002
[0466]
L1 is a bond, R1 and R2 are each a hydrogen atom, ring
[0467]
[Chem. 129]
Figure imgf000187_0003
[0468]
wherein W is =CR6- (R6 is -COOC2H5, -COOH, -CONH2, -CN or - CH2OH) ) and L2 is -S02- can be produced by the following Method U.
[Method U]
[0469]
[Chem. 130]
Figure imgf000188_0001
Figure imgf000188_0002
Figure imgf000188_0003
Figure imgf000188_0004
(II) CP)
[0470]
wherein the symbol is as defined above.
[0471]
(Step 1) In this step, compound (CXV) or a salt thereof and compound (CXXIX) or a salt thereof are subjected to a
condensation reaction to convert same to compound (II) or a salt thereof.
Compound (CXV) or a salt thereof can be produced
according to Method A.
Compound (CXXIX) or a salt, thereof may be commercially available products, or can also be produced according to a method known per se or a method analogous thereto. The amount of compound (CXXIX) to be used is. about..1 - 2 molar equivalents per 1 mol of compound (CXV) .
This step can be performed by a method according to that of Method A, Step 3.
[0472]
(Step 2)
In this step, compound (II) or a salt thereof is
subjected to hydrolysis to convert- - same to compound (Im) or a salt thereof.
This step can be performed by a method according to that of Method A, Step 2.
[0473]
(Step 3)
In this step, compound (Im) or a salt thereof and
compound (CXXX) are subjected to a condensation reaction to convert same to compound (In) or a salt thereof.
Compound (CXXX) may be a commercially available product and the amount of compound (CXXX) to be used is about 1 - 2 molar equivalents, per 1 mol of compound (Im) .
This step can be performed by a method according to that of Method 0, Step 3.
[0474]
(Step 4)
In this step, compound (In) or a salt thereof is treated with trifluoroacetic anhydride and pyridine to convert same to compound (Io) or a salt thereof. The amount of trifluoroacetic anhydride to be used is about 1 - 20 molar equivalents per 1 mol of compound (In) .
Pyridine is used as a solvent.
The reaction temperature is generally about -20°C - about 100°C, preferably about 20°C - about 50°C, and the reaction time is generally about 0.5 hr - about 48 hr, preferably about 0.5 hr - about .24 hr.
[0475]
(Step 5)
In this step, compound (II) or a salt thereof is
subjected to a reduction reaction to produce compound (Ip) or a salt thereof.
This step can be performed by a method according to that of Method T, Step 3, "reduction reaction with metal hydride".
[0476]
[Method V]
Compound (Iq) :
[0477]
[Chem. 131]
Figure imgf000190_0001
[0478]
wherein each symbol is as defined above, which is the compound of the present invention (I' ) wherein the partial structure:
[0479]
[Chem. 132]
Figure imgf000190_0002
[0480] is
[0481]
[Chem. 133]
Figure imgf000191_0001
, and
[0482]
L1 is a bond, can be produced in the same manner as in Method and using a compound of the following formula (CXXXI) :
[0483]
[Chem. 134]
Figure imgf000191_0002
(CXXXI)
[0484]
wherein each symbol is as defined above.
[0485]
[Method W]
Compound (Ir) :
[0486]
Chem. 135]
Figure imgf000191_0003
[0487] wherein each symbol is as defined above, which is the compound of the present invention (I' ) wherein the partial structure:
[0488]
[Chem. 136]
Figure imgf000192_0001
and
■0491'
L is optionally halogenated C1 alkylene, can be produced in the same manner as in Method F-l and using a compound of the following formula (CXXXII) :
[0492]
[Chem. 138]
Figure imgf000192_0002
(CXXXII)
[0493]
wherein each symbol is as defined above.
[0494]
[Method X]
Compound ( Is ) : [0495]
[Chem. 139]
Figure imgf000193_0001
[0496]
wherein each symbol, is as defined above, which is the compound of the present invention (I' ) wherein the partial structure:
[0497]
[Chem. 140]
Figure imgf000193_0002
[0498]
is
[0499]
[Chem. 141]
Figure imgf000193_0003
r and [0500]
L1 is optionally halogenated C2 alkylene, can be produced in the same manner as in Method F-2 and using a compound of the following formula (CXXXII) :
[0501]
[Chem. 142]
Figure imgf000194_0001
(CXXXII)
[0502]
wherein each symbol is as defined above.
[0503]
[Method Y] . .
Compound ( It ) :
[0504]
[Chem. 143]
Figure imgf000194_0002
[0505]
wherein each symbol is as defined above, which is the compound of the present invention (Ι') wherein the partial structure:
[0506]
[Chem. 144]
Figure imgf000194_0003
[0507]
is
[0508]
[Chem. 145]
Figure imgf000195_0001
[0509]
L1 is -0-, can be produced in the same manner as in Method and using a compound of the following formula (CXXXIII) :
[0510]
[Chem. 146]
Figure imgf000195_0002
(CXXXIII)
[0511]
wherein each symbol is as defined above.
[0512]
When compound (I' ) has an optical isomer, a stereoisomer, a regioisomer or a rotamer, these are also encompassed in compound (I' ) , and can be obtained as a single product
according to a synthesis method and separation method known per se. For example, when compound (Ι') has an optical isomer, the optical isomer resolved from the compound is also encompassed in compound (I' ) ·
[0513]
The optical isomer can be produced according to a method known per se. Specifically, the optical isomer is obtained using an optically active synthetic intermediate or by
subjecting the racemic final product to an optical resolution according to a known method.
[0514] The method of optical resolution may be a method known per se, such as a fractional recrystallization method, a chiral column method, a diastereomer method etc.
1) Fractional recrystallization method
A method wherein a salt of a racemate with an optically active compound (e.g., (t)-mandelic acid, (-)-mandelic acid,
(+) -tartaric acid, (-) -tartaric acid, (+) -1-phenethylamine,
(-) -1-phenethylamine, cinchonine, (-) -cinchonidine, brucine etc.) is formed, which is separated by a fractional
recrystallization method, and if desired, a neutralization step to give a free optical isomer.
[0515]
2) Chiral column method
A method wherein a racemate or a salt thereof is applied to a column (a chiral column) for separation of an optical isomer to allow separation. In the case of a liquid
chromatography, for example, a mixture of the optical isomers is applied to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) , CHIRAL series (manufactured by Daicel Corporation) and the like, and developed with water, various buffers (e.g., phosphate buffer, etc.) and organic solvents (e.g., ethanol, methanol, isopropanol, acetonitrile,
trifluoroacetic acid, diethylamine, etc.) as an eluent, solely or in admixture to separate the optical isomer.
[0516]
3) Diastereomer method
A method wherein a racemic mixture is converted to a diastereomeric mixture by chemical reaction with an optically active reagent, which is made into a single substance by a typical separation means (e.g., a fractional recrystallization method, a chromatography method etc.) and the like, and is subjected to a chemical treatment such as hydrolysis reaction and the like to separate an optically active reagent moiety, whereby an optical isomer is obtained. For example, when compound (Ι') contains hydroxy group or primary or secondary amino group in a molecule, the compound and an optically active organic acid (e.g., MTPA [oc-methoxy-a-
(trifluoromethyl ) phenylacetic acid], (-) -menthoxyacetic acid etc.) and the like are subjected to condensation reaction to give diastereomers of the ester compound or the amide compound, respectively. When compound (I' ) has a carboxylic acid group, the compound and an optically active amine or an optically active alcohol reagent are subjected to condensation reaction to give diastereomers of the amide compound or the ester
compound, respectively. The separated diastereomer is
converted to an optical isomer of the original compound by acid hydrolysis or base hydrolysis reaction.
[0517]
When the compound (Ι') is obtained as a free compound, it can be converted into a desired salt by a method known per se or a modification thereof; conversely, when it is obtained as a salt, it can be converted into a free form or another desired salt by a method known per se or a modification thereof.
[0518]
Compound (Ι') may be used as a prodrug. The prodrug of compound (I/) means a compound which can be converted into compound (Ι') by reaction with an enzyme, gastric acid, or the like under physiological conditions in the living body. In other words, it means a compound which can be converted into compound (Ι') by enzymatic oxidation, reduction, hydrolysis or the like, or a compound which can be converted into compound (Ι') by hydrolysis with gastric acid or the like.
[0519]
Examples of the prodrug of compound (I' ) include a
compound in which amino of compound (Ι') is acylated, alkylated, or phosphorylated (e.g., the amino group of compound (Ι') is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-
2-oxo-l, 3-dioxolen-4-yl ) methoxycarbonylated,
tetrahydrofuranylated, pyrrolidylmethylated,
pivaloyloxymethylated, or tert-butylated) ; a compound in which hydroxyl group of compound (Ι') is acylated, alkylated, phosphorylated, or borated (e.g., a hydroxy group of compound (Ι') is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or
dimethylaminomethylcarbonylated) ; a compound in which carboxy group of compound (I' ) is esterified or amidated (e.g., a compound in which carboxy group of compound (Ι') is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5- methyl-2-oxo-l , 3-dioxolen-4-yl) methyl esterified,
cyclohexyloxycarbonylethyl esterified, or methylamidated) .
These compounds can be produced from compound (Ι') by a method known per se.
The prodrug of compound (Ι') may also be one which is converted to compound (Ι') under physiological conditions as described in "IYAKUHIN no KAIHATSU (Development of
Pharmaceuticals)", Vol. 7 (Design of Molecules), p. 163-198 (HIROKAWA SHOTEN) .
[0520]
Compound (I/) may be a crystal, and both single crystal form and a crystalline mixture are encompassed in the compound (Ι') of the present invention. The crystal can be produced by crystallization by a crystallization method known per se.
[0521]
Compound (Ι') and a prodrug thereof [hereinafter
sometimes to be abbreviated as the compound of the present invention] may be useful as a safe medicament based on an RORyt modulating action. In another embodiment, since the compound of the present invention may be superior in RORyt binding capability, it may be superior in RORyt modulating activity, and may also be useful as a safe medicament based on RORyt activation action.
For example, the medicament of the present invention containing the compound of the present invention may be useful for a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as a prophylactic or
therapeutic agent for RORyt related diseases, Thl7 cell related diseases and IL-17A or IL-17F related diseases, more
specifically, the diseases described in (1) - (4) below.
(1) inflammatory diseases (e.g., rheumatoid arthritis, acute pancreatitis, chronic pancreatitis, asthma_, .bronchial asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD) , inflammatory bone disease, pulmonary sarcoidosis, inflammatory bowel disease, celiac disease,
Behcet's syndrome, hepatitis, alcoholic hepatic fibrosis, alcoholic hepatitis, alcoholic cirrhosis, hepatitis B viral hepatopathy, primary biliary cirrhosis (PBG), primary
sclerosing cholangitis (PSC) , transient cerebral ischemic attack (TIA) , systemic inflammatory response syndrome (SIRS) , dry eye, glaucoma, uveitis, orbital cellulitis, idiopathic orbital inflammation, age-related macular degeneration,
postoperative or posttraumatic inflammation, hepatopathy, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicosis, pulmonary sarcoidosis, autoimmune anemia, Good Basucha syndrome, Graves' disease, hashimoto' s thyroiditis, vasculitis, Basedow's disease, sinusitis, allergic rhinitis, chronic hypertrophic rhinitis etc.),
(2) autoimmune diseases (e.g., rheumatoid arthritis,
ankylopoietic spondylarthritis, psoriasis, multiple sclerosis (MS) , polymyositis, optic nervemyelitis (NMO) , chronic
inflammatory demyelinating polyneuropathy (CIDP) ,
dermatomyositis (DM), polyarteritis nodosa (PN), mixed
connective tissue disease (MCTD) , amyotrophic lateral sclerosis (ALS) , Guillain-Barre syndrome, myasthenia gravis, Parkinson's disease, spinal muscular atrophy, spinocerebellar atrophy, progressive supranuclear palsy, Fisher syndrome, central
nervous system lupus, acute disseminated encephalomyelitis, multiple system atrophy, Huntington's disease, Alzheimer's disease, cerebrovascular dementia, diffuse Lewy body disease, cerebrovascular diseases, cerebral infarction, transient
cerebral ischemic attack, cerebral hemorrhage, spinal cord vascular disorder, spinal cord infarction, polyneuritis,
Lambert-Eaton syndrome, muscular dystrophy, metabolic myopathy, inflammatory myopathy, inclusion body myositis, encephalitis, meningitis, Sjogren's syndrome, systemic lupus erythematosus, scleroderma, pemphigus, profundus lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, inflammatory bowel disease (IBD), ulcerative colitis (UC) , Crohn's disease, graft versus host disease, Addison's disease, abnormal immunoresponse, arthritis, dermatitis, radiodermatitis , sarcoidosis, type 1 diabetes etc . ) ,
(3) bone or joint degenerative diseases (e.g., rheumatoid arthritis, osteoporosis, osteoarthritis etc.),
(4) neoplastic diseases [e.g., malignant tumor, angiogenesis glaucoma, infantile Hemangioma, multiple myeloma, acute
myeloblastic leukemia, chronic sarcoma, multiple myeloma, chronic myeloid leukemia, metastasis melanoma, Kaposi's sarcoma, vascular proliferation, cachexia, metastasis of the breast cancer, cancer (e.g., colorectal cancer (e.g., familial
colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor and the like), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma and the like) , mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer and the like), gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma and the like), breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ,
inflammatory breast cancer and the like), ovarian cancer (e.g., ovarian epithelial carcinoma, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor and the like), prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone dependent prostate cancer and the like), liver cancer (e.g., primary liver cancer, extrahepatic bile duct cancer and the like), thyroid cancer (e.g., medullary thyroid carcinoma and the like), renal cancer (e.g., renal cell carcinoma, transitional cell carcinoma in kidney and ureter and the like) , uterine cancer, uterine body cancer, brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma and the like) , melanoma
(melanoma) , sarcoma, urinary bladder cancer, hematologic cancer and the like including multiple myeloma, hypophyseal adenoma, glioma, acoustic schwannoma, retinoblastoma, head and neck carcinoma, pharyngeal cancer, laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gall urinary bladder cancer, penile cancer, ureter cancer, testis tumor, vulvar cancer, cervical cancer, uterine body cancer, uterus sarcoma, cholionic disease, vaginal cancer, skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin' s disease,
myelodysplastic syndrome, acute lymphocytic leukemia, chronic lymphocytic leukemia, adult T cell leukemia, chronic bone marrow proliferative disease, pancreatic endocrine tumor, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary) .
[0522]
Preferably, the medicament of the present invention may be useful as a prophylactic or therapeutic agent for neoplastic disease and the like.
[0523]
In another embodiment, the medicament of the present invention may be useful as a prophylactic or therapeutic agent for preferably autoimmune disease, inflammatory disease, bone or articular disease or neoplastic disease, particularly preferably, psoriasis, inflammatory bowel disease (IBD), ulcerative colitis (UC) , Crohn's disease (CD), rheumatoid arthritis, multiple sclerosis, uveitis, asthma, ankylopoietic spondylarthritis, systemic lupus erythematosus (SLE) , chronic obstructive pulmonary diseases, ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, head and neck carcinoma, prostate cancer or uterine . body cancer.
Here, the above-mentioned "prophylaxis" of a disease
-means, for example, administration of a medicament containing the compound of the present invention to patients who are expected to have a high risk of the onset due to some factor relating to the disease but have not developed the disease or patients who have developed the disease but do not have a subjective symptom, or administration of a medicament
containing the compound of the present invention to patients who are feared to show recurrence of the disease after
treatment of the disease.
[0524]
The medicament of the present invention is expected to show superior pharmacokinetics (e.g., a half-life of the drug in plasma), low toxicity (e.g., HERG inhibition, CYP inhibition, CYP induction) , and decreased drug interaction. The compound of the present invention may be directly used as a medicament, or as the medicament of the present invention by producing a pharmaceutical composition by mixing with a pharmaceutically acceptable carrier by a means known per se and generally used in a production method of pharmaceutical preparations. The medicament of the present invention may be orally or
parenterally administered safely to mammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep and goats) .
[0525]
A medicament containing the compound of the present invention may be safely administered solely or by mixing with a pharmacologically acceptable carrier according to a method known per se (e.g., the methoc? described in the Japanese
Pharmacopoeia etc.) as the production method of a
pharmaceutical preparation, and in the form of, for example, tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal and the like) , pill, powder, granule, capsule (including soft capsule, microcapsule) , troche, syrup, liquid, emulsion, suspension, release control preparation (e.g., immediate-release
preparation, sustained-release preparation, sustained-release microcapsule), aerosol, film (e.g., orally disintegrating film, oral mucosa-adhesive film), injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip infusion, transdermal
absorption type preparation, ointment, lotion, adhesive
preparation, suppository (e.g., rectal suppository, vaginal suppository) , pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like, orally or parenterally (e.g., intravenous, intramuscular, subcutaneous, intraorgan,
intranasal, intradermal, instillation, intracerebral,
intrarectal, intravaginal , intraperitoneal and intratumor administrations, vicinity of tumor, and lesion) .
The content of the compound of the present invention in the medicament of the present invention is about 0.01 to 100% by weight of the whole medicament. While the dose varies depending on the subject of administration, administration route, disease and the like, for example, for an oral
preparation to a cancer patient (body weight about 60kg) , it is about 0.1 mg/kg body weight to 30 mg/kg body weight, preferably about 1 mg/kg body weight to 20 mg/kg body weight as an active ingredient (compound (I' ) ) for one day, which is administered once to several times, preferably once to 2 or 3 times per day.
The pharmacologically acceptable carrier, which may be used for the production of the medicament of the present
invention, may be exemplified by various organic or inorganic carrier materials that are conventionally used as preparation materials, for example, excipient, lubricant, binding agent and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like for liquid preparations.
Furthermore, when necessary, ordinary additives such as
preservative, antioxidant, colorant, sweetening agent,
adsorbing agent, wetting agent and. the like may also be used as appropriate in an appropriate amount.
[0526]
Examples of the excipient include lactose, white sugar,
D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binding agent include crystalline
cellulose, white sugar> D-mannitol, dextrin,
hydroxypropylcellulose, hydroxypropylmethylcellulose,
polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, carboxymethylcellulose sodium and the like.
Examples of the disintegrant include starch,
carboxymethylcellulose, carboxymethylcellulose calcium,
carboxymethylstarch sodium, L-hydroxypropylcellulose and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium
carbonate, sodium citrate and the like.
Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate,
laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate and the like;
hydrophilic polymers such as poly(vinyl alcohol), polyvinylpyrrolidone, carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; and the like.
[0527]
Examples of the isotonic agent include glucose, D- sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates, citrates and the like.
Examples of the soothing agent include benzyl alcohol and the like.
Examples of the preservative include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol,
dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfites, ascorbic acid, a-tocopherol and the like.
[0528]
For the prophylaxis or treatment of various diseases, the compound of the present invention may also be used together with other medicaments. In the following, a medicament to be used when the compound of the present invention is used
together with other drug is referred to as "the combination agent of the present invention".
Specifically, the compound of the present invention can be used in combination with drugs such as hormonal therapeutic agent, chemotherapeutic agent, immunotherapeutic agent or medicament inhibiting actions of cell growth factor and receptor thereof and the like. In the following, a drug that can be used in combination with the compound of the present invention is to be abbreviated as a "concomitant drug".
[0529]
As the "hormonal therapeutic agent", for example,
fosfestrol, diethylstylbestrol, chlorotrianisene,
medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol ,
gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti-estrogen (e.g., tamoxifen citrate,
toremifene citrate) , pill preparation, mepitiostane ,
testrolactone, aminoglutethimide, LH-RH agonist (e.g.,
goserelin acetate, buserelin, leuprorelin acetate) , droloxifene, epitiostanol, ethinylestradiol sulfonate, aromatase inhibitor
(e.g., fadrozole hydrochloride, anastrozole, retrozole,
exemestane, vorozole, formestane) , anti-androgen (e.g., . . flutamide, bicartamide, nilutamide, enzalutamide ) , 5a-reductase inhibitor (e.g., finasteride, epristeride, dutasteride) ,
adrenocortical hormone drug (e.g., dexamethasone, predonisolone, betamethasone, triamcinolone) , androgen synthesis inhibitor
(e.g., abiraterone) , retinoid and drugs that retard retinoid metabolism (e.g., liarozole) , thyroid gland hormone, and DDS
(Drug Delivery System) preparation thereof are used.
[0530]
As the "chemotherapeutic agent", for example, alkylating agents, metabolic antagonists, antitumor antibiotics, and plant-derived antitumor drugs may be used.
[0531]
As the "alkylating agent", for example, nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl,
cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol , melphalan, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine,
streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine,
pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesin, and DDS preparations thereof may be used.
[0532]
As the "metabolic antagonist", for example,
mercaptopurine, 6-mercaptopurine riboside, thioinosine,
methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drug (e.g.,
fluorouracil , tegafur, UFT, doxifluridine, carmofur,
gallocitabine, emitefur, capecitabine ) , aminopterin,
nelzarabine, leucovorin calcium, tabloid, butocine, folinate calcium, levofolinate calcium, cladribine, emitefur,
fludarabine, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, tiazofurin, ambamustine, bendamustine, and DDS preparations thereof may be used.
[0533]
As the "antitumor antibiotic", for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin
hydrochloride, bleomycin sulfate, peplomycin sulfate,
daunorubicin hydrochloride, doxorubicin hydrochloride,
aclarubicin hydrochloride, pirarubicin hydrochloride,
epirubicin hydrochloride, neocarzinostatin, mithramycin, sarkomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS preparations thereof (e.g., Doxorubicin encapsulated PEG ribosome) may be used.
[0534]
As the "plant-derived antitumor drug", for example, etoposide, etoposide phosphate, vinblastine sulfate,
vincristine sulfate, vindesine sulfate, tenyposide, paclitaxel, docetaxel, cabazitaxel, vinorelbine, and DDS preparations thereof may be used.
[0535]
As the "immunotherapeutic agent", for example, picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon,
interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium parvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody (e.g., ipilimumab,
tremelimumab) , anti-PD-1 antibody (e.g., nivolumab,
pembrolizumab) , anti-PD-Ll antibody may be used.
[0536] The "cell growth factors" in the "medicament inhibiting actions of cell growth factor and receptor thereof" may be any substance that promotes cell proliferation, which is normally peptide having not more than 20,000 molecular weight, and capable of exhibiting the activity at low concentrations by binding to a receptor, and specifically
(1) EGF (epidermal growth factor) or substances possessing substantially the same activity as EGF (e.g., TGFa) ;
(2) insulin or substances possessing substantially the same activity as insulin (e.g., insulin, IGF (insulin-like growth factor) -1, IGF-2),
(3) FGF (fibroblast growth factor) or substances possessing substantially the same activity as FGF (e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10) , and
(4) other cell growth factors (e.g., GSF (colony stimulating factor), EPO (erythropoietin), IL-2 ( interleukin-2 ) , NGF (nerve growth factor) , PDGF (platelet-derived growth factor) , TGFP (transforming growth factor β) , HGF (hepatocyte growth factor) , VEGF (vascular endothelial growth factor) , heregulin,
angiopoietin) ; may be used.
[0537]
The "cell growth factor receptor" may be any receptor capable of binding to the aforementioned cell growth factors, and specifically, EGF receptor, heregulin receptor (e.g., HER3) , insulin receptor, IGF receptor-1, IGF , receptor-2 , FGF receptor- 1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (e.g., Tie2) , PDGF receptor, and the like may be used.
[0538]
As the "medicament inhibiting actions of cell growth factor and receptor thereof", for example, EGF inhibitor, TGFa inhibitor, heregulin inhibitor, insulin inhibitor, IGF
inhibitor, FGF inhibitor, KGF inhibitor, CSF inhibitor, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFp inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin
inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor inhibitor, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF
receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor, VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3
inhibitor, c-Kit inhibitor, Src inhibitor, PKC inhibitor, Smo inhibitor, ALK inhibitor, ROR1 inhibitor, Trk inhibitor, Ret inhibitor,- mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1/2) inhibitor, MET inhibitor, CDK inhibitor, Akt inhibitor, ERK inhibitor, PI3K inhibitor, and the like are used. More specifically, anti-VEGF antibody (e.g., Bevacizumab,
Ramucurumab) , anti-HER2 antibody (e.g., Trastuzumab,
Pertuzumab) , anti-EGFR antibody (e.g., Cetuximab, Panitumumab, Matuzumab, Nimotuzumab) , anti-HGF antibody, Imatinib, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib,
Vatalanib, Ibrutinib, Bosutinib, Cabozantinib, Crizotinib,
Alectinib, Vismodegib, Cedirani-b,. Tivantinib, Quizartinib,
Dovitinib, Axitinib, Motesanib, Nilotinib, 6- [4- (4- ethylpiperazin-l-ylmethyl ) phenyl] -N- [1 (R) -phenylethyl] -7H- pyrrolo [2, 3-d] pyrimidin-4-amine (AEE-788), Vandetanib,
Temsirolimus , Everolimus, Enzastaurin, Tozasertib, 2- [N- [3- [4- [5- [N- ( 3-fluorophenyl ) carbamoylmethyl] -lH-pyrazol-3- ylamino] q-uinazo-lin-7—yloxy] propyl ] -N-ethylamino] ethyl phosphate (AZD-1152) , 4- [9-chloro-7- (2, 6-difluorophenyl) -5H-primido [5, 4- d] [2 ] benzazepin-2-ylamino] benzoic acid, N- [2-methoxy-5- [ (E) -2- (2,4, 6-trimethoxyphenyl) vinylsulfonylmethyl] phenyl] glycine sodium salt (ON-1910Na) , Volasertib, Selumetinib, Trametinib, N- [2 (R) , 3-dihydroxypropoxy] -3, 4-difluoro-2- (2-fluoro-4- iodophenylamino) benzamide (PD-0325901) , Bosutinib, Regorafenib, Afatinib, Idelalisib, Ceritinib, Dabrafenib, and the like may be used.
[0539]
Besides the above-mentioned drugs, L-asparaginase, L- arginase, arginine deiminase, aceglatone, procarbazine
hydrochloride, protoporphyrin-cobalt complex salt, mercuric hematoporphyrin-sodium, topoisomerase I inhibitor (e.g., irinotecan, topotecan, indotecan, Indimitecan) , topoisomerase II inhibitor (e.g., sobuzoxane) , differentiation-inducing factor (e.g., retinoid, vitamin D) , other angiogenesis
inhibitor (e.g., fumagillin, shark extract, COX-2 inhibitor), a-blocker (e.g., tamsulosin hydrochloride), bisphosphonic acid (e.g., pamidronate, zole.dronate) , thalidomide, lenalidomide, pomalidomide, 5-azacytidine, decitabine, proteasome inhibitor (e.g., bortezomib, carfilzomib, ixazomib) , NEDD8 inhibitor (e.g., Pevonedistat) , UAE inhibitor, PARP inhibitor (e.g.,
Olaparib, Niraparib, Veliparib) , antitumor antibodies such as anti-CD20 antibody (e.g., Rituximab, Obinutuzumab) , anti-CCR4 antibody (e.g., Mogamulizumab) and the like, antibody drug complex (e.g., trastuzumab emtansine, brentuximab vedotin) , and the like may also be used as a concomitant drug.
In another embodiment, for example, when the compound of the present invention may be used as an RORyt inhibitor, Thl7 cell inhibitor, IL-17A or IL-17F inhibitor, it may be used in combination with the following drugs.
(1) non-steroidal anti-inflammatory drug (NSAIDs)
(i) Classical NSAIDs
alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumeton, acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin,
mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, piroxicam, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone,
allopurinol, sodium aurothiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone or a salt thereof and the like. (ii) cyclooxygenase inhibitor (COX-1 selective inhibitor, COX-2 selective inhibitor and the like)
salicylic acid derivatives (e.g., celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac, indomethacin, loxoprofen and the like.
(iii) nitric oxide-releasing NSAIDs
[0540]
(2) disease-modifying anti-rheumatic drugs (DMARDs)
(i) Gold preparation
aurano.fin and the like.
(ii) penicillamine
D-penicillamine .
(iii) aminosalicylic acid preparation
sulfasalazine, mesalamine, olsalazine, balsalazide.
(iv) antimalarial drug
chloroquine and the like.
(v) pyrimidine synthesis inhibitor - leflunomide and the like. -
(vi) tacrolimus
[0541]
(3) anti-cytokine drug
(I) protein drug
(i) TNF inhibitor
etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, PASSTNF-a, soluble TNF-a receptor, TNF-a binding protein, anti-TNF-a antibody and the like.
(ii) interleukin-1 inhibitor
anakinra (interleukin-1 receptor antagonist) , soluble interleukin-1 receptor and the like.
(iii) interleukin-6 inhibitor
tocilizumab (anti-interleukin-6 receptor antibody) , anti- interleukin-6 antibody and the like.
(iv) interleukin-10 drug
interleukin-10 and the like.
(v) interleukin-12/23 inhibitor ustekinumab, briakinumab (anti-interleukin-12/23 antibody) and the like,
(vi) B cell activation inhibitor
Rituxan, Benlysta and the like.
(vii) costimulatory molecule-related protein drug
Abatacept and the like.
(II) non-protein drug,
(i) MAPK inhibitor
BMS-582949 and the like.
(ii) gene modulator
inhibitor of molecule involved in signal transduction, such as N-F-K, NF-κΒ, IKK-!, IKK-2, AP-1 and -the like, and the like.
(iii) cytokine production inhibitor
iguratimod, tetomilast and the like.
(iv) TNF-a converting enzyme inhibitor
(v) interleukin-ΐβ converting enzyme inhibitor -
Belnacasan and the like. .. .
(vi) interleukin-6 antagonist
HMPL-004 and the like.
(vii) interleukin-8 inhibitor.
IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparixin and the like.
(viii) chemokine antagonist
CCR9 antagonist (Vercirnon sodium), CCX025, N-{4-chloro-
2- [ ( l-oxidopyridin-4-yl ) carbonyl] phenyl } -4- (propan-2- yloxy) benzenesulfonamide) , MCP-1 antagonist and the like.
(ix) interleukin-2 receptor antagonist
denileukin, diftitox and the like.
(x) therapeutic vaccines
TNF-a vaccine and the like,
(xi) gene therapy drug
gene therapy drugs aiming at promoting the expression of gene having an anti-inflammatory action such as interleukin-4 , interleukin-10 , soluble interleukin-1 receptor, soluble TNF-a receptor and the like,
(xii) antisense compound
ISIS-104838 and the like.
[0542]
(4) integrin inhibitor
natalizumab, vedolizumab, AJM300, TRK-170, E-6007 and the like. . - -.
(5) immunomodulator (immunosuppressant)
methotrexate, cyclophosphamide, MX-68, atiprimod
dihydrochloride, Abatacept, CKD-461, rimexolone, cyclosporine, tacrolimus, gusperimus, azathioprine, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like. (6) proteasome inhibitor
Velcade and the like.
(7) JAK inhibitor .
tofacitinib and the like.
(8) steroid
dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide,
fluocinolone acetonide, predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone, fluorometholone,
beclomethasone dipropionate, estriol and the like.
(9) angiotensin converting enzyme inhibitor
enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.
[0543]
(10) angiotensin II receptor antagonist
candesartan cilexetil, valsartan, irbesartan, olmesartan, eprosartan and the like.
(11) diuretic drug
hydrochlorothiazide, spironolactone, furosemide,
indapamide, bendrofluazide, cyclopenthiazide and the like.
(12) cardiotonic drug digoxin, dobutamine and the like.
(13) β receptor antagonist
carvedilol, metoprolol, atenolol and the like.
(14) Ca sensitizer
Caldaret hydrate and the like.
(15) Ca channel antagonist
nifedipine, diltiazem, verapamil and the like.
(16) anti-platelet drug, anticoagulator
heparin, aspirin, warfarin and the like.
(17) HMG-CoA reductase inhibitor
atorvastatin, simvastatin and the like.
[0544]
(18) contraceptive
(i) sex hormone or derivatives thereof
gestagen or a derivative thereof (progesterone, 17a- hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone , -norethisterone enanthate,
norethindrone, norethindrone acetate, norethynodrel ,
levonorgestrel, norgestrel, ethynodiol diacetate, desogestrel, norgestimate, gestodene, progestin, etonogestrel , drospirenone, dienogest, trimegestone, nestorone, chlormadinone acetate, mifepristone, nomegestrol acetate, Tosagestin, TX-525,
ethinylestradiol/TX525 or a combination agent of a gestagen or a derivative thereof and an estrogen or a derivative thereof (estradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enanthate, estradiol hexahydrobenzoate, estradiol phenylpropionate, estradiol undecanoate, estradiol valerate, estrone, ethinylestradiol, mestranol) and the like.
(ii) antiestrogen
ormeloxifene, mifepristone, Org-33628 and the like.
(iii) spermatocide
ushercell and the like.
[0545]
(19) others
(i) T cell inhibitors (ii) inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolate mofetil and the like.
(iii) adhesion molecule inhibitor
Alicaforsen sodium, . selectin inhibitor, ELAM-1 inhibitor, VCAM-1 inhibitor, ICAM-1 inhibitor and the like.
(iv) thalidomide
(v) cathepsin inhibitor
(vi) matrix metalloprotease (MMPs) 'inhibitor
V-85546 and the like.
(vii) glucose-6-phosphate dehydrogenase inhibitor
(viii) Dihydroorotate dehydrogenase (DHODH) inhibitor
(ix) phosphodiesterase IV(PDE IV) inhibitor
roflumilast, apremilast, CG-1088 and the like.
(x) ) phospholipase A2 inhibitor
(xi) iNOS inhibitor
VAS-203 and the like.
(xii) microtubule stimulating drug —
paclitaxel and the like.
(xiii) microtuble inhibitor
reumacon and the like.
(xiv) MHC class II antagonist
(xv) prostacyclin agonist
iloprost and the like.
(xvi) CD4 antagonist
zanolimumab and the like.
(xvii) CD23 antagonist
(xviii) LTB4 receptor antagonist
DW-1350 and the like.
(xix) 5-lipoxygenase inhibitor
zileuton and the like.
(xx) cholinesterase inhibitor
galanthamine and the like.
(xxi) tyrosine kinase inhibitor
Tyk2 inhibitor (WO 2010/142752) and the like.
(xxii) carepsin B inhibitor (xxiii) adenosine deaminase inhibitor
pentostatin and the like.
(xxiv) osteogenesis stimulator
(xxv) dipeptidylpeptidase inhibitor
(xxvi) collagen agonist
(xxvii) capsaicin cream
(xxviii) hyaluronic acid derivative
synvisc (hylan G-F 20), orthovisc and the like.
(xxix) glucosamine sulfate
(xxx) amiprilose
(xxxi) CD-20 inhibitor
rituximab, ibritumomab, tositumomab, ofatumumab and the like .
(xxxii) BAFF inhibitor
belimumab, tabalumab, atacicept, Blisibimod and the like.
(xxxiii) CD52 inhibitor
a GT.tuzurr.ac and the like.
[0546]
Other concomitant drugs besides the above-mentioned include, for example, antibacterial agent, antifungal agent, antiprotozoal agent, antibiotic, antitussive and expectorant drug, sedative, anesthetic, antiulcer drug, antiarrhythmic agent, hypotensive diuretic drug, anticoagulator, tranquilizer, antipsychotic, antitumor drug, hypolipidemic drug, muscle relaxant, antiepileptic drug, antidepressant, antiallergic drug, cardiotonic drug, therapeutic drug for arrhythmia, vasodilator, vasoconstrictor, therapeutic drug for diabetes, antinarcotic, vitamin, vitamin derivative, antiasthmatic, therapeutic agent for pollakisuria/anischuria, therapeutic agent for atopic dermatitis, therapeutic agent for allergic rhinitis,
hypertensor, endotoxin-antagonist or -antibody, signal
transduction inhibitor, inhibitor of inflammatory mediator activity, antibody to inhibit inflammatory mediator activity, inhibitor of anti-inflammatory mediator activity, antibody to inhibit anti-inflammatory mediator activity and the like. Specific examples thereof may include the following.
[0547]
(1) antibacterial agent
(i) sulfa drug
sulfamethizole, sulfisoxazole, sulfamonomethoxine, salazosulfapyridine, silver sulfadiazine and the like.
(ii) quinolone antibacterial agent .
nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.
(iii) antiphthisic
isoniazid, ethambutol (ethambutol hydrochloride) , p- aminosalicylic acid (calcium p-aminosalicylate) , pyrazinamide, ethionamide, protionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
(iv) antiacidfast bacterium drug- diaphenylsulfone, rifampicin and the like.
(v) antiviral drug
idoxuridine, acyclovir, vidarabine, gancyclovir and the like.
[0548]
(vi) anti-HIV agent
zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, ritonavir and the like.
(vii) antispirochetele
(viii) antibiotic
tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin, cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil, cefamandole, cefotoam, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin, cefmenoxime , cefpodoxime proxetil, cefpirome, cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or a salt a salt thereof, griseofulvin, lankacidin-group [Journal of Antibiotics (J.
Antibiotics), 38, 877-885(1985)], azole compound [2- [ ( 1R, 2R) -2- (2, 4-difluorophenyl ) -2-hydroxy-l-methyl-3- (lH-1, 2, 4-triazol-l- yl) propyl] -4- [4- (2, 2, 3, 3-tetrafluoropropoxy) phenyl] -3 (2H, 4H) - 1, 2 , 4-triazolone, fluconazole, itraconazole and the like] and the like .
[0549] -
(2) antifungal agent
(i) polyethylene antibiotic (e.g., amphotericin B, nystatin, trichomycin)
(ii) griseofulvin, pyrrolnitrin and the like
(iii) cytosine metabolism antagonist (e.g., flucytosine)
(iv) imidazole derivative (e.g., econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole)
(v) triazole derivative (e.g., fluconazole, itraconazole)
(vi) thiocarbamic acid derivative (e.g., trinaphthol) and the like.
(3) antiprotozoal agent
metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like.
[0550]
(4) antitussive and expectorant drug
ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol
hydrochloride, ephedrine hydrochloride, methylephedrine
hydrochloride, noscapine hydrochloride, alloclamide,
chlophedianol, picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol, terputaline, oxypetebanol , morphine hydrochloride, dextropethorfan hydrobromide, oxycodone
hydrochloride, dimorphan phosphate, tipepidine hibenzate, pentoxyverine citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethylcysteine hydrochloride, carbocysteine and the like.
(5) sedative
chlorpromazine hydrochloride, atropine sulfate,
phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamylal sodium, nitrazepam, estazolam, flurazepam, haloxazolam, triazolam, flunitrazepam, bromovalerylurea, chloral hydrate, triclofos sodium and the like.
[0551]
(6) anesthetic
(6-1) local anesthetic
cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine
hydrochloride, ethyl aminobenzoate, oxethazaine and the like. (6-2) general anesthetic
(i) inhalation anesthetic (e.g., ether, halothane, nitrous oxide, isoflurane, enflurane) ,
(ii) intravenous anesthetic (e.g., ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium, pentobarbital) and the like.
(7) antiulcer drug
histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrine, oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin and the like.
(8) antiarrhythmic agent
(i) sodium channel blocker (e.g., quinidine, procainamide, disopyramide, ajmaline, lidocaine, mexiletine, phenytoin) ,
(ii) β-blocker (e.g., propranolol, alprenolol, bufetolol hydrochloride, oxprencicl , atenolol, - acebuto-Lol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride) , (iii) potassium channel blocker (e.g., amiodarone) ,
(iv) calcium channel blocker (e.g., verapamil, diltiazem) and the like.
[0552]
(9) hypotensive diuretic drug
hexamethonium bromide, clonidine hydrochloride,
hydrochlorothiazide, trichlormethiazide, furosemide, ethacrynic acid, bumetanide, mefruside, azosemide, spironolactone,
potassium canrenoate, triamterene, amiloride, acetazolamide, D- mannitol, isosorbide, aminophylline and the like.
(10) anticoagulator
heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor/ antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium
citrate, ozagrel sodium, ethyl icosapentate, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline,
dipyridamole, tisokinase, urokinase, streptokinase and the like.
(11) tranquilizer
diazepam, lorazepam, oxazepam, chlordiazepoxide,
medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like.
(12) antipsychotic
chlorpromazine hydrochloride, prochlorperazine,
trifluoperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride,
haloperidol, bromperidol, spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.
[0553]
(13) antitumor drug
6-0- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin,
adriamycin, neocarzinostatin, cytosine arabinoside,
fluorouracil, tetrahydrofuryl-5-fluorouracil ,. picibanil,
lentinan, levamisole, bestatin, azimexon, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, peplomycin sulfate, vincristine sulfate,
vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, busulfan, thiotepa, procarbazine hydrochloride,
5 cisplatin, azathioprine, mercaptopurine, tegafur, carmofur,
cytarabine, methyltestosterone, testosterone propionate,
testosterone enanthate, mepitiostane, fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelin acetate and the like. (14) hypolipidemic drug
0 clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2- phenylpropoxy) phenyl] propionate [Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull), 38, 2792-2796 (1990)],
pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sulfate sodium and the like.5 (15) muscle relaxant
pridinol, tubocurarine, pancuronium, tolperisone
hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, chlorzoxazone, eperisone, tizanidine and the like. (16) antiepileptic drug
0 phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, tripethadione, carbamazepine, phenobarbital, primidone,
sulthiame, sodium valproate, clonazepam, diazepam, nitrazepam and the like.
[0554]
5 (17) antidepressant
imipramine, clomipramine, noxiptiline; phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride and the0 like.
(18) antiallergic drug
diphenhydramine, chlorpheniramine, tripelennamine, metodilamine, clemizole, diphenylpyraline, methoxyphenamine, - - sodium cromoglicate, tranilast, repirinast ,-.amlexanox, -.. -5 ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast and the like.
(19) cardiotonic drug
trans-n-oxocamphor, terephyllol, aminophylline, 5 etilefrine, dopamine, dobutamine, denopamine, aminophylline, vesinarine, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.
(20) vasodilator
10 oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine, methyldopa, guanabenz and the like.
(21) vasoconstrictor
dopamine, dobutamine denopamine and the like.
(22) hypotensive diuretic
-■is hexamethonium bromide, pentolinium, mecamylamine,
ecarazine, clonidine, diltiazem, nifedipine and the like.
(23) therapeutic drug for diabetes
tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon,
20 glymidine, glipuzide, phenformin, puformin, metformin and the like.
[0555]
(24) antinarcotic
levallorphan, nalorphine, naloxone or a salt thereof and 25 the like.
(25) liposoluble vitamins
(i) vitamin A: vitamin Ai, vitamin A2 and retinol palmitate
(ii) vitamin D: vitamin Di, D2, D3, D4and D5
(iii) vitamin E: a-tocopherol, β-tocopherol, γ-tocopherol, δ -
30 tocopherol, dl-a-tocopherol nicotinate
(iv) vitamin K: vitamin Ki, ]¾, K3and K4
(v) folic acid (vitamin M) and the like.
(26) vitamin derivative
various derivatives of vitamins, for example, vitamin D3 35 derivatives such as 5 , 6-trans-cholecalciferol, 2,5- hydroxycholecalciferol, 1-a-hydroxycholecalciferol , calcipotriol and the like, vitamin D2 derivatives such as 5, 6- trans-ergocalciferol and the like, and the like.
(27) antiasthmatic
isoprenaline hydrochloride, salbutamol sulfate,
procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlkast
hydrate, seratrodast, dexamethasone, predonisolone,
hydrocortisone, hydrocortisone sodium succinate, beclometasone dipropionate, ciclesonide and the like.
(28) therapeutic agent for pollakisuria/anischuria
flavoxate hydrochloride and the like.
(29) therapeutic agent for atopic dermatitis
sodium cromoglicate and the like.
[0556]
(30) therapeutic agent for allergic rhinitis
sodium cromoglicate, chlorpheniramine maleate,
alimemazine tartrate, clemastine fumarate, homochlorcyclizine hydrochloride, fexofenadine, mequitazine, ketotifen fumarate, cetirizine hydrochloride, oxatomide, azelastine, ebastine, epinastine hydrochloride, loratadine and the like.
(31) hypertensor
dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.
(32) others
hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandins and the like.
[0557]
For combined use, the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention and the concomitant drug may be administered to an administration subject simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the dose clinically used, and may be appropriately selected depending on an administration subject, administration route, disease, combination and the like.
The administration form of the combined use is not particularly limited, and the compound of the present invention and a concomitant drug only need to be combined on
administration. Examples of such administration mode include the following:
(1) administration of a single preparation obtained by
simultaneously processing the compound of the present invention and the concomitant drug, (2) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route, (3) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two kinds of
preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes in a staggered manner (e.g., administration in the order of the compound of the present invention and the concomitant drug, or in the reverse order) and the like.
The mixing ratio of the compound of the present invention and a concomitant drug in the combination agent of the present invention can be appropriately selected based on the subject of administration, administration route, disease and the like. For example, while the content of the compound of the present invention in the combination agent of the present invention varies depending on the preparation form, it is generally about 0.01 - 100 wt%, preferably about 0.1 - 50 wt%, more preferably about 0.5.. - 20 wt%, of the whole preparation.
[0558]
The content of the concomitant drug in the combination agent of the present invention varies depending on the
preparation form, and generally about 0.01 to 99.99% by weight, preferably about 0.1 to 50% by weight, further preferably about 0.5 to 20% by weight, of the entire preparation.
While the content of the additive such as a carrier and the like in the combination agent of the present invention varies depending on the form of a preparation, it is generally about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the preparation.
When the compound of the present invention and the concomitant drug are separately prepared, the same content may be adopted.
The dose varies depending on the kind of the compound of the present invention, administration route, symptom, age of patients and the like. For example, for oral administration to patients (body weight about 60 kg) with inflammatory bowel disease (IBD) , about 0.1 mg/kg body weight - about 30 mg/kg body weight, preferably about 1 mg/kg body weight - 20 mg/kg body weight, of compound (-1'-) can be administered once to several portions per day.
The dose of the medicament of the present invention as a sustained-release preparation varies depending on the kind and content of compound (Ι'), dosage form, period of sustained drug release, subject animal of administration (e.g., mammals such as mouse, rat, hamster, guinea pig, rabbit, cat, dog, bovine, horse, swine, sheep, monkey, human and the like) , and
administration object. For example, for application by
parenteral administration, about 0.1 to about 100 mg of compound (I' ) needs to be released from the administered preparation per 1 week.
[0559]
Any amount of the concomitant drug can be adopted as long as the side effects do not cause a. problem.. The daily dosage in terms of the concomitant drug varies depending on the severity, age, sex, body weight, sensitivity ' difference of the subject, administration period, interval, and nature,
pharmacology, kind of the pharmaceutical preparation, kind of effective ingredient, and the like, and not particularly restricted, and the amount of a drug is, in the case of oral administration for example, generally about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, further preferably about 0.1 to 100 mg, per 1 kg of a mammal and this is generally
administered once to 4-times divided in a day.
When the combination agent of the present invention is administered, the compound of the present invention and the concomitant drug can be administered simultaneously, or may be administered in a staggered manner. When administered at a time interval, the interval varies depending on the effective ingredient, dosage form and administration method, and, for example, when the concomitant drug is administered first, a method in which the compound of the present invention is administered within time range of from for 1 minute to 3 days, preferably from for 10 minutes to 1 day, more preferably from for 15 minutes to 1 hour, after administration of the
concomitant drug is included. When the compound of the present invention is administered first, a method in which the
concomitant drug is administered within time range of from for 1 minute to 1 day, preferably from for 10 minutes to 6 hours, more preferably from for 15 minutes to 1 hour after
administration of the compound of the present invention is included .
[Examples]
[0560] The present invention is explained in more detail in the following by referring to Examples, Formulation Examples and Experimental Examples, which are not to be construed as limitative and may be modified without departing from the scope of the invention. . ....
Unless particularly specified, the elution in column chromatography in the Examples was performed under observation by TLC (Thin Layer Chromatography) . For TLC observation,
60F254 manufactured by Merck was used as a TLC plate, and the solvent used as an elution solvent for column chromatography was used as a developing solvent. For detection, a UV detector was adopted. In silica gel column chromatography, NH means use of aminopropylsilane-bonded silica gel, and Di-oi means use of 3- (2 , 3-dihydroxypropoxy) propylsilane-bonded silica gel. In preparative HPLC (high performance liquid chromatography) , C18 means use of octadecyl-bonded silica gel. The ratios of elution solvents are volume mixing ratios, unless otherwise specified. The room temperature generally means a temperature about 10°C to 35°C. For drying extracts, sodium sulfate or magnesium sulfate was used.
The abbreviations in the present specification or the Examples mean as follows.
[0561]
LC: liquid chromatography
MS: mass analysis spectrum
ESI: Electrospray ionization
M: molecular weight of the compound
M: mol concentration
N: normal concentration
NMR: nuclear magnetic resonance spectrum
Hz: hertz
J: coupling constant
m: multiplet
q: quartet
t: triplet d: doublet
dd: double doublet
ddd: double double doublet
s: singlet
dt : double triplet
sxt: sextet
brs : broad singlet
quin: quintet
quant.: quantitative
tBu: tert-butyl
sat . : saturated
aq. : aqueous
AcOH: acetic acid
ADDP: 1,1'- (azodicarbonyl ) dipiperidine
Boc: tert-butyloxycarbonyl group
Boc20: di-tert-butyl dicarbonate
CDI : carbonyldiimidazole
CPME: cyclopentyl methyl ether
DCM: dichloromethane
DIAD: diisopropyl azodicarboxylate
DIPEA: N-ethyl-N-isopropylpropan-2-amine
DMAP: 4-dimethylaminopyridine
DME: dimethoxyethane
DMF: N, N-dimethylformamide
DMSO: dimethyl sulfoxide
Et20: diethyl ether
EtOAc, AcOEt: ethyl acetate
EtOH: ethanol
HATU: 2- (3H- [1, 2, 3] triazolo [4, 5-b] pyridin-3-yl) -1, 1, 3, 3- tetramethylisouronium hexafluorophosphate (V)
IPE: diisopropyl ether
KOtBu: potassium tert-butoxide
LiHMDS: lithium 1, 1 , 1 , 2 , 2 , 2-hexamethyldisilane
m-CPBA: m-chloroperoxybenzoic acid
MeOH: methanol MsCl : methanesulfonyl chloride
NaOMe: sodium methoxide
NaOtBu: sodium tert-butoxide
NBS : N-bromosuccinimide
nBuOH: n-butyl alcohol
nBuLi: n-butyllithium
NCS: N-chl.orosuccinimide
NMP: N-methyl-2-pyrrolidone
OXONE: potassium peroxymonosulfate
Pd (dppf) C12-CH2C12 : 1, 1' -bis (diphenylphosphino) ferrocene- palladium ( II ) dichloride-dichloromethane complex
Pd/C(en): palladium-activated carbon ethylenediamine complex (Pd:3.5-6.5%)
Pd(OAc) 2 : palladium ( II ) diacetate
Pd (PPh3) 2C12: bis (triphenylphosphine ) palladium ( II ) dichloride Pd2 (dba) 3: tris (dibenzylideneacetone ) dipalladium ( 0 )
Pd-C: palladium on carbon
PdCl2 (dppf) : 1, 1' - bis (diphenylphosphino) ferrocenedichloropalladium ( II )
PE: petroleum ether
Ph3P: triphenylphosphine
RuPhos Pd Gl, RuPhos-Pd-Gl : (RuPhos) palladium ( II )
phenethylamine chloride
Ruphos pre-catalyst : chloro (2-dicyclohexylphosphino-2 ' , 6' -di-i- propoxy-1, 1' -biphenyl) [2- (2-aminoethylphenyl) ] palladium ( II ) , methyl-t-butyl ether adduct -
Ruphos : 2-dicyclohexylphosphino-2 ' , 6' -diisopropoxy-1 , 1' - biphenyl
T3P: 1.6 M 2 , 4 , 6-tripropyl-l , 3 , 5 , 2 , 4 , 6-trioxatriphosphorinane- 2 , 4 , 6-trioxide/ethyl acetate solution or DMF solution
t-Bu3P: tri-t-butylphosphine
TEA: triethylamine
Tf20: triflic anhydride, trifluoromethanesulfonic anhydride - TFA: trifluoroacetic acid
TFAA: trifluoroacetic anhydride THF: tetrahydrofuran
TsOH*H20: p-toluenesulfonic acid monohydrate
WSOHC1: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide
hydrochlorideXANTPHOS : 4, 5-bis (diphenylphosphino) -9, 9- dimethylxanthene
XPHOS Pd G2: chloro (2-dicyclohexylphosphino-2 ' , 4 ' , 6' - triisopropyl-1, 1' -biphenyl) [2- (2' -amino-1, 1' - biphenyl) ] palladium ( II )
Xphos, XPHOS: 2-dicyclohexylphosphino-2' , 4 ' , 6' - triisopropylbiphenyl
[0562]
Reference Example 1
4- ( (2-methoxyphenyl) amino) -N- ( 4-sulfamoylbenzyl) chromane-6- carboxamide
A) 4-oxochromane-6-carboxylic acid
To a solution of 6-bromo-2 , 3-dihydro-4H-chromen-4-one
(6.0 g, 26.40 mmol) in- DMF (70 mL) and H20 (7 mL) were added
Pd(PPh3)2Cl2 (1.85g, 2.60 mmol) and TEA (10.7 g, 105.70 mmol).
The mixture was stirred at 80 °C for 48 h under CO atmosphere. The mixture was diluted with water. The solid was filtered, washed with MeOH, and dried in vacuo to give the title compound
(2.8 g, yield 55.1%) as white solids.
[0563]
B) methyl 4-oxochromane-6-carboxylate
To a solution of 4-oxochromane-6-carboxylic acid (400.0 mg, 2.60 mmol) in MeOH (-10 mL) was added S0C12 (569.7 mg, 4.80 mmol) dropwise. The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound (370 mg, yield 86.2%) as white solids.
[0564]
C) methyl 4- ( (2-methoxyphenyl) amino) chromane-6-carboxylate
To a solution of methyl 4-oxochromane-6-carboxylate
(200.0 mg, 0.96 mmol) and 2-methoxyaniline (155.3 mg, 1.26 mmol) in DCM (5 mL) was added a DCM solution of TiCl4 (1M, 1.45 mL, 1.45 mmol). The mixture was stirred at room temperature overnight. Then, a solution of NaCNBH3 (121.9.0 mg, 1.94 mmol) in MeOH (2 mL) was added to the mixture and stirred at room temperature for 1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (250.0 mg, yield 82.2%) as grey solids.
MS (ESI+) , found 314.1 (M+H)
[0565]
D) 4- ( (2-methoxyphenyl) amino) chromane-6-carboxylic acid
To a solution of methyl 4-((2- methoxyphenyl) amino) chromane-6-carboxylate (250.0 mg, 0.80 mmol) in MeOH (4 mL) was added 4N NaOH aq. (4 mL, 16.00 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was acidified to pH = 6 with IN HC1 aq., and extracted with EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The white solid was washed with Et20 to afford the title compound (200.0 mg, 83.7% yield) as white solids.
[0566]
E) 4- ( (2-methoxyphenyl) amino) -N- ( 4-sulfamoylbenzyl ) chromane-6- carboxamide
To a mixture of 4- ( (2-methoxyphenyl) amino) chromane-6- carboxylic acid (180.0 mg, 0.60 mmol), HATU (240.0 mg, 0.66 mmol) and DIPEA (193.8 mg, 1.50 mmol) in THF (10 mL) was added 4- (aminomethyl) benzenesulfonamide hydrochloride (133.0 mg, 0.66 mmol) . The mixture was stirred at room temperature for 2 h. The reaction mixture was extracted with EtOAc and water, the organic layer was washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the title compound (70.0 mg, 24.9% yield) . as white solids.
Prep-HPLC [Gilson-GX281] conditions
Column: Waters X-Bridge C18: 100 mm x 30 mm, 5 μπι Mobile Phase: from 65% [water + 10 mM NH4HCO3] and 35% [CH3CN] to 45% [water + 10 mM NH4HCO3] and 55% [CH3CN] in 8 min, then changed to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.2 min and under this condition for 3.8 min
Flow rate: 20 mL/min
Column temperature: room temperature
MS (ESI+), found 468.1 (M+H)
1H NMR (400 MHz , DMSO-d6) 5:2.00-2.08 (2H, m) , 3.75 (3H, s) , 4.22-4.29 (2H, m) , 4.45-4.49 (2H, m) , 4.74 (1H, t, J= 3.8 Hz), 4.92 (1H, d, J= 8.0 Hz), 6.60-6.64 (1H, m) , 6.80-6.89 (4H, m) , 7.30 (2H, s), 7.45 (2H, d, J= 8.0Hz), 7.76 (3H, d, J= 8.4Hz), 7.92 (1H, d, J= 1.2Hz), 8.98 (1H, d, J= 5.6 Hz).
[0567]
Reference Example 2
4- (2-methoxyphenoxy) -N- ( 4-sulfamoylbenzyl ) chromane-6- carboxamide
A) methyl 4-hydroxychromane-6-carboxylate
To a solution of methyl 4-oxochromane-6-carboxylate
(370.0 mg, 1.80 mmol) in DCM (5 mL) and MeOH (5 mL) was added NaBH4 (169.7 mg, 4.50 mmol). The mixture was stirred at room temperature for 1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (350.0 mg, yield 93.7%) as a white solid
[0568]
B) methyl 4- (2-methoxyphenoxy) chromane-6-carboxylate
To a mixture of methyl 4-hydroxychromane-6-carboxylate (150.0 mg, 0.70 mmol), 2-methoxyphenol (178.0 mg, 1.4 mmol) and t-Bu3P (377.9 mg, 1.40 mmol) in THF (4 mL) was dropwise added a solution of 1, 1' - (azodicarbonyl) -dipiperidine (363.0 mg, 1.40 mmol) in THF (2 mL) . The mixture was stirred at room
temperature for 4 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/ EtOAc = 20/ 1, v/v) to afford the title compound (180.0 mg, 79.5% yield) as a
colorless oil.
MS (ESI+), found 337.2 (M+Na)
[0569]
C) 4- (2-methoxyphenoxy) chromane-6-carboxylic acid
To a solution of methyl 4- (2-methoxyphenoxy) chromane-6- carboxylate (180.0 mg, 0.6 mmol) in MeOH (4 mL) was added 4N NaOH aq. (4 mL, 16.00 mmol) . The mixture was stirred at room temperature for 4 h. The reaction mixture was acidified to pH = 6 with IN HC1 aq. , and extracted with EtOAc and water. The organic layer was washed with brine, dried over Na2SO4,
filtered and concentrated in vacuo. The resulting white solid was washed with Et20 to afford^ the title, compound (160.0 mg, 93.0% yield) .
[0570]
D) 4- (2-methoxyphenoxy) -N- ( 4-sulfamoylbenzyl ) chromane-6- carboxamide
To a mixture of 4- ( 2-methoxyphenoxy) chromane-6-carboxylic acid (160.0 mg, 0.50 mmol), HATU (230.0 mg, 0.55 mmol) and DIPEA (158.4 mg, 1.23 mmol) in THF (10 mL) was added 4- (aminomethyl) benzenesulfonamide (122.0 mg, 0.55 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was extracted with EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the title compound (125.0 mg, 50.1% yield) as white solids.
Prep-HPLC [Gilson-GX281] conditions, Column: Waters X-Bridge C18: 100 mm x 30 mm, 5 μιπ; Mobile Phase: from 60% [water + 10 mM NH4HCO3] and 40% [CH3CN] to 40% [water + 10 itiM NH4HCO3] and 60% [CH3CN] in 8 min, then changed to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.2 min and under this condition for 3.8 min; Flow rate: 20 mL/min; Column temperature: room temperature MS (ESI+), found 469.1 (M+H)
1H NMR (400 MHz, DMSO-d6) 6:2.05-2.13 (2H, m) , 3.75 (3H, s) , 4.25-4.35 (2H, m) , 4.51 (2H, d, J= 6.0 Hz), 5.40 (1H, t, J= 1.0 Hz), 6.88-6.94 (2H, m) , 6.98-7.05 (2H, m) , 7.18-7.20 (1H, m) , 7.30 (2H, s), 7.46 (2H, d, J= 8.4 Hz), 7.78 (2H, d, J= 8.4 Hz), 7.82 (1H, d, J= 8.4 Hz), 7.95 (1H, d, J= 0.7 Hz), 9.00 (1H, t, J= 5.6 Hz).
[0571]
The compounds described in Reference Examples 1 to 2 are below (Table 1-1) .
[0572]
[Table 1-1]
Figure imgf000234_0001
[0573]
Example 3
4- ( (2-methoxyphenyl) amino) -N- (4-sulfamoylbenzyl) chromane-7- carboxamide
A) methyl 4-oxochromane-7-carboxylate
To a solution of 4-oxochromane-7-carboxylic acid (500.0 mg, 2.60 mmol) and TEA (394.9, 3.90 mmol) in MeOH (10 mL) was added S0C12 (773.9 mg, 6.50mmol) dropwise. The mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with EtOAc . The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (450.0 mg, yield 83.9%) as grey solids.
[0574]
B) methyl 4- ( (2-methoxyphenyl) amino) chromane-7-carboxylate
To a solution of methyl 4-oxochromane-7-carboxylate
(120.0 mg, 0.58 mmol) and 2-methoxyaniline (100.3 mg, 0.81 mmol) in DCM (5 mL) was added a solution of TiCl4 (0.88 mL, IN, 0.88 mmol) in DCM. The mixture was stirred at room temperature overnight. Then, a solution of NaCNBH3 (73.0 mg, 1.16 mmol) in MeOH (2 mL) was added to the reaction. The mixture was stirred at room temperature for .1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (70.0 mg, yield 38.4%) as white solids.
MS (ESI+), found 314.3 (M+H)
[0575]
C) 4- ( (2-methoxyphenyl) amino) chromane-7-carboxylic acid.
To a solution of methyl 4- ( (2- methoxyphenyl) amino) chromane-7-carboxylate (65.0 mg, 0.20 mmol) in MeOH (4 ml) was added 4N NaOH aq. (4 mL, 16.00 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was acidified to pH = 6 with IN HC1 aq., and extracted with EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The resulting white solid was washed with Et20 to afford the title compound (60.0 mg, 96.6% yield) as white solids.
[0576]
D) 4- ( (2-methoxyphenyl) amino) -N- ( 4-sulfamoylbenzyl ) chromane-7- carboxamide
To a mixture of 4- ( (2-methoxyphenyl) amino) chromane-7- carboxylic acid (65.0 mg, 0.22 mmol), HATU (99.0 mg, 0.25 mmol) and DIPEA (70.0 mg, 0.54 mmol) in THF (10 mL) was added 4- (aminomethyl) benzenesulfonamide hydrochloride (58.0 mg, 0.26 mmol) . The mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with EtOAc and water, the organic layer was washed with brine, dried over Na2SO4,and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the title compound (31.0 mg, 30.5% yield) as white solids .
Prep-HPLC [Gilson-GX281] conditions, Column: Waters X-Bridge C18: 100 mm x 30 mm, 5 μπι; Mobile Phase: from 65% [water + 10 mM NH4HCO3] and 35% [CH3CN] to 45% [water + 10 mM NH4HCO3] and 55% [CH3CN] in 8 min, then changed to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.2 min and under this condition for 3.8 min; Flow rate: 20 mL/min; Column temperature: room temperature MS (ESI+), found 468.1 (M+H)
1H NMR (400 MHz, DMSO-d6) 5:2.00-2.09 (2H, m) , 3.76 (3H, s) , 4.21-4.29 (2H, m) ,. 4.52 (2H, d, J= 6 Hz), 4.74-4.79 (1H, m) , 4.93 (1H, d, J= 8.4 Hz), 6.60-6.64 (1H, m) , 6.77-6.86 (3H, m) , 7.31-7.41 (5H, m) , 7.47(2H, d, J= 8.4Hz), 7.78 (2H, d, J=
8.4Hz), 9.08 (1H, t, J= 5.8 Hz).
[0577]
Example 4
4- (2-methoxyphenoxy) -N- (4-sulfamoylbenzyl) chromane-7- carboxamide
A) methyl 4-hydroxychromane-7-carboxylate
To a solution of methyl 4-oxochromane-7-carboxylate
(200.0 mg, 0.97 mmol) in DCM (5 mL) and MeOH (5 mL) was added NaBH4 (91.7 mg, 2.42 mmol). The mixture was stirred at room temperature for 1 h. Water was added, the mixture was and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (160.0 mg, yield 79.2%) as white solids.
MS (ESI+), found 209.2 (M+H)
[0578]
B) methyl 4- (2-methoxyphenoxy) chromane-7-carboxylate
To a mixture of methyl 4-hydroxychromane-7-carboxylate (160.0 mg, 0.70 mmol), 2-methoxyphenol (190.8 mg, 1.40 mmol) and t-Bu3P (310.9 mg, 1.40 mmol) in THF (4 mL) was dropwise added a solution of 1, 1' - (azodicarbonyl) -dipiperidine (387.8 mg, 1.40 mmol) in THF (2 mL) . The mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with EtOAc, the organic layer was washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. . The residue was purified by column chromatography (PE/ EtOAc = 20/ 1) to afford the title compound (170.0 mg, 70.4% yield) as a colorless oil.
MS (ESI+), found 337.1 (M+Na)
[0579]
C) 4- (2-methoxyphenoxy) chromane-7-carboxylic acid
To a solution of methyl 4- ( 2-methoxyphenoxy) chromane-7- carboxylate (170.0 mg, 0.50 mmol) in MeOH (4 mL) was added 4N NaOH aq. (4 mL, 16.00 mmol) . The mixture was stirred at room temperature for 4 h. The reaction mixture was acidified to pH = 6 with IN HC1 aq., and extracted with EtOAc. The organic layer was washed brine, dried over Na2SO4, filtered and
concentrated in vacuo. The resulting white solid was washed with Et20 to afford the title compound (150.0 mg, 92.4% yield) as white solids.
[0580]
D) 4- (2-methoxyphenoxy) -N- ( 4-sulfamoylbenzyl ) chromane-7- carboxamide
To a mixture of 4- (2-methoxyphenoxy) chromane-7-carboxylic acid (170.0 mg, 0.50 mmol), HATU (190.0 mg, 0.55 mmol) and DIPEA (193.8 mg, 1.50 mmol) in THF (10 mL) was added 4- (aminomethyl) benzenesulfonamide (122.0 mg, 0.55 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by Prep-HPLC to afford the title compound (110.0 mg, 47.0% yield) as white solids.
Prep-HPLC [Gilson-GX281] conditions
Column: Waters X-Bridge C18 : 100 mm x 30 mm, 5 μηα
Mobile Phase: from 60% [water + 10 mM NH4HCO3] and 40% [CH3CN] to 40% [water + 10 mM NH4HCO3] and 60% [CH3CN] in 8 min, then changed to 5% [water + 10 mM NH4HCO3] and 95% [CH3CN] in 0.2 min and under this condition for 3.8 min
Flow rate: 20 mL/min
Column temperature: room temperature
MS (ESI+), found 469.1 (M+H)
2H NMR (400 MHz, DMSO-d6) δ:2.05-2.13 (2H, m) , 3.77 (3H, s) , 4.25-4.33 (2H, m) , 4.51 (2H, d, J= 5.6 Hz), 5.37 (1H, t, J= 3.6 Hz), 6.88-6.93 (1H, m) , 6.99-7.06 (2H, m) , 7.15-7.17 (1H, m) , 7.32 (2H, s), 7.38-7.43 (3H, m) , 7.48 (2H, d, J= 8.4Hz), 7.78 (2H, d, J= 8.4 Hz), 9.12 (1H, t, J= 5.6 Hz).
[0581]
Example 5
4- (2=methoxybenzyl ) -N- ( (1- (methylsulfonyl) piperidin-4- yl) methyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7-carboxamide
A) 4- (2-methoxybenzyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxylic acid
A mixture of methyl 4- (2-methoxybenzyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxylate (99 mg, 0.32 mmol) and 2 N NaOH (2 mL, 4.00 mmol) in MeOH (2 mL) was stirred at 40°C overnight. The mixture was acidified with 2 N HC1 and extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and
concentrated in vacuo to give the title compound (91 mg, 0.305 mmol, 97%) as a colorless oil. This product was subjected to the next reaction without further purification.
MS (ESI+), found 300.3 (M+H)
1H NMR (300 MHz, CDC13) 6:3.46-3.55 (2H, m) , 3.86 (3H, s) , 4.25 (2H, t, J = 4.5 Hz), 4.50-4.56 (2H, m) , 6.57 (1H, dd, J = 8.9, 5.1 Hz), 6.84-6.94 (2H, m) , 7,07-7.13 (1H, m) , 7.23-7.28 (1H, m) , 7.43-7.62 (2H, m) . (A C02H peak was omitted)
[0582]
B) 4- (2-methoxybenzyl) -N- ( (1- (methylsulfonyl) piperidin-4- yl)methyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxamide
To a mixture of 4- (2-methoxybenzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylic acid (91.4 mg, 0.31 mmol),. (1- (methylsulfonyl) piperidin-4-yl) methanamine hydrochloride (84 mg, 0.37 mmol) and TEA (0.128 mL, 0.92 mmol) in DMF(dry) (1 mL) was added HATU (139 mg, 0.37 mmol) . The mixture was stirred at room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The
organic layer was separated, washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 10% MeOH in EtOAc) to give the title compound (50.2 mg, 0.106 mmol, 34.7%) as colorless foam.
1H NMR (300 MHz, CDC13) 5:1.29-1.44 (2H, m) , 1.66-1.91 (3H, m) , 2.58-2.71 (2H, m) , 2.76 (3H, s) , 3.33 (2H, t, J = 6.2 Hz), 3.47-3.54 (2H, m) , 3.80 (2H, d, J = 12.1 Hz), 3.87 (3H, s), 4.23-4.30 (2H, n) , 4.51 (2H, s) , 6.05 (1H, s) , 6.58 (1H,. d, J = 8.7 Hz), 6.87-6.95 (2H, m) , 7.10 (1H, d, J = 5.7 Hz), 7.17-7.25 (3H, m) .
[0583]
Example 6
4- (2- (methoxymethyl) benzyl) -N- ( (1- (methylsulfonyl ) piperidin-4- yl) methyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7-.carboxamide
A) ethyl 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate
To a solution of ethyl 3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylate (0.600 g, 2.90 mmol) in DMF(dry) (12 mL) were added NaH (60% in oil, 0.174 g, 4.34 mmol) and stirred at room
temperature for 10 min. To the mixture was added 1- ( chloromethyl ) -2- (methoxymethyl ) benzene (0.593 g, 3.47 mmol). The mixture was stirred at room temperature overnight. The resulting mixture was extracted with AcOEt and H20. The
organic extract was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound (1.050 g, 3.08 mmol, 106%) as a light brown oil. This product was subjected to the next reaction without further purification.
[0584]
B) 4- (2- (methoxymethyl) benzyl ) -3, 4-dihydro-2H-l , 4-benzoxazine- 7-carboxylic acid
An 8N NaOH aq. (4 mL, 32.00 mmol) was added to a solution of ethyl 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate (1.05 g, 3.08 mmol) in THF (10 mL) and EtOH (10 mL) at room temperature. The mixture was stirred at 70°C under N2 for 1 h. The mixture was neutralized with 6N HCl at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The resultant solid was suspended in 33% EtOAc in hexane and collected by filtration to give the title compound (0.720 g, 2.298 mmol, 74.7%) as light brown solids.
[0585]
C) 4- (2- (methoxymethyl) benzyl) -N- ( ( 1- (methylsulfonyl ) piperidin- 4-yl) methyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7-carboxamide
To a mixture of 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro- 2H-1, 4-benzoxazine-7-carboxylic acid (150 mg, 0.48 mmol), (1- (methylsulfonyl) piperidin-4-yl) methanamine hydrochloride (130 mg, 0.57 mmol), HATU (221 mg, 0.58 mmol) and DMF (5 mL) was added DIPEA (0.25 mL, 1.43 mmol). After being stirred at room temperature overnight, the reaction mixture was guenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SCO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and crystallized from IPE-hexane to give the title compound (125 mg, 0.256 mmol, 53.6%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:2.58-2.70 (2H, m) , 2.82 (3H, s) , 3.11 (2H, t, J = 6.0 Hz), 3.30-3.35 (8H, m) , 3.42 (2H, t, J = 4.2 Hz), 3.49-3.58 (2H, m) , 4.24 (2H, t, J = 4.3 Hz), 4.51 (2H, s), 4.59 (2H, s), 6.51 (1H, d, J = 8.7 Hz), 7.11-7.16 (1H, m) , 7.21-7.30 (4H, m) , 7.35-7.41 (1H, m) , 8.07-8.16 (1H, m) .
[0586]
Example 7
N- (2-hydroxy-l- (1- (methylsulfonyl) piperidin-4-yl ) ethyl) -4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxamide
A) tert-butyl 4- (2-methoxy-l- (( (4- (2- (methoxymethyl) benzyl) - 3, 4-dihydro-2H-l , 4-benzoxazin-7-yl) carbonyl) amino) -2- oxoethyl) piperidine-l-carboxylate
To a mixture of DIPEA (217 μΐ, 1.24 mmol), 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylic acid (130 mg, 0.41 mmol) , tert-butyl 4- ( l-amino-2- methoxy-2-oxoethyl ) piperidine-l-carboxylate (169 mg, 0.62 mmol) in DMF(dry) (4149 μΐ) was added HATU (237 mg, 0.62 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo . The residue was used for next reaction without further purification.
MS (ESI+), found 568.3 (M+H)
[0587]
B) methyl ( ( (4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazin-7-yl) carbonyl) amino) (piperidin-4-yl ) acetate
hydrochloride
A mixture of tert-butyl 4- (2-methoxy-l- ( ( (4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4-benzoxazin-7- yl) carbonyl) amino) -2-oxoethyl) piperidine-l-carboxylate (233 mg, 0.41 mmol) and 4M HC1 in AcOEt (10 mL, 40.00 mmol) was stirred at room temperature under N2 overnight. The resultant
suspension was concentrated in vacuo. The solid was used for next reaction without further purification.
MS (ESI+), found 468.3 (M-HC1+H)
[0588]
C) methyl (( (4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazin-7-yl) carbonyl) amino) (1- (methylsulfonyl ) piperidin-4- yl) acetate
MsCl (63.9 μΐ, 0.82 mmol) and TEA (571 μΐ, 4.10 mmol) were added to a solution of methyl (((4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l , 4-benzoxazin-7- yl) carbonyl) amino) (piperidin-4-yl) acetate hydrochloride (207 mg, 0.41 mmol) in THF (4100 μΐ) at room temperature. The mixture was stirred at room temperature under N2 for 2 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 50% EtOAc in hexane) to give the title compound (50 mg, 0.092 mmol, 22.35%) as white solids.
MS (ESI+), found 546.2 (M+H)
1H NMR (300 MHz, CDC13) 5:1.36-1.66 (2H, m) , 1.69-1.89 (2H, m) , 1.93-2.11 (2H, m) , 2.56-2.71 (2H, m) , 2.72-2.77 (3H, m) , 3.41 (3H, s), 3.42-3.49 (2H, m) , 3.73-3.87 (5H, m) , 4.22-4.33 (2H, m) , 4.51 (2H, s) , 4.57-4.65 (2H, m) , 4.79-4.90 (1H, m) , 6.49- 6.61 (1H, m) , 6.61-6.75 (1Ή, m) , 7.22 (1H, s) , 7.26-7.32 (3H, m) , 7.32-7.43 (1H, m) .
[0589]
D) N- (2-hydroxy-l- (1- (methylsulfonyl ) piperidin-4-yl ) ethyl) -4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxamide
LiBH4 (3.83 mg, 0.18 mmol) was added to a solution of methyl (( (4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazin-7-yl ) carbonyl) amino) (1- (methylsulfonyl ) piperidin-4- yDacetate (48 mg, 0.09 mmol) in THF (1759 μΐ) at 0°C. The mixture was stirred at 50 °C under N2 for 1 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The solid was
crystallized from EtOAc-hexane to give the title compound (30 mg, 0.058 mmol, 65.9%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:1.19-1.33 (2H, m) , 1.63-1.85 (3H, m) , 2.52-2.68 (2H, m) , 2.82 (3H, s) , 3.33 (3H, s), 3.38-3.62 (6H, m) , 3.79-3.90 (1H, m) , 4-.-20-4.30 (2H, m) , 4.51 (2H, s) , 4.60 (3H, s), 6.48-6.56 (1H, m) , 7.06-7.18 (1H, m) , 7.28 (4H, d, J = 12.1 Hz), 7.34-7.44 (1H, m) , 7.57-7.69 (1H, m) .
[0590]
Example 8
4- (2- (difluoromethoxy) benzyl) -N- ( (1- (methylsulfonyl ). piperidin- 4-yl) methyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxamide
A) ethyl 4- (2- (difluoromethoxy) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate
NaH (60% in oil, 57.9 mg, 1.45 mmol) was added to a solution of ethyl 3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylate (150 mg, 0.72 mmol) in DMF(dry) (3 mL) at 0°C. After stirring at room temperature for 10 min, 1- (bromomethyl ) -2- (difluoromethoxy) benzene (0.166 mL, 1.09 mmol) was added to the mixture . at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, . washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 30% EtOAc in hexane) to give the title
compound (263 mg, 0.724 mmol, 100 %) as a pale yellow oil.
MS (ESI+), found 364.2 (M+H)
[0591]
B) 4- (2- (difluoromethoxy) benzyl) -N- ( il(methylsulfonyl) piperidin-4-yl) methyl) -3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxamide
To a solution of ethyl 4- (2- (difluoromethoxy) benzyl) -3, 4- dihydro-2H-l , 4-benzoxazine-7-carboxylate (263 mg, 0.72 mmol) in THF (1 mL) and MeOH (1 mL) was added 8N NaOH aq. (2 mL, 16.00 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was stirred at 70°C for 2 h. The mixture was neutralized with 2N HC1 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. To a mixture of the residue and (1- (methylsulfonyl) piperidin-4- yl ) methanamine hydrochloride (199 mg, 0.87 mmol) in DMF (3 mL) were added HATU (413 mg, 1.09 mmol) and DIPEA (0.378 mL, 2.17 mmol) at 0°C. The mixture was stirred at room temperature overnight. The mixture was quenched with water at room
temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) . The residue was crystallized from EtOAc-hexane to give the title compound (205 mg, 0.402 mmol, 55.6%) as off- white solids.
1H NMR (300 MHz , DMSO-d6) 5:1.07-1.27 (2H, m) , 1.53-1.80 (3H, m) , 2.58-2.70 (2H, m) , 2.82 (3H, s) , 3.11 (2H, t, J = 6.2 Hz), 3.44-3.60 (4H, m) , 4.24 (2H, t, J = 4.3 Hz), 4.57 (2H, s) , 6.50-6.58 (1H, m) , 7.16-7.30 (6H, m) , 7.31-7.40 (1H, m) , 8.13 (1H, t, J = 5.7 Hz) .
[0592] - Example 9
N- ( (1- (methylsulfonyl ) piperidin-4-yl ) methyl) -4- (2- (trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxamide
A) ethyl 4- (2- (trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate
NaH (60% in oil, 34.7 mg, 1.45 mmol) was added to a solution of ethyl 3 , 4-dihydro—2H-1 , 4-benzoxazine-7-carboxylate (150 mg, 0.72 mmol) in DMF(dry) (3mL) at 0°C. After stirring at room temperature for 10 min, 1- (bromomethyl ) -2- (trifluoromethoxy) benzene (369 -mg, 1.45 mmol) was .added to the mixture at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and
concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 25% EtOAc in hexane) to give the title compound (250 mg, 0.656 mmol, 91%) as a colorless oil.
MS (ESI+), found 382.2 (M+H)
1H NMR (300 MHz, CDC13) 5:1.31-1.37 (3H, m) , 3.47-3.54 (2H, m) , 4.25-4.33 (4H, m) , 4.61 (2H, s) , 6.48-6.53 (1H, m), 7.20-7.36 (4H, m) , 7.50 (2H, dq, J = 4.4, 2.2 Hz).
[0593]
B) 4- (2- (trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxylic acid
2N aq.NaOH (3 mL, 6.00 mmol) was added to a solution of ethyl 4- (2- (trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate (250 mg, 0.66 mmol) in MeOH (8 mL) at room temperature. The mixture was stirred at 40 °C overnight. The mixture was neutralized with IN HC1 aq. at 0°C and diluted with water. The precipitate was collected by filtration, washed with water, dried in vacuo to give the title compound (210 mg, 0.594 mmol, 91%) as white powder.
MS (ESI+), found 354.2 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:3.51 (2H, t, J = 4.3 Hz), 4.25 (2H, t, J = 4.3 Hz), 4.65 (2H, s), 6.53 (1H, d, J = 8.3 Hz), 7.23 (1H, d, J = 1.9 Hz), 7.29-7.45 (5H, m) , 12.20 (1H, brs).
[0594]
C) N- ( (1- (methylsulfonyl) piperidin-4-yl) methyl) -4- (2-
(trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxamide
HATU (121 mg, 0.32 mmol) was added to a solution of 4- (2-
(trifluoromethoxy) benzyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxylic acid (80 mg, 0.23 mmol), (1-
(methylsulfonyl) piperidin-4-yl)methanamine hydrochloride (51.8 mg, 0.23 mmol) and DIPEA (0.158 mL, 0.91 mmol) in DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give a colorless oil. The oil was crystallized from EtOH-water to give the title compound (84 mg, 0.159 mmol, 70.3%) as white powder.
1H NMR (300 MHz, DMSO-d6) 5:1.08-1.24 (2H, m) , 1.50-1.75 (3H, m) , 2.59-2.73 (2H, m) , 2.82 (3H, s) , 3.11 (2H, t, J = 6.2 Hz), 3.45-3.57 (4H, m) , 4.24 (2H, t, J = 4.3 Hz), 4.62 (2H, s) , 6.51 (1H, d, J = 9.1 Hz), 7.24-7.44 (6H, m) , 8.13 (1H, t, J = 5.7 Hz) .
[0595]
Example 12
4- (2- (methoxymethyl) benzyl) -N- ( 4-sulfamoylbenzyl ) -3, 4-dihydro- 2H-1 , 4-benzoxazine-7-carboxamide
HATU (136 mg, 0.36 mmol) was added to a mixture of 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylic acid (80 mg, 0.26 mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (68.2 mg, 0.31 mmol) and DIPEA (145 mg, 1.12 mmol) in DMF(dry) (1 mL) at room temperature.. The mixture was, stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with60%-100%EtOAc in hexane) to give a colorless oil. The oil was crystallized from EtOAc-IPE to give the title compound (87 mg, 0.181 mmol, 70.8%) as white powder.
1H NMR (300 MHz, DMSO-d6) 5:3.33 (3H, s) , 3.44 (2H, t, J = 4.3 Hz), 4.25· (2H, t, J = 4.3 Hz), 4.43-4.55 (4H, m) , 4.61 (2H, s) , 6.53 (1H, d, J = 7.9 Hz), 7.13 (1H, dd, J = 4.5 Hz), 7.22-7.45 (9H, m) , 7.75 (2H, d, J = 7.6 Hz), 8.73 (1H, t, J = 6.0 Hz).
[0596]
Example 13
4- (2- (methoxymethyl) benzyl) -N- ( 4-sulfamoylbenzyl ) -3, 4-dihydro-
2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide
A) 7-bromo-3, 4-dihydro-2H-pyrido [3, 2-b] [l,4]oxazine
To a solution of 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine (500 mg, 3.67 mmol) in DMF (10 mL) was added NBS (719 mg, 4.04 mmol) at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was quenched with sat. NaHCO3 aq. ' and water at 0°C and stirred at 0°C for 20 min. The precipitate was collected by filtration. The solid was washed with water and dried in vacuo to give the title compound (549 mg, 2.55 mmol, 69.5%) as brown solids. . .
MS (ESI+), found 215.2 (M+H)
1H NMR (300 MHz, CDC13) 5:3.50-3.58 (2H, m) , 4.18-4.26 (2H, m) , 4.82 (1H, brs), 7.10 (1H, d, J = 1.9 Hz), 7.72 (1H, d, J = 2.3 Hz) . [0597]
B) 7-bromo-4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [l,4]oxazine
To a solution of 7-bromo-3, 4-dihydro-2H-pyrido [3, 2- b] [l,4]oxazine (549 mg, 2.55 mmol) in DMF(dry) (10 rtiL) was added 60% NaH in oil (123 mg, 3.06 mmol) at 0°C. The mixture was stirred at 0°C under N2 for 10 min. 1- ( chloromethyl ) -2- . . (methoxymethyl ) benzene (523 mg, 3.06 mmol) was added to the mixture at 0°C. The mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title
compound (660 mg, 1.890 mmol, 74.0%) as white solids.
MS (ESI+), found 349.1 (M+H)
1H NMR (300 MHz, CDC13) 5:3.28-3.33 (2H, m), 3.35 (3H, s) ,
4.11-4.20 (2H, m) , 4.48 (2H, s) , 4.89 (2H,- s), 7.08 (1H, d, J = 2.3 Hz), 7.18-7.31 (3H, m) , 7.33-7.41 (1H, m) , 7.79 (1H, d, J = 1.9 Hz) .
[0598]
C) methyl 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [ 3 , 2-b] [1, 4] oxazine-7-carboxylate
To a solution of 7-bromo-4- (2- (methoxymethyl) benzyl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine (510 mg, 1.46 mmol), TEA (0.407 mL, 2.92 mmol) in DMF(dry) (23.233 mL) and MeOH (4.65 mL) was added PdCl2(dppf) (107 mg, 0.15 mmol) at room
temperature. The mixture was stirred at 100 °C under CO (0.5 Mpa) for 5 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was. separated, washed with water and brine, dried over MgS04 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 20% EtOAc in hexane) to give the title compound (210 mg, 0.640 mmol, 43.8%). MS (ESI+) , found 329.1 (M+H) 1H NMR (300 MHz, CDC13) 5:3.33 (3H, s) , 3.37-3.44 (2H, m) 3.86 (3H, s), 4.11-4.18 (2H, m) , 4.47 (2H, s), 5.00-5.08 (2H, m) ,
7.18-7.25 (1H, m) , 7.26-7.31 (2H, m) , 7.35-7.40 (1H, m) , 7.50 (1H, d, J = 1.9 Hz), 8.40-8.53 (1H, m) .
[0599]
D) 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine--7-carboxylic acid
An 8N NaOH aq. (0.4 mL, 3.20 mmol) was added to a
solution of methyl 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazine-7-carboxylate (200 mg, 0.61 mmol) in EtOH (2 mL) and THF (2 mL) at room temperature. The mixture was stirred at room temperature under N2 for 2 h. Then, it was warmed up to 50 °C and stirred at 60 °C under N2 for 1 h. The mixture was neutralized with IN HC1 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (140 mg, 0.445 mmol, 73.1%) as white solids.
MS (ESI+), found 315.1 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:3.28 (3H, s) , 3.41-3.49 (3H, m) ,
4.17-4.25 (2H, m) , 4.43-4.56 (2H, m) , 4.88-5.04 (2H, m) , 7.12- 7.18 (1H, m) , 7.23-7.30 (2H, m) , 7.30-7.33 (1H, m) , 7.34-7.39 (1H, m) , 8.22-8.27 (1H, m) .
[0600]
E) 4- (2- (methoxymethyl) benzyl) -N- ( 4-sulfamoylbenzyl ) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4 ] oxazine-7-carboxamide
4- (Aminomethyl ) benzenesulfonamide hydrochloride (26.6 mg, 0.12 mmol), DIPEA (0.042 mL, 0.2.4 mmol) and HATU (45.4 mg, 0.12 mmol) were added to a solution of 4- (2- (methoxymethyl) benzyl) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (25 mg, 0.08 mmol) in DMF(dry) (2 mL) at room temperature. The mixture was stirred at room temperature under N2 for 2 h. The mixture was quenched with water at room temperature and
extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (21 mg, 0.044 mmol, 54.7%) as white solids. 1H NMR (300 MHz, DMSO-d6) 5:3.29 (3H, s) , 3.39-3.50 (2H, m) , 4.15-4.26 (2H, m) , 4.45-4.53 (4H, m) , 4.92 (2H, s), 7.12-7.18
(1H, m) , 7.23-7.32 (4H, m) , 7.34-7.40 (1H, m) , 7.43-7.50 (3H, m). , 7.77 (2H, d, J = 8,5 Hz), 8.25 (1H, d, J = 1.9 Hz), 8.85
(1H, s) .
[0601]
Example 14
N- ( (5- (ethylsulfonyl) pyridin-2-yl ) methyl ) -4- (2-
(methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide hydrochloride
A) 5- (ethylsulfonyl) pyridine-2-carbonitrile
A mixture of 5-bromopicolinonitrile (14.7 g, 80.33 mmol), sodium ethanesulfinate (13.3 g, 114.54 mmol) and DMSO (100 rtiL) was stirred at 100 °C under nitrogen atmosphere for 20 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 30% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (7.74 g, 39.4 mmol, 49.1%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:1.14 (3H, t, J = 7.4 Hz), 3.51 (2H, q, J = 7.2 Hz), 8.36 (1H, dd, J = 8.3, 0.8 Hz), 8.56 (1H, dd, J = 8.1, 2.5 Hz), 9.20 (1H, dd, J = 2.3, 0.8 Hz).
[0602]
B) 1- (5- (ethylsulfonyl) pyridin-2-yl ) methanamine hydrochloride
A mixture of 5- (ethylsulfonyl ) pyridine-2-carbonitrile (8.86 g, 45.15 mmol), 6N HC1 aq. (15 mL, 90.00 mmol), 10% Pd on carbon (50% wet, 2.39 g, 2.25 mmol) and MeOH (150 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room
temperature for 2 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The - - solid was suspended in EtOH, collected by filtration and dried in vacuo to give the title compound (9.65 g, 40.8 mmol, 90%) as white solids.
MS (ESI+), found 201.3 (M-HC1+H)
1H NMR (300 MHz, DMSO-d6) 5:1.13 (3H, t, J = 7.4 Hz), 3.46 (2H, q, J = 7.6 Hz), 4.35 (2H, brs), 7.80 (1H, d, J = 8.3 Hz), 8.38 (1H, dd, J = 8.3, 2.3 Hz), 8.57 (3H, brs), 9.05 (1H, d, J = 1.9 Hz) . - . .
[0603]
C) N- ( (5- (ethylsulfonyl) pyridin-2-yl)methyl) -4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxamide hydrochloride
To a solution of 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine-7-earboxylic acid (50 mg, 0.16 mmol) , 1- (5- (ethylsulfonyl) pyridin-2-yl ) methanamine
hydrochloride (37.7 mg, 0.16 mmol)- in DMF (2 mL) were added HATU (72.6 mg, 0.19 mmol) and DIPEA (0.083 mL, 0.48 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water at room
temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 100% EtOAc in hexane) . 4M HC1 in EtOAc (0.1 mL, 0.40 mmol) was added to the residue in MeOH (4.000 mL) at 0°C. Et20 (abt. 10 mL) was added dropwise to the mixture and the precipitate was collected by filtration. The solid was washed with Et20 and dried in vacuo to give the title compound (35.0 mg, 0.066 mmol, 41.3%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:1.05-1.18 (3H, m) , 3.29 (3H, s) , 3.32-3.53 (4H, m) , 4.23 (2H, t, J = 4.3 Hz), 4.49 (2H, s) , 4.58-5.15 (5H, m) , 7.11-7.21 (1H, m) , 7.24-7.32 (2H, m) , 7.34- 7.42 (1H, m) , 7.49-7.61 (2H, m) , 8.20-8.31 (2H, m) , 8.95 (1H, d, J = 1.9 Hz), 9.08 (1H, t, J = 5.9 Hz).
[0604]
Example 15
4- (2- (methoxymethyl) benzyl) -N- (4- (methylsulfamoyl) benzyl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide
A) 4- (benzylsulfanyl) benzonitrile
Pd2(dba)3 (0.302 g, 0.33 mraol) was added to a mixture of 4-bromobenzonitrile (3 g, .16.48 mmol) , phenylmethanethiol (2.252 g, 18.13 mmol), XANTPHOS (0.381 g, 0.66 mmol) and DIPEA (5.76 mL, 32.96 mmol) in toluene (30 mL) at room temperature. The mixture was stirred at 1.00 °C under Ar overnight. After cooling, the mixture was passed through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 25% EtOAc in hexane) to give yellow solids. The solid was washed with hexane-IPE and dried in vacuo to give the title compound (3.18 g, 14.11 mmol, 86%) as pale yellow solids.
MS (ESI-), found 224.0 (M-H)
λη NMR (300 MHz, CDC13) 5:4.20 (2H, s) , 7.25-7.38 (7H, m) , 7.50 (2H, d, J = 7.6 Hz) .
[0605]
B) 4-cyanobenzenesulfonyl chloride
NCS (1.778 g, 13.32 mmol) was added to a suspension of 4- (benzylsulfanyl) benzonitrile (1 g, 4.44 mmol) in AcOH (10 mL) - water (3.5 mL) at 0°C. The mixture was stirred at room
temperature for 2 h. The mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15% - 20% EtOAc in hexane) to give white solids. The solids were washed with hexane and dried in vacuo to give the title compound (0.701 g, 3.48 mmol, 78%) as white solids.
1H NMR (300 MHz, CDC13) 5:7.91-7.97 (2H, m) , 8.15-8.21 (2H, m) .
[0606]
C) 4-cyano-N-methylbenzenesulfonamide
A methylamine-methanol solution (1348 mg, 17.36 mmol) was added to a solution of 4-cyanobenzenesulfonyl chloride (700 mg, 3.47 mmol) in THF (30 mL) at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and neutralized with IN HC1 aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSCO4 and concentrated in vacuo to give the title compound (660 mg, 3.36 mmol, 97%) as off-white solids.
MS (ESI-), found 195.0 (M-H)
λΗ NMR (300 MHz, CDC13) 5:2.72 (3H, d, J = 5.3 Hz), 4.47 (1H, d,J = 4.5 Hz), 7.81-7.86 (2H, m) , .7.95-8.01 (2H, m) .
[0607]
D) 4- (aminomethyl) -N-methylbenzenesulfonamide
CoCl2 (265 mg, 2.04 mmol) was added to a solution of 4- cyano-N-methylbenzenesulfonamide (200 mg, 1.02 mmol) in MeOH (10 mL) at 0°C. After stirring at 0°C for 5 min, NaBH4 (386 mg, 10.19 mmol) was added to the mixture and stirred at room
temperature overnight. The mixture was quenched with 2N HC1 aq. at room temperature and stirred for 10 min. The mixture was neutralized with 25% aq. ammonia and concentrated in vacuo.
The residue was extracted with EtOAc twice. The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 20% MeOH in EtOAc) to give the title compound (115 mg, 0.574 mmol, 56.3%) as white amorphous solids.
MS (ESI+), found 201.3 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:1.89 (2H, brs), 2.39 (3H, s) , 3.79 (2H, s), 7.00-7.56 (3H, m) , 7.67-7.73 (2H, m) .
[0608]
E) 4- (2- (methoxymethyl ) benzyl) -N- (4- (methylsulfamoyl) benzyl) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide
HATU (50.8 mg, 0.13 mmol) was added to a mixture of 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxylic acid (30 mg, 0.10 mmol), 4-
(aminomethyl ) -N-methylbenzenesulfonamide (22.93 mg, 0.11 mmol) and DIPEA (54.3 mg, 0.42 mmol) in DMF(dry) (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 60% -90% EtOAc in hexane) to give a colorless oil. The oil was crystallized from EtOAc-IPE to give the title
compound (41.0 mg, 0.083 mmol, 87%) as white powder.
1H NMR (300 MHz, DMSO-d6) 5:2.39 (3H, d, J = 5.3 Hz), 3.29 (3H, s), 3.44 (2H, brs), 4.20 (2H, brs), 4.45-4.5.5 (4H, m) , 4.92 (2H, . s), 7.11-7.19 (1H, m) , 7.26 (2H, dd, J = 5.3, 3-8 Hz), 7.34- 7.53 (5H, m) , 7.73 (2H, d, J = 8.3 Hz), 8.26 (1H, d, J = 1.9 Hz), 8.86 (1H, t, J = 5.9 Hz).
[0609]
Example 16
N- ( 3-fluoro-4-sulfamoylbenzyl ) -4- (2- (methoxymethyl ) benzyl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide
A) 4- (benzylsulfanyl) -3-fluorobenzonitrile
Pd2(dba)3 (0.275 g, 0.30 mmol) was added to a mixture of 4-bromo-3-fluorobenzonitrile (3 g, 15.00 mmol),
phenylmethanethiol (2.049 g, 16.50 mmol), XANTPHOS (0.347 g, 0.60 mmol) and DIPEA (5.24 mL, 30.00 mmol) in toluene (30 mL) at room temperature. The mixture was stirred at 100 °C under Ar overnight. After cooling, the mixture was passed through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 25% EtOAc in hexane) to give the title compound (3.82 g, 15.70 mmol, 105%) as yellow solids.
1H NMR (300 MHz, CDC13) 5:4.20 (2H, s) , 7.27-7.36 (8H, m) .
[0610]
B) 4-cyano-2-fluorobenzenesulfonyl chloride
NCS (3.29 g, 24.66 mmol) was added to a suspension of 4- (benzylsulfanyl) -3-fluorobenzonitrile (2 g, 8.22 mmol) in AcOH (20 mL) - water (7 mL) at 0°C. The mixture -was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 30% EtOAc in hexane) to give the title compound (1.720 g, 7.83 mmol, 95%) as a colorless oil.
1H NMR (300 MHz, CDC13) 5:7.64-7.74 (2H, m) , 8.13 (1H, dd, J = 8.1, 7.0 Hz) .
[0611]
C) 4-cyano-2-fluorobenzenesulfonamide
An ammonia solution in MeOH (2.76 mL, 19.35 mmol) was added to a solution of 4-cyano-2-fluorobenzenesulfonyl chloride (850 mg, 3.87 mmol) in THF (30 mL) at-0°C. The mixture was stirred at room temperature for 2 ti. The mixture was diluted with water, neutralized with IN HC1 aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (700 mg, 3.50 mmol, 90%) as pale yellow solids.
MS (ESI-), found 199.0 (M-H)
1H NMR (300 MHz, DMSO-d6) 5:7.86-8.01 (4H, m) , 8.12 (1H, dd, J = 10.0, 1.3 Hz) .
[0612]
D) 4- (aminomethyl) -2-fluorobenzenesulfonamide hydrochloride
A mixture of 4-cyano-2-fluorobenzenesulfonamide (200 mg, 1.00 mmol), 10% Pd-C (50% wet, 100 mg, 0.94 mmol) in MeOH (8 mL) and cone. HC1 (80 μΐ, 0.96 mmol) was hydrogenated under balloon pressure at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give the title compound (230 mg, 0.956 mmol, 96%) as off-white solid as crude product.
1H NMR (300 MHz, DMSO-d6) 5:4.11 (2H, d, J = 4.9 Hz), 7.46 (1H, dd, J = 8.3, 1.5 Hz), 7.59-7.62 (1H, m) , 7.70-7.85 (3H, m) , 8.58 (3H, brs) .
[0613]
E) N- (3-fluoro-4-sulfamoylbenzyl) -4- (2- (methoxymethyl ) benzyl) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4 ] oxazine-7-carboxamide
HATU (50.8 mg, 0.13 mmol) was added to a mixture of 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3, 2- b] [1, 4] oxazine-7-carboxylic acid (30 mg, 0.10 mmol), crude 4- (aminomethyl) -2-fluorobenzenesulfonamide hydrochloride (25.3 mg, 0.10 initial) .and DIPEA (54.3 mg, 0.42 mmol) in DMF(dry) (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSCO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 60% -100% EtOAc in hexane) to give a colorless oil. The oil was crystallized from EtOAc-IPE to give the title compound (33.0 mg, 0.066 mmol, 69.1%) as white powder.
1H NMR (300 MHz, DMSO-d6) δ:3.29 (3H, s), 3.44 (2H, t, J = 4.3 Hz), 4.21 (2H, t, J = 4.5 Hz), 4.45-4.52 (4H, m) , 4.92 (2H, s) , 7.12-7.18 (1H, m) , 7.23-7.39 (5H, m) , 7.45 (1H, d, J = 1.9 Hz), 7.60 (2H, s) , 7.74 (1H, t, J = 7.9 Hz), 8.25 (1H, d, J = 2.3 Hz) , 8.86 (1H, t, J = 5.1 Hz) .
[0614]
Example 17
N- (3-fluoro-4- (methylsulfamoyl ) benzyl) -4- (2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxamide
A) 4-cyano-2-fluoro-N-methylbenzenesulfonamide
A methylamine in MeOH (1503 mg, 19.35 mmol) was added to a solution of 4-cyano-2-fluorobenzene-l-sulfonyl chloride (850 mg, 3.87 mmol) in THF (30 mL) at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and neutralized withlN HC1 aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% -45% EtOAc in hexane) to give the title compound (550 mg, 2.57 mmol, 66.3%) as off-white solids.
MS (ESI-), found 213.0 (M-H)
1H NMR (300 MHz, DMSO-d6) 5:2.54 (3H, s), 7.88-7.97 (2H, m) , 8.05 (1H, brs), 8.15 (1H, d, J = 9.9 Hz).
[0615]
B) 4- (aminomethyl) -2-fluoro-N-methylbenzenesulfonamide CoCl2 (121 mg, 0.93 mmol) was added to a solution of 4- cyano-2-fluoro-N-methylbenzenesulfonamide (100 mg, 0.47 mmol) in MeOH (5 mL) at 0°C. After stirring at 0°C for 5 min, NaBH4 (177 mg, 4.67 mmol) was added to the mixture and stirred at room temperature overnight. The mixture was quenched with 2N HC1 aq. at room temperature and stirred for 10 min. The mixture was neutralized with 25% aq. ammonia and concentrated in vacuo. The residue was extracted with EtOAc twice. The combined organic layers were concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 15% MeOH in EtOAc) to give the title compound (73.0 mg, 0.334 mmol, 71.7%) as white amorphous solids.
MS (ESI+), found 219. 3 (M+H)
1R NMR (300 MHz, DMSO-d6) 5:1.60-2.40 (2H, br) , 2.45-2.47 (3H, s), 3.78 (2H, s), 7.29-7.35 (1H, m) , 7;38-7.43 (1H, m) , 7.68 (1H, t, J = 7.7 Hz) . (An exchangeable proton was omitted)
[0616]
C) N- (3-fluoro-4- (methylsulfamoyl ) benzyl ) -4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxamide
HATU (50.8 mg, 0.13 mmol) was added to a mixture of 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-p'yrido [3,2- b] [1, 4] oxazine-7-carboxylic acid (30 mg, 0.10 mmol), 4- (aminomethyl) -2-fluoro-N-methylbenzenesulfonamide (25.00 mg, 0.11 mmol) and DIPEA (54.3 mg, 0.42 mmol) in DMF(dry) (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 60% - 90% EtOAc in hexane) to give a colorless oil. The oil was triturated with IPE, and dried in vacuo to give the title compound (19.00 mg, 0.037 mmol, 38.7%) as off-white solids .
1H NMR (300 MHz, DMS0-d6) 5:2.48 (3H, s) , 3.29 (3H, s), 3.45 (2H, brs), 4.21 (2H, brs) , 4.45-4.54 (4H, m) , 4.92 (2H, s) , 7.16 (1H, d, J = 4.4 Hz), 7.24-7.39 (5H, m) , 7.45 (1H, d, J = 1.9 Hz), 7.63-7.76 (2H, m) , 8.26 (1H, d, J = 1.9 Hz), 8.87 (1H, s) .
[0617]
Example 18
4- ( 5-fluoro-2- (methoxymethyl ) benzyl ) -N- ( 4-sulfamoylbenzyl ) -3 , 4- dihydro-2H-pyrido [ 3 , 2-b] [1,4] oxazine-7-carboxamide
A) tert-butyl 7-bromo-2 , 3-dihydro-4H-pyrido [3, 2--b] [ 1 , 4 ] oxazine- 4-carboxylate
To a solution of 7-bromo^3, 4-dihydro-2H-pyrido [3, 2- b] [1, 4] oxazine (1.93 g, 8.97 mmol) in THF(dry) (40 mL) was added LiHMDS (8.28 mL, 10.77 mmol) at 0°C. Boc20 (2.500 mL, 10.77 mmol) was added to the mixture at 0°C. The mixture was stirred at room temperature under N2 for 2 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title compound (2.60 g, 8.25 mmol, 92%) as a pale yellow oil.
MS (ESI+), found 258.9 (M-tBu+2H)
[0618]
B) methyl 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4 ] oxazine-7- carboxylate
To a solution of tert-butyl 7-bromo-2 , 3-dihydro-4H- pyrido [3, 2-b] [1, 4] oxazine-4-carboxylate (2.6 g, 8.25 mmol), TEA (2.300 mL, 16.50 mmol) in DMF (25 mL) /MeOH (5 mL) was added PdCl2(dppf) (0.302 g, 0.41 mmol) at room temperature. The mixture was stirred at 100°C under CO (0.7 MPa) for 5 h. The mixture was quenched with water at- room temperature and
extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 30% EtOAc in hexane) to give 4-tert-butyl 7- methyl 2H-pyrido [3, 2-b] [ 1 , 4 ] oxazine-4 , 7 ( 3H) -dicarboxylate
(0.370 g, 1.257 mmol, 15.24%) as light brown solids and the title compound (1.100 g, 5.66 mmol, 68.7%) as light brown solids.
MS (ESI+), found 195.1 (M+H)
1R NMR (300 MHz, CDC13) 5:3.62 (2H, td, J = 4.5, 2.3 Hz), 3.86 (3H, s), 4.15-4.28 (2H, m) , 5.47 (1H, brs) , 7.52 (1H, d, J = 1.5 Hz), 8.37 (1H, d, J = 1.9 Hz).
[0619]
C) (2-bromo-4-fluorophenyl) methanol
To a solution of 2-bromo-4-fluorobenzoic acid (3 g, 13.70 mmol) in THF(dry) (60 mL) was added 1M Borane-tetrahydrofuran complex in THF (19.18 mL, 19.18 mmol) at 0°C. The mixture was stirred at room temperature under N2 for 2 h. The mixture was neutralized with IN HCl at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound as a colorless oil.
[0620]
D) 2-bromo-4-fluoro-1- (methoxymethyl ) benzene
To a mixture of (2-bromo-4-fluorophenyl) methanol (1.80 g, 8.78 mmol) and DMF (30 mL) was added NaH (60% in oil, 428 mg, 10.70 mmol) at room temperature. After being stirred at room temperature for 5 min, Mel (0.82 mL, 13.11 mmol) was added to the mixture. After being stirred at room temperature overnight, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 1% - 10% EtOAc in hexane) to give the title compound (1.620 g, 7.40 mmol, 84%) as a colorless oil.
1H NMR (300 MHz, CDC13) 5:3.46 (3H, s) , 4.48 (2H, s) , 7.04 (1H, td, J = 8.3, 2.6 Hz), 7.30 (1H, dd, J = 8.3, 2.6 Hz), 7.43 (1H, dd, J = 8.5, 6.2 Hz) . [0621]
E) 5-fluoro-2- (methoxymethyl) benzaldehyde
To a mixture of 2-bromo-4-fluoro-1- (methoxymethyl ) benzene (1.62 g, 7.40 mmol) and THF (30 mL) was added 1.6 M n-BuLi in hexane (5.6 mL, 8.96 mmol) at -78°C. After being stirred at - 78°C for 1 h, DMF (1.0 mL, 12.91 mmol) was added to the mixture. After being stirred at -78 °C for 2 h, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column .chromatography (silica gel, eluted with 1%- 10% EtOAc in hexane) to give the title compound (1.000 g, 5.95 mmol, 80%) as a colorless oil.
1H NMR (300 MHz, CDC13) δ:3.46 (3H, s),.4.80 (2H, s) , 7.26-7.33 (1H, m) , 7.53-7.62 (2H, m) , 10.21 (1H, d, J = 1.5 Hz).
[0622]
F) ( 5-fluoro-2- (methoxymethyl ) phenyl ) methanol
To a mixture of 5-fluoro-2- (-methoxymethyl ) benzaldehyde (1.00 g, 5.95 mmol) and MeOH (10 mL) was added NaBH4 (408 mg, 10.78 mmol) at 0°C. After being stirred at room temperature for 1 h, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was subjected to the next reaction without further purification.
[0623]
G) 2- (chloromethyl) -4-fluoro-1- (methoxymethyl) benzene
To a mixture of (5-fluoro-2- (methoxymethyl ) phenyl ) methanol (1.01 g, 5.93 mmol) and THF (10 mL) was added S0C12 (2.0 mL, 27.40 mmol) at 0°C. After being stirred at 50 °C for 2 h, the mixture was concentrated in vacuo to give the title compound (1.280 g, 6.79 mmol, 114%) as an orange oil.
1H NMR (300 MHz, CDC13) 5:3.35-3.42 (3H, m) , 4.42-4.70 (4H, m) , 6.90-7.05 (1H, m) , 7.11-7.18 (1H, m) , 7.28-7.36 (1H, m) .
[0624]
H) 4- (5-fluoro-2- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [ 1, 4 ] oxazin.e-7-carboxylic acid
To a mixture of 2- (chloromethyl) -4-fluoro-1- (methoxymethyl) benzene (107 mg, 0.57 mmol) and DMF (3 mL) was added NaH (60% in oil, 17 mg, 0.43 mmol) . After being stirred at room temperature for 5 min, 2- (chloromethyl) -4-fluoro-1- (methoxymethyl) benzene (107 mg, 0.57 mmol) was added to the mixture. After being stirred at room temperature for 2 h, 2 M NaOH aq. (0.36 mL, 0.72 mmol) was added to the mixture. After being stirred at room temperature overnight, the mixture was acidified with IN HC1 aq. and extracted with EtOAc. The
organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was subjected to the next reaction without further purification.
[0625]
I ) 4- ( 5-fluoro-2- (methoxymethyl ) benzyl ) -N- ( 4-sulfamoylbenzyl ) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide
To a mixture of 4- (5-fluoro-2- (methoxymethyl) benzyl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (84 mg, 0.25 mmol), [4- (aminomethyl) benzenesulfonamide hydrochloride (70 mg, 0.31 mmol), HATU (123 mg, 0.32 mmol) and DMF (3 mL) was added DIPEA (0.13 mL, 0.74 mmol). After being stirred at room temperature overnight, the reaction mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 10.0% EtOAc in hexane) and then crystallized from EtOH-hexane to give the title compound (43.0 mg, 0.086 mmol, 34.0%) as white solids.
1H NMR (300 MHz, DMSO-d6) δ:3.28 (3H, s) , 3.49 (2H, t, J = 4.3 Hz) , 4.23 (2H, t, J = 4.3 Hz), 4.44-4.53 (4H, m) , 4.90 (2H, s) , 6.93 (1H, dd, J = 10.2, 3.0 Hz), 7.07 (lH, td, J = 8.5, 2.6 Hz), 7.29 (2H, s), 7.37-7.50 (4H, m) , 7.76 (2H, d, J = 8.3 Hz), 8.24 (1H, d, J = 2.3 Hz), 8.86 (1H, t, J = 6.0 Hz).
[0626]
Example 19 4- ( ( 5-fluoro-3- (methoxymethyl ) p.yridin-2-yl ) methyl) -N- (4- sulfamoylbenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7^ carboxamide
A) 2-chloro-5-fluoronicotinic acid
A mixture of Ph3P (1.874 g, 7.14 mmol) , Pd(OAc)2 (0.802 g,
3.57 mmol) and TEA (59.7 mL, 428.59 mmol) in DMF(dry) (80 mL) was stirred at room temperature - under Ar for 20 min. To. the mixture was added formic acid (2.74 mL, 71.43 mmol), and the mixture was stirred at room temperature under Ar for 5 min. To the mixture was added 2 , 6-dichloro-5-fluoronicotinic acid (15 g, 71.43 mmol) and the mixture was stirred at 100 °C under Ar overnight. The mixture was cooled to at 0°C, added water (150 mL) , and stirred for 20 min. The mixture was filtrated through a pad of celite, that was rinsed with water. The filtrate was basified to pH 9 with 8N NaOH and washed twice with EtOAc. 35% HC1 was added slowly to pH 1 and the solution was saturated with NaCl. The mixture was extracted with EtOAc (5 times) .
The organic layer was dried over Na2SO4 and concentrated in vacuo. The residual DMF was removed by azetropic evaporation with toluene. The precipitate was collected by filtration and washed with 50% EtOAc/Hexane to. give the title compound (8.08 g, 46.0 mmol, 64.4%) as yellow powder.
MS (ESI-), found 174.2 (M-H)
1H NMR (300 MHz, DMSO-d6) 5:8.21 (1H, dd, J = 8.3, 3.0 Hz), 8.63 (1H, d, J = 3.0 Hz). (A C02H peak was omitted)
[0627]
B) (2-chloro-5-fluoropyridin-3-yl) methanol
CDI (1.293 g, 7.98 mmol) was added to a solution of 2- chloro-5-fluoronicotinic acid (1 g, 5.70 mmol) in THF (23 mL) at room temperature. After stirring at room temperature for lh, the mixture was added to a solution of NaBH4 (0.647 g, 17.09 mmol) in water (23.00 mL) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was
diluted with brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (0.620 g, 3.84 mmol, 67.4%) as white solids.
MS (ESI+) , found 162.3 (M+H)
1H NMR (300 MHz, CDC13) 5:2.08 (1H, t, J = 5.9 Hz), 4.78 (2H, d, J = 5.7 Hz), 7.67-7.73 (1H, m) , 8.18 (1H, d, J = 3.0 Hz).
[0628]
C) 2-chloro-5-fluoro-3- (methoxymethyl) pyridine
NaH (60% in oil, 230 mg, 5.76 mmol) was added to a
solution of (2-chloro-5-fluoropyridin-3-yl ) methanol (620 mg, 3.84 mmol) in THF (dry) (8 mL) at 0°C. After stirring at room temperature for lh, Mel (599 mg, 4.22 mmol) was added to the mixture at 0°C. The mixture was stirred at room temperature for 4 h. The mixture was diluted with EtOAc and 0.5N NaOH aq. at room temperature. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 1% - 10% EtOAc in hexane) to give the title
compound (530 mg, 3.02 mmol, 79%) as a colorless oil.
MS (ESI+), found 176.3 (M+H)
1H NMR (300 MHz, CDC13) 5:3.52 (3H, s), 4.50 (2H, s), 7.59-7.65 (1H, m) , 8.17 (1H, d, J = 3.0 Hz) .
[0629]
D) methyl 5-fluoro-3- (methoxymethyl ) pyridine-2-carboxylate
A mixture of 2-chloro-5-fluoro-3- (methoxymethyl ) pyridine (100 mg, 0.57 mmol), PdCl2(dppf) (83 mg, 0.11 mmol) and TEA (0.238 mL, 1.71 mmol) in MeOH (4 mL) and DMF (0.5 mL) was stirred under CO atmosphere (0.7 MPa) at 80°C for 6h. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted -with 10% - 50% EtOAc in hexane) to give the title compound (107 mg, 0.537 mmol, 94%) as white solids.
MS (ESI+), found 200.3 (M+H)
1H NMR (300 MHz, CDC13) 5:3.53 (3H, s) , 3.99 (3H, s) , 4.88 (2H, s), 7.82-7.88 (lH, m) , 8.45 (1H, d, J = 2.6. Hz).
[0630]
E) (5-fluoro-3- (methoxymethyl) pyridin-2-yl) methanol
LiBH4 (22.97 mg, 1.05 mmol) - was added to a solution of methyl 5-fluoro-3- (methoxymethyl) pyridine-2-carboxylate (105 mg, 0.53 mmol) in THF (3 mL) at room temperature. The mixture was stirred at room temperature under N2 for 2 h. The mixture was quenched with brine at 0°C and extracted twice with EtOAc. The combined organic layers were dried over Na2SCO4 and concentrated in vacuo to give the title compound (80 mg, 0.467 mmol, 89%) as a pale yellow oil. .
MS (ESI+), found 172.4 (M+H)
1H NMR (300 MHz, CDCI3) δ:3.45 (3H, s) , 4.00-4.40 (1H, br) , 4.43 (2H, s), 4.69 (2H, s) , 7.51 (1H, dd, J = 8.7, 2.6 Hz), 8.33 (1H, d, J .= 2.6 Hz) .
[0631]
F) (5-fluoro-3- (methoxymethyl) pyridin-2-yl) methyl
methanesulfonate
MsCl (0.040 mL, 0.51 mmol) was added to a solution of (5- fluoro-3- (methoxymethyl) pyridin-2-yl) methanol (80 mg, 0.47 mmol) and TEA (0.072 mL, 0.51 mmol) in THF (3 mL) at 0°C. The mixture was stirred at room temperature under dry atmosphere (with a CaCl2 tube) for 3 h. The mixture was poured into water at room temperature and extracted twice with EtOAc. The
combined organic layers were washed with brine, dried over
MgSO4 ' and concentrated in vacuo to give the title compound
(60.0 mg, 0.241 mmol, 51.5%) as a purple oil.
MS (ESI+), found 250.2 (M+H)
1H NMR (300 MHz, CDC13) 5:3.06 (3H, s) , 3.48 (3H, s) , 4.58 (2H, s), 5.36 (2H, s), 7.56 (1H, dd, J = 8.7, 2.6 Hz), 8.40 (1H, d, J = 2.6 Hz).
[0632]
G) methyl 4- ( (5-fluoro-3- (methoxymethyl) pyridin-2-yl ) methyl ) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxylate
NaH (60% in oil, 16.05 mg, 0.40 mmol) was added to a solution of methyl 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7- carboxylate (39.0 mg, 0.20 mmol) in DMF(dry) (2 mL) at 0°C.
After stirring at room temperature for 10 min, (5-fluoro-3-
(methoxymethyl) pyridin-2-yl ) methyl methanesulfonate (60 mg, 0.24 mmol) was added the mixture at room temperature. The mixture was stirred at room temperature under dry atmosphere
(with a CaCl2 tube) for 3 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 30% - 50% EtOAc in hexane) to give the title compound (55.0 mg, 0.158 mmol, 79%) as white solids.
MS (ESI+), found 348.2 (M+H) ,
1H NMR (300 MHz, CDC13) 5:3.42 (3H, s) , 3.59-3.66 (2H, m) , 3.85 (3H, s), 4.11-4.20 (2H, m) , 4.61 (2H, s) , 5.00 (2H, s) , 7.46- 7.51 (2H, m) , 8.29 (1H, d, J = 2.6 Hz), 8.41 (1H, d, J = 1.9 Hz) .
[0633]
H) 4- ( (5-fluoro-3- (methoxymethyl) pyridin-2-yl)methyl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid
A mixture of methyl 4- ( (5-fluoro-3- (methoxymethyl) pyridin-2-yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2- b] [1, 4] oxazine-7-carboxylate (55 mg, 0.15 mmol) and 2M NaOH aq. (0.761 mL, 1.52 mmol) in MeOH (3 mL) was stirred at 50°C for 2h. The mixture was slightly acidified (pH5) by IN HC1 aq. at 0°C and diluted with water. MeOH was removed by evaporation and precipitate was collected by filtration, washed with water, . dried in vacuo to give the title compound (33.0 mg, 0.099 mmol, 65.0%) as white powder.
MS (ESI+), found 334.2 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:3.36 (3H, s) , 3.62 (2H, t, J = 4.5 Hz), 4.21 (2H, t, J = 4.5 Hz), 4.60 (2H, s), 4.97 (2H, s) , 7.27 (1H, d, J = 1.9 Hz), 7.67 (1H, dd, J = 9.4, 3.0 Hz), 8.17 (1H, d, J = 1.9 Hz), 8.39 (1H, d, J = 3.0 Hz), 12.20-12.70 (1H, br) .
[0634] I ) 4- ( ( 5-fluoro-3- (methoxymethyl) pyri.din-2-yl ) methyl ) -N- ( 4- sulfamoylbenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide
HATU (47.9 mg, 0.13 mmol) was added to a mixture of 4- ( ( 5-fluoro-3- (methoxymethyl ) pyridin-2-yl ) methyl ) -3 , 4-dihydro- 2H-pyrido [3, 2-b] [ 1 , 4 ] oxazine-7-carboxylic acid (30 mg, 0.09 mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (20.04 mg, 0.09 mmol) and DIPEA (51.2 mg, 0.40 mmol) in DMF(dry) (1 mL) at room temperature. The mixture, was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% -10% MeOH in EtOAc) to give white solids. The solid was washed with EtOAc-IPE, and dried in vacuo to give the title compound (27.0 mg, 0.054 mmol, 59.8%) as off-white solids.
1H NMR (300 MHz, DMSO-d6) 5:3.37 (3H, s), 3.62 (2H, t, J = 4.3 Hz), 4.21 (2H, t, J = 4.3 Hz), 4.48 (2H, d, J = 5.7 Hz), 4.61 . (2H, s), 4.94 (2H, s) , 7.29 (2H, s) , 7.39-7.47 (3H, m) , 7.64- 7.78 (3H, m) , 8.18 (1H, d, J = 1.9 Hz), 8.39 (1H, d, J = 3.0 Hz) , 8.81 (1H, t, J = 5.8 Hz) .
[0635]
Example 21
4- (2 , 3-difluoro-6- (methoxymethyl) benzyl) -N- ( 4-sulfamoylbenzyl) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide
A) (2-bromo-3, 4-difluorophenyl ) methanol
CDI (0.958 g, 5.91 mmol) was added to a solution of 2- bromo-3, 4-difluorobenzoic acid (1 g, 4.22 mmol) in THF (23 mL) at room temperature. After stirring at room temperature for lh, the mixture was added to a solution of NaBH4 (0.479 g, 12.66 mmol) in water (23.00 mL) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was
diluted with brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was .purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (0.820 g, 3.68 mmol, 87%) as white solids.
1H NMR (300 MHz, CDC13) 5:1.98 (1H, t, J = 6.2 Hz), 4.74 (2H, d, J = 6.4 Hz), 7.12-7.30 (2H, m) .
[0636]
B) 2-bromo-3, 4-difluoro-1- (methoxymethyl ) benzene
NaH (60% in oil, 221 mg, 5.52 mmol) was added to a
solution of (2-bromo-3, 4-difluorophenyl) methanol (820 mg, 3.68 mmol) in THF(dry) (10 mL) at 0°C. After stirring at 0°C for 30 min, Mel (1044 mg, 7.35 mmol) was added the mixture at 0°C.
The mixture was stirred at room temperature under N2 for 3 days . The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column, chromatography (silica gel, eluted with 0% - 10% EtOAc in hexane) to give the title
compound (730 mg, 3.08 mmol, 84%) as a pale yellow oil.
1H NMR (300 MHz, CDC13) 5:3.46 (3H, s), 4.49 (2H, s) , 7.10-7.26 (2H, m) .
[0637]
C) 2, 3-difluoro-6- (methoxymethyl) benzaldehyde
1.3 M n-BuLi in hexane (2.375 mL, 3.09 mmol) was added to a solution of 2-bromo-3 , 4-difluoro-1- (methoxymethyl ) benzene (610 mg, 2.57 mmol) in THF(dry) (12 mL) at -78°C. After
stirring at -78°C under Ar for 1 h, DMF (0.299 mL, 3.86 mmol) was added to the mixture and stirred at -78 °C under Ar for 2 h. The mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 1% - 10% EtOAc in hexane) to give the title compound (260 mg, 1.397 mmol, 54.3%) as a colorless oil.
1H NMR (300 MHz, CDC13) 5:3.49 (3H, s) , 4.77 (2H, s) , 7.36-7.49 (2H, m) , .10.48 (1H, s) .
[0638]
D) (2, 3-difluoro-6- (methoxymethyl) phenyl) methanol
NaBH4 (106 mg, 2.79 mmol) was added to a solution of 2,3- difluoro-6- (methoxymethyl) benzaldehyde (260 mg, 1.40 mmol) in MeOH (3 mL) at 0°C. The mixture was stirred at room
temperature for 2 h. The mixture was quenched with sat. NH4C1 aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (210 mg, 1.116 mmol, 80%) as a colorless oil.
1H NMR (300 MHz, CDC13) 5:3.15 (1H, t, J = 6.6 Hz), 3.42 (3H, s), 4.53 (2H, s), 4.74 (2H, dd, J = 6.4, 2.3 Hz), 7.03-7.13 (2H, m) .
[0639]
E) 2- (chloromethyl) -3, 4-difluoro-1- (methoxymethyl) benzene
S0C12 (0.5 mL, 6.85 mmol) was added to a solution of
(2, 3-difluoro-6- (methoxymethyl) phenyl) methanol (100 mg, 0.53 mmol) at 0°C. The mixture was stirred at room temperature under dry atmosphere (with a Si02 tube) for 3 h. The mixture was concentrated in vacuo to give the title compound (110 mg, 0.532 mmol, 100%) as a pale yellow oil. This product was subjected to the next reaction without further purification.
[0640]
F) 4- (2, 3-difluoro-6- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid
NaH (60% in oil, 35.5 mg, 0.89 mmol) was added to a solution of methyl 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7- carboxylate (86 mg, 0.44 mmol) in DMF(dry) (2 mL) at 0°C.
After stirring at room temperature for 10 min, 2-
( chloromethyl) -3, 4-difluoro-1- (methoxymethyl) benzene (110 mg, 0.53 mmol) was added the mixture at room temperature. The mixture was stirred at room temperature -under dry atmosphere (with a CaCl2 tube) for 3 h. To the mixture was added 2N NaOH (1.109 mL, 2.22 mmol) and the mixture was stirred at room temperature for 3 days. The mixture was acidified by IN HC1 aq. at 0°C and concentrated in vacuo. The residue was washed with water and IPE, dried in vacuo to give the title compound (72.0 mg, 0.206 mmol, 46.3%) as light brown solids.
MS (ESI+), found 351.2 (M+H)
[0641]
G) 4- (2, 3-difluoro-6- (methoxymethyl ) benzyl) -N- (4- sulfamoylbenzyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide
HATU (109 mg, 0.29 mmol) was added to a mixture of 4-
(2, 3-difluoro-6- (methoxymethyl) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazine-7^carboxylic acid (72 mg, 0.21 mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (45.8 mg, 0.21 mmol) and DIPEA (117 mg, 0.90 mmol) in DMF(dry) (1 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 60% - 90% EtOAc in hexane) to give white solids.
The solid was washed with EtOAc-IPE, and dried in vacuo to give the title compound (47.0 mg, 0.091 mmol, 44.1%) as white powder. 1H NMR (300 MHz, DMSO-d6) δ : 3.24 (3H, s), 3.33-3.39 (2H, m) , 4.13 (2H, t, J = 4.3 Hz), 4.46-4.55 (4H, m) , 4.95 (2H, s) ,
1.22-1. AS (7H, m) , 7.77 (2H, d, J = 8.2 Hz), 8.31 (1H, d, J =' 1.9 Hz), 8.88 (1H, t, J = 5.7 Hz) .
[0642]
Example 22
4- (2- (methoxymethyl) benzyl) -N- ( (1- (methylsulfonyl) piperidin-4- yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7- carboxamide
A) 1- (chloromethyl) -2- (methoxymethyl) benzene
NaOMe (2.037 g, 37.70 mmol) was added to a solution of 1,2-bis (chloromethyl) benzene (6.6 g, 37.70 mmol) in MeOH (120 mL) at room temperature. The mixture was stirred at 80 °C under N2 for 10 h and at 60 °C overnight. After cooling, the mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 3% - 5% EtOAc in
hexane) to give the title compound (1.520 g, 8.91 mmol, 23.63%) as a colorless oil.
1H NMR (300 MHz, CDC13) 5:3.42 (3H, s), 4.60 (2H, s) , 4.71 (2H, s) , 7.25-7.41 (4H, m) .
[0643]
B) 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3, 2- b] [ 1 , 4 ] oxazine-7-carboxylic acid
To a mixture of 1- (chloromethyl) -2- (methoxymethyl) benzene (629 mg, 3.69 mmol) and DMF (15 iriL) was added NaH (217 mg, 5.43 mmol) at 0°G. After being stirred at 0°C for 5 min, 1- ( chloromethyl ) -2- (methoxymethyl ) benzene (629 mg, 3.69 mmol) was added to the mixture. After being stirred at 0°C for 5 h, 2 M NaOH aq. (4.0 mL, 8.00 mmol) was added to the mixture. After being stirred at room temperature overnight, the mixture was extracted with water. The aqueous layer was acidified with IN HC1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (629 mg, 2.002 mmol, 73.3%) as a brown oil. MS (ESI+), found 315.3 (M+H)
[0644]
C) 4- (2- (methoxymethyl) benzyl ) -N- ( ( 1- (methylsulfonyl ) piperidin- 4-yl)methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [ 1 , 4 ] oxazine-7- carboxamide
To a mixture of 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (101 mg, 0.17 mmol) , (1- (methylsulfonyl) piperidin-4-yl ) methanamine
hydrochloride (51 mg, 0.22 mmol), HATU (83 mg, 0.22 mmol) and DMF (3 mL) was added DIPEA (90 μΐ,, 0.52 mmol). After being stirred at room temperature for 4 h, the mixture was quenched with sat. NH4CI aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and crystallized from IPE-hexane to give the title compound (30.0 mg, 0.061 mmol, 36.7%) as white solids.
1H NMR (300 MHz, CDC13) 5:1.79-1.93 (5H, m) , 2.59-2.73 (2H, m) , 2.77 (3H, s), 3.30-3.38 (5H, m) , 3.38-3.45 (2H, m) , 3.75-3.88 (2H, m) , 4.13-4.20 (2H, m) , 4.49 (2H, s) , 5.00 (2H, s) , 6.03- 6.16 (1H, m) , 7.16-7.21 (1H, m) , 7.27-7.32 (2H, m) , 7.34-7.41 (2H, m) , 8.18 (1H, d, J = 1.9 Hz) .
[0645]
Example 23
4- (2- (methoxymethyl) benzyl) -N- ( (5- (methylsulfonyl ) pyridin-2- yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [ 1 , 4 ] oxazine-7- carboxamide
A) 5- (methylsulfonyl) pyridine-2-carbonitrile
A mixture of 5-bromopicolinonitrile (25 g, 136.61 mmol) and methanesulfinic acid, sodium salt (19.52 g, 191.25 mmol) in DMSO (200mL) was stirred at 100°C for 24h. The mixture was cooled to 50 °C and water (250 mL) was added to the mixture.
After stirring at 50 °C overnight, the precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (20.62 g, 113 mmol, 83%) as white crystals.
1H NMR (300 MHz, CDC13) 5:3.17 (3H, s) , 7.93 (1H, dd, J = 7.9, 0.8 Hz), 8.41 (1H, dd, J = 7.9, 2.3 Hz), 9.25 (1H, dd, J = 2.3, 0.8 Hz) .
[0646]
B) 1- (5- (methylsulfonyl)pyridin-2-yl)methanamine hydrochloride
A mixture of 5- (methylsulfonyl ) pyridine-2-carbonitrile (10 g, 54.88 mmol), 6N HC1 aq. (18.29 mL, 109.77 mmol) and 10% Pd-C (50% wet, 1 g, 9.40 mmol) in EtOH (100 mL) was
hydrogenated under middle pressure (0.45MPa) at room
temperature overnight. Water (10 mL) was added and the
catalyst was removed by filtration. The filtrate was
concentrated in vacuo to dryness. The solid was suspended in EtOH and collected by filtration, dried in vacuo to give the title compound (6.30 g, 28.3 mmol, 51.5%) as pale yellow powder. MS (ESI+), found 187.1 (M-HC1+H)
1H NMR (300 MHz, DMSO-d6) 5:3.37 (3H, s) , 4.33 (2H, q, J = 5.3 Hz), 7.81 (1H, d, J = 8.3 Hz), 8.41 (1H, dd, J = 8.1, 2.5 Hz), 8.70 (3H, brs) , 9.09 (1H, d, J = 1.9 Hz) .
[0647]
C) 4- (2- (methoxymethyl) benzyl) -N- ( (5- (methylsulfonyl ) pyridin-2- yl)methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide
To a mixture of 4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (103 mg, 0.17 mmol ) , 1- ( 5- (methylsulfonyl ) pyridin-2-yl ) methanamine
hydrochloride (64 mg, 0.34 mmol), HATU (138 mg, 0.36 mmol) and DMF (3 mL) was added DIPEA (0.12 mL, 0.69 mmol). After being stirred at room temperature overnight, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc . The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (44.0 mg, 0.091 mmol, 53.5%) as white solids.
1H NMR (300 MHz, CDC13) 5:3.11 (3H, s) , 3.35 (3H, s), 3.39-3.44 (2H, m) , 4.13-4.22 (2H, m) , 4.49 (2H, s) , 4.84 (2H, d, J = 5.3 Hz)-, 5.02 (2H, s), 7.12-7.23 (2H, m) , 7.27-7.30 (2H, m) , 7.34- 7.40 (1H, m) , 7.44 (1H, d, J = 1.9 Hz), 7.55 (1H, d, J = 8.7 Hz), 8.20 (1H, dd, J = 8.3, 2.3 Hz), 8.31 (1H, d, J = 2.3 Hz), 9.09 (1H, d, J = 1.5 Hz) .
[0648]
Example 25
1- (2- (methoxymethyl) benzyl) -N- ( 4-sulfamoylbenzyl ) -2, 3-dihydro- lH-pyrido [2 , 3-b] [1, 4] oxazine-6-carboxamide
A) 6-bromo-2-methoxypyridin-3-amine
To a mixture of 2-methoxypyridin-3-amine (4.95 g, 39.87 mmol) and DMF (50 mL) was added NBS (7.98 g, 44.84 mmol) at 0°C. After being stirred at 0°C for 1 h, the mixture was quenched with sat. NH4CI aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SCO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 20% EtOAc in hexane) to give the title
compound (4.41 g, 21.72 mmol, 54.5%) as brown solids.
MS (ESI+), found 203.0, 205.0 (M+H)
1H NMR (300 MHz, CDC13) 5:3.75 (2H, brs) , 3.98 (3H, s) , 6.76
(1H, d, J = 7.6 Hz), 6.87 (1H, d, J = 7.9 Hz).
[0649]
B) 3-amino-6-bromopyridin-2-ol
A mixture of 6-bromo-2-methoxypyridin-3-amine (442 mg,
2.18 mmol), 30% HBr/AcOH (5 mL, 25.50 mmol) and water (2 mL) was stirred at 80°C for 1 h. The mixture was diluted with
EtOAc and extracted with water. The organic layer was
neutralized with 8 N NaOH aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column
chromatography (silica gel, eluted with 30% - 70% EtOAc in hexane) to give the title compound (299 mg, 1.582 mmol, 72.7%) as pale yellow solids.
MS (ESI+), found 189.0, 191.0 (M+H)
[0650]
C) 6-bromo-lH-pyrido [2, 3-b] [ 1 , 4 ] oxazin-2 ( 3H) -one
To a mixture of 3-amino-6-bromopyridin-2-ol (3.65 g,
19.31 mmol), TEA (3.5 mL, 25.11 mmol) and THF (50 mL) was added 2-bromoacetyl chloride (2.0 mL, 23.89 mmol). After being stirred at room temperature overnight, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. To a mixture of the residue and DMF (50 mL) was added K2GO3 (5.07 g, 36.68 mmol). After being stirred at 100°C for 1 h, the mixture was poured into sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column
chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title compound (3.03 g, 13.23 mmol, 68.5%) .as white solids.
MS (ESI+), found 229.0, 230.9 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:4.81 (2H, s) , 7.15 (1H, d, J = 7.9 Hz), 7.23 (1H, d, J = 7.9 Hz), 10.94 (1H, s) .
[0651]
D) 6-bromo-2, 3-dihydro-lH-pyrido [2, 3-b] [l,4]oxazine
To a mixture of 6-bromo-lH-pyrido [2, 3-b] [1, 4] oxazin- 2(3H)-one (3.03 g, 13.23 mmol) and THF (50 mL) was added borane methylsulfide complex (3.0 mL, 31.63 mmol) under nitrogen atmosphere. After being stirred at 60 °C for 1 h, the mixture was quenched with MeOH. (50 mL) and stirred at room temperature for 1 h. The mixture was concentrated. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexarie) to give the title compound (2.79 g, 12.97 mmol, 98%) as white solids.
MS (ESI+), found 215.2, 217.2 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:3.23-3.29 (2H, m) , 4.23-4.29 (2H, m) , 6.22 (1H, brs) , 6.85 (1H, d, J = 8.3 Hz), 6.92 (1H, d, J = 7.9 Hz) .
[0652]
E) tert-butyl 6-bromo-2, 3-dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine- 1-carboxylate
To a mixture of 6-bromo-2 , 3-dihydro-lH-pyrido [2 , 3- b] [1, 4] oxazine (1.20 g, 5.58 mmol), Boc20 (2.0 mL, 8.61 mmol) and THF (20 mL) was added LiHMDS (5.5 mL, 7.15 mmol) at 0°C. After being stirred at room temperature overnight, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column
chromatography (silica gel, eluted with 5% - 20% EtOAc in hexane) to give the title compound (1.280 g, 4.06 mmol, 72.8%)- as white solids.
MS (ESI+), found 315.2, 317.1 (M+H)
1H NMR (300 MHz, CDC13) 5:1.54 (9H, s) , 3.86 (2H, dd, J = 5.3, 4.2 Hz), 4.38 (2H, dd, J = 5.3, 4.2 Hz), 7.07 (1H, d, J = 8.3 Hz) , 8.11 (1H, brs) .
[0653]
F) 1-tert-butyl 6-methyl 2, 3-dihydro-lH-pyrido [2, 3- b] [1,4] oxazine-1, 6-dicarboxylate
To a mixture of tert-butyl 6-bromo-2 ,.3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-l-carboxylate (1.28 g, 4.06 mmol) , TEA (1.2 mL, 8.61 mmol), DMF (20 mL) and MeOH (5 mL) was added PdCl2(dppf) (151 mg, 0.21 mmol) . After being stirred at 100°C under CO (0.7 MPa) for 7 h, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 30% EtOAc in hexane) to give the title compound (1.020 g, 3.47 mmol, 85%) as white solids.
MS (ESI+), found 295.3 (M+H)
1H NMR (300 MHz, CDC13) 5:1.56 (9H, s), 3.90-3.94 (2H, m) , 3.94 (3H, s), 4.37-4.44 (2H, m) , 7.78 (lH, d, J = 8.3 Hz), .8.46 (1H, d, J = 8.3 Hz) .
[0654]
G) methyl 2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6- carboxylate hydrochloride
To a mixture of 1-tert-butyl 6-methyl 2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-1, 6-dicarboxylate (113 mg, 0.38 mmol) and MeOH (5 mL) was added 4 M HCl/EtOAc (5 mL, 20.00 mmol) . After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was subjected to the next reaction without further purification.
[0655]
H) 1- (2- (methoxymethyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid
To a mixture of 1- (chloromethyl) -2- (methoxymethyl) benzene (90 mg, 0.53 mmol) and DMF (5 mL) was added NaH (60% in oil, 38 mg, 0.95 mmol) at 0°C. After being stirred at 0°C for 5 min, 1- (chloromethyl) -2- (methoxymethyl) benzene (90 mg, 0.53 mmol.) was added to the mixture. After being stirred at room temperature for 7 h, 2 M NaOH aq. (0.60 mL, 1.20 mmol) was added to the mixture. After being stirred at room temperature overnight, the mixture was extracted with water. The aqueous layer was acidified with IN HC1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was subjected to the next reaction without further purification.
MS (ESI+), found 315.3 (M+H)
[0656]
I) 1- (2- (methoxymethyl) benzyl) -N- (4-sulfamoylbenzyl) -2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide
To a mixture of 1- (2- (methoxymethyl) benzyl) -2, 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (121 mg, 0.38 mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (118 mg, 0.53 mmol), HATU (195 mg, 0.51 mmol) and DMF (5 mL) was added DIPEA (0.20 mL, 1.15 mmol). After being stirred at room
temperature for 3 h, the reaction mixture was quenched with sat. NH4C1 aq. and , extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 100% EtOAc in hexane) and then crystallized from EtOAc-hexane to give the title compound (15.00 mg, 0.031 mmol-, 8.08%) as white solids.
1H NMR (300 MHz, CDC13) δ:3.39 (3H, s), 3.44-3.50 (2H, m) ,
4.43-4.48 (2H, m) , 4.49 (2H, s) , 4.62 (2H, s), 4.66 (2H, d, J = 6.4 Hz), 4.74 (2H, s) , 6.89 (1H, d, J = 7.9 Hz), 7.15-7.21 (1H, m) , 7.29-7.41 (3H, m) , 7.48 (2H, d, J = 8.3 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.04-8.12 (1H, m) .
-[-0657]
Example 26
4- (3-methoxyphenyl) -N- (4-sulfamoylbenzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxamide
A) methyl 3-oxo-3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylate
To a solution of methyl 4-amino-3-hydroxybenzoate (10 g, 59.82 mmol) and NaHCO3 (5.53 g, 65.80 mmol) in EtOAc (50 mL) and water (50 mL) was added 2-chloroacetyl chloride (4.7.6 mL, 59.82 mmol) at 0°C. The mixture was stirred at room
temperature for 0.5 h, diluted with EtOAc and THF to become solution, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated. To a solution of the residue in NMP (50 mL) was added K2CO3 (8.27 g, 59.82 mmol) at room temperature. The mixture was stirred at room temperature overnight, cooled to 0°C, diluted with water. The precipitates were collected by filtration, washed with water, and dried to give the title compound (11.80 g, 57.0 mmol, 95%) as off-white solids.
[0658]
B) methyl 3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylate
A mixture of methyl 3-oxo-3 , 4-dihydro-2H-l , 4-benzoxazine- 7-carboxylate (1 g, 4.83 mmol) and boron trifluoride ether complex (1.273 mL, 10.14 mmol) in THF (20 mL) was stirred at 0°C for 20 min. To the mixture was. added NaBH4 (0.383 g, 10.14 mmol), which was stirred at 0°C at 1 h and room temperature overnight. EtOAc (ca. 1 mL) was added, followed by IN HC1 aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (0.916 g, 4.74 mmol,. 98%) as pale yellow solids.
[0659]
C) methyl 4- ( 3-methoxyphenyl ) -3 , 4-dihydro-2H-l , 4-benzoxazine-7- carboxylate
Pd2(dba)3 (35.5 mg, 0.04 mmol) and XPHOS (37.0 mg, 0.08 mmol) were added to a mixture of methyl 3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxylate (150 mg, 0.78 mmol), l-bromo-3- methoxybenzene (218 mg, 1.16 mmol) and K3PO4 (330 mg, 1.55 mmol) in toluene (5 mL) at room temperature. The mixture was stirred at 100 °C overnight. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4. and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 25% EtOAc in hexane) to give white solids. The solids were washed with EtOAc-IPE and dried in vacuo to give the title compound (90 mg, 0.301 mmol, 38.7%) as a light brown oil.
MS (ESI+), found 300.3 (M+H)
1H NMR (300 MHz, CDC13) 5:3.72-3.75 (2H, m) , 3.80 (3H, s) , 3.85 (3H, s), 4.28-4.35 (2H, m), 6.72-6.87 (4H, m) , 7.19-7.36 (1H, m) , 7.42 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 1.9 Hz).
[0660]
D) 4- (3-methoxyphenyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylic acid
2N NaOH aq. (1.503 mL, 3.01 mmol) was added to a solution of methyl 4- (3-methoxyphenyl) -3, 4~dihydro-2H-l, 4-benzoxazine-7- carboxylate (90 mg, 0.30 mmol) in MeOH (4 mL) at room
temperature. The mixture was stirred at room temperature overnight. The mixture was acidified by IN HC1 aq. at 0°C (pH4.0) and diluted with water. The precipitate was collected, washed with water, dried in vacuo to give the title compound (60.0 mg, 0.210 mmol, 69.9%) as pale orange powder.
MS (ESI+) , found 286.3 (M+H)
1H NMR (300 MHz, DMSO-d6) 6:3.68-3.79 (5H, m) , 4.24-4.35 (2H, m) , 6.75-6.82 (2H, m) , 6.85-6.94 (2H, m) , 7.25-7.41 (3H, m) , 12.35 (1H, s) .
[0661]
E) 4- (3-methoxyphenyl) -N- (4-sulfamoylbenzyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide
HATU (56.0 mg, 0.15 mmol) was added to a solution of 4- ( 3-methoxyphenyl ) -3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylic acid (30 mg, 0.11 mmol), 4- (aminomethyl ) benzenesulfonamide hydrochloride (25.8 mg, 0.12 mmol) and DIPEA (59.8 mg, 0.46 mmol) in DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 70% - 100% EtOAc in hexane) to give a colorless oil. The oil was treated with EtOAc-IPE and dried in vacuo to give the title compound (24.00 mg, 0.053 mmol, 50.3%) as white powder.
1H NMR (300 MHz, DMSO-d6) 5:3.69-3.79 (5H, m) , 4.29 (2H, brs) , 4.48 (2H, d, J = 5.7 Hz), 6.73-6.90 - (4H, m) , 7.27-7.47 (7H, m) , 7.76 (2H, d, J = 8.3 Hz) , 8.81-8.88 (1H, m) .
[0662]
Example 27
4- (3-ethoxyphenyl) -N- (4-sulfamoylbenzyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxamide
A) methyl 4- (3-ethoxyphenyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylate
Pd2(dba)3 (35.5 mg, 0.04 mmol) and XPHOS (37.0 mg, 0.08 mmol) were added to a mixture of methyl 3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate (150 mg, 0.78 mmol), l-bromo-3- ethoxybenzene (234 mg, 1.16 mmol) and K3PO4 (330 mg, 1.55 mmol) in toluene (5 mL) at room temperature. The mixture was stirred at 100 °C overnight. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 20% EtOAc in hexane) to give white solids. The solids were washed with EtOAc-IPE and dried in vacuo to give the title compound (88 mg, 0.281 mmol, 36.2%) as orange amorphous solids.
MS (ESI+), found 314.2 (M+H) -
1H NMR (300 MHz, CDC13) 5:1.41 (3H, t, J = 7.0 Hz), 3.70-3.76 (2H, m) , 3.85 (3H, s) , 3.95-4.08 (2H, m) , 4.29-4.35 (2H, m) , 6.70-6.87 (4H, m) , 7.22-7.33 (1H, m) , 7.42 (1H, dd, J = 8.7, 1.9 Hz), 7.53 (1H, d, J = 1.9 Hz).
[0663]
B) 4- (3-ethoxyphenyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylic acid
2N NaOH aq. (1.404 mL, 2.81 mmol) was added to a solution of methyl 4- ( 3-ethoxyphenyl ) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxylate (88 mg, 0.28 mmol) in MeOH (4 mL) at room
temperature. The mixture was stirred at room temperature overnight. The mixture was acidified by IN HC1 aq. at 0°C and diluted with water. The precipitate was collected, washed with water, dried in vacuo to give an oil. The oil was crystallized from EtOAc-hexane to give the title compound (68.0 mg, 0.227 mmol, 81%) as pale orange powder.
MS (ESI+), found 300.3 (M+H)
XH NMR (300 MHz, DMSO-d6) 5:1.32 (3H, t, J = 7.0 Hz), 3.70-3.78 (2H, m) , 4.03 (2H, q, J = 6.9 Hz), 4.25-4.34 (2H, m) , 6.75-6.90 (4H, m) , 7.28-7.36 (3H, m) , 12.38 (1H, brs).
[0664]
C) 4- (3-ethoxyphenyl) -N- ( 4-sulfamoylbenzyl ) -3 , 4-dihydro-2H-l, 4- benzoxazine-7-carboxamide
HATU (53.4 mg, 0.14 mmol) was added to a solution of 4- ( 3-ethoxyphenyl) -3, 4-dihydro-2H-l , 4-benzoxazine-^7-carboxylic acid (30 mg, 0.10 mmol), 4- (aminomethyl) benzenesulfonamide hydrochloride (24.55 mg, 0.11 mmol) and DIPEA (57.0 mg, 0.44 mmol) in DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 70% - 90% EtOAc in hexane) to give a pale pink oil. The oil was treated with EtOAc-IPE and dried in vacuo to give the title compound (32.0 mg, 0.068 mmol, 68.3%) as white powder.
1H NMR (300 MHz, DMSO-d6) 5:1.32 (3H, t, J = 6.6 Hz), 3.73 (2H, brs), 4.02 (2H, d, J - 7.2 Hz), 4.29 (2H, brs), 4.48 (2H, d, J
= 4.5 Hz), 6.71-6.92 (4H, m) , 7.28-7.55 (7H, m) , 7.76 (2H, d, J
= 7.6 Hz), 8.84 (1H, brs) .
[0665]
Example 29
4- (2- (methoxymethyl) benzyl) -N- (1- (4- (methylsulfon.yl ) phenyl) cyclopropyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide
A) N- (1- (4-bromophenyl) cyclopropyl) -4- (2- (methoxymethyl ) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxamide
To a mixture of 4- (2- (methoxymethyl) benzyl) -3, 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (420 mg, 0.69 mmol) , 1- (4-bromophenyl) cyclopropanamine (402 mg, 1.90 mmol) , HATU (786 mg, 2.07 mmol) and DMF (10 mL) was added DIPEA (0.50 mL, 2.86 mmol) . After being stirred at room temperature
overnight, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (NH silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (259 mg, 0.509 mmol, 73.3%) as white solids.
MS (ESI+), found 508.2, 510.1 (M+H) -
1H NMR (300 MHz, CDC13) 5:1.34 (4H, dt, J = 7.5, 1.9 Hz), 3.35 (3H, s), 3.37-3.42 (2H, m) , 4.13-4.19 (2H, m) , 4.48 (2H, s) , 5.00 (2H, s), 6.57 (1H, s) , 7.14-7.21 (3H, m) , 7.27-7.32 (2H, m) ,' 7.35-7.43 (4H, m) , 8.19 (1H, d, J = 2.3 Hz).
[0666]
B) 4- (2- (methoxymethyl) benzyl) -N- (1- (4-
(methylsulfonyl) phenyl) cyclopropyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide
To a mixture of N- ( 1- ( 4-bromophenyl ) cyclopropyl ) -4- ( 2- (methoxymethyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide (230 mg, 0.45 mmol),
methanesulfinic acid sodium salt (94 mg, 0.92 mmol), L-proline (11 mg, 0.10 mmol), NaOH (8 mg, 0.20 mmol) and DMSO (10 mL) was added copper(I) iodidel (9 mg, 0.05 mmol). After being stirred at 110 °C under nitrogen atmosphere for 30 h, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 100% EtOAc in hexane and_MH silica gel, eluted with 30% - 70% EtOAc in hexane) to give the title compound (24.00 mg, 0.047 mmol, 10.4%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:1.31-1.42 (4H, m) , 3.17 (3H, s) , 3.29 (3H, s), 3.45 (2H, t, J = 4.0 Hz), 4.21 (2H, t, J = 4.3 Hz), 4.49 (2H, s), 4.92 (2H, s) , 7.10-7.18 (lH,_m), 7.23-7.31 (2H, m) , 7.33-7.41 (3H, m) , 7.46 (1H, d, J = 1.9 Hz), 7.76-7.84 (2H, m) , 8.26 (1H, d, J = 1.9 Hz) ,- 9.01 (1H, s).
[0667]
Example 31
4- (4-methoxyphenyl) -N- ( 4-sulfamoylbenzyl ) -3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxamide
A) methyl 4- (4-methoxyphenyl) -3, 4-dihydro-2H-l ,.4-benzoxazine-7- carboxylate
Pd2(dba)3 (35.5 mg, 0.04 mmol) was added to a mixture of methyl 3 , 4-dihydro-2H-l , 4-benzoxazine-7-carboxylate (150 mg, 0.78 mmol), l-bromo-4-methoxybenzene (218 mg, 1.16 mmol), Xphos (37.0 mg, 0.08 mmol) and K3PO4 (330 mg, 1.55 mmol) in toluene (5 mL) at room temperature. The mixture was stirred at 100 °C overnight. The mixture was poured into water at room
temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 25% EtOAc in hexane) to give white solids. The solid was washed with EtOAc-IPE and dried in vacuo to give the title compound (65.0 mg, 0.217 mmol, 28.0%) as a light brown oil.
MS (ESI+), found 300.3 (M+H)
[0668]
B) 4- (4-methoxyphenyl) -3, 4=dihydro-2H-l, 4-benzoxazine-7- carboxylic acid
2N NaOH aq. (0.543 mL, 1.09 mmol) was added to a solution of methyl 4- (4-methoxyphenyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylate (65 mg, 0.22 mmol) in MeOH (3 mL) at room
temperature. The mixture was stirred at room temperature for 3 days. To the mixture were added MeOH (2 mL) and 2N NaOH aq. (0.543 mL, 1.09 mmol) and the mixture was stirred at 50°C for 5 h. The mixture was acidified by IN HC1 aq. at 0°C (pH5.0) and diluted with water. The precipitate was collected, washed with water, dried in vacuo to give the title compound (22.00 mg, 0.077. mmol, 35.5%) as pale orange powder.
MS (ESI+), found 286.3 (M+H)
[0669]
C) 4- (4-methoxyphenyl) -N- (4-sulfamoylbenzyl) -3, 4-dihydro-2H- 1 , 4-benzoxazine-7-carboxamide
HATU (41.0 mg, 0.11 mmol) was added to a solution of 4- ( 4-methoxyphenyl) -3, 4-dihydro-2H-l , 4-benzoxazine-7-carboxylic acid (22 mg, 0.08 mmol), 4- (aminomethyl ) benzenesulfonamide hydrochloride (17.2 mg, 0.08 mmol) and DIPEA (43.9 mg, 0.34 mmol) in DMF (1 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc . The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 70% - 100% EtOAc in hexane) to give a pale pink oil. The oil was treated with EtOAc-IPE and dried in vacuo to give the title compound (11.00 mg, 0.024 mmol, 31.5%) as white powder.
1H NMR (300 MHz, DMSO-d6) 5:3.63-3.70 (2H, m) , 3.78 (3H, s) , 4.27-4.34 (2H, m) , 4.47 (2H, d, J = 5.7 Hz), 6.50 (1H, d, J = 8.7 Hz), 7.01 (2H, d, J = 9.1 Hz), 7.22-7.32 (5H, m) , 7.36-7.46 (3H, m) , 7.76 (2H, d, J = 7.5 Hz), 8.79 (1H, t like).
[0670]
Example 37
1- ( 3-cyclopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl ) -2 , 3-" dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide
A) methyl 2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6- carboxylate
To a mixture of 1-tert-butyl 6-methyl 2 , 3-dihydro-lH- pyrido [2 , 3-b] [1, 4 ] oxazine-1, 6-dicarboxylate (905 mg, 3.08 mmol) and MeOH. (_5 mL) was added 4.M .HCl/EtOAc (10 mL, 40.00 mmol) . After being stirred at room temperature overnight, the mixture was concentrated. The residue was dissolved in MeOH (10 mL) and Amberlyst A26 (937 mg, 3.08 mmol) was added to the mixture. After being stirred at room temperature for 1 h, the insoluble material was filtered off. The filtrate was concentrated in vacuo to give the title compound (605 mg, 3.12 mmol,- 101%) as yellow solids.
[0671]
B) methyl 1- ( 3-cyclopropylphenyl ) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylate
A mixture of methyl 2, 3-dihydro-lH-pyrido [2, 3- b] [1, 4] oxazine-6-carboxylate (193 mg, 0.99 mmol), l-bromo-3- cyclopropylbenzene (380 mg, 1.93 mmol), Pd2(dba)3 (45 mg, 0.05 mmol), XPHOS (52 mg, 0.11 mmol), K3PO4 (423 mg, 1.99 mmol) and toluene (10 mL) was stirred under nitrogen atmosphere at 100°C for 16 h. After being cooled^ the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 70% EtOAc in hexane) to give the title compound (133 mg, 0.429 mmol, 43.1%) as pale yellow solids.
MS (ESI+), found 311.3 (M+H)
1H NMR (300 MHz, CDC13) 5:0.66-0.75 (2H, m) , 0.98-1.09 (2H, m) , 1.83-1.97 (1H, m) , 3.74-3.80 (2H, m) , 3.92 (3H, s) , 4.49-4.55 (2H, m) , 6.92-6.98 (2H, m) , 6.99-7.07 (2H, m) , 7.29-7.38 (1H, m) , 7.60 (1H, d, J = 7.9 Hz) .
[0672]
C) 1- (3-cyclopropylphenyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6=carboxylic acid
To a mixture of methyl 1- ( 3-cyclopropylphenyl ) -2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylate (129 mg, 0.42 mmol) and MeOH (5 mL) was added 2 M NaOH aq. (1.0 mL, 2.00 mmol) . After being stirred at 60 °C for 1 h, the mixture was acidified with 1 N HC1 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give an oil. The oil was crystallized from EtOAc- hexane to give the title compound (113 mg, 0.381 mmol, 92%) . MS (ESI+), found 297.3 (M+H)
[0673]
D) 1- ( 3-cyclopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl ) -2 , 3- dihydro-lH-pyrido [2 , 3--b] [1,4] oxazine-6-carboxamide
To a mixture of 1- ( 3-cyclopropylphenyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxylic acid (59 mg, 0.20 mmol), (4- (methylsulfonyl ) phenyl ) methanamine hydrochloride (54 mg,
0.24 mmol), DIPEA (0.18 mL, 1.03 mmol), DMAP (26 mg, 0.21 mmol) and EtOAc (3 mL) was added T3P in EtOAc (0.24 mL, 0.41 mmol). After being stirred at 60°C overnight, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SCO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H20 in acetonitrile
containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO3 aq. and brine, dried over Na2SO4 and concentrated. The residue was crystallized from EtOAc- hexane to give the title compound (50.0 mg, 0.108 mmol, 54.2%) as white solids.
1H NMR (300 MHz, CDC13) 5:0.65-0.76 (2H, m) , 0.97-1.07 (2H, m) , 1.84-1.98 (1H, m) , 3.03 (3H, s) , 3.74-3.80 (2H, m) , 4.50-4.57 (2H, m) , 4.69 (2H, d, J = 6.4 Hz), 6.90-6.98 (2H, m) , 6.99-7.05 (1H, m) , 7.11 (1H, d, J = 8.3 Hz), 7.28-7.37 (1H, m) , 7.54 (2H, d, J = 8.3 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.89 (2H, d, J = 8.3 Hz) , 8.11 (1H, t, J = 6.2 Hz) .
[0674]
Example 51
4- (4-cyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -3, 4- dihydro-2H-l , 4-benzoxazine-7-carboxamide
A) 4-tert-butyl 7-methyl 2 , 3-dihydro-4H-l , 4-benzoxazine-4 , 7- dicarboxylate A mixture of methyl 3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylate (10.07 g, 52.13 mmol), Boc20 (14:52 mL, 62.56 mraol), TEA (8.72 mL, 62.56 mmol) and DMAP (3.18 g, 26.07 mmol) in THF (200 mL) was stirred at 50°C for 3 h. The mixture was quenched with brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%- 30% EtOAc in hexane) to give the title compound (9.90 g, 33.8 mmol, 64.7%) as white solids.
[0675]
B) 4- (tert-butoxycarbonyl ) -3, 4-dihydro-2H-l , 4-benzoxazine-7- carboxylic acid
A mixture of 4-tert-butyl 7-methyl 2 , 3-dihydro-4H-l , 4- benzoxazine-4 , 7-dicarboxylate (6.9 g, 23.52 mmol) and lithium hydroxide (23.52 mL, 94.10 mmol) in THF (20 mL) and MeOH (20.00 mL) was stirred at 50 °C for 2 h. The mixture was quenched with IN HC1 aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was washed with IPE-hexane to give the title compound (5.38 g, 19.26 mmol, 82%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:1.50 (9H, s), 3.70-3.94 (2H, m) , 4.16-4.33 (2H, m) , 7.35 (1H, d, J = 1.9 Hz), 7.41-7.49 (1H, m) , 7.93 (1H, d, J = 8.7 Hz), 12.76 (1H, brs).
[0676]
C) tert-butyl 7- (( 4- (methylsulfonyl ) benzyl ) carbamoyl ) -2H-1 , 4- benzoxazine-4 (3H) -carboxylate
HATU (7.08 g, 18.62 mmol) was added to a mixture of 4- (tert-butoxycarbonyl) -3, 4-dihydro-2H-l, 4-benzoxazine-7-^
carboxylic acid (4 g, 14.32 mmol), (4-
(methylsulfonyl) phenyl ) methanamine (2.92 g, 15.75 mmol) and DIPEA (11.01 mL, 63.02 mmol) in DMF (20mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc-hexane to give the title compound (4.49 g, 10.06 mmol, 70.2%) as off-white solids. The mother liquor was concentrated in vacuo and the residue was purified by column chromatography (silica gel, eluted with 50% - 90% EtOAc in hexane) to give the title compound (0.800 g, 1.792 mmol, 12.51%) as white amorphous solids.
MS (ESI+), found 447.3 (M+H)
1H NMR (300 MHz, CDC13) 5:1.55 (9H, s) , 3.04 (3H, s) , 3.85-3.91 (2H, m) , 4.23-4.29 (2H, m) , 4.72 (2H, d, J = 6.0 Hz), 6.52 (1H, t, J = 6.0 Hz), 7.27-7.36 (2H, m) , 7.53 (2H, d, J = 5.1 Hz), 7.87-7.97 (3H, m) . .
[0677]
D) N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H-l, 4-benzoxazine- 7-carboxamide
4N HC1 in EtOAc (-29.4 mL, 117^58 mmol) was added to a suspension of tert-butyl 7-((4-
(methylsulfonyl) benzyl) carbamoyl) -2H-1, 4-benzoxazine-4 (3H) - carboxylate (5.25 g, 11.76 mmol) in EtOAc (90 mL) at 0°C. The mixture was stirred at room temperature for 2 h. To the
mixture was added TFA (20 mL, 259.60 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was neutralized with IN NaOH aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was crystallized from EtOAc-IPE to give the title compound (4.06 g, 11.72 mmol, 100%) as off-white solids.
MS (ESI+), found 347.2 (M+H)
1ti NMR (400 MHz, DMSO-d6) 5:3.18 (3H, s), 3.31-3.35 (2H, m, overlapped by H20) , 4.11 (2H, t, J = 4.3 Hz), 4.49 (2H, d, J = 5.9 Hz), 6.39 (1H, s) , 6.56 (1H, d, J = 8.3 Hz), 7.25 (1H, s) , 7.29 (1H, d, J = 8.4 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 8.73 (1H, t, J = 6.0 Hz).
[0678] E) 4- (4-cyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -3, 4- dihydro-2H-l , 4-~benzoxazine-7-carboxamide
A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H-
1 , 4-benzoxazine-7-carboxamide (100 mg, 0.29 mmol.) , l-bromo-4- cyclopropylbenzene (85 mg, 0.43 mmol), Ruphos pre-catalyst
(21.04 mg, 0.03 mmol) , - NaOtBu (83 mg, 0.87 mmol) and DME (3 mL) was heated at 120 °C for 3 h under microwave irradiation. The mixture was filtered through celite and concentrated in vacuo.
The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (55.0 mg, 0.119 mmol, 41.2%) as off-white solids.
1H NMR (300 MHz, DMSO-d6) 5:0.62-0.72 (2H, m) , 0.89-1.00 (2H, m) , 1.85-2.00 (1H, m) , 3.18 (3H, s) , 3.64-3.75 (2H, m) , 4.24-
4.35 (2H, m) , 4.51 (2H, d, J = 5.7 Hz), 6.66 (1H, d, J = 8.7 Hz), 7.09-7.23 (4H, m) , 7.28 (1H, dd, J = 8.5, 2.1 Hz), 7.39
(1H, d, J = 1.9 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J =
8.7 Hz), 8.86 (1H, t, J = 5.9 Hz).,-
[0679]
Example 52
4- (2-ethoxy-4-fluorobenzyl) -N- (4- (methylsulfonyl ) benzyl ) -3, 4- dihydro-2H-l , 4-benzoxazine-7-carboxamide
A) 2-ethoxy-4-fluorobenzaldehyde
A mixture of K2CO3 (8878 mg, 64.23 mmol), ethyliodide (2.226 mL, 27.83 mmol) and 4-fluoro-2-hydroxybenzaldehyde (3000 mg, 21.41 mmol) in DMSO (30 mL) was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 20% EtOAc in hexane) to give the title compound (3270 mg, 19.45 mmol, 91%) as white solids.
1H NMR (300 MHz, CDC13) 5:1.50 (3H, t, J = 7.0 Hz), 4.13 (2H, q, J = 6.8 Hz), 6.61-6.77 (2H, m) , 7.86 (1H, dd, J = 8.5, 7.0 Hz), 10.39 (1H, s) .
[0680] B) (2-ethoxy-4-fluorophenyl ) methanol
NaBH4 (956 mg, 25.28 mmol) was added to a solution of 2- ethoxy-4-fluorobenzaldehyde (3270 mg, 19.45 mmol) in THF (40 mL) and MeOH (10.0 mL) at room temperature. The mixture was stirred with water bath for 90 min. The mixture was quenched with water at room temperature, and evaporated to remove excess amount of THF-MeOH. The residue was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title
compound (3316 mg, 19.49 mmol, 100%) as white solids.
1H NMR (300 MHz, CDC13) 5:1.45 (3H, t,. J = 7.0 Hz), 2.21 (1H, t, J = 6.6 Hz), 4.06 (2H, q, J = 7.2 Hz), 4.64 (2H, d, J = 6.8 Hz), 6.56-6.66 (2H, m) , 7.21 (1H, t, J = 7.4 Hz).
[0681]
C) 1- ( chloromethyl ) -2-ethoxy-4-fluorobenzene
A mixture of (2-ethoxy-4-fluorophenyl) methanol (1.6 g, 9.40 mmol), S0C12 (0.686 mL, 9.40 mmol) and CH3CN (30 mL) was stirred at room temperature for 15min. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (1.790 g, 9.49 mmol, 101%) as a colorless oil. This product was subjected to the next reaction without further purification.
1ti NMR (300 MHz, CDC13) 5:1.46 (3H, t, J = 7.0 Hz), 4.07 (2H, q, J = 7.2 Hz), 4.62 (2H, s), 6.56-6.67 (2H, m) , 7.30 (1H, dd, J = 8.1, 6.6 Hz) .
[0682]
D) 4- (2-ethoxy-4-fluorobenzyl) -N- (4- (methylsulfonyl ) benzyl ) - 3, 4-dihydro-2H-l , 4-benzoxazine-7-carboxamide
A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H-
1 , 4-benzoxazine-7-carboxamide (100 mg, 0.29 mmol), 1- ( chloromethyl) -2-ethoxy-4-fluorobenzene (65.3 mg, 0.35 mmol), sodium iodide (43.3 mg, 0.29 mmol) and K2CO3 (80 mg, 0.58 mmol) in DMF (3 mL) was stirred at 50 °C overnight. The mixture was quenched with brine at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over. MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 100% EtOAc in hexane) to give the title compound (53.0 mg, 0.106 mmol, 36.8%) as off-white solids.
λΗ NMR (300 MHz, DMSO-d6) 5:1.36 (3H, t, J = 7.0 Hz), 3.17 (3H, s), 3.47 (2H, t, J = 4.3 Hz), 4.09 (2H, q, . J = 7.1 Hz), 4.21 (2H, t, J = 4.2 Hz), 4.39-4.55 (4H, m) , 6.57-6.76 (2H, m) , 6.93 (1H, dd, J = 11.3, 2.6 Hz), 7.13 (1H, dd, J = 8.3, 7.2 Hz), 7.27-7.37 (2H, m) , 7.52 (2H, d, J = 8.7 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.77 (1H, t, J = 5.9 Hz).
[0683]
The compounds described in Examples 3 to 53 are below (Table 2- 1 - Table 2-8) . . . .
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
[0691]
[Table 2-8]
Figure imgf000297_0001
[0692]
5 The compounds described in Examples 10, 11, 20, 24, 28,
30, 32-36 and 38-50 were synthesized in the same manner as in the reaction and purification described in the Examples.
[0693]
Example 53
0 4- (4-isopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro- 2H-1 , 4-benzoxazine-7-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -3 , 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol) , l-bromo-4- isopropylbenzene (32 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg,5 8.00 μmol), RuPhos (3.73 mg, 8.00 μmol), NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under
microwave irradiation. The reaction mixture was diluted with AoOEt (3 mL) and quenched with H20 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous 0 layer was extracted with EtOAc (2 mL) . The combined organic
-■■ layer was evaporated by blowing away with the air at 60 °C. -The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at5 60°C to afford the title compound (18.2 mg, 0.0392 mmol, 49%).
[0694]
Example 57 4- (3-ethoxyphenyl) -N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- 1 , 4-benzoxa.zine-7-carboxami.de. .... . .. . . ..
A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol) , 3- bromophenetole (32 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol), RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130 °C for 2 h under
microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H2O (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5:95→100:0). Pure fractions were combined and concentrated by. blowing away with the air at 60°C to afford the title compound (22.9 mg, 0.0491 mmol, 64%).
[0695]
Example 68
4- (3-ethoxy-4-methoxyphenyl ) -N- (4- (methylsulfonyl ) benzyl ) -3, 4- dihydro-2H-l , 4-benzoxazine-7-carboxamide
A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol), 4-bromo-2- ethoxy-l-methoxybenzene (37 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (0.023 g, ,0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H2O (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60°C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (22.9 mg, 0.0461 mmol, 58%).
[0696] Example 75
4- ( 3-isopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro- 2H-1 , 4-benzoxazine-7-carboxamide
A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- 1 , 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol), l-bromo-3- isopropylbenzene (32 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol), RuPhos (3.73 mg, 8.00 μmol), NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130 °C for 2 h under
microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H2O (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5 : 95→100 :→0 ) . Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (21.9 mg, 0.0471 mmol, 59%) .
[0697]
Example 77
N- (4- (methylsulfonyl) benzyl) -4- (4- (1-
(trifluoromethyl) cyclopropyl) phenyl) -3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxamide
A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol), (l-bromo-4- (1- (trifluoromethyl) cyclopropyl) benzene (32 mg, 0.160 mmol),
RuPhos Pd Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H20 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The
combined organic layer was evaporated by blowing away with the air at 60°C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5:95→ 100:0). Pure fractions were combined and concentrated by blowing away with the air at 60 °C to afford the title compound (22.2 mg, 0.0.4.18 mmol, 52%).
[0698]
Example 78
4- (3, 5-diethylphenyl) -N- (4- (methylsulfonyl ) benzyl ) -3, 4-dihydro- 2H-1 , 4-benzoxazine-7-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -3, 4-dihydro-2H-
1.4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol), 1-bromo-
3.5-diethylbenzene (34 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol), RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130 °C for 2 h under
microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H20 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (23 mg, 0.0481 mmol, 60%).
[0699]
Example 79
4- ( 3-cyclopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl) -3,4- dihydro-2H-l , 4-benzoxazine-7-carboxamide
A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H-
1 , 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol), l-bromo-3- cyclopropylbenzene (32 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μιτιοΐ) , NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130 °C for 2 h under
microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H20 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5:95→100:0). Pure fractions were combined and concentxated by blowing away with the air at 60°C to afford the title compound (19.8 mg, 0.0428 mmol, 54%).
[0700]
The compounds described in Examples 54 to 104 , are below (Table 3-1 - Table 3-8) .
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
[0708]
[Table 3-8]
Figure imgf000309_0001
[0709]
The compounds described in Examples 54-56, 58-67, 69-74,
76, and 80-104 were synthesized in the same manner as in the reaction and purification described in the Examples.
[0710]
Example 105
N- (4- (methylsulfonyl ) benzyl) -4- (quinoxalin-6-yl) -3, 4-dihydro- 2H-1 , 4-benzoxazine-7-carboxamide
A mixture of N- (4- (methylsulfonyl) benzyl) -3, 4-dihydro-2H- 1 , 4-benzoxazine-7-carboxamide (0.028 g, 0.08 mmol) , 6- bromoquinoxaline (33 mg, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 μmol), RuPhos (3.73 mg, 8.00 μηαοΐ) , NaOtBu (0.023 g, 0.240 mmol) and D E (1 mL) was heated at 130 °C for 2 h under
microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H20 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 itiM NH4HCO3 aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (18.3 mg, 0.0368 mmol, 48%).
[0711]
The compounds described in Examples 105 to 141 are below
Figure imgf000310_0001
Figure imgf000311_0001
Figure imgf000312_0001
Figure imgf000313_0001
Figure imgf000314_0001
[0717]
[Table
Figure imgf000315_0001
[0718]
The compounds described in Examples 106-141 were
synthesized in the same manner as in the reaction and
purification described in the Examples.
[0719]
Example 145
1- (4-cyclopropylphenyl) -N- (2-fluoro-4- (methylsulfonyl ) benzyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide
A) (E) -2-fluoro-4- (methylsulfonyl ) benzaldehyde oxime
To a mixture of 2-fluoro-4- (methylsulfonyl ) benzaldehyde (305 mg, 1.51 mmol) and MeOH (10 mL) was added hydroxylamine hydrochloride (205 mg, 2.95 mmol) . After being stirred at room temperature for 1 h, 10% Pd-C (50% wet, 154 mg, 0.14 mmol) was added to the mixture. After being stirred at room temperature under hydrogen atmosphere overnight, the insoluble material was filtered off. TEA was added to the filtrate and the mixture was concentrated. The residue was suspended in EtOAc. The insoluble material was filtered off and the filtrate was
concentrated. The residue was purified by column
chromatography (NH silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title .compound (218 mg, 1.004 mmol, 66.5%) as white solids.
1H NMR (300 MHz, DMSO-d5) 5:3.29 (3H, s) , 7.79 (1H, dd, J = 8.3, 1.5 Hz), 7.86 (1H, dd, J = 9.8, 1.9 Hz), 7.96-8.05 (1H, m) , 8.29 (1H, s) , 12.04 (1H, s) .
[0720]
B) 1- (2-fluoro-4- (methylsulfonyl) phenyl) methanamine
hydrochloride
To a mixture of (E) -2-fluoro-4-
(methylsulfonyl ) benzaldehyde oxime (217 mg, 1.00 mmol), 2 M HC1 in MeOH (1.0 mL, 2.00 mmol) and MeOH (5 mL) was added 10% Pd-C (50% wet, 100 mg, 0.09 mmol). After being stirred at room temperature under hydrogen atmosphere overnight, the insoluble material was filtered off and the filtrate was concentrated in vacuo to give the title compound (162 mg, 0.676 mmol, 67.7%) as white solids.
MS (ESI+), found 204.3 (M-HC1+H)
1H NMR (300 MHz, DMSO-d6) 5:3.30 (3H, s) , 4.17' (2H, s), 7.78- 7.93 (3H, m) , 8.28 (3H, brs).
[0721]
C) methyl 1- ( 4-cyclopropylphenyl ) -2, 3-d : hydro-": H-pyr i do [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylate
A mixture of methyl 2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylate (51 mg, 0.26 mmol), l-bromo-4- cyclopropylbenzene (70 μL, 0.52 mmol), Pd2(dba)3 (13 mg, 0.01 mmol), XPHOS (12 mg, 0.03 mmol), K3PO4 (113 mg, 0.53 mmol) and toluene (5 mL) was stirred under nitrogen atmosphere at 100°C for 16 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (31.0 mg, 0.100 mmol, 38.0%) as pale yellow solids.
MS (ESI+), found 311.3 (M+H)
[0722]
D) 1- (4-cyclopropylphenyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid
To a mixture of methyl 1- (4-cyclopropylphenyl) -2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylate (30 mg, 0.10 mmol) in THF (1 mL) and MeOH (3 mL) was added 2 M NaOH aq.
(0.15 mL, 0.30 mmol). After being stirred at 60°C overnight, the mixture was acidified with 1 M HC1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was subjected to the next reaction without further purification.
[0723]
E) 1- ( 4-cyclopropylphenyl ) -N- (2-fl-uoro-4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
To a mixture of 1- ( 4-cyclopropylphenyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (29 mg, 0.10 mmol), 1- (2-fluoro-4- (methylsulfonyl ) phenyl) methanamine hydrochloride (29 mg, 0.12 mmol), HATU (62 mg, 0.16 mmol) and DMF (3 mL) was added DIPEA (70 μL, 0.40 mmol) . After being stirred at room temperature for 3 h, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 70% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H20 in acetonitrile containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat.
NaHCO3 aq. and brine, dried over Na2SO4 and concentrated. The residue was suspended in IPE and collected by filtering to give the title compound (19.00 mg, 0.039 mmol, 40.3%) as white solids .
1H NMR (300 MHz, CDC13) 5:0.67-0.77 (2H, m) , 0.96-1.07 (2H, m) , 1.86-1.99 (1H, m) , 3.03 (3H, s) , 3.72-3.78 (2H, m) , 4.51-4.57 (2H, m) , 4.72 (2H, d, J = 6.4 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.10-7.18 (4H, m) , 7.58-7.71 (4H, m) , 8.08 (1H, t, J = 6.2 Hz).
[0724]
Example 146
1- (3-cyclopropyl-5-methylphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6-carboxamide
A) 1- (tert-butoxycarbonyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid
To a mixture of 1-tert-butyl 6-methyl 2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-1 , 6-dicarboxylate (1.52 g, 5.16 mmol) , THF (5 mL) and MeOH (15 mL) was added 2 M NaOH aq. (5.0 mL, 10.00 mmol). After being stirred at room temperature overnight, the mixture was acidified with 1 M HC1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over
Na2SCO4 and concentrated to give the title compound as crude product, which was subjected to the next reaction without further purification.
[0725]
B) tert-butyl 6- (( 4- (methylsulfonyl ) benzyl ) carbamoyl ) -2 , 3- dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-l-carboxylate
To a mixture of 1- (tert-butoxycarbonyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid (1.45 g, 5.17 mmol), ( 4- (methylsulfonyl ) phenyl ) methanamine (1.15 g, 6.21 mmol), HATU (2.95 g, 7.76 mmol) and DMF (30 mL) was added DIPEA (2.7 mL, 15.50 mmol). After being stirred at room temperature overnight, the mixture, was poured into water and extracted with EtOAc.
The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column
chromatography (silica gel, eluted with 30% - 70% EtOAc in hexane) to give the title compound (2.220 g, 4.96 mmol, 96%) as white solids.
MS (ESI+), found 448.2 (M+H)
1H NMR (300 MHz, CDC13) 5:1.56 (9H, s), 3.03 (3H, s) , 3.90-3.97 (2H, m) , 4.39-4.46 (2H, m) , 4.70 (2H,. d, J = 6.4 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.83-7.94 (3H, m) , 8.17 (1H, t, J = 5.5 Hz), 8.45 (1H, d, J = 8.7 Hz) .
[0726]
C) N- (4- (methylsulfonyl) benzyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
To a mixture of tert-butyl 6-((4- (methylsulfonyl) benzyl) carbamoyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [1, 4] oxazine-l-carboxylate (2.22 g, 4.96 mmol) and MeOH (10 mL) was added 4 M HC1 in EtOAc (10 mL, 40.00 mmol) . After being stirred at 60°C for 2 h, the mixture was concentrated. The residue was dissolved in water, basified with sat. NaHCCO3 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was washed with IPE to give the title compound (1.300 g, 3.74 mmol, 75%) as pale yellow solids.,
MS (ESI+), found 348.1 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:3.17 (3H, s), 3.33-3.38 (2H, m) , 4.26-4.34 (2H, m) , 4.50 (2H, d, J = 6.4 Hz), 6.94 (1H, d, J = 7.9 Hz), 7.46 (1H, d, J = 7.9 Hz), 7.52 (2H, d, J = 8.7 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.82 (1H, t, J = 6.4 Hz). (An
exchangeable proton was omitted)
[0727] " '"
D) 3-cyclopropyl-5-methylphenol
To a solution of 3-bromo-5-methylphenol (500 mg, 2.67 mmol), cyclopropylboronic acid (344 mg, 4.01 mmol),
tricyclohexylphosphine (150 mg, 0.53 mmol) and potassium
phosphate (1702 mg,. 8..02 mmol) in toluene .(10 mL) /water (2.00 mL) was added Pd(OAc)2 (60.0 mg, 0.27 mmol) at room temperature. The mixture was stirred at 100 °C under Ar overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 30% EtOAc in hexane) to give the title compound (144 mg, 0.972 mmol,
36.3%) as a pale orange oil.
1H NMR (300 MHz, CDC13) 5:0.62-0.70 (2H, m) , 0.86-0.97 (2H, m) , 1.74-1.87 (1H, m) , 2.26 (3H, s) , 4.57 (1H, s), 6.33 (1H, s) , 6.43 (1H, s) , 6.49 (1H, s) .
[0728]
E) 3-cyclopropyl-5-methylphenyl trifluoromethanesulfonate
To a solution of 3-cyclopropyl-5-methylphenol (144 mg, 0.97 mmol) in pyridine (3 mL) was added Tf20 (0.197 mL, 1.17 mmol) at 0°C. The mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 20% EtOAc in hexane) to give the title compound (227 mg, 0.810 mmol, 83%) as a colorless oil.
1R NMR (300 MHz, CDC13) 5:0.64-0.74 (2H, m) , 0.96-1.05 (2H, m) , 1.82-1.94 (1H, m) , 2.34 (3H, s) , 6.74 (1H, s), 6.84 (1H, s), 6.88 (1H, s) .
[0729]
F) 1- ( 3-cyclopropyl-5-methylphenyl ) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (70 mg, 0.20 mmol), 3- cyclopropyl-5-methylphenyl trifluoromethanesulfonate (120 mg, 0.43 mmol), Ruphos pre-catalyst (15 mg, 0.02 mmol), NaOtBu (55 mg, Q.57 mmol) and DME (3 mL) was stirred at 120 °C for 2 h under microwave irradiation. After being cooled, the mixture was filtered through celite and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) , suspended in IPE and collected by
filtering to give the title compound (22.00 mg, 0.046 mmol, 22.86%) as white solids.
1H NMR (300 MHz, CDC13) 5:0.64-0.73 (2H, m) , 0.94-1.04 (2H, m) , 1.80-1.92 (1H, m) , 2.33 (3H, s) , 3.03 (3H, s) , 3.71-3.79 (2H, m) , 4.49-4.56 (2H, m) , 4.69 (2H, d, J = 6.4 Hz), 6.72-6.78 (2H, m) , 6.83 (1H, s) , 7.09 (1H, d, J = 7.9 Hz), 7.54 (2H, d, J = 8.7 Hz), 7.67 (1H, d, J = 8.3 Hz), 7.89 (2H, d, J = 8.7 Hz), 8.11 (1H, t, J = 6.4 Hz) .
[0730]
Example 147
1- (3-cyclopropyl-4-methylphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxamide A) 3-cyclopropyl-4-methylphenol
To a solution of 3-bromo-4-methylphenol (500 mg, 2.67 mmol), cyclopropylboronic acid (344 mg, 4.01 mmol),
tricyclohexylphosphine (150 mg, 0.53 mmol) and potassium
phosphate (1702 mg, 8.02 mmol) in toluene (10 mL) /water (2.00 mL) was added Pd(0Ac)2 (60.0 mg, 0.27 mmol) at room temperature. The mixture was stirred at 100 °C under Ar overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 30% EtOAc in hexane) to give the title compound (361 mg, 2.436 mmol, 91%) as an orange oil.
1H NMR (300 MHz, CDC13) 6:0.54-0.66 (2H, m) , 0.86-0.97 (2H, m) , 1.79-1.92 (1H, m) , 2.33 (3H, s) , 4.51 (1H, s) , 6.45 (1H, d, J = 2.6 Hz) , 6.56 (1H, dd, J = 8.1, 2.8 Hz) , 6.99 (1H, d, J = 7.9 Hz) .
[0731]
B) 3-cyclopropyl-4-methylphenyl trifluoromethanesulfonate
To a solution of 3-cyclopropyl-4-methylphenol (361 mg,
2.44 mmol) in pyridine (7 mL) was added Tf20 (0.494 mL, 2.92 mmol) at 0°C. The mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2%- 20% EtOAc in
hexane) to give the title compound (576 mg, 2.055 mmol, 84%) as a colorless oil.
[0732]
C) 1- ( 3-cyclopropyl-4-methylphenyl ) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxamide (70 mg, 0.20 mmol), 3- cyclopropyl-4-methylphenyl trifluoromethanesulfonate (113 mg, 0.40 mmol) , Ruphos pre-catalyst (14.68 mg, 0.02 mmol), NaOtBu (58.1 mg, 0.60 mmol) and DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (70.0 mg, .0.14.7. mmol , 72.7%) as pale yellow solids.
1H NMR (300 MHz, DMSO-d6) 5:0.56-0.67 (2H, m) , 0.84-0.98 (2H, m) , 1.86-1.98 (1H, m) , 2.39 (3H, s) , 3.18 (3H, s) , 3.67-3.77 (2H, m) , 4.42-4.57 (4H, m) , 6.87-6.98 (2H, m) , 7.05 (1H, dd, J = 7.9, .2.3 Hz), 7.23 (1H, d, J = 7.9 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 8.94 (1H, t, J = 6.4 Hz) .
[0733]
Example 148
1- ( 5-cyclopropyl-2-methylphenyl ) -N- (4- (methylsulfonyl ) benzyl ) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6-carboxami.de
A) 5-cyclb.propyl-2-methylphenol
To a solution of 5-bromo-2-methylphenol (500 mg, 2.67 mmol), cyclopropylboronic acid (344 mg, 4.01 mmol),
tricyclohexylphosphine (150 mg, 0.53 mmol) and potassium
phosphate (1702 mg, 8.02 mmol) in toluene (10 mL) /water (2.00 mL) was added diacetoxypalladium (60.0 mg, 0.27 mmol) at room temperature. The mixture was stirred at 100 °C under Ar
overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSCO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 30% EtOAc in- hexane) to give the title compound (192 mg, 1.296 mmol, 48.5%) as a pale yellow oil.
1H NMR (300 MHz, CDC13) 5:0.57-0.70 (2H, m) , 0.85-0.98 (2H, m) , 1.81 (1H, tt, J = 8.4, 5.2 Hz), 2.20 (3H, s) , 4.58 (1H, s) , 6.49 (1H, d, J = 1.5 Hz), 6.59 (1H, dd, J = 7.7, 1.7 Hz), 6.99 (1H, d, J = 7.6 Hz) . [0734]
B) 5-cyclopropyl-2-methylphenyl trifluoromethanesulfonate
To a solution of 5-cyclopropyl-2-methylphenol (106 mg, 0.72 mmol) in pyridine (2 mL) was added Tf20 (0.145 mL, 0.86 mmol) at 0°C. The mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 20% EtOAc in hexane) to give the title compound (113 mg, 0.403 mmol, 56.4%) as a colorless oil.
[0735]
C) 1- ( 5-cyclopropyl-2-methylphenyl ) -N- (4- (methylsulfonyl) benzyl) -2 , 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide (70 mg, 0.20 mmol), 5- cyclopropyl-2-methylphenyl trifluoromethanesulfonate (113 mg, 0.40 mmol), Ruphos pre-catalyst (14.68 mg, 0.02 mmol), NaOtBu (58.1 mg, 0.60 mmol) and DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (85 mg, 0.178 mmol, 88%) as yellow solids.
1H NMR (300 MHz, DMSO-d6) 5:0.59-0.73 (2H, m) , 0.84-0.99 (2H, m) , 1.83-1.95 (1H, m) , 2.08 (3H, s) , 3.17 (3H, s) , 3.50-3.62
(1H, m) , 3.74-3.87 (1H, m) , 4.43-4.61 (4H, m) , 6.34 (1H, d, J = 8.3 Hz), 6.99 (1H, dd, J = 7.9, 1.9 Hz), 7.06 (1H, d, J = 1.9 Hz), 7.25 (1H, d, J = 7.9 Hz), 7.44 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.3 Hz) , 7.81-7.91 (2H, m) , 8.92 (1H, t, J = 6.4 Hz) .
Figure imgf000324_0001
Figure imgf000325_0001
[0739]
The compounds described in Examples 142-144 and 149-151 were synthesized in the same manner as in the reaction and purification described in the Examples.
[0740]
Example 152
5- ( 4-isopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -2,3,4,5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide
The mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (0.029 g, 0.08 mmol) , l-bromo-4-isopropylbenzene (0.032 g, 0.160 mmol), RuPhos-Pd-Gl (5.83 mg, 8.00 pmol) , RuPhos (3.73 mg, 8.00 pmol), NaOtBu
(0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was
diluted with AcOEt (3 mL) and quenched with H2O (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The
combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC
(Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5:95 → 100:0). Pure fractions were combined and concentrated by blowing away with the air at 60 °C to afford the title compound (8.7 mg, 0.0182 mmol, 22.7%).
[0741]
Example 162
5- ( 4-fluoro-3-methoxyphenyl ) -N- (4- (methylsulfonyl) benzyl) - 2,3,4, 5-tetrahydro-l, 5-benzoxazepine-8-carboxamide
A) methyl 4- (bis (tert-butoxycarbonyl) amino) -3- ( (tert- butoxycarbonyl ) oxy) benzoate
A mixture of methyl 4-amino-3-hydroxybenzoate (30 g,
179.47 mmol) and Boc20 (125 mL,' 538.40 mmol) in THF (400 mL) was stirred at room temperature for 3 days. The mixture was concentrated, in vacuo to give the title compound (85 g, 182 mmol, 101%) as a light brown oil. This product was subjected to the next reaction without further purification.
[0742]
B) 5-tert-butyl 8-methyl 3, 4-dihydro-l, 5-benzoxazepine-5, 8 (2H) - dicarboxylate
K2CO3 (75 g, 545.44 mmol) was .added, to a solution of methyl 4- (bis (tert-butoxycarbonyl) amino) -3- ( (tert- butoxycarbonyl ) oxy) benzoate (85 g, 181.81 mmol) in MeOH (500 mL) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo.. The residue was diluted with acetone (200 mL) . To the
suspension were added 1 , 3-dibromopropane (44.0 g, 218.18 mmol) and K2CO3 (25.1 g, 181.81 mmol), and the mixture was stirred at 50 °C overnight. After cooling, the mixture was concentrated in vacuo. The residue was diluted with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 15% EtOAc in hexane) to give pale yellow solids. The solids were washed with EtOAc-IPE and dried in vacuo to give the title compound (13.10 g, 42.6 mmol, 23.44%) as white powder.
MS (ESI+), found 208.3 (M+H) 1H NMR (300 MHz, DMSO-d6) 5:1.39 (9H, s), 1.90-2.02 (2H, m) , 3.64 (2H, brs), 3.83 (3H, s) , 4.09 (2H, t, J = 5.3 Hz), 7.38 (1H, d, J = 8.3 Hz), 7.50 (1H, d, J = 2.3 Hz), 7.59 (1H, dd, J = 8.3, 1.9 Hz) .
[0743]
C) 5- (tert-butoxycarbonyl) -2, 3, 4, 5-tetrahydro-l , 5- benzoxazepine-8-carboxylic acid ..
2N aq. NaOH (56.9 mL, 113.88 mmol) was added to a
solution of 5-tert-butyl 8-methyl 3 , 4-dihydro-l , 5- benzoxazepine-5, 8 (2H) -dicarboxylate (7 g, 22.78 mmol) in MeOH (105 mL) -THF (21 mL) at room temperature. The mixture was stirred at 40°C for 1 h. The mixture was acidified by IN HC1 aq. at 0°C and diluted with water. Precipitates were collected by filtration, washed with water and dried in vacuo to give the title compound (6.46 g, 22.02 mmol, 97%) as white powder.
MS (ESI+), found 194.4 (M-Boc+2H)
1H NMR (300 MHz, DMSO-d6) 5:1.39 (9H, brs), 1.89-2.01 (2H, m) , 3.64 (2H, brs), 4.08 (2H, t, J = 5.1 Hz), 7.35 (1H, d, J = 8.3 Hz), 7.48... (1H, d, J = 1.9 Hz), 7.57 (1H, dd, J - 8.3, 2.3 Hz), 13.00 (1H, brs) .
[0744]
D) tert-butyl 8- ( (4- (methylsulfonyl ) benzyl) carbamoyl) -3, 4- dihydro-1, 5-benzoxazepine-5(2H) -carboxylate
HATU (7.26 g, 19.09 mmol) was added to a mixture of 5- (tert-butoxycarbonyl ) -2 , 3 , 4 , 5-tetrahydro-l , 5-benzoxazepine-8- carboxylic acid (4 g, 13.64 mmol), (4-
(methylsulfonyl ) phenyl ) methanamine (2.78 g, 15.00 mmol) and DIPEA (10.48 mL, 60.00 mmol) in DMF (25mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtQAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 70%- 95% EtOAc in hexane) to give the title compound (6.63 g, 14.40 mmol, 106%) as white solids. MS (ESI+), found 361.2 (M-Boc+2H)
1H NMR (300 MHz, CDC13) 5:1.45 (9H, brs) , 2.04-2.13 (2H, m) , 3.04 (3H, s), 3.75 (2H, brs), 4.08-4.20 (2H, m) , 4.72 (2H, d, J = 6.0 Hz), 6.55 (1H, brs), 7.33-7.44 (3H, m) , 7.54 (2H, d, J = 8.3 Hz), 7.91 (2H, d, J = 8.3 Hz.)..
[0745]
E) N- (4- (methylsulfonyl) benzyl) -2 , 3 , 4 , 5-tetrahydro-l , 5- benzoxazepine-8-carboxamide
TFA (20 mL, 259.60 mmol) was added to a suspension of tert-butyl 8- ( (4- (methylsulfonyl ) benzyl) carbamoyl) -3, 4-dihydro- 1, 5-benzoxazepine-5 (2H) -carboxylate (5.3 g, 11.51 mmol) in EtOAc (90 mL) at 0°C. The mixture was stirred at room
temperature overnight. To the mixture was added TFA (30 mL, 389.39 mmol) at room temperature. The mixture was stirred at room temperature overnight. TFA (20 mL, 259.60 mmol) was added to the mixture at room temperature and stirred for 5h. The mixture was neutralized with 8N NaOH aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over .Mg.SO4 and concentrated in vacuo to give the title compound (4.37 g, 12.12 mmol, 105%) as off-white solids .
MS (ESI+), found 361.2 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:1.90 (2H-, t, J = 5.5 Hz), 3.15-3.21 (5H, m) , 4.05 (2H, t, J = 5.7 Hz), 4.50 (2H, d, J = 5.7 Hz), 5.90 (1H, s), 6.77 (1H, d, J = 8.3 Hz), 7.35-7.39 (2H, m) ,
7.50-7.56 (2H, m) , 7.84-7.89 (2H, m) , 8.81 (1H, t, J = 5.9 Hz).
[0746]
F) 5- (4-fluoro-3-methoxyphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2,3,4, 5-tetrahydro-l , 5-benzoxazepine-8-carboxamide
-■■ The mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1, 5-benzoxazepine-8-carboxamide (29 mg, 0.08 mmol), 2-fluoro-5-bromoanisole (33 mg, 0.160 mmol), RuPhos-Pd-Gl (5.83 mg, 8.00 pmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (23 mg, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H20 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (5.7 mg, 0.0118 mmol, 15%).
[0747]
Example 166
5- (3-ethoxy-4-methoxyphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2,3,4, 5-tetrahydro-l, 5-benzoxazepine-8-carboxamide
A mixture of N- ( 4- (methylsulfonyl) benzyl ) -2, 3, 4 , 5- tetrahydro-1, 5-benzoxazepine-8-carboxamide (29 mg, 0.08 mmol), 4-bromo-2-ethoxy-l-methoxybenzene (37 mg, 0.160 mmol), RuPhos- Pd-Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (23 mg, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched. with H20 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5 : 95→100 : 0 ) .. Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (7.4 mg, 0.0145 mmol, 18%).
[0748]
Example 167
5- (3, 5-dimethoxyphenyl) -N- (4- (methylsulfonyl ) benzyl) -2,3,4,5- tetrahydro-1 , 5-benzoxazepine=8-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1, 5-benzoxazepine-8-carboxamide (29 mg, 0.08 mmol), l-bromo-3, 5-dimethoxybenzene (35 mg, 0.160 mmol), RuPhos-Pd-Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (23 mg, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H20 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5:95→100:0). Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (10.1 mg, 0.0203 mmol, 15%).
[0749]
Example 175
5- (3, 5-diethylphenyl) -N- (4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (29 mg, 0.08 mmol), l-bromo-3, 5-diethylbenzene (34 mg, 0.160 mmol), RuPhos-Pd-Gl (5.83 mg, 8.00 μmol) , RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (23 mg, 0.240 mmol) and DME (1 mL) was heated at 130°C for 2 h under microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H20 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus Triart C18, eluted with MeCN/10 mM NH4HCO3 aq. 5 : 95→100 : 0 ) . Pure fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (14.4 mg, 0.0292 mmol, 37%).
[0750]
The compounds described in Examples 152 to 192 are below (Table 6-1 - Table 6-6) .
Figure imgf000331_0001
Figure imgf000332_0001
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
[0757]
The compounds described in Examples 153-161, 163-165,
168-174, and 176-192 were synthesized in the same manner as in the reaction and purification described in the Examples.
[0758]
Example 194
1- ( 4-cyclopropyl-3-methylphenyl ) -N- (4- (methylsulfonyl ) benzyl ) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide A) 4-cyclopropyl-3-methylphenol
To a solution of 4-bromo-3-methylphenol (500 mg, 2.67 mmol), cyclopropylboronic acid (344 mg, 4.01 mmol) ,
tricyclohexylphosphine (150 mg, 0.53 mmol) and potassium
phosphate (1702 mg, 8.02 mmol) in toluene (10 mL) /water (2.00 mL) was added Pd(0Ac)2 (60.0 mg, 0.27 mmol) at room temperature. The mixture was stirred at 100 °C under Ar overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over
MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 2% - 30% EtOAc in hexane) to give the title compound (300 mg, 2.024 mmol, 76%) as an orange oil.
1H NMR (300 MHz, CDC13) 5:0.50-0.59 (2H, m) , 0.81-0.91 (2H, m) , 1.71-1.85 (1H, m) , 2.37 (3H, s) , 4.55 (1H, s), 6.57 (1H, dd, J = 8.3, 2.6 Hz), 6.64 (1H, d, J = 2.6 Hz), 6.88 (1H, d, J = 8.3 Hz) .
[0759]
B) 4-cyclopropyl-3-methylphenyl trifluoromethanesulfonate
To a solution of 4-cyclopropyl-3-methylphenol (300 mg,
2.02 mmol) in pyridine (3 mL) was added Tf20 (0.410 mL, 2.43 mmol) at 0°C. The mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO4 and concentrated in vacuo to give the title compound (510 mg, 1.820 mmol, 90%) as a yellow oil. The obtained oil was used for next reaction without further purification.
[0760]
C) 1- (4-cyclopropyl-3-methylphenyl). -N- (4- · -
(methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxamide (60 mg, 0.17 mmol), 4- cyclopropyl-3-methylphenyl trifluoromethanesulfonate (97 mg, 0.35 mmol) , Ruphos pre-catalyst (12.59 mg, 0.02 mmol) , NaOtBu (49.8 mg, 0.52 mmol) and DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. The mixture was filtered through celite and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) and (NH silica gel, eluted with 30% - 100% EtOAc in hexane) to give the title compound (52.0 mg, 0.109 mmol, 63.0%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:0.56-0.66 (2H, m) , 0.87-0.98 (2H, m) , 1.84-1.96 (1H, m) , 2.31-2.43 (3H, m) , 3.17 (3H, s), 3.68- 3.79 (2H, m) , 4.42-4.58 (4H, m) , 6.95-7.10 (3H, m) , 7.14 (1H, d, J = 1.9 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.7 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.94 (1H, t, J = 6.4 Hz).
[0761]
The compounds described in Examples 193 to 195 are below
(Table 7) .
[0762]
[Table 7]
Figure imgf000338_0001
[0763]
The compounds described in Examples 193 and 195 were synthesized in the same manner as in the reaction and
purification described in the Examples. [0764]
Example 196
N- (4- (methylsulfonyl) benzyl) -5- (quinoxalin-6-yl ) -2,3,4,5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide
The mixture of N- ( 4- (methylsulfonyl ) benzyl) -2 , 3, 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (0.029 g, 0.08 mmol) , 6-bromoquinoxaline (0.033 g, 0.160 mmol), RuPhos Pd Gl (5.83 mg, 8.00 pmol), RuPhos (3.73 mg, 8.00 μmol) , NaOtBu (0.023 g, 0.240 mmol) and DME (1 mL) was heated at 130 °C for 2 h under
microwave irradiation. The reaction mixture was diluted with AcOEt (3 mL) and quenched with H20 (1 mL) , and stirred for 2 min. The organic layer was separated and then the aqueous layer was extracted with EtOAc (2 mL ) . The combined organic layer was evaporated by blowing away with the air at 60 °C. The residue was purified by preparative HPLC (Actus. Triart C18, eluted with MeCN/10 mM NH4HCO3 aq . 5:95 → 100:0) . Pure
fractions were combined and concentrated by blowing away with the air at 60°C to afford the title compound (5.6 mg, 0.0115 mmol, 14.3%) . .
[0765]
The compounds described in Examples 196 to 220 are below (Table 8-1 - Table 8-4) .
Figure imgf000340_0001
Figure imgf000341_0001
Figure imgf000342_0001
[0769]
[Table 8-4]
Figure imgf000343_0001
[0770]
The compounds described in Examples 197 and 220 were synthesized in the same manner as in the reaction and
purification described in the Examples.
[0771]
Example 223
N- (4- (methylsulfonyl) benzyl) -4- (2-phenylethyl) -3, 4-dihydro-2H- 1, 4-benzoxazine-7-carboxamide
To a solution of N- (4- (methylsulfonyl) benzyl) -3, 4- dihydro-2H-l , 4-benzoxazine-7-carboxamide (50 mg, 0.14 mmol) and 2-phenylacetaldehyde (0.024 mL, 0.22 mmol) in AcOH (0.1 mL) and MeOH (1 mL) was added borane-2-picoline complex (23.16 mg, 0.22 mmol) at room temperature. The mixture was stirred at 60 °C under N2 overnight. The mixture was neutralized with sat.
NaHCO3 aq. at 0°C and extracted with EtOAc . The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. . The residue was purified by column chromatography (silica gel, eluted with 20% - 100% EtOAc in hexane) to give the title compound (55.0 mg, 0.122 mmol, 85 %) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:2.83 (2H, t, J = 7.4 Hz),, 3.18 (3H, s), 3.27-3.33 (2H, m) , 3.51-3.63 (2H, m) , 4.09 (2H, t, J = 4.3 Hz), 4.52 (2H, d, J = 5.7 Hz), 6.80 (1H, d, J = 8.7 Hz), 7.17- 7.34 (6H, m) , 7.42 (1H, dd, J = 8.5, 2.1 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.88 (2H, d, J = 8.3 Hz) , 8.80 (1H, t, J = 6.0 Hz) .
[0772]
Example 227
4- (2-ethoxy-4-fluorobenzyl) -N- (4- (methylsulfonyl ) benzyl) -3-oxo- 3, 4-dihydro-2H-l , 4-benzoxazine-7-carboxamide
A) ethyl 3-oxo-3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylate
A suspension of 3-oxo-3 , 4-dihydro-2H-l , 4-benzoxazine-7- carboxylic acid (1000 mg, 5.18 mmol) and H2SO4 (0.276 mL, 5.18 mmol) in EtOH (25 mL) was refluxed overnight. After being cooled to rt, the reaction mixture was evaporated. The mixture was poured into sat. NaHCO3 aq. at room temperature and
extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was suspended in IPE and filtered to give the title compound (487 mg, 2.202 mmol, 42.5%) as brown solids.
1H NMR (300 MHz, DMSO-d6) 5:1.29 (3H, t, J = 7.0 Hz), 4.27 (2H, q, J = 7.1 Hz), 4.64 (2H, s), 6.98 (1H, d, J = 7.9 Hz), 7.43
(1H, d, J = 1.9 Hz), 7.58 (1H, dd, J = 8.1, 1.7 Hz), 11.06 (1H, s) -
[0773]
B) ethyl 4- (2-ethoxy-4-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylate
NaH (60% in oil, 26.3 mg, 0.66 mmol) was added to a solution of ethyl 3-oxo-3, 4-dihydro-2H-l, 4-benzoxazine-7- carboxylate (112 mg, 0.50 mmol) and 1- (chloromethyl) -2-ethoxy- 4-fluorobenzene (100 mg, 0.53 mmol) in DMF(dry) (4 mL) at room temperature. The mixture was stirred at room temperature for 3 days. The mixture was poured into water . and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, eluted with 5% - 25% EtOAc in hexane) to give the title
compound (94 mg, 0.252 mmol, 49.9%) as off-white solids.
MS (ESI+), found 374.3 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:1.28 (3H, t, J = 7.0 Hz), 1.36 (3H, t, J = 7.0 Hz), 4.11 (2H, q, J = 6.8 Hz), 4.27 (2H, q, J = 6.9 Hz), 4.85 (2H, s) , 5.04 (2H, s) , 6.67 (1-H-, -td, J = 8.5, 2.3 Hz), 6.93 (1H, dd, J = 11.1, 2.5 Hz), 6.99-7.09 (2H, m) , 7.48 (1H, d, J = 1.5 Hz), 7.56 (1H, dd, J = 8.3, 1.9 Hz).
[0774]
C) 4- (2-ethoxy-4-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-l, 4- benzoxazine-7-carboxylic acid
• 2N NaOH (0.378 mL, 0.76 mmol) was added to a solution of ethyl 4- (2-ethoxy-4-fluorobenzyl) -3-oxo-3, 4-dihydro-2H-l , 4- benzoxazine-7-carboxylate (94 mg, 0.25 mmol) in MeOH (0.8 mL) and THF (1.600 mL) at room temperature. The mixture was
stirred at room temperature for 4h. The mixture was slightly acidified with IN HC1 aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (91 mg, 0.264 mmol, 105%) as white solids.
[0775]
D) 4- (2-ethoxy-4-fluorobenzyl) -N- (4- (methylsulfonyl ) benzyl) -3- ■oxo-3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxamide
(4- (methylsulfonyl) phenyl )methanamine (53.7 mg, 0.29 mmol), HATU (110 mg, 0.29 mmol) and DIPEA (0.092 mL, 0.53 mmol) were added to a solution of 4- (2-ethoxy-4--fluorobenzyl) -3-oxo- 3, 4-dihydro-2H-l, 4-benzoxazine-7-carboxylic acid (91 mg, 0.26 mmol) in DMF(dry) (3.0 mL) . The mixture was stirred at room temperature overnight. The mixture was poured into sat NaHCO3 aq. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give off-white solids. The solids were crystallized from EtOAc- hexane to give the title compound (62.0 mg, 0.121 mmol, 45.9%) as off-white solids.
1H NMR (300 MHz, DMSO-d6) 5:1.37 (3H, t, J = 7.0 Hz), 3.17 (3H, s), 4.11 (2H, q, J = 7.2 Hz), 4.53 (2H, d, J = 6.0 Hz), 4.83 (2H, s), 5.04 (2H, s) , 6.67 (1H, td, J = 8.5, 2.6 Hz), 6.94 (1H, dd, J = 11.3, 2.3 Hz), 6.99-7.10 (2H, m) , 7.47-7.60 (4H, m) , 7.87 (2H, d, J = 8.3 Hz), 9.09 (1H, t, J = 6.0 Hz).
[0776]
Example 229
1- (4-fluoro-3-isopropyl-5-methylphenyl) -N- (4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A) 2- ( 5-bromo-2-fluoro-3-methylphenyl ) propan-2-ol
1.6 M n-BuLi in hexane (7.94 mL, 12.70 mmol) was added to a solution of bis ( isopropyl ) amine (2.246 mL, 15.87 mmol) in THF(dry) (10 mL) at -78 °C. The mixture was stirred at -7.8 °C under Ar for 30 min. The solution of 4-bromo-l-fluoro-2- methylbenzene (1.338 mL, 10.58 mmol) in THF was added. The mixture was stirred at -78 °C under Ar for 1 h. Propan-2-one (0.935 mL, 12.70 mmol) was added. The mixture was stirred at - 78°C under Ar for 2 h. The mixture was poured into IN HC1 aq. and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 3% - 12% EtOAc in hexane) to give the title
compound (1.780 g, 7.20 mmol, 68.1%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:1.-46 (6H, d, J = 1.1 Hz), 2.21 (3H, d, J = 2.6 Hz), 5.39 (1H, s), 7.32-7.42 (1H, m) , 7.55 (1H, dd, J = 6.8, 2.6 Hz) .
[0777]
B) 5-bromo-2-fluoro-1-isopropyl-3-methylbenzene
To a mixture of 2- ( 5-bromo-2-fluoro-3- methylphenyl)propan-2-ol (300 mg, 1.21 mmol) in TFA (5000 μΐ, 64.90 mmol) was added triethylsilane (580 μΐ, 3.64 mmol) at 0°C, and the mixture was stirred for 4h. The reaction mixture was concentrated at reduced pressure, diluted with water, and
5 extracted with EtOAc. The extract was washed with saturated
aqueous NaHCCO3 and brine, then dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 0%- 5%EtOAc in hexane) to give the title compound (217 mg, 0.939 mmol, 77%) l-o as a colorless oil.
1H NMR (300 MHz, DMSO-d6) 5:1.19 (6H, d, J = 7.2 Hz), 2.21 (3H, d, J = 2.3 Hz), 3.13 (1H, spt, J = 6.9 Hz), 7.27-7.39 (2H, m) .
[0778]
C) 1- (4-fluoro-3-isopropyl-5-methylphenyl) -N- (4-
15 (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide (60 mg, 0.17 mmol), 5- bromo-2-fluoro-l-isopropyl-3-methylbenzene (59.9 mg, 0.26 mmol).,..
20 chloro (2-dicyclohexylphosphino-2' , 6' -di-i-propoxy-1 , 1' - biphenyl) [2- (2-aminoethylphenyl )] palladium ( II ) , methyl-t-butyl ether adduct (12.59 mg, 0.02 mmol), NaOtBu (49.8 mg, 0.52 mmol) and DME (2mL) was heated at 120 °C for 1 h under microwave
irradiation. The mixture was filtered through celite and
25 concentrated in vacuo. The residue was purified by column
chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to white solids. The solids were crystallized from
EtOAc-hexane to give the title compound (34.0 mg, 0.068 mmol, 39.6%) as white solids.
30 1H NMR (300 MHz, CDC13) 5:1.25 (6H, d, J = 6.8 Hz), 2.28 (3H, d, J = 1.9 Hz), 3.03 (3H, s) , 3.24 (1H, dt, J = 13.7, 6.9 Hz),
3.67-3.81 (2H, m) , 4.48-4.60 (2H, m) , 4.69 (2H, d, J = 6.4 Hz), 6.83-7.02 (3H, m) , 7.54 (2H, d, J = 7.9 Hz), 7.67 (1H, d, J = 7.9 Hz), 7.89 (2H, d, J = 8.3 Hz), 8.10 (1H, t, J = 6.6 Hz).
35 [0779] Example 232
1- (3, 5-dicyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -2, 3- dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6-carboxamide
A) 3 , 5-dicyclopropylphenol
A mixture of 3 , 5-dibromophenol (1 g, 3.97 mmol) , 3,5- dibromophenol (1 g, 3.97 mmol), cyclopropylboronic acid (1.705 g, 19.85 mmol), tricyclohexylphosphine (0.223 g, 0.79 mmol) and K3PO4 (2.53 g, 11.91 mmol) in toluene (20 mL) and water (4.0 mL) was stirred at 100°C overnight. The mixture was filtered, the filtrate was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (512.8 mg, 2.94 mmol, 74.1%) as white amorphous solids.
MS (ESI-), found 173.0 (M-H)
1H NMR (300 MHz, CDC13) 5:0.62-0.71 (4H, m) , 0.87-0.97 (4H, m) , 1.75-1.87 (2H, m) , 4.72 (1H, s), 6.27-6.33 (2H, m) , 6.42-6.47 (1H, m) . ... .
[0780]
B) 3 , 5-dicyclopropylphenyl trifluoromethanesulfonate
To a solution of 3 , 5-dicyclopropylphenol (510 mg, 2.93 mmol) in pyridine (10 mL) was added Tf20 (0.593 mL, 3.51 mmol) at 0°C. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 0% - 20% EtOAc in hexane) to give the title compound (680 mg, 2.22 mmol, 75.7%) as a colorless oil.
1H NMR (300 MHz, CDCI3) 5:0.65-0.75 (4H, m) , 0.95-1.07 (4H, m) , 1.80-1.96 (2H, m) , 6.67-6.73 (2H, m) , 6.80-6.85 (1H, m) .
[0781]
C) 1- (3, 5-dicyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (60 mg, 0.17 mmol) , 3 , 5-dicyclopropylphenyl trifluoromethanesulfonate (58.2 mg, 0.19 mmol), Ruphos pre-catalyst (12.59 mg, 0.02 mmol), NaOtBu (49.8 mg, 0.52 mmol) and DME (3 mL) was heated at 120°C for 1 h under microwave irradiation. The mixture was quenched with water and extracted with EtOAc. The organic layer was
separated and dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% E-tOAc in hexane) to -give the title
compound (36.4 mg, 0.072 mmol, 41.8%) as white amorphous solids.
1H NMR (300 MHz, DMSO-d6) 5:0.63-0.72 (4H, m) , 0.87-0.98 (4H, m) , 1.82-1.94 (2H, m) , 3.17 (3H, s) , 3.67-3.79 (2H, m) , 4.40- 4.49 (2H, m) , 4.52 (2H, d, J = 6.4 Hz), 6.66 (1H, s) , 6.79 (2H, d, J = 1.5 Hz) , 7.01 (1H, d, J = 8.3 Hz), 7.46 (1H, d, J = 7.9 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.95 (1H, t, J = 6.4 Hz) .
[0782]
Example 233
1- ( 4-fluoro-3-isopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide
A) 4-fluoro-3- (prop-l-en-2-yl ) phenol
To a solution of 3-^bromo-4-fluorophenol (1- g, 5.24 mmol), prop-l-en-2-ylboronic acid (0.755 mL, 7.85 mmol),
tricyclohexylphosphine (0.294 g, 1.05 mmol) and potassium phosphate (3.33 g, 15.71 mmol) in toluene (10 mL) /water (2.00 mL) was added Pd(OAc)2 (0.118 g, 0.52 mmol) at room temperature. The mixture was stirred at 100°C under Ar overnight. The mixture was quenched with water at room temperature and
extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 20% EtOAc in hexane) to give the title
compound (0.423 g, 2.78 mmol, 53.1%) as a pale yellow oil.
1H NMR (300 MHz, CDC13) 5:2.12 (3H, d, J = 0.8 Hz), 4.67 (1H, brs), 5.23 (2H, s) , 6.62-6.70 (1H, m) , 6.71-6.79 (1H, m) , 6.85- 6.96 (1H, m) .
[0783]
B) 4-fluoro-3-isopropylphenol
A mixture of 4-fluoro-3- (prop-l-en-2-yl) phenol (423 mg,
2.78 mmol) and 10% Pd-C (50% wet, 296 mg, 0.28 mmol) in THF (5 mL) /MeOH (5.00 mL) was hydrogenated under balloon pressure at room temperature for 3 h. The catalyst was removed by
filtration and the filtrate was concentrated in vacuo. A mixture of the residue and 10% Pd-C (50% wet, 296 mg, 0.28 mmol) in THF (5 mL) /MeOH (5.00 mL) was hydrogenated under balloon pressure again at room temperature overnight. The catalyst was removed by filtration and the filtrate was
concentrated in vacuo. The residue was purified by column chromatography (NH■ silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (307 mg, 1.991 mmol, 71.6%) as a colorless oil.
XH NMR (300 MHz, CDC13) 5:1.23 (6H, d, J = 6.8 Hz), 3.10-3.26 (1H, m)., 4.66. (lH, s) , 6.54-6.62 (IE, m) , 6.70 (1H, dd, J = 5.9, 3.2 Hz), 6.86 (1H, dd, J = 9.8, 8.7 Hz).
[0784]
C) 4-fluoro-3-isopropylphenyl trifluoromethanesulfonate
To a solution of 4-fluoro-3-isopropylphenol (307 mg, 1.99 mmol) in pyridine (3 mL) was added Tf20 (0.404 mL, 2.39 mmol) at 0°C. The mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine and dried over MgSO^ and
concentrated in vacuo. The residue was purified by column chromatography (si-lica gel, eluted with 2% - 10% EtOAc in hexane) to give the title compound (292 mg, 1.020 mmol, 51.2%) as a colorless oil.
1H NMR (300 MHz, CDC13) 5:1.26 (6H, d, J = 6.8 Hz), 3.18-3.33 (1H, m) , 7.05-7.10 (2H, m) , 7.11-7.17 (1H, m) .
[0785] D) 1- (4-fluoro-3-isopropylphenyl) -N- (4- (methylsulfonyl) benzyl) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide (60 mg, 0.17 mmol) , 4- fluoro-3-isopropylphenyl trifluoromethanesulfonate (99 mg, 0.35 mmol), Ruphos pre-catalyst (12.59 mg, 0.02 mmol), NaOtBu (49.8 mg, 0.52 mmol) and DME (3.5 mL) was heated at 120 °C for 3 h under microwave irradiation. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (35.0 mg, 0.072 mmol, 41.9%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:1.23 (6H, d, J = 6.8 Hz), 3.11-3.25 (4H, m) , 3.71-3.82 (2H, m) , 4.45-4.58 (4H, m) , 6.96 (1H, d, J = 8.3 Hz), 7.18-7.28 (2H, m) , 7.29-7.36 (1H, m) , 7.43-7.58 (3H, m) , 7.87 (2H, d, J = 8.7 Hz), 8.96 (1H, t, J = 6.4 Hz).
[0786] .. .
Example 234
4- (3, 5-dicyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl ) -3, 4- dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide
A) 3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid
4 N lithium hydroxide (3.86 mL, 15.45 mmol) was added to a solution of methyl 3, 4-dihydro-2H-pyrido [ 3 , 2-b] [ 1 , 4 ] oxazine- 7-carboxylate (1 g, 5.15 mmol) in MeOH (10 mL) - THF (10 mL) at room temperature. After being stirred at 60 °C for overnight, the reaction mixture was poured into water, neutralized with 6 N HC1 and extracted with EtOAc-THF. The organic layer was dried over MgSO4 and concentrated in -vacuo to give crystals, which were collected by filtration and washed with IPE-hexane to give the title compound (692.9 mg, 3.85 mmol, 74.7%) as white powder. This product was subjected to the next reaction without further purification.
1H NMR (300 MHz, DMSO-d6) 5:3.41-3.50 (2H, m) , 4.11 (2H, t, J = 4.5 Hz), 7.23-7.26 (1H, m) , 7.61 (1H, brs), 8.16 (1H, d, J =
1.9 Hz) , 12.43 (1H, brs) .
[0787]
B) N- (4- (methylsulfonyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxamide
To a solution of 3 , 4-dihydro-2H-pyrido [ 3 , 2- b] [1, 4] oxazine-7-carboxylic acid (690 mg, 3.83 mmol) , (4- (methylsulfonyl ) phenyl ) methanamine (780 mg, 4.21 mmol) and
DIPEA (1.309 mL, 7.66 mmol) in DMF (14 mL) was added 2- OH[1,2,3] triazolo [4 , 5-b] pyridin-3-yl) -1, 1,3,3- tetramethylisouronium hexafluorophosphate (V) (1747 mg, 4.60 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and the resulting precipitate was collected by filtration and washed with water to give the title compound (112 mg, 0.322 mmol, 8.42%) as white solids.
MS (ESI+), found 348.2 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:3.18 (3H, s), 3.37-3.49 (2H, m) , 4.06-4.16 (2H, m) , 4.51 (2H, d, J = 5.7 Hz}., .7.33-7.43 (2H, m) , 7.54 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 8.18 (1H, d, J = 1.9 Hz), 8.84 (1H, t, J = 6.0 Hz).
[0788]
C) 4- (3, 5-dicyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) -
3.4-dihydro-2H-pyrido [ 3 , 2-b] [1,4] oxazine-7-carboxamide
A mixture of N- (4- (methylsulfonyl ) benzyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazine-7-carboxamide (110 mg, 0.32 mmol),
3.5-dicyclopropylphenyl trifluoromethanesulfonate (107 mg, 0.35 mmol), Ruphos pre-catalyst (23.07 mg, 0.03 mmol), NaOtBu (91 mg, 0.95 mmol) and DME (5 mL) was heated at 120°C for 3 h under microwave irradiation. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated and dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% -80% EtOAc in hexane) to give the title compound (2.3. mg, 4.57 μmol, 1.4%) as a colorless viscous oil. 1H NMR (300 MHz, CDC13) 5:0.65-0.72 (4H, m) , 0.91-0.99 (4H, m) , 1.81-1.93 (2H, m) , 3.04 (3H, s) , 3.86-3.93 (2H, m) , 4.30-4.37 (2H, m) , 4.72 (2H, d, J = 6.0 Hz) , 6.45 (1H, t, J = 6.2 Hz) , 6.64-6.68 (1H, m) , 6.83 (2H, d, J = 2.3 Hz), 7.48-7.56 (3H, m) , 7.91 (2H, d, J = 8.7 Hz), 8.16 (1H, d, J = 2.3 Hz).
[0789]
Example 235
1- (3, 5-dicyclopropylphenyl) -N- (4-sulfamoylbenzyl) -2, 3-dihydro- lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide
A) methyl 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro-lH- pyrido [2, 3-b] [1,4] oxazine-6-carboxylate
A mixture of methyl 2 , 3-dihydro-lH-pyrido [2 , 3- b] [1, 4 ] oxazine-6-carboxylate (98 mg, 0.50 mmol) , 3,5- dicyclopropylphenyl trifluoromethanesulfonate (173 mg, 0.56 mmol), Pd2(dba)3 (24 mg, 0.03 mmol), XPHOS (25 mg, 0.05 mmol),
K3PO4 (201 mg, 0.95 mmol) and toluene (5 mL) was stirred at
120 °C under microwave irradiation for 2 h. After being cooled, the mixture was poured into water and extracted with EtOAc.
The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column
chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (46.0 mg, 0.131 mmol, 26.0%) as pale yellow solids.
MS (ESI+), found 351.2 (M+H)
[0790]
B) 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid
To a mixture of methyl 1- ( 3 , 5-dicyclopropylphenyl ) -2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylate (46 mg, 0.13 mmol) and MeOH (3 mL) was added 2 M NaOH aq. (0.30 mL, 0.60 mmol) . After being stirred at 50°C for 3 h, the mixture was acidified with 1 N HC1 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was subjected to the next reaction without further purification. [0791]
C) 1- (3, 5-dicyclopropylphenyl) -N- ( 4-sulfamoylbenzyl ) -2, 3- dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6-carboxamide
To a mixture of 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (44 mg, 0.13 mmol) , 4- (aminomethyl) benzenesulfonamide hydrochloride (46 mg, 0.21 mmol), HATU (74 mg, 0.19 mmol) and DMF (3 mL) was added DIPEA (70 μΕ, 0.40 mmol). After being stirred at room
temperature overnight, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 100% EtOAc in hexane) and then by preparative HPLC (L- Column 2 ODS, eluted with H20 in acetonitrile containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO3 aq. and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (42.0 mg, 0.083 mmol, 63.6%) as white solids.
1H NMR (300 MHz, DMSQ-d6) 5:0.64-0.73 (4H,_ m) , 0.88-0.98 (4H, m) , 1.83-1.95 (2H, m) , 3.69-3.77 (2H, m) , 4.43-4.52 (4H, m) , 6.66 (1H, s), 6.79 (2H, d, J = 1.5 Hz), 7.01 (1H, d, J = 8.3 Hz), 7.29 (2H, s), 7.41-7.50 (3H, m) , 7.75 (2H, d, J = 8.3 Hz), 8.89 (1H, t, J = 6.4 Hz) .
[0792]
Example 244
1- (3, 5-dicyclopropylphenyl) -N- ( (5- (methylsulfonyl) pyridin-2- yl)methyl) =2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6- carboxamide
To a solution of 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro- lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid (25 mg, 0.07 mmol) , (5- (methylsulfonyl) pyridin-2-yl ) methanamine
hydrochloride (18.21 mg, 0.08 mmol) and DIPEA (0.038 mL, 0.22 mmol) in DMF (2.0 mL) was added HATU (33.9 mg, 0.09 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title compound (22.8 mg, 0.045 mmol, 60.8%) as pale-yellow amorphous solids .
1ti NMR (300 MHz, DMSO-d6) δ:0.64-0.73 (4H, m) , 0.88-0.97 (4H, m) , 1.83-1.95 (2H, m) , 3.30 (3H, s) , 3.70-3.80 (2H, m) , 4.42- 4.52 (2H, m) , 4.65 (2H, d, J = 6.0 Hz), 6.67 (1H, s), 6.80 (2H, d, J = 1.5 Hz), 7.02 (1H, d, J = 8.3 Hz), 7.43-7.54 (2H, m) , 8.27 (1H, dd, J = 8.3, 2.3 Hz), 8.92-9.04 (2H, m) .
[0793]
Example 246
1- (3, 5-dicyclopropylphenyl) -N- ( (5- (methylsulfonyl ) pyrimidin-2- yl ) methyl ) -2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1, 4 ] oxazine-6- carboxamide
A) 5- (methylsulfonyl ) pyrimidine-2-carbonitrile
A mixture of 5-bromopyrimidine-2-carbonitrile (1.00 g, 5.43 mmol), sodium methanesulfinate (844 mg, 8.27. mmol) and DMSO (10 mL) was stirred at 100 °C under nitrogen atmosphere for 20 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) , followed by suspending in IPE. The precipitate was collected by filtration and dried in vacuo to give the title compound (0.572 g, 3.12 mmol, 57.5%) as pale yellow solids.
1H NMR (300 MHz, CDC13) 5:3.23 (3H, s), 9.34 (2H, s) .
[0794]
B) 1- (5- (methylsulfonyl ) pyrimidin-2-yl ) methanamine
hydrochloride
A mixture of 5- (methylsulfonyl) pyrimidine-2-carbonitrile (566 mg, 3.09 mmol), 6N HC1 aq. (1.0 mL, 6.00 mmol), 10% Pd-C (50% wet, 180 mg, 0.17 mmol) and MeOH (15 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room temperature for 30 min. The insoluble material was removed by filtration and washed with water. The filtrate was concentrated in vacuo. The solid was suspended in MeOH, collected by filtration and dried in vacuo to give the title compound (490 mg, 2.191 mmol, 70.9%) as white solids.
MS (ESI+) , found 188.3 (M-HC1+H)
1H NMR (300 MHz, DMSO-d6) 5:3.47 (3H, s) , 4.47 (2H, s), 8.59 (3H, brs) , 9.37 (2H, s) .
[0795]
C) 1- (3, 5-dicyclopropylphenyl ) -N- ( (5- (methylsulfonyl ) pyrimidin- 2-yl)methyl) -2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6- carboxamide
To a mixture of 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (31 mg, 0.09 mmol ) , 1- ( 5- (methylsulfonyl ) pyrimidin-2-yl ) methanamine
hydrochloride (54 mg, 0.24 mmol), HATU (72 mg, 0.19 mmol) and DMF (3 mL) was added DIPEA (80 μΤ, 0.46 mmol). After being stirred at room temperature overnight, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel eluted with 10% - 30% EtOAc in hexane) and crystallized from EtOH-hexane to give the title compound (11.00 mg, 0.022 mmol, 23.61%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:0.64-0.74 (4H, m) , 0.88-0.98 (4H, m) , 1.82-1.96 (2H, m) , 3.40 (3H, s) , 3.75 (2H, t, J = 4.3 Hz), 4.48 (2H, t, J = 4.2 Hz), 4.78 (2H, d, J = 5.9 Hz), 6.67 (1H, s), 6.81 (2H, d, J = 1.5 Hz), 7.02 (1H, d, J = 8.1 Hz), 7.46 (1H, d, J = 8.1 Hz), 8.-83 (1H, t, J = 5.9 Hz), 9.23 (2H, s).
[0796]
Example 247
1- (3, 5-dicyclopropylphenyl) -N- (4- (ethylsulfonyl ) benzyl) -2, 3- dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide
To a solution of 1- ( 3, 5-dicyclopropylphenyl) -2 , 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (30 mg, 0.09 mmol) , ( 4- (ethylsulfonyl) phenyl) methanamine hydrochloride
(23.13 mg, 0.10 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (2.0 mL) was added HATU (40.7 mg, 0.11 mmol) at room
temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with
EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title compound (21.7 mg, 0.042 mmol, 47.0%) as colorless amorphous solids.
1H NMR (300 MHz, DMSO-d6) 5:0.64-0.72 (4H, m) , 0.88-0.97 (4H, m) , 1.08 (3H, t, J = 7.6 Hz), 1.82-1.95 (2H, m) , 3.25 (2H, q, J = 7.6 Hz), 3.68-3.77 (2H, m) , 4.42-4.49 (2H, m) , 4.53 (2H, d, J = 6.8 Hz), 6.64-6.68 (1H, m) , 6.79 (2H, d, J = 1.5 Hz), 7.01
(1H, d, J = 8.3 Hz), 7.47 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.3 Hz) , 7.82 (2H, d, J = 8.3 Hz), 8.95 (1H, t, J = 6.4 Hz) .
[0797]
Example 248
methyl ( ( ( 1- ( 3 , 5-dicyclopropylphenyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [1, 4] oxazin-6-yl) carbonyl) amino) (4- (methylsulfonyl ) phenyl) acetate
A) (diallylamino) ( 4- (methylsulfanyl ) phenyl ) acetic acid
A mixture of (4- (methylthio) phenyl) boronic acid (3.5 g, 20.83 mmol), 2-oxoacetic acid hydrate (1.917 g, 20.83 mmol) and diallylamine (2.57 mL, 20.83 mmol) in CH3CN (25 mL) was stirred at 80°C for 8h. The mixture was cooled to room temperature and white precipitates were collected using IPE to give the title compound (5.41 g, 19.50 mmol, 94%).
MS (ESI+) , found 278.2 (M+H)
1H NMR (300 MHz, CDC13) 5:2.48 (3H, s) 3.12 - 3.23 (2H, m) 3.25 - 3.37 (2H, m) 4.46 (1H, s) 5.11 - 5.26 (4H, m) 5.73 - 5.94 (2H, m) 7.20 (2H, d, J=8.69 Hz) 7.35 (2H, d, J=8.31 Hz). (The C02H peak was omitted)
[0798] B) methyl (diallylamino) ( 4- (methylsulfanyl ) phenyl ) acetate
To a mixture of (diallylamino) (4- (methylsulfanyl ) phenyl) acetic acid (1.63 g, 5.88 mmol) in MeOH (10 mL) and toluene (25 mL) was added
(diazomethyl ) trimethylsilane in hexanes (14.69 mL, 8.81 mmol) at 5°C. After the mixture was stirred at room temperature for 14 hrs and concentrated in vacuo. The residue was purified by Si02 column chromatography (hexane/EA=95/5 to 80/20) to give the title compound (1.70 g, 5.83 mmol, 99%) as a colorless oil. MS (ESI+) , found 292.1 (M+H)
[0799]
C) methyl 2- (diallylamino) -2- (4- (methylsulfinyl) phenyl) acetate m-CPBA (1334 mg, 5.41 mmol) was added to a solution of methyl (diallylamino) (4- (methylsulfanyl ) phenyl) acetate (1051 mg, 3.61 mmol) in EtOAc (20 mL) at 0°C and the reaction mixture was stirred overnight at room temperature. The reaction mixture was passed through NH silica gel pad (EtOAc) and concentrated in vacuo to give the title compound (1085 mg, 3.53 mmol, 98%) as a. pale yellow oil. „
[0800]
D) methyl (4- (methylsulfonyl) phenyl) (oxo) acetate
To a mixture of methyl 2- (diallylamino) -2- (4- (methylsulfinyl ) phenyl ) acetate (1085 mg, 3.53 mmol) in MeOH (10.00 mL) , water (10.00 mL) and THF (10 mL) was added OXONE (4340 mg, 7.06 mmol) at 5°C. After the mixture was stirred at room temperature overnight, the mixture was made basic with aqueous NaHCO3, and extracted with EtOAc. The organic layer was separated and washed with brine, dried over MgS04 and concentrated in vacuo. The residue was purified by S1O2 column chromatography (hexane/EA=20/80 to 50/50) to give the title compound (264 mg, 1.090 mmol, 30.9%) as white solids.
1H NMR (300 MHz, CDC13) 5:3.04 (3H, s) , 3.31-3.51 (2H, m) ,
3.54-3.70 (2H, m) , 3.74 (3H, s), 5.11-5.27 (4H, m) , 5.33 (1H, s)_, 5.83-6.01 (2H, m) , 7.57-7.66 (2H, m) , 7.87-7.96 (2H, m) .
[0801] E) methyl (hydroxyimino) ( 4- (methylsulfonyl ) phenyl ) acetate
Hydroxylamine hydrochloride (89 mg, 1.29 mmol) was added to a solution of methyl ( 4- (methylsulfonyl ) phenyl ) (oxo) acetate (260 mg, 1.07 mmol) in pyridine (3 mL) at room temperature. The mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 0. IN HC1 and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 60% EtOAc in hexane) to give the title compound (247 mg, 0.960 mmol, 89.7%) as white solids.
[0802]
F) methyl amino ( 4- (methylsulfonyl ) phenyl ) acetate
A mixture of methyl (hydroxyimino) (4- (methylsulfonyl ) phenyl) acetate (240 mg, 0.93 mmol) and 10% Pd-C (50% wet, 99 mg, 0.93 mmol) in MeOH (6 mL) and THF (2.00 mL) was hydrogenated under balloon pressure at room temperature for 4 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to gi_ve__.the title compound (235 mg, 0.966 mmol, 104%) as a pale yellow oil.
1H NMR (300 MHz, CDC13) 5:1.97 (2H, brs), 3.05 (3H, s), 3.73 (3H, s), 4.74 (1H, brs), 7.60-7.66 (2H, m) , 7.91-7.98 (2H, m) .
[0803]
G) methyl ( ( (1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro-lH- pyrido [2 , 3-b] [1, 4] oxazin-6-yl) carbonyl) amino) (4-
(methylsulfonyl ) phenyl) acetate
To a solution of 1- ( 3 , 5-dicyclopropylphenyl ) -2 , 3-dihydro- lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid (100 mg, 0.30 mmol), methyl amino ( 4- (methylsulfonyl ) phenyl ) acetate (80 mg, 0.33 mmol) and DIPEA (0.152 mL, 0.89 mmol) in DMF (2.0 mL) was added HATU (136 mg, 0.36 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (145.8 mg, 0.260 mmol, 87%) as white amorphous solids.
1H NMR (300 MHz, DMSO-d6) 5:0.63-0.72 (4H, m) , 0.87-0.96 (4H, m) , 1.82-1.94 (2H, m) , 3.22 (3H, s) , 3.69 (3H, s) , 3.71-3.80 (2H, m) , 4.40-4.53 (2H, m) , 5.80 (1H, d, J = 7.6 Hz), 6.65-6.69 (1H, m) , 6.79 (2H, d, J = 1.5 Hz), 7.00 (1H, d, J = 8.3 Hz),
7.44 (1H, d, J = 7.6 Hz), 7.71 (2H, d, J = 8.3 Hz), 7.93 (2H, d,
J = 8.3 Hz), 8.87 (1H, d, J = 7.6 Hz).
[0804]
Example 249
1- (2, 6-dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl ) benzyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide
A) 2 , 6-dicyclopropylpyridin-4-ol
A mixture of 2 , 6-dibromopyridin-4-ol (1.06 g, 4.19 mmol), cyclopropylboronic acid (1.76 g, 20.49 mmol), Pd(OAc)2 (99 mg, 0.44 mmol), tricyclohexylphosphine (235 mg, 0.84 mmol) and
K3PO4 (2.76 g, 13.00 mmol) in toluene (10 mL) and water (2.0 mL) was stirred at 100°C overnight. After being cooled, the mixture was poured into water and extracted with 2-butanone. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column
chromatography (silica gel, eluted with 0%- 20% MeOH in EtOAc) to give the title compound (0.305 g, 1.741 mmol, 41.5%) as pale yellow solids.
MS (ESI+), found 176.4 (M+H)
1H NMR (300 MHz, DMSO-d6) 6:0.75-0.81 (8H, m) , 1.80-1.89 (2H, m) , 6.38 (2H, s) , 10.11 (1H, s) .
[0805]
B) 2 , 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate
To a mixture of 2, 6-dicyclopropylpyridin^4-ol (305 mg, 1.74 mmol) and pyridine (10 mL) was added Tf20 (0.35 mL, 2.07 mmol) at 0°C. After being stirred at room temperature under N2 overnight, the mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was washed with citric acid aq. and brine and dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 1% - 5% EtOAc in hexane) to give the title compound (373 mg, 1.214 mmol, 69.7%) as a colorless oil. MS (ESI+), found 308.0 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:0.85-1.02 (8H, m) , 2.07-2.20 (2H, m) , 7.25 (2H, s) .
[0806]
C) 1- (2, 6-dicyclopropylpyridin-4-yl ) -N- (4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of N- (4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (45 mg, 0.13 mmol), 2 , 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate (77 mg, 0.25 mmol), Ruphos pre-catalyst (10 mg, 0.01 mmol) and NaOtBu (33 mg, 0.34 mmol) in DME (3 mL) was stirred at 120°C for 1 h under microwave irradiation. After being cooled, the mixture was filtered through celite and concentrated. The residue was purified by column chromatography (..silica gel, eluted with 20% - 80% EtOAc in hexane and then NH silica gel, eluted with 20% - 50% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (27.0 mg, 0.054 mmol, 41.3%) as white solids. 1ti NMR (300 MHz, DMSO-d6) 5:0.80-0.90 (8H, m) , 1.90-2.02 (2H, m) , 3.18 (3H, s) , 3.83 (2H, t, J = 4.2 Hz), 4.45 (2H, t, J = 4.2 Hz), 4.54 (2H, d, J = 6.4 Hz), 6.93 (2H, s), 7.51-7.59 (3H, m) , 7.60-7.67 (1H, m) , 7.87 (2H, d, J = 8.7 Hz) , 9.08 (1H, t, J = 6.4 Hz) .
[0807]
Example 250
1- ( 3 , 5-dicyclopropylphenyl) -N- ( (5- (ethylsulfonyl ) pyridin-2- yl) methyl) -2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6- carboxamide
To a mixture of 1- ( 3, 5-dicyclopropylphenyl ) -2 , 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-.6-c.a.rb.oxylic acid (30 mg, 0.09 mmol) and 1- ( 5- (ethylsulfonyl ) pyridin-2-yl ) methanamine hydrochloride (25.3 mg, 0.11 mmol). in DMF (3.000 mL) were added HATU (50.9 mg, 0.13 mmol) and DIPEA (0.047 mL, 0.27 mmol) at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water at room temperature and
extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (45.0 mg, 0.087 mmol, 97%) as pale yellow solids.
1H NMR (300 MHz, DMSO-d6) 5:0.62-0.74 (4H, m) , 0.86-1.00 (4H, m) , 1.12 (3H, t, J = 7.4 Hz), 1.83-1.96 (2H, m) , 3.39 (2H, q, J = 7.2 Hz), 3.69-3.82 (2H, m) , 4.48 (2H, t, J = 4.3 Hz), 4.67 (2H, d, J = 6.0 Hz), 6.67 (1H, s) , 6.81 (2H, d, J = 1.5 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.43-7.57 (2H, m) , 8.24 (1H, dd, J = 8.3, 2.3 Hz), 8.91-9.04 (2H, m) .
[0808]
Example 251
1- (3, 5-dicyclopropylphenyl ) -N- ( 2-hydroxy-l- (4- (methylsulfonyl ) phenyl) ethyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
To a stirred solution of methyl (((l-(3,5- dicyclopropylphenyl ) -2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazin-6- yl) carbonyl) amino) (4- (methylsulfonyl ) phenyl) acetate (130 mg, 0.23 mmol) in MeOH (3.0 mL) was added NaBH4 (43.8 mg, 1.16 mmol) at room temperature. "After being stirred at room
temperature for 1 h, the mixture was quenched with sat NaHCO3 aq. and diluted with water. The mixture was extracted with EtOAc. The organic layer was separated and dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and crystallized with EtOAc-hexane to give the title compound (86.2 mg, 0.162 mmol, 69.8%) as white powder.
1H NMR (300 MHz, DMSO-d6) 5:0.63-0.72 (4H, m) , 0.87-0.97 (4H, m) , 1.81-1.94 (2H, m) , 3.18 (3H, s) , 3.68-3.83 (4H, m) , 4.42- 4.52 (2H, m) , 4.99-5.11 (1H, m) , 5.14-5.22 (1H, m) , 6.66 (1H, s), 6.79 (2H, d, J = 1.5 Hz), 7.01 (1H, d, J = 8.3 Hz), 7.42 (1H, d, J = 7.9 Hz), 7.60 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz), 8.59 (1H, d, J = 7.9 Hz).
[0809]
Example 252
1- (2-cyano-5-cyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide
A) 4-cyclopropyl-2-hydroxybenzonitrile
A mixture of 4-bromo-2-hydroxybenzonitrile (1 g, 5.05 mmol) , cyclopropylboronic acid (0.651 g, 7.58 mmol) ,
tricyclohexylphosphine (0.283 g, 1.01 mmol), Pd(OAc)2 (0.113 g, 0.51 mmol) and K3PO4 (3.22 g, 15.15 mmol) in DME (10 mL) -water (2 mL) was heated at 100°C for 10 h under microwave irradiation. After cooling, the mixture was partitioned between EtOAc and IN HC1. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 40% EtOAc in hexane) to give the title compound (0.560 g, 3.52 mmol, 69.7%) as off-white solids.
[0810]
B) 2-cyano-5-cyclopropylphenyl trifluoromethanesulfonate
To a solution of 4-cyclopropyl-2-hydroxybenzonitrile (560 mg, 3.52 mmol) in pyridine (10 mL) was added Tf20 (0.713 mL, 4.22 mmol) at 0°C. The mixture was stirred at room temperature under N2 for 4 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 15% EtOAc in hexane) to give the title compound (190 mg, 0.652 mmol, 18.54%) as a colorless oil.
MS (ESI-), found 289.9 (M-H)
1H NMR (300 MHz, CDC13) 5:0.79-0.87 (2H, m) , 1.14-1.26 (2H, m) , 1.95-2.05 (1H, m) , 7.11 (1H, s) , 7.14 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 7.9 Hz) .
[0811]
C) 1- ( 2-cyano-5-cyclopropylphenyl ) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (60 mg, 0.17 mmol), 2- cyano-5-cyclopropylphenyl trifluoromethanesulfonate (75 mg, 0.26 mmol), RuPhos precatalyst (12.59 mg, 0.02 mmol), NaOtBu (49.8 mg, 0.52 mmol) and DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. After cooling, the mixture was filtered through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 20% - 100% EtOAc in hexane) to give a colorless oil. The oil was precipitated from EtOAc-IPE to give the title compound (16.00 mg, 0.033 mmol, 18.96%) as white powder.
1H NMR (300 MHz, DMSO-d6) 5:0.77-0.88 (2H, m) , 1.05-1.12 (2H, m) , 1.98-2.09 (1H, m) , 3.17 (3H, s) , 3.81 (2H, brs), 4.47-4.58 (4H, m) , 6.81 (1H, d, J = 8.3 Hz), 7.20 (1H, dd, J = 8.1, 1.7 Hz), 7.35 (1H, d, J = 1.5 Hz), 7.47-7.57 (3H, m) , 7.79-7.89 (3H, m) , 9.03 (1H, t, J = 5.9 Hz) .
[0812]
Example 253
1- (3, 5-dicyclopropylphenyl) -N—( (1- (methylsulfonyl ) piperidin-4- yl) methyl) -2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6- carboxamide
To a solution of 1- ( 3 , 5-dicyclopropylphenyl ) -2 , 3-dihydro- lH-pyrido [2, 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid (30 mg, 0.09 mmol), ( 1- (methylsulfonyl ) piperidin-4-yl ) methanamine
hydrochloride (22.44 mg, 0.10 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (2.0 mL) was added HATU (40.7 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title
compound (37.2 mg, 0.073 mmol, 82%) as colorless amorphous solids.
1H NMR (300 MHz, DMSO-d6) 5:0.63-0.73 (4H, m) , 0.87-0.97 (4H, m) , 1.09-1.26 (2H, m) , 1.58-1.77 (3H, m) , 1.81-1.94 (2H, m) , 2.58-2.71 (2H, m) , 2.83 (3H, s) , 3.13-3.21 (2H, m) , 3.46-3.60 (2H, m) , 3.67-3.78 (2H, m) , 4.38-4.50 (2H, m) , 6.66 (1H, s) , 6.78 (2H, d, J = 1.5 Hz), 7.01 (1H, d, J = 7.9 Hz), 7.45 (1H, d, J = 7.9 Hz), 8.26 (1H, t, J = 6.4 Hz).
[0813]
Example 254
5- (2-cyano-5-cyclopropylphenyl) -N- (4- (methylsulfonyl ) benzyl) - 2,3,4, 5-tetrahydro-l , 5-benzoxazepine-8-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3, 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (60 mg, 0.17 mmol), 2-cyano-5-cyclopropylphenyl trifluoromethanesulfonate (72.7 mg, 0.25 mmol), RuPhos precatalyst (12.13 mg, 0.02 mmol), NaOtBu (48.0 mg, 0.50 mmol) and DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. After cooling, the mixture was filtered through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 20% - 100% EtOAc in hexane) to give a colorless oil. The oil was purified by column chromatography (silica gel, eluted with.70% - 100% EtOAc in hexane) to give the title compound (6.00 mg, 0.012 mmol, 7.19%) as a pale yellow oil.
[0814]
Example 259
4- (3, 5-dicyclopropylphenyl) -N- ( (5- (ethylsulfonyl) pyridin-2- yl ) methyl ) -3 , 4-dihydro-2H-pyrido [ 3 , 2-b] [1,4] oxazine-7- carboxamide
A) methyl 4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [ 1 , 4 ] oxazine-7-carboxylate A mixture of methyl 3, 4-dihydro-2H-pyrido [3, 2- b] [1, 4 ] oxazine-7-carboxylate (500 mg, 2.57 mmol), 3,5- dicyclopropylphenyl trifluoromethanesulfonate (946 mg, 3.09 mmol), XPHOS Pd G2 (203 mg, 0.26 mmol), XPHOS (123 mg, 0.26 mmol), Cs2C03 (1678 mg, 5.15 mmol) and DME (20 mL) was stirred at 120 °C under microwave irradiation for 2 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (692.5 mg, 1.976 mmol, 77%) as white amorphous solids.
1H NMR (300 MHz, CDC13) 5:0.66-0.73 (4H, m) , 0.91-0.99 (4H, m) , 1.81-1.93 (2H, m) , 3.87 (3H, s) , 3.88-3.92 (2H, m) , 4.28-4.37 (2H, m) , 6.64-6.69 (IH, m) , 6.84 (2H, d, J = 1.9 Hz), 7.59 (IH, d, J = 1.9 Hz), 8.40 (IH, d, J = 1.9 Hz).
[0815]
B) 4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4 ] oxazine-7-carboxylic acid
4 N lithium hydroxide (2.461 mL, 9.85 mmol) was added to a solution of methyl 4- ( 3 , 5-dicyclopropylphenyl ) -3 , 4-dihydro- 2H-pyrido [ 3 , 2-b] [ 1 , 4 ] oxazine-7-carboxylate (690 mg, 1.97 mmol) in MeOH (6.9 mL) - THF (6.9 mL) at room temperature. After being stirred at 60 °C for lh, the reaction mixture was poured into water, neutralized with 6 N HC1 and extracted with EtOAc- THF. The organic layer was dried over MgSO4 and concentrated in vacuo to give crystals, which were collected by filtration and washed with IPE-hexane to give the title compound (578.8 mg, 1.721 mmol, 87%) as white powder.
[0816]
C) 4- (3, 5-dicyclopropylphenyl) -N- ( (5- (ethylsulfonyl) pyridin-2- yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide
To a solution of 4- (3, 5-dicyclopropylphenyl) -3, 4-dihydro- 2H-pyrido [ 3 , 2-b] [1, 4 ] oxazine-7-carboxylic acid (30 mg, 0.09 mmol) , 1- (5- (ethylsulfonyl) pyridin-2-yl) methanamine hydrochloride (23.22 mg, 0.10 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (2.0 mL) was added HATU (40.7 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc- The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title
compound (21.6 mg, 0.042 mmol, 46.7%) as white amorphous solids.
[0817]
Example 260
4- (3, 5-dicyclopropylphenyl ) -N- ( (1- (methylsulfonyl) piperidin-4- yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide
To a solution of 4- ( 3 , 5-dicyclopropylphenyl ) -3 , 4-dihydro- 2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (30 mg, 0.09 mmol) , (1- (methylsulfonyl ) piperidin-4-yl ) methanamine
hydrochloride (22.44 mg, 0.10 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (2.0 mL) was added HATU (40.7 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title
compound (27.5 mg, 0.054 mmol, 60.4%) as white amorphous solids. 1H NMR (300 MHz, DMSO-d6) 5:0.61-0.70 (4H, m) , 0.86-0.96 (4H, m) , 1.08-1.27 (2H, m) , 1.54-1.69 (1H, m) , 1.70-1.80 (2H, m) , 1.81-1.92 (2H, m) , 2.58-2.72 (2H, m) , 2.83 (3H, s) , 3.14 (2H, t, J = 6.2 Hz), 3.47-3.61 (2H, m) , 3.80-3.92 (2H, m) , 4.22-4.34 (2H, m) , 6.59 (1H, s) , 6.84 (2H, d, J = 1.9 Hz), 7.49 (1H, d, J = 1.9 Hz), 8.12 (1H, d, J = 1.9 Hz), 8.31 (1H, t, J = 5.7 Hz) .
[0818]
Example 261 4- (3, 5-dicyclopropylphenyl) -N- ( (5- (methylsulfonyl) pyridin-2- yl) methyl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7- carboxamide
To a solution of 4- ( 3 , 5-dicyclopropylphenyl ) -3 , 4-dihydro- 2H-pyrido [3, 2-b] [1, 4 ] oxazine-7-carboxylic acid (30 mg, 0.09 mmol) , (5- (methylsulfonyl ) pyridin-2-yl ) methanamine
hydrochloride (21.85 mg, 0.10 mmol) and DIPEA (0.046 mL, 0.27 mmol) in DMF (2.0 mL) was added HATU (40.7 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title
compound (25.7 mg, 0.051 mmol, 57.1%) as white amorphous solids.
[0819]
Example 262
1- ( 3-cyclopropyl-5-methoxyphenyl) -N- (4- (methylsulfonyl) benzyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide
A) 1- (benzyloxy) -3-bromo-5-methoxybenzene
To a mixture of 3-bromo-5-methoxyphenol (1.00 g, 4.93 mmol) and K2CO3 (0.681 g, 4.93 mmol) in DMF (5 mL) was added (bromomethyl ) benzene (0.702 mL, 5.91 mmol) at room temperature. The mixture was stirred at room temperature for 14 hrs and poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4 and concentrated. The residue was purified by purified by column chromatography (Si02, eluted with 0% - 10% EtOAc in hexane) to give the title
compound (1.29 g, 4.40 mmol, 89%) as a colorless oil.
1H NMR (300 MHz, CDC13) δ : ppm 3.76 (3H, s) 5.01 (2H, s) 6.46
(1H, t, J=2.27 Hz) 6.65 - 6.70 (1H, m) 6.73 - 6.78 (1H, m) 7.29
- 7.45 (5H, m) .
[0820]
B) 1- (benzyloxy) -3-cyclopropyl-5-methoxybenzene
A mixture of 1- (benzyloxy) -3-bromo-5-methoxybenzene (1.26 g, 4.30 mmol), K3PO4 (1.368 g, 6.45 mmol) and
cyclopropylboronic acid (1.108 g, 12.89 mmol) in toluene (10 mL) and H20 (2 mL) was degassed with Ar and then Pd(OAc)2
(0.096 g, 0.43 mmol) was added thereto. The mixture was
stirred at 100 °C under Ar for 14 hrs and poured into water and EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%- 10% EtOAc in hexane) to give the title compound (1.05 g, 4.13 mmol, 96%) as a pale brown oil.
1H NMR (300 MHz, CDC13) 5:0.63 - 0.76 (2H, m) 0.87 - 1.00 (2H, m) 1.77 - 1.93 (1H, m) 3.76 (3H, s) 5.02 (2H, s) 6.26 (1H, s) 6.32 (1H, s) 6.34 (1H, d, J=2.27 Hz) 7.28 - 7.47 (5H, m) .
[0821]
C) 3-cyclopropyl-5-methoxyphenol
A mixture of 1- (benzyloxy) -3-cyclopropyl-5-methoxybenzene (1.03 g, 4.05 mmol) and 10% Pd-C (50% wet, 0.259 g, 0.12 mmol) in EtOH (25 mL) was stirred under H2 (1 atm) at room
temperature for 24 hrs. The catalyst was removed by filtration. The filtrate was concentrated and then the residue was purified by column chromatography (silica gel, eluted with 2%- 15% EtOAc in hexane) to give the title compound (0.30 g, 1.827 mmol,
45.1%) as a colorless oil.
1H NMR (300 MHz, CDC13) 5:ppm 0.61 - 0.72 (2H, m) 0.87 - 1.00 (2H, m) 1.71 - 1.88 (1H, m) 3.76 (3H, s) 4.65 (1H, s) 6.12 - 6.16 (1H, m) 6.20 (1H, s) 6.22 - 6.26 (1H, m) .
[0822]
D) 3-cyclopropyl-5-methoxyphenyl trifluoromethanesulfonate
To a cold mixture of 3-cyclopropyl-5-methoxyphenol (0.29 g, 1.77 mmol) in pyridine (5 mL) was added Tf20 (0.358 mL, 2.12 mmol) at 5°C. After stirring at the same temperature for 30 min, the reaction mixture was quenched with 10% aqueous citric acid and then the product was extracted with EtOAc. The
extract was washed with 10% aqueous citric acid and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5%- 20% EtOAc in hexane) to give the title compound (0.423 g, 1.428 mmo'l, 81%) as a colorless oil.
1H NMR (300 MHz, CDC13) 5:0.64 - 0.77 (2H, m) 0.95 - 1.07 (2H, m) 1.82 - 1.96 (1H, m) 3.80 (3H, s) 6.55 (1H, d, J=1.51 Hz) 6.56 - 6.59 (1H, m) 6.60 - 6.65 (1H, m) .
[0823]
E) 1- (3-cyclopropyl-5-methoxyphenyl ) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (60 mg, 0.17 mmol) , 3- cyclopropyl-5-methoxyphenyl trifluoromethanesulfonate (61.4 mg, 0.21 mmol), NaOtBu (16.60 mg, 0.17 mmol) and Ruphos pre- catalyst (12.59 mg, 0.02 mmol) in DME (3 mL) was heated at
120°C for lhr under microwave irradiation. More Ruphos pre- catalyst (12.59 mg, 0.02 mmol) was added thereto, and the mixture was heated again at 120 °C for lhr under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The extract was washed with aq. NH4C1 and brine, dried over MgSO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5- 95% EtOAc in hexane) to give a crude product, which was further purified by preparative HPLC to give the title compound (20 mg, 0.041 mmol, 23.46%) as white solids.
1H NMR (300 MHz, CDC13) 5:0.65 - 0.75 (2H, m) 1.00 (5H, d,
J=6.42 Hz) 1.87 (1H, s) 3.73 - 3.77 (2H, m) 3.79 (3H, s) 4.49 - 4.56 (2H, m) 4.69 (2H, d, J=6.42 Hz) 6.46 - 6.51 (1H, m) 6.53 - 6.59 (2H, m) 7.16 (1H, d, J=8.31 Hz) 7.54 (2H, d, J=8.31 Hz) 7.68 (1H, d, J=8.31 Hz) 7.89 (2H, d, J=8.31 Hz) 8.07 - 8.16 (1H, m) .
[0824]
Example 263
5- (6-cyclopropyl-l-methyl-lH-indazol-4-yl) -N- (4- (methylsulfonyl) benzyl) -2, 3, 4, 5-tetrahydro-l , 5-benzoxazepine-8- carboxamide
A) 4-bromo-2-fluoro-6-methoxybenzaldehyde
A solution of 28% NaOMe in MeOH (9.60 g, 49.77 iranol) in MeOH (50.0 mL) was added dropwise to a suspension of 4-bromo- 2, 6-difluorobenzaldehyde (10 g, 45.25 mmol) in MeOH (50 mL) at 0°C. The mixture was stirred at 50°C under N2 for 10 h. After cooling, the mixture was concentrated in vacuo and the residue was suspended in water. The mixture was acidified by IN HC1 and extracted with EtOAc twice. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 15% EtOAc in hexane) to give the title compound (6.51 g, 27.9 mmol, 61.7%) as white solids.
1H NMR (300 MHz, CDC13) 5:3.94 (3H, s) , 6.91-6.99 (2H, m) ,
10.36 (1H, d, J = 1.1 Hz) .
[0825]
B) 6-bromo-4-methoxy-lH-indazole
A mixture of 4-bromo-2-fluoro-6-methoxybenzaldehyde (6.5 g, 27.89 mmol) and hydrazine monohydrate (27.9 g, 557.86 mmol) in ethylene glycol (30 mL) was stirred at 95°C under N2
overnight. After cooling, the mixture was quenched with water (200 mL) at 0°C and precipitate was collected by filtration, washed with water. The obtained solid was dissolved in EtOAc and dried over MgSO4. Insoluble material was removed off by filtration and the filtrate was concentrated in vacuo to give the title compound (5.90 g, 26.0 mmol, 93%)- as off-white solids. MS (ESI+), found 227.2 (M+H)
1H NMR (300 MHz, CDC13) 5:3.96 (3H, s) , 6.62 (1H, d, J = 1.1 Hz), 7.24-7.29 (1H, m) , 8.10 (1H, d, J = 0.8 Hz)-, 10.19 (1H, brs) .
[0826]
C) 6-bromo-4-methoxy-l-methyl-lH-indazole
NaH (60% in oil, 0.194 g, 4.84 mmol) was added to a solution of 6-bromo-4-methoxy-lH-indazole (1 g, 4.40 mmol) in DMF (dry) (5 mL) at 0°C. After stirring at room temperature for 10 min, Mel (0.413 mL, 6.61 mmol) was added to the mixture at 0°C. The mixture was stirred at 0°C for 2 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (0.570 g, 2.36 mmol, 53.7 mmol) .
MS (ESI+) , found 241.2 (M+H)
1H NMR (300 MHz, CDC13) 5:3.95 (3H, s), 3.99 (3H, s), 6.58 (1H, d, J = 1.1 Hz), 7.16 (1H, t, J = 1.1 Hz), 7.98 (1H, d, J = 0.8 Hz) .
[0827]
D) 6-cyclopropyl-4-methoxy-1-methyl-lH-indazole
A mixture of 6-bromo-4-methoxy-l-methyl-lH-indazole (570 mg, 2.36 mmol), cyclopropylboronic acid (305 mg, 3.55 mmol), tricyclohexylphosphine (133 mg, 0.47 mmol), Pd(OAc)2 (53.1 mg, 0.24 mmol) and K3PO4 (1506 mg, 7.09 mmol) in toluene (10 mL) and water (0.5 mL) was heated at 100 °C for 3 h under microwave irradiation. After cooling, the mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% -40% EtOAc in hexane) to give the title
compound (420 mg, 2.077 mmol, 88%) as pale yellow solids.
MS (ESI+), found 203.3 (M+H)
1H NMR (300 MHz, CDC13) 5:0.75-0.82 (2H, m) , 0.93-1.05 (2H, m) , 1.98-2.08 (1H, m) , 3.93-4.01 (6H, m) , 6.22 (1H, s) , 6.66 (1H, s) , 7.94 (1H, d, J = 0.8 Hz) .
[0828]
E) 6-cyclopropyl-l-methyl-lH-indazol-4-ol
Aluminum chloride (237 mg, 1.78 mmol) was added to a solution of 6-cyclopropyl-4-methoxy-l-methyl-lH-indazole (120 mg, 0.59 mmol) and dodecyl mercaptan (0.426 mL, 1.78 mmol) in toluene (3 mL) at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was quenched with IN HC1 aq. at room temperature and adjusted pH 5 by sat. NaHCCO3 aq. The mixture was extracted with EtOAc, washed with brine, and dried over MgSCO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 60% EtOAc in hexane) to give the title compound (80 mg, 0.425 mmol, 71.6%) as white solids.
MS (ESI+) , found 189.4 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:0.65-0.73 (2H, m) , 0.90-0.98 (2H, m) , 1.89-1.99 (1H, m) , 3.91 (3H, s), 6.13 (1H, d, J = 0.8 Hz), 6.71 (1H, s), 7.88 (1H, d, J = 0.8 Hz), 9.97 (1H, s) .
[0829]
F) 6-cyclopropyl-1 -methyl-lH-indazol -4 -yl
trifluoromethanesulfonate
To a solution of 6-cyclopropyl-l-methyl-lH-indazol-4-ol
(80 mg, 0.43 mmol) in pyridine (2 mL) was added Tf20 (0.086 mL, 0.51 mmol) at 0°C. The mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with citric acid aq. and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted withl0% - 50% EtOAc in hexane) to give the title compound (110 mg, 0.343 mmol, 81%) as a pale orange oil.
MS (ESI+), found 321.2 (M+H)
1H NMR (300 MHz, CDC13) 5:0.75-0.85 (2H, m) , 1.04-1.13 (2H, m) , 2.02-2.12 (1H, m) , 4.04-4.09 (3H, m) , 6.79 (1H, s) , 7.10 (1H, s) , 7.96 (1H, s) .
[0830]
G) 5- ( 6-cyclopropyl -1 -methyl-IH-indazol-4 -yl) -N- (4-
(methylsulfonyl) benzyl) -2, 3, 4, 5-tetrahydro-l, 5-benzoxazepine-8- carboxamide
A mixture of N- (4- (methylsulfonyl ) benzyl) -2, 3, 4, 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (60 mg, 0.17 mmol), 6-cyclopropyl- 1-methyl-lH-indazol-4 -yl trifluoromethanesulfonate (53.3 mg, 0.17 mmol), RuPhos
precatalyst (24.26 mg, 0.03 mmol) and NaOtBu (48.0 mg, 0.50 mmol) in DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. After cooling, the mixture was filtered through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 50% - 100% EtOAc in hexane) to give a brown oil. The oil was purified by column chromatography (NH silica gel, eluted with 80% - 100% EtOAc in hexane) to give white amorphous solids, which was recrystallized from EtOAc-IPE to give the title compound (9.00 mg, 0.017 mmol, 10.19%) as white powder.
1H NMR (300 MHz, DMSO-d6) 5:0.78 (2H, d, J = 4.9 Hz), 0.92-0.99 (2H, m) , 1.90-2.03 (3H, m) , 3.19 (3H, s) , 3.90 (3H, s), 4.00 (2H, brs), 4.22 (2H, s) , 4.54 (2H, d, J = 5.3 Hz);, 6.58 (1H, s) , 6.76-6.88 (3H, m) , 7.40 (1H, d, J = 4.4 Hz), 7.54-7.61 (3H, m) , 7.89 (2H, d, J = 7.5 Hz), 9.08 (1H, s) .
[0831]
Example 264
1- ( 6-cyclopropyl-l-methyl-lH-indazol-4-yl) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxamide (60 mg, 0.17 mmol), 6- cyclopropyl-l-methyl-lH-indazol-4-yl trifluoromethanesulfonate (55.3 mg, 0.17 mmol), RuPhos precatalyst (25.2 mg, 0.03 mmol) and NaOtBu (49.8 mg, 0.52 mmol) in DME (3 mL) was heated at 120°C for 3 h under microwave irradiation. After cooling, the mixture was filtered through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane then 0% - 5% MeOH in EtOAc) to give pale yellow
amorphous solids, which was recrystallized from EtOAc-IPE to give the title compound (31.0 mg, 0.060 mmol, 34.7%) as off- white powder.
1H NMR (300 MHz, DMSO-d6) 5:0.76-0.89 (2H, m) , 0.98-1.02 (2H, m) , 2.03-2.13 (1H, m) , 3.18 (3H, s) , 3.90 (2H, brs), 4.02 (3H, s), 4.48-4.60 (4H, m) , 6.83-6.89 (2H, m) , 7.24 (1H, s) , 7.43 (1H, d, J = 8.3 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.73 (1H, s), 7.87 (2H, d, J = 8.3 Hz), 9.00 (1H, t, J = 6.4 Hz).
[0832]
Example 265
1- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5-
(methylsulfonyl) pyridin-2-yl) methyl ) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
A) methyl 1- (2, 6-dicyclopropylpyridin-4-yl ) -2, 3-dihydro-lH- pyrido [2 , 3-b] [1,4] oxazine-6-carboxylate
A mixture of methyl 2 , 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylate (165 mg, 0.85 mmol), 2,6- dicyclopropylpyridin-4-yl trifluoromethanesulfonate (287 mg, 0.93 mmol), Pd2(dba)3 (38.9 mg, 0.04 mmol), XPHOS (40.5 mg, 0.08 mmol), K3PO4 (361 mg, 1.70 mmol) and DME (3.0 mL) was stirred at 120 °C under microwave irradiation for 2 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (184.3 mg, 0.524 mmol, 61.7%) as pale yellow solids.
[0833]
B) 1- (2, 6-dicyclopropylpyridin-4-yl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid
4 N lithium hydroxide (0.647 mL, 2.59 mmol) was added to a solution of methyl 1- (2, 6-dicyclopropylpyridin-4-yl) -2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylate (182 mg, 0.52 mmol) in MeOH (2.0 mL) - THF (2.0 mL) at room temperature. After being stirred at 60°C for lh, the reaction mixture was quenched with water, neutralized with 6 N HC1 and extracted with EtOAc-THF. The organic layer was dried over MgSO4 and concentrated in vacuo to give the title compound (152.7 mg, 0.453 mmol, 87%) as pale yellow amorphous solids. This product was subjected to the next reaction without further purification.
[0834]
C) 1- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5-
(methylsulfonyl) pyridin-2-yl ) methyl ) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
To a solution of 1- (2, 6-dicyclopropylpyridin-4-yl) -2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (20 mg, 0.06 mmol) , ( 5- (methylsulfonyl ) pyridin-2-yl ) methanamine
hydrochloride (14.52 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title
compound (15.7 mg, 0.031 mmol, 52.4%) as pale yellow amorphous solids .
1H NMR (300 MHz, DMSO-d6) 5:0.80-0.92 (8H, m) , 1.91-2.02 (2H, m) , 3.30 (3H, s) , 3.80-3.90 (2H, m) , 4.41-4.51 (2H, m) , 4.67
(2H, d, J = 6.0 Hz), 6.94 (2H, s) , 7.48-7.69 (3H, m) , 8.27 (1H, dd, J = 8.3, 2.3 Hz), 9.01 (1H, d, J = 1.9 Hz), 9.11 (1H, t, J
= 6.0 Hz) .
[0835]
Example 266
1- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5- (ethylsulfonyl) pyridin-
2-yl ) methyl) -2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6- carboxamide
To a solution of 1- (2 , 6-dicyclopropylpyridin-4-yl) -2 , 3- dihydro-lH-pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxylic acid (20 mg, 0.06 mmol), 1- (5- (ethylsulfonyl) pyridin-2-yl ) methanamine
hydrochloride (15.44 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title
compound (20.7 mg, 0.040 mmol, 67.2%) as pale yellow amorphous solids .
1H NMR (300 MHz, DMSO-d6) 5:0.79-0.91 (8H, m) , 1.09-1.15 (3H, m) , 1.89-2.02 (2H, m) , 3.39 (2H, q, J = 7.6 Hz), 3.80-3.90 (2H, m) , 4.42-4.51 (2H, m) , 4.68 (2H, d, J = 6.2 Hz), 6.94 (2H, s) , 7.49-7.68 (3H, m) , 8.24 (1H, dd, J = 8.3, 2.3 Hz), 8.96 (1H, d, J = 1.9 Hz), 9.11 (1H, t, J = 6.2 Hz).
[0836]
Example 267
1- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (1- (methylsulfonyl) piperidin-4-yl) methyl) -2, 3-dihydro-lH- pyrido [2, 3-b] [1,4] oxazine-6-carboxamide
To a solution of 1- (2 , 6-dicyclopropylpyridin-4-yl) -2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (20 mg, 0.06 mmol), ( 1- (methylsulfonyl ) piperidin-4-yl) methanamine hydrochloride (14.92 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title
compound (16.8 mg, 0.033 mmol, 55.4%) as white amorphous solids.
1H NMR (300 MHz, DMSO-d6) 5:0.79-0.91 (8H, m) , 1.10-1.28 (2H, m) , 1.63-1.77 (3H, m) , 1.89-2.02 (2H, m) , 2.59-2.74 (2H, m) , 2.83 (3H, s), 3.14-3.25 (2H, m) , 3.47-3.60 (2H, m) , 3.77-3.87 (2H, m) , 4.38-4.47 (2H, m) , 6.92 (2H, s) , 7.50-7.66 (2H, m) , 8.39 (1H, t, J = 5.7 Hz) .
[0837]
Example 268 1- (2, 6-dicyclopropylpyridin-4-yl) -N- ( 2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A) methyl ( ( ( 1- (2 , 6-dicyclopropylpyridin-4-yl) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [1, 4] oxazin-6-yl) carbonyl) amino) (4-
(methylsulfonyl) phenyl) acetate
To a solution of 1- (2, 6-dicyclopropylpyridin-4-yl ) -2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (70 mg, 0.21 mmol), methyl 2-amino-2- ( 4- (methylsulfonyl ) phenyl ) acetate (55.5 mg, 0.23 mmol) and DIPEA (0.106 mL, 0.62 mmol) in DMF
(2.0 mL) was added HATU (95 mg, 0.25 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 40% - 70% EtOAc in hexane) to give the title compound (94.0 mg, 0.167 mmol, 81%) as white amorphous solids.
MS (ESI+) , found 563.2
1H NMR (300 MHz, CDC13) 5:0.85-0.95 (4H, m) , 0.95-1.04 (4H, m) , 1.82-1.96 (2H, m) , 3.04 (3H, s) , 3.74-3.85 (5H, m) , 4.48-4.56 (2H, m) , 5.85 (1H, d, J = 7.2 Hz), 6.73 (2H, s), 7.55 (1H, d, J = 7.9 Hz), 7.65-7.74 (3H, m) , 7.94 (2H, d, J = 8.7 Hz), 8.66 (1H, d, J = 7.2 Hz) .
[0838]
B) 1- (2, 6-dicyclopropylpyridin-4-yl ) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
To a mixture of methyl ( ( (1- (2, 6-dicyclopropylpyridin-4- yl) -2, 3-dihydro-lH-pyrido [2, 3-b] [ 1 , 4 ] oxazin-6- yl ) carbonyl ) amino) ( 4- (methylsulfonyl ) phenyl ) acetate (90 mg, 0.16 mmol) in MeOH (3 mL) was added NaBH4 (30.3 mg, 0.80 mmol) at room temperature. After being stirred at room temperature for 1 h, the mixture was quenched with sat. NaHCO3 aq. and diluted with water. The mixture was extracted with EtOAc. The organic layer was separated and dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (64.2 mg, 0.120 mmol, 75%) as white amorphous solids.
1H NMR (300 MHz, DMSO-d6) 5:0.79-0.90 (8H, m) , 1.89-2.02 (2H, m) , 3.19 (3H, s) , 3.73-3.90 (4H, m) , 4.39-4.52 (2H, m) , 5.02- 5.12 (1H, m) , 5.16-5.24 (1H, m) , 6.93 (2H, s) , 7.49-7.55 (1H, m) , 7.58-7.67 (3H, m) , 7.88 (2H, d, J = 8.7 Hz), 8.71 (1H, d, J = 7.6 Hz) .
[0839]
Example 269
1- (3, 5-dicyclopropylphenyl) -N- (4- (S- methylsulfonimidoyl ) benzyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
A) ( (E) - (4-cyanophenyl) (methyl) ^4-sulfanylidene) cyanamide
To a mixture of 4- (methylthio) benzonitrile (3.01 g, 20.17 mmol), cyanamide (1.02 g, 24.26 mmol), KOtBu (2.70 g, 24.06 mmol) and MeOH (60 mL) was added NBS (5.33 g, 29.95 mmol).
After being stirred at room temperature overnight, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was subjected to the next reaction without further purification .
[0840]
B) ((4-cyanophenyl) (methyl ) oxido^4-sulfanylidene ) cyanamide
To a mixture of ( (E) -( 4-cyanophenyl ) (methyl) -λ4- sulfanylidene) cyanamide (3.82 g, 20.19 mmol), K2CO3 (5.52 g, 39.94 mmol) and EtOH (50 mL) was added m-CPBA (5.94 g, 24.10 mmol) at 0°C. After being stirred at room temperature
overnight, the mixture was quenched with Na2S2O3 aq. and
extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 20% - 100% EtOAc in hexane) to give the title compound (0.825 g, 4.02 mmol, 19.91%) as a light brown oil.
MS (ESI+) , found 206.1
1H NMR (300 MHz, CDC13) 5:3.39 (3H, s), 7.96-8.03 (2H, m) , 8.12-8.19 (2H, m) .
[0841]
C) 4- (S-methylsulfonimidoyl) benzonitrile
To a mixture of ( (4-cyanophenyl) (methyl ) oxido-λ4- sulfanylidene) cyanamide (825 mg, 4.02 mmol) and THF (30 mL) was added TFAA (1.7 mL, 12.04 mmol) at 0°C. After being stirred at room temperature for 3 h, the mixture was concentrated. The residue was dissolved in MeOH (30 mL) and K2CO3 (2.69 g, 19.46 mmol) was added to the mixture. After being stirred at room temperature overnight, the insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (275 mg, 1.526 mmol, 38.0%) as white solids.
MS (ESI+) , found 181.1
1H NMR (300 MHz, DMSO-d6) 5:3.13 (3H, d, J = 1.1 Hz), 4.52 (1H, s) , 8.10 (4H, s) .
[0842]
D) 1- ( 4- (S-methylsulfonimidoyl) phenyl ) methanamine hydrochloride
A mixture of 4- ( S-methylsulfonimidoyl ) benzonitrile (55 mg, 0.31 mmol), 6N HC1 aq. (0.10 mL, 0.60 mmol), 10% Pd-C (50% wet, 19 mg, 0.02 mmol) and MeOH (5 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room temperature for 4 h. The
insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was subjected to the next reaction without further purification.
[0843]
E) 1- (3, 5-dicyclopropylphenyl) -N- (4- (S- methylsulfonimidoyl ) benzyl ) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
To a mixture of 1- (3, 5-dicyclopropylphenyl) -2, 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (31 mg, 0.09 mmol) , 1- ( 4- (S-methylsulfonimidoyl) phenyl ) methanamine
hydrochloride (67 mg, 0.30 mmol), HATU (72 mg, 0.19 mmol) and DMF (3 mL) was added DIPEA (80 μΐ,, 0.46 mmol). After being stirred at room temperature for 2 h, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H20 in acetonitrile
containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO3 aq. and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (21.00 mg, 0.042 mmol, 45.3%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:0.64-0.74 (4H, m) , 0.88-0.97 (4H, m) , 1.82-1.95 (2H, m) , 3.03 (3H, s) , 3.73 (1H, t, J = 3.8 Hz), 4.16 (1H, brs), 4.4.6 (2H, t, J = 3.8 Hz), 4.51 (2H, d, J = 6.4 Hz), 6.66 (1H, s), 6.79 (2H, d, J = 1.5 Hz), 7.01 (1H, d, J = 8.3 Hz), 7.47 (3H, dd, J = 8.3, 3.8 Hz), 7.86 (2H, d, J = 8.3 Hz), 8.91 (1H, t, J = 6.6 Hz). (An exchangeable proton was omitted)
[0844]
Example 270
1- ( 3-cyclopropyl-5- ( 1-methoxyethyl ) phenyl) -N- ( 4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A) 1 , 3-dibromo-5- ( 1-ethoxyethoxy) benzene
To a mixture of 3 , 5-dibromophenol (2.04 g, 8.10 mmol), ethyl vinyl ether (1.5 mL, 15.69 mmol) and THF (20 mL) was added TsOH-H20 (75 mg, 0.39 mmol). After being stirred at room temperature for 5 h, the mixture was quenched with sat. NaHCCO3 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 1% - 5% EtOAc in hexane) to give the title compound (2.050 g, 6.33 mmol, 78%) as a yellow oil. XR NMR (300 MHz , CDC13) 5:1.21 (3H, t, J = 7.0 Hz), 1.49 (3H, d, J = 5.3 Hz), 3.53 (1H, dq, J = 9.3, 7.1 Hz), 3.75 (1H, dq, J = 9.2, 7.1 Hz), 5.35 (1H, q, J = 5.4 Hz), 7.10-7.12 (2H, m) , 7.29 (1H, t, J = 1.5 Hz) .
[0845]
B) 1- ( 3-bromo-5- (1-ethoxyethoxy) phenyl ) ethanol
To a mixture of 1, 3-dibromo-5- ( 1-ethoxyethoxy) benzene (2.05 g, 6.33 mmol) and THF (20 mL) was added 1.6 M n-BuLi in hexane (4.3 mL, 6.88 mmol) under nitrogen atmosphere at -78 °C. After being stirred at -78 °C for 1 h, acetaldehyde (2.5 mL,
12.50 mmol) was added to the mixture. After being stirred at - 78 °C for 2 h, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 30%
EtOAc in hexane) to give the title compound (0.608 g, 2.103 mmol, 33.2%) as a yellow oil.
1H NMR (300 MHz, DMSO-d6) 5:1.10 (3H, t, J = 7.2 Hz), 1.29 (3H, d, J = 6.4 Hz), 1.38 (3H, d, J = 5.3 Hz), 3.49 (1H, dq, J = 9.5, 7.2 Hz), 3.65 (1H, dq, J = 9.4, 7.1 Hz), 4.61-4.73 (1H, m) , 5.27 (1H, d, J = 4.5 Hz), 5.49 (1H, q, J = 5.0 Hz), 6.95 (1H, s), 7.05 (1H, t , J = 2.1 Hz), 7.13 (1H, s).
[0846]
C) l-bromo-3- (1-ethoxyethoxy) -5- ( 1-methoxyethyl ) benzene
To a mixture of 1- ( 3-bromo-5- ( 1- ethoxyethoxy) phenyl ) ethanol (608 mg, 2.10 mmol), Mel (0.40 mL, 6.40 mmol) and THF (10 mL) was added NaH (60% in oil, 101 mg, 2.53 mmol). After being stirred at room temperature for 1 h, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 1% - 10% EtOAc in hexane) to give the title compound (579 mg, 1.910 mmol, 91%) as a pale yellow oil.
1H NMR (300 MHz, DMSO-d6) 5:1.09 (3H, t, J = 7.2 Hz), 1.30 (3H, d, J = 6.4 Hz), 1.39 (3H, d, J = 5.3 Hz), 3.13 (3H, s) , 3.50 (1H, dq, J = 9.2, 7.1 Hz), 3.65 (1H, dq, J = 9.5, 7.2 Hz), 4.23-4.34 (1H, m) , 5.52 (1H, q, J = 5.2 Hz), 6.91-6.96 (1H, m) , 7.07-7.14 (2H, m) .
' [0847]
D) l-cyclopropyl-3- ( 1-ethoxyethoxy) -5- ( 1-methoxyethyl) benzene
A mixture of l-bromo-3- ( 1-ethoxyethoxy) -5- ( 1- methoxyethyl ) benzene (578 nag, 1.91 mmol) , cyclopropylboronic acid (322 mg, 3.75 mmol), Pd(OAc)2 (44 mg, 0.20 mmol),
tricyclohexylphosphine (111 mg, 0.40 mmol) and K3PO4 (1.23 g, 5.79 mmol) in toluene (20 mL) and water (4 mL) was stirred under nitrogen atmosphere at 100 °C overnight. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 1%- 5% EtOAc in hexane) to give the title compound (485 mg, 1.835 mmol, 96%) as a yellow oil.
λΗ NMR (300 MHz, DMSO-d6) 5:0.61-0.69 (2H, m) , 0.88-0.98 (2H, m) , 1.09 (3H, t, J = 7.0 Hz), 1.28 (3H, d, J = 6.8 Hz), 1.37
(3H, d, J = 4.9 Hz), 1.81-1.94 (1H, m) , 3.10 (3H, s) , 3.41-3.55 (1H, m) , 3.58-3.71 (1H, m) , 4.16-4.27 (1H, m) , 5.38-5.49 (1H, m) , 6.54 (1H, s) , 6.62-6.70 (2H, m) .
[0848]
E) 3-cyclopropyl-5- ( 1-methoxyethyl) phenol
To a mixture of l-cyclopropyl-3- ( 1-ethoxyethoxy) -5- ( 1- methoxyethyl) benzene (485 mg, 1.83 mmol) and THF (15 mL) was added HC1 (2.7 mL, 5.40 mmol). After being stirred at room temperature for 3 h, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 20%
EtOAc in hexane) to give the title compound (340 mg, 1.768 mmol, 96%) as a yellow oil.
MS (ESI+), found 191.1 1H NMR (300 MHz, DMSO-d6) 5:0.55-0.63 (2H, m) , 0.85-0.94 (2H, m) , 1.26 (3H, d, J = 6.4 Hz), 1.75-1.87 (1H, m) , 3.08 (3H, s), 4.14 (1H, q, J = 6.4 Hz), 6.31 (1H, t, J = 2.1 Hz), 6.42-6.48 (2H, m) , 9.20 (1H, s) .
[0849]
F) 3-cyclopropyl-5- (1-methoxyethyl ) phenyl
trifluoromethanesulfonate
To a mixture of 3-cyclopropyl-5- ( 1-methoxyethyl) phenol (340 mg, 1.77 mmol) and pyridine (10 mL) was added Tf20 (0.36 mL, 2.13 mmol) at 0°C. After being stirred at room temperature under N2 overnight, the mixture was quenched with water and extracted with EtOAc. The organic layer was washed with 0. IN HC1 and brine and dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 1% - 5% EtOAc in hexane) to give the title compound (484 mg, 1.492 mmol, 84%) as a colorless oil.
MS (ESI+) , found 323.0
1H NMR (300 MHz, CDC13) 5:0.68-0.77 (2H, m) , 1.00-1.11 (2H, m) , 1.40 (3H, d, J = 6.4 Hz), 1.87-2.00 (1H, m) , 3.23 (3H, s) , 4.27 (1H, q, J = 6.4 Hz), 6.81-6.85 (1H, m) , 6.97-7.00 (1H, m) , 7.01-7.05 (1H, m) .
[0850]
G) 1- ( 3-cyclopropyl-5- (1-methoxyethyl) phenyl) -N- (4- (methylsulfonyl ) benzyl) -2, 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide (59 mg, 0.17 mmol), 3- cyclopropyl-5- ( 1-methoxyethyl ) phenyl trifluoromethanesulfonate (115 mg, 0.35 mmol), Ruphos pre-catalyst (14 mg, 0.02 mmol) and NaOtBu (35 mg, 0.36 mmol) in DME (3 mL) was stirred at 120°C for 2 h under microwave irradiation. After being cooled, the mixture was filtered through celite and concentrated. The residue was purified by column chromatography (NH silica gel, eluted with 20% - 50% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H20 in acetonitrile containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO3 aq. and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (54.0 mg, 0.104 mmol, 61.0%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:0.66-0.75 (2H, m) , 0.91-1.00 (2H, m) , 1.33 (3H, d, J = 6.4 Hz), 1.88-2.02 (1H, m) , 3.14 (3H, s) , 3.17 (3H, s), 3.77 (2H, t, J = 4.0 Hz), 4.28 (1H, q, J = 6.2 Hz), 4.44-4.50 (2H, m) , 4.53 (2H, d, J = 6.4 Hz), 6.89 (1H, s) , 6.93 (1H, s), 7.02 (1H, s) , 7.07 (1H, d, J = 7.9 Hz), 7.47 (1H, d, J = 8.3 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.87 (2H, d, J = 8.3 Hz) , 8.97 (1H, t, J = 6.6 Hz).
[0851]
Example 271
1- (3, 5-dicyclopropylphenyl) -N- (4- (N, S- dimethylsulfonimidoyl ) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A) 4- (N, S-dimethylsulfonimidoyl) benzonitrile
To a mixture of 4- ( S-methylsulfonimidoyl ) benzonitrile (109 mg, 0.60 mmol) and formic acid (3 mL, 0.60 mmol) was added paraformaldehyde (55 mg, 1.83 mmol) . After being stirred at 100°C overnight, the mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (30.0 mg, 0.154 mmol, 25.5%) as white solids.
MS (ESI+), found 195.1 (M+H)
1H NMR (300 MHz, DMSO-d6) 5:2.46 (3H, s) , 3.20 (3H, s), 7.97- 8.04 (2H, m) , 8.08-8.16 (2H, m) .
[0852]
B) 1- ( 4- (N, S-dimethylsulfonimidoyl ) phenyl ) methanamine
hydrochloride
A mixture of 4- (N, S-dimethylsulfonimidoyl ) benzonitrile (29 mg, 0.15 mmol), 6N HC1 aq. (50 \iL, 0.30 mmol), 10% Pd-C (50% wet, 10 mg, 9.40 μmol) and MeOH (5 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room temperature for 6 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was subjected to the next reaction without further purification.
MS (ESI+), found 199.1 (M-HC1+H)
[0853]
C) 1- (3, 5-dicyclopropylphenyl) -N- (4- (N, S- dimethylsulfonimidoyl) benzyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [1, 4] oxazine-6-carboxamide
To a mixture of 1- ( 3 , 5-dicyclopropylphenyl ) -2 , 3-dihydro- lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (30 mg, 0.09 mmol ) , 1- ( 4- (N, S-dimethylsulfonimidoyl ) phenyl) methanamine hydrochloride (35 mg, 0.15 mmol), HATU (72 mg, 0.19 mmol) and DMF (3 mL) was added DIPEA (80 yL, 0.46 mmol). After being stirred at room temperature overnight, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc . The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H20 in acetonitrile
containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO3 aq. and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (20.00 mg, 0.039 mmol, 43.4%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:0.63-0.73 (4H, m) , 0.88-0.98 (4H, m) , 1.83-1.95 (2H, m) , 2.45 (3H, s) , 3.07 (3H, s) , 3.73' (2H, t, J = 4.2 Hz), 4.43-4.49 (2H, m) , 4.52 (2H, d, J = 6.4 Hz), 6.66 (1H, s), 6.79 (2H, d, J = 1.5 Hz), 7.01 (1H, d, J = 8.1 Hz), 7.44-7.55 (3H, m) , 7.76 (2H, d, J = 8.3 Hz), 8.93 (1H, t, J = 6.4 Hz) .
[0854]
Example 272
5- (2 , 6-dicyclopropylpyridin-4-yl ) -N- (4- (methylsulfonyl) benzyl) - 2,3,4, 5-tetrahydro-l , 5-benzoxazepine-8-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (100 mg, 0.28 mmol), 2 , 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate (102 mg, 0.33 mmol) , Ruphos pre-catalyst (20.22 mg, 0.03 mmol) , NaOtBu
(80 mg, 0.83 mmol) and DME (3.5 mL) was heated at 120°C for 1 h under microwave irradiation. The mixture was diluted with
EtOAc and filtered through celite. The filtrate was evaporated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 10% - 100% EtOAc in hexane) and column chromatography (NH, silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (33.0 mg, 0.064 mmol,
22.98%) as pale yellow solids.
1H NMR (300 MHz, DMSO-d6) 5:0.69-0.82 (8H, m) , 1.80 (2H, brs) , 1.95-2.09 (2H, m) , 3.19 (3H, s) , 3.89 (2H, brs), 4.00-4.11 (2H, m) , 4.56 (2H, d, J = 6.0 Hz), 6.46 (2H, s), 7.49-7.64 (5H, m) , 7.82-7.92 (2H, m) , 9.17 (1H, s) .
[0855]
Example 273
1- (2, 6-dicyclopropylpyridin-4-yl) -N- (2-fluoro-4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
To a mixture of 1- ( 2 , 6-dicyclopropylpyridin-4-yl ) -2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (25 mg, 0.07 mmol), (2-fluoro-4- (methylsulfonyl ) phenyl ) methanamine hydrochloride (26 mg, 0.11 mmol), HATU (54 mg, 0.14 mmol) and DMF (2 mL) was added DIPEA (40 μΐ^ 0.23 mmol). After being stirred at room temperature overnight, the reaction mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column
chromatography (silica gel, eluted with 20% - 100% EtOAc in hexane) and then by preparative HPLC (L-Column 2 ODS, eluted with H20 in acetonitrile containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO3 aq.
and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (20.00 mg, 0.038 mmol, 51.6%) as white solids. 1R NMR (300 MHz, DMSO-d6) 5:0.80-0.90 (8H, m) , 1.91-2.03 (2H, m) , 3.25 (3H, s) , 3.80-3.89 (2H, m) , 4.42-4.49 (2H, m) , 4.57 (2H, d, J = 6.0 Hz), 6.93 (2H, s), 7.50-7.60 (2H, m) , 7.61-7.68 (1H, m) , 7.71-7.81 (2H, m) , 9.05 (1H, t, J = 6.0 ,Hz).
[0856] .
Example 274
1- (2, 6-dicyclopropylpyridin-4-yl) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl ) ethyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide (shorter retention time)
Optical resolution of 1- ( 2 , 6-dicyclopropylpyridin-4-yl ) -
N- (2-hydroxy-l- (4- (methylsulfonyl ) phenyl) ethyl) -2, 3-dihydro-lH- pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxamide (60 mg, 0.11 mmol) was performed by preparative chiral HPLC. The factions with a shorter retention time gave the title compound (23.8 mg, 39.7%) as white amorphous solids.
Preparative chiral HPLC condition, Column : CHIRALPAK AD
(NF001); Column Size : 50 mmID x 500 mmL; Eluent :
Hexane/EtOH=200/800 (v/v) ; Flow rate : 60 mL/min; Pressure : 0.2 Mpa; Detector & sens. : UV 220 nm; Temperature :30°C
[0857]
Example 275
1- (2, 6-dicyclopropylpyridin-4-yl) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide (longer retention time)
Optical resolution of 1- (2, 6-dicyclopropylpyridin-4-yl) -
N- (2-hydroxy-l- (4- (methylsulfonyl ) phenyl ) ethyl) -2, 3-dihydro-lH- pyrido [2 , 3-b] [ 1, 4 ] oxazine-6-carboxamide (60 mg, 0.11 mmol) was performed by preparative chiral HPLC. The factions with a longer retention time gave the title compound (26.0 mg, 43.3%) as white amorphous solids. The preparative chira;l HPLC
condition was the same as described in Example 274.
[0858]
Example 276
4- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl) pyridin-2-yl) methyl ) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide
A) methyl 4- (2, 6-dicyclopropylpyridin-4-yl ) -3, 4-dihydro-2H- pyrido [3, 2-b] [1,4] oxazine-7-carboxylate
A mixture of methyl 3 , 4-dihydro-2H-pyrido [ 3 , 2- b] [1, 4] oxazine-7-carboxylate (240 mg, 1.24 mmol) , 2,6- dicyclopropylpyridin-4-yl trifluoromethanesulfonate (418 mg, 1.36 mmol), XPHOS Pd G2 (97 mg, 0.12 mmol), XPHOS (58.9 mg, 0.12 mmol), Cs2CO3 (805 mg, 2.47 mmol) and DME (5.0 mL) was stirred at 120 °C under microwave irradiation for 2 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was dried over MgSCu and
concentrated. The residue was purified by column
chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (346.3 mg, 0.985 mmol, 80%) as pale yellow amorphous solids. This product was subjected to the next reaction without further purification.
MS (ESI+) , found 352.3
[0859]
B) 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H-pyrido [3,2- b] [ 1 , 4 ] oxazine-7-carboxylic acid
4 N lithium hydroxide (1.227 mL, 4.91 mmol) was added to a solution of methyl 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [ 3 , 2-b] [ 1 , 4 ] oxazine-7-carboxylate (345 mg, 0.98 mmol) in MeOH (3.5 mL) - THF (3.5 mL) at room temperature. After being stirred at 60°C for 1 h, the reaction mixture was poured into water, neutralized with 6 N HC1 and extracted with EtOAc-THF. The organic layer was dried over MgSO4 and
concentrated in vacuo to give the title compound (276.7 mg, 0.820 mmol, 84%) as pale yellow amorphous solids.
MS (ESI+),. found 338.2
- 1H MR (300 MHz, DMSO-d6) 5:0.82-0.89 (8H, m) , 1.89-2.04 (2H, m) , 3.91-4.01 (2H, m) , 4.27-4.38 (2H, m) , 7.13 (2H, s) , 7.51 (1H, d, J = 1.9 Hz), 8.29 (1H, d, J = 1.9 Hz), 12.85 (1H, brs) .
[0860]
C) 4- ( 2 , 6-dicyclopropylpyridin-4-yl ) -N- ( ( 5- (methylsulfonyl) pyridin-2-yl) methyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide
To a solution of 4- (2 , 6-dicyclopropylpyridin-4-yl ) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (20 mg, 0.06 mmol) , (5- (methylsulfonyl ) pyridin-2-yl) methanamine
hydrochloride (14.52 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (19.1 mg, 0.038 mmol, 63.7%) as white amorphous solids.
1H NMR (300 MHz, DMSO-d6) 5:0.83-0.89 (8H, m) , 1.88-2.01 (2H, m) , 3.31 (3H, s) , 3.91-4.01 (2H, m) , 4.28-4.38 (2H, m) , 4.65 (2H, d, J = 5.7 Hz), 7.13 (2H, s), 7.58 (1H, d, J = 8.3 Hz), 7.66 (1H, d, J = 1.9 Hz), 8.28 (1H, dd, J = 8.3, 2.3 Hz), 8.34 (1H, d, J = 2.3 Hz), 9.00 (1H, d, J = 1.9 Hz), 9.16 (1H, t, J = 5.9 Hz) .
[0861]
Example 277
4- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5- (ethylsulfonyl) pyridin- 2-yl) methyl) -3 , 4-dihydro-2H-pyrido [ 3 , 2-b] [ 1 , 4 ] oxazine-7- carboxamide
To a solution of 4- (2 , 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (20 mg, 0.06 mmol), 1- (5- (ethylsulfonyl) pyridin-2-yl) methanamine
hydrochloride (15.44 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at. room temperature. The mixture was stirred at room temperature for lh. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (25.8 mg, 0.050 mmol, 84%) as white amorphous solids.
1H NMR (300 MHz, DMSO-d6) 5:0.80-0.90 (8H, m) , 1.12 (3H, t, J = 7.6 Hz), 1.90-2.01 (2H, m) , 3.39 (2H, q, J = 7.6 Hz), 3.91-4.00 (2H, m) , 4.30-4.38 (2H, m) , 4.66 (2H, d, J = 6.0 Hz), 7.13 (2H, s), 7.59 (1H, d, J = 8.3 Hz), 7.66 (1H, d, J = 1.9 Hz), 8.25 (1H, dd, J = 8.3, 1.9 Hz), 8.34 (1H, d, J = 1.9 Hz), 8.96 (1H, d, J = 1.9 Hz), 9.16 (1H, t, J = 6.0 Hz).
[0862]
Example 278
4- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (1- (methylsulfonyl ) piperidin-4-yl) methyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1,4] oxazine-7-carboxamide
To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (20 mg, 0.06 mmol), ( 1- (methylsulfonyl) piperidin-4-yl ) methanamine hydrochloride (14.92 mg, 0.07 mmol) and DIPEA (0.030 rtiL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for lh. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSC^ and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 100% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (17.1 mg, 0.033 mmol, 56.4%) as white crystals .
1H NMR (300 MHz, DMSO-d6) 5:0.79-0.90 (8H, m) , 1.11-1.28 (2H, m) , 1.57-1.71 (1H, m) , 1.71-1.83 (2H, m) , 1.88-1.99 (2H, m) , 2.58-2.74 (2H, m) , 2.83 (3H, s) , 3.12-3.20 (2H, m) , 3.48-3.61 (2H, m) , 3.88-3.99 (2H, m) , 4.27-4,37 (2H, m) , 7.12 (2H, s),
7.60 (1H, d, J = 1.9 Hz), 8.27 (1H, d, J = 1.9 Hz), 8.42 (1H, t,
J = 5.7 Hz) .
[0863]
Example 279
4- (2, 6-dicyclopropylpyridin-4-yl ) -N- (4- (methylsulfonyl) benzyl) - 3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamide
To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (20 mg, 0.06 mmol) , (4- (methylsulfonyl) phenyl) methanamine (12.08 mg, 0.07 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was stirred at room temperature for lh. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50 - 100% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (25.2 mg, 0.050 mmol, 84%) as white crystals.
1H NMR (300 MHz, DMSO-d6) 5:0.86 (8H, s) , 1.89-1.99 (2H, m) , 3.19 (3H, s), 3.91-3.99 (2H, m) , 4.29-4.38 (2H, m) , 4.56 (2H, d, J = 6.0 Hz), 7.13 (2H, s) , 7.56 (2H, d, J = 8.7 Hz), 7.64 (1H, d, J = 1.9 Hz), 7.88 (2H, d, J = 8.7 Hz), 8.32 (1H, d, J = 1.9 Hz) , 9.07 (1H, t, J = 6.0 Hz) .
[0864]
Example 280
4- (2, 6-dicyclopropylpyridin-4-yl ) -N- (2-fluoro-4- (methylsulfonyl) benzyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4 ] oxazine-7-carboxamide
To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [ 3 , 2-b] [1, 4] oxazine-7-carboxylic acid (20 mg, 0.06 mmol), 4- (2, 6-dicyclopropylpyridin-4-yl ) -3, 4-dihydro-2H- pyrido [ 3 , 2-b] [ 1 , 4 ] oxazine-7-carboxylic acid (20 mg, 0.06 mmol) and DIPEA (0.030 mL, 0.18 mmol) in DMF (2.0 mL) was added HATU (27.0 mg, 0.07 mmol) at room temperature. The mixture was' stirred at room temperature for 1 h. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and ■concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) and crystallized from EtOAc-hexane to give the title compound (17.8 mg, 0.034 mmol, 57.5%) as white crystals.
1H NMR (300 MHz, DMSO-d6) 5:0.77-0.93 (8H, m) , 1.87-2.00 (2H, m) , 3.26 (3H, s) , 3.90-4.00 (2H, m) , 4.27-4.38 (2H, m) , 4.56 (2H, d, J = 5.7 Hz), 7.13 (2H, s) , 7.56-7.67 (2H, m) , 7.71-7.82 (2H, m) , 8.32 (1H, d, J = 2.3 Hz), 9.05 (1H, t, J = 5.7 Hz).
[0865]
Example 281
4- (2, 6-dicyclopropylpyridin-4-yl) -N- (2-hydroxy-l- (1- (methylsulfonyl) piperidin-4-yl) ethyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazine-7-carboxamide
A) methyl ( ( (4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazin-7-yl) carbonyl) amino) (1- (methylsulfonyl) piperidin-4-yl ) acetate
To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [3, 2-b] [ 1 , 4 ] oxazine-7-carboxylic acid (60 mg, 0.18 mmol), methyl 2-amino-2- ( 1- (methylsulfonyl ) piperidin-4- yl)acetate hydrochloride (56.1 mg, 0.20 mmol) and DIPEA (0.091 mL, 0.53 mmol) in DMF (2.0 mL) was added HATU (81 mg, 0.21 mmol) at room temperature. The mixture was stirred at room temperature for lh. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 50 - 100% EtOAc in hexane) to give the title compound (93.5 mg, 0.164 mmol, 92%) as white amorphous solids.
MS (ESI+) , found 570.2
1H NMR (300 MHz, DMSO-d6) 5:0.77-0.91 (8H, m) , 1.25-1.51 (2H, m) , 1.65-1.86 (2H, m) , 1.87-2.02 (3H, m) , 2.62-2.75 (2H, m) , 2.85 (3H, s) , 3.52-3.64 (2H, m) , 3.66 (3H, s), 3.91-4.00 (2H, m) , 4.27-4.45 (3H, m) , 7.14 (2H, s) , 7.65 (1H, d, J = 1.9 Hz), 8.33 (1H, d, J = 1.9 Hz), 8.57 (1H, d, J = 7.6 Hz).
[0866]
B) 4- (2, 6-dicyclopropylpyridin-4-yl ) -N- (2-hydroxy-l- (1- (methylsulfonyl) piperidin-4-yl ) ethyl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1,4] oxazine-7-carboxamide
To a mixture of methyl 2- ( 4- (2 , 6-dicyclopropylpyridin-4- yl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamido) -2- (1- (methylsulfonyl) piper.idin-4-yl ) acetate (90 mg, 0.16 mmol) in MeOH (3 mL) was added NaBH4 (29.9 mg, 0.79 mmol) at room
temperature. After being stirred at room temperature for 2 h, the mixture was quenched with sat. NaHCO3 aq. and extracted with EtOAc. The organic layer was separated and dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title compound (68.7 mg, 0.127 mmol, 80%) as white amorphous solids.
[0867]
Example 282
4- (2, 6-dicyclopropylpyridin-4-yl) -N- (2-hydroxy-l- (4-
(methylsulfonyl) phenyl) ethyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4] oxazine-7-carboxamide
A) methyl ( ( (4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4-dihydro-2H- pyrido [3, 2-b] [1, 4] oxazin-7-yl) carbonyl) amino) (4- (methylsulfonyl) phenyl) acetate
To a solution of 4- (2, 6-dicyclopropylpyridin-4-yl) -3, 4- dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine-7-carboxylic acid (70 mg, 0.21 mmol), methyl 2-amino-2- (4- (methylsulfonyl) phenyl) acetate (55.5 mg, 0.23 mmol) and DIPEA (0.106 mL, 0.62 mmol) in DMF (2.0 mL) was added HATU (95 mg, 0.25 mmol) at room temperature. The mixture was stirred at room temperature for lh. The
mixture was quenched with sat. NaHCO3 aq. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (92.6 mg, 0.165 mmol, 79%) as white amorphous solids.
MS (ESI+) , found 563.2
1H NMR (300 MHz, DMSO-d6) 5:0.79-0.91 (8H, m) , 1.88-1.98 (2H, m) , 3.23 (3H, s) , 3.68 (3H, s), 3.90-3.99 (2H, m) , 4.28-4.38 (2H, m) , 5.84 (1H, d, J = 7.2 Hz), 7.13 (2H, s), 7.67 (1H, d , J = 1.9 Hz), 7.75 (2H, d, J = 8.3 Hz), 7.95 (2H, d , J = 8.3 Hz), 8.34 (1H, d, J = 1.9 Hz ) , 9.23 (1H, d, J = 7.2 Hz) .
[0868]
B) 4- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( 2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -3, 4-dihydro-2H-pyrido [3,2- b] [1, 4 ] oxazine-7-carboxamide
To a mixture of methyl 2- (4- (2, 6-dicyclopropylpyridin-4- yl) -3, 4-dihydro-2H-pyrido [3, 2-b] [1,4] oxazine-7-carboxamido) -2- (4- (methylsulfonyl ) phenyl) acetate (90 mg, 0.16 mmol) in MeOH (3.0 mL) was added NaBH4 (30.3 mg, 0.80 mmol) at room
temperature. After being stirred at room temperature for 2 h, the mixture was quenched with sat. NaHCO3 aq. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 80% EtOAc in hexane) to give the title compound (72.3 mg, 0.135 mmol, 85%) as white amorphous solids.
[0869]
Example 283
5- ( 6-cyclopropyl-l-methyl-IH-pyrazolo [ 3 , 4-b] pyridin-4-yl ) -N- ( 4- (methylsulfonyl) benzyl) -2,3,4, 5-tetrahydro-l , 5-benzoxazepine-8- carboxamide
A) 6-cyclopropyl-l-methyl-lH-pyrazolo [3, 4-b] pyridin-4-ol
A mixture of l-methyl-lH-pyrazol-5-amine (200 mg, 2.06 mmol) and ethyl 3-cyclopropyl-3-oxopropanoate (322 mg, 2.06 mmol) in AcOH (3 mL) was stirred at 100°C overnight. The mixture was concentrated in vacuo. The residue was washed with EtOAc-IPE and dried in vacuo to give the title compound (65.0 mg, 0.344 mmol, 16.68%) as off-white solids.
MS (ESI+) , found 190.4
1H NMR (400 MHz, DMSO-d6) δ : 0.93-0.99 (2H, m) , 1.07-1.13 (2H, m) , 2.15 (1H, s), 3.84 (3H, s), 5.90 (1H, brs) , 7.90 (1H, s), 10.90-11.90 (1H, br) .
[0870] B) 6-cyclopropyl-l-methyl-lH-pyrazolo [3, 4-b] pyridin-4-yl trifluoromethanesulfonate
Tf20 (0.070 mL, 0.41 mmol) was added to a solution of 6- cyclopropyl-l-methyl-lH-pyrazolo [3, 4-b] pyridin-4-ol (65 mg, 0.34 mmol) in pyridine (2 mL) at 0°C. The mixture was stirred at room temperature under N2 for 1 h. The mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound (92 mg, 0.286 mmol, 83%) as a colorless oil.
MS (ESI+) , found 322.2
1H NMR (300 MHz, CDC13) 5:1.09-1.21 (2H, m) , 1.23-1.37 (2H, m) , 2.29 (1H, tt, J = 8.3, 4.9 Hz), 4.07 (3H, s) , 6.48 (1H, s), 8.08 (1H, s) .
[0871]
C) 5- ( 6-cyclopropyl-l-methyl-IH-pyrazolo [3 , 4-b] pyridin-4-yl ) -N- (4- (methylsulfonyl ) benzyl) -2,3,4, 5-tetrahydro-l, 5- benzoxazepine-8-carboxamide
A mixture of N- ( 4- (methylsulfonyl ) benzyl ) -2 , 3 , 4 , 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (65 mg, 0.18 mmol), 6-cyclopropyl-l-methyl-lH-pyrazolo [3, 4-b] pyridin-4-yl
trifluoromethanesulfonate (87 mg, 0.27 mmol), Ruphos
precatalyst (13.14 mg, 0.02 mmol) and NaOtBu (52.0 mg, 0.54 mmol) in DME (3 mL) was stirred under microwave irradiation at 120°C for 3h. After cooling, the mixture was passed through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 60% - 90% EtOAc in hexane) to give a colorless oil. The oil was triturated with EtOAc-IPE and the precipitates were dried in vacuo to give the title compound (21.00 mg, 0.040 mmol, 21.90%) as white powder.
1H NMR (300 MHz, DMSO-d6) 5:0.84-0.90 (2H, m) , 1.01-1.08 (2H, m) , 2.03-2.11 (3H, m) , 3.19 (3H, s) , 3.88 (3H, s) , 4.05-4.21 (4H, m) , 4.57 (2H, d, J = 6.0 Hz), 6.13 (1H, s), 7.39 (1H, d, J = 8.3 Hz), 7.56-7.65 (4H, m) , 7.86-7.92 (3H, m) , 9.19 (1H, s) .
[0872]
Example 284
(2S) -1- (2, 6-dicyclopropylpyridin-4-yl) -2-methyl-N- ( (5-
(methylsulfonyl) pyridin-2-yl ) methyl ) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide
A) tert-butyl ( (2S) -1- ( (3-bromopyridin-2-yl) oxy) propan-2- yl ) carbamate
ADDP (10.88 g, 43.10 mmol) was added to a solution of 3- bromopyridin-2-ol (5 g, 28.74 mmol), ( S ) -tert-butyl (1- hydroxypropan-2-yl ) carbamate (6.04 g, 34.48 mmol) and BU3P
(10.64 mL, 43.10 mmol) in THF (dry) (96 mL) at room temperature. The mixture was stirred at room temperature under N2 for 2 h. The mixture was concentrated in vacuo to half volume, filtered with washing with IPE and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title compound (5.46 g, 16.49 mmol, 57.4%) as a colorless oil.
1R NMR (300 MHz, CDC13) 5:1.26-1.33 (3H, m) , 1.44 (9H, s) , 4.12 (1H, q, J = 6.9 Hz), 4.25-4.40 (2H, m) , 4.82 (1H, brs) , 6.78 (1H, dd, J = 7.6, 4.9 Hz), 7.81(1H, dd, J = 7.7, 1.7 Hz), 8.02- 8.13 (1H, m) .
[0873]
B) ( 2S ) -1- ( ( 3-bromopyridin-2-yl ) oxy) propan-2-amine
To tert-butyl ( ( 2S ) -1- ( ( 3-bromopyridin-2-yl ) oxy) propan-2- yl) carbamate (5000 mg, 15.10 mmol) was added TFA (15 mL, 194.70 mmol). The mixture was stirred at room temperature for 10 min, concentrated in vacuo. The residue was neutralized with sat. NaHCO3 aq. and extracted with EtOAc-THF (twice.) . The organic layer was separated, washed with water and brine, dried over MgSCO4 and concentrated in vacuo to give the title compound
(3500 mg, 15.15 mmol, 100%) as a colorless oil. This product was subjected to the next reaction without further purification.
1H NMR (300 MHz, CDC13) 6:1.43 (3H, d, J = 6.8 Hz), 3.75 (1H, td, J = 6.7, 3.6 Hz), 4.35-4.46 (1H, m) , 4.49-4.61 (1H, m) , 6.84 (1H, dd, J = 7.6, 4.9 Hz), 7.83 (1H, d, J = 7.6 Hz), 8.06 (1H, d, J = 4.2 Hz). (The NH2 proton was omitted.)
[0874]
C) (3S) -3-methyl-3, 4-dihydro-2H-pyrido [3, 2-b] [1, 4] oxazine
To a solution of ( 2S ) -1- ( ( 3-bromopyridin-2-yl ) oxy) propan- 2-amine (3500 mg, 15.15 mmol) , t-Bu3P (613 mg, 3.03 mmol) and KOtBu (3399 mg, 30.29 mmol) in THF (dry) (15 mL)- was added
Pd2(dba)3 (1387 mg, 1.51 mmol) at room temperature. The mixture was stirred at 70°C under Ar for 3 h. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 0% - 20% MeOH in EtOAc) to give the title compound (1070 mg, 7.12 mmol, 47.0%) as light brown solids.
MS (ESI+) , found 151.0 (M+H)
[0875]
D) (2S) -6-bromo-2-methyl-2, 3-dihydro-lH-pyrido [2, 3- b] [1,4] oxazine
NBS (1.395 g, 7.84 mmol) was added to a solution of (S)-
2-methyl-2, 3-dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine (1.07 g, 7.12 mmol) in DMF (11.87 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was quenched with water at 0°C and extracted with EtOAc (twice) . The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 60% EtOAc in hexane) to give the title
compound (1.010 g, 4.41 mmol, 61.9%) as pale yellow solids. MS (ESI+) , found 229.0
1H NMR (300 MHz, CDC13) δ:1.20 (3H, d, J = 6.4 Hz), 3.50-3.62 (1H, m) , 3.75 (1H, brs) , 3.92 (1H, dd, J = 10.8, 8.1 Hz), 4.34 (1H, dd, J = 10.8, 2.8 Hz), 6.73(1H, d, J = 7.9 Hz), 6.90 (1H, d, J = 7.9 Hz) .
[0876]
E) tert-butyl (2S) -6-bromo-2-methyl-2, 3-dihydro-lH-pyrido [2, 3- b] [1, 4 ] oxazine-l-carboxylate
DMAP (539 mg, 4.41 mmol) was added dropwise to a solution of (S) -6-bromo-2-methyl-2 , 3-dihydro-lH-pyrido [2,3- b] [1, 4] oxazine (1010 mg, 4.41 mmol) and Boc20 (1.536 mL, 6.61 mmol) in THF (14.70 mL) at 0°C. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 15% - 50% EtOAc in hexane) to give the title compound (1170 mg, 3.55 mmol, 81%) as a pale yellow oil. MS (ESI+), found 329.0 (M+H)
1H NMR (300 MHz, CDC13) 5:1.23 (3H, d, J = 6.8 Hz), 1.55 (9H, s), 4.18-4.30 (2H, m) , 4.57-4.70 (1H, m) , 7.07 (1H, d, J = 8.3 Hz) , 8.23 (1H, d, J = 8.3 Hz) .
[0877]
F) 1-tert-butyl 6-methyl (2S) -2-methyl-2 , 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-1, 6-dicarboxylate
A mixture of tert-butyl (2S) -6-bromo-2-methyl-2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-l-carboxylate (1.1695 g, 3.55 mmol), Pd (dppf) C12-CH2C12 (0.145 g, 0.18 mmol) and TEA (0.990 mL, 7.11 mmol) in DMF (13.16 mL) and MeOH (22.37 mL) was stirred under CO atmosphere (0.5 MPa) at 100°C for 5h. After cooling, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, eluted with 15% -60% EtOAc in hexane) to give the title
compound (0.940 g, 3.05 mmol, 86%) as a pale yellow oil.
MS (ESI+), found 309.1 (M+H)
1H NMR (300 MHz, CDC13) 5:1.24-1.30 (3H, m) , 1.52-1.60 (9H, m) , 3.90-3.98 (3H, m) , 4.21-4.34 (2H, m) , 4.64 (1H, q, J = 6.8 Hz), 7.74-7.82 (1H, m) , 8.55(1H, d, J = 8.3 Hz).
[0878]
G) (2S) -1- (tert-butoxycarbonyl) -2-methyl-2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid
A mixture of 1-tert-butyl 6-methyl ( 2S ) -2-methyl-2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-1, 6-dicarboxylate (110 mg, 0.36 initio1) and 2N NaOH (0.535 mL, 1.07 mmol) in THF (2 mL) and MeOH (1 mL) was stirred at room temperature for 3h. The
mixture was acidified with IN HC1 aq. at 0°C and diluted with water. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSCO4 and concentrated in vacuo to give the title compound (103 mg, 0.350 mmol, 98%) as pale yellow amorphous solids.
MS (ESI+), found 295.3 (M+H)
1R NMR (300 MHz, CDC13) 5:1.22-1.37 (3H, m) , 1.58 (9H, s) , 4.33 (2H, dd, J = 4.9, 1.9 Hz), 4.70 (1H, dt, J = 7.0, 1.8 Hz), 7.85 (1H, d, J = 8.3 Hz), 8.64 (1H, d, J = 8.3 Hz). (The C02H peak was omitted. )
[0879]
H) tert-butyl (2S) -2-methyl-6- (( (5- (methylsulfonyl) pyridin-2- yl ) methyl ) carbamoyl ) -2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine- 1-carboxylate
HATU (186 mg, 0.49 mmol) was added to a solution of (2S)- 1- (tert-butoxycarbonyl) -2-methyl-2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxylic acid (103 mg, 0.35 mmol), (5-
(methylsulfonyl) pyridin-2-yl ) methanamine hydrochloride (78 mg, 0.35 mmol) and DIPEA (199 mg, 1.54 mmol) in DMF (1.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (120 mg, 0.259 mmol, 74.1%) as off-white amorphous solids.
MS (ESI+) , found 463.2
1H NMR (300 MHz, CDC13) 5:1.28 (3H, d, J = 6.9 Hz), 1.57 (9H, s), 3.09 (3H, s), 4.27-4.36 (2H, m) , 4.68 (1H, d, J = 7.2 Hz), 4.85 (2H, d, J = 6.4 Hz), 7.55 (1H, d, J = 8.7 Hz), 7.86 (1H, d, J = 8.3 Hz), 8.17 (1H, dd, J = 8.1, 2.5 Hz), 8.46-8.59 (2H, m) , 9.10 (1H, d, J = 2.7 Hz).
[0880]
I) (2S) -2-methyl-N- ( (5- (methylsulfonyl ) pyridin-2-yl) methyl) - 2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine-6-carboxamide
A mixture of tert-butyl (2S) -2-methyl-6- ( ( (5-
(methylsulfonyl ) pyridin-2-yl ) methyl) carbamoyl) -2, 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-l-carboxylate (120 mg, 0.26 mmol) and TFA (1 mL, 12.98 mmol) in EtOAc (0.5 mL) was stirred at room temperature for 3h. The mixture was neutralized with 8N NaOH aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (95 mg, 0.262 mmol, 101%) as white solids.
MS (ESI+) , found 363.2
1H NMR (300 MHz, DMSO-d6) 5:1.09-1.20 (3H, d, J = 6.6 Hz), 3.30 (3H, s), 3.53 (1H, brs)', 3.87 (1H, dd, J = 11.0/ 7.6 Hz), 4.33 (1H, dd, J = 10.6, 1.5 Hz), 4.63 (2H, d, J = 6.0 Hz), 6.81-6.88 (1H, m) , 6.95 (1H, d, J = 7.9 Hz), 7.49 (2H, t, J = 8.1 Hz), 8.26 (1H, dd, J = 8.3, 2.3 Hz), 8.87 (1H, t, J = 6.0 Hz), 8.99 (1H, d, J = 2.5 Hz) .
[0881]
J) (2S) -1- (2, 6-dicyclopropylpyridin-4-yl) -2-methyl-N- ( (5- (methylsulfonyl ) pyridin-2-yl ) methyl) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of ( 2S ) -2-methyl-N- (( 5- (methylsulfonyl ) pyridin-
2-yl ) methyl ) -2 , 3-dihydro-lH-pyrido [2 , 3-b] [1,4] oxazine-6- carboxamide (60 mg, 0.17 mmol), 2 , 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate (153 mg, 0.50 mmol), Ruphos
precatalyst' (12.06 mg, 0.02 mmol), Ruphos (7.73 mg, 0.02 mmol) and NaOtBu (47.7 mg, 0.50 mmol) in DME (3 mL) was stirred under microwave irradiation at 120 °C for 3h. After cooling,
insoluble material was removed off by filtration. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0% - 10% MeOH in EtOAc) and column chromatography (silica gel, eluted with 70% - 100% EtOAc in hexane) to give a pale yellow amorphous solid, which was washed with EtOAc-IPE and dried in vacuo to give the title compound (3.00 mg, 5.77 μmol, 27.3%) as white amorphous solids .
1H NMR (300 MHz, CDC13) 5:0.85-1.05 (8H, m) , 1.39 (3H, d, J = 6.8 Hz), 1.82-1.92 (2H, m) , 3.09 (3H, s) , 4.01-4.10 (1H, m) , 4.36 (2H, d, J = 2.3 Hz), 4.86 (2H, d, J = 6.4 Hz), 6.72 (2H, s), 7.48 (1H, d, J = 8.1 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.77 (1H, d, J = 8.3 Hz), 8.17 (1H, dd, J = 8.3, 2.3 Hz), 8.45 (1H, t, J = 6.0 Hz), 9.11 (1H, d, J = 1.9 Hz).
[0882]
Example 285
1- (2-cyano-5-cyclopropylphenyl ) -N- (4- (methylsulfonyl ) benzyl) - 1,2,3, 4-tetrahydropyrido [2 , 3-b] [1,4] oxazepine-7-carboxamide
A mixture of N- (4- (methylsulfonyl ) benzyl) -2, 3, 4, 5- tetrahydro-1 , 5-benzoxazepine-8-carboxamide (35 mg, 0.10 mmol) ,
2-cyano-5-cyclopropylphenyl trifluoromethanesulfonate (42.4 mg, 0.15 mmol), Ruphos precatalyst (7.08 mg, 9.71 pmol) and NaOtBu (28.0 mg, 0.29 mmol) in DME (3 mL) was stirred under microwave irradiation at 120 °C for 3h. After cooling, the mixture was passed through a celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (3.00 mg, 5.97 μmol, 6.15%) as pale yellow amorphous solids.
1H NMR (300 MHz, CDC13) 5:0.74-0.94 (2H, m) , 1.07-1.19 (2H, m) , 1.87-1.96 (1H, m) , 2.18 (2H, t, J = 6.0 Hz), 3.03 (3H, s) , 4.04-4.12 (2H, m) , 4.63-4.72 (4H, m) , 6.85-6.91 (2H, m) , 6.98 (1H, d, J = 1.5 Hz), 7.54 (3H, dd, J = 8.1, 5.1 Hz), 7.73 (1H, d, J = 8.3 Hz), 7.90 (2H, d, J = 7.6 Hz), 8.17 (1H, t, J = 6.2 Hz) .
[0883]
Example 286
4- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl) pyridin-2-yl) methyl) chromane-7-carboxamide A) 4-oxochromane-7-carbonitrile
A mixture of 7-bromochroman-4-one (1.99 g, 8.76 mmol) , zinc cyanide (1.23 g, 10.48 mmol), Pd(Ph3P)4 (295 mg, 0.26 mmol) and DMF (20 mL) was stirred at 80°C under nitrogen atmosphere overnight. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 30% EtOAc in hexane) to give the title compound (0.236 g, 1.363 mmol, 15.55%) as pale yellow solids.
[0884]
B) N' - ( (4E) -7-cyano-2, 3-dihydro-4H-chromen-4-ylidene) -4- methylbenzenesulfonohydrazide
To a mixture of 4-oxochromane-7-carbonitrile (230 mg, 1.33 mmol) and EtOH (15 mL) was added p-toluenesulfonyl hydrazide (259 mg, 1.39 mmol) . After being stirred at 90°C for 3 h, the mixture was concentrated. The residue was washed with Et20 and dried in vacuo to give the title compound (299 mg, 0.876 mmol, 65.9%) as pale orange solids.
MS (ESI+) , found 342.1
[0885]
C) 4- (2, 6-dicyclopropylpyridin-4-yl ) -2H-chromene-7-carbonitrile
To a mixture of 2 , 6-dicyclopropylpyridin-4-yl
trifluoromethanesulfonate (497 mg, 1.62 mmol), N'-((4E)-7- cyano-2, 3-dihydro-4H-chromen-4-ylidene) -4- methylbenzenesulfonohydrazide (499 mg, 1.46 mmol), Pd2(dba)3 (67 mg, 0.07 mmol), Xphos (139 mg, 0.29 mmol) and CPME (30 mL) was added lithium t-butoxide (272 mg, 3.40 mmol). After being stirred under nitrogen atmosphere at 90 °C for 1 h, the mixture was poured into sat. NH4C1 aqr and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column
chromatography (NH silica gel, eluted with 1% - 5% EtOAc in hexane and silica gel, eluted with 1% - 5% EtOAc in hexane) to give the title compound (374 mg, 1.190 mmol, 81%) as yellow solids .
MS (ESI+) , found 315.1
[0886]
D) 4- (2, 6-dicyclopropylpyridin-4-yl) chromane-7-carbonitrile To a mixture of 4- ( 2 , 6-dicyclopropylpyridin-4-yl ) -2H- chromene-7-carbonitrile (374 mg, 1.19 mmol) and MeOH (15 mL) was added Pd/C (en) (259 mg, 0.12 mmol). After being stirred under hydrogen atmosphere at room temperature overnight, the insoluble material was removed by filtration, and the filtrate was concentrated. The residue was purified by column
chromatography (silica gel, eluted with 1% - 10% EtOAc in hexane) to give the title compound (138 mg, 0.436 mmol, 36.7%) as white solids.
MS (ESI+) , found 317.1
[0887]
E) 4- (2, 6-dicyclopropylpyridin-4-yl ) chromane-7-carboxylic acid
To a mixture of 4- (2 , 6-dicyclopropylpyridin-4- yl) chromane-7-carbonitrile (138 mg, 0.44 mmol) and nBuOH (10 mL) was added 8 M NaOH aq. (-0.50 mL, 4.00 mmol). After being stirred at 90°C overnight, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was subjected to the next reaction without further purification .
[0888]
F) 4- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5- (methylsulfonyl) pyridin-2-yl ) methyl) chromane-7-carboxamide
To a mixture of 4- ( 2 , 6-dicyclopropylpyridin-4- yl ) chromane-7-carboxylic acid (24 mg, 0.07 mmol), (5- (methylsulfonyl ) pyridin-2-yl ) methanamine hydrochloride (28 mg, 0.13 mmol), HATU (54 mg, 0.14 mmol) and DMF (1 mL) was added DIPEA (0.12 mL, 0.69 mmol). After being stirred at room temperature overnight, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SCO4 and concentrated. The residue was purified by preparative HPLC (L-Column 2 ODS, eluted with H20 in
acetonitrile containing 0.1% TFA) . The desired fraction was diluted with EtOAc, washed with sat. NaHCO3 aq. and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (32.0 mg, 0.064 mmol, 89%) as white solids.
1H NMR (300 MHz, DMSO-d6) 5:0.81-0.86 (8H, m) , 1.94 (2H, quin, J = 6.3 Hz), 2.00-2.13 (1H, m) , 2.20-2.32 (1H, m) , 3.31 (3H, s) , 4.14-4.25 (3H, m) , 4.64 (2H, d, J = 5.7 Hz), 6.80 (2H, s) , 6.87 (1H, s), 7.33-7.44 (2H, m) , 7.57 (1H, d, J = 8.3 Hz), 8.28 (1H, dd, J = 8.3, 2.3 Hz), 9.00 (1H, d, J = 1.9 Hz), 9.19 (1H, t, J = 5.9 Hz) .
[0889]
Example 28.7
(R) -1- (2, 6-dicyclopropylpyridin-4-yl) -2-methyl-N- ( (5- (methylsulfonyl) pyridin-2-yl ) methyl ) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
A) tert-butyl ( ( 2R) -1- ( ( 3-bromopyridin-2-yl ) oxy) propan-2- yl ) carbamate
ADDP (4.35 g, 17.24 mmol) was added to a solution of 3- bromopyridin-2-ol (2 g, 11.49 mmol), Bu3P (4.25 mL, 17.24 mmol) and (R) -tert-butyl ( l-hydroxypropan-2-yl ) carbamate (2.014 g, 11.49 mmol) in THF (dry) (100 mL) at room temperature. The mixture was stirred at room temperature under N2 overnight.
The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 30% EtOAc in hexane) to give the title
compound (2.52 g, 7.61 mmol, 66.2%) as a colorless oil.
MS (ESI+), found 331.2 (M+H)
λΕ NMR (300 MHz, CDC13) 5:1.30 (3H, d, J = 6.6 Hz), 1.44 (9H, s), 4.06-4.17 (1H, m) , 4.32 (2H, dd, J = 4.5, 1.5 Hz), 4.70- 5.00 (1H, br), 6.79 (1H, dd, J = 7.6, 4.9 Hz), 7.81 (1H, dd, J = 7.7, 1.7 Hz), 8.06 (1H, dd, J = 4.9, 1.9 Hz) .
[0890] B) tert-butyl (2R) -2-methyl-2 , 3-dihydro-lH-pyrido [ 2 , 3- b] [1, 4 ] oxazine-l-carboxylate
A mixture of tert-butyl ( (2R) -1- ( (3-bromopyridin-2- yl) oxy) propan-2-yl) carbamate (2.52 g, 7.61 mmol), N^N2- dimethylethane-1, 2-diamine (0.335 g, 3.80 mmol), copper(I) iodide (0.725 g, 3.80 mmol) and cesium carbonate (4.96 g, 15.22 mmol) in THF (150 mL) was stirred at 70°C under Ar overnight. After cooling, insoluble material was removed off by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15% - 50% EtOAc in hexane) to give the title compound ^(0.080 g, 0.320 mmol, 4.20%) as a pale orange oil.
MS (ESI+), found 251.4 (M+H)
λΕ NMR (300 MHz, CDC13) 5:1.25 (3H, d, J = 6.9 Hz), 1.55 (9H, s), 4.21-4.32 (2H, m) , 4.53-4.69 (1H, m) , 6.85-6.95 (1H, m) , 7.87-7.98 (1H, m) , 8.33 (1H, d, J = 7.9 Hz).
[0891]
C) (2R) -2-methyl-2, 3-dihydro-lH-pyrido [2, 3-b] [l,4]oxazine
TFA (1.2 mL, 15.58 mmol) was added to a solution of tert- butyl (2R) -2-methyl-2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-l- carboxylate (80 mg, 0.32 mmol) in EtOAc (0.5 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was neutralized with 8N NaOH aq. at 0°C and extracted five times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (50.0 mg, 0.333 mmol, 104%) as light brown solids.
MS (ESI+), found 151.4 (M+H)
[0892]
D) (2R) -6-bromo-2-methyl-2, 3-dihydro-lH-pyrido [2, 3- b] [1,4] oxazine
NBS (65.2 mg, 0.37 mmol) was added to a solution of (2R)- 2-methyl-2, 3-dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine (50 mg, 0.33 mmol) in DMF (1 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was quenched with water at 0°C and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 20% - 50% EtOAc in hexane) to give the title compound
(35.0 mg, 0.153 mmol, 45.9%) as pale yellow solids.
MS (ESI+), found 229.3 (M+H)
1H NMR (300 MHz, CDC13) 5:1.20 (3H, d, J = 6.4 Hz), 3.55 (1H, ddd, J = 8.0, 6.3, 3.0 Hz), 3.65-3.88 (1H, br) , 3.92 (1H, dd, J = 10.8, 8.1 Hz), 4.29-4.37 (1H, m) , 6.69-6.78 (1H, m, J = 7.9 Hz), 6.87-6.93 (1H, m, J = 7.9 Hz).
[0893]
E) tert-butyl (2R) -6-bromo-2-methyl-2 , 3-dihydro-lH-pyrido [2 , 3- b] [ 1 , 4 ] oxazine-l-carboxylate
DMAP (18.67 mg, 0.15 mmol) was added dropwise to a
solution of (2R) -6-bromo-2-methyl-2 , 3-dihydro-lH-pyrido [2 , 3- b] [1, 4] oxazine (35 mg, 0.15 mmol) and Boc20 (0.053 mL, 0.23 mmol) in THF (1 mL) at 0°C. The mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title
compound (38.0 mg, 0.115 mmol, 76%) as a colorless oil.
MS (ESI+), found 329.2 (M+H)
1H NMR (300 MHz, CDCI3) 5:1.23 (3H, d, J = 6.8 Hz), 1.55 (9H, s), 4.20-4.31 (2H, m) , 4.63 (1H, dt, J = 6.9, 2.0 Hz), 7.08 (1H, d, J = 8.3 Hz), 8.23 (1H, d, J = 7.9 Hz).
[0894]
F) 1-tert-butyl 6-methyl (2R) -2-methyl-2 , 3-dihydro-lH- pyrido [2, 3-b] [1,4] oxazine-1, 6-dicarboxylate
A mixture of tert-butyl (2R) -6-bromo-2-methyl-2, 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-l-carboxylate (38 mg, 0.12 mmol), Pd(dppf)Cl2'CH2Cl2 (4.71 mg, 5.77 pmol) and TEA (0.032 mL, 0.23 mmol) in DMF (1 mL) and MeOH (3 mL) was stirred under CO atmosphere (0.5 MPa) at 100°C for 6h. After cooling, the mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15% - 60% EtOAc in hexane) to give the title compound (32.0 mg, 0.104 mmol, 90%) as a pale yellow oil.
MS (ESI+), found 309.3 (M+H)
1H NMR (300 MHz, CDC13) 5:1.28 (3H, d, J = 6.8 Hz), 1.57 (9H, s), 3.95 (3H, s), 4.28 (2H, dd, J = 4.5, 2.3 Hz), 4.64 (1H, d, J = 6.8 Hz), 7.79 (1H, d, J = 8.3 Hz), 8.56 (1H, d, J = 8.3 Hz).
[0895]
G) (2R) -1- (tert-butoxycarbonyl) -2-methyl-2 , 3-dihydro-lH- pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxylic acid
A mixture of 1-tert-butyl 6-methyl (2R) -2-methyl-2 , 3- dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-1, 6-dicarboxylate (32 mg, 0.10 mmol) and 2N NaOH (0.156 mL, 0.31 mmol) in THF (1 mL) and MeOH (0.5 mL) was stirred at room temperature for 3h. The mixture was acidified with IN HC1 aq. at 0°C and diluted with water. The mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (30.0 mg,
0.102 mmol, 98%) as pale yellow amorphous solids.
MS (ESI+), found 295.3 (M+H)
[0896]
H) tert-butyl (2R) -2-methyl-6- ((( 5- (methylsulfonyl ) pyridin-2- yl) methyl) carbamoyl) -2, 3-dihydro-lH-pyrido [2, 3-b] [1,4] oxazine- 1-carboxylate
HATU (54.3 mg, 0.14 mmol) was added to a solution of
(2R) -1- (tert-butoxycarbonyl) -2-methyl-2, 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-6-carboxylic acid (30 mg, 0.10 mmol), (5- (methylsulfonyl ) pyridin-2-yl ) methanamine hydrochloride
(22.70 mg, 0.10 mmol) and DIPEA (58.0 mg, 0.45 mmol) in DMF (0.7 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (35.0 mg, 0.076 mmol, 74.2%) as white amorphous solids .
MS (ESI+), found 463.2 (M+H)
[0897]
I) (2R) -2-methyl-N- ( (5- (methylsulfonyl) pyridin-2-yl) methyl) - 2 , 3-dihydro-lH-pyrido [2 , 3-b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of tert-butyl (2R) -2-methyl-6- ( ( (5- (methylsulfonyl) pyridin-2-yl) methyl) carbamoyl) -2, 3-dihydro-lH- pyrido [2, 3-b] [1, 4] oxazine-l-carboxylate (35 mg, 0.08 mmol) and TFA (1 mL, 12.98 mmol) in EtOAc (0.5 mL) was stirred at room temperature for 3h. The mixture was neutralized with 8N NaOH aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSCO4 and concentrated in vacuo to give the title compound (25.00 mg, 0.069 mmol, 91%) as white solids.
MS (ESI+), found 363.2
[0898]
J) (R) -1- (2, 6-dicyclopropylpyridin-4-yl) -2-methyl-N- ( (5- (methylsulfonyl ) pyridin-2-yl ) methyl ) -2 , 3-dihydro-lH-pyrido [2,3- b] [ 1 , 4 ] oxazine-6-carboxamide
A mixture of ( 2R) -2-methyl-N- (( 5- (methylsulfonyl ) pyridin-
2-yl) methyl) -2, 3-dihydro-lH-pyrido [2, 3-b] [1, 4] oxazine-6- carboxamide (25 mg, 0.07 mmol), 2 , 6-dicyclopropylpyridin-4-yl trifluoromethanesulfonate (63.6 mg, 0.21 mmol), Ruphos
precatalyst (5.03 mg, 6.90 μmol) , Ruphos (3.22 mg, 6.90 μmol) and NaOtBu (19.89 mg, 0.21 mmol) in DME (3 mL) was stirred under microwave irradiation at 120 °C for 3h. After cooling, insoluble material was removed off by filtration. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 70% - 100% EtOAc in hexane) to give a pale yellow amorphous solid, which was washed with IPE and dried in vacuo to give the title compound (4.00 mg, 7.70 μmol, 11.16%) as pale yellow amorphous solids.
1H NMR (300 MHz, CDC13) 5:0.82-1.05 (8H, m) , 1.39 (3H, d, J = 6.4 Hz), 1.75-2.00 (2H, brs) , 3.09 (3H, s) , 3.98-4.16 (1H, m) , 4.36 (2H, d, J = 2.3 Hz), 4.86 (2H, d, J = 6.0 Hz), 6.70 (2H, s), 7.50 (1H, d, J = 8.3 Hz), 7.56 (1H, d, J = 7.9 Hz), 7.78
(1H, d, J = 7.9 Hz), 8.17 (1H, dd, J = 8.1, 2.5 Hz), 8.38-8.51 (1H, m) , 9.10 (1H, d, J = 1.9 Hz).
[0899]
Example 288
5- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl) pyridin-2-yl) methyl) -2, 3,4,5- tetrahydropyrido [ 3 , 2-b] [1,4] oxazepine-8-carboxamide
A) 3- ( (2-bromopyridin-3-yl) oxy) propan-l-amine
To a solution of 2-bromopyridin-3-ol (3 g, 17.24 mmol) ,
3-aminopropan-l-ol (1.439 mL, 18.97 mmol) and PPh3 (5.43 g, 20.69 mmol) in THF (dry) (120 mL) was added DIAD (4.02 mL, 20.69 mmol) at 0°C. The mixture was stirred at room
temperature under N2 for 3 days. The mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 20% MeOH in EtOAc) to give the title compound (2.72 g, 11.77 mmol, 68.3%) as brown solids.
1H NMR (300 MHz, DMSO-d6) 5:1.74-1.87 (2H, m) , 2.72 (2H, t, J =
6.6 Hz), 3.22-3.48 (2H, m) , 4.16 (2H, t, J = 6.2 Hz), 7.39 (1H, dd, J = 8.3, 4.5 Hz), 7.46-7.73 (1H, m) , 7.95 (1H, dd, J = 4.7,
1.7 Hz) .
[0900]
B) 2, 3, 4, 5-tetrahydropyrido [3, 2-b] [ 1 , 4 ] oxazepine
To a solution of 3- ( ( 2-bromopyridin-3-yl ) oxy) propan-1- amine (738 mg, 3.19 mmol), t-Bu3P (129 mg, 0.64 mmol) and KOtBu (717 mg, 6.39 mmol) in THF (dry) (32 mL) was added Pd2(dba)3 (292 mg, 0.32 mmol) at room temperature. The mixture was stirred at 70°C under Ar overnight. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 20% MeOH in EtOAc) to give the title compound (195 mg, 1.298 mmol, 40.7%) as light brown solids.
1H NMR (300 MHz, DMSO-d6) 5:1.90 (2H, quin, J = 5.8 Hz), 3.16- 3.26 (2H, m) , 4.02-4.10 (2H, m) , 6.04 (1H, brs), 6.60 (1H, dd, J = 7.7, 4.7 Hz), 7.10 (1H, dd, J = 7.7, 0.9 Hz), 7.70 (1H, dd, J = 4.9, 1.5 Hz) .
[0901]
C) 8-bromo-2 , 3 , 4 , 5-tetrahydropyrido [ 3 , 2-b] [ 1 , 4 ] oxazepine
To a solution of 2, 3, 4, 5-tetrahydropyrido [3, 2- b] [1, 4] oxazepine (102 mg, 0.68 mmol) in DMF (3 mL) was added NBS (127 mg, 0.71 mmol) at 0°C. The mixture was stirred at 0°C for 3 h. The mixture was neutralized with sat. NaHCO3 aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title compound (84 mg, 0.367 mmol, 54.0%) as off-white solids.
1H NMR (300 MHz, CDCi3) 5:1.99-2.10 (2H, m) , 3.37 (2H, td, J = 5.8, 3.6 Hz), 4.13-4.20 (2H, m) , 4.72 (1H, brs), 7.27-7.30 (1H, m) , 7.83 (1H, d, J = 1.9 Hz).
[0902]
D) tert-butyl 8-bromo-3, 4-dihydropyrido [3, 2-b] [1, 4 ] oxazepine- 5 (2H) -carboxylate
To a solution of 8-bromo-2 , 3, 4 , 5-tetrahydropyrido [ 3 , 2- b] [1, 4] oxazepine (84 mg, 0.37 mmol) and DMAP (44.8 mg, 0.37 mmol) in THF (4 mL) was added Boc20 (0.102 mL, 0.44 mmol) at room temperature. The mixture was stirred at 50 °C overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (101 mg, 0.307 mmol, 84%) as white solids.
[0903]
E) 5-tert-butyl 8-methyl 3 , 4-dihydropyrido [ 3 , 2- b] [1,4] oxazepine-5 , 8 (2H) -dicarboxylate
To a mixture of tert-butyl 8-bromo-3 , 4-dihydropyrido [ 3 , 2- b] [ 1 , 4 ] oxazepine-5 (2H) -carboxylate (101 mg, 0.31 mmol) and TEA (0.086 mL, 0.61 mmol) in DMF (8 mL, 0.31 mmol) and MeOH (2 mL, 49.44 mmol) was added PdCl2 (dppf) (22.45 mg, 0.03 mmol). After being stirred at 100°C under CO (0.5 MPa) for 5 h, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 30% - 80% EtOAc in hexane) to give the title
compound (86 mg, 0.279 mmol, 91%) as white solids.
1H NMR (300 MHz, CDC13) 5:1.47 (9H, s) , 2.11 (2H, quin, J = 5.8 Hz), 3.81 (2H, t, J = 5.9 Hz), 3.94 (3H, s) , 4.17-4.24 (2H, m) , 7.90 (1H, d, J = 1.9 Hz), 8.76 (1H, d, J = 1.9 Hz).
[0904]
F) methyl 2, 3, 4, 5-tetrahydropyrido [3, 2-b] [1, 4] oxazepine-8- carboxylate
To a solution of 5-tert-butyl 8-methyl 3,4- dihydropyrido [ 3 , 2-b] [1, 4] oxazepine-5, 8 (2H) -dicarboxylate (86 mg, 0.28 mmol) in MeOH (1 mL) was added 4M HC1 in EtOAc (1 mL, 2.00 mmol) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture concentrated in vacuo.
Amberlyst A21 (500 mg) was added to the mixture of the residue in MeOH (3.0 mL) , and the mixture was stirred at room
temperature for 20 min. The mixture was filtered and the filtrate was evaporated in vacuo to give the title compound
(58.0 mg, 0.279 mmol, 100%) as a pale yellow oil.
MS (ESI+), found 209.2 (M+H)
[0905]
G) methyl 5- (2, 6-dicyclopropylpyridin-4-yl) -2, 3, 4, 5- tetrahydropyrido [3 , 2-b] [1,4] oxazepine-8-carboxylate
A mixture of methyl 2 , 3 , 4 , 5-tetrahydropyrido [3 , 2- b] [ 1 , 4 ] oxazepine-8-carboxylate (58 mg, 0.28 mmol), 2,6- dicyclopropylpyridin-4-yl trifluoromethanesulfonate (103 mg, 0.33 mmol), XPHOS Pd G2 (21.92 mg, 0.03 mmol), XPHOS (13.28 mg, 0.03 mmol) and Cs2CO3 (182 mg, 0.56 mmol) in DME (5.0 mL) was stirred at 120°C under microwave irradiation for 2 h. After being cooled, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (100 mg, 0.274 mmol, 98%) as pale yellow solids .
1H NMR (300 MHz, CDC13) 5:0.75-0.86 (4H, m) , 0.92-1.00 (4H, m) , 1.75-1.89 (2H, m) , 2.13 (2H, quin, J = 6.0 Hz), 3.93 (3H, s), 4.05 (2H, t, J = 6.0 Hz), 4.23 (2H, t, J = 6.0 Hz), 6.65 (2H, s), 7.84 (1H, d, J = 1.9 Hz), 8.63 (1H, d, J = 1.9 Hz).
[0906]
H) 5- (2, 6-dicyclopropylpyridin-4-yl) -2,3,4,5- tetrahydropyrido [ 3 , 2-b] [ 1 , 4 ] oxazepine-8-carboxylic acid
To a solution of methyl 5- (2 , 6-dicyclopropylpyridin-4- yl ) -2 , 3 , 4 , 5-tetrahydropyrido [ 3 , 2-b] [1,4] oxazepine-8-carboxylate (100 mg, 0.27 mmol) in MeOH (1 mL) and THF (1 mL) was added 2 M NaOH aq. (0.137 mL, 0.27 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was neutralized with IN HC1 at 0°C and extracted with EtOAc . The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give the title compound (85 mg, 0.242 mmol, 88%) as pale yellow solids.
MS (ESI+) , found 352.3 (M+H)
[0907]
I) 5- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5-
(methylsulfonyl) pyridin-2-yl ) methyl ) -2 , 3 , 4 , 5- tetrahydropyrido [3, 2-b] [1,4] oxazepine-8-carboxamide
To a solution of 5- (2, 6-dicyclopropylpyridin-4-yl) -
2,3,4, 5-tetrahydropyrido [3, 2-b] [1, 4] oxazepine-8-carboxylic acid (42 mg, 0.12 mmol), ( 5- (methylsulfonyl ) pyridin-2-yl) methanamine (26.7 mg, 0.14 mmol) and DI'PEA (0.063 mL, 0.36 mmol) in DMF (3 mL) was added HATU (68.2 mg, 0.18 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with water at room temperature and
extracted with EtOAc/THF (1:1). The organic layer was
separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0% - 20% MeOH in EtOAc) to give the title compound (47.0 mg, 0.090 mmol, 76%) as pale yellow solids. 1H NMR (300 MHz, DMSO-d6) 5:0.90 (8H, brs) , 1.19-1.31 (3H, m) , 1.88-2.13 (4H, m) , 4.06 (2H, brs), 4.19 (2H, t, J = 5.9 Hz), 4.68 (2H, d, J = 5.7 Hz), 6.74 (2H, s), 7.52 (1H, dd, J = 8.5, 4.3 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.91 (1H, d, J = 1.9 Hz), 8.29 (1H, dd, J = 8.1, 2.5 Hz), 8.49-8.79 (2H, m) , 9.02 (1H, d, J = 1.9 Hz), 9.38 (1H, t, J = 5.9 Hz).
[0908]
Example 289
5- (2, 6-dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl ) benzyl) - 2,3,4, 5-tetrahydropyrido [3, 2-b] [1, 4] oxazepine-8-carboxamide
To a solution of 5- (2 , 6-dicyclopropylpyridin-4-yl) - 2,3,4, 5-tetrahydropyrido [ 3 , 2-b] [1,4] oxazepine-8-carboxylic acid (42 mg, 0.12 mmol), ( 4- (methylsulfonyl ) phenyl) methanamine (26.6 mg, 0.14 mmol) and DIPEA (0.063 mL, 0.36 mmol) in DMF (3 mL) was added HATU (68.2 mg, 0.18 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 30% - 100% EtOAc in hexane) to give the title compound (51.0 mg, 0.098 mmol, 82%) as off-white solids.
1H NMR (300 MHz, DMSO-d6) 5:0.71-0.89 (8H, m) , 1.78-1.92 (2H, m) , 2.05 (2H, t, J = 5.9 Hz), 3.19 (3H, s) , 4.01 (2H, t, J = 5.7 Hz), 4.17 (2H, t, J = 5.9 Hz), 4.58 (2H, d, J = 6.0 Hz), 6.75 (2H, s) , ' 7.59 (2H, d, J = 8.3 Hz), 7.82-7.93 (3H, m) , 8.53 (1H, d, J = 2.3 Hz), 9.25 (1H, t, J = 5.9 Hz).
[0909]
Example 290
4- (2, 6-dicyclopropylpyridin-4-yl ) -N- ( (5-
(methylsulfonyl ) pyridin-2-yl ) methyl ) chromane-7-carboxamide
(shorter retention time)
[0910]
Example 291 4- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5-
(methylsulfonyl) pyridin-2-yl ) methyl ) chromane-7-carboxamide (longer retention time)
4- (2, 6-dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl ) pyridin-2-yl ) methyl ) chromane-7-carboxamide
(24.7 mg) was subjected to optical resolution by chiral column chromatography. The fraction having a shorter retention time was concentrated to give the compound of Example 290 (7 mg,>99.9%ee) and the fraction having a longer retention time was concentrated to give the compound of Example 291 (7 mg, 99.3%ee) .
purification condition by chiral column chromatography column: CHIRALPAK IB (MB001) 20 x 250 mm, 5 μιη
mobile phase: CO2/MeOH=600/400 (v/v)
pressure: 100 bar
flow Rate: 50 mL/min
temperature: 35°C
detection: UV 220 nm
concentration: 1 mg/mL (MeOH/TFE=l/l , v/v)
injection volume: 2 mL
load: 2 mg
solubility: 1 mg/ (MeOH/TFE=l/l, v/v)
[0911]
The compounds described in Examples 221 to 291 are below (Table 9-1 - Table 9-11) .
Figure imgf000416_0001
Figure imgf000417_0001
Figure imgf000418_0001
Figure imgf000419_0001
Figure imgf000420_0001
Figure imgf000421_0001
Figure imgf000422_0001
Figure imgf000423_0001
Figure imgf000424_0001
Figure imgf000425_0001
[0922]
[Table 9-11]
Figure imgf000426_0001
[0923]
The compounds described in Examples 221-222, 224-226, 228,
230-231, 236-243, 245, and 255-258 were synthesized in the same manner as in the reaction and purification described in the Examples .
[0924]
Example 292
5- (2, 6-Dicyclopropylpyridin-4-yl) -N- (4- (methylsulfonyl ) benzyl) - 5,6,7, 8-tetrahydro-l, 5-naphthyridine-2-carboxamide
A) 2 , 6-Dicyclopropylpyridin-4-ol
A mixture of 2 , 6-dibromopyridin-4-ol (1.06 g, 4.19 mmol) , cyclopropylboronic acid (1.76 g, 20.49 mmol), Pd(0Ac)2 (99 mg, 0.44 mmol), tricyclohexyl phosphine (235 mg, 0.84 mmol), K3PO4 (2.76 g, 13.00 mmol) in toluene (10 mL) and water (2 mL) was stirred at 100 °C overnight. After being cooled, the mixture was poured into water and extracted with 2-butanone. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column
chromatography (silica gel, eluted with 0%- 20% MeOH in EtOAc) to give the title compound (0.305 g, 1.741 mmol, 42%) as pale yellow solids.
1H NMR (300 MHz, DMSO-d6):5 0.75-0.81 (8H, m) , 1.80-1.89 (2H, m) , 6.38 (2H, s) , 10.11 (1H, s).
MS m/z 176.4 [M+H]+.
[0925]
B) 2 , 6-Dicyclopropylpyridin-4-yl trifluoromethanesulfonate
To a mixture of 2 , 6-dicyclopropylpyridin-4-ol (305 mg,
1.74 mmol) and pyridine (10 mL) was added Tf20 (0.35 mL, 2.07 mmol) at 0°C. After being stirred at room temperature under N2 overnight, the mixture was quenched with water at 0°C and extracted with EtOAc. The organic layer was washed with aqueous citric acid and brine and dried over Na2SO4 :and
concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 1% - 5% EtOAc in hexane) to give the title compound (373 mg, 1.214 mmol, 70%) as a colorless oil.
1H NMR (300 MHz, DMSO-d6):5 0.85-1.02 (8H, m) , 2.07-2.20 (2H, m) , 7.25 (2H, s) .
MS m/z 308.0 [M+H]+.
[0926]
C) tert-Butyl 6-Bromo-3, 4-dihydro-l, 5-naphthyridine-l (2H) - carboxylate
To a mixture of 6-bromo-l , 2 , 3 , 4-tetrahydro-l , 5- naphthyridine (2 g, 9.39 mmol), Boc20 (2.62 mL, 11.26 mmol) and THF (40 mL) was added 1.3 M LiHMDS in THF (8.66 mL, 11.26 mmol) at 0°C. After being stirred at room temperature overnight, the mixture was quenched with sat. NH4C1 aq. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (silica gel, eluted with 5% - 30% EtOAc in hexane) to give the title compound (2.37 g, 7.57 mmol, 81%) as pale yellow solids.
1H NMR (300 MHz, CDC13):5 1.53 (9H, s), 1.92-2.06 (2H, m) ,
2.92-2.98 (2H, m) , 3.68-3.76 (2H, m) , 7.24 (1H, d, J = 8.7 Hz), 7.99 (1H, d, J = 8.7 Hz) .
MS m/z 313.2, 315.2[M+H]+.
[0927]
D) 1-tert-Butyl 6-methyl 3 , 4-dihydro-l , 5-naphthyridine-l , 6 ( 2H) - dicarboxylate
To a mixture of tert-butyl 6-bromo-3, 4-dihydro-l, 5- naphthyridine-1 (2H) -carboxylate (8.70 g, 27.78 mmol) and TEA (7.75 mL, 55.56 mmol) in a mixture of DMF (80 mL) and MeOH (80 mL) was added PdCl2(dppf) (1.016 g, 1.39 mmol) . The mixture was stirred at 100°C under CO, 0.5 MPa (0.00 mmol) for 6 hrs . MeOH was removed by evaporation, and then the residue was poured into water and 10% aqueous citric acid, and extracted with EtOAc, and then the extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was passed through a pad of Si02 (ca. 200 g) using EtOAc. The eluent was concentrated in vacuo, and then the precipitate was collected by IPE, which was recrystallized from EtOAc-IPE. All of the filtrates were purified by column chromatography (silica gel, eluted with 5% - 60% EtOAc in hexane) to give white solids. The precipitates and the white solids were mixed together to give the title compound (6.74 g, 23.1 mmol, 83%) as white solids .
1R NMR (300 MHz, CDC13):5 1.55 (9H, s) 1.96-2.09 (2H, m) 2.97- 3.12 (2H, m) 3.71-3.81 (2H, m) 3.98 (3H, s) 7.90-7.98 (1H, m) 8.29 (1H, d, J=8.69 Hz) .
MS m/z 293.0 [M+H]+.
[0928]
E) Methyl 5, 6, 7 , 8-tetrahydro-l, 5-naphthyridine-2-carboxylate To a mixture of 1-tert-butyl 6-methyl 3, 4-dihydro-l, 5- naphthyridine-1, 6 (2H) -dicarboxylate (3.00 g, 10.26 mmol) in MeOH (25 mL) was added 4N HCl/EtOAc (25.7 mL, 102.62 mmol). The mixture was stirred at 60 °C for 1 hr. MeOH was removed by evaporation, and then the residue was poured into water and made slightly basic with 8N NaOH (ca. 13 mL) and extracted with EtOAc-THF. The extract was washed with brine, dried (MgSO4) and concentrated in vacuo to give the title compound (1.67 g, 8.69 mmol, 85%) as pale brown solids.
1H NMR (300 MHz, CDC13):5 1.93-2.15 (2H, m) 2.95-3.08 (2H, m) 3.31-3.45 (2H, m) 3.93 (3H, s) 4.27-4.48 (1H, m) 6.70 (1H, d, J=8.31 Hz) 7.79 (1H, d, J=8.31 Hz).
MS m/z 193.0 [M+H]+.
[0929]
F) Methyl 5- (2, 6-dicyclopropylpyridin-4-yl) -5, 6, 7, 8-tetrahydro- 1, 5-naphthyridine-2-carboxylate A mixture of methyl 5, 6, 7 , 8-tetrahydro-l, 5-naphthyridine- 2-carboxylate (219 mg, 1.14 mmol) , 2 , 6-dicyclopropylpyridin-4- yl trifluoromethanesulfonate (350 mg, 1.14 mmol), Pd2(dba)3 (52.1 mg, 0.06 mmol), XPHOS (54.3 mg, 0.11 mmol), K3PO4 (484 mg, 2.28 mmol) in DME (5 mL) was stirred at 120°C under microwave irradiation for 2 hrs . After being cooled, the mixture was filtered through Celite and the filtrate was evaporated in vacuo. The residue was purified by column chromatography
(silica gel, eluted with 5% - 50% EtOAc in hexane) to give the title compound (380 mg, 1.087 mmol, 95%) as a light brown oil. 1tt NMR (300 MHz, CDC13):5 0.83-0.92 (4H, m) , 0.94-1.04 (4H, m) , 1.87 (2H, tt, J = 8.0, 4.9 Hz), 2.09-2.20 (2H, m) , 3.10 (2H, t, J = 6.4 Hz), 3.65-3.74 (2H, m) , 3.96 (3H, s), 6.73 (2H, s), 7.33 (1H, d, J = 8.7 Hz), 7.80 (ΙΗ,' d, J = 8.7 Hz) .
MS m/z 350.2 [M+H]+.
[0930]
G) 5- (2, 6-Dicyclopropylpyridin~4-yl ) -5,6,7, 8-tetrahydro-l, 5- naphthyridine-2-carboxylic acid
To a solution of methyl 5- (2, 6-dicyclopropylpyridin-4- yl) -5, 6, 7, 8-tetrahydro-l, 5-naphthyridine-2-carboxylate (380 mg,
1.09 mmol) in THF (4 mL) was added 4N LiOH (1.36 mL, 5.44 mmol) at room temperature. The mixture was stirred at 60 °C for 2 hrs.
The mixture was neutralized with IN HC1 at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give the title compound (299 mg, 0.891 mmol, 82%) as a pale yellow oil.
MS m/z 336.1 [M+H]+.
[0931]
H) 5- (2, 6-Dicyclopropylpyridin-4-yl) -N- (4-
(methylsulfonyl) benzyl) -5,6,7, 8-tetrahydro-l, 5-naphthyridine-2- carboxamide
To a solution of 5- (2 , 6-dicyclopropylpyridin-4-yl) - 5, 6, 7 , 8-tetrahydro-l, 5-naphthyridine-2-carboxylic acid (150 mg, 0.45 mmol), (4- (methylsulfonyl ) phenyl) methanamine (91 mg, 0.49 mmol), DIPEA (0.229 mL, 1.34 mmol) in DMF (4 mL) was added HATU (204 mg, 0.54 mmol) at room temperature. The mixture was stirred at room temperature for 1 hr . The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10 % - 60% EtOAc in hexane) to give a gum, which was solved again in EtOAc, washed with water and brine (for removing DMF) , dried over MgSO4, concentrated in vacuo and crystallized from EtOAc-IPE to give the title compound (150 mg, 0.298 mmol, 67%) as white solids. 1H NMR (300 MHz, DMSO-d6):5 0.79-0.89 (8H, m) 1.88-1.97 (2H, m) 2.00-2.11 (2H, m) 2.96 (2H, s) 3.18 (3H, s) 3.70 (2H, s) 4.55- 4.61 (2H, m) 6.89 (2H, s) 7.44-7.51 (1H, m) 7.52-7.60 (2H, m) 7.67-7.77 (1H, m) 7.83-7.92 (2H, m) 9.09 (1H, t, J=6.23 Hz). MS m/z 503.3 [M+H]+.
[0932]
Example 293
5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- ( (5- (methylsulfonyl) pyridin-2-yl ) methyl) -5,6,7, 8-tetrahydro-l, 5- naphthyridine-2-carboxamide
A) 5- (Methylsulfonyl) pyridine-2-carbonitrile
A mixture of 5-bromopicolinonitrile (25.0 g, 136.61 mmol) and sodium methanesulfinate (19.52 g, 191.25 mmol) in DMSO (200 mL) was stirred at 100°C for 24 hrs . The mixture was cooled to 50°C and water (250 mL) was added thereto. After stirring at 50°C overnight, the precipitate was collected by filtration, washed with water and dried in vacuo to give the title compound (20.6 g, 113 mmol, 83%) as white crystals.
1H NMR (300 MHz, CDC13):5 3.17 (3H, s) , 7.93 (1H, dd, J = 7.9, 0.8 Hz), 8.41 (1H, dd, J = 7.9, 2.3 Hz), 9.25 (1H, dd, J = 2.3, 0.8 Hz) .
[0933]
B) (5- (Methylsulfonyl) pyridin-2-yl) methanamine hydrochloride A mixture of 5- (methylsulfonyl ) pyridine-2-carbonitrile (10 g, 54.88 mmol) , 6N HC1 (18.29 mL, 109.77 mmol) and 10% Pd-C (50% wet, 1.00 g, 9.40 mmol) in EtOH (100 mL) was hydrogenated under middle pressure (0.45 MPa) at room temperature overnight.
Water (10 mL) was added thereto and the catalyst was removed by filtration. The filtrate was concentrated in vacuo to dryness.
The solid was suspended in EtOH and collected by filtration, dried in vacuo to give the title compound (6.30 g, 28.3 mmol,
52%) as pale yellow powders.
1H NMR (300 MHz, DMSO-d6):5 3.37 (3H, s) , 4.33 (2H, q, J = 5.3 Hz), 7.81 (1H, d, J = 8.3 Hz), 8.41 (1H, dd, J = 8.1, 2.5 Hz), 8.70 (3H, brs), 9.09 (1H, d, J = 1.9 Hz).
MS m/z 187.1 [M+H]+.
[0934]
C) 5- (2, 6-Dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl ) pyridin-2-yl) methyl) -5,6,7, 8-tetrahydro-l , 5- naphthyridine-2-carboxamide
To a solution of 5- (2, 6-dicyclopropylpyridin-4-yl) - 5, 6, 7, 8-tetrahydro-l, 5-naphthyridine-2-carboxylic acid (25 mg, 0.070 mmol), ( 5- (methylsulfonyl ) pyridin-2-yl ) methanamine
hydrochloride (18.3 mg, 0.08 mmol), DIPEA (0.038 mL, 0.22 mmol) in DMF (2.0 mL) was added HATU (34.0 mg, 0.09 mmol) at room temperature. The mixture was stirred at room temperature for 2 hrs. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (19.1 mg, 0.038 mmol, 51%) as white amorphous solids.
1H NMR (300 MHz, DMSO-d6):5 0.75-0.92 (8H, m) , 1.88-2.00 (2H, m) , 2.01-2.12 (2H, m) , 2.98 (2H, t, J = 6.4 Hz), 3.30 (3H, s), 3.72 (2H, t, J = 5.7 Hz), 4.70 (2H, d, J = 6.4 Hz), 6.90 (2H, s), 7.48 (1H, d, J = 8.7 Hz), 7.54 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 8.7 Hz), 8.28 (1H, dd, J = 8.3, 2.3 Hz), 9.01 (1H, d, J = 2.3 Hz), 9.14 (1H, t, J = 5.7 Hz).
MS m/z 504.3 [M+H]+. [0935]
Example 294
5- (2, 6-Dicyclopropylpyridin-4-yl) -N- ( (5- (ethylsulfonyl) pyridin- 2-yl) methyl) -5,6,7, 8-tetrahydro-l , 5-naphthyridine-2-carboxamide A) 5- (Ethylsulfonyl) pyridine-2-carbonitrile
To a stirred solution of 5-bromopicolinonitrile (3.60 g, 19.68 mmol) in DMSO (25 mL) were added sodium ethanesulfinate (3.20 g, 27.6 mmol), and the reaction mixture was stirred at 100°C under Ar atmosphere for 16 hrs. The filtrate was poured into water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give white solids. The residue was crystallized from EtOAc-hexane to give the title compound (2.69 g, 13.71 mmol, 70%) as white solids.
1H NMR (300 MHz, CDC13):5 1.35 (3H, t, J = 7.6 Hz), 3.21 (2H, q, J = 7.3 Hz), 7.92 (1H, dd, J = 8.1, 0.9 Hz), 8.37 (1H, dd, J = 7.9, 2.3 Hz), 9.20 (1H, dd, J = 2.3, 0.8 Hz).
[0936]
B) ( 5- (Ethylsulfonyl ) pyridin-2-yl ) methanamine hydrochloride
A mixture of 5- (ethylsulfonyl ) pyridine-2-carbonitrile
(528 mg, 2.69 mmol), 6N HC1 aq. (1.0 mL, 6.00 mmol), 10% Pd-C (50% wet, 180 mg, 0.17 mmol) and MeOH (15 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room temperature for 30 min.
The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The solid was suspended in
EtOH, collected by filtration and dried in vacuo to give the title compound (516 mg, 2.180 mmol, 81%) as white solids.
1R NMR (300 MHz, DMSO-d6):5 1.13 (3H, t, J = 7.4 Hz), 3.46 (2H, q, J = 7.2 Hz), 4.35 (2H, brs), 7.80 (1H, d, J = 8.3 Hz), 8.38 (1H, dd, J = 8.3, 2.3 Hz), 8.54 (3H, brs), 9.06 (1H, d, J = 1.9
Hz) .
MS m/z 201.3 [M+H]+.
[0937]
C) 5- (2, 6-Dicyclopropylpyridin-4-yl) -N- ( (5- (ethylsulfonyl)pyridin-2-yl)methyl) -5, 6, 7, 8-tetrahydro-l, 5- naphthyridine-2-carboxamide
To a solution of 5- (2, 6-dicyclopropylpyridin-4-yl) - 5, 6, 7, 8-tetrahydro-l, 5-naphthyridine-2-carboxylic acid (25 mg, 0.070 mmol) , ( 5- (ethylsulfonyl ) pyridin-2-yl) methanamine
hydrochloride (19.41 mg, 0.08 mmol), DIPEA (0.038 mL, 0.22 mmol) in DMF (2.0 mL) was added HATU (34.0 mg, 0.09 mmol) at room temperature. The mixture was stirred at room temperature for 1 hr. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in. vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (25.8 mg, 0.050 mmol, 67%) as white amorphous solids.
1H NMR (300 MHz, DMSO-d6):5 0.79-0.88 (8H, m) , 1.12 (3H, t, J = 7.2 Hz), 1.88-2.00 (2H, m) , 2.00-2.12 (2H, m) , 2.98 (2H, t, J = 5.9 Hz), 3.38 (2H, q, J = 7.2 Hz), 3.71 (2H, t, J = 5.9 Hz), 4.70 (2H, d, J = 6.4 Hz), 6.90 (2H, s) , 7.48 (1H, d, J = 8.3 Hz), 7.55 (1H, d, J = 8.3 Hz), 7.73 (1H, d, J = 8.3 Hz), 8.24 (1H, dd, J = 8.3, 2.3 Hz), 8.96 (1H, d, J = 1.9 Hz), 9.15 (1H, t, J = 6.0 Hz) .
MS m/z 518.3 [M+H]+.
[0938]
Example 295
Ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin-4-yl) -5, 6,7,8- tetrahydro-1 , 5-naphthyridin-2-yl ) carbonyl) amino) methyl ) -5- (methylsulfonyl ) benzoate
A) Ethyl 2-cyano-5- (methylsulfonyl) benzoate
To a solution of ethyl 2-cyano-5-fluorobenzoate (1.00 g, 5.18 mmol) in DMSO (10 mL) was added sodium methanesulfinate (0.581 g, 5.69 mmol) at room temperature. The. mixture was stirred 130 °C overnight. The mixture was quenched with water at 0°C and the precipitate was collected by filtration. The solid was washed with water and dried in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (0.920 g, 3.63 mmol, 70%) as white solids.
1H NMR (300 MHz, CDC13):5 1.48 (3H, t, J = 7.2 Hz), 3.13 (3H, s), 4.53 (2H, q, J = 7.2 Hz), 8.03 (1H, d, J = 8.3 Hz), 8.23 (1H, dd, J = 8.3, 1.9 Hz), 8.69 (1H, d, J = 1.9 Hz).
[0939]
B) Ethyl 2- (aminomethyl) -5- (methylsulfonyl) benzoate
hydrochloride
A mixture of ethyl 2-cyano-5- (methylsulfonyl ) benzoate (920 mg, 3.63 mmol), 6N HC1 (2 mL, 12.00 mmol), 10% Pd-C (50% wet, 387 mg, 0.36 mmol) in MeOH (20 mL) was stirred under hydrogen atmosphere (0.45 MPa) at room temperature for 3 hrs . The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The solid was suspended in EtOH/Et20, collected by filtration and dried in vacuo to give the title compound (921 mg, 3.14 mmol, 86%) as white solids.
1H NMR (300 MHz, DMSO-d6):5 1.38 (3H, t, J = 7.2 Hz), 3.32 (3H, s), 4.34-4.48 (4H, m) , 7.88 (1H, d, J = 8.3 Hz), 8.26 (1H, dd, J = 8.1, 2.1 Hz), 8.36 (3H, brs) , 8.44 (1H, d, J = 1.9 Hz). MS m/z 258.1 [M+H]+.
[0940]
C) Ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin-4-yl) -5, 6, 7, 8- tetrahydro-1 , 5-naphthyridin-2-yl ) carbonyl) amino) methyl) -5- (methylsulfonyl) benzoate
To a solution of 5- (2, 6-dicyclopropylpyridin-4-yl) - 5, 6, 7 , 8-tetrahydro-l, 5-naphthyridine-2-carboxylic acid (150 mg, 0.45 mmol), ethyl 2- (aminomethyl) -5- (methylsulfonyl ) benzoate hydrochloride (158 mg, 0.54 mmol) and DIPEA (0.391 mL, 2.24 mmol) in DMF (3 mL) was added HATU (204 mg, 0.54 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was neutralized with sat. NaHCO3 aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 50% EtOAc in hexane) to give the title compound (204 mg, 0.355 mmol, 79%) as pale yellow solids. λΗ NMR (300 MHz, DMSO-d6):5 0.79-0.89 (8H, m) , 1.39 (3H, t, J = 7.2 Hz), 1.88-1.99 (2H, m) , 2.05 (2H, quin, J = 6.1 Hz), 2.97 (2H, t, J = 6.4 Hz), 3.25 (3H, s) , 3.71 (2H, t, J = 5.9 Hz), 4.42 (2H, q, J = 7.1 Hz), 4.85 (2H, d, J = 6.0 Hz), 6.89 (2H, s), 7.47 (1H, d, J = 8.7 Hz), 7.69 (2H, t, J = 9.3 Hz), 8.07- 8.14 (1H, m) , 8.32 (1H, d, J = 1.9 Hz), 9.01 (1H, t, J = 6.4 Hz) .
MS m/z bib.2 [M+H]+.
[0941]
Example 296
5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (2- (hydroxymethyl ) -4- (methylsulfonyl ) benzyl ) -5 , 6, 7 , 8-tetrahydro-l , 5-naphthyridine-2- carboxamide
To a solution of ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin- 4-yl) -5, 6, 7, 8-tetrahydro-l, 5-naphthyridin-2- yl) carbonyl) amino) methyl ) -5- (methylsulfonyl) benzoate (40 mg, 0.070 initio1) in EtOH (2.3 mL) was added NaBH4 (5.27 mg, 0.14 mmol) at room temperature. The mixture was stirred at room temperature under N2 overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 30% - 100% EtOAc in hexane) to give the title compound (27.0 mg, 0.051 mmol, 73%) as white solids.
1H NMR (300 MHz, DMSO-d6):5 0.73-0.92 (8H, m) , 1.87-2.12 (4H, m) , 2.96 (2H, t, J = 6.2 Hz), 3.17 (3H, s) , 3.70 (2H, t, J = 5.7 Hz), 4.56 (2H, d, J = 6.0 Hz), 4.72 (2H, d, J = 5.3 Hz), 5.50 (1H, t, J = 5.3 Hz), 6.89 (2H, s) , 7.48 (2H, dd, J = 8.3, 4.5 Hz), 7.75 (2H, dd, J = 17.9, 8.1 Hz), 7.97 (1H, s), 9.00 (1H, t, J = 6.0 Hz).
MS m/z 533.3 [M+H]+.
[0942]
Example 297
2- ( ( ( (5- (2 , 6-Dicyclopropylpyridin-4-yl) -5, 6, 7, 8-tetrahydro-l, 5- naphthyridin-2-yl) carbonyl) amino) methyl) -5- (methylsulfonyl) benzoic acid
To a solution of ethyl 2- ( ( ( ( 5- ( 2 , 6-dicyclopropylpyridin-
4-yl) -5, 6, 7, 8-tetrahydro-l, 5-naphthyridin-2- yl) carbonyl) amino) methyl) -5- (methylsulfonyl ) benzoate (164 mg, 0.29 mmol) in THF (1 mL) and EtOH (1 mL) was added 2N NaOH (2.0 mL, 4.0 mmol) at room temperature. The mixture was stirred at room temperature for 3 hrs . The mixture was neutralized with AcOH at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with EtOAc to give the title compound (38.0 mg, 0.070 mmol, 24%) as pale yellow solids.
1H NMR (300 MHz, DMSO-d6):5 0.79-0.89 (8H, m) , 1.88-1.98 (2H, m) , 2.05 (2H, quin, J = 5.9 Hz), 2.96 (2H, t, J = 6.4 Hz), 3.24 (3H, s), 3.71 (2H, t, J = 5.9 Hz), 4.87 (2H, d, J = 6.4 Hz), 6.89 (2H, s), 7.47 (1H, d, J = 8.7 Hz), 7.64 (1H, d, J = 8.3 Hz), 7.71 (1H, d, J = 8.7 Hz), 8.06 (1H, dd, J = 8.1, 2.1 Hz), 8.35 (1H, d, J = 2.3 Hz), 9.05 (1H, t, J = 6.2 Hz), 13.66 (1H, brs) .
MS m/z 547.2 [M+H]+.
[0943]
Example 298
5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (2-hydroxy-l- (4- (methylsulfonyl ) phenyl ) ethyl ) -5 , 6, 7 , 8-tetrahydro-l , 5- naphthyridine-2-carboxamide
A) 2- (4- (Methylsulfonyl) phenyl) -2-oxoethyl acetate
To a solution of TEA (0.553 mL, 3.97 mmol) in DMF (8 mL) was added AcOH (0.227 mL, 3.97 mmol) at room temperature. The mixture was stirred at room temperature for 5 min. A solution of 2-bromo-l- ( 4- (methylsulfonyl ) phenyl ) ethanone (1.00 g, 3.61 mmol) in DMF (7.00 mL) was added to the mixture dropwise at room temperature. The mixture was stirred at room temperature for 2 hrs. The mixture was quenched with water at room
temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with EtOAc/hexane (1:1, v/v) and dried in vacuo to give the title compound (0.806 g, 3.15 mmol, 87%) as pale yellow solids.
1H NMR (300 MHz, DMSO-d6):5 2.16 (3H, s), 3.30 (3H, s), 5.52 (2H, s), 8.07-8.14 (2H, m) , 8.16-8.22 (2H, m) .
[0944]
B) 2- (Hydroxyimino) -2- ( 4- (methylsulfonyl ) phenyl ) ethyl acetate
To a solution of 2- (4- (methylsulfonyl) phenyl) -2-oxoethyl acetate (800 mg, 3.12 mmol) and hydroxylamine hydrochloride (260 mg, 3.75 mmol) in- EtOH was added AcOK (368 mg, 3.75 mmol) at room temperature. The mixture was stirred at 70°C overnight. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (884 mg, 3.26 mmol, quantitative) as a pale yellow oil as a crude product, which was used in the next step without further purification.
MS m/z 272.0 [M+H]+.
[0945] .
C) 2-Amino-2- (4- (methylsulfonyl ) phenyl) ethyl acetate
hydrochloride and 2-amino-2- ( 4- (methylsulfonyl ) phenyl ) ethanol hydrochloride
A mixture of 2- (hydroxyimino) -2- ( 4- (methylsulfonyl) phenyl) ethyl acetate (88.4 mg, 3.26 mmol), 6N HC1 (1 mL, 6.00 mmol), 10% Pd-C (50% wet, 347 mg, 0.33 mmol) and MeOH (20 mL) was stirred under hydrogen atmosphere (3 atm) at room temperature for 5 hrs . The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The solid was suspended in EtOH/Et20, collected by filtration and dried in vacuo to give a mixture of the title compounds (647 mg) as white solids, which was used in the next step without further purification.
MS m/z 258.1 [M+H]+ and 216.1 [M+H]+.
[0946] D) tert-Butyl (2-hydroxy-l- ( 4-
(methylsulfonyl) phenyl) ethyl) carbamate
To a solution of a mixed 2-amino-2- ( 4- (methylsulfonyl) phenyl) ethyl acetate hydrochloride and 2-amino- 2- (4- (methylsulfonyl) phenyl) ethanol hydrochloride (647 mg) and TEA (1.54 mli, 11.01 mmol) in THF (6 mL) and MeOH (6 rtiL) was added B0C2O (0.614 mL, 2.64 mmol) at room temperature. The mixture was stirred at room temperature for 3 days . The
mixture was quenched with water at room temperature and
extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (323 mg, 1.02 mmol, 47%) as white solids.
1H NMR (300 MHz, CDC13):5 1.43 (9H, brs), 1.86-1.95 (1H, m) ,
3.05 (3H, s), 3.75-4.01 (2H, m) , 4.84 (1H, brs), 5.42 (1H, d, J = 5.3 Hz), 7.53 (2H, d, J = 8.3 Hz), 7.93 (2H, d, J = 8.7 Hz).
[0947]
E) 2-Amino-2- ( 4- (methylsulfonyl ) phenyl ) ethanol hydrochloride
To a solution of tert-butyl (2-hydroxy-l- ( 4-
(methylsulfonyl ) phenyl) ethyl) carbamate (323 mg, 1.02 mmol) in MeOH (2 mL) was added 4M HC1 in EtOAc (2 mL, 8.00 mmol) at room temperature. The mixture was stirred at room temperature for 3 hrs. The mixture was diluted with IPE (4.0 mL) and the
precipitating solid was collected by filtration. The solid was washed with IPE and dried in vacuo to give the title compound
(212 mg, 0.842 mmol, 82%) as white solids.
1H NMR (300 MHz, DMSO-d6):5 3.24 (3H, s), 3.65-3.85 (2H, m) , 4.44 (1H, t, J = 5.7 Hz), 5.58 (1H, t, J = 4.9 Hz), 7.77 (2H, d, J = 8.7 Hz), 7.99 (2H, d, J = 8.3 Hz), 8.64 (3H, brs). (An exchangeable proton was omitted. )
MS m/z 216.1 [M+H]+.
[0948]
F) 5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -5,6,7, 8-tetrahydro-l , 5- naphthyridine-2-carboxamide
To a mixture of 5- ( 2 , 6-dicyclopropylpyridin-4-yl ) - 5, 6, 7, 8-tetrahydro-l, 5-naphthyridine-2-carboxylic acid (150 mg, 0.45 mmol), DIPEA (0.094 mL, 0.54 mmol) and 2-amino-2- ( 4- (methylsulfonyl ) phenyl ) ethanol hydrochloride (135 mg, 0.54 mmol) in EtOH (2.24 mL) was added 4- (4, 6- dimethoxy [1.3.5] triazin-2-yl ) -4-methylmorpholinium chloride hydrate (186 mg, 0.67 mmol) . After being stirred at room temperature overnight, the mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 5% - 80% EtOAc in hexane) to give the title
compound (66.6 mg, 0.125 mmol, 28%) as white colorless foam.
[0949]
Example 299
5- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl ) ethyl ) -5 , 6, 7 , 8-tetrahydro-l , 5- naphthyridine-2-carboxamide ( shorter retention time)
Example 300
5- (2, 6-Dicyclopropylpyridin-4-yl) -N- (2-hydroxy-l- (4- (methylsulfonyl) phenyl) ethyl) -5, 6, 7, 8-tetrahydro-l, 5- naphthyridine-2-carboxamide (longer retention time)
Optical resolution of 5- (2, 6-dicyclopropylpyridin-4-yl) - N- (2-hydroxy-l- (4- (methylsulfonyl ) phenyl ) ethyl) -5, 6, 7, 8- tetrahydro-1 , 5-naphthyridine-2-carboxamide (66.6 mg) was
performed by preparative chiral HPLC. The factions with a shorter retention time gave Example 299 (24.1 mg, 0.045 mmol, 10%) as white solids. The factions with a longer retention time gave Example 300 (19.4 mg, 0.036 mmol, 8%) as white solids. Preparative chiral HPLC condition
Column : CHIRALPAK AD (JG001)
Column Size : 50 mmID x 500 mmL
Eluent : Hexane/2-propanol=450/550 (v/v)
Flow rate : 60 mL/min Pressure : 0.3 Mpa
Detector & sens. : UV 220 nm
Temperature :30°C
Example 299
[a]D 25 -16.4 (c 0.2520, MeOH)
1H NMR (300 MHz, CDC13):5 0.82-0.92 (4H, m) , 0.94-1.01 (4H, m) , 1.86 (2H, tt, J = 7.9, 4.9 Hz), 2.14 (2H, quin, J = 6.1 Hz), 2.54 (1H, brs), 2.94-3.07 (5H, m) , 3.63-3.74 (2H, m) , 4.00-4.10
(2H, m) , 5.23-5.34 (1H, m) , 6.71 (2H, s) , 7.40 (1H, d, J = 8.3 Hz), 7.63 (2H, d, J = 8.3 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.94
(2H, d, J = 8.3 Hz), 8.61 (1H, d, J = 7.6 Hz).
MS m/z 533.2
Example 300
[a]D 25 +16.2 (c 0.2520, MeOH)
1H NMR (300 MHz, CDC13) : δ 0.82-0.92 (4H, m) , 0.94-1.01 (4H, m) , 1.86 (2H, tt, J = 7.9, 4.9 Hz), 2.14 (2H, quin, J = 6.1 Hz), 2.54 (1H, brs), 2.94-3.07 (5H, m) , 3.63-3.74 (2H, m) , 4.00-4.10 (2H, m) , 5.23-5.34 (1H, m) , 6.71 (2H, s) , 7.40 (lH, d, J = 8.3 Hz), 7.63 (2H, d, J = 8.3 Hz), 7.81 (1H, d, J = 8.7 Hz), 7.94 (2H, d, J = 8.3 Hz), 8.61 (1H, d, J = 7.6 Hz).
MS m/z 533.2
[0950]
Example 301
N- (2-Carbamoyl-4- (methylsulfonyl) benzyl) -5- (2, 6- dicyclopropylpyridin-4-yl ) -5, 6, 7, 8-tetrahydro-l, 5- naphthyridine-2-carboxamide
To a solution of 2- ( ( ( ( 5- ( 2 , 6-dicyclopropylpyridin-4-yl ) - 5,6,7, 8-tetrahydro-l, 5-naphthyridin-2- yl ) carbonyl ) amino) methyl ) -5- (methylsulfonyl ) benzoic acid (135 mg, 0.25 mmol) , lH-benzo[d] [1, 2, 3] triazol-l-ol, ammonium salt (113 mg, 0.74 mmol) and TEA (0.172 mL, 1.23 mmol) in DMF (3 mL) was added WSOHC1 (95 mg, 0.49 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was neutralized with sat. NaHCO3 aq.. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 50% - 100% EtOAc in hexane) to give the title compound (67.0 mg, 0.123 mmol, 50%) as white solids.
1H NMR (300 MHz , DMSO-d6):5 0.78-0.89 (8H, m) , 1.86-2.11 (4H, m)., 2.95 (2H, t, J = 6.4 Hz), 3.22 (3H, s) , 3.70 (2H, t, J = 5.9 Hz), 4.69 (2H, d, J = 6.4 Hz), 6.89 (2H, s), 7.46 (1H, d, J = 8.7 Hz), 7.59 (1H, d, J = 7.9 Hz), 7.66-7.79 (2H, m) , 7.90- 8.01 (2H, m) , 8.25 (1H, s) , 9.06 (1H, t, J = 6.2 Hz).
MS m/z 546.3 [M+H]+.
[0951]
Example 302
N- (2-Cyano-4- (methylsulfonyl ) benzyl) -5- (2, 6- dicyclopropylpyridin-4-yl ) -5, 6, 7, 8-tetrahydro-l , 5- naphthyridine-2-carboxamide
To a solution of N- (2-carbamoyl-4- (methylsulfonyl ) benzyl ) -5- ( 2 , 6-dicyclopropylpyridin-4-yl ) - 5, 6, 7, 8-tetrahydro-l, 5-naphthyridine-2-carboxamide (51 mg, 0.090 mmol) in pyridine (2 mL) was added TFAA (0.053 mL, 0.37 mmol) at 0°C. The mixture was stirred at room temperature under N2 for 3 hrs . The mixture was neutralized with sat.
NaHCCO3 aq. at 0°C and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10% - 100% EtOAc in hexane) to give the title compound (33.0 mg, 0.063 mmol, 67%) as off-white solids.
1ti NMR (300 MHz, DMSO-d6):5 0.78-0.89 (8H, m) , 1.88-1.99 (2H, m) , 2.06 (2H, quin, J = 6.1 Hz), 2.98- (2H, t, J = 6.4 Hz), 3.29 (3H, s), 3.71 (2H, t, J = 5.9 Hz), 4.74 (2H, d, J = 6.0 Hz), 6.90 (2H, s), 7.47 (1H, d, J = 8.7 Hz), 7.71 (2H, dd, J = 8.5, 2.5 Hz), 8.18 (1H, dd, J = 8.3, 1.9 Hz), 8.39 (1H, d, J = 1.9 Hz) , 9.25 (1H, t, J = 6.0 Hz) .
MS m/z 528.2 [M+H]+.
[0952] The compounds of the Examples are shown in the following tables (Table 9-12 - Table 9-13) . In these tables, MS
represents an observed molecular ion (found) .
[0953]
[Table 9-12]
Figure imgf000442_0001
[0954]
[Table 9-13]
Figure imgf000443_0001
[0955]
The compounds of Examples 303 to 381 are below (Table 9-
14 - Table 9-25) . The compounds of Examples 303 to 381 below were synthesized in the similar manner as in the reaction and purification described in the Examples 1-302.
Figure imgf000444_0001
Figure imgf000445_0001
Figure imgf000446_0001
Figure imgf000447_0001
Figure imgf000448_0001
Figure imgf000449_0001
Figure imgf000450_0001
Figure imgf000451_0001
Figure imgf000452_0001
Figure imgf000453_0001
Figure imgf000454_0001
[0967]
[Table 9-25]
Figure imgf000455_0001
[0968]
Experimental Example 1
RORyt binding test using fluorescent-labeled synthetic ligand
The binding activity of the test compound to RORyt was measured by a time resolved fluorescence resonance energy transfer method (TR-FRET) utilizing histidine-tagged RORyt, the fluorescent-labeled synthetic ligand and terbium-labeled anti- histidine tag antibody ( Invitrogen) .
First, 4 μΐ, of a test compound diluted with an assay buffer (20 mM Tris-HCl (pH 7.5), 100 mM NaCl, 1 mM DTT, 0.1% BSA) was added to a 384 well plate.
Then, 4 μΐ, of the mixture of RORyt and the terbium- labeled anti-histidine tag antibody diluted with the assay buffer were added so that their final concentrations were 2 nM and 1 nM, respectively. Finally, 4 μΐι of the fluorescent- labeled synthetic ligand diluted with the assay buffer was added to make the final concentration of 120 nM. The mixture .was incubated at room temperature for 120 min, and fluorescence .intensity (excitation wavelength 320 nm, fluorescence
wavelength 520 nm) was measured by Envision ( PerkinElmer) . The results (% of inhibition of the fluorescent-labeled synthetic ligand binding to RORyt by a test compound at 1 μΜ ) measured by the above-mentioned method are shown in Table 10.
The fluorescent-labeled synthetic ligand: 5- ( (2Z) -2- ( (1- (difluoroboryl) -3, 5-dimethyl-lH-pyrrol-2-yl) methylene) -2H- pyrrol-5-yl) -N- (2- ( ( 3 , 5-difluoro-4-
' (trimethylsilyl) phenyl) amino) -1- (4- (methoxymethyl) phenyl) -2- oxoethyl ) pentanamide
[0969]
Experimental Example 1 has shown that the compound of the present invention has a binding capability to RORyt .
[0970]
Experimental Example 2
Jurkat reporter test
A human IL-17 ROR response element was inserted into the .upstream of luciferase of pGL 4.28 reporter vector (Promega) iand RORyt sequence was inserted into the downstream of CMV promoter. Jurkat cells (Clontech Laboratories, Inc) used for the reporter test were generated by stably introducing reporter vector and RORgt expression vector. The cells were cultured in a culture medium (RPMI-1640 ( Invitrogen) , 10% FCS (AusGeneX) , ,100 U/mL penicillin, 100 pg/mL streptomycin) . On the day of the test, frozen cells were collected by a centrifugal
operation (1000 rpm, 5 min) and suspended in PBS (phosphate buffered saline) (Invitrogen) .
The cells were suspended in a cholesterol-depleted reaction medium (RPMI-1640, 10% Lipid reduced FCS (HyClone) , 10 mM HEPES (pH 7.5), 100 U/mL penicillin, 100 pg/mL streptomycin, 5 μΜ lovastatin) or a normal medium (RPMI-1640, 10% FCS (AusGeneX) , 10 mM HEPES (pH 7.5), 100 U/mL penicillin, 100 μg/mL
streptomycin). After doxycycline (final concentration, 1.25 μg/mL) was added to cell suspension of 1X106 cells/mL, cells .were seeded into a 384 well plate by 20 μL (final density, .20, 000 cells/well) . After that, a test compound diluted with the reaction medium was added by 5 yL, and the cells were cultured overnight in an incubator. Bright-Glo (Promega) was .added by 25 μL, and the mixture was stirred at room temperature for 10 min, and the luminescence level was measured by Envision (PerkinElmer) . The results (% of control of the luminescence level of a test compound at 3 μΜ) measured by the above- mentioned method are shown in Table 10.
[0971]
Experimental Example 2 has shown that the compound of the present invention has an activity to modulate transcription of RORyt .
[0972]
[Table 10-1]
Figure imgf000458_0001
Figure imgf000459_0001
Figure imgf000460_0001
[0975]
Experimental Example 3
Mouse Thl7 cell differentiation test
CD4 positive naive T cells were collected from the spleen cells of BALB/c mice (female, 8-llw, Charles River Laboratories Japan, Inc.) using CD4+CD62L+ T Cell Isolation kit II (Miltenyi
Biotec) . The CD4 positive naive T cells in a 96 well plate (3xl05 cells/well) were stimulated (37 °C for culture) with anti-mouse CD3e antibody (Bio X cell) (10 yg/mL, solid phase) and anti-CD28 antibody (Bio X cell) (5 yg/mL) for 4 days in the presence of anti-IFN-γ antibody (BioLegend) , anti-IL-4 antibody (BioLegend) , anti-IL-2 antibody (BioLegend) , IL-6, TGF-β and IL-23 to differentiate into Thl7 cells. The compound was dissolved in DMSO and then added thereto. The cells were cultured under these conditions for 4 days, and differentiation of the Thl7 cells was evaluated by using the concentration of IL-17A, which was measured by ELISA, in the culture supernatant obtained by centrifugation .
The results (% of control of a test compound at 3 μΜ) evaluated by the above-mentioned method are shown in Table 11.
[0976]
Experimental Example 3 has shown that the compound of the present invention has an activity to modulate IL-17A production in cells derived from mouse spleen.
[0977]
[Table 11-1]
Figure imgf000462_0001
Figure imgf000463_0001
Figure imgf000464_0001
1), 2), 3) and 4) are mixed and filled in a gelatin capsule .
[0981]
Formulation Example 2 (production of tablet) 1) compound of Example 1 : 30 g
2) lactose : 50 g
3) cornstarch : 15 g
4) carboxymethylcellulose calcium : 44 g
5) magnesium stearate : 1 g
1000 tablets total 140 g
The total amount of 1), 2) and 3) and 4) (30 g) is kneaded with water, vacuum dried, and sieved. The sieved powder is mixed with 4) (14 g) and 5) (1 g) , and the mixture is punched by a tableting machine, whereby 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.
[0982]
Formulation Example 3
(1) the compound of Example 1 10.0 g
(2) lactose 70.0 g
(3) cornstarch 50.0 g
(4) soluble starch 7.0 g
(5) magnesium stearate 3.0 g
The compound of Example 1 (10.0 g) and magnesium stearate (3.0 g) are granulated in aqueous solution (70 mL) of soluble starch (7.0 g as soluble starch) and then dried, the resulting mixture is mixed with lactose (70.0 g) and cornstarch (50.0 g) (lactose, cornstarch, soluble starch and magnesium stearate are all products in compliance with Japanese Pharmacopoeia 14th Edition). The mixture compressed to give tablets.
[Industrial Applicability]
[0983]
The compound of the present invention may have an RORyt modulating action, and useful as an agent for the prophylaxis or treatment of cancer and the like.
This application is based on provisional patent
application Nos. 62/372,522 and 62/485,170 filed in the USA, the contents of which are incorporated in full herein.

Claims

[CLAIMS] [Claim 1] A compound represented by the formula (I' ) :
[Chem. 1]
9 R1 R2
wherein
ring A is an optionally further substituted ring;
L1 is a bond, optionally halogenated C1-2 alkylene, -NH- or -0-;
R1 and R2 are each independently a hydrogen atom or a substituent ;
R1 and R2 may be bonded together with an adjacent carbon atom to form an optionally further substituted ring, or R1 and R2 may be joined together to form an oxo group;
ring D is an optionally further substituted ring;
L2 is -SO2-, -S(=0)- or -S (=0) (=NR4) -;
R4 is a hydrogen atom or a substituent;
R3 is a substituent;
a partial structure:
[Chem. 2]
r
X is a carbon atom or a nitrogen atom;
n is an integer of 1 or 2;
ring B is an optionally further substituted 6- or 7- membered oxygen-containing heterocycle;
Y1, Y2 and Y3 are each independently a carbon atom or a nitrogen atom;
ring C is an optionally further substituted 6-membered aromatic ring; and
Y4 is =CH- or =N-, or a salt thereof..
[Claim 2]
The compound according to claim 1, wherein the ring A is [Chem. 4]
L is a bond;
R is a hydrogen atom or a hydroxymethyl group;
R2 is a hydrogen atom;
ring D is
[Chem. 5]
wherein W is =CR6- or =N-;
R6 is a hydrogen atom, -C02C2H5, -CH2OH, -C02H, -CONH2 or -
CN;
L2 is -SO2-; and
R3 is -CH3 or -C2H5, or a salt thereof.
[Claim 3]
The compound according to claim 1, wherein the partial structure :
[Chem. 6]
is
[Chem. 7]
wherein
X is a carbon atom or a nitrogen atom;
n is an integer of 1 or 2;
ring B is an optionally further substituted 6- or 7- membered oxygen-containing heterocycle;
Y1, Y2 and Y3 are each independently a carbon atom or a nitrogen atom; and
ring C is an optionally further substituted 6-membered aromatic ring, or a salt thereof.
[Claim 4]
1- (2, 6-Dicyclopropylpyridin-4-yl ) -N- (4- (methylsulfonyl) benzyl) -2, 3-dihydro-lH-pyrido [2, 3- b] [ 1 , 4 ] oxazine-6-carboxamide or a salt thereof.
[Claim 5]
4- (2, 6-Dicyclopropylpyridin-4-yl) -N- ( (5- (methylsulfonyl) pyridin-2-yl) methyl) chromane-7-carboxamide or a salt thereof.
[Claim 6]
5- (2, 6-Dicyclopropylpyridin-4-yl) -N- (4-
(methylsulfonyl) benzyl) -5,6,7, 8-tetrahydro-l , 5-naphthyridine-2- carboxamide or a salt thereof.
[Claim 7]
Ethyl 2- ( ( ( (5- (2, 6-dicyclopropylpyridin-4-yl) -5, 6, 7, 8- tetrahydro-1 , 5-naphthyridin-2-yl ) carbonyl) amino) methyl ) -5- (methylsulfonyl) benzoate or a salt thereof.
[Claim 8]
A medicament comprising the compound according to claim 1 or a salt thereof.
[Claim 9]
The medicament according to claim 8, which is a RORYt modulator .
[Claim 10]
The medicament according to claim 8, which is a
prophylactic or therapeutic agent for cancer.
[Claim 11]
A method of modulating RORyt in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.
[Claim 12]
A method for the prophylaxis or treatment of cancer in a mammal, comprising administering an effective amount of the compound- according to claim 1 or a salt thereof to the mammal.
[Claim 13]
The compound according to claim 1 or a salt thereof for use in the prophylaxis or treatment of cancer.
[Claim 14]
Use of the compound according to claim 1 or a salt thereof in the production of an agent for the prophylaxis or treatment of cancer.
PCT/JP2017/029695 2016-08-09 2017-08-08 Heterocyclic compounds with an ror(gamma)t modulating activity WO2018030550A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201662372522P 2016-08-09 2016-08-09
US62/372522 2016-08-09
US201762485170P 2017-04-13 2017-04-13
US62/485170 2017-04-13

Publications (1)

Publication Number Publication Date
WO2018030550A1 true WO2018030550A1 (en) 2018-02-15

Family

ID=59895349

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2017/029695 WO2018030550A1 (en) 2016-08-09 2017-08-08 Heterocyclic compounds with an ror(gamma)t modulating activity

Country Status (1)

Country Link
WO (1) WO2018030550A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020035556A1 (en) 2018-08-17 2020-02-20 Leo Pharma A/S Novel heteroaromatic modulators of the retinoid-related orphan receptor gamma
WO2020035557A1 (en) 2018-08-17 2020-02-20 Leo Pharma A/S Novel heteroaromatic modulators of the retinoid-related orphan receptor gamma
WO2021136339A1 (en) * 2019-12-31 2021-07-08 广东东阳光药业有限公司 Amide compound with bicyclic structure and use thereof in drug
CN114702402A (en) * 2022-04-20 2022-07-05 诚达药业股份有限公司 Synthetic method of fluorophenyl amino acid hydrochloride
US11673889B2 (en) 2019-09-23 2023-06-13 Nanjing Zhengxiang Pharmaceuticals Co., Ltd. Substituted imidazo[4,5-c][1,8]naphthyridines as phosphodiesterase inhibitors
WO2023130054A3 (en) * 2021-12-31 2023-08-10 Accro Bioscience (Hk) Limited Heteroaryl compounds as inhibitors of irak4, compositions and applications thereof

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002080928A1 (en) 2001-04-03 2002-10-17 Merck & Co., Inc. N-substituted nonaryl-heterocyclo amidyl nmda/nr2b antagonists
WO2005033072A2 (en) 2003-09-30 2005-04-14 Scios Inc. Heterocyclic amides and sulfonamides
WO2008021926A2 (en) 2006-08-09 2008-02-21 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, and/or ap-1, and/or nf-kb activity and use thereof
WO2009012221A1 (en) 2007-07-13 2009-01-22 Board Of Regents, The University Of Texas System Heterocyclic modulators of cannabinoid receptors
WO2010142752A1 (en) 2009-06-11 2010-12-16 F. Hoffmann-La Roche Ag Janus kinase inhibitor compounds and methods
WO2011073276A1 (en) 2009-12-16 2011-06-23 Evotec Ag Benzoxazine aryl sulfonamide derivatives as kv1.3 modulators
WO2012031197A1 (en) 2010-09-03 2012-03-08 Forma Therapeutics, Inc. Novel compounds and compositions for the inhibition of nampt
WO2015083130A1 (en) 2013-12-06 2015-06-11 Aurigene Discovery Technologies Limited Fused pyridine and pyrimidine derivatives as ror gamma modulators
KR20150110901A (en) 2014-03-20 2015-10-05 현대약품 주식회사 Compounds that binding with PPARG(Peroxisome Proliferator Activated Receptor-Gamma) but not act as an agonist and pharmaceutical composition for diseases related with PPARG containing the same as an active ingredient
WO2015159233A1 (en) * 2014-04-16 2015-10-22 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl ether compounds as ror gamma modulators
WO2016040505A1 (en) 2014-09-10 2016-03-17 Epizyme, Inc. Smyd inhibitors
WO2016039408A1 (en) * 2014-09-11 2016-03-17 武田薬品工業株式会社 Heterocyclic compound

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002080928A1 (en) 2001-04-03 2002-10-17 Merck & Co., Inc. N-substituted nonaryl-heterocyclo amidyl nmda/nr2b antagonists
WO2005033072A2 (en) 2003-09-30 2005-04-14 Scios Inc. Heterocyclic amides and sulfonamides
WO2008021926A2 (en) 2006-08-09 2008-02-21 Bristol-Myers Squibb Company Modulators of glucocorticoid receptor, and/or ap-1, and/or nf-kb activity and use thereof
US20090075995A1 (en) 2006-08-09 2009-03-19 Bristol-Myers Squibb Company MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-kB ACTIVITY AND USE THEREOF
WO2009012221A1 (en) 2007-07-13 2009-01-22 Board Of Regents, The University Of Texas System Heterocyclic modulators of cannabinoid receptors
WO2010142752A1 (en) 2009-06-11 2010-12-16 F. Hoffmann-La Roche Ag Janus kinase inhibitor compounds and methods
WO2011073276A1 (en) 2009-12-16 2011-06-23 Evotec Ag Benzoxazine aryl sulfonamide derivatives as kv1.3 modulators
WO2012031197A1 (en) 2010-09-03 2012-03-08 Forma Therapeutics, Inc. Novel compounds and compositions for the inhibition of nampt
WO2015083130A1 (en) 2013-12-06 2015-06-11 Aurigene Discovery Technologies Limited Fused pyridine and pyrimidine derivatives as ror gamma modulators
KR20150110901A (en) 2014-03-20 2015-10-05 현대약품 주식회사 Compounds that binding with PPARG(Peroxisome Proliferator Activated Receptor-Gamma) but not act as an agonist and pharmaceutical composition for diseases related with PPARG containing the same as an active ingredient
WO2015159233A1 (en) * 2014-04-16 2015-10-22 Glenmark Pharmaceuticals S.A. Aryl and heteroaryl ether compounds as ror gamma modulators
WO2016040505A1 (en) 2014-09-10 2016-03-17 Epizyme, Inc. Smyd inhibitors
WO2016039408A1 (en) * 2014-09-11 2016-03-17 武田薬品工業株式会社 Heterocyclic compound

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
"Chemical and Pharmaceutical Bulletin", CHEM. PHARM. BULL, vol. 38, 1990, pages 2792 - 2796
"The Chemical Society of Japan", 1991, article "Jikken Kagaku Kouza 20, Organic Synthesis II"
"The Chemical Society of Japan", 1991, article "Jikken Kagaku Kouza 22, Organic Synthesis IV"
ACS MEDICINAL CHEMISTRY LETTERS, vol. 6, no. 9, 2015, pages 998 - 1003
BIOORGANIC & MEDICINAL CHEMISTRY, vol. 20, no. 8, 2010, pages 2560 - 2563
CHEMMEDCHEM, vol. 4, no. 10, 2009, pages 1615 - 1629
IYAKUHIN; KAIHATSU: "Development of Pharmaceuticals", DESIGN OF MOLECULES, vol. 7, pages 163 - 198
JOURNAL OF ANTIBIOTICS, vol. 38, 1985, pages 877 - 885
P. J. KOCIENSKI: "Thieme", 2004
THEODORA W. GREENE; PETER G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY- INTERSCIENCE
THEODORA W. GREENE; PETER G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE
THEODORA W. GREENE; PETER G. M. WUTS: "Protective Groups in Organic Synthesis", 2007, WILEY-INTERSCIENCE

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020035556A1 (en) 2018-08-17 2020-02-20 Leo Pharma A/S Novel heteroaromatic modulators of the retinoid-related orphan receptor gamma
WO2020035557A1 (en) 2018-08-17 2020-02-20 Leo Pharma A/S Novel heteroaromatic modulators of the retinoid-related orphan receptor gamma
US11673889B2 (en) 2019-09-23 2023-06-13 Nanjing Zhengxiang Pharmaceuticals Co., Ltd. Substituted imidazo[4,5-c][1,8]naphthyridines as phosphodiesterase inhibitors
WO2021136339A1 (en) * 2019-12-31 2021-07-08 广东东阳光药业有限公司 Amide compound with bicyclic structure and use thereof in drug
CN113121463A (en) * 2019-12-31 2021-07-16 广东东阳光药业有限公司 Amide compound with bicyclic structure and application thereof in medicines
WO2023130054A3 (en) * 2021-12-31 2023-08-10 Accro Bioscience (Hk) Limited Heteroaryl compounds as inhibitors of irak4, compositions and applications thereof
CN114702402A (en) * 2022-04-20 2022-07-05 诚达药业股份有限公司 Synthetic method of fluorophenyl amino acid hydrochloride
CN114702402B (en) * 2022-04-20 2024-01-30 诚达药业股份有限公司 Synthetic method of fluoro-phenyl amino acid hydrochloride

Similar Documents

Publication Publication Date Title
US11851449B2 (en) Heterocyclic amide compounds having an RORvt inhibitory action
US9630924B2 (en) Heterocyclic compound
WO2018030550A1 (en) Heterocyclic compounds with an ror(gamma)t modulating activity
EP3325490B1 (en) 1-substituted 1,2,3,4-tetrahydro-1,7-naphthyridin-8-amine derivatives and their use as ep4 receptor antagonists
US10053468B2 (en) Heterocyclic compound
US10000488B2 (en) Heterocyclic compound
WO2017014321A1 (en) Oxadiazole derivatives useful as hdac inhibitors
WO2015068856A1 (en) Pyrazole for the treatment autoimmune disorders
WO2016199943A1 (en) Heterocyclic compounds
JP6280912B2 (en) Heterocyclic compounds
EP3124487A1 (en) Heterocyclic compound

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17768528

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17768528

Country of ref document: EP

Kind code of ref document: A1