WO2014168262A1 - Kinase inhibitors containing cyclopropane skeleton - Google Patents

Kinase inhibitors containing cyclopropane skeleton Download PDF

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Publication number
WO2014168262A1
WO2014168262A1 PCT/JP2014/060992 JP2014060992W WO2014168262A1 WO 2014168262 A1 WO2014168262 A1 WO 2014168262A1 JP 2014060992 W JP2014060992 W JP 2014060992W WO 2014168262 A1 WO2014168262 A1 WO 2014168262A1
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optionally substituted
compound
group
alkyl
heterocyclic group
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PCT/JP2014/060992
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French (fr)
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Yuji Kogami
Satoshi Shuto
Mitsuhiro Arisawa
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D.D.P. Corporation
National University Corporation Hokkaido University
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Publication of WO2014168262A1 publication Critical patent/WO2014168262A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D215/12—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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

Definitions

  • the present invention relates to novel compound ' s having a tyrosine kinase inhibitory action, which is useful for the prophylaxis or treatment of proliferative diseases associated with kinase signaling pathway such as tumor or cancer, fibrotic diseases, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, tuberous
  • Tropomysosin Related kinases are a family of receptor tyrosine kinases composed of three family members, TrkA, - TrkB and TrkC.
  • the Trks bind with high affinity to, and mediate the signal transduction induced by the Neurotrophin family of ligands whose prototype members are Nerve Growth Factor (NGF) , Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin-3, -4 and -5 (NT-3, NT-4 and NT-5) .
  • NGF Nerve Growth Factor
  • BDNF Brain-Derived Neurotrophic Factor
  • NT-3, NT-4 and NT-5 Neurotrophin-3, -4 and -5
  • p75 a co-receptor lacking enzymatic activity
  • TrkA-NGF interaction was shown as a requirement for the survival of certain peripheral neuron populations involved in mediating pain signaling.
  • TrkA receptor kinase the subversion of this receptor and its signaling pathway in certain malignancies has also been documented.
  • reports of aberrant, expression of NGF and TrkA receptor kinase are implicated in the development and progression of human prostatic carcinoma and pancreatic ductal adrenocarcinoma and activating chromosomal rearrangements of Trks in acute
  • AML myelogenous leukemia
  • Trk receptor and ligand have also been reported in a variety of tumor types including multiple myeloma, melanoma, neuroblastoma, ovary and pancreatic carcinoma.
  • the neurotrophines and their corresponding Trk receptor subtypes have been shown to exert a variety of pleiotropic responses on malignant cells, including enhanced tumor invasiveness and chemotaxis, activation of apoptosis, stimulation of clonal growth, and altered cell morphology.
  • Trk signaling has been observed in carcinomas of the prostate, breast, thyroid, colon, malignant melanomas, lung carcinomas, glioblastomas, pancreatic carcinoids and a wide variety of pediatric and neuroectodermal- derived tumors including Wilm' s tumor, neuroblastomas and medulloblastomas .
  • Neurotrophins and their receptor subtypes have been implicated in these cancers either through autocrine or paracrine mechanisms involving carcinoma cells and the surrounding parenchymal and stromal tissues.
  • profound or significantly attenuated reduction of bone pain caused by prostate cancer metastasis has recently been achieved by utilization of an anti-NGF antibody.
  • the oncogenic properties of Trk signaling in multiple tumor types makes the modulation of the Trk receptor signaling a potentially
  • RTKs Receptor tyrosine kinases
  • Tyrosine kinase activity is an absolute requirement for signal transduction through this class of receptor.
  • Trk family of RTKs is frequently expressed in lung, breast, pancreatic and prostate cancers as well as in certain type of acute myelogenous leukemia and congenital fibrosarcoma.
  • the tyrosine kinase activity of Trk is believed to promote the unregulated activation of cell proliferation machinery.
  • inhibitors of either TrkA, TrkB, or TrkC kinases, individually or in combination have utility against some of the most common cancers such as brain, melanoma, multiple myeloma, squamous cell, bladder, gastric, pancreatic, breast, head, neck, esophageal, prostate, colorectal, lung, renal, ovarian,
  • Fms-like tyrosine kinase 3 (Flt-3) is also receptor type tyrosine kinase and one of the most frequently mutated genes in acute myeloid leukemia (AML) .
  • AML acute myeloid leukemia
  • high levels of wild-type Flt3 have been reported for blast cells of some AML patients without Flt3 mutations. These high levels may be associated with worse prognosis.
  • An object of the present invention is to provide a compound useful for the prophylaxis or treatment of proliferative diseases associated with kinase signaling pathway such as tumor or cancer, fibrotic diseases, restenosis associated " with angioplasty, polycystic kidney disease, aberrant angiogehesis disease, tuberous sclerosis complex, hair loss, and Alzheimer's disease.
  • proliferative diseases associated with kinase signaling pathway such as tumor or cancer, fibrotic diseases, restenosis associated " with angioplasty, polycystic kidney disease, aberrant angiogehesis disease, tuberous sclerosis complex, hair loss, and Alzheimer's disease.
  • R 1 and R 2 are each independently hydrogen, an optionally hydrogen
  • R 1 and R 2 in combination form, together with the adjacent nitrogen atom, optionally substituted 4- to 7-membered ring, and R 3 is -W 21 -R 30 ,
  • W 21 is bond, -0-, -S(0)p- (wherein p is an integer of 0 to 2) or -NRa- (wherein Ra is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) ;
  • R 30 is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • R 4 is an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted carbocyclyl-alkyl group or an optionally substituted
  • the carbon atom marked with * is an asymmetric carbon atom
  • the present invention relates to
  • R 2 is hydrogen
  • R 30 is hydrogen or optionally substituted Ci-10 alkyl
  • R 3 is -W 21 -R 30 , wherein
  • W 21 is -0-
  • R 30 is hydrogen or optionally substituted Ci_io alkyl; and R 4 is optionally substituted C 6 -io aryl or an optionally
  • Compound (I) has a tyrosine kinase inhibitory action on Trk receptors such as TrkA, TrkB, TrkC or other tyrosine kinase receptors such as Flt-3, and is useful for the prophylaxis or treatment of proliferative diseases associated with kinase signaling pathway such as tumor or cancer, fibrotic diseases, restenosis associated with angioplasty, polycystic kidney
  • halogen in the present specification means, unless otherwise specified, fluorine, chlorine, bromine or iodine.
  • hydrocarbon group of the "optionally substituted hydrocarbon group” in the present specification means, unless otherwise specified, Ci-io alkyl, C 2 -io alkenyl, C 2 -io alkynyl, C3-10 cycloalkyl, C 3 -i 0 cycloalkenyl, C4-10 cycloalkadienyl, C 6 _ 14 aryl, C7-13 aralkyl, Cg-13 arylalkenyl or the like.
  • Ci-10 alkyl in the present specification means, unless otherwise specified, 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, 2-ethylbutyl, heptyl, octyl, nonyl, decyl or the like.
  • Ci- 6 alkyl is preferable, and C1-3 alkyl is more preferable.
  • Ci-6 alkyl in the present specification means, unless otherwise specified, 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, 2-ethylbutyl or the like.
  • Ci-3 alkyl in the present specification means, unless otherwise specified, methyl, ethyl, propyl, isopropyl or the like.
  • the C2-10 alkenyl in the present specification means, unless otherwise specified, ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3- pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl or the like. Among them, 2 -6 alkenyl is preferable.
  • the . C 2 -6 alkenyl in the present specification means, unless otherwise specified, ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl,
  • the C2-10 alkynyl in the present specification means, unless otherwise specified, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
  • the C 2 -6 alkynyl in the present specification means, unless otherwise specified, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
  • the C3-10 cycloalkyl in the present specification means, unless otherwise specified, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or the like. Among them, C 3 - 8 cycloalkyl is preferable.
  • the C3-8 cycloalkyl in the present specification means, unless otherwise specified, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.
  • the C4-7 cycloalkyl in the present specification means, unless otherwise specified, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
  • the C3-10 cycloalkenyl in the present specification means, unless otherwise specified, 2-cyclopenten-l-yl, 3-cyclopenten-l- yl, 2-cyclohexen-l-yl, 3-cyclohexen-l-yl or the like. Among them, C 3 -8 cycloalkenyl is preferable. - [0035] -
  • the C 3 _8 cycloalkenyl in the present specification means, unless otherwise specified, 2-cyclopenten-l-yl, 3-cyclopenten-l- yl, 2-cyclohexen-l-yl, 3-cyclohexen-l-yl or the like.
  • the C 4 _7 cycloalkenyl in the present specification means, unless otherwise specified, 2-cyclopenten-l-yl, 3-cyclopenten-l- yl, 2-cyclohexen-l-yl,. 3-cyclohexen-l-yl or the like.
  • the C 4 _io cycloalkadienyl in the present specification means, unless, otherwise specified, 2, -cyclopentadien-l-yl, 2,4- cyclohexadien-l-yl, 2, 5-cyclohexadien-l-yl or the like. Among them, C 4 -8 cycloalkadienyl is preferable.
  • the C4-8 cycloalkadienyl in the present specification means, unless otherwise specified, 2 , 4-cyclopentadien-l-yl, 2,4- cyclohexadien-l-yl, 2, 5-cyclohexadien-l-yl or the like.
  • the C4-7 cycloalkadienyl in the present specification means, unless otherwise specified, 2, 4-cyclopentadien-l-yl, 2,4- cyclohexadien-l-yl, 2, 5-cyclohexadien-l-yl or the like.
  • C4-10 cycloalkadienyl are each optionally fused with benzene to form a fused ring group.
  • the fused ring group include indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • C3-10 cycloalkyl, C3-10 cycloalkenyl and C4-10 cycloalkadienyl may be each a " C 7 -io. bridged hydrocarbon group.
  • Examples of the C7-10 bridged hydrocarbon group include bicyclo [2.2.1] heptyl (norbornyl) ,
  • cycloalkenyl and C4-10 cycloalkadienyl each optionally forms a spiro ring group together with C3-10 cycloalkane, C 3 _i 0 cycloalkene or C4-10 cycloalkadiene .
  • Examples of the C3-10 cycloalkane, C3-10 cycloalkene and C4-10 cycloalkadiene include rings corresponding to the above-mentioned C3-10 cycloalkyl, C3-10 cycloalkenyl and C4-10 cycloalkadienyl.
  • the spiro ring group include spiro [4.5] decan-8-yl and the like.
  • the Cg-14 aryl group in the present specification means, unless otherwise specified, phenyl, naphthyl, anthryl,
  • phenanthryl acenaphthyl, biphenylyl or the like.
  • Ce-io aryl is preferable.
  • the C6-10 aryl group in the present specification means, unless otherwise specified, phenyl, naphthyl or the like.
  • the C7-13 aralkyl group in the present specification means, unless otherwise specified, benzyl, phenethyl, naphthylmethyl, biphenylylmethyl or the like.
  • Ce-13 arylalkenyl group in the present specification means, unless otherwise specified, styryl or the like.
  • optionally substituted carbocyclyl-alkyl group in the present specification mean, unless otherwise specified, C3-10 cycloalkyl, C3-10 cycloalkenyl, C4-10 cycloalkadienyl, C6-1.4 aryl or the like.
  • heterocyclic group of the "optionally substituted heterocyclic group” and the “heterocyc!yl” moiety of the “optionally substituted heterocyclyl-alkyl group” in the present specification mean, unless otherwise specified, an "aromatic heterocyclic group” or a “non-aromatic heterocyclic group”.
  • Ci-io alkyl such as 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, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like.
  • Ci_ 6 alkyl is preferable, and C1-3 alkyl is more preferable.
  • a 4- to 7- membered (preferably 5- or 6-menbered) monocyclic aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, or a fused
  • fused aromatic heterocyclic group examples include a group derived from a fused ring wherein a ring corresponding to the 4- to 7- membered monocyclic aromatic heterocyclic group and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) , a 5-membered aromatic
  • heterocycle containing one sulfur atom e.g., thiophene
  • a benzene ring fused, and the like.
  • aromatic heterocyclic group examples include
  • monocyclic aromatic heterocyclic groups such as furyl (e.g., 2- furyl, 3-furyl) , thienyl (e.g., 2-thienyl, 3-thienyl)., pyridyl . (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) , pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl) , , pyrazinyl (e.g., 2-pyrazinyl) , pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl) , pyrazo
  • thiazolyl e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl
  • isothiazolyl (e. g. , 3-isothiazolyl, 4-isothiazolyl, 5- isothiazolyl) , oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5- oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl) , oxadiazolyl (e.g., 1, 2, 4-oxadiazol-5-yl, 1,3,4- oxadiazol-2-yl) , thiadiazolyl (e.g., 1, 3, 4-thiadiazol-2-yl) , triazolyl (e.g., 1, 2, 4-triazol-l-yl, 1, 2 , 4-triazol-3-yl, 1,2,3- triazol-l-yl, 1, 2, 3-triazol-2-yl, 1, 2 , 3-triazol-4-yl) , o
  • tetrazolyl e.g., tetrazol-l-yl, tetrazol-5-yl
  • triazinyl e.g., 1, 2, 4-triazin-l-yl, 1, 2, 4-triazin-3-yl
  • quinolyl e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl
  • isoquinolyl e.g., 3-isoquinolyl
  • quinazolyl e.g., 2- quinazolyl, 4-quinazolyl
  • quinoxalyl e.g., 2-quinoxalyl, 6- quinoxalyl
  • benzofuranyl e.g., 2-benzofuranyl, 3-benzofuranyl
  • benzothienyl e.g., 2-benzothienyl, 3-benzothienyl
  • benzoxazolyl e.g., 2-benzoxazolyl
  • benzisoxazolyl e.g., 7- benzisoxazolyl
  • benzothiazolyl e.g., 2-benzothiazolyl
  • benzimidazolyl e.g., benzimidazol-l-yl, benzimidazol-2-yl, benzimidazol-5-yl
  • benzotriazolyl e.g., lH-1, 2, 3-benzotriazol- 5-yl
  • indolyl e.g., indol-l-yl, indol-2-yl, indol-3-yl, indol- 5-yl
  • indazolyl e.g., lH-indazol-3-yl
  • pyrrolopyrazinyl e.g., lH-pyrrolo [2, 3-b] pyrazin-2-yl, lH-pyrrolo [2, 3-b] pyrazin-6-yl
  • imidazopyridinyl e.g., lH-imidazo [4, 5-b] pyridin-2-yl, 1H- imidazopyridin
  • imidazopyrazinyl e.g., lH-imidazo [4, 5-b] pyrazin-2-yl
  • pyrazolopyridinyl e.g., IH-pyrazolo [4, 3-c] pyridin-3-yl
  • pyrazolothienyl e.g., " 2H-pyrazolo [3, 4-b] thiophen-2-yl
  • pyrazolotriazinyl e.g., pyrazolo [5, 1-c] [1, 2, 4] triazin-3-yl
  • pyridopyridyl e.g., pyrido [2, 3-b] pyridin-3-yl
  • thienopyridyl e.g., thieno [2, 3-b] pyridin-3-yl
  • fused non-aromatic heterocyclic group examples include a group derived from a fused ring wherein a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) , a 5- membered aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring are fused, a group wherein the above-mentioned group is partially saturated, and the like.
  • a fused ring wherein a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole
  • non-aromatic heterocyclic group examples include
  • azetidinyl e.g., 1- azetidinyl, 2-azetidinyl, 3-azetidinyl
  • pyrrolidinyl e.g., 1-pyrrolidinyl, 2-pyrrolidinyl
  • piperidyl e.g., piperidino, 2-piperidyl, 3-piperidyl, -piperidyl
  • morpholinyl e.g., morpholino
  • thiomorpholinyl e.g.,
  • thiomorpholino e.g., 1-piperazinyl, 2-piperazinyl, 3-piperazinyl
  • piperazinyl e.g., 1-piperazinyl, 2-piperazinyl, 3-piperazinyl
  • hexamethyleniminyl e.g., hexamethylenimin-l-yl
  • oxazolidinyl e.g., oxazolidin-2-yl
  • -thiazolidinyl e.g., ⁇ thiazolidin-2-yl
  • imidazolidinyl e.g., imidazolidih-2-yl, imidazolidin-3-yl
  • oxazoliriyl e.g., oxazolin-2-yl
  • thiazolinyl e.g., thiazolin-2-yl
  • imidazolinyl e.g., imidazolin-2-yl, imidazolin-3-yl
  • dioxolyl e.g., 1, 3-dioxol-4- yl
  • dioxolanyl e.g., 1, 3-dioxolan-4-yl
  • dihydrooxadiazolyl e.g., 4, 5-dihydro-l, 2, 4-oxadiazol-3-yl
  • pyranyl e.g., 4- pyranyl
  • tetrahydropyranyl e.g., 2-tetrahydropyranyl, 3- tetrahydropyranyl, 4-tetrahydropyranyl
  • thiopyranyl e.g., 4- thiopyranyl
  • tetrahydrothiopyranyl e.g., 2- tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4- tetrahydrothiopyranyl
  • tetrahydrofuryl e.g., tetrahydrofuran-
  • dihydrotriazolyl e.g., 2, 3-dihydro-lH-l, 2, 3-triazol-l-yl
  • tetrahydrotriazolyl e.g. , 2, 3, 4, 5-tetrahydro-lH-l, 2 , 3-triazol- l-yl
  • dihydroindolyl e.g., 2, 3-dihydro-lH-indol-l-yl
  • dihydroisoindolyl e.g., 1, 3-dihydro-2H-isoindol-2-yl
  • dihydrobenzofuranyl e.g., 2 , 3-dihydro-l-benzofuran-5-yl
  • dihydrobenzodioxinyl e.g., . 2, 3-dihydro-l, 4-benzodioxinyl
  • dihydrobenzodioxepinyl e.g., 3, -dihydro-2H-l, 5- benzodioxepinyl
  • tetrahydrobenzofuranyl e.g., 4,5,6,7- tetrahydro-l-benzofuran-3-yl
  • chromenyl - e. g.
  • 4- to 7-membered ring in the present specification means, unless otherwise specified, benzene, C 4 - 7 cycloalkane, C 4 - 7 cycloalkene, C 4 _ 7 cycloalkadiene, 4- to 7-membered monocyclic aromatic heterocycle or 4- to 7-membered monocyclic non-aromatic heterocycle.
  • Examples of the C 4 _7 cycloalkane, C 4 - 7 cycloalkene and C 4 -7 cycloalkadiene include rings corresponding to the above- mentioned C4-7 cycloalkyl, C 4 - 7 cycloalkenyl and C4-7
  • Examples of the 4- to .7-membered ' monocyclic aromatic heterocycle and 4- to 7-membered monocyclic non- aromatic heterocycle include rings corresponding to the above- mentioned 4- to 7-membered monocyclic aromatic heterocyclic group and 4- to 7-membered monocyclic non-aromatic heterocyclic group.
  • alkylene of the "optionally substituted alkylene” in the present specification means, unless otherwise specified, a linear or branched alkylene having 1 to 10 carbon atoms,
  • alkylene examples include methylene ' (-(3 ⁇ 4-) , ethylene (-CH 2 CH2-.) , methylmethylene (- CH(CH 3 )-), 1,2-propylene (-CH 2 CH (CH 3 ) -) , 1, 3-propylene (-CH 2 CH 2 CH 2 - ) , 1,2-butylene (-CH 2 CH (CH 2 CH 3 ) -) , 1,3-butylene (-CH 2 CH 2 CH (CH 3 ) -) , 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) , 2-methyltetramethylene (- CH 2 CH(CH 3 )CH 2 CH 2 -) , pentamethylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) and the like.
  • hydrocarbon group including carbocyclyl moiety and alkyl moiety
  • heterocyclic group including heterbcyclyl moiety
  • 4- to 7-membered ring and alkylene optionally have substituents (preferably 1 to 7, more preferably 1 to 5, still more preferably 1 to 3) selected from the following Subsutituent A at substitutable positions.
  • Ci_ 6 alkoxy C 2 - 6 alkenyloxy, C 2 -6 alkynyloxy, C 3 - 8
  • cycloalkyloxy C 3 -s cycloalkenyloxy, C 4 _8 cycloalkadienyloxy, C6-14 aryloxy, C 7 _i 3 aralkyloxy, heterocyclyloxy; formyl, Ci_ 6 alkyl-carbonyl, C 2 _ 6 alkenyl-carbonyl, C 2 -6 alkynyl- carbonyl, C 3 - 8 cycloalkyl-carbonyl, C 3 _ 8 cycloalkenyl-carbonyl, C 4 - 8 cycloalkadienyl-carbonyl, C 6 -i4 aryl-carbonyl, C7-13 aralkyl- carbonyl, heterocyclylcarbonyl;
  • alkynylsulfanyl C 3 - 8 cycloalkylsulfanyl, C 3 _ 8 cycloalkenylsulfanyl, C 4 - 8 cycloalkadienylsulfanyl, C 6 _i 4 arylsulfanyl, C 7 -i 3
  • sulfonyl (sulfo) , Ci_ 6 alkylsulfonyl, C 2 _6 alkenylsulfonyl, C 2 _ 6 alkynylsulfonyl, C 3 _ 8 cycloalkylsulfonyl, C 3 - 8 cycloalkenylsulfonyl, C4-8 cycloalkadienylsulfonyl, C 6 -i4 arylsulfonyl-, C 7 -i 3
  • cycloalkadienylamino mono- or di-C6-i4 arylamino, mono- or di-C 7 _ 13 aralkylamino, mono- or di-heterocyclylamino; carbamoyl, mono- or di-Ci-6 alkyl-carbamoyl, mono- or di-C2-6
  • alkenyl-carbamoyl mono- or di-C 2 - 6 alkynyl-carbamoyl, mono- or di-C 3 _8 cycloalkyl-carbamoyl, mono- or di-C 3 -8 cycloalkenyl- carbamoyl, mono- or di-C 4 _8 cycloalkadienyl-carbamoyl, mono- or di-C 6 _i4 aryl-carbamoyl, mono- or di-C 7 -i3 aralkyl-carbamoyl, mono- or di-heterocyclylcarbamoyl;
  • Ci- 6 alkyl selected from Ci- 6 alkyl, C2-6 alkenyl, C 2 -6 alkynyl, C 3 - 8 cycloalkyl, C3-8 cycloalkenyl, C4-8 cycloalkadienyl, C 6 _i aryl, C 7 _i 3 aralkyl, C6-14 aryl—C 2 -6 alkenyl and a heterocyclic group.
  • R 1 and R 2 are each independently hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R 1 and R 2 in combination form, together with the adjacent nitrogen atom, an optionally substituted 4- to 7-membered ring.
  • R 1 and R 2 are each independently
  • Ci_i 0 alkyl including .optionally substituted C 3 _ 8 cycloalkyl-Ci- 3 alkyl, optionally substituted C 7 -i 3 aralkyl (C 6 -io aryl-Ci-3 alkyl) ) , optionally substituted C 6 -i 4 aryl or an optionally substituted non-aromatic heterocyclic group,
  • Ci_ 6 alkyl optionally substituted C3-8 cycloalkyl-Ci-3 alkyl, optionally substituted C 7 -i 3 aralkyl ( C 6 -io aryl-Ci_ 3 alkyl) , optionally
  • R 1 is optionally substituted Ci_ 6 alkyl, optionally substituted C 3 -s cycloalkyl-Ci-3 alkyl,
  • R 2 is hydrogen.
  • R 1 is still more preferably
  • Ci-6 alkyl (preferably Ci_ 3 alkyl) optionally having
  • substituent (s) (preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from
  • C7-13 aralkyl ( C 6 -i 0 aryl-Ci_ 3 alkyl) (preferably phenyl-Ci-3 alkyl) wherein the C 6 -io aryl moiety (preferably phenyl)
  • Ci_6 alkoxy preferably Ci_3 alkoxy
  • heterocyclic group preferably a 5- or 6-membered nitrogen- containing saturated heterocyclic group, e.g., piperidyl
  • R 1 is particularly preferably C 3 -s cycloalkyl-Ci- 3 alkyl
  • R 3 is -W 21 -R 30
  • 2 1 is bond, -0-, -S(0)p- (wherein p is an integer of 0 to 2) or -NRa- (wherein Ra is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group);
  • R 30 is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
  • 2 1 is preferably -0-.
  • R 30 is preferably hydrogen or optionally substituted Ci-10 alkyl (including optionally substituted G7-13 aralkyl (C 6 -io aryl- C 1 -3 alkyl) ) , more preferably
  • Ci-6' alkyl preferably Ci_ 3 alkyl
  • substituent (s) (preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from
  • Ci_6 alkoxy (preferably C 1 -3 alkoxy)
  • a heterocyclic group preferably an aromatic heterocyclic group, more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl
  • a heterocyclic group preferably an aromatic heterocyclic group, more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl
  • C7-13 aralkyl (Ce-io aryl-Ci_ 3 alkyl) (preferably phenyl-Ci_ 3 alkyl) .
  • R 3 is preferably (1) -OH
  • Ci_6 alkoxy (preferably C1-3 alkoxy)
  • a heterocyclic group preferably an aromatic heterocyclic group more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl
  • a heterocyclic group preferably an aromatic heterocyclic group more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl
  • R is more preferably -OH.
  • R 4 is an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally
  • R 4 is still more preferably
  • heterocyclic group preferably pyridyl
  • heterocyclic group fused with benzene preferably quinolyl, indazolyl, indolyl
  • benzene preferably quinolyl, indazolyl, indolyl
  • substituent (s) preferably quinolyl, indazolyl, indolyl
  • R 4 is particularly preferably a 5- or 6- membered nitrogen- containing aromatic heterocyclic group fused with benzene
  • compound (I) include the following compounds.
  • R 1 is optionally substituted Ci_ 6 alkyl, optionally substituted C 3 _ 8 cycloalkyl-Ci-3 alkyl, optionally substituted C 7 _i 3 aralkyl (C 6 -io aryl-Ci-3 alkyl), optionally substituted ⁇ - ⁇ aryl or an
  • R 2 is hydrogen
  • R 3 is -W 21 -R 30 , wherein
  • R 30 is hydrogen or optionally substituted Ci_io alkyl
  • R 4 is optionally substituted ⁇ - ⁇ a yl or an optionally
  • R 1 is optionally substituted " Ci- 6 alkyl, optionally substituted C 3 - a cycloalkyl-Ci- 3 alkyl, optionally substituted C 7 _i 3 aralkyl (C6-io aryl-Ci-3 alkyl) , optionally substituted ⁇ - ⁇ aryl or an
  • R 2 is hydrogen
  • R 3 is - 21 -R 30 , wherein
  • W 21 is -0-; and R 30 is
  • Ci-6 alkyl optionally having substituent (s) (preferably 1 to 5, more preferably 1 to 3, ⁇ ⁇ still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from
  • Ci_6 alkoxy (preferably Ci_ 3 alkoxy)
  • a heterocyclic group preferably an aromatic heterocyclic group, more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl
  • a heterocyclic group preferably an aromatic heterocyclic group, more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl
  • C7-13 aralkyl (C 6 -io . aryl-Ci- 3 alkyl) (preferably phenyl-Ci- 3 alkyl) ;
  • R 4 is optionally substituted C 6 -io aryl or an optionally
  • Ci-6 alkyl (preferably Ci_ 3 alkyl) optionally having
  • substituent (s) (preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from
  • C 7 _i3 aralkyl (C 6 -io aryl-Ci_ 3 alkyl) (preferably phenyl-Ci-3 alkyl) wherein the C 6 -i 0 aryl moiety (preferably phenyl)
  • Ci-6 alkoxy preferably Ci_ 3 alkoxy
  • C6-10 aryl preferably phenyl
  • heterocyclic group preferably a 5- or 6-membered nitrogen- containing saturated heterocyclic group, e.g., piperidyl
  • R 2 is hydrogen
  • Ci-e alkoxy (preferably Ci_ 3 alkoxy)
  • a heterocyclic group preferably an aromatic heterocyclic group, more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl
  • a heterocyclic group preferably an aromatic heterocyclic group, more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl
  • heterocyclic group preferably pyridyl
  • heterocyclic group fused with benzene preferably quinolyl, indazolyl, indolyl
  • benzene preferably quinolyl, indazolyl, indolyl
  • substituent (s) preferably quinolyl, indazolyl, indolyl
  • Ci-6 alkyl (preferably Ci_ 3 alkyl) optionally having
  • substituent (s) (preferably 1 to 5., more preferably 1 to 3, still more preferably 1 or " 2 substituents, particularly preferably 1 substituent) selected from (a) hydroxy,
  • substituents more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from Ci_ s alkoxy (preferably C1-3 alkoxy) ,
  • heterocyclic group preferably a 5- or 6-membered nitrogen- containing saturated heterocyclic group, e.g., piperidyl
  • R 2 is hydrogen
  • R 3 is -OH
  • R 4 is. a 5- or 6- membered nitrogen-containing aromatic
  • heterocyclic group fused with benzene preferably quinolyl, indazolyl, indolyl, more preferably quinolyl, indazolyl
  • compound (I) can be the following optical isomer:
  • compound (I) can be the following geometi isomer:
  • a pharmacologically acceptable salt is preferable.
  • examples of such salt include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • the salts with inorganic bases include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salts, magnesium salts and the like; aluminum salts; ammonium salts, and the like .
  • examples of the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,
  • tromethamine [tris (hydroxymethyl)methylamine] , tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N- dibenzylethylenediamine and the. like.
  • salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.
  • Compound (I) may be a non-solvate (e.g., anhydride) or a solvate (e.g., hydrate).
  • compound (I) stereoisomer, a positional .isomer and a rotamer, these are also included in compound (I) , as well as each can be obtained as a single product by a synthesis method or separation method known per se.
  • compound (I) contains an optical isomer
  • an optical isomer resolved from the compound is also encompassed in compound (I) .
  • Compound (I) may also be a crystal.
  • the crystal of compound (I) can be produced by
  • the melting point sometimes varies depending on the measurement device, measurement condition and the like.
  • the crystal in the present specification may be a crystal showing a melting point different from the values described in the present specification as long as the difference is within a general error range.
  • each starting compound may form a salt as long as it does not inhibit the reaction, and examples of the salt include those exemplified as the salts of the compound represented by the aforementioned formula (I) .
  • the starting compounds without indication of specific production method are easily commercially available, or can be produced according to a method known per se or a method
  • 2 1 ' is -0-, -S- or -NRa- (wherein Ra is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) ,
  • R 30 ' is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group
  • P 1 is a carboxy-protecting group
  • P 2 is a hydroxy-protecting group
  • X 1 is halogen or trichloroacetimidoyloxy
  • ⁇ X 2 is chlorine, bromine or iodine
  • Examples of the "carboxy-protecting group" for P 1 include a Ci-6 alkyl group, a C 7 -n aralkyl group (e.g., benzyl), a phenyl group, a trityl group, a substituted silyl group (e.g.,
  • P 1 is preferably a Ci- 6 alkyl group, more preferably methyl or ethyl.
  • Examples of the "hydroxy-protecting group" for P 2 include a Ci-6 alkyl group, a phenyl group, a trityl group, a C 7 _io aralkyl group (e.g., benzyl), a formyl group, a Ci_ 6 alkyl-carbonyl group, a benzoyl group, a C 7 io aralkyl-carbonyl group (e.g.,
  • benzylcarbonyl a 2-tetrahydropyranyl group, a 2- tetrahydrofuranyl group, a substituted silyl group (e.g.,
  • substituted silyl group more preferably tert-butyldiethylsilyl.
  • Compound (A-V) can be produced by reacting compound (A-VI) with compound (B-I) .
  • Compound (A-VI) and compound (B-I) may be a commercially - available product, or can be produced according to a method known per se or a method analogous thereto.
  • the amount of compound (B-I) to be used is generally 0.5 to 100 mol, preferably . 1 to 10 mol, per 1 mol of compound (A-VI).
  • this reaction can be carried out in the presence of a base in a solvent inert to the reaction.
  • Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium
  • the amount of the base to be used is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A-VI) .
  • Examples of the acid include pyridinium p-toluenesulfonate, toluenesulfonic acid and the like.
  • the amount of the acid is generally 1 to 100 mol
  • ethers e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.
  • esters e.g., ethyl acetate etc.
  • aromatic hydrocarbons e.g., benzene, toluene etc.
  • aliphatic hydrocarbons e.g., hexane etc.
  • amides e.g., ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide etc.
  • halogenated hydrocarbons e.g.,
  • the reaction temperature is generally -25 to 150°C
  • the reaction time is generally 1 to 100 hr, preferably 1 to 72 hr.
  • the product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
  • Compound (A-IV) can be produced by subjecting compound (A- V) to deprotection.
  • the deprotection can be carried out by treating compound (A-V) with tetrabutylammonium fluoride in a solvent inert to the reaction.
  • the amount of the tetrabutylammonium fluoride to be used is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A-V) .
  • ethers e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.
  • esters e.g., ethyl acetate etc.
  • aromatic hydrocarbons e.g., benzene, toluene etc.
  • aliphatic hydrocarbons e.g., hexa eetc.
  • halogenated hydrocarbons e.g., dichloromethane
  • the reaction temperature is generally -25 to 1 " 00°C,
  • the reaction time is generally 1 to 72 hr, preferably 1 to 18 hr.
  • the product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
  • Compound (A-III) can be produced by subjecting compound (A- IV) to oxidation.
  • the oxidation can be carried out using dimethyl sufoxide in the presence of an activating agent and a base.
  • the amount of the dimethyl sufoxide to be used is generally 1 to 300 mol, preferably 1 to 100 mol, per 1 mol of compound (A- IV). '
  • activating agent examples include pyridine-sulfur trioxide complex, acetic anhydride, . oxalyl chloride and the like.
  • the amount of the activating agent to be used is generally 0.1 to 50 mol, preferably 0.1 to 10 mol, per 1 mol of the
  • dimethyl sufoxide examples include tertially amine such as triethylamine, trimethylamine, pyridine and the like.
  • the amount of the base to be used is generally 1 to 50 mol, preferably 1 to 10 mol, per 1 mol of compound (A-IV) .
  • This reaction can be carried out in dimethyl sufoxide.
  • the oxidation can be also carried out using Dess-Martin agent in a solvent inert to the reaction.
  • Dess-Martin agent examples include Dess-Martin periodinane and the like.
  • the amount of the Dess-Martin agent to be used is generally the amount of the Dess-Martin agent to be used.
  • This reaction can be carried out in a solvent inert to the reaction.
  • halogenated hydrocarbons e.g., dichloromethane, chloroform, carbon
  • tetrachloride 1, 2-dichloroethane etc.
  • ethers e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.
  • esters e.g., ethyl acetate etc.
  • acetonitrile and mixtures of two or more kinds thereof.
  • the reaction temperature is generally -100 to 100°C, preferably -78 to 50°C.
  • the reaction time is generally 1 to 72 hr, preferably 1 to 18 hr.
  • the product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to . separation means such as washing, recrystallization, distillation, chromatography and the like.
  • Compound (A-II) can be produced by subjecting compound (A- III) to chlorovinylation or bromovinylation or iodovinylation.
  • the chlorovinylation or bromovinylation or iodovinylation can be carried out using a chlorovinylating agent, a
  • Examples of the vinyl chlorovinylating agent include chloroform in the presence of chromium(II) chloride, examples of the bromovinylating agent include bromoform in the presence of chromium (II) chloride, and examples of the iodovinylating agent include iodoform in the presence of chromium (II) chloride.
  • the amount of the chlorovinylating agent, bromovinylating agent or iodovinylating, agent to be used is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A-III) .
  • solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.), esters (e.g., ethyl acetate etc.), aromatic hydrocarbons (e.g., benzene, toluene etc.), aliphatic hydrocarbons (e.g., hexane etc.) and mixtures of two or more kinds thereof.
  • ethers e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.
  • esters e.g., ethyl acetate etc.
  • aromatic hydrocarbons e.g., benzene, toluene etc.
  • aliphatic hydrocarbons e.g., hexane etc.
  • the reaction temperature is generally -100 to 100°C, preferably -20 to 50°C.
  • the reaction time is generally 1 to 72 hr, preferably 1 to 18 hr.
  • the product is obtained as a single compound .or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
  • Compound (A-I) can be produced by subjecting compound (A- II) to a coupling reaction with compound (C-I) .
  • Compound (C-I) may be a commercially available product, or can be produced according to a method known per se or a method analogous thereto.
  • the amount of compound (C-I) to be used is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A-II) .
  • the coupling reaction can be carried out in the presence of a metal catalyst and a base in a solvent inert to the reaction.
  • the catalyst examples include a palladium compound [e.g., palladium(II) acetate, tetrakis (triphenylphosphine) palladium (0 ) , dichlorobis (triphenylphosphine) palladium (II) ,
  • a palladium compound e.g., palladium(II) acetate, tetrakis (triphenylphosphine) palladium (0 ) , dichlorobis (triphenylphosphine) palladium (II) ,
  • the amount of the catalyst to be used is generally 0.0001 - 1.0 mol, preferably 0.01 to 0.1 mol, per 1 mol of compound (A- II) .
  • the metal catalyst can be used together with a phosphine ligand.
  • phosphine ligand examples include triphenylphosphine, 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, tri-tert- butylphosphine and the like.
  • the amount of the phosphine ligand to be used is generally
  • Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium
  • the amount of the base to be used is generally 1 to 50, mol, preferably 1 to 10 mol, per 1 mol of compound (A-II) .
  • ethers e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.
  • esters e.g., ethyl acetate etc.
  • aromatic hydrocarbons e.g., " benzene, toluene etc.
  • aliphatic hydrocarbons e.g., hexane etc.
  • amides e.g., N, -dimethylformamide, ⁇ ,. ⁇ - dimethylacetamide etc.
  • halogenated hydrocarbons e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.
  • mixtures of two or more kinds thereof e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.
  • the reaction temperature is generally -20 to 200°C, preferably 0 to 150°C.
  • the reaction time is generally 1 to 72 hr, preferably 1 to 18 hr.
  • the product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
  • Compound (Int) can be produced by subjecting compound (A-I) to deprotection.
  • the deprotection can be carried out by treating compound (A-I) with an alkali.
  • alkali to be used examples include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide,
  • the amount of the alkali or acid to be used is generally 0.01 to 500 mol, preferably 0.1 to 100 mol, per 1 mol of compound (A-I).
  • This reaction is generally carried out in a solvent inert to the reaction.
  • ethers e.g., methanol, ethanol, propanol etc.
  • hydrocarbons e.g., benzene, toluene, cyclohexane, hexane etc.
  • halogenated hydrocarbons e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.
  • ethers e.g., diethyl ether
  • reaction temperature is generally 0 to 200°C
  • the reaction time is generally 1 to 200 hr, preferably 1 to 72 hr.
  • the deprotection can also be carried out by treating compound (A-I) with an acid.
  • Examples of the acid to be used include organic or
  • inorganic acid such as hydrochloric acid, sulfonic acid, formic acid, acetic acid, trifluoroacetic acid and the like.
  • the amount of the acid to be used is generally 0.01 to 500 mol, preferably 0.1 to 100 mol, per 1 mol of compound (A-I).
  • This reaction is generally carried out in a solvent inert to the reaction.
  • ethers e.g., methanol, ethanol, propanol etc .
  • hydrocarbons e.g., benzene, toluene, cyclohexane, hexane etc.
  • halogenated hydrocarbons e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.
  • ethers e.g., diethyl ⁇ ether
  • the reaction temperature is generally 0 to 200°C
  • the reaction time is generally.1 to 200 hr, preferably 1 to 72 hr.
  • the deprotection can also be carried out by subjecting compound (A- I) to hydrogenation .
  • the hydrogenation can be carried out using hydrogen or a hydrogen donating agent (e.g., cyclohexadiene) in the presence ⁇ of a catalyst (e.g., palladium, palladium hydroxide, platinum etc. ) .
  • a hydrogen donating agent e.g., cyclohexadiene
  • a catalyst e.g., palladium, palladium hydroxide, platinum etc.
  • the amount of the catalyst be used is generally 0.001 to 10 mol, preferably 0.01 to 1 mol, per 1 mol of compound (A-I). This reaction is generally carried out in a solvent inert to the reaction.
  • ethers e.g., methanol, ethanol, propanol etc.
  • hydrocarbons e.g., benzene, toluene, cyclohexane, hexane etc.
  • halogenated hydrocarbons e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.
  • ethers e.g., diethyl ether
  • the reaction temperature is generally 0 to 200°C
  • the reaction time is generally 1 to 200 hr, preferably 1 to 72 hr.
  • the product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
  • Compound (I) can be produced by reacting the reactive derivative of compound (Irit) with compound (D-I) .
  • Examples of the reactive derivative of compound (Int) include acid halides such as acid chlorides, acid bromides and the like; acid amides with pyrazole, imidazole, benzotriazole and the like; mixed acid anhydrides with as acetic acid, propionic acid, butyric acid and the like; acid azides;
  • activated esters such as diethoxyphosphate ester
  • diphenoxyphosphate ester diphenoxyphosphate ester, p-nitrophenyl ester, 2, 4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, ester with INK hydroxysuccinimide, ester with N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole, ester with 6-chloro-l- hydroxybenzotriazole, ester with l-hydroxy-lH-2-pyridone, and the like; activated thioesters such as 2-pyridyl thioester, 2- benzothiazolyl thioester and the like, and the like.
  • compound (I) can also be produced by directly reacting compound (Int) with compound (D-I) in the presence of a condensing agent, instead of using the reactive derivative .
  • the condensing agent examples include N, N ' -disubstituted carbodiimides such as ⁇ , ⁇ ' -dicyclohexylcarbodiimide, l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) hydrochloride and the like; azolides such as N, N ' -carbonyldiimidazole and the like; dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-l, 2- dihydroquinoline, phosphorus oxychloride, alkoxyacetylene and the like; 2-halogenopyridiniums such as 2-chloromethylpyridinium iodide, 2-fluoro-l-methylpyridinium iodide and the like;
  • phosphorylcyanides such as diethylphosphorylcyanide and the like; 2- (7-azabenzotriazol-l-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU) , 0- (7-azabenzotriazol-l-yl) - ⁇ , ⁇ , ⁇ ' , ⁇ ' -tetramethyluronium tetrafluoroborate (TATU) and the like, as well as resin-supported condensing agents such as crosslinked polystyrene-supported 2-alkoxy-l-alkoxycarbonyl-l, 2-dihydroquinone, crosslinked polystyrene-supported DCC (PS-DCC) and the like.
  • PS-DCC crosslinked polystyrene-supported DCC
  • Compound (D-I) may be a commercially available product, or can be produced according to a method known per se or a method analogous thereto.
  • the amount of compound (D-I) to be used is generally about 0.8 to 5 mol per 1 mol of compound (Int).
  • This reaction is preferably carried out in the presence of a base.
  • Examples of the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate and the like, and organic amines such as triethylamine, pyridine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and the like.
  • the amount of the base to be used is generally 0.5 to 20 mol, preferably 0.8 to 10 mol, per 1 mol of compound (Int).
  • This reaction can be carried out in a solvent inert to the reaction.
  • ethers e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.
  • esters e.g., ethyl acetate etc.
  • aromatic hydrocarbons e.g., benzene, toluene etc.
  • aliphatic hydrocarbons e.g., hexane etc.
  • amides e.g., N, N-dimethylformamide, N,N- dimethylacetamide etc.
  • halogenated hydrocarbons e.g.,
  • the reaction temperature is generally 0 to 200°C
  • the reaction time is generally 1 to 200 hr, preferably 1 to 72 hr.
  • Compound (I) can be isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
  • Compound (I) wherein R 3 is -S (0) -R 30 ' or -S (0) 2 -R 30 ' (wherein R 30' is as defined above) can be produced by subjecting compound (I) wherein R 3 is -S-R 30 ' to oxidation.
  • the oxidation can be carried out using an oxidant in a solvent inert to the reaction.
  • oxidant examples include m-chloroperbenzoic acid and the like.
  • the amount of the oxidant to be used is generally 0.5 to
  • ethers e.g., diethyl ether, tetrahydrofuran, 1 , 2-dimethoxyethane etc.
  • esters e.g., ethyl acetate etc.
  • aromatic hydrocarbons e.g., benzene, toluene etc.
  • aliphatic hydrocarbons e.g., hexane etc.
  • amides e.g., N,N-dimethylformamide, N,N- dimethylacetamide etc.
  • halogenated hydrocarbons e.g.,
  • the reaction temperature is generally -20 to 200°C
  • the reaction time is generally 1 to 200 hr, preferably 1 to 72 hr.
  • Compound (I) wherein R is -OH, -SH or -NH 2 can be produced by subjecting compound (I) wherein R 3 is -O-P 2 , -S-P 3 or -NH-P 4 (wherein P 2 is as defined above, P 3 is a sulfanyl-protecting group, and P 4 is an amino-protecting group) to deprotection.
  • Examples of the sulfanyl-protecting group for P 3 include a i- ⁇ alkyl group, a .phenyl group, a trityl group, a C 7 -io aralkyl group (e.g., benzyl), a Ci-6 alkyl-carbonyl group, a benzoyl group, a C 7 -io aralkyl-carbonyl group (e.g., benzylcarbonyl), a Ci_6
  • alkoxy-carbonyl group . a C6-1 aryloxy-carbonyl group (e.g., phenyloxycarbonyl) , a C7-14 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl) , a 2- tetrahydropyranyl group, a Ci_6 alkylamino-carbonyl group (e.g., methylaminocarbonyl, ethylaminocarbonyl) and the like.
  • These protecting groups are optionally substituted by 1 to 3
  • substituents selected from a halogen atom, a Ci-6 alkyl group, a Ci-6 alkoxy group and a nitro group.
  • amino-protecting group for P 4 examples include a formyl group, a Ci-6 alkyl-carbonyl group, a Ci-6 alkoxy-carbonyl group, a benzoyl group, a C 7 _io aralkyl-carbonyl group (e.g., benzylcarbonyl), a C7-14 aralkyloxy-carbonyl group (e.g.,
  • substituted silyl group e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert- butyldiethylsilyl
  • a C 2 -6 alkenyl group e.g., 1-allyl
  • protecting groups are optionally substituted by 1 to 3 substituents selected from a halogen, atom, a- Ci_ 6 alkoxy group and a nitro group.
  • compound (I) wherein R 3 is -OH can be produced by subjecting compound (I) wherein R 3 is -0-CH 2 -phenyl to catalytic hydrogenation.
  • the catalytic hydrogenation is generally carried out in the presence of a metal catalyst under hydrogen atmosphere.
  • metal catalyst examples include palladium carbon, palladium hydroxide, platinum oxide, Raney-nickel, Raney-cobalt and the like.
  • the amount of the metal catalyst to be used is generally 0.001 to 10 mol, preferably 0.01 to 1 mol, per 1 mol of the above-mentioned compound (I) .
  • the hydrogen pressure is generally 1 to 100 atm.
  • solvent is not particularly limited as long as the reaction proceeds, examples thereof include alcohols (e.g., methanol, ethanol etc.), ethers (e.g., diethyl ether, .
  • hydrocarbons e.g., benzene, toluene etc.
  • aliphatic hydrocarbons e.g., benzene, toluene etc.
  • hydrocarbons e.g., hexane etc.
  • hydrocarbons e.g., hexane etc.
  • the reaction temperature is generally 0 to 200°C
  • the reaction time is generally 1 to 20.0 hr, preferably 1 to 72 hr.
  • Compound (I) wherein R 3 is -NRa-R 30 can also be produced by reacting compound (I) wherein R 3 is -NH-R 30 with Ra-X 1 .
  • P 2 ' is a ' hydroxyl-protecting group, and the other symbols are as defined above.
  • Examples of the "hydroxy-proteeting group" for P 2 ' include a Ci-6 alkyl group, a phenyl group, a trityl group, a C 7 _io aralkyl group (e.g., benzyl) , a formyl group, a i-e alkyl-carbonyl group, a benzoyl group, a C 7 _io aralkyl-carbonyl group (e.g.,
  • benzylcarbonyl a 2-tetrahydropyranyl group, a 2- tetrahydrofuranyl group, a substituted silyl group (e.g.,
  • trimethylsilyl triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert-butyldiethylsilyl, tert- .
  • butyldiphenylsilyl , a C 2 -6 alkenyl group (e.g., 1-allyl) and the like.
  • These protecting-groups are optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci_6 alkyl group, a Ci-6 alkoxy group and a nitro group.
  • P 2 ' is preferably a C 7 _i 0 aralkyl group optionally substituted by a Ci_ 5 alkoxy group, more preferably p-methoxybenzyl .
  • Compound (A-XIV) can be produced by subjecting compound (A-
  • the reduction can be carried out by reacting compound (A-V) with a reducing agent in a solvent inert to the reaction.
  • Examples of the reducing agent include lithium aluminum hydride, sodium aluminum hydride, sodium bis (2- methoxyethoxy) aluminum hydride, diisobutylaluminum hydride and the like.
  • the amount of the reducing agent is generally 0.5 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (A-V) .
  • solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc . ) , aromatic hydrocarbons (e.g., benzene, toluene etc.), aliphatic hydrocarbons (e.g., hexane etc.) and mixtures of two or more -kinds thereof.
  • ethers e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc .
  • aromatic hydrocarbons e.g., benzene, toluene etc.
  • aliphatic hydrocarbons e.g., hexane etc.
  • the reaction temperature is generally -25 to 100°C
  • the reaction time is generally 0.5 to 120 hr, preferably 1 to 18 hr.
  • the product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
  • Compound (A-XITI) can be produced by subjecting compound (A-XIV) to protection.
  • the protection can be carried out by reacting compound (A- XIV) with a hydroxyl-protecting agent in a solvent inert to the reaction.
  • hydroxyl-protecting agent examples include p- methoxybenzyl chloride, p-methoxybenzyl bromide, p-methoxybenzyl iodide, p-methoxybenzyl trichloroacetimidate and the like.
  • the amount of the hydroxyl-protecting agent is generally 1 to 100 mol, preferably 1 to 3 mol, per 1 mol of compound (A-XIV) .
  • reaction can be carried out in the presence of a base.
  • Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium
  • metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert- butoxide and the like
  • metal hydrides such as sodium hydride, potassium hydride and the like
  • organic amines such as triethylamine, pyridine, diisopropylethylamine, 1,8- diazabicyclo [5.4.0] undec-7-ene and the like.
  • the amount of the base is generally 1 to 100 mol
  • reaction can be carried out in the presence of an acid.
  • Examples of the acid include pyridinium p-toluenesulfonate, toluenesulfonic acid and the like.
  • the amount of the acid is generally 1 to 100 mol
  • ethers e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.
  • esters e.g., ethyl acetate etc.
  • aromatic hydrocarbons e.g., benzene, toluene etc.
  • aliphatic hydrocarbons e.g., hexane etc.
  • amides e.g., N, N-dimethylformamide, N,N- dimethylacetamide etc.
  • halogenated . hydrocarbons e.g., dichloromethane, chloroform, carbon . tetrachloride, 1,2- dichloroethane etc.
  • mixtures of two or more kinds thereof e.g., dichloromethane, chloroform, carbon . tetrachloride, 1,2- dichloroethane etc.
  • the reaction temperature is generally -25 to 100°C, preferably 0 to 25°C.
  • the reaction time is generally 0.5 to 120 hr, preferably 1 to 18 hr.
  • the product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
  • Compound (A-XII) can be produced by subjecting compound (A-
  • the reaction can be carried out according to the method similar to Step 2.
  • Compound (A-XI) can be produced by subjecting compound (A- XII) to oxidation.
  • the reaction can be carried out according to the method similar to Step 3.
  • Compound (A-X) can be produced by subjecting compound (A- XI) to chlorovinylation or bromovinylation or iodovinylation .
  • the reaction can be carried out according to the method similar to Step 4.
  • Compound (A-IX) can be produced by subjecting compound (A- X) to deprotection.
  • the deprotection can be carried out by treating compound (A-X) with 2, 3-dichloro-5, 6-dicyano-p-benzoquinone in a solvent inert to the reaction.
  • the amount of the 2, 3-dichloro-5, 6-dicyano-p-benzoquinone is. generally 1 to 100 mol, preferably 1 to 3. mol, per 1 mol of compound (A-X) .
  • ethers e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.
  • esters e.g., ethyl acetate etc.
  • aromatic hydrocarbons e.g., benzene, toluene etc.
  • aliphatic hydrocarbons e.g., hexane etc.
  • amides e.g., N, N-dimethylformamide, N,N- dimethylacetamide etc.
  • halogenated hydrocarbons e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.
  • mixtures of two or more kinds thereof e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.
  • the reaction temperature is generally -25 to 100°C, preferably 0 to 25°C.
  • the reaction time is generally 0.5 to 120 hr, preferably 1 to 18- hr.
  • the product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
  • Compound (A-VIII) can be produced by subjecting compound (A-IX) to a coupling reaction with compound (C-I) .
  • the reaction can be carried out according to the method similar to .Step 5.
  • Step 15 and Step 16 Compound (A-VII) can be produced by subjecting compound (A- VIII) to oxidation.
  • Compound (Int) can be produced by subjecting compound (A-
  • the oxidation can be carried out by oxidizing compound (A-
  • the oxidation of compound ' (A-VII) to compound (Int) can be carried out using 2-methyl-2-butene, NaC10 2 , and NaH 2 P0 4 in tert- BuOH.
  • the amount of the 2-methyl-2-butene is generally 1 to 100 mol, preferably 10 to 30 mol, per 1 mol of compound (A-VII) .
  • the amount of the NaC10 2 is generally 1 to 100 mol, preferably 1 to 3 mol, per 1 mol of compound (A-VII).
  • the amount of the Na3 ⁇ 4P0 4 is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A-VII).
  • the reaction temperature is generally -25 to 100°C
  • the reaction time is generally 0.5 to 120 hr, preferably 1 to 18 hr.
  • the product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
  • protecting group generally used in peptide chemistry and the like may be introduced into these groups. By removing the protecting group as necessary after the reaction, the objective compound can be -obtained.
  • amino-protecting group examples include those exemplified for P 4 .
  • Examples of the carboxy-protecting group include those exemplified for P 1 . ⁇
  • hydroxy-protecting group examples include those exemplified for P 2 or P 2 ' .
  • Examples of the protected carbonyl group include a cyclic acetal (e.g., 1, 3-dioxane) , an acyclic acetal (e.g., di-Ci- 6 alkyl acetal) and the like.
  • a cyclic acetal e.g., 1, 3-dioxane
  • an acyclic acetal e.g., di-Ci- 6 alkyl acetal
  • Examples of the sulfanyl-protecting group include those exemplified for P 3 .
  • Examples of the method for removing the above-mentioned protecting group include a method known per se, for example, the method described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980) and the like. Specifically, a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, a reduction method and the like.
  • Compound (I) obtained by each of the above-mentioned production methods can be isolated and purified by a known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.
  • Each starting compound obtained by each of the above-mentioned production methods can be isolated and purified by a known means similar to those mentioned above. In addition, these starting compounds may be used without isolation as a reaction mixture and as a starting material of the next reaction.
  • Compound (I) shows low toxicity and can be used as an agent for the prophylaxis or treatment of various diseases to be mentioned later for mammals (e.g., humans, mice, rats, rabbits, dogs, cats, bovines, horses, pigs, monkeys) as they are or by admixing with a pharmacologically acceptable carrier and the like to give a pharmaceutical composition.
  • mammals e.g., humans, mice, rats, rabbits, dogs, cats, bovines, horses, pigs, monkeys
  • organic or inorganic carriers conventionally used as materials for pharmaceutical preparations are used as a pharmacologically acceptable carrier, which are added as excipient, lubricant, binder and disintegrant for solid- preparations; solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid
  • compositions preparations, and the like.
  • an additive for pharmaceutical preparations such as preservative, antioxidant, colorant, sweetening agent and the like can be used.
  • excipient examples include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, microcrystalline cellulose, low-substituted
  • hydroxypropyl cellulose sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate and magnesium aluminate metasilicate .
  • Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.
  • binder examples include pregelatinized starch, saccharose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose,
  • microcrystalline cellulose sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low- substituted hydroxypropyl cellulose.
  • physiological saline physiological saline
  • Ringer's solution alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.
  • solubilizing agent examples include
  • suspending agent examples include
  • surfactants such as stearyltriethanolamine, sodium lauryl
  • hydrophilic polymers such as polyvinyl alcohol,
  • methylcellulose ⁇ hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like; polysorbates;
  • Preferred examples of the isotonicity agent include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose.
  • buffers such as phosphates, acetates, carbonates and citrates.
  • Preferred examples of the soothing agent include benzyl alcohol.
  • Preferred examples of the preservative include p- hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl
  • the antioxidant include sulfites and ascorbates.
  • the colorant include water-soluble edible tar pigments (e.g., foodcolors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like), water insoluble lake pigments (e.g.,
  • sweetening agent examples include
  • saccharin sodium dipotassium glycyrrhizinate, aspartame and stevia.
  • the pharmaceutical composition containing compound (I) can be safely administered solely or by mixing with a
  • pharmacologically acceptable carrier according to a method known per se as a production method of a pharmaceutical preparation, and in the form of, for example, tablet, pill, powder, granule, capsule, 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 preparation
  • ointment lotion, adhesive preparation
  • suppository e.g., rectal suppository, vaginal suppository
  • the pharmaceutical composition can be produced by a method conventionally used in the technical field of pharmaceutical preparation, for example, the method described in the Japanese Pharmacopoeia and the like.
  • compound (I), and the like it is, for example, about 0.1 to 100 wt%.
  • the compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity and the like) and a few side effects. Therefore, it can be used as an agent for the prophylaxis or treatment or a diagnostic of
  • various diseases in a mammal e.g., human, bovine, horse, dog, cat, monkey, mouse, rat
  • a mammal e.g., human, bovine, horse, dog, cat, monkey, mouse, rat
  • a mammal e.g., human, bovine, horse, dog, cat, monkey, mouse, rat
  • a mammal e.g., human, bovine, horse, dog, cat, monkey, mouse, rat
  • compound (I) has a tyrosine kinase inhibitory action on Trk receptors such as TrkA, TrkB, TrkC or other tyrosine kinase receptors such as Flt-3. It is useful as an agent for the prophylaxis or treatment of proliferative diseases
  • kinase signaling pathway such as tumor or cancer (e.g., prostate cancer, breast cancer, thyroid cancer, colon cancer, malignant melanomas, lung cancer, glioblastomas,
  • tumor or cancer e.g., prostate cancer, breast cancer, thyroid cancer, colon cancer, malignant melanomas, lung cancer, glioblastomas,
  • pancreatic cancer pancreatic cancer
  • fibrotic diseases restenosis associated with angioplasty
  • polycystic kidney disease aberrant
  • angiogenesis disease tuberous sclerosis complex, hair loss, and Alzheimer's disease.
  • the dose of compound (I) can be appropriately selected according to the subject of administration, administration route, target disease, symptom and the like.
  • the dose of compound (I) for oral administration to an adult patient with diabetes, obesity, dyslipidemia, steatohepatitis, cachexia, or muscular atrophy is generally about 0.001 - 50 mg/kg body weight . , preferably about 0.01 - 45 mg/kg body weight, more preferably about 0.1 - 2 mg/kg, as a single dose of the active ingredient "compound (I)". This amount is desirably administered 1-3 times per day.
  • compound (I) can be used in combination with a drug other than compound ( I ) .
  • Examples of the drug that can be used in combination with the compound (I) (hereinafter sometimes to be abbreviated as concomitant drug) hormonal therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, medicaments inhibiting the action of cell growth factors or cell growth factor receptors and the like.
  • hormone therapeutic agents examples include fosfestrol, diethylstylbestrol, chlorotrianisene,
  • medroxyprogesterone acetate megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti- estrogens (e.g., tamoxifen citrate, toremifene citrate), pill preparations, mepitiostane, testrolactone, aminoglutethimide,
  • LH-RH agonists e.g., goserelin acetate, buserelin, leuprorelin
  • droloxifene e.g., droloxifene
  • epitiostanol e.g., ethinylestradiol sulfonate
  • aromatase inhibitors e.g., fadrozole hydrochloride, anastrozole,
  • retrozole exemestane, vorozole, ⁇ formestane
  • anti-androgens e.g., flutamide, bicartamide, . nilutamide
  • aderenal cortex hormone drugs e.g., dexamethasone, prednisolone, betamethasone, triamcinolone
  • androgen synthesis inhibitors e.g., finasteride, epristeride
  • abiraterone retinoid and drugs that retard retinoid metabolism (e.g., liarozole) , and the like.
  • chemotherapeutic agents examples include:
  • alkylating agents antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and the like.
  • alkylating agents examples include nitrogen
  • streptozocin pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide,
  • zinostatin stimalamer adozelesin, cystemustine, bizelesin, DDS preparations thereof, and the like.
  • antimetabolites examples include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine
  • 5-FU drugs e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emitefur, capecitabine
  • aminopterine e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emitefur, capecitabine
  • aminopterine nelzarabine
  • leucovorin calcium tabloid, butocine, calcium folinate, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin
  • 5-FU drugs e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emitefur, capecitabine
  • aminopterine nelzarabine
  • leucovorin calcium tabloid, butocine, calcium folinate, le
  • piritrexim piritrexim, idoxuridine, mitoguazone, thiazophrine, ambamustine, bendamustine, DDS preparations thereof, and the like.
  • anticancer antibiotics examples include
  • actinomycin-D 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, sarcomycin,
  • plant-derived anticancer agents include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, DDS preparations thereof, and the like.
  • immunotherapeutic agents examples include:
  • Biological Response Modifiers e.g., picibanil, krestin, sizofiran, lentinan, ubenimex, interferons, interleukins, macrophage colony-stimulating factor, granulocyte colony- stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole,. polysaccharide K,
  • procodazole anti-CTLA4 antibody
  • anti-CTLA4 antibody anti-CTLA4 antibody
  • Example of the "cell growth factors” of the “medicaments inhibiting the action of cell growth factors or cell growth factor receptors” include any substances that promote cell proliferation, which are normally peptides having not more than 20,000 molecular weight that are capable of exhibiting their activity at low concentrations by binding to a receptor, including
  • EGF epidermal growth factor
  • TGFa tumor necrosis factor
  • insulin or substances possessing substantially the same activity as insulin e.g;, insulin, IGF (insulin-like growth . factor) -1, IGF-2] ,
  • FGF fibroblast growth factor
  • substances possessing substantially the same activity as FGF e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10] , and
  • CSF colony stimulating factor
  • EPO erythropoietin
  • IL-2 interleukin-2
  • NGF nerve growth factor
  • PDGF platelet-derived growth factor
  • GF transforming growth factor ⁇
  • HGF hepatocyte growth factor
  • VEGF vascular endothelial growth factor
  • angiopoietin angiopoietin, and the like] .
  • Examples of the "cell growth factor receptors” include any receptors capable of binding to the aforementioned cell growth factors, including 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.
  • EGF receptor e.g., HER3
  • insulin receptor e.g., IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2
  • VEGF receptor e.g., angiopoietin receptor (e.g., Tie2)
  • PDGF receptor e.g., PDGF receptor, and the like.
  • EGF inhibitor As the “medicaments inhibiting the action of cell growth factors or cell growth factor receptors", EGF inhibitor, TGFa inhibitor, heregulin inhibitor, insulin inhibitor, IGF inhibitor,
  • FGF inhibitor KGF inhibitor, CSF inhibitor, EPO inhibitor, IL-2 »
  • NGF 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
  • Raf inhibitor Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src inhibitor, PKC inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1/2)
  • anti-VEGF antibody e.g., Bevacizumab
  • anti-HER2 anti-HER2
  • anti-EGFR antibody e.g., Cetuximab, Panitumumab, Matuzumab, Nimotuzumab
  • anti- VEGFR antibody Imatinib, Erlotinib, Gefit.inib, Sorafenib
  • Temsirolimus, Everolimus, Enzastaurin N-[4-[4-(4- methylpiperazin-l-yl) -6- (3-methyl-lH-pyrazol-5- ylamino) pyrimidin-2-ylsulfanyl] phenyl] cyclopropanecarboxamide
  • decitabine bortezomib
  • antitumor antibody e.g., anti-CD20 antibody
  • toxin labeled antibody and the like can also be used.
  • the administration time of compound (I) and the concomitant drug is not restricted, and these can be administered to an administration subject simultaneously, or may be administered in a staggered manner.
  • the administration mode is not particularly limited, and compound (I) and the concomitant drug only need to be combined. Examples
  • the indication of "Buch” means use of Buch sepacore preparative chromatography system (produced by Buch) , and one or several columns selected from cartridge columns Si6M-12x75mm, 12xl50mm, 40x75mm and 40xl50mm produced by the same manufacturer were used depending on the amount of sample.
  • the indication of "Purif” means use of Moritex Purif preparative chromatography system (produced by Moritex) , and one or several columns selected from cartridge columns 20, 35, 60,.200 and 400 produced by the same manufacturer were used depending on the amount of sample.
  • Silica gel 60N spherical shape, neutral, 40 to 100 um, produced by Kanto Chemicals
  • PTLC thin layer chromatography
  • LCMS liquid chromatography-mass spectrometry
  • ESI electrospray ionization
  • a liquid chromatography apparatus an apparatus produced by waters was used.
  • a separation column Develosil C30-UG-5 (50 x 4.6 mm, Nomura Kagaku Co., Ltd.) was used.
  • elution condition means that measurement was performed by elution with a linear gradient of 5 to 100% .
  • (v/v) Solution B from 0 minute to 5 minutes and then with 100% Solution B until 6 minutes.
  • the indication "B" for elution condition means that measurement was performed by elution with 30% (v/v) Solution B from 0 minute to 5 minute and then with 100% (v/v) Solution B until 6 minutes.
  • Tetrabutylammonium fluoride (1 M in THF, 2.3 mL, 2.30 mmol) was added to a solution of tert-butyl ( (2- ( ( ( - methoxybenzyl) oxy) methyl) -2- ( (methoxymethoxy) methyl) cyclopropyl)methoxy) diphenylsilane (609 mg, 1.14 mmol) in THF (3.0 mL) . After stirred at room
  • Dess-Martin periodinane (590 mg, 1.39 mmol) was added to a solution of (2- (( (4-methoxybenzyl) oxy) methyl) -2- ( (methoxymethoxy) methyl) cyclopropyl) methanol (344 mg, 1.16 mmol) in CH 2 C1 2 (10 mL) at 0°C under Ar atmosphere .. After stirred at room temperature for 2 h, the reaction mixture was poured into sat. aq. NaHC0 3 , and the organic substances were extracted with CHCI 3 . The organic layer was dried over Na 2 S0 4 , and concentrated in vacuo.
  • Dess-Martin periodinane (1.2 eq.) was added to a solution of compound (A-VIII) (0.625 mmol) and pyridine (1.0 mL) in CH 2 C1 2 (6.0 mL) at 0°C under Ar atmosphere. After stirring at room temperature for 2 h, the reaction mixture was poured into sat. aq. NaHC0 3 and sat. aq. Na 2 S 2 0 3 , and the organic substances were extracted with CHC1 3 . The organic layer was washed with brine, dried over anhydrous Na 2 S0 4 , concentrated in vacuo to give the corresponding compound (A-VII) .

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Abstract

The invention provides compound (I): wherein each symbol is as defined in the specification, having a tyrosine kinase inhibitory action on Trk receptors such as TrkA, TrkB, TrkC or other tyrosine kinase receptors such as Flt-3, which is useful for the prophylaxis or treatment of proliferative diseases associated with kinase signaling pathway such as tumor or cancer, fibrotic diseases, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, tuberous sclerosis complex, hair loss, and Alzheimer's disease.

Description

DESCRIPTION
KINASE INHIBITORS CONTAINING CYCLOPROPANE SKELETON
Field of the Invention
[0001]
The present invention relates to novel compound's having a tyrosine kinase inhibitory action, which is useful for the prophylaxis or treatment of proliferative diseases associated with kinase signaling pathway such as tumor or cancer, fibrotic diseases, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, tuberous
sclerosis complex, hair loss, and Alzheimer's disease.
Background of the Invention
[0002]
Tropomysosin Related kinases (Trk) are a family of receptor tyrosine kinases composed of three family members, TrkA, - TrkB and TrkC. The Trks bind with high affinity to, and mediate the signal transduction induced by the Neurotrophin family of ligands whose prototype members are Nerve Growth Factor (NGF) , Brain-Derived Neurotrophic Factor (BDNF) and Neurotrophin-3, -4 and -5 (NT-3, NT-4 and NT-5) . In addition, a co-receptor lacking enzymatic activity, p75, has been identified which binds all neurotrophines (NTs) with low affinity and regulates
neurotrophin signaling. A critical role of the Trks and their ligands during the development of the central and peripheral nervous systems have been established through gene disruption studies in mice. In particular, TrkA-NGF interaction was shown as a requirement for the survival of certain peripheral neuron populations involved in mediating pain signaling. In addition of these developmental consequences of Trk signaling, the subversion of this receptor and its signaling pathway in certain malignancies has also been documented. Of particular note are reports of aberrant, expression of NGF and TrkA receptor kinase are implicated in the development and progression of human prostatic carcinoma and pancreatic ductal adrenocarcinoma and activating chromosomal rearrangements of Trks in acute
myelogenous leukemia (AML) ,. thyroid and breast cancers and receptor point mutations predicted to be constitutively
activating in colon tumors. In addition to these activation mechanisems, elevated Trk receptor and ligand have also been reported in a variety of tumor types including multiple myeloma, melanoma, neuroblastoma, ovary and pancreatic carcinoma. The neurotrophines and their corresponding Trk receptor subtypes have been shown to exert a variety of pleiotropic responses on malignant cells, including enhanced tumor invasiveness and chemotaxis, activation of apoptosis, stimulation of clonal growth, and altered cell morphology. These effects have been observed in carcinomas of the prostate, breast, thyroid, colon, malignant melanomas, lung carcinomas, glioblastomas, pancreatic carcinoids and a wide variety of pediatric and neuroectodermal- derived tumors including Wilm' s tumor, neuroblastomas and medulloblastomas . Neurotrophins and their receptor subtypes have been implicated in these cancers either through autocrine or paracrine mechanisms involving carcinoma cells and the surrounding parenchymal and stromal tissues. In addition, profound or significantly attenuated reduction of bone pain caused by prostate cancer metastasis has recently been achieved by utilization of an anti-NGF antibody. Overall, the oncogenic properties of Trk signaling in multiple tumor types makes the modulation of the Trk receptor signaling a potentially
attractive therapeutic intervention point .in different
malignancies.
[0003] "
Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular tyrosine kinase domain. In general, RTKs are activated by ligand-induced oligomerization and tyrosine autophosphorylation of specific intracellular
substrates such as PLCy, PI3 kinase, ras, and raf/MEK/Erkl . Tyrosine kinase activity is an absolute requirement for signal transduction through this class of receptor.
[0004]
The Trk family of RTKs is frequently expressed in lung, breast, pancreatic and prostate cancers as well as in certain type of acute myelogenous leukemia and congenital fibrosarcoma. The tyrosine kinase activity of Trk is believed to promote the unregulated activation of cell proliferation machinery.. It is believed that inhibitors of either TrkA, TrkB, or TrkC kinases, individually or in combination, have utility against some of the most common cancers such as brain, melanoma, multiple myeloma, squamous cell, bladder, gastric, pancreatic, breast, head, neck, esophageal, prostate, colorectal, lung, renal, ovarian,
gynecological, thyroid cancer, and certain type of hematological malignancies.
[0005]
Fms-like tyrosine kinase 3 (Flt-3) is also receptor type tyrosine kinase and one of the most frequently mutated genes in acute myeloid leukemia (AML) . Besides, high levels of wild-type Flt3 have been reported for blast cells of some AML patients without Flt3 mutations. These high levels may be associated with worse prognosis.
[0006]
As compounds having a cyclopropane ring, the following compounds are known.
[0007] .
(1) Journal of the American Chemical Society (2009), 131(21), 7230-7231
[0008]
RN 1147818-18-5.
Figure imgf000004_0001
[0009]
(2) Journal of Organic Chemistry (1999), 64(1), 282-286 [0010]
RN 220368-17-2
Figure imgf000005_0001
, and
RN 220368-21-8
Figure imgf000005_0002
[0011]
(3) Journal of Organic Chemistry (1993), 58(6), 1295- [0012]
RN 148164-45-8
Figure imgf000005_0003
, and
RN 148164-44-7
OHC
HO. "R Ph [0013]
(4) Journal of Organic Chemistry (1973), 38 ( 18 ), 3140-4 [0014]
RN 40587-58-4
Figure imgf000005_0004
RN 40587-59-5
Figure imgf000006_0001
Summary of the Invention
[0015]
An object of the present invention is to provide a compound useful for the prophylaxis or treatment of proliferative diseases associated with kinase signaling pathway such as tumor or cancer, fibrotic diseases, restenosis associated" with angioplasty, polycystic kidney disease, aberrant angiogehesis disease, tuberous sclerosis complex, hair loss, and Alzheimer's disease.
[0016]
The present inventors have found for the first time that a compound represented by the formula (I) :
[0017]
Figure imgf000006_0002
[0018]
wherein
R1 and R2 are each independently hydrogen, an optionally
substituted hydrocarbon group or an optionally substituted heterocyclic group, or
R1 and R2 in combination form, together with the adjacent nitrogen atom, optionally substituted 4- to 7-membered ring, and R3 is -W21-R30,
wherein
. W21 is bond, -0-, -S(0)p- (wherein p is an integer of 0 to 2) or -NRa- (wherein Ra is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) ; and
R30 is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
R4 is an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted carbocyclyl-alkyl group or an optionally substituted
heterocyclyl-alkyl group;
the carbon atom marked with * is an asymmetric carbon atom, and the carbon atom marked with ** is an asymmetric carbon atom, or a salt thereof [hereinafter sometimes to be referred to as compound (I)] has a tyrosine kinase inhibitory action on Trk receptors such as TrkA, TrkB, TrkC or other tyrosine kinase receptors such as Flt-3, and is useful the prophylaxis or treatment of proliferative diseases associated with kinase signaling pathway such as tumor or cancer, fibrotic diseases, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, tuberous sclerosis complex, hair loss, and Alzheimer's disease. Based on this finding, the present inventors have conducted intensive studies and completed the present invention.
[0019]
Accordingly, the present invention relates to
[1] compound (I) ;
[2] compound (I) wherein R1 is optionally substituted Ci_6 alkyl, optionally substituted C3-8 cycloalkyl-Ci-3 alkyl, optionally substituted C7-13 aralkyl, optionally substituted C6-io aryl or an optionally substituted 5- or 6-membered non-aromatic
heterocyclic group, and R2 is hydrogen;
[3] compound (I) wherein R3 is -W21-R30, wherein
21 is -0-; and
R30 is hydrogen or optionally substituted Ci-10 alkyl;
[4] compound .(I) wherein R4 is optionally substituted C6-io aryl or an optionally substituted aromatic heterocyclic group;
[5] compound (I) wherein R1 is optionally substituted Ci_6 alkyl, optionally substituted C3- 8 cycloalkyl-Ci-3 alkyl, optionally substituted C7-13 aralkyl, optionally substituted C6-io aryl or an optionally substituted 5- or 6-membered non-aromatic heterocyclic group, and R2 is
hydrogen;
R3 is -W21-R30, wherein
W21 is -0-; and
R30 is hydrogen or optionally substituted Ci_io alkyl; and R4 is optionally substituted C6-io aryl or an optionally
substituted aromatic heterocyclic group;
[6] a pharmaceutical composition comprising compound (I), and a pharmaceutically acceptable carrier;
[7] the composition of the above-mentioned [6], which is an agent for the prophylaxis or treatment of proliferative disease;
[8] the composition of the above-mentioned [6], which is
tyrosine kinase inhibitor;
[9] a method for the prophylaxis or treatment of proliferative disease in a mammal, which comprises administering an effective amount of compound (I) to the mammal;
and the like.
Effect of the Invention
[0020]
Compound (I) has a tyrosine kinase inhibitory action on Trk receptors such as TrkA, TrkB, TrkC or other tyrosine kinase receptors such as Flt-3, and is useful for the prophylaxis or treatment of proliferative diseases associated with kinase signaling pathway such as tumor or cancer, fibrotic diseases, restenosis associated with angioplasty, polycystic kidney
disease, aberrant angiogenesis disease, tuberous sclerosis complex, hair loss, and Alzheimer's disease.
Detailed Description of the Invention
[0021]
The definition of each symbol in the formula (I) is
described in detail in the following.
[0022] The "halogen" in the present specification means, unless otherwise specified, fluorine, chlorine, bromine or iodine.
[0023]
The "hydrocarbon group" of the "optionally substituted hydrocarbon group" in the present specification means, unless otherwise specified, Ci-io alkyl, C2-io alkenyl, C2-io alkynyl, C3-10 cycloalkyl, C3-i0 cycloalkenyl, C4-10 cycloalkadienyl, C6_14 aryl, C7-13 aralkyl, Cg-13 arylalkenyl or the like.
[0024]
The Ci-10 alkyl in the present specification means, unless otherwise specified, 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, 2-ethylbutyl, heptyl, octyl, nonyl, decyl or the like. Among them, Ci-6 alkyl is preferable, and C1-3 alkyl is more preferable.
[0025]
The Ci-6 alkyl in the present specification means, unless otherwise specified, 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, 2-ethylbutyl or the like.
[0025]
The Ci-3 alkyl in the present specification means, unless otherwise specified, methyl, ethyl, propyl, isopropyl or the like.
[0027]
The C2-10 alkenyl in the present specification means, unless otherwise specified, ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3- pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl or the like. Among them, 2-6 alkenyl is preferable.
[0028] The.C2-6 alkenyl in the present specification means, unless otherwise specified, ethenyl, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl,
1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3- pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl or the like.
[0029] . . ..
The C2-10 alkynyl in the present specification means, unless otherwise specified, 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^
1-heptynyl, 1-octynyl or the like. Among them, C2-6 alkynyl is preferable .
[0030]
The C2-6 alkynyl in the present specification means, unless otherwise specified, 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 or the like.
[0031]
The C3-10 cycloalkyl in the present specification means, unless otherwise specified, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl or the like. Among them, C3-8 cycloalkyl is preferable.
[0032]
The C3-8 cycloalkyl in the present specification means, unless otherwise specified, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like.
[0033]
The C4-7 cycloalkyl in the present specification means, unless otherwise specified, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or the like.
[0034]
The C3-10 cycloalkenyl in the present specification means, unless otherwise specified, 2-cyclopenten-l-yl, 3-cyclopenten-l- yl, 2-cyclohexen-l-yl, 3-cyclohexen-l-yl or the like. Among them, C3-8 cycloalkenyl is preferable. - [0035] -
The C3_8 cycloalkenyl in the present specification means, unless otherwise specified, 2-cyclopenten-l-yl, 3-cyclopenten-l- yl, 2-cyclohexen-l-yl, 3-cyclohexen-l-yl or the like.
[0036
The C4_7 cycloalkenyl in the present specification means, unless otherwise specified, 2-cyclopenten-l-yl, 3-cyclopenten-l- yl, 2-cyclohexen-l-yl,. 3-cyclohexen-l-yl or the like.
[0037]
The C4_io cycloalkadienyl in the present specification means, unless, otherwise specified, 2, -cyclopentadien-l-yl, 2,4- cyclohexadien-l-yl, 2, 5-cyclohexadien-l-yl or the like. Among them, C4-8 cycloalkadienyl is preferable.
[0038]
The C4-8 cycloalkadienyl in the present specification means, unless otherwise specified, 2 , 4-cyclopentadien-l-yl, 2,4- cyclohexadien-l-yl, 2, 5-cyclohexadien-l-yl or the like.
- [0039]
The C4-7 cycloalkadienyl in the present specification means, unless otherwise specified, 2, 4-cyclopentadien-l-yl, 2,4- cyclohexadien-l-yl, 2, 5-cyclohexadien-l-yl or the like.
[0040]
The above-mentioned C3-10 cycloalkyl, C3-10 cycloalkenyl and
C4-10 cycloalkadienyl are each optionally fused with benzene to form a fused ring group. Examples of the fused ring group include indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like.
- [0041]
In addition, the above-mentioned C3-10 cycloalkyl, C3-10 cycloalkenyl and C4-10 cycloalkadienyl may be each a "C7-io. bridged hydrocarbon group. Examples of the C7-10 bridged hydrocarbon group include bicyclo [2.2.1] heptyl (norbornyl) ,
bicyclo [2..2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2 ] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, adamantyl and the like.
[0042] .
Moreover, the above-mentioned C3_i0 cycloalkyl, -C3-i0
cycloalkenyl and C4-10 cycloalkadienyl each optionally forms a spiro ring group together with C3-10 cycloalkane, C3_i0 cycloalkene or C4-10 cycloalkadiene . Examples of the C3-10 cycloalkane, C3-10 cycloalkene and C4-10 cycloalkadiene include rings corresponding to the above-mentioned C3-10 cycloalkyl, C3-10 cycloalkenyl and C4-10 cycloalkadienyl. Examples of the spiro ring group include spiro [4.5] decan-8-yl and the like.
[0043] '
The Cg-14 aryl group in the present specification means, unless otherwise specified, phenyl, naphthyl, anthryl,
phenanthryl, acenaphthyl, biphenylyl or the like. Among them, Ce-io aryl is preferable.
[0044]
The C6-10 aryl group in the present specification means, unless otherwise specified, phenyl, naphthyl or the like.
[0045]
The C7-13 aralkyl group in the present specification means, unless otherwise specified, benzyl, phenethyl, naphthylmethyl, biphenylylmethyl or the like.
[0046]
The Ce-13 arylalkenyl group in the present specification means, unless otherwise specified, styryl or the like.
[0047]
The "carbocyclic group" of the "optionally substituted carbocyclic group" and the "carbocyclyl" moiety of the
"optionally substituted carbocyclyl-alkyl group" in the present specification mean, unless otherwise specified, C3-10 cycloalkyl, C3-10 cycloalkenyl, C4-10 cycloalkadienyl, C6-1.4 aryl or the like.
[0048]
The "heterocyclic group" of the "optionally substituted heterocyclic group" and the "heterocyc!yl" moiety of the "optionally substituted heterocyclyl-alkyl group" in the present specification mean, unless otherwise specified, an "aromatic heterocyclic group" or a "non-aromatic heterocyclic group".
[0049]
The "alkyl" moiety of the "optionally substituted
carbocyclyl-alkyl group" and the "alkyl" moiety of the
"optionally substituted heterocyclyl-alkyl group" in the present- specification mean, unless otherwise specified, Ci-io alkyl such as 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, 2-ethylbutyl, heptyl, octyl, nonyl, decyl and the like. Among them, Ci_6 alkyl is preferable, and C1-3 alkyl is more preferable.
[0050]
The aromatic heterocyclic group in the present
specification means, unless otherwise specified, a 4- to 7- membered (preferably 5- or 6-menbered) monocyclic aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, or a fused
(bicyclic or tricyclic) aromatic heterocyclic group. Examples of the fused aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to the 4- to 7- membered monocyclic aromatic heterocyclic group and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) , a 5-membered aromatic
heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring are fused, and the like.
[0051]
Preferable examples of the aromatic heterocyclic group include
monocyclic aromatic heterocyclic groups such as furyl (e.g., 2- furyl, 3-furyl) , thienyl (e.g., 2-thienyl, 3-thienyl)., pyridyl . (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) , pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl) , , pyrazinyl (e.g., 2-pyrazinyl) , pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl) , pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl) ,
thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl) ,
isothiazolyl . (e. g. , 3-isothiazolyl, 4-isothiazolyl, 5- isothiazolyl) , oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5- oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl) , oxadiazolyl (e.g., 1, 2, 4-oxadiazol-5-yl, 1,3,4- oxadiazol-2-yl) , thiadiazolyl (e.g., 1, 3, 4-thiadiazol-2-yl) , triazolyl (e.g., 1, 2, 4-triazol-l-yl, 1, 2 , 4-triazol-3-yl, 1,2,3- triazol-l-yl, 1, 2, 3-triazol-2-yl, 1, 2 , 3-triazol-4-yl) ,
tetrazolyl (e.g., tetrazol-l-yl, tetrazol-5-yl) , triazinyl (e.g., 1, 2, 4-triazin-l-yl, 1, 2, 4-triazin-3-yl) and the like;
fused aromatic heterocyclic groups such as
quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl) , isoquinolyl (e.g., 3-isoquinolyl) , quinazolyl (e.g., 2- quinazolyl, 4-quinazolyl) , quinoxalyl (e.g., 2-quinoxalyl, 6- quinoxalyl) , benzofuranyl (e.g., 2-benzofuranyl, 3-benzofuranyl) , benzothienyl (e.g., 2-benzothienyl, 3-benzothienyl) ,
benzoxazolyl (e.g., 2-benzoxazolyl) , benzisoxazolyl (e.g., 7- benzisoxazolyl) , benzothiazolyl (e.g., 2-benzothiazolyl) ,
benzimidazolyl (e.g., benzimidazol-l-yl, benzimidazol-2-yl, benzimidazol-5-yl) , benzotriazolyl (e.g., lH-1, 2, 3-benzotriazol- 5-yl) , indolyl (e.g., indol-l-yl, indol-2-yl, indol-3-yl, indol- 5-yl) , indazolyl (e.g., lH-indazol-3-yl) , pyrrolopyrazinyl (e.g., lH-pyrrolo [2, 3-b] pyrazin-2-yl, lH-pyrrolo [2, 3-b] pyrazin-6-yl ) , imidazopyridinyl (e.g., lH-imidazo [4, 5-b] pyridin-2-yl, 1H- imidazo [4, 5-c] pyridin-2-yl, 2H-imidazo [1, 2-a]pyridin-3-yl) , thienopyridinyl (e.g., thieno [2, 3-b] pyridin-3-yl) ,
imidazopyrazinyl (e.g., lH-imidazo [4, 5-b] pyrazin-2-yl) ,
pyrazolopyridinyl (e.g., IH-pyrazolo [4, 3-c] pyridin-3-yl) ,
pyrazolothienyl (e.g., "2H-pyrazolo [3, 4-b] thiophen-2-yl) , pyrazolotriazinyl (e.g., pyrazolo [5, 1-c] [1, 2, 4] triazin-3-yl) , pyridopyridyl (e.g., pyrido [2, 3-b] pyridin-3-yl) , thienopyridyl (e.g., thieno [2, 3-b] pyridin-3-yl) and the like;
and the like.
[0052]
The non-aromatic heterocyclic group in the present
specification- means, unless otherwise specified, a 4- to 7- membered (preferably 5- or 6-menbered) monocyclic non-aromatic heterocyclic group containing, as a ring-constituting, atom besides carbon atoms, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, or a fused
(bicyclic or tricyclic) non-aromatic heterocyclic group.
Examples of the fused non-aromatic heterocyclic group include a group derived from a fused ring wherein a ring corresponding to the 4- to 7-membered monocyclic non-aromatic heterocyclic group and 1 or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine) , a 5- membered aromatic heterocycle containing one sulfur atom (e.g., thiophene) and a benzene ring are fused, a group wherein the above-mentioned group is partially saturated, and the like.
[0053]
Preferable examples of the non-aromatic heterocyclic group include
monocyclic non-aromatic heterocyclic groups such as
azetidinyl (e.g., 1- azetidinyl, 2-azetidinyl, 3-azetidinyl) , pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl) , piperidyl (e.g., piperidino, 2-piperidyl, 3-piperidyl, -piperidyl) , morpholinyl (e.g., morpholino) , thiomorpholinyl (e.g.,
thiomorpholino) , piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, 3-piperazinyl) , hexamethyleniminyl (e.g., hexamethylenimin-l-yl) , oxazolidinyl (e.g., oxazolidin-2-yl) , -thiazolidinyl (e.g., ■thiazolidin-2-yl) , imidazolidinyl (e.g., imidazolidih-2-yl, imidazolidin-3-yl) , oxazoliriyl (e.g., oxazolin-2-yl) ,
thiazolinyl (e.g., thiazolin-2-yl) , imidazolinyl (e.g., imidazolin-2-yl, imidazolin-3-yl) , dioxolyl (e.g., 1, 3-dioxol-4- yl) , . dioxolanyl (e.g., 1, 3-dioxolan-4-yl) , dihydrooxadiazolyl (e.g., 4, 5-dihydro-l, 2, 4-oxadiazol-3-yl) , pyranyl (e.g., 4- pyranyl) , tetrahydropyranyl (e.g., 2-tetrahydropyranyl, 3- tetrahydropyranyl, 4-tetrahydropyranyl) , thiopyranyl (e.g., 4- thiopyranyl) , tetrahydrothiopyranyl (e.g., 2- tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4- tetrahydrothiopyranyl) , tetrahydrofuryl (e.g., tetrahydrofuran-
3-yl, tetrahydrofuran-2-yl) , pyrazolidinyl (e.g., pyrazolidin-1- yl, pyrazolidin-3-yl) , pyrazolinyl (e . g. , pyrazolin-l-yl) , tetrahydropyrimidinyl (e.g., tetrahydropyrimidin-l-yl) ,
dihydrotriazolyl (e.g., 2, 3-dihydro-lH-l, 2, 3-triazol-l-yl) , tetrahydrotriazolyl (e.g. , 2, 3, 4, 5-tetrahydro-lH-l, 2 , 3-triazol- l-yl) and the like;
fused non-aromatic heterocyclic groups such as
dihydroindolyl (e.g., 2, 3-dihydro-lH-indol-l-yl) ,
dihydroisoindolyl (e.g., 1, 3-dihydro-2H-isoindol-2-yl) ,
dihydrobenzofuranyl (e.g., 2 , 3-dihydro-l-benzofuran-5-yl) , dihydrobenzodioxinyl (e.g.,. 2, 3-dihydro-l, 4-benzodioxinyl) , dihydrobenzodioxepinyl (e.g., 3, -dihydro-2H-l, 5- benzodioxepinyl) , tetrahydrobenzofuranyl (e.g., 4,5,6,7- tetrahydro-l-benzofuran-3-yl) , chromenyl - (e. g. , 4H-chromen-2-yl, 2H-chromen-3-yl) , dihydrochromenyl (e.g., 3, 4-dihydro-2H- chromen-2-yl) , dihydroquinolinyl (e.g., 1, 2-dihydroquinolin-4- yl) , tetrahydroquinolinyl (e.g., 1, 2, 3, -tetrahydroquinolin-4- yl) , dihydroisoquinolinyl (e.g., 1, 2-dihydroisoquinolin-4-yl) , tetrahydroisoquinolinyl (e.g., 1,2,3, 4-tetrahydroisoquinolin-4- yl) , dihydrophthalazinyl (e.g., 1, 4-dihydrophthalazin-4-yl) and the like;
and the like.
[0054]
The "4- to 7-membered ring" of the "optionally substituted
4- to 7-membered ring" in the present specification means, unless otherwise specified, benzene, C4-7 cycloalkane, C4-7 cycloalkene, C4_7 cycloalkadiene, 4- to 7-membered monocyclic aromatic heterocycle or 4- to 7-membered monocyclic non-aromatic heterocycle. Examples of the C4_7 cycloalkane, C4-7 cycloalkene and C4-7 cycloalkadiene include rings corresponding to the above- mentioned C4-7 cycloalkyl, C4-7 cycloalkenyl and C4-7
cycloalkadienyl . Examples of the 4- to .7-membered 'monocyclic aromatic heterocycle and 4- to 7-membered monocyclic non- aromatic heterocycle include rings corresponding to the above- mentioned 4- to 7-membered monocyclic aromatic heterocyclic group and 4- to 7-membered monocyclic non-aromatic heterocyclic group.
[0055]
. The "alkylene" of the "optionally substituted alkylene" in the present specification means, unless otherwise specified, a linear or branched alkylene having 1 to 10 carbon atoms,
preferably 1 to 6 carbon atoms. Examples of the alkylene include methylene '(-(¾-) , ethylene (-CH2CH2-.) , methylmethylene (- CH(CH3)-), 1,2-propylene (-CH2CH (CH3) -) , 1, 3-propylene (-CH2CH2CH2- ) , 1,2-butylene (-CH2CH (CH2CH3) -) , 1,3-butylene (-CH2CH2CH (CH3) -) , 1,4-butylene (-CH2CH2CH2CH2-) , 2-methyltetramethylene (- CH2CH(CH3)CH2CH2-) , pentamethylene (-CH2CH2CH2CH2CH2-) and the like.
[0056]
The hydrocarbon group (including carbocyclyl moiety and alkyl moiety) , heterocyclic group (including heterbcyclyl moiety), 4- to 7-membered ring, and alkylene optionally have substituents (preferably 1 to 7, more preferably 1 to 5, still more preferably 1 to 3) selected from the following Subsutituent A at substitutable positions.
[0057]
[Subsutituent A]
C1-6 alkyl, C2_6 alkenyl, C2-e alkynyl, C3_s cycloalkyl, C3-g
cycloalkenyl, C4-8 cycloalkadienyl, C6-14 aryl, C7_i3 aralkyl, C6-i4 aryl—C2-6 alkenyl, heterocyclic group;
hydroxy, Ci_6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C3-8
cycloalkyloxy, C3-s cycloalkenyloxy, C4_8 cycloalkadienyloxy, C6-14 aryloxy, C7_i3 aralkyloxy, heterocyclyloxy; formyl, Ci_6 alkyl-carbonyl, C2_6 alkenyl-carbonyl, C2-6 alkynyl- carbonyl, C3-8 cycloalkyl-carbonyl, C3_8 cycloalkenyl-carbonyl, C4-8 cycloalkadienyl-carbonyl, C6-i4 aryl-carbonyl, C7-13 aralkyl- carbonyl, heterocyclylcarbonyl;
carboxy, Ci-6 alkoxy-carbonyl,. C2-6 alkenyloxy-carbonyl, C2-6
alkynyloxy-carbonyl, C3-8 cycloalkyloxy-carbonyl, C3_8
cycloalkenyloxy-carbonyl, C4-8 cycloalkadienyloxy-carbonyl, C6-14 aryloxy-carbonyl, C7_i3 aralkyloxy-carbonyl,
heterocyclyloxycarbonyl;
Ci-6 alkyl-carbonyloxy, C2-6 alkenyl-carbonyloxy, C2-6 alkynyl- carbonyloxy, C3-8 cycloalkyl-carbonyloxy, C3-8 cycloalkenyl- carbonyloxy, C4-8 cycloalkadienyl-carbonyloxy, C6-14 aryl- carbonyloxy, C7-i3 aralkyl-carbonyloxy, heterocyclylcarbonyloxy; sulfanyl, Ci-6 alkylsulfanyl, C2_6 alkenylsulfanyl, C2.6
alkynylsulfanyl, C3-8 cycloalkylsulfanyl, C3_8 cycloalkenylsulfanyl, C4-8 cycloalkadienylsulfanyl, C6_i4 arylsulfanyl, C7-i3
aralkylsulfanyl, heterocyclylsulfanyl;
sulfinyl, Ci-6 alkylsulfinyl, C2_6 alkenylsulfinyl, C2_6 ■ alkynylsulfinyl, C3-8 cycloalkylsulfinyl, C3-8 cycloalkenylsulfinyl, C4-8 cycloalkadienylsulfinyl, C6-i4 arylsulfinyl, C-i3
aralkylsulfinyl, heterocyclylsulfinyl;
sulfonyl (sulfo) , Ci_6 alkylsulfonyl, C2_6 alkenylsulfonyl, C2_6 alkynylsulfonyl, C3_8 cycloalkylsulfonyl, C3-8 cycloalkenylsulfonyl, C4-8 cycloalkadienylsulfonyl, C6-i4 arylsulfonyl-, C7-i3
aralkylsulfonyl, heterocyclylsulfonyl;
Ci-6 alkylsulfonyloxy, C2-6 alkenylsulfonyloxy, C2_s
alkynylsulfonyloxy, C3_8 cycloalkylsulfonyloxy, C3_8
cycloalkenylsulfonyloxy, C4-8 cycloalkadienylsulfonyloxy, Ce-i4 arylsulfonyloxy, C7-13 aralkylsulfonyloxy,
heterocyclylsulfonyloxy; · · ■
amino, mono- or di-Ci-6 alkylamino, mono- or di-C2_6 alkenylamino, mono-, or di-C2_6 alkynylamino, mono- or di-C3-8 cycloalkylamino, mono- or di-C3-8 cycloalkenylamino, mono- or di-C4-8
cycloalkadienylamino, mono- or di-C6-i4 arylamino, mono- or di-C7_ 13 aralkylamino, mono- or di-heterocyclylamino; carbamoyl, mono- or di-Ci-6 alkyl-carbamoyl, mono- or di-C2-6
alkenyl-carbamoyl, mono- or di-C2-6 alkynyl-carbamoyl, mono- or di-C3_8 cycloalkyl-carbamoyl, mono- or di-C3-8 cycloalkenyl- carbamoyl, mono- or di-C4_8 cycloalkadienyl-carbamoyl, mono- or di-C6_i4 aryl-carbamoyl, mono- or di-C7-i3 aralkyl-carbamoyl, mono- or di-heterocyclylcarbamoyl;
thiocarbamoyl, mono- or di-Ci-6 alkyl-thiocarbamoyl, mono- or di-
C2-6 alkenyl-thiocarbamoyl, mono- or di-C2-6 alkynyl-thiocarbamoyl, mono- or di-C3-8 cycloalkyl-thiocarbamoyl, mono- or di-C3-8
cycloalkenyl-thiocarbamoyl, mono- or di-C4_8 cycloalkadienyl- thiocarbamoyl, mono- or di-C6-i4 aryl-thiocarbamoyl, mono- or di-
C7_i3 aralkyl-thiocarbamoyl, mono- or di- heterocyclylthiocarbamoyl;
halogen;
cyano;
nitre;
oxo; and
thioxo.
[0058]
These substituents optionally have substituents (preferably
1 to 7, more preferably 1 to 5, still more preferably 1 to 3) selected from Ci-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkenyl, C4-8 cycloalkadienyl, C6_i aryl, C7_i3 aralkyl, C6-14 aryl—C2-6 alkenyl and a heterocyclic group.
[0059]
R1 and R2 are each independently hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or R1 and R2 in combination form, together with the adjacent nitrogen atom, an optionally substituted 4- to 7-membered ring.
[00,60]
R1 and R2 are each independently
preferably hydrogen, optionally substituted Ci_i0 alkyl (including .optionally substituted C3_8 cycloalkyl-Ci-3 alkyl, optionally substituted C7-i3 aralkyl (C6-io aryl-Ci-3 alkyl) ) , optionally substituted C6-i4 aryl or an optionally substituted non-aromatic heterocyclic group,
more preferably hydrogen, optionally substituted Ci_6 alkyl, optionally substituted C3-8 cycloalkyl-Ci-3 alkyl, optionally substituted C7-i3 aralkyl ( C6-io aryl-Ci_3 alkyl) , optionally
substituted C6-io aryl or an optionally substituted 5- or 6- membered non-aromatic heterocyclic group.
[0061]
Further more preferably, R1 is optionally substituted Ci_6 alkyl, optionally substituted C3-s cycloalkyl-Ci-3 alkyl,
optionally substituted C7-i3 aralkyl ( C6-io aryl-Ci_3 alkyl) ,
optionally substituted C6_io aryl or an optionally substituted 5- or 6-membered non-aromatic heterocyclic group, and R2 is hydrogen.
[0062]
R1 is still more preferably
(1) Ci-6 alkyl (preferably Ci_3 alkyl) optionally having
substituent (s) (preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from
(a) hydroxy,
(b) carboxy,
(c) mono- or di-Ci_6 alkylamino (preferably di-Ci_3 alkylamino) , and
(d) a 5- or 6-membered aromatic heterocyclic group (e.g., pyridyl)
(2) C3-8 cycloalkyl-Ci_3 alkyl (preferably C5-6 cycloalkyl-Ci_3 alkyl),
(3) C7-13 aralkyl ( C6-i0 aryl-Ci_3 alkyl) (preferably phenyl-Ci-3 alkyl) wherein the C6-io aryl moiety (preferably phenyl)
optionally has (preferably 1 to 5,. more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from Ci_6 alkoxy (preferably Ci_3 alkoxy) ,
(4) C6-io aryl (preferably phenyl), or (5) a 5- or 6-membered nitrogen-containing non-aromatic
heterocyclic group (preferably a 5- or 6-membered nitrogen- containing saturated heterocyclic group, e.g., piperidyl) .
[0063]
R1 is particularly preferably C3-s cycloalkyl-Ci-3 alkyl
(preferably C5-6 cycldalkyl-Ci-3 alkyl, particularly preferably cyclohexylmethyl) .
[0064]
R3 is -W21-R30
wherein
21 is bond, -0-, -S(0)p- (wherein p is an integer of 0 to 2) or -NRa- (wherein Ra is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group); and
R30 is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
[0065]
21 is preferably -0-.
[0066]
R30 is preferably hydrogen or optionally substituted Ci-10 alkyl (including optionally substituted G7-13 aralkyl (C6-io aryl- C1-3 alkyl) ) , more preferably
(1) hydrogen,
(2) Ci-6' alkyl (preferably Ci_3 alkyl) optionally having
substituent (s) (preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from
(a) Ci_6 alkoxy (preferably C1-3 alkoxy) , and
(b) a heterocyclic group (preferably an aromatic heterocyclic group, more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl) , or
(3) C7-13 aralkyl (Ce-io aryl-Ci_3 alkyl) (preferably phenyl-Ci_3 alkyl) .
[0067]
R3 is preferably (1) -OH,
(2) -O-Ci-6 alkyl (preferably -O-C1-3 alkyl) optionally having substituent (s) (preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from
(a) Ci_6 alkoxy (preferably C1-3 alkoxy) , and'
(b) a heterocyclic group (preferably an aromatic heterocyclic group more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl), or
(3) -0-C7-i3 aralkyl (-O-C1-3 alkyl-C6-io aryl) (preferably -O-C1-3 alkyl-phenyl) .
R is more preferably -OH.
[0068]
R4 is an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally
substituted carbocyclyl-alkyl group or an optionally substituted heterocyclyl-alkyl group.
R4 is
preferably an optionally substituted carbocyclic group or an optionally substituted heterocyclic group,
more preferably optionally substituted C6-io aryl or an optionally substituted aromatic heterocyclic group,
further more preferably optionally substituted C6-io aryl or an optionally substituted nitrogen-containing aromatic heterocyclic group.
[0069]
R4 is still more preferably
(1) C6_io aryl (preferably phenyl) ,
(2) a 5- or 6- membered nitrogen-containing aromatic
heterocyclic group (preferably pyridyl) , or
(3) a 5- or 6- membered nitrogen-containing aromatic
heterocyclic group fused with benzene (preferably quinolyl, indazolyl, indolyl) , which optionally has substituent (s)
(preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly" preferably 1 substituent) selected from Ci-6 alkoxy (preferably Ci-3 alkoxy) .
R4 is particularly preferably a 5- or 6- membered nitrogen- containing aromatic heterocyclic group fused with benzene
(preferably quinolyl, indazolyl, indolyl, more preferably quinolyl, indazolyl) .
[0070]
Preferable examples of compound (I) include the following compounds.
[Compound A]
Compound (I) wherein
R1 is optionally substituted Ci_6 alkyl, optionally substituted C3_ 8 cycloalkyl-Ci-3 alkyl, optionally substituted C7_i3 aralkyl (C6-io aryl-Ci-3 alkyl), optionally substituted Οβ-ιο aryl or an
optionally substituted 5- or 6-membered non-aromatic
heterocyclic group;
R2 is hydrogen;
R3 is -W21-R30, wherein
21 is -0-; and
R30 is hydrogen or optionally substituted Ci_io alkyl
(including optionally substituted C7-i3 aralkyl (C6-io aryl-Ci_ 3 alkyl) ) ; and
R4 is optionally substituted Οε-ιο a yl or an optionally
■substituted aromatic heterocyclic group.
[0071]
[Compound B]
Compound (I) wherein
R1 is optionally substituted" Ci-6 alkyl, optionally substituted C3- a cycloalkyl-Ci-3 alkyl, optionally substituted C7_i3 aralkyl (C6-io aryl-Ci-3 alkyl) , optionally substituted Οε-ιο aryl or an
optionally substituted 5- or 6-membered non-aromatic
heterocyclic group;
R2 is hydrogen;
R3 is - 21-R30, wherein
W21 is -0-; and R30 is
(1) hydrogen,
(2) Ci-6 alkyl (preferably Ci_3 alkyl) optionally having substituent (s) (preferably 1 to 5, more preferably 1 to 3, ■■ still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from
(a) Ci_6 alkoxy (preferably Ci_3 alkoxy) , and
(b) a heterocyclic group (preferably an aromatic heterocyclic group, more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl) , or
(3) C7-13 aralkyl (C6-io . aryl-Ci-3 alkyl) (preferably phenyl-Ci- 3 alkyl) ; and
R4 is optionally substituted C6-io aryl or an optionally
substituted nitrogen-containing aromatic heterocyclic group.
[0072]
[Compound C]
Compound (I) wherein
R1 is
(1) Ci-6 alkyl (preferably Ci_3 alkyl) optionally having
substituent (s) (preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from
(a) hydroxy,
(b) carboxy,
(c) mono- , or di-Ci-6 alkylamino (preferably di-Ci_3 alkylamino) ,
■ and
(d) a 5- or 6-membered aromatic heterocyclic group (e.g., pyridyl)
(2) C3-a cycloalkyl-Ci-3 alkyl (preferably C5-6 cycloalkyl-Ci_3 alkyl) ,
(3) C7_i3 aralkyl (C6-io aryl-Ci_3 alkyl) (preferably phenyl-Ci-3 alkyl) wherein the C6-i0 aryl moiety (preferably phenyl)
optionally has (preferably 1 to 5, more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from Ci-6 alkoxy (preferably Ci_3 alkoxy) , (4) C6-10 aryl (preferably phenyl), or
(5) a 5- or 6-membered nitrogen-containing non-aromatic
heterocyclic group (preferably a 5- or 6-membered nitrogen- containing saturated heterocyclic group, e.g., piperidyl) ;
R2 is hydrogen;
R3 is
(1) -OH,
(2) -O-Cx-6 alkyl (preferably -O-C1-3 alkyl) optionally having substituent (s) (preferably 1 to. 5, more preferably 1 to 3, still more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from
(a) Ci-e alkoxy (preferably Ci_3 alkoxy) , and
(b) a heterocyclic group (preferably an aromatic heterocyclic group, more preferably an aromatic bicyclic heterocyclic group, e.g., quinolyl), or
(3) -O-C7-13 aralkyl (-O-C1-3 alkyl-C6-io aryl) (preferably -O-C1-3 alkyl-phenyl) ; and
R4 is
(1) C6-10 aryl (preferably phenyl) ,
(2) a 5- or 6- membered nitrogen-containing aromatic
heterocyclic group (preferably pyridyl) , or
(3) a 5- or 6- membered nitrogen-containing aromatic
heterocyclic group fused with benzene (preferably quinolyl, indazolyl, indolyl) , which optionally has substituent (s)
(preferably 1 to 5, more preferably 1 to 3, still more
preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from Ci_6 alkoxy (preferably Ci_3 alkoxy) .
[0073]
[Compound D]
Compound (I) wherein
R1 is
(1) Ci-6 alkyl (preferably Ci_3 alkyl) optionally having
substituent (s) (preferably 1 to 5., more preferably 1 to 3, still more preferably 1 or" 2 substituents, particularly preferably 1 substituent) selected from (a) hydroxy,
(b) carboxy,
(c) mono- or di-Ci-6 alkylamino (preferably di-Ci_3 alkylamino) , and
(d) a 5- or 6-membered aromatic heterocyclic group (e.g., pyridyl)
(2) C3-8 cycloalkyl-Ci-3 alkyl (preferably C5-6 cycloalkyl-Ci_3.
alkyl) ,
(3) C7-13 aralkyl (Ce-ιο aryl-Ci-3 alkyl) (preferably phenyl-d-3 alkyl) wherein the C6-io aryl moiety (preferably phenyl)
optionally has (preferably 1 to 5, more preferably 1 to 3, still
h
more preferably 1 or 2 substituents, particularly preferably 1 substituent) selected from Ci_s alkoxy (preferably C1-3 alkoxy) ,
(4) C6-10 aryl (preferably phenyl), or
(5) a 5- or 6-membered nitrogen-containing non-aromatic
heterocyclic group (preferably a 5- or 6-membered nitrogen- containing saturated heterocyclic group, e.g., piperidyl) ;
R2 is hydrogen;
R3 is -OH; and
R4 is. a 5- or 6- membered nitrogen-containing aromatic
heterocyclic group fused with benzene (preferably quinolyl, indazolyl, indolyl, more preferably quinolyl, indazolyl) .
[0074]
The carbon atom marked with * and the carbon atom marked with ** are each an asymmetric carbon atom. That is, compound (I) can be the following optical isomer:
[0075]
Figure imgf000027_0001
Figure imgf000027_0002
(lab) (Ibb)
[0076]
or a mixture. thereof (including racemate) .
[0077]
In addition, compound (I) can be the following geometi isomer:
[0078]
Figure imgf000027_0003
[0079]
or a mixture thereof.
[0080]
As a salt of the compound represented by the formula (I) , a pharmacologically acceptable salt is preferable. Examples of such salt include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.'
[0081] Preferable examples of the salts with inorganic bases include alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salts, magnesium salts and the like; aluminum salts; ammonium salts, and the like .
[0082]
Preferable-, examples of the salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine,
tromethamine [tris (hydroxymethyl)methylamine] , tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N- dibenzylethylenediamine and the. like.
[0083]
Preferable examples of the salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
[0084]
Preferable examples of the salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
[0085]
Preferable examples of the salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
Preferable examples of the salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.
[0086]
Compound (I) may be a non-solvate (e.g., anhydride) or a solvate (e.g., hydrate).
[0087]
When compound (I) contains an optical isomer, a
stereoisomer, a positional .isomer and a rotamer, these are also included in compound (I) , as well as each can be obtained as a single product by a synthesis method or separation method known per se. For example, when compound (I) contains an optical isomer, an optical isomer resolved from the compound is also encompassed in compound (I) .
[0088]
Compound (I) may also be a crystal.
[0089]
The crystal of compound (I) can be produced by
crystallizing compound (I) by applying a crystallization method known per se.
[0090]
Generally, the melting point sometimes varies depending on the measurement device, measurement condition and the like. The crystal in the present specification may be a crystal showing a melting point different from the values described in the present specification as long as the difference is within a general error range.
[0091]
The production methods of compound (I) are explained in the following.
[0092]
Compound (I) of the present invention can be produced, for example, by the method shown in the following Reaction Scheme 1. In the following reaction schemes, each starting compound may form a salt as long as it does not inhibit the reaction, and examples of the salt include those exemplified as the salts of the compound represented by the aforementioned formula (I) .
[0093]
The starting compounds without indication of specific production method are easily commercially available, or can be produced according to a method known per se or a method
analogous thereto.
[0094]
Compound (I) wherein R3 is -W21'-R30' (wherein W21' and R30' are as defined below) can be produced according to Scheme 1.
[0095]
Figure imgf000030_0001
[0096]
wherein
21' is -0-, -S- or -NRa- (wherein Ra is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group) ,
R30' is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,
P1 is a carboxy-protecting group,
P2 is a hydroxy-protecting group,
X1 is halogen or trichloroacetimidoyloxy,
■ X2 is chlorine, bromine or iodine, and
the other symbols are as defined above.
[0097]
Examples of the "carboxy-protecting group" for P1 include a Ci-6 alkyl group, a C7-n aralkyl group (e.g., benzyl), a phenyl group, a trityl group, a substituted silyl group (e.g.,
trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert-butyldiethylsilyl, tert- butyldiphenylsilyl) , a C2-6 alkenyl group (e.g., 1-allyl) and the like. These protecting groups are optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci_e alkoxy group and a nitro group. P1 is preferably a Ci-6 alkyl group, more preferably methyl or ethyl.
[0098]
Examples of the "hydroxy-protecting group" for P2 include a Ci-6 alkyl group, a phenyl group, a trityl group, a C7_io aralkyl group (e.g., benzyl), a formyl group, a Ci_6 alkyl-carbonyl group, a benzoyl group, a C7io aralkyl-carbonyl group (e.g.,
benzylcarbonyl) , a 2-tetrahydropyranyl group, a 2- tetrahydrofuranyl group, a substituted silyl group (e.g.,
trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert-butyldiethylsilyl, tert- butyldiphenylsilyl) , a C2-6 alkenyl group (e.g., 1-allyl) and the like. These protecting-groups are optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci-6 alkyl group, a Ci-g alkoxy group and a nitro group. P2 is preferably a
substituted silyl group, more preferably tert-butyldiethylsilyl.
[0099]
Step 1
Compound (A-V) can be produced by reacting compound (A-VI) with compound (B-I) .
Compound (A-VI) and compound (B-I) may be a commercially - available product, or can be produced according to a method known per se or a method analogous thereto.
The amount of compound (B-I) to be used is generally 0.5 to 100 mol, preferably.1 to 10 mol, per 1 mol of compound (A-VI).
When X1 is halogen, this reaction can be carried out in the presence of a base in a solvent inert to the reaction.
Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium
carbonate, potassium carbonate and the like, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert- butoxide and the like, metal hydrides such as sodium hydride, potassium hydride and the like, and. organic amines- such as triethylamine, pyridine, diisopropylethylamine, 1,8- diazabicyclo [5.4.0] undec-7-ene and the like. The amount of the base to be used is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A-VI) .
When X1 is trichloroacetimidoyloxy, this reaction can be carried out in the presence of an acid in a solvent inert to the reaction.
Examples of the acid include pyridinium p-toluenesulfonate, toluenesulfonic acid and the like.
The amount of the acid is generally 1 to 100 mol,
preferably 1 to 3 mol, per 1 mol of compound (A-VI) .
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.), esters (e.g., ethyl acetate etc.), aromatic hydrocarbons (e.g., benzene, toluene etc. ), aliphatic hydrocarbons (e.g., hexane etc.), amides (e.g., Ν,Ν-dimethylformamide, N,N- dimethylacetamide etc.), halogenated hydrocarbons (e.g.,
dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.) and mixtures of two or more kinds thereof.
The reaction temperature is generally -25 to 150°C,
preferably 0 to 50°C.
The reaction time is generally 1 to 100 hr, preferably 1 to 72 hr.
The product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
[0100],
Step 2 1 ' ■ ■ '·.
Compound (A-IV) can be produced by subjecting compound (A- V) to deprotection.
For example, when P2 is tert-butyldiphenylsilyl, the deprotection can be carried out by treating compound (A-V) with tetrabutylammonium fluoride in a solvent inert to the reaction. The amount of the tetrabutylammonium fluoride to be used is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A-V) .
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.), esters (e.g., ethyl acetate etc.), aromatic hydrocarbons (e.g., benzene, toluene etc.), aliphatic hydrocarbons (e.g., hexa eetc.), halogenated hydrocarbons (e.g., dichloromethane,
chloroform, carbon tetrachloride, 1, 2-dichloroethane etc.) and mixtures of two or more kinds thereof.
The reaction temperature is generally -25 to 1"00°C,
preferably 0 to 50°C.
The reaction time is generally 1 to 72 hr, preferably 1 to 18 hr.
The product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
[0101]
Step 3
Compound (A-III) can be produced by subjecting compound (A- IV) to oxidation.
The oxidation can be carried out using dimethyl sufoxide in the presence of an activating agent and a base.
The amount of the dimethyl sufoxide to be used is generally 1 to 300 mol, preferably 1 to 100 mol, per 1 mol of compound (A- IV).'
Examples of the activating agent include pyridine-sulfur trioxide complex, acetic anhydride, . oxalyl chloride and the like.
The amount of the activating agent to be used is generally 0.1 to 50 mol, preferably 0.1 to 10 mol, per 1 mol of the
dimethyl sufoxide. Examples of the base include tertially amine such as triethylamine, trimethylamine, pyridine and the like.
The amount of the base to be used is generally 1 to 50 mol, preferably 1 to 10 mol, per 1 mol of compound (A-IV) .
This reaction can be carried out in dimethyl sufoxide.
Alternatively, the oxidation can be also carried out using Dess-Martin agent in a solvent inert to the reaction.
Examples of the Dess-Martin agent include Dess-Martin periodinane and the like.
The amount of the Dess-Martin agent to be used is generally
1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A- IV).
This reaction can be carried out in a solvent inert to the reaction.
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include halogenated hydrocarbons, (e.g., dichloromethane, chloroform, carbon
tetrachloride, 1, 2-dichloroethane etc.), ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.), esters (e.g., ethyl acetate etc.), acetonitrile and mixtures of two or more kinds thereof.
The reaction temperature is generally -100 to 100°C, preferably -78 to 50°C.
The reaction time is generally 1 to 72 hr, preferably 1 to 18 hr.
The product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to. separation means such as washing, recrystallization, distillation, chromatography and the like.
[0102]
Step 4
Compound (A-II) can be produced by subjecting compound (A- III) to chlorovinylation or bromovinylation or iodovinylation. The chlorovinylation or bromovinylation or iodovinylation can be carried out using a chlorovinylating agent, a
bromovinylating agent or an iodovinylating agent in a solvent inert to the reaction.
Examples of the vinyl chlorovinylating agent include chloroform in the presence of chromium(II) chloride, examples of the bromovinylating agent include bromoform in the presence of chromium (II) chloride, and examples of the iodovinylating agent include iodoform in the presence of chromium (II) chloride.
The amount of the chlorovinylating agent, bromovinylating agent or iodovinylating, agent to be used is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A-III) .
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.), esters (e.g., ethyl acetate etc.), aromatic hydrocarbons (e.g., benzene, toluene etc.), aliphatic hydrocarbons (e.g., hexane etc.) and mixtures of two or more kinds thereof.
The reaction temperature is generally -100 to 100°C, preferably -20 to 50°C.
The reaction time is generally 1 to 72 hr, preferably 1 to 18 hr.
The product is obtained as a single compound .or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
[0103]
Step 5
Compound (A-I) can be produced by subjecting compound (A- II) to a coupling reaction with compound (C-I) .
Compound (C-I) may be a commercially available product, or can be produced according to a method known per se or a method analogous thereto. The amount of compound (C-I) to be used is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A-II) .
The coupling reaction can be carried out in the presence of a metal catalyst and a base in a solvent inert to the reaction.
Examples of the catalyst include a palladium compound [e.g., palladium(II) acetate, tetrakis (triphenylphosphine) palladium (0 ) , dichlorobis (triphenylphosphine) palladium (II) ,
dichlorobis (triethylphosphine) palladium (II) ,
tris (dibenzylideneacetone) dipalladium (0) , a complex of
palladium(II) acetate and 1, 1' -bis (diphenylphosphino) ferrocene, etc . ] .
The amount of the catalyst to be used is generally 0.0001 - 1.0 mol, preferably 0.01 to 0.1 mol, per 1 mol of compound (A- II) .
The metal catalyst can be used together with a phosphine ligand.
Examples of the phosphine ligand include triphenylphosphine, 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene, tri-tert- butylphosphine and the like.
The amount of the phosphine ligand to be used is generally
0.01 to 10 mol, preferably 0.1 to 5 mol, per 1 mol of compound (A-II).
Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium
carbonate, potassium carbonate and the like, and basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate and the like.
The amount of the base to be used is generally 1 to 50, mol, preferably 1 to 10 mol, per 1 mol of compound (A-II) .
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.), esters, (e.g., ethyl acetate etc.), aromatic hydrocarbons (e.g.," benzene, toluene etc.), aliphatic hydrocarbons (e.g., hexane etc.), amides (e.g., N, -dimethylformamide, Ν,.Ν- dimethylacetamide etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.) and mixtures of two or more kinds thereof.
The reaction temperature is generally -20 to 200°C, preferably 0 to 150°C.
The reaction time is generally 1 to 72 hr, preferably 1 to 18 hr.
The product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
[0104]
Step 6
Compound (Int) can be produced by subjecting compound (A-I) to deprotection.
For example, when P1 is methyl or ethyl, the deprotection can be carried out by treating compound (A-I) with an alkali.
Examples of the alkali to be used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide,
potassium hydroxide and the like.
The amount of the alkali or acid to be used is generally 0.01 to 500 mol, preferably 0.1 to 100 mol, per 1 mol of compound (A-I).
. This reaction is generally carried out in a solvent inert to the reaction.
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., methanol, ethanol, propanol etc.), hydrocarbons (e.g., benzene, toluene, cyclohexane, hexane etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.), ethers (e.g., diethyl ether,
tetrahydrofuran, dioxane etc.), water and mixtures of two or more kinds thereof. The reaction temperature is generally 0 to 200°C,
preferably 0 to 150°C.
The reaction time is generally 1 to 200 hr, preferably 1 to 72 hr.
For example, when P1 is trityl, the deprotection can also be carried out by treating compound (A-I) with an acid.
Examples of the acid to be used include organic or
inorganic acid such as hydrochloric acid, sulfonic acid, formic acid, acetic acid, trifluoroacetic acid and the like.
. The amount of the acid to be used is generally 0.01 to 500 mol, preferably 0.1 to 100 mol, per 1 mol of compound (A-I).
This reaction is generally carried out in a solvent inert to the reaction.
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., methanol, ethanol, propanol etc . ) , hydrocarbons (e.g., benzene, toluene, cyclohexane, hexane etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.), ethers (e.g., diethyl■ ether,
tetrahydrofuran, dioxane etc.), water and mixtures of two or more kinds thereof.
The reaction temperature is generally 0 to 200°C,
preferably 0 to 150°C.
The reaction time is generally.1 to 200 hr, preferably 1 to 72 hr.
For example, when P1 is benzyl or p-methoxybenzyl, the deprotection can also be carried out by subjecting compound (A- I) to hydrogenation .
The hydrogenation can be carried out using hydrogen or a hydrogen donating agent (e.g., cyclohexadiene) in the presence · of a catalyst (e.g., palladium, palladium hydroxide, platinum etc. ) .
The amount of the catalyst be used is generally 0.001 to 10 mol, preferably 0.01 to 1 mol, per 1 mol of compound (A-I). This reaction is generally carried out in a solvent inert to the reaction.
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., methanol, ethanol, propanol etc.), hydrocarbons (e.g., benzene, toluene, cyclohexane, hexane etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.), ethers (e.g., diethyl ether,
tetrahydrofuran, dioxane etc.), water and mixtures of two or more kinds thereof.
The reaction temperature is generally 0 to 200°C,
preferably 0 to 150°C.
The reaction time is generally 1 to 200 hr, preferably 1 to 72 hr.
The product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
[0105]
Step 7
Compound (I) can be produced by reacting the reactive derivative of compound (Irit) with compound (D-I) .
Examples of the reactive derivative of compound (Int) include acid halides such as acid chlorides, acid bromides and the like; acid amides with pyrazole, imidazole, benzotriazole and the like; mixed acid anhydrides with as acetic acid, propionic acid, butyric acid and the like; acid azides;
activated esters such as diethoxyphosphate ester,
diphenoxyphosphate ester, p-nitrophenyl ester, 2, 4-dinitrophenyl ester, cyanomethyl ester, pentachlorophenyl ester, ester with INK hydroxysuccinimide, ester with N-hydroxyphthalimide, ester with 1-hydroxybenzotriazole, ester with 6-chloro-l- hydroxybenzotriazole, ester with l-hydroxy-lH-2-pyridone, and the like; activated thioesters such as 2-pyridyl thioester, 2- benzothiazolyl thioester and the like, and the like.
Alternatively, compound (I) . can also be produced by directly reacting compound (Int) with compound (D-I) in the presence of a condensing agent, instead of using the reactive derivative .
Examples of the condensing agent include N, N ' -disubstituted carbodiimides such as Ν,Ν' -dicyclohexylcarbodiimide, l-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC) hydrochloride and the like; azolides such as N, N ' -carbonyldiimidazole and the like; dehydrating agents such as N-ethoxycarbonyl-2-ethoxy-l, 2- dihydroquinoline, phosphorus oxychloride, alkoxyacetylene and the like; 2-halogenopyridiniums such as 2-chloromethylpyridinium iodide, 2-fluoro-l-methylpyridinium iodide and the like;
phosphorylcyanides such as diethylphosphorylcyanide and the like; 2- (7-azabenzotriazol-l-yl) -1, 1, 3, 3-tetramethyluronium hexafluorophosphate (HATU) , 0- (7-azabenzotriazol-l-yl) - Ν,Ν,Ν' ,Ν' -tetramethyluronium tetrafluoroborate (TATU) and the like, as well as resin-supported condensing agents such as crosslinked polystyrene-supported 2-alkoxy-l-alkoxycarbonyl-l, 2-dihydroquinone, crosslinked polystyrene-supported DCC (PS-DCC) and the like.
Compound (D-I) may be a commercially available product, or can be produced according to a method known per se or a method analogous thereto.
The amount of compound (D-I) to be used is generally about 0.8 to 5 mol per 1 mol of compound (Int).
This reaction is preferably carried out in the presence of a base.
Examples of the base include basic salts such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium hydrogen carbonate and the like, and organic amines such as triethylamine, pyridine, diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and the like. The amount of the base to be used is generally 0.5 to 20 mol, preferably 0.8 to 10 mol, per 1 mol of compound (Int).
This reaction can be carried out in a solvent inert to the reaction.
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.), esters (e.g., ethyl acetate etc.), aromatic hydrocarbons (e.g., benzene, toluene etc. ) , aliphatic hydrocarbons (e.g., hexane etc.), amides (e.g., N, N-dimethylformamide, N,N- dimethylacetamide etc.), halogenated hydrocarbons (e.g.,
dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.) and mixtures of two or more kinds thereof.
The reaction temperature is generally 0 to 200°C,
preferably 0 to 150°C.
The reaction time is generally 1 to 200 hr, preferably 1 to 72 hr.
Compound (I) can be isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
[0106]
Compound (I) wherein R3 is -S (0) -R30' or -S (0) 2-R30' (wherein R30' is as defined above) can be produced by subjecting compound (I) wherein R3 is -S-R30' to oxidation.
The oxidation can be carried out using an oxidant in a solvent inert to the reaction.
Examples of the oxidant include m-chloroperbenzoic acid and the like.
The amount of the oxidant to be used is generally 0.5 to
100 mol, preferably 0.8 to 10 mol, per 1 mol of the above- mentioned compound (I).
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1 , 2-dimethoxyethane etc.), esters (e.g., ethyl acetate etc.), aromatic hydrocarbons (e.g., benzene, toluene etc.), aliphatic hydrocarbons (e.g., hexane etc.), amides (e.g., N,N-dimethylformamide, N,N- dimethylacetamide etc.), halogenated hydrocarbons (e.g.,
dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.) and mixtures of two or more kinds thereof.
The reaction temperature is generally -20 to 200°C,
preferably' 0 to 150°C.
The reaction time is generally 1 to 200 hr, preferably 1 to 72 hr.
[0107]
Compound (I) wherein R is -OH, -SH or -NH2 can be produced by subjecting compound (I) wherein R3 is -O-P2, -S-P3 or -NH-P4 (wherein P2 is as defined above, P3 is a sulfanyl-protecting group, and P4 is an amino-protecting group) to deprotection.
Examples of the sulfanyl-protecting group for P3 include a i-ζ alkyl group, a .phenyl group, a trityl group, a C7-io aralkyl group (e.g., benzyl), a Ci-6 alkyl-carbonyl group, a benzoyl group, a C7-io aralkyl-carbonyl group (e.g., benzylcarbonyl), a Ci_6
alkoxy-carbonyl group, . a C6-1 aryloxy-carbonyl group (e.g., phenyloxycarbonyl) , a C7-14 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl) , a 2- tetrahydropyranyl group, a Ci_6 alkylamino-carbonyl group (e.g., methylaminocarbonyl, ethylaminocarbonyl) and the like. These protecting groups are optionally substituted by 1 to 3
substituents selected from a halogen atom, a Ci-6 alkyl group, a Ci-6 alkoxy group and a nitro group.
Examples of the amino-protecting group for P4 include a formyl group, a Ci-6 alkyl-carbonyl group, a Ci-6 alkoxy-carbonyl group, a benzoyl group, a C7_io aralkyl-carbonyl group (e.g., benzylcarbonyl), a C7-14 aralkyloxy-carbonyl group (e.g.,
benzyloxycarbonyl, a 9-fluorenylmethoxycarbonyl) , a trityl group, a phthaloyl group, an N, N-dimethylaminomethylene group, a
substituted silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert- butyldiethylsilyl) , a C2-6 alkenyl group (e.g., 1-allyl) and the like. These protecting groups are optionally substituted by 1 to 3 substituents selected from a halogen, atom, a- Ci_6 alkoxy group and a nitro group.
[0108]
For example, compound (I) wherein R3 is -OH can be produced by subjecting compound (I) wherein R3 is -0-CH2-phenyl to catalytic hydrogenation.
The catalytic hydrogenation is generally carried out in the presence of a metal catalyst under hydrogen atmosphere.
Examples of the metal catalyst include palladium carbon, palladium hydroxide, platinum oxide, Raney-nickel, Raney-cobalt and the like.
The amount of the metal catalyst to be used is generally 0.001 to 10 mol, preferably 0.01 to 1 mol, per 1 mol of the above-mentioned compound (I) .
The hydrogen pressure is generally 1 to 100 atm.
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include alcohols (e.g., methanol, ethanol etc.), ethers (e.g., diethyl ether, .
tetrahydrofuran, 1, 2-dimethoxyethane etc. ), aromatic
hydrocarbons (e.g., benzene, toluene etc.), aliphatic
hydrocarbons (e.g., hexane etc.) and mixtures of two or more kinds thereof.
The reaction temperature is generally 0 to 200°C,
preferably 0 to 150°C.
The reaction time is generally 1 to 20.0 hr, preferably 1 to 72 hr.
[0109]
Compound (I) wherein R3 is -NRa-R30 can also be produced by reacting compound (I) wherein R3 is -NH-R30 with Ra-X1.
This reaction is carried out according to the method similar to Step 1.
[0110] Compound (I) wherein R3 is -w21'-R30' , (wherein W21' and R30' are as defined below) can also be produced according to Scheme 2 [0111]
Scheme 2
Figure imgf000044_0001
Figure imgf000044_0002
[0112]
wherein P2' is a 'hydroxyl-protecting group, and the other symbols are as defined above.
[0113]
Examples of the "hydroxy-proteeting group" for P2' include a Ci-6 alkyl group, a phenyl group, a trityl group, a C7_io aralkyl group (e.g., benzyl) , a formyl group, a i-e alkyl-carbonyl group, a benzoyl group, a C7_io aralkyl-carbonyl group (e.g.,
benzylcarbonyl) , a 2-tetrahydropyranyl group, a 2- tetrahydrofuranyl group, a substituted silyl group (e.g.,
trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- butyldimethylsilyl, tert-butyldiethylsilyl, tert-.
butyldiphenylsilyl) , a C2-6 alkenyl group (e.g., 1-allyl) and the like. These protecting-groups are optionally substituted by 1 to 3 substituents selected from a halogen atom, a Ci_6 alkyl group, a Ci-6 alkoxy group and a nitro group. . P2' is preferably a C7_i0 aralkyl group optionally substituted by a Ci_5 alkoxy group, more preferably p-methoxybenzyl .
[0114]
Step 8
Compound (A-XIV) can be produced by subjecting compound (A-
V) to reduction.
The reduction can be carried out by reacting compound (A-V) with a reducing agent in a solvent inert to the reaction.
Examples of the reducing agent include lithium aluminum hydride, sodium aluminum hydride, sodium bis (2- methoxyethoxy) aluminum hydride, diisobutylaluminum hydride and the like.
The amount of the reducing agent is generally 0.5 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound (A-V) .
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc . ) , aromatic hydrocarbons (e.g., benzene, toluene etc.), aliphatic hydrocarbons (e.g., hexane etc.) and mixtures of two or more -kinds thereof.
The reaction temperature is generally -25 to 100°C,
preferably 0 to 25°C.
The reaction time is generally 0.5 to 120 hr, preferably 1 to 18 hr.
The product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
[0115]
Step 9.
Compound (A-XITI) can be produced by subjecting compound (A-XIV) to protection. The protection can be carried out by reacting compound (A- XIV) with a hydroxyl-protecting agent in a solvent inert to the reaction.
Examples of the hydroxyl-protecting agent include p- methoxybenzyl chloride, p-methoxybenzyl bromide, p-methoxybenzyl iodide, p-methoxybenzyl trichloroacetimidate and the like.
The amount of the hydroxyl-protecting agent is generally 1 to 100 mol, preferably 1 to 3 mol, per 1 mol of compound (A-XIV) .
When p-methoxybenzyl chloride, p-methoxybenzyl bromide or p-methoxybenzyl iodide is used as a hydroxyl-protecting agent, the reaction can be carried out in the presence of a base.
Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium
carbonate, potassium carbonate and the like, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert- butoxide and the like, metal hydrides such as sodium hydride, potassium hydride and the like, and organic amines such as triethylamine, pyridine, diisopropylethylamine, 1,8- diazabicyclo [5.4.0] undec-7-ene and the like.
The amount of the base is generally 1 to 100 mol,
preferably 1 to 5 mol, per 1 mol of compound (A-XIV) .
When p-methoxybenzyl trichloroacetoimidate is used as a hydroxyl-protecting agent, the reaction can be carried out in the presence of an acid.
Examples of the acid include pyridinium p-toluenesulfonate, toluenesulfonic acid and the like..
The amount of the acid is generally 1 to 100 mol,
preferably 1 to 3 mol, per 1 mol of compound (A-XIV) .
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.), esters (e.g., ethyl acetate etc.), aromatic hydrocarbons (e.g., benzene, toluene etc.), aliphatic hydrocarbons (e.g., hexane etc.), amides (e.g., N, N-dimethylformamide, N,N- dimethylacetamide etc.), halogenated . hydrocarbons (e.g., dichloromethane, chloroform, carbon . tetrachloride, 1,2- dichloroethane etc.) and mixtures of two or more kinds thereof.
The reaction temperature is generally -25 to 100°C, preferably 0 to 25°C.
The reaction time is generally 0.5 to 120 hr, preferably 1 to 18 hr.
The product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
[0116]
Step 10
Compound (A-XII) can be produced by subjecting compound (A-
XIII) to deprotection.
The reaction can be carried out according to the method similar to Step 2.
[0117]
Step 11
Compound (A-XI) can be produced by subjecting compound (A- XII) to oxidation.
The reaction can be carried out according to the method similar to Step 3.
[0118]
Step 12
Compound (A-X) can be produced by subjecting compound (A- XI) to chlorovinylation or bromovinylation or iodovinylation .
The reaction can be carried out according to the method similar to Step 4.
[0119]
Step 13
Compound (A-IX) can be produced by subjecting compound (A- X) to deprotection. For example, when P2' is a p-methoxybenzyl group, the deprotection can be carried out by treating compound (A-X) with 2, 3-dichloro-5, 6-dicyano-p-benzoquinone in a solvent inert to the reaction.
The amount of the 2, 3-dichloro-5, 6-dicyano-p-benzoquinone is. generally 1 to 100 mol, preferably 1 to 3. mol, per 1 mol of compound (A-X) .
While the solvent is not particularly limited as long as the reaction proceeds, examples thereof include ethers (e.g., diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane etc.), esters (e.g., ethyl acetate etc.)., aromatic hydrocarbons (e.g., benzene, toluene etc.), aliphatic hydrocarbons (e.g., hexane etc.), amides (e.g., N, N-dimethylformamide, N,N- dimethylacetamide etc. ) , halogenated hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane etc.) and mixtures of two or more kinds thereof.
The reaction temperature is generally -25 to 100°C, preferably 0 to 25°C.
The reaction time is generally 0.5 to 120 hr, preferably 1 to 18- hr.
The product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
[0120]
Step 14
Compound (A-VIII) can be produced by subjecting compound (A-IX) to a coupling reaction with compound (C-I) .
The reaction can be carried out according to the method similar to .Step 5.
[0121]
Step 15 and Step 16 Compound (A-VII) can be produced by subjecting compound (A- VIII) to oxidation.
Compound (Int) can be produced by subjecting compound (A-
VII) to oxidation.
The oxidation can be carried out by oxidizing compound (A-
VIII) to convert to compound (A-VII) , and then by oxidizing compound (A-VII) to convert to compound (Int) .
The oxidation of compound (A-VIII) to compound (A-VII) can be carried out according to the method similar to Step 3.
The oxidation of compound ' (A-VII) to compound (Int) can be carried out using 2-methyl-2-butene, NaC102, and NaH2P04 in tert- BuOH.
The amount of the 2-methyl-2-butene is generally 1 to 100 mol, preferably 10 to 30 mol, per 1 mol of compound (A-VII) .
The amount of the NaC102 is generally 1 to 100 mol, preferably 1 to 3 mol, per 1 mol of compound (A-VII).
The amount of the Na¾P04 is generally 1 to 100 mol, preferably 1 to 10 mol, per 1 mol of compound (A-VII).
The reaction temperature is generally -25 to 100°C,
preferably 0 to 25°C.
The reaction time is generally 0.5 to 120 hr, preferably 1 to 18 hr.
The product is obtained as a single compound or mixture, and can be used directly as the reaction mixture or as a crude product for the next reaction, or can be also isolated from the reaction mixture according to a conventional method, and can be easily purified according to separation means such as washing, recrystallization, distillation, chromatography and the like.
[0122]
In the above-mentioned reactions, when the starting compound has an amino group, a carboxy group, a hydroxy group, a carbonyl group or a sulfanyl group as a substituent, a
protecting group generally used in peptide chemistry and the like may be introduced into these groups. By removing the protecting group as necessary after the reaction, the objective compound can be -obtained.
[0123]
Examples of the amino-protecting group include those exemplified for P4.
Examples of the carboxy-protecting group include those exemplified for P1. ·
Examples of the hydroxy-protecting group include those exemplified for P2 or P2' .
Examples of the protected carbonyl group include a cyclic acetal (e.g., 1, 3-dioxane) , an acyclic acetal (e.g., di-Ci-6 alkyl acetal) and the like.
Examples of the sulfanyl-protecting group include those exemplified for P3.
[0124]
Examples of the method for removing the above-mentioned protecting group include a method known per se, for example, the method described in Protective Groups in Organic Synthesis, John Wiley and Sons (1980) and the like. Specifically, a method using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide) and the like, a reduction method and the like.
[0125]
Compound (I) obtained by each of the above-mentioned production methods can be isolated and purified by a known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. Each starting compound obtained by each of the above-mentioned production methods can be isolated and purified by a known means similar to those mentioned above. In addition, these starting compounds may be used without isolation as a reaction mixture and as a starting material of the next reaction. [0126]
Compound (I) shows low toxicity and can be used as an agent for the prophylaxis or treatment of various diseases to be mentioned later for mammals (e.g., humans, mice, rats, rabbits, dogs, cats, bovines, horses, pigs, monkeys) as they are or by admixing with a pharmacologically acceptable carrier and the like to give a pharmaceutical composition.
[0127]
Here, various organic or inorganic carriers conventionally used as materials for pharmaceutical preparations are used as a pharmacologically acceptable carrier, which are added as excipient, lubricant, binder and disintegrant for solid- preparations; solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid
preparations, and the like. Where necessary, an additive for pharmaceutical preparations such as preservative, antioxidant, colorant, sweetening agent and the like can be used.
[0128]
Preferable examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, microcrystalline cellulose, low-substituted
hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate and magnesium aluminate metasilicate .
Preferred examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.
Preferable examples of the binder include pregelatinized starch, saccharose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose,
microcrystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone.
[0129] -
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicic acid and low- substituted hydroxypropyl cellulose.
Preferable examples of the solvent include water for
injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.
Preferred examples of the solubilizing agent include
polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, tris (hydroxymethyl) aminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.'"
[0130]
Preferred examples of the suspending agent include
surfactants such as stearyltriethanolamine, sodium lauryl
sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate and the like; hydrophilic polymers such as polyvinyl alcohol,
polyvinylpyrrolidone, sodium carboxymethylcellulose,
methylcellulose, · hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like; polysorbates; and
polyoxyethylene hydrogenated castor oil.
Preferred examples of the isotonicity agent include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose.
. Preferred examples of the buffer include buffers such as phosphates, acetates, carbonates and citrates.
Preferred examples of the soothing agent include benzyl alcohol.
[0131]
_ Preferred examples of the preservative include p- hydroxybenzoate, chlorobutanol, benzyl alcohol, phenethyl
alcohol, dehydroacetic acid and sorbic acid.
Preferred examples of the antioxidant include sulfites and ascorbates. Preferable examples of the colorant include water-soluble edible tar pigments (e.g., foodcolors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like), water insoluble lake pigments (e.g.,
aluminum salts of the aforementioned water-soluble edible tar pigment), and natural pigments (e.g., beta-carotene, chlorophyll, red iron oxide) .
Preferable. examples of the sweetening agent include
saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia.
[0132]
The pharmaceutical composition containing compound (I) can be safely administered solely or by mixing with a
pharmacologically acceptable carrier according to a method known per se as a production method of a pharmaceutical preparation, and in the form of, for example, tablet, pill, powder, granule, capsule, 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 preparation, ointment, lotion, adhesive preparation, suppository (e.g., rectal suppository, vaginal suppository) , pellet, nasal
preparation, pulmonary preparation, eye drop and the like, orally or parenterally (e.g., intravenous, intramuscular,
subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal and intratumor administrations, administration to the vicinity of tumor, and direct administration to the lesion) .
[0133]
The pharmaceutical composition can be produced by a method conventionally used in the technical field of pharmaceutical preparation, for example, the method described in the Japanese Pharmacopoeia and the like.
While the content of compound (I) in the pharmaceutical composition varies depending on the dosage form, dose of
compound (I), and the like, it is, for example, about 0.1 to 100 wt%.
[0134] -
The compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity and the like) and a few side effects. Therefore, it can be used as an agent for the prophylaxis or treatment or a diagnostic of
various diseases in a mammal (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat) ,;
[0135]
Since compound (I) has a tyrosine kinase inhibitory action on Trk receptors such as TrkA, TrkB, TrkC or other tyrosine kinase receptors such as Flt-3. It is useful as an agent for the prophylaxis or treatment of proliferative diseases
associated with kinase signaling pathway such as tumor or cancer (e.g., prostate cancer, breast cancer, thyroid cancer, colon cancer, malignant melanomas, lung cancer, glioblastomas,
pancreatic cancer) , fibrotic diseases, restenosis associated with angioplasty, polycystic kidney disease, aberrant
angiogenesis disease, tuberous sclerosis complex, hair loss, and Alzheimer's disease.
[0136]
The dose of compound (I) can be appropriately selected according to the subject of administration, administration route, target disease, symptom and the like. For example, the dose of compound (I) for oral administration to an adult patient with diabetes, obesity, dyslipidemia, steatohepatitis, cachexia, or muscular atrophy is generally about 0.001 - 50 mg/kg body weight., preferably about 0.01 - 45 mg/kg body weight, more preferably about 0.1 - 2 mg/kg, as a single dose of the active ingredient "compound (I)". This amount is desirably administered 1-3 times per day.
[0137]
Moreover, compound (I) can be used in combination with a drug other than compound ( I ) .
[0138]
Examples of the drug that can be used in combination with the compound (I) (hereinafter sometimes to be abbreviated as concomitant drug) hormonal therapeutic agents, chemotherapeutic agents, immunotherapeutic agents, medicaments inhibiting the action of cell growth factors or cell growth factor receptors and the like.
[0139]
Examples of the "hormonal therapeutic agents" include fosfestrol, diethylstylbestrol, chlorotrianisene,
medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti- estrogens (e.g., tamoxifen citrate, toremifene citrate), pill preparations, mepitiostane, testrolactone, aminoglutethimide,
LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin) , droloxifene, epitiostanol, ethinylestradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole,
retrozole, exemestane, vorozole, · formestane) , anti-androgens (e.g., flutamide, bicartamide, . nilutamide) , ^5a-reductase
inhibitors (e.g., finasteride, epristeride) , aderenal cortex hormone drugs (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone), androgen synthesis inhibitors (e.g.,
abiraterone) , retinoid and drugs that retard retinoid metabolism (e.g., liarozole) , and the like.
[0140]
Examples of the "chemotherapeutic agents" include
alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and the like.
[0141] Examples of the "alkylating agents" include nitrogen
mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalan, dacarbazine, ranimustine,■ sodium estramustine
phosphate, 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, DDS preparations thereof, and the like.
[0142]
Examples of the "antimetabolites" include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine
hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmofur, gallocitabine, emitefur, capecitabine) , aminopterine, nelzarabine, leucovorin calcium, tabloid, butocine, calcium folinate, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine, hydroxycarbamide, pentostatin,
piritrexim, idoxuridine, mitoguazone, thiazophrine, ambamustine, bendamustine, DDS preparations thereof, and the like.
[0143]
Examples of the "anticancer antibiotics" include
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, sarcomycin,
carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, DDS preparations
thereof, and the like.
[0144] Examples of the "plant-derived anticancer agents" include etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, DDS preparations thereof, and the like.
[0145]
Examples of the "immunotherapeutic agents" include
Biological Response Modifiers (e.g., picibanil, krestin, sizofiran, lentinan, ubenimex, interferons, interleukins, macrophage colony-stimulating factor, granulocyte colony- stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole,. polysaccharide K,
procodazole, anti-CTLA4 antibody), and the like.
[0146]
Example of the "cell growth factors" of the "medicaments inhibiting the action of cell growth factors or cell growth factor receptors" include any substances that promote cell proliferation, which are normally peptides having not more than 20,000 molecular weight that are capable of exhibiting their activity at low concentrations by binding to a receptor, including
(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., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2) , NGF (nerve growth factor) , PDGF (platelet-derived growth factor) , GF (transforming growth factor β) , HGF (hepatocyte growth factor) , VEGF (vascular endothelial growth factor) , heregulin,
angiopoietin, and the like] .
[0147] Examples of the "cell growth factor receptors" include any receptors capable of binding to the aforementioned cell growth factors, including 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.
[0148]
As the "medicaments inhibiting the action of cell growth factors or cell growth factor receptors", 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, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1/2)
inhibitor, MET inhibitor, CDK inhibitor, Akt inhibitor, ERK inhibitor and the like are used. More specifically as such agents, anti-VEGF antibody (e.g., Bevacizumab) , anti-HER2
antibody (e.g., Trastuzumab, Pertuzumab) , anti-EGFR antibody (e.g., Cetuximab, Panitumumab, Matuzumab, Nimotuzumab) , anti- VEGFR antibody, Imatinib, Erlotinib, Gefit.inib, Sorafenib,
Sunitinib, Dasatinib, Lapatinib, Vatalanib, 4- ( 4-fluoro-2- methyl-lH-indol-5-yloxy) -6-methoxy-7- [3- (1- pyrrolidinyl) propoxy] quinazoline (AZD-2171) , Lestaurtinib,
Pazopanib, Canertinib, Tandutinib, 3- (4-bromo-2, 6- difluorobenzyloxy) -5- [3- [4- (1- pyrrolidinyl) butyl] ureido] isothiazole-4-carboxamide (CP-547632) , Axitinib, N- (3, 3-dimethyl-2, 3-dihydro-lH-indol-6-yl) -2- (pyridin4-ylmethylamino) pyridine-3-carboxamide (AMG-706) , 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, N-[4-[4-(4- methylpiperazin-l-yl) -6- (3-methyl-lH-pyrazol-5- ylamino) pyrimidin-2-ylsulfanyl] phenyl] cyclopropanecarboxamide
(VX-680), phosphoric acid 2- [N- [3- [4- [5- [N- (3- fluorophenyl) carbamoylmethyl] -lH-pyrazol-3-ylamino] quinazolin-7- yloxy] propyl] -N-ethylamino] ethyl ester (AZD-1152), 4-[9-chloro- 7- (2, 6-difluorophenyl ) -5H-pyrimido [5, 4-d] [2] benzazepin-2- ylamino] benzoic acid (MLN-8054) , N- [2-methoxy-5- [ (E) -2- (2,4, 6- trimethoxyphenyl) vinylsulfonylmethyl] phenyl] glycine sodium salt (ON-1910Na) , 4- [ 8-cyclopentyl-7 (R) -ethyl-5-methyl-6-oxo-5, 6, 7, 8- tetrahydropteridin-2-ylamino] -3-methoxy-N- (l-methylpiperidin-4- yl)benzamide (BI-2536) , 5- (4-bromo-2-chlorophenylamino) -4- fluoro-l-methyl-lH-benzimidazole-6-carbohydroxamic acid 2- hydroxyethyl ester (AZD-6244) , N- [2 (R) , 3-dihydroxypropoxy] -3, 4- difluoro-2- (2-fluoro-4-iodophenylamino) benzamide (PD-0325901) and the like are used.
[0149]
In addition to the aforementioned drugs, L-asparaginase, aceglatone, procarbazine hydrochloride, protoporphyrin-cobalt complex salt, mercuric hematoporphyrin-sodium, topoisomerase I inhibitors (e.g., irinotecan, topotecan) , topoisomerase II inhibitors (e.g.,- sobuzoxane) , differentiation inducers (e.g., retinoid, vitamin D) , other angiogenesis inhibitors (e.g., humagillin, shark extract, COX-2 inhibitor), a-blockers (e.g., tamsulosin hydrochloride), bisphosphonic acids (e.g.,
pamidronate, zoledronate) , thalidomide, 5-azacytidine,
decitabine, bortezomib, antitumor antibody (e.g., anti-CD20 antibody) , toxin labeled antibody and the like can also be used.
[0150]
The administration time of compound (I) and the concomitant drug is not restricted, and these can be administered to an administration subject simultaneously, or may be administered in a staggered manner. The administration mode is not particularly limited, and compound (I) and the concomitant drug only need to be combined. Examples
[0151]
The present invention will be further specifically
explained with reference to examples. However, the scope of the present invention is not limited to the following examples. In the examples, for thin layer chromatography (TLC) , Precoated Silica Gel 60 F254 (produced by Merck, product number: 5715-1M) was used. After development with chloroform:methanol (1:0 to 1:1) or ethyl acetate :hexane (1:0 to 0:1), spots were observed by UV irradiation (254 run) or color development with ninhydrine or phosphomoribdic acid solution in ethanol. For drying organic solvent, anhydrous magnesium sulfate or anhydrous sodium sulfate was used. As for column chromatography, the indication of "Buch" means use of Buch sepacore preparative chromatography system (produced by Buch) , and one or several columns selected from cartridge columns Si6M-12x75mm, 12xl50mm, 40x75mm and 40xl50mm produced by the same manufacturer were used depending on the amount of sample. As for column chromatography, the indication of "Purif" means use of Moritex Purif preparative chromatography system (produced by Moritex) , and one or several columns selected from cartridge columns 20, 35, 60,.200 and 400 produced by the same manufacturer were used depending on the amount of sample. For flash column chromatography, Silica gel 60N (spherical shape, neutral, 40 to 100 um, produced by Kanto Chemicals) was used. Preparative thin layer chromatography (hereinafter abbreviated as "PTLC") was performed by using one or several plates of PLC Plate Silica Gel 60 F254 (20 x 20 cm, thickness: 2 mm, concentration zone: 4 cm, produced by Merck, product number: 13793-1M) were used depending on the amount of sample.
[0152]
The indication of "LCMS" means that mass spectrum was measured by. liquid chromatography-mass spectrometry (LC/MS) . Platform-LC type mass spectrometry . apparatus ZQ2000 (produced by Micromass) was used as the mass spectrometer, and the
measurement was performed by the electrospray ionization (ESI) method. As a liquid chromatography apparatus, an apparatus produced by waters was used. As a separation column, Develosil C30-UG-5 (50 x 4.6 mm, Nomura Kagaku Co., Ltd.) was used.
Elution was generally performed at a flow rate of 1 ml/minute, and Solution A = water [containing 0.1% (v/v) formic acid] and Solution B = acetonitrile [containing 0.1% (v/v) formic acid] were used as solvents.
[0153]
In the tables mentioned below, the data . indicated by "RT" mean data of liquid chromatography retention time. In the columns of "Mass", data of mass spectrometry were shown (the indication "N.D" means that no molecular ion peak was detected). In the columns of "method", elution conditions of the liquid chromatography are described. For the indication of retention time in the liquid chromatography, the indication "A" for .
elution condition means that measurement was performed by elution with a linear gradient of 5 to 100% . (v/v) Solution B from 0 minute to 5 minutes and then with 100% Solution B until 6 minutes. Similarly, the indication "B" for elution condition means that measurement was performed by elution with 30% (v/v) Solution B from 0 minute to 5 minute and then with 100% (v/v) Solution B until 6 minutes. Further, for the compounds with the indication C in the elution conditions, Elution was performed at a flow rate of 1 ml/minute, and Solution A = water [containing 13.3 mM ammonium formate/ 6.7 mM formic acid] and Solution B = [6 mM ammonium formate/3 mM formic acid in water: acetonitrile (1:9, v/v)] were used as solvents. Measurement was performed under elution condition with a linear gradient of 0 to 100% (v/v) Solution B from 0 minute to 5 minutes and then with 100% Solution B until 6 minutes.
[0154]
Synthesis of Compound (A-V-02-033) Pyridinium p-toluenesulfonate (6.0 mg, 0.025 mmol) was added to a solution of ethyl 2-(((tert- butyldiphenylsilyl) oxy)methyl) -1-
(hydroxymethyl) cyclopropanecarboxylate (178 mg, 0.442 mmol) and 4-methoxybenzyl 2, 2, 2-trichloroacetimidate (153 mL, 0.739 mmol) in CH2C12 (4.40 mL) under Ar atmosphere. After stirred at room temperature for 24 h, the reaction mixture was poured into sat. aq. NaHC03, and the organic substances were extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na2S0, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 20:1) to give the desired product (128 mg, 0.251 mmol, 57%) as a colorless oil. ethyl 2- ( ( (tert-butyldiphe.nylsilyl) oxy)methyl) -1- ( ( (4- methoxybenzyl) oxy) methyl) cyclopropanecarboxylate
1H-NMR (CDC13, 500 MHz) δ: 7.63 (d, J = 7.32 Hz, 4H) , 7.43-7.34 (m, 6H) , 7.17 (d, J = 8.54 Hz, 2H) , 6.80 (d, J = 8.54 Hz, 2H) , 4.39 (s, 2H) , 4.11 (q, J = 7.32 Hz, 2H) , 3.81-3,70 (m, 3H) , 3.78 (s, 3H), 3.64 (d, J = 10.7 Hz, 1H) , 1.92-1.84 (m, 1H) , 1.39 (dd, J = 8.78, 4.39 Hz, 1H) , 1.24 (t, J = 7.32 Hz, 3H) , 1-03 (s, 9H) , 0.83 (dd, ;J = 6.83, 4.39 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ:
173.8, 159.1, 135.6, 135.5, 133.6, 133.5, 130.4 , 129.7 , 129.3, 127.7, 127.6, 113.7, 68.4, 63.0, 60.7, 55.2, 28.5, 28.2, 26.8, 19.2, 18.3, 14.2; HR-MS (ESI) calcd for C32H o05 aSi 555.2537
[,(M+Na)+], found 555.2539
[0155]
Synthesis of Compound (A-V-02-001)
CH3OCH2CI (4.30 mL, .56.2 mmol) was added to a solution of ethyl 2- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -1- (hydroxymethyl) cyclopropanecarboxylate (12.2 g, 29.6 mmol) and iPr2EtN (12.6 mL, 74.0 mmol) in CH2C12 (60 mL) at 0°C under Ar atmosphere. After stirred at room temperature for 12 h, the reaction mixture was poured into sat. aq. NaHC03, and the organic substances were extracted with AcOEt. The organic layer was washed successively with 1 N HC1, sat. aq. NaHC03 and brine. The organic layer was dried over anhydrous Na2S04, and concentrated in vacuo to give the desired product.
ethyl 2- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -1-
( (methoxymethoxy),methyl) cyclopropanecarboxylate
1H-NMR (CDCI3, 500 MHz) δ: 7.66 (d, J = 6.30 Hz, 4H) , 7.44-7.37 (m, 6H), 4.59 (d, J = 6.59 Hz, 1H) , 4.57 (d, J = 6.59 Hz, 1H) , 4.14 (q, J =.7.16 Hz, 2H) , 3.83 (d, J = 10.9 Hz, 1H) , 3.79 (dd, J = 7.45, 7.45 Hz, 2H) , 3.73 (d, J = 10.9 Hz, 1H) , 3.29 (s, 3H) , 1.91 (dddd, J = 9.16, 7.45, 7.45, 5.73 Hz, 1H) , 1.44 (dd, J = 9.16, 4.58 Hz, 1H) , 1.25 (t, J = 7.16 Hz, 3H) , 1.05 (s, 9H) , 0.88 (dd, J = 5.73, 4.58 Hz, 1H) ; 13C-NMR (CDCI3, 125 MHz) δ: 173.6,
135.5, 133.5, 133.4, 129.7, 127.7, 127.6, 96.5, 66.7, 62.8, 60.8, 55.1, 28.5, 27.9, 26.8, 19.1, 18.2 , 14.2; HR-MS (ESI) , calcd for C26H3605 aSi 479.2224 [(M+Na)+], found 479.2224
[0156]
Synthesis of Compound (A-XIV-02-001)
L1BH4 (1.61 mg, 74.0 mmol) was added to a solution of ethyl 2- ( ( (tert-butyldiphenylsilyl) oxy) methyl) -1-
( (methoxymethoxy) methyl) cyclopropanecarboxylate in dry-THF (110 mL) under argon atmosphere. After stirred at 80 °C for 20 h, a solution of 1 N HC1/THF (1:1, 10 mL) was added to the reaction^ mixture, and the organic substances were extracted with AcOEt. The organic layer was washed successively with sat. aq. NaHC03 and brine, dried over anhydrous Na2S04,. and concentrated in vacuo.
[0157]
Synthesis of Compound (A-XIV-02-033)
L1BH4 (52.7 mg, 2.42 mmol) was added to a solution of ethyl 2- ( ( (tert-butyldiphenylsilyl) oxy)methyl) -1- ( ( (4- methoxybenzyl) oxy) methyl) cyclopropanecarboxylate (643 mg, 1.21 mmol) in dry-THF (5.0 mL) under argon atmosphere. After stirred at 80°C for 18 h, a solution of 1 N HC1/THF (1:1, 10 mL) was added to the reaction mixture, and the organic substances were extracted with AcOEt. The organic layer was washed successively with sat. aq. NaHCC>3 and brine, dried over anhydrous a2S04, and . concentrated in vacuo.
[0158] Synthesis of Compound (A-XIII-01-001)
Pyridinium p-toluenesulfonate (661 mg, 2.63 mmol) was added to a solution of (2- (( (tert-butyldiphenylsilyl) oxy) methyl) -1- ( (methoxymethoxy) methyl) cyclopropyl) methanol and 4-methoxybenzyl 2,2,2-trichloroacetimidate (16.7 g, 59.2 mmol) in CH2C12 (47 mL) under Ar atmosphere. After stirred at room temperature for 2 days, the reaction mixture was poured into sat. aq. NaHC03, and the organic substances were extracted with AcOEt. The organic layer was washed with brine, dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, hexane :AcOEt = 20:1) to give a desired product (10.6 g, 19.8 mmol, 3 steps 67%) as a colorless oil.
tert-butyl ( (2-( ( (4-methoxybenzyl) oxy) methyl) -2- ( (methoxymethoxy)methyl) cyclopropyl) methoxy) diphenylsilane
XH-NMR (CDC13, 500 MHz) δ: 7.69-7.66 (m, 4H) , 7.42-7.35 (m, 6H) , 7.24 (d, J = 7.45 Hz), 6.86 (d, J = 7.45 Hz, 2H) , 4.55 (d, J = 6.87 Hz, 1H) , 4.52 (d, J = 6.87 Hz, 1H),,4.49 (d, J = 12.0 Hz, 1H) , 4.45 (d, J = 12.0 Hz, 1H) , 3.83-3.79 (m, 4H) , 3.68 (dd, J = 9.74, 6.87 Hz, 1H) , 3.59 (d, J = 10.3 Hz, 1H) , 3.56 (d, J = 10.3 Hz, lH), -3.34 (s, 2H), 3.23 (s, 3H) , 1.16 (dddd, J = 7.45, 6.87, 6.30, '5.16 Hz, 1H) , 1.04 (s, 9H) , 0.68 (dd, J = 7.45, 5.16 Hz, 1H) , 0.45 (dd, J = 5.16, 5.16 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 159.0, 135.6, 135.6, 133.9, 133.8, 130.7, 129.5, 129.1, 127.6, 127.6, 113.7, 113.6, 96.3, 74.0, 72.1, 67.7, 63.6, 55.2, 55.0, 26.8, 24.6, 23.9, 19.2, 13.4; HR-MS (ESI) calcd for C32H4205NaSi 557.2694 [(M+Na)+], found 557.2693
[0159]
Synthesis of Compound (A-XIII-02-001)
CH30CH2C1 (200 mL, 2.58 mmol) was added to a solution of (2-
( ( (tert-butyldiphenylsilyl) oxy) methyl) -1- ( ( (4- methoxybenzyl) oxy) methyl) cyclopropyl) methanol and iPr2EtN (464 mL, 2.72 mmol) in CH2C12 (3.0 mL) at 0°C under Ar atmosphere. After stirred at room temperature for 24 h, the reaction mixture was poured into sat. aq. NaHC03, and the organic substances were extracted with AcOEt. The organic layer.was washed successively with 1 N HC1, sat. aq. NaHC03 and brine. The organic layer was dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 4:1) to give a desired product (545 mg, 1.02 mmol, 2 steps 84%) as a. colorless oil.
tert-butyl ( (2-( ( (4-methoxybenzyl) oxy) methyl) -2- ( (methoxymethoxy) methyl) cyclopropyl) methoxy) diphenylsilane
1H-NMR (CDC13, 500 MHz) δ: 7.66-7.64 (m, 4H) , 7.42-7.35 (m, 6H) , 7.17 (d, J = 8.54 Hz, 2H) , 6.80 (d, J = 8.54 Hz, 2H) , 4.65 (d, J = 6.59 Hz, 1H) , 4.59 (d, J = 6.59 Hz, 1H) , 4.38 (d, J = 11.7 Hz, 1H) , 4.35 (d, J = 11.7 Hz, 1H) , 3.79 (dd, J = 11.2, 7.29 Hz, 1H) , 3.78 (s, 3H), 3.63 (dd, J = 11.2, 6.83 Hz, 1H) , 3.49-3.30 (m, 4H) , 3.33 (s, 3H) , 1.20-1.13 (m, 1H) , 1.03 (s, 9H) , 0.68 (dd, J = 8.79, 4.88 Hz, 1H) , 0.42 (dd, J = 5.37, 4.88 Hz, 1H) ; 13C-NMR (CDCI3, 125 MHz) δ: 159.0, 135.6, 135.6, 133.9, 133.9, 130.6, 129.5, 129.2, 127.6, 127.6, 113.6, 95.9, 72.5, 71.9, 69.7, 63.5, 55.2, 55.0, 26.8, 24.7, 23.7, 19.2, 13.4; HR-MS (ESI) calcd for C32H4205NaSi 557.2694 [(M+Na)+], found 557.2692
[0160]
Synthesis of Compound (A-XII-01-001)
Tetrabutylammonium fluoride (1 M in THF, 18 mL, 18.0 mmol) was added to a solution of tert-butyl ( (2- (( (4- methoxybenzyl) oxy) methyl) -2- ( (methoxymethoxy) methyl) cyclopropyl) methoxy) diphenylsilane (6.44 g, 12.0 mmol) in THF (60 mL) . After stirred at room temperature for 8 h, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 3:1) to give the desired product (3.00 g, 10.1 mmol, 84%) as a colorless oil.
(2- ( ( (4-methoxybenzyl) oxy)methyl) -2-
( (methoxymethoxy) methyl) cyclopropyl.) methanol
½-NMR (CDCI3, 500 MHz) δ: 7.27-7.24 (m, 2H) ,. 6.90-6.86 (m, 2H) , 4.63 (d, J = 6.87 Hz, 1H) , 4.62 (d, J = 6.87 Hz, 1H) , 4.47 (d, J = 12.0 Hz, 1H) , 4.43 (d, J = 12.0 Hz, 1H) , 4.11 (d, J = 10.3 Hz, 1H) , 3.95 (ddd, J = 12.0, 10.4, 5.16 Hz, 1H), .3.89 (dd, J = 10.4, 1.15 Hz, 1H) , 3.81 (s, 3H) , 3.36 (s, 3H) , 3.28 (d, J = 10.3 Hz, lH) , 3.26 (ddd, J = 12.2, 12.0,. 1.72 Hz, 1H) , 2.99 (dd, J = 10.4, 1.72 Hz, 1H) , 2.82 (d, J = 10.4 Hz, 1H) , 1.21 (dddd, J = 12.2, 8.59, 5.73, 5.16 Hz, lH) , 0.82 (dd, J = 8.59, 5.16 Hz, 1H) , 0.47 (ddd, J = 5.73, 5.16, 1.15 Hz, 1H) ;· 13C-NMR (CDC13, 125 MHz) δ: 159.1, 130.3, 129.2, 113.7, 96.5, 74.0, 72.4, 68.4, 62.8, 55.5, 55.2, 24.8, 23.2, 14.4; HR-MS (ESI) calcd for Ci6H2405Na 319.1516 [(M+Na)+], found 319.1513
[0161]
Synthesis of Compound (A-XII-02-001)
Tetrabutylammonium fluoride (1 M in THF, 2.3 mL, 2.30 mmol) was added to a solution of tert-butyl ( (2- ( ( ( - methoxybenzyl) oxy) methyl) -2- ( (methoxymethoxy) methyl) cyclopropyl)methoxy) diphenylsilane (609 mg, 1.14 mmol) in THF (3.0 mL) . After stirred at room
temperature for 3 h, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 3:1) to give the desired product in
quantitative yield as a colorless oil.
(2- ( ( (4-methoxybenzyl) oxy)methyl) -2- ( (methoxymethoxy) methyl) cyclopropyl) methanol
1H-NMR . (CDCI3, 400 MHz) δ: 7.28-7.24 (m, 2H) , 6.90-6.86 (m, 2H) , 4.60 (d, J = 6.80 Hz, 1H) , 4.58 (d, J = 6.80 Hz, lH) , 4.51 (d, J = 11.3 Hz, 1H), 4.46 (d, J = .11.3 Hz, 1H) , 3.99 (d, J = 9.97 Hz, 1H) , 3.98 (dd, J = 10.4, 1.36 Hz, 1H) , 3.92 (dd, J = 11.6, 3.88 Hz, 1H), 3.80 (s, 3H) , 3.33 (s, 4H) , 3.16 (dd, J = 11.6, 10.9 Hz, 1H) , 3.13 (dd, J = 9.97, 0.91 Hz, lH) , 2.90 (dd, J = 10.4, 0.91 Hz, 1H) , 1.24 (dddd, J = 10.4, 8.61, 5.44, 4.98 Hz, 1H) , 0.80 (dd, J = 8.61, 5.15 Hz, 1H) , 0.45 (dd, J = 5.44, 5.15 Hz, 1H) ; 13C-NMR (CDCI3, 125 MHz) δ: 159.3, 129.5, 129.4, 113.8, 96.1, 73.0, 72.1, 70.1, 62.8, 55.2, 55.1, 25,1, 23.3, 14.5; HR-MS
(ESI) calcd for Ci6H2405Na 319.1516 [(M+Na)+], found 319.1517
[0162]
Synthesis of Compound (A-XI-01-001) Dess-Martin periodinane (5.14 g, 12.1 mmol) was added to a (2- ( ( (4-methoxybenzyl) oxy) methyl) -2-
( (methoxymethoxy) methyl) cyclopropyl) methanol (3.00 g, 10.1 mmol) in CH2C12 (84 mL) at 0°C under Ar atmosphere. After stirred at room temperature for 3.5 h, the reaction mixture was poured into sat. aq. NaHC03, and the organic substances were extracted with CHC13. The organic layer was dried over Na2S04, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 4:1) to give the desired product (2.94 g, 10.0 mmol, 99%) as a colorless oil.
2- (( (4-methoxybenzyl) oxy)methyl) -2- ( (methoxymethoxy) methyl) cyclopropanecarbaldehyde
¾-NMR (CDCI3, 500 MHz) δ: 9.52 (d, J = 4.58 Hz, lH) , 7.24 (d, J = 8.59 Hz, 2H) , 6.88 (d, J = 8.59 Hz, 2H) , 4.56 (d, J = 6.30 Hz, 1H) , 4.53 (d, J = 6.30 Hz, 1H) , 4.46 (d, J = 12.0 Hz, 1H) , 4.45 (d, J = 12.0 Hz, 1H) , 3.93 (d, J = 10.9 Hz, 1H) , 3.81 (s, 3H) , 3.68. (d, J = 9.74 Hz, 1H) , 3.51 (d, J = 10.9 Hz, 1H) , 3.30 (s, 3H) , 3.24 (d, J = 9.74 Hz, 1H) , 1.97 (ddd, J = 8.02, 5.16, 4.58 Hz, lH), 1.50 (dd, J = 5.16, 5.16 Hz, 1H) , 1.26 (dd, J = 8.02, 5.16 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 199.6, 159.2, 129.9, 129.2, 113.7, 96.3, 72.6, 72.0, 65.8, 55.2, 55.2, 33.4, 31.0, 17.2; HR-MS (ESI) calcd for Ci6H2205Na 317.1359 [(M+Na)+], found 317.1362
[0163]
Synthesis of Compound (A-XI-02-001)
Dess-Martin periodinane (590 mg, 1.39 mmol) was added to a solution of (2- (( (4-methoxybenzyl) oxy) methyl) -2- ( (methoxymethoxy) methyl) cyclopropyl) methanol (344 mg, 1.16 mmol) in CH2C12 (10 mL) at 0°C under Ar atmosphere .. After stirred at room temperature for 2 h, the reaction mixture was poured into sat. aq. NaHC03, and the organic substances were extracted with CHCI3. The organic layer was dried over Na2S04, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 4il) to give the desired product (322 mg, 1.09 mmol, 94%) as a colorless oil. 2- ( ( (4-methoxybenzyl) oxy)methyl) -2- ( (methoxymethoxy) methyl) cyclopropanecarbaldehyde
1H-NMR (CDCI3, 400 MHz) δ: 9.44 (d, J = 4.53 Hz, 1H) , 7.21 (d, J = 8.61 Hz, 1H), 6.87 (d, J = 8.60 Hz, 1H) , 4.60 (d, J = 6.57 Hz, 1H) , 4.58 (d, J = 6.57 Hz, 1H) , 4.39 (d, J = 11.8 Hz, 1H) , 4.38 (d, J = 11.8 Hz, 1H) , 3.81 (d, J = 10.0 Hz, 1H) , 3.80 (s, 3H) , 3.73 (d, J = 10.0 Hz, IH) , 3.39 (d, J = 10.4 Hz, 1H) , 3.36 (d, J = 10.4 Hz, 1H), 3.33 (s, 3H) , 1.97 (ddd, J = 7.69, 5.44, 4.53 Hz, 1H) , 1.50 (dd, J = 5.44, 4.98 Hz, IH) , 1.24 (dd, J = 7.69, 4.98 Hz, IH) ; 13C-NMR (CDC13, 125. MHz) δ: 199.7, 159.2, 129.9, 129.3, 113.7, 96.3, 72.7, 70.2, 67.7, 55.2, 55.2, 33.4, 31.2, 16.9; HR- MS (ESI) calcd for Ci6H2205Na 317.1359 [(M+Na)+], found 317.1359 [0164]
Synthesis of Compound (A-X-01-001)
A solution of 2- (( (4-methoxybenzyl) oxy)methyl) -2-
( (methoxymethoxy) methyl) cyclopropanecarbaldehyde (2.92 g, 9.92 mmol), CHI3 (7.92 g, 64.5 mmol) and MS3A (8.0 g) in THF (65 mL) was added dropwise to a solution of CrCl2 (7.92 g, 64.5 mmol) in THF (33 mL) at 0°C over 15 min under Ar atmosphere. After
stirred for 4 h, H20 was added to the reaction mixture, and the mixture was filtrated through celite and the organic substances were extracted with ether. The organic layer was dried over
Na2S04, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 20:1) to give the desired product (3.02 g, 7.22 mmol, 73%) as a colorless oil. 1- ( ( (2- ( (E) -2-iodovinyl) -1- ( (methoxymethoxy) methyl) cyclopropyl) methoxy) methyl) -4- methoxybenzene
XH-NMR (CDCI3, 500 MHz) δ: 7.23 (d, J = 8.53 Hz, 2H) , 6.87 (d, J = 8.53 Hz, 2H) , 6.34 (dd, J = 14.4, 8.53 Hz, IH) , 6.07 (d, J = 14.4 Hz, IH) , 4.60 (d, J = 6.73 Hz, IH) , 4.58 (d, J = 6.73 Hz, IH) , 4.44 (s, 2H), 3.80 (s, 3H) , 3.70 (d, J = 10.3 Hz, 1H),3.56 (d, J = 9.43 Hz, IH), 3.43 (d, J = 10.3 Hz, IH) , 3.36 (s, 3H) , 3.19 (d, J = 9.43 Hz, IH) , 1.57. (ddd, J = 8.53, 8.53, 5.84 Hz, IH) , 0.97 (dd, J = 8.53, 5.38 Hz, IH) , 0.74 (dd, J = 5.84, 5.38 Hz, 1H) ; 13C-NMR (CDCI3, 125 MHz) δ: 159.1, 144.2, 130.3, 129.1,
113.7, 96.3, 74.3, 72.9, 72.5, 72.3, 67.4, 55.3, 55.2, 27.3, 26.8, 15.6; HR-MS (ESI) calcd for C17H2304INa 441.0533 [(M+Na)+], found 441.0532
[0165]
Synthesis of Compound (A-X-02-001)
A solution of 2- ( ( ( 4-methoxybenzyl) oxy) methyl) -2- ( (methoxymethoxy) methyl) cyclopropanecarbaldehyde (322 mg, 1.09 mmol) and CHI3 (901 mg, 2.29 mmol) in THF (4.0 mL) was . added dropwise to a solution of CrCl2 (871 mg, 7.09 mmol) in THF (7.0 mL) at 0°C over 15 min under Ar atmosphere. After stirred for 4 h, H20 was added to the reaction mixture, and the organic substances were extracted with ether. The organic layer was dried.over Na2S04, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanerAcOEt = 20:1) to give the desired product (381 mg, 0.916 mmol, 84%) as a colorless oil.
1- ( ( (2- ( (E) -2-iodovinyl) -1-
( (methoxymethoxy) methyl) cyclopropyl) methoxy) methyl) -4- methoxybenzene
¾-NMR (CDCI3, 500 MHz) δ: 7.29 (d, J = 8.59 Hz, 2H) , 6.90 (d, J = 8.59 Hz, 2H) , 6.25 (dd, J = 14.3, 8.59 Hz, 1H) , 6.06 (d, J = 14.3 Hz, 1H) , 4.60 (s, 2Ή) , 4.50 (d, J = 11.7 Hz, 1H) , 4.38 (d, J = 11.7 Hz, 1H) , 3.81 (s, 3H) , 3.62 (d, J = 10.0 Hz, 1H) , 3.60 (d, J = 10.0 Hz, 1H) , 3.33 (s, 3H) , 3.32 (d, J = 10.3 Hz, 1H) , 3.26 (d, -J = 10.3 Hz, 1H) , 1.59. (ddd, J = 8.59, 8.59, 5.16 Hz, 1H), 0.95 (dd, J = 8.59, 5.16 Hz, 1H) , 0.71 (dd, J = 5.16, 5.16 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 159.1, 144.3, 130.2, 129.3,
113.8, 96.2, 74.2, 72.7, 71.2, 69.2, 55.2, 55.1, 27.5, 27.0, 15.6; HR-MS (ESI) calcd for Ci7H2304INa 441.0533 [(M+Na)+], found 441.0531
[0166]
Synthesis of Compound (A-IX-01-001)
2, 3-Dichloro-5, 6-dicyano-p-benzoquinone (3.63 g, 16.0 mmol) was added to a solution of 1- (( (2- ( (E) -2-iodovinyl) -1- ( (methoxymethoxy) methyl) cyclopropyl)methoxy) methyl) -4- methoxybenzene (6.34 g, 15.2 mmol) in CH2C12 (150 mL) and H20 (7.0 mL) . After stirred for 3.5 h at room temperature, the reaction mixture was poured into sat. aq. NaHCC>3, and the organic
substances were extracted with CHC13. The organic layer was washed with sat. aq. NaCl, dried over Na2S04, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 4:1) to give the desired product (4.36 g, 14.6 mmol, 96%) as a colorless oil.
(2- ( (E) -2-iodovinyl) -1-
( (methoxymethoxy) methyl) cyclopropyl) methanol
1H-NMR (CDCI3, 500 MHz) δ: 6.35 (dd, J = 14.3, 8.60 Hz, 1H) , 6.13 (d, J = 14.3 Hz, 1H) , 4.65 (d, J = 6.30 Hz, 1H) , 4.62 (d, J = 6.30 Hz, 1H) , 3.76 (d, J = 10.3 Hz, 1H),3.63 (d, J = 6.30 Hz,. 1H) , 3.51 (d, J = 10.3 Hz, 1H), 3.49 (d, J = 6.30 Hz, 1H) , 3.40 (s, 3H) , 2.35 (dd, J = 6.30, 3.44 Hz, 1H) , 1.69 (ddd, J = 8.60, 8.01, 5.73 Hz, 1H), 0.95 (dd, J ="8.01, 5.16 Hz, 1H) , 0.72 (dd, J = 5.73, 5.16 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 144.0, 96.4, 74.8, 69.5, 68.9, 55.5, 28.9, 27.3, 15.4; HR-MS (ESI) calcd for C9H1503INa 320.9958 [(M+Na)+], found 320.9958
[0167]
Synthesis of Compound (A-IX-02-001)
2, 3-Dichloro-5, 6-dicyano-p-benzoquinone (1.19 g, 5.24 mmol) was added to a solution of 1- (( (2- ( (E) -2-iodovinyl) -1- ( (methoxymethoxy) methyl) cyclopropyl) methoxy) methyl) -4- methoxybenzene (1.99 g, 4.76 mmol) in CH2C12 (48 mL) and H20 (2.0 mL) . After stirred for 5.5 h, the reaction mixture was poured into sat. aq. NaHC03, and the organic substances were extracted with CHCI3. The organic layer was washed with sat. aq. NaCl, dried over Na2S04, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane:AcOEt = 4:1) to give the desired product (1.33 g, 4.46 mmol, 94%) as a colorless oil.
(2- ( (E) -2-iodovinyl) -1- ( (methoxymethoxy) methyl) cyclopropyl) methanol 1H-NMR (CDCI3, 500 MHz) δ: 6.37 (dd, J = 14.3, 8.02 Hz, 1H) , 6.15 (d, J = 14.3 Hz, 1H), 4.63 (s, 2H) , 3.85 (dd,. J = 12.0, 5.73 Hz, 1H) , 3.57 (dd, J = 12.0, 5.16 Hz, 1H) , 3.51 (s, 2H) , 3.38 (s, 3H) , 2.19 (dd, J = 5.73, 5.16 Hz, 1H), 1.63 (ddd, J = 8.59, 8.02, 5 5.73 Hz, 1H), 0.93 (dd, J = 8.59, 5.73 Hz, 1H) , 0.78 (dd, J =
5.73, 5.73 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 143.8, 96.3, 74.8, 73.5, 64.4, 55.4, 29.0, 27.7, 15.7; HR-MS (ESI) calcd for
C9Hi503INa 320.9958 [(M+Na)+], found 320.9959
[0168]
10 Synthesis of Compound (A-VIII)
Compound (A-IX) (25 mg, 0.084 mmol) , boronic acid or its pinacol ester (0.13 mmol) and CsC03 (56 mg, 0.17 mmol) in DMF (1.3 ml) was stirred in the presence of Pd(OAc)2 (5.7 mg, 0.0084 mmol) and triphenylphosphine (4.4 mg, 0.017 mmol) at room
15 temperature or refluxing temperature for 3-24 h under Ar
atmosphere. The reaction mixture was filtrated through celite, and the filtrate was poured into sat. aq. NaCl, and the organic substances were extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column
20 chromatography (NH silica gel, AcOEt in hexane) to give the
corresponding compound (A-VIII) .
[0169]
Compound-A-VIII-02-002
(1- ( (methoxymethoxy) methyl) -2- ( (E) -2- (quinolin-6-
25 yl) vinyl) cyclopropyl) methanol
a colorless oil; ¾-NMR (CDCI3, 500 MHz) δ: 8.81 (dd, J = 4.01, 1.72 Hz, 1H), 8.05 (d, J = 8.02 Hz, 1H) , 7.98 (d, J = 8.02 Hz, 1H) , 7.72 (dd, J = 8.59, 1.72 Hz, 1H) , 7.59 (s, lH) , 7.34 (dd, J = 8.59, 4.01 Hz, 1H), 6.68 (d, J = 15.5 Hz, 1H) , 6.23 (dd, J =
30 16.0, 8.60 Hz, 1H), 4.68 (s, 2H) , 3.97 (d, J = 11.5 Hz, lH) ,
3.70 (d, J = 11.5 Hz, 1H) , 3.65 (d, J = 9.74 Hz, 1H) , 3.56 (d, J = 9.74 Hz, 1H) , 3.41 (s, 3H) , 2.94 (s, 1H) , 1.80 (ddd, J = 8.60, 8.02, 5.16 Hz, 1H), 1.05 (dd, J = 8.02, 5.16 Hz, 1H), 0.89 (dd, J = 5.16, 5.16 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 149.6, 147.5,
35 135.8, 135.4, 130.3, 129.3, 128.4, 127.1, 124.5, 124.5, 121.3, 96.3, 73.6, 64.2, 55.3, 29.9, 25.4, 16.7; HR-MS (ESI) calcd for
Ci8H2i03NNa 322.1414 [ (M+Na)+] , found 322.1413
[0170]
Compound-A-VIII-02-004
tert-butyl 5- ( (E) -2- (2- (hydroxymethyl) -2-
( (methoxymethoxy) methyl) cyclopropyl) inyl) -lH-indazole-1- carboxylate
a colorless oil; ^- MR . (CDC13, 500 MHz) δ: 8.12 (s, 1H) , 8.07 (d, J = 9.06 Hz, 1H) , 7.60 (s, 1H) , 7.55 (d, .J = 9.06 Hz, 1H) , 6.65 (d, J = 15.4 Hz, 1H) , 6.12 (dd, J = 15.4, 8.16 Hz, 1H) , 4.67 (s, 2H) , 3.93 (d, J = 11.8 Hz, 1H) , 3.68 (d, J = 11.8 Hz, 1H) , 3.61 (d, J = 9.97 Hz, 1H) , 3.57 (d, J = 9.97 Hz, 1H) , 3.40 (s, 3H) , 2.35 (s, 1H), 1.78 (ddd, J = 8.16, 8.16, 5.44 Hz, 1H) , 1.73 (s, 9H) , 1.02 (dd, J = 8.16, 4.98 Hz, 1H) , 0.86 (dd, J = 5.44, 4.98 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 149.1, 139.6, 138.8, 133.3, 130.5, 128.6, 127.0, 126.2, 117.9, 114.5, 96.3, 84.8, 73.9, 64.7, 55.3, 29.6, 28.1, 25.3, 16.6; HR-MS (ESI) calcd for C2iH2805 2Na
411.1890 [(M+Na)+], found 411.1886
[0171]
Compound-A-VI11-02-003
tert-butyl 5- ('(E) -2- (2- (hydroxymethyl) -2-
( (methoxymethoxy) methyl) cyclopropyl) vinyl) -lH-indole-1- carboxylate
a colorless oil; 1H-NMR (CDC13, 500 MHz) δ: 8.03 (d, J = 8.02 Hz, 1H) , 7.55 (d, J = 2.87 Hz, 1H) , 7.48 (s, 1H, aromatic), 7.31 (d, J = 8.02 Hz, 1H) , 6.63 (d, J = 15.5 Hz, 1H) , 6.51 (d, J = 2.87 Hz, 1H) , 6.06 (dd, J = 16.0, 8.60 Hz, 1H) , 4.66 (s, 2H) , 3.89 (d, J = 11.5 Hz, 1H) , 3.68 (d, J = 11.5 Hz, 1H) , 3.64 (d,' J = 10.3 Hz, 1H), 3.50 (d, J = 9.74 Hz, 1H) , 3.39 (s, 3H), 2.33 (s, 1H) , 1.75 (ddd, J = 8.60, 8.02, 5.72 Hz, 1H) , 1.66 (s, 9H) , 0.99 (dd, J = 8.60, 5.16 Hz, 1H) , 0.84 (dd, J = 5.72, 5.16 Hz, 1H) ; 13C-NMR (CDCI3, 125 MHz) δ: 149.6, 134.3, 132.0, 131.6, 130.8, 126.7, 126.2, 122.3, 118.2, 115.0, 107.3, 96.3, 83.6, 73.8, 64.5, 55.2, 29.5, 28.1, 25.2, 16.5; HR-MS (ESI) calcd for C22H2905N a 410.1938 [(M+Na)+], found 410.1939 Compound-A-VI11-02-001
(1- ( (methoxymethoxy) methyl) -2- ( (E) -2- (quinolin-3- yl) vinyl) cyclopropyl) methanol
5 a colorless oil;. XH-NMR (CDC13, 500 MHz) δ: 8.93 (s, 1H) , 8.05 (d, J = 8.59 Hz, 1H) , 7.99 (s, 1H) , 7.76 (d, J = 8.59 Hz, 1H) , 7.65 (dd, J = 8.59, 7.45 Hz, 1H) , 7.52 (dd, J = 8.59, 7.45 Hz, 1H) , 6.69 (d, J = 16.0 Hz, 1H) , 6.31 (dd, J = 16.0, 8.59 Hz), 4.68 (s, 2H) , 3.97 (d, J = 12.0 Hz, 1H) , 3.70 (d, J = 16.0 Hz, 1H) , 3.61
10 (s, 2H) , 3.42 (s, 3H) , 2.34 (s, 1H) , 1.83 (ddd, J = 8.59, 8.02, 5.16 Hz, 1H) , 1.07 (dd, J = 8.02, 5.16 Hz, 1H) , 0.93 (dd, J = 5.16, 5.16 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 149.1, 147.0, 131.3, 131.3, 130.2, 128.9, 128.9, 128.0, 127.6, 127.6, 126.9, 96.3, 73.8, 64.4, 55.4, 30.1, 25.6, 16.8; HR-MS (ESI) calcd for
15 C18H2i03NNa 322.1414 [(M+Na)+], found 322.1415
[0173]
Campound-A-VI11-01-002
(1- ( (methoxymethoxy) methyl) -2- ( (E) -2- (quinolin-6- yl) vinyl) cyclopropyl) methanol
20 a colorless oil; ¾-NMR (CDC13, 400 MHz) δ: 8.84 (dd, J = 4.01,
I.72 Hz, 1H) , 8.09 (d, J = 8.59 Hz, 1H) , 8.01 (d, J = 8.59
Ηζ,ΙΗ), 7.78 (dd, J = 8.59, 1.72 Hz, 1H) , 7.62 (d, J = 1.72 Hz,' lH) , 7.37 (dd, J = 8.59, 4.01 Hz, 1H) , 6.71 (d, J = 15.5 Hz, 1H) , 6.22 (dd, J = 15.5, 8.59 Hz, 1H) , 4.65 (d, J = 6.87 Hz, 1H) ,
25 4.62 (d, J = 6.87 Hz, 1H) , 3.85 (d, J = 10.3 Hz, 1H) , 3.72 (dd, J = 11.5, 3.44 Hz, 1H), 3.68 (d, J = 10.3 Hz,.1H) , 3.60 (d, J =
II.5, 6.30 Hz, 1H) , 3.30 (s, 3H) , 2.48 - 2.45 (m, 1H) , 1.89 (ddd, J = 8.59, 8.02, 5.73 Hz, 1H) , 1.07 (dd, J = 8.02, 5.00 Hz, 1H) , 0.84 (dd, J = 5.73, 5.00 Hz, 1H) ; 13C-NMR (CDC13, 100 MHz) δ:
30 149.8, 147.7, 135.9, 135.5, 130.2, 130.2, 129.5, 128.5, 126.9, -124.7, 121.4, 96.4, 69.8, 69.3, 55.3, 29.8, 25.3, 16.5; HR-MS
(ESI) calcd for Ci8H2i03NNa 322.1414. [(M+Na)+], found 322.1412
[Q174]
Coittpound-A-VI11-01-004
35 tert-butyl 5- ( (E) -2- (2- (hydroxymethyl ) -2- ( (methoxymethoxy) methyl) cyclopropyl) vinyl) -lH-indazole-1- carboxylate
a colorless oil; 1H-N R (CDCI3, 500 MHz) δ: 8.12 (s, 1H) , 8.08 (d, J = 8.60 Hz, 1H) , 7.60 (s, 1H) , 7.55 (d, J = 8.60 Hz, 1H) , 6.63 (d, J = 15.5 Hz, 1H) , 6.10 (dd, J = 15.5, 8.59 Hz, 1H), 4.65 (d, J = 6.87 Hz, 1H) , 4.61 (d, J = 6.87 Hz, 1H) , 3.83 (d, J = 10.3 Hz, 1H), 3.69 (dd, J = 11.5, 4.01 Hz, 1H)., 3.66 (d, J - 10.3 Hz, lH,), 3.59 (dd, J = 11.5, 6.30 Hz, 1H) , 3.30 (s, 3H) , 2.39 (dd, J = 6.30, 4.01 Hz, 1H) , 1.85 (ddd, J = 8.59, 8.02, 5.73 Hz, 1H) , 1.73 (s, 9H), 1.04 (dd, J = 8.02, 5.16 Hz, 1H) , 0.80 (dd, J = 5.73, 5.16 Hz, 1H) ; 13C-NMR (CDC13, 100 MHz) δ: 149.1, 139.6, 138.8, 133.4, 130.2, 128.6, 126.8, 126.3, 117.9, 114.5, 96.3, 84.8, 69.7, 69.2, 55.3, 29.5, 28.1, 25.0, 16.2; HR-MS (ESI) calcd for C2iH2805 2Na 411.1890 [(M+Na)+], found 411.1890
[0175] ■
Contpo nd-A-VIII-01-003
tert-butyl 5- ( (E) -2- (2- (hydroxymethyl) -2-
( (methoxymethoxy)methyl) cyclopropyl) vinyl) -lH-indole-1- carboxylate
a colorless oil; 1H-NMR (CDC13, 500 MHz) δ: 8.03 (d, J = 7.70 Hz, 1H) , 7.56 (d, J = 3.62. Hz, 1H) , 7.47 (d, J = 1.36 Ηζ,ΐΗ), 7.31 (dd, J = 7.70, 1.36 Hz, 1H) , 6.62 (d, J = 15.9 Hz, 1H) , 6.52 (d, J = 3.62 Hz, 1H) , 6.05 (dd, J = 15.9, 8.15 Hz, 1H) , 4.65 (d, J = 6.65 Hz, 1H) , 4.61 (d, J = 6.65 Hz, 1H) , 3.81 (d, J = 10.4 Hz, 1H) , 3.68 (d, J = 11.3 Hz, 1H) , 3.67 (d, J = 10.4. Hz, 1H) , 3.59 (d, J = 11.3 Hz, 1H), 3.30 (s, 3H) , 2.46 (s, 1H), 1.84 (ddd, J.= 8.61, 8.15, 5.44 Hz, 1H) , 1.67 (s, 9H/ Boc) , 1.02 (dd, J = 8.61, 5.44 Hz, 1H) , 0.79 (dd, J = 5.44, 5.44 Hz, 1H) ; 13C-NMR (CDCI3, 125 MHz) δ: 149.6, 134.3, 132.1, 131.3, 130.8, 126.8, 122.2, 118.2, 115.1, 107.3, 96.4, 83.7, 70..4, 69.7, 55.3, 29.3, 28.2, 25.2, 16.2; HR-MS (ESI) calcd for C22H2905 a 410.1938 t(M+Na)+], found 410.1940
[0176]
Carapound-A-VIII-01-ΌΟΙ
(1- ( (methoxymethoxy) methyl) -2- ( (E) -2- (quinolin-3- yl) vinyl ) cyclopropyl) methanol
a colorless oil; 1H-NMR (CDCI3, 400 MHz) δ: 8.95 (d, J = 2.27 Hz, 1H) , 8.05 (d, J = 8.61 Hz, 1H) , 7.98 (d, J = 2.27 Ηζ,ΙΗ), 7.77 (d, J = 8.16 Hz, 1H) , 7.65 (dd, J = 8.61, 7.20 Hz, 1H) , 7.52 (dd, J = 8.16, 7.20 Hz, 1H), 6.69,(d, J = 15.9 Hz, 1H) , 6.30 (dd, J = 15.9, 8.61 Hz, 1H), 4.65 (d, J = 6.34 Hz, 1H) , 4.62 (d, J = 6.34 Hz, 1H) , 3.87 (d, J = 10.4 Hz,. 1H) , 3.72 (d, J = 11.3 Hz, 1H) , 3.67 (d, J = 10.4 Hz, lH) , 3.60 (d, J = 11.3 Hz, 1H) , 3.31 (s, 3H) , 2.48 (s, 1H), 1.90 (ddd, J = 8.61, 8.15, 5.89 Hz, 1H) , 1.09 (dd, J = 8.15, 5.44 Hz, 1H) , 0.86 (dd, J = 5.89, 5.44 Hz, 1H) ; 13C-NMR (CDCI3, 100 MHz) δ: 149.0, 147.0, 131.4, 131.3, 130.2, 129.0, .128.9, .128.1, 127.6, 127.5, 126.9, 96.3, 69.6," 69.0, 55.3, 30.0, 25.4, 16.5; HR-MS (ESI) calcd for Ci8H2i03NNa 322.141
[(M+Na)+], found 322.1412
[0177]
Synthesis of Compound (A-VII)
Dess-Martin periodinane (1.2 eq.) was added to a solution of compound (A-VIII) (0.625 mmol) and pyridine (1.0 mL) in CH2C12 (6.0 mL) at 0°C under Ar atmosphere. After stirring at room temperature for 2 h, the reaction mixture was poured into sat. aq. NaHC03 and sat. aq. Na2S203, and the organic substances were extracted with CHC13. The organic layer was washed with brine, dried over anhydrous Na2S04, concentrated in vacuo to give the corresponding compound (A-VII) .
[0178]
Synthesis of Compound (Int)
NaC102 (1.5 eq. ) was added to a solution of compound (A- VII) (2.08 mmol), 2-methyl-2-butene (30 eq. ) and NaH2P04 · 2H20 (2 eq.) in tert-BuOH (17 mL) and H20 (4.0 mL) . After stirring at room temperature for 2 h, the reaction mixture was poured into 1 HCl, and the organic substances were extracted with AcOEt. The organic layer was washed with brine, dried anhydrous Na2S04, concentrated in vacuo to give the corresponding compound (Int).
[0179]
Int-I-02-002 1- ( (methoxymethoxy) methyl) -2- ( (E) -2- (quinolin-6- yl) vinyl) cyclopropanecarboxylic acid
mp 162-163°C (a colorless plate from acetone); 1H-N R (CDC13, 500 MHz) δ: 8.86 (dd, J = 4.59, 1.72 Hz 1H) , 8.14 (d, J = 8.59 Hz, 1H) , 8.11 (d, J = 8.59 Hz, 1H), 8.02 (dd, J = 8.02, 1.72 Hz, 1H) , 7.52 (s, 1H), 7.42 (dd, J = 8.02, 4.59 Hz, 1H) , 6.78 - 6.70 (m, 1H) , 4.75 (s, 2H) , 4.19 (d, J = 10.3 Hz, 1H) , 3.56 (d, J = 10.3 Hz, 1H) , 3.44 (s, 3H) , 2.18 (ddd, J = 8.02, 8.02, 5.73 Hz, 1H) , 1.92 (dd, J = 5.73, 5.73 Hz, 1H), 1.49 (dd, J = 8.02, 5.73 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 174.3, 147.9, 145.4, 137.6,
136.3, 131.0, 130.1, 128.8, 126.9, 126.7, 125.6, 121.5, 96.4, 70.5, 55.3, 32.5, 29.1, 19.6; HR-MS (ESI) calcd for Ci8Hi804N
312.1241 [(M-H)"], found 312.1247
[0180]
Int-I-02-004
2- ( (E) -2- (1- (tert-butoxycarbonyl) -lH-indazol-5-yl) vinyl) -1- ( (methoxymethoxy) methyl) cyclopropanecarboxylic acid
a colorless oil; 1H-NMR (CDC13, 500 MHz) δ: 8.11 (s, 1H) , 8.04 (d, J = 8.59 Hz, 1H) , 7.58 (s, 1H) , 7.52 (d, J = 8.59 Hz, 1H) , 6.68 (d, J = 15.5 Hz, 1H) , 6.24 (dd, J = 15.5, 9.16 Hz, 1H) , 4.68 (s, 2H) , 4.01 (d, J = 10.3 Hz, 1H) , 3.54 (d, J = 10.3 Hz, 1H) , 3.39 (s, 3H) , 2.19 (ddd, J = 9.16, 8.59, 7.45 Hz, 1H) , 1.75 (dd, J = 7.45, 5.73 Hz, 1H) , 1.71 (s, 9H) , 1.43 (dd, J = 8.59, 5.73 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 177.0, 149.0, 139.6, 138.9,
133.1, 131.7, 127.2, 126.6, 126.1, 118.2, 114.5, 96.4, 84.9, 70.1, 55.3, 31.8, 30.6, 28.1, 20.1; HR-MS (ESI) calcd for
C2iH2506N2Na 401.1718 [(M-H)"], found 401.1724 - [0181]
Int-I-02-003
2- ( (E) -2- (1- (tert-butoxycarbonyl) -lH-indol-5-yl ) vinyl) -1- ( (methoxymethoxy) methyl) cyclopropanecarboxylic acid
a colorless oil; 1H-NMR (CDC13, 500 MHz) δ: 8.00 (d, J = 5.73 Hz, 1H) , 7.53. (d, J = 3.43 Hz, 1H) , 7.47 (s, 1H) , 7.29 (d, J = 5.73 Hz, 1H) , 6.67 (d, J = 16.0 Hz, 1H) , 6.48 (d, J = 3.43 Hz, 1H) , 6.18 (dd, J = 16.0, 9.16 Hz, 1H) , 4.68 (s, 2H) , 3.98 (d, J = 10.9 Hz, 1H) , 3.53 (d, J = 10.9 Hz, 1H) , 3.38 (s, 3H) , 2.17 (ddd, J = 9.16, 8.59, 7.46 Hz, 1H) , 1.74 (dd, J = 7.46, 5.15 Hz, 1H) , 1.65 (s, 9H), 1.40 (dd, J = 8.59, 5.15 Hz, 1H) ; 13C-N R (CDC13 125 MHz) δ: 177.3, 149.6, 134.5, 132.8, 131.9, 130.8, 126.2, 124.8, 122.6, 118.4, 115.1, 96.4, 83.6, 70.3, 55.3, 31.7, 30.9, 28.1, 20.1; HR-MS (ESI) calcd for C22H2606 400.1766 [ (M-H) "] , found 400.1770
[0182]
Int-I-02-001
1- ( (methoxymethoxy) methyl) -2- ( (E) -2- (quinolin-3- yl) vinyl) cyclopropanecarboxylic acid
mp 136-137°C (a colorless plate from acetone); 1H-NMR (CDC13, 500 MHz) δ: 9.30 (s, 1H) , 8.17 (d, J = 8.02 Hz, 1H) , 7.88 (s, 1H) , 7.75 (d, J = 8.02 Hz, 1H) , 7.64 (dd, J = 8.02, 6.87 Hz, 1H) , 7.51 (dd, J = 8.02, 6.87 Hz, 1H) , 6.84 (dd, J = 16.0, 9.14 Hz, 1H) , 6.70 (d, J = 16.0 Hz, 1H) , 4.78 (s, 2H) , 4.16 (d, J = 10.3 Hz, 1H-) , 3.72 (d, J = 10.3 Hz, 1H) , 3.47 (s, 3H) , 2.18.. (ddd, J = 9.14, 9.14, 6.87 Hz, 1H) , 1.87 (dd, J = 6.87, 5.16 Hz, 1H) , 1.48 (dd, J = 9.14, 5.16 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 174.2, 146.6, 144.6, 134.0, 131.7, 130.7, 129.4, 128.3, 127.6, 127.3, 127.3, 127.0, 96.5, 70.2, 55.3, 32.3, 29.4, 19.9; HR-MS (ESI) calcd for C18Hig04N 312.1244 [(M-H)"], found 312.1247
[0183]
Int-I-01-002
1- ( (methoxymethoxy) methyl) -2- ( (E) -2- (quinolin-6- yl) vinyl) cyclopropanecarboxylic acid
mp 166-167°C (a colorless plate from EtOH) ; 1H-NMR (CDC13, 500 MHz) δ: 8.88 (dd, J = 4.59, 1.72 Hz, 1H) , 8.14 (d, J = 8.02 Hz, 1H), 8.06 (d, J = 8.02 Ηζ,ΙΗ), 7.80 (dd, J = 8.60, 1.72 Hz, 1H) , 7.67 (s, 1H), 7.41 (dd, J = 8.60, 4.59 Hz, 1H) , 6.90 (d, J =
16.0 Hz, 1H) , 6.23 (dd, J = 16.0, 8.02 Hz, 1H) , 4.70 (d, J =
6.87 Hz, 1H) , 4.66 (d, J = 6.87 Hz, 1H) , 3.94 (d, J = 10.9 Hz, 1H) , 3.85 (d, J = 10.9 Hz, 1H), 3.33 (s, 3H) , 2.65 (ddd, J =
8.02, 8.02, 7.45 Hz, 1H) , 1.84 (dd, J = 8.02, 4.58 Hz, 1H), 1.31 (dd, J = 7.45, 4.58 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 177.8, 149.6, 147.2-, 136.5, 135.3, 132.1, 129.0, 128.5, 128.4, 127.2,. 125.2, 121.5, 96.6, 66.5, 55.4, 30.6, 30.2, 20.7; HR-MS (ESI) calcd for C18H1804N 312.1244 [ (M-H) "] , found 312.1248
[0184]
Int-I-01-004
2- ( (E) -2- (1- (tert-butoxycarbonyl) -lH-indazol-5-yl) vinyl) -1-
( (methoxymethoxy) methyl) cyclopropanecarboxylic acid
a colorless oil; 1H-NMR (CDC13, 500 MHz) δ: 8.16 (s, 1H) , 8.11 (d,
J = 8.59 Hz, 1H) , 7.63 (s, 1H), 7.58 (d, J = 8.59 Hz, 1H) , 6.71 (d, J = 15.5 Hz, 1H) , 6.10 (dd, J = 15.5, 8.02 Hz, 1H) , 4.68 (d, J = 6.30 Hz, 1H) , 4.65 (d, J = 6.30 Hz, 1H) , 3.87 (d, J = 10.9 Hz, 1H), 3.83 (d, J = 10.9 Hz, 1H) , 3.32 (s, 3H) , 2.60 (ddd, J = 8.59, 8.02, 8.02 Hz, 1H) , 1.80 (dd, J = 8.59, 5.16 Hz, 1H) , 1.73 (s, 9H),1.29 (dd, J = 8.02, 5.16 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz) δ: 178.9, 149.0, 139.6, 139.1, 132.8, 132.5, 127.0, 126.3, 126.2, 118.4, 114.6, 96.5, 85.0, 66.2, 55.3, 30.4, 30.3, 28.1, 20.7;
HR-MS (ESI) calcd for C2iH2506 2 401.1718 [(M-H)"], found 401.1718 [0185]
Int-I-01-003
2- ( (E) -2- (1- (tert-butoxycarbonyl) -lH-indol-5-yl) vinyl) -1- ( (methoxymethoxy) methyl) cyclopropanecarboxylic acid
a colorless oil; ^H-NMR (CDC13, 500 MHz) δ: 8.05 (d, J = 8.59 Hz, 1H) , 7.57 (d, J = 3.43 Hz, 1H) , 7.50 (s, 1H) , 7.33 (d, J = 8.59 Hz, 1H), 6.69 (d, J = 16.0 Hz, 1H) , 6.53 (d, J = 3.43 Hz, 1H) , 6.04 (dd, J = 16.0, 8.02 Hz, 1H) , 4.67 (d, J = 6.30 Hz, 1H) ,
4.64 (d, J = 6.30 Hz, 1H) , 3.83 (s, 2H) , 3.32 (s, 3H), 2.58 (ddd, J = 8.60, 8.02, 7.45 Hz, 1H) , 1.79 (dd, J = 8.60, 5.14...Hz, 1H) , 1.67 (s, 9H), 1.27 (dd, J = 7.45, 5.14 Hz, 1H) ; 13C-NMR (CDC13, 125 MHz.) δ: 179.5, 149.6, 134.6, 133.6, 131.6, 130.8, 126.4, 124.4, 122.3, 118.6, 115.1, 107.3, 96.5, 83.7, 66.2, 55.3, 30.6, 30.3, 28.1, 20.6; HR-MS (ESI) calcd for .C22H2706 Na 424.1731
[(M+Na)+], found 424.17.31
[0186]
Int-I-01-001
1- ( (methoxymethoxy) methyl) -2- ( (E) -2- (quinolin-3- yl) vinyl) cyclopropanecarboxylic acid
mp 135-137°C (a colorless plate from acetone); ¾-NMR (CDC13, 500 MHz) δ: 9.02 (d, J = 1.46 Hz, 1H) , 8.12 (d, J = 8.78 Hz, 1H) , 8.06 (d,. J = 1.46 Ηζ,ΙΗ), 7.80 (d, J = 8.78 Hz, 1H) , 7.69 (dd, J = 8.78, 7.31 Hz, 1H) , 7.55 (dd, J = 8.78, 7.31 Hz, 1H) , 6.78 (d, J = 16.1 Hz, 1H) , 6.33 (dd, J = 16.1, 8.78 Hz, 1H) , 4.72 (d, J = 6.83 Hz, 1H) , 4.68 (d, J = 6.83 Hz, 1H) , 4.00 (d, J = 10.7 Hz, lH), 3.86 (d, J = 10.7 Hz, 1H) , 3.35 (s, 3H) , 2.68 (ddd, J =
8.78, 8.78, 7..81 Hz, 1H) , 1.85 (dd, J = 8, 78, 5.37 Hz, 1H) , 1.33 (dd, J = 7.81, 5.37 Hz, 1H) ; 13C-NMR (CDC13, 100 MHz) δ: 177.6, 148.4, 146.4, 132.5, 130.0, 129.7, 129.5, ' 129.2, .128.4, 128.1, 127.8, 127.2, 96.6, 66.5, 55.4, 30.8, 30.1, 20.7; HR-MS (ESI) calcd for Ci8H1804N 312.1244 [ (M-H)'"] , found 312.1247
[0187]
Synthesis of Compound (I)
Compound (Int) (0.269 mmol) , HOBt (0.15 eq.) and amine (D- I) (1.17 eq.) in CH2C12 (2.7 mL) were treated with PS-DCC (1.27 mmol/g, 1.17 eq. ) at room temperature for 12 h. Then PS- Isocyanate (1.37 mmol/g, 2.34 eq.) and MP-Carbonate (3.21 mmol/g,5.43 eq.) were added to the reaction mixture. After 12 h, these resins were filtered, and the filtrate was concentrated in vacuo to give the corresponding compound (I) .
[0188] .
For further deprotection, the compound obtained above was subjected to the next step. A mixture of the compound obtained above and 6 M HCl/MeOH (1.0 mL) was stirred at room temperature for 5 min, and the reaction mixture was concentrated in vacuo to give the corresponding compound (I) .
[0189] ·
Compound-Ι-Ό9-001
1- (hydroxymethyl) -N-phenethyl-2- ( (E) -2- (quinolin-3- yl) vinyl) cyciopropanecarboxamide
mp 85-87°C (a yellow needle from MeOH and hexane); 1H-NMR (CD3OD, 500 MHz) δ: 9.21 (d, J = 2.29 Hz, 1H) , 8.97 (s, 1H) , 8.24 (d, J = ' 8.59 Hz, 1H) , 8.15 (d, J = 8.59 Hz, 1H) , 8.06 (dd, J = 7.45, 7.45 Hz, 1H), 7.92 (old, J = 8.02, 7.45 Hz, 1H) , 7.18-7.16 (m, 4H) , 7.06-7.02 (m, 1H) , 6.86 (d, J = 16.0 Hz, 1H) , 6.50 (dd, J = 16.0, 9.74 Hz, IH) , 3.86 (d, J = 11.5 Hz, 1H) , 3.48 (q, J = 7.44 Hz, 2H), 3.46 (d, J = 11.5 Hz, 1H) , 2.78 (q, J = 7.44 Hz, 2H) , 2.15 (ddd, J = 9.74, .6.30, 5.16 Hz, IK), 1.67 (dd, J = 5.16, 5.16 Hz, 1H), 1.20 (dd, J = 8.60, 5.16 Hz, 1H) ; 13C-NMR (CD3OD, 125 MHz) δ: 173.2, 144.4, 142.1, 140.4, 137.9, 137.2, 135.3, 133.7, 131.4, 130.5, 130.3, 129.8, 129.4, 127.3, 125.4, 121.6, 67.0, 42.2, 36.6, 36.4, 29.7, 18.4; HR-MS (ESI) calcd for - C24H2402 2 a 395.1730 [(M+Na ) +] , found 395.1729
[0190],
Compound- I - 09 - 009
1- (hydroxymethyl) -N- (3-hydroxypropyl) -2- ( (E) -2- (quinolin-3- yl) vinyl) cyclopropanecarboxamide
mp 142-146°C (a yellow needle from MeOH and hexane) ; ¾-NMR
(CD3OD, 400 MHz) δ: 9.16 (s, 1H) , 8.92 (s, 1H) , 8.16 (d, J = 8.16 Hz, 1H), 8.07 (d, J = 8.16 Hz, 1H) , 7.98 (dd, J = 8.16, 7.25 Hz, 1H) , 7.83 (d, J = 8.61, 7.25 Hz, 1H) , 6.80 (d, J = 15.9 Hz, 1H) ,
6.46 (dd, J = 15.9, 9.06 Hz, 1H) , 3.75 (d, J = 11.8 Hz, 1H) , 3.50 (d, J = 11.8 Hz, IH) , 3.4 (t, J = 6.12 Hz, 2H) , 3.26 (dt, J = 6.79, 3.62 Hz, 2H) , 2.08 (ddd, J = 9.06, 8.61, 6.34 Hz, IH) , 1.62-1.58 (m, 3H) , 1.14 (dd, J = 8.61, 4.98 Hz, IH) ; 13C-NMR
(CD3OD, 100 MHz) δ: 173.4, 144.7, 142.0, 138.2, 137.1, 135.3, 133.7, 131.4, 130.6, 130.4, 125.5, 121.7, 67.0, 60.3, 37.6, 36.6, 33.2, 29.5, 18.4; HR-MS (ESI) calcd for Ci^C^ a 349.1523
[(M+Na)+], found 349.1529 '.
[0191]
Contpound-I-09-017
N- (2- (dimethylamino) ethyl) -1- (hydroxymethyl) -2- ( (E) -2- (quinolin- 3-yl) vinyl) cyclopropanecarboxamide
mp 127-129°C (a colorless prism from EtOH) ; 1H-NMR (CD3OD, 500 MHz) δ: 8.98 (s, IH) , 8.76 (s, IH) , 7.98 (d, J = 8.02 Hz, IH) , 7.88 (d, J = 8.02 Hz, IH) , 7.79 (dd, J = 8.02, 7.45 Hz, IH) , 7.62 (dd, J = 8.02, 7.45 Hz, IH) , 6.62 (d, J = '16.0 Hz, IH) , 6.31 (dd, J = 16.0, 9.16 Hz, IH) , 3.59-3.23 (m, 6H) , 2.64 (s, 3H) , 2.61 (s, 3H) , 1.91 (ddd, J = 9.16, 8.59, 6.31 Hz, 1H) , 1.44 (dd, J = 6.31, 4.58 Hz, 1H) , 1.01 (dd, J = 8.59, 4.58 Hz, 1H) ; 13C-NMR (CD3OD, 125 MHz) δ: 174.3, 144.5, 142.3, 137.9, 136.7, 135.4, 133.6, 131.5, 130.5, 130.4, 125.8, 121.5, 66.8, 58.4, 44.0, 36.8, 36.2, 29.8, 19.0; HR-MS (ESI) calcd for . C20H26O2N3
340.2020 [ (M + H)+], found 340.2020
[0192] .
Compound-I-09-025
2- (1- (hydroxymethyl) -2- ( (E) -2- (quinolin-3- yl) vinyl) cyclopropanecarboxamido) acetic acid
mp >290°C (a colorless prism from MeOH); XH-NMR (CD3OD, 500 MHz) δ: 8.79 (d, J = 2.27 Ηζ,ΙΗ), 8Λ6 (d, J = 2.27 Ηζ,ΙΗ), 7.88 (d, J = 8.60 Hz, 1H) , 7.83 (d, J = 8.16 Hz, 1H) , 7.62 (dd, J = 8.16, 1.36 Hz, 1H), 7.50 (dd, J = 8.60, 1.36 Hz, 1H) , 6.71 (d, J = 16,2 Hz, 1H) , 6.33 (dd, J = 16.2, 9.51 Hz, 1H) , 3.84 (d, J = 17.2 Hz, 1H), 3.83 (d, J = 11.8 Hz, 1H) , 3.67 (d, J = 17.2 Hz, 1H) , 3.52 (d, J = 11.8 Hz, 1H) , 2.05 (ddd, J = 9.51, 8.60, 6.34 Hz, 1H) , 1.57 (dd, J = 6.34, 4.98 Hz, 1H) , 1.10 (dd, J = 8.60, 4.98 Hz, 1H) ; 13C-NMR (CD3OD, 125 MHz) δ: 176.3, 173.0, 150.1, 147.5, 133.3, 132.9, 132.4, 130.5, 129.8, 129.3, 128.7, 128.3, 128.2, 67.5, 45.1, 36.1, 30.0, 18.2; HR-MS (ESI) calcd for
Ci8Hi704N2 325.1194 [ (M - H) +] , found 325.1202
[0193]
Compound-I-09-033
N- (cyclohexylmethyl) -1- (hydroxymethyl) -2- ( (E) -2- (quinolin-3- yl) vinyl) cyclopropanecarboxamide
mp 121°C (a colorless prism from EtOH) ; 1H-NMR (CD3OD, 500 MHz) δ: 9.26 (d, J = 2.29 Hz, 1H) , 9.06 (d, J = 2.29 Hz., 1H) , 8.27 (d,
J = 8.02 Hz, 1H) , 8.17 (d, J = 8.59 Hz, 1H) , 8.10 (dd, J. = 8.02,. 6.87 Hz, 1H), 7.95 (dd, J = 8.59, 6.87 Hz, 1H) , 6.89 (d, J = 16.0 Hz, 1H), 6.56 (dd, J = 16.0, 9.16 Hz, 1H) , 3.91 (d, J = 12.0 Hz, 1H),- 3.51 (d, J = 12.0 Hz, 1H) , 3.13 (dd, J = 13.2, 6.87 Hz, 1H) , 3.06 (dd, J = 13.2, 6.30 Hz, 1H) , 2.19-2.15 (m, lH), 1.72-0.85 (m, 13H) ; 13C-NMR (CD3OD, .125 MHz) δ: 173.2, 144.3, 142.5, 137.7, 137.6, 135.6, 133.9, 131.7, 130.6, 130.4, 125.3, 121.3, 67.2, 46.8, 39.2, 36.6, 31.8 , 29.6, 27.4 , 27.0, 26.9, 18.3; HR-MS (ESI) calcd for C23H2802N2Na 387.2043 [ (M+Na) +] , found 387.2042
[0194]
5 Compound-I-09-041
1- (hydroxymethyl) -N- (3-methoxybenzyl) -2- ( (E) -2- (quinolin-3- yl) vinyl) cyclopropanecarboxamide
a yellow oil; 1H-NMR (CD3OD, 500 MHz) δ: 9.12 (s, 1H) , 8.86 (s, 1H) , 8.21 (d, J = 8.59 Hz, 1H) , 8.17 (d, J = 8.59 Hz, 1H),.8.09
10 (dd, J = 8.59, 6.87 Hz, 1H) , 7.94 (dd, J = 8.59, 6.87 Hz, 1H) , 6.98 (t, J = 8.02 Hz, 1H) , 6.85 (d, J = 16.0 Hz, 1H) , 6.81 (d, J = 7.45 Hz, 1H) , 6.75 (s, 1H), 6.46-6.39 (m, 2H) , 4.52 (d, J = 14.9 Hz, 1H) , 4.28 (d, J = 14.9 Hz, 1H) , 3.88 (d, J = 11.5 Hz, 1H) , 3.66 (dd, J = 11.5 Hz, 1H) , 3.43 (s, 3H) , 2.17 (ddd, J =
15 8.59, 6.30, 6.30 Hz, 1H) , 1.74 (dd, J = 6.30, 5.16 Hz, 1H) , 1.27 (dd, J = 6.30, 5.16 Hz, 1H) ; 13C-NMR (CD3OD, 125 MHz) δ: 173.1, 161.0, 144.3, 142.3, 141.9, 137.8, 137.2, 135.5, 133.7, 131.5, 130.5, 130.4, 130.3, 125.4, 121.4, 120.6, 113.9, 113.0, 67.0, 55.4, 44.1, 36.9, 29.1, 18.2; HR-MS (ESI) calcd for C24H2403 2 a
20 411.1679 [ (M+Na) +] , found 411.1677
[0195]
Compound-I-09-049
1- (hydroxymethyl) -N-isopropyl-2- ( (E) -2- (quinolin-3- yl) vinyl ) cyclopropanecarboxamide
25 mp 93-97°C (a colorless prism from MeOH) ; 1H-NMR (CD3OD, 500 MHz) δ: 9.26 (d, J = 2.29 Hz, 1H) , 9.06 (d, J = 2.29 Hz, 1H) , 8.27 (d, J = 8.02 Hz, 1H) , 8.17 (d, J = 8.59 Hz, 1H) , 8.10 (dd, J = 8.02, 6.87 Hz, 1H) , 7.94 (dd, J. = 8.59, 6.87 Hz, 1H) , 6.89 (d, J = 16.0 Hz, 1H) , 6.57 (dd, J = 16.0, 9.74 Hz, 1H) , 4.04-3.99 (m,
30 ■ 1H) , 3.88 (d, J = 12.0 Hz, 1H) , 3.52 (d, J = 12.0 Hz, 1H), 2.16 (ddd, J = 9.74, 8.60, 5.73 Hz, 1H), 1.68 (dd, J = 5.73, 5.16 Hz, 1H) , 1.21 (dd, J = 8.60, 5.16 Hz,. 1H) , 1.17 (d, J = 6.87- Hz, 3H) , 1.08 (d, J = 6.30 Hz, 3H) ; 13C-NMR (CD3OD, 125 MHz) δ: 172.3, 144.2, 142.4, 137.6, 137.4, 135.6, 133.8, 131.6, 130.6, 130.4,
35 125.3, 121.3, 67.2, 42.8, 36.6, 29.5, 22.8, 22.7, 18.3; HR-MS (ESI) calcd for Ci9H2202 2 a 333.1574 [(M+Na)+], found 333.1571
[0196]
Conrpound-I-09-057
1- (hydroxymethyl) -N- (piperidin-3-yl) -2- ( (E) -2- (quinolin-3- yl) vinyl) cyclopropanecarboxamide
a yellow oil; XH-NMR (CD3OD, 500 MHz) δ: 9.28 (d, J = 2.29 Ηζ,ΙΗ), 9.08 (d, J = 2.29 Hz, 1H) , 8.29-7.94 (m, 4H) , 6.93-6.89 (m, 1H) , 6.60-6.54 (m, 1H) , 4.11-4.09 (m, 1H) , 3.86-3.63 (m, 2H) , 3.42- 3.31 (m, 1H) , 3.00-2.76 (m, 3H)', 2.21-2.17 (m, 1H) , 2.02-0.88 (m, 6H); 13C-NMR (CD3OD, 125 MHz) δ: 173.0, 144.2, 142.4, 137.6,
137.4, 135.6, 133.8, 131.6, 130.6,- 130.4, 125.3, 121.3, 67.2, 42.8, 36.6, 29.5, 22.8, 22.7, 18.3 ; 'HR-MS (ESI) calcd for
C2iH2602 3 352.2020 [ (M + H)+], found 352.2019
[0197]
Campound-I-09-065
1- (hydroxymethyl) -N-phenyl-2- ( (E) -2- (quinolin-3- yl) vinyl) cyclopropanecarboxamide
mp 79-85°C (amorphous yellow solid); 1H-NMR (CD3OD, 500 MHz) δ: 9.24 (d, J = 2.29 Hz, 1H) , 9.03 (s, 1H) , 8.24 (d, J = 8.02 Hz, 1H), 8.13 (d, J = 8.59 Hz, 1H) , 8.08-8.05 (m, 1H) , 7.93-7.99 (m,.. 1H) , 7.51-7.49 (m, 2H) , 7.28 (dd, J = 8.59, 8.02 Hz, 2H) , 7.07 (d, J = 7.45, 6.87 Hz, 1H) , 6.94 (d, J = 16.0 Hz, 1H) , 6.50 (dd, J = 1.6.0, 9.17 Hz, 1H) , 4.08 (d, J = 12.0 Hz, 1H) , 3.59 (d, J = 12.0 Hz, 1H) , 2.29 (ddd, J = 9.17, 8.59, 6.30 Hz, lH) , 1.81 (dd, J = 6.30, 5.16 Hz, 1H), 1.31 (dd, J = 8.59, 5.16 Hz, 1H) ; 13C-NMR (CD3OD, 125 MHz) δ: 171.5, 144.3, 142.6, 139.5, 137.5, 136.9,
135.5, 133.6, 131.5, 130.5, 130.4, 129.9, 129.9, 125.7, 125.4, 121.4, 121.4, 121.2, 67.1, 37.2, 30.6, 18.6; HR-MS (ESI) calcd for C22H2o02 2Na 367.1417 [(M+Na)+], found 367.1414
[0198]
Compound-1-01-004
2- ( (E) -2- (lH-indazol-5-yl) vinyl) -1- (hydroxymethyl) -N- phenethylcyclopropanecarboxamide
mp 134-136°C (a colorless prism from EtOH) ; 1H-NMR (CD3OD, 400 MHz) δ: 8.53 (s, 1H) , 7.75 (d, J = 8.96 Hz, 1H) , 7.73 (s, 1H) , 7.54 (d, J = 8.96 Hz, 1H) , 7.19-7.06 (m, 5H) , 6.59 (d,. J = 15.7 Hz, 1H), 6.17 (dd, J = 15.7, 8.08 Hz, lH) , 3.79 (d, J = 12.1 Hz, 1H) , 3.64 (d, J = 12.1 Hz, 1H) , 3.40-3.35 (m, 2H) , 2.72 (t, J = 7.18 Hz, 2H), 2.14 (ddd, J = 8.52, 8.08, 6.29 Hz, 1H) , 1.44 (dd, J = 8.52, 4.49 Hz, 1H) , 0.93 (dd, J = 6.2.9, 4.49 Hz, 1H) ; 13C-NMR (CD3OD, 100 MHz) δ: 175.6, 140.5, 135.0, 132.5, 132.3, 131.0, 129.9, 129.5, 129.3, .127.4, 122.8, 120.2, 112.4, 62.3, 42.4, 36.6, 33.6, 29.7, 19.0; HR-MS (ESI) calcd for C22H2302 3 a 384.1683 [(M+Na)+], found 384.1679 ' ■
[0199]
Compound-I-01-012
2- ( (E) -2- (lH-indazol-5-yl) inyl) -1- (hydroxymethyl) -N- (3- hydroxypropyl) cyclopropanecarboxamide
mp 100-103°C (a colorless needle from EtOH and hexane) ; 1H-NMR
(CD3OD, 500 MHz) δ: 8.75 (s, 1H) , 7.90 (d, J = 9.17 Hz, 1H) , 7.85 (s, 1H) , 7.66 (d, J = 9.17 Hz, 1H) , 6.68 (d, J = 15.5 Hz, 1H) , 6.28 (dd, J = 15.5, 8.00 Hz, 1H) , 3.93 (d, J = 12.1 Hz, 1H) , 3.75 (d, J = 12.1 Hz, 1H) , 3.59 (t, J = 6.30 Hz, 2H) , 3.33 (q, J = 6.02 Hz, 2H) , 2.26 (ddd, J = 9.40, 8.00, 6.90 Hz, 1H) , 1.75- 1.70 (m, 2H), 1.53 (dd, J = 9.40, 5.35 Hz, 1H) , 1.04 (dd, J = 6.90, 5.35 Hz, 1H) ; 13C-NMR (CD3OD, 125 MHz) δ: 175.7, 140.3, 135.6, 132.3, 132.0, 131.8, 129.8, 122.4, 120.3, 112.7, 62.3, 60.5, 38.0, 33.7, 33.1, 29.6, 19.1; HR-MS (ESI) calcd for
Ci7H2i03N3 a 338.1475 [(M+Na)+], found 338.1474
[0200]
Compound-1-01-020
2- ( (E) -2- (lH-indazol-5-yl) vinyl) -N- (2- (dimethylamino) ethyl) -1- (hydroxymethyl) cyclopropanecarboxamide
mp 130-133°C (a colorless prism from EtOH and hexane) ; 1H-NMR (CD3OD, 500 MHz) δ: 8.74 (s, 1H) , 7.89 (d, J = 9.16 Hz, 1H) , 7.85 (s, 1H) , 7.66 (d, J = 9.16 Hz, 1H) , 6.70 (d, J = 16.0 Hz, 1H) , 6.28 (dd, J = 16.0, 8.02 Hz, 1H) , 3.98 (d, J = 12.6 Hz, 1H) , 3.80 (d, J = 12.6 Hz, 1H) , 3.62 (t, J = 5.73 Hz, 1H) , 3.61 (t, J = 5.73 Hz, 1H) , 3.30 (t, J = 5.73 Hz, 1H) , 2.93 (s, 3H) , 2.92 (s, 3H) , 2.33 (ddd, J = 8.59, 8.02, 6.30 Hz, 1H) , 1.56 (dd, J = 8.59, 4.58 Hz, 1H) , 1.10 (dd, J = 6.30, 4.58 Hz, 1H) ; 13C-NMR (CD3OD, 100 MHz) δ: 176.9, 140.8, 133.6, 133.5, 133.5, 128.7, 127.7, 123.6, 119.9, 112.0, 61.9, 58.8, 43.9, 36.3, 33.7, 30.3, 19.8;
HR-MS (ESI) calcd for C^s^ 329.1972 [ (M + H)+], found
329.1969
[0201]
Compound.-1-01-028
2-(2-( (E)-2-(lH-indazol-5-yl)vinyl)-l-
(hydroxymethyl) cyclopropanecarboxamido) acetic acid
mp 78-81°C (a colorless prism from EtOH) ; ^i-NMR (CD3OD, 400 MHz) δ: 8.57 (s, 1H), 7.83 (d, J = 9.06 Hz, 1H) , 7.82 (s, 1H) , 7.63 (d, J = 9.06 Hz, 1H) , 6.71 (d, J = 15.9 Hz, 1H) , 6.28 (dd, CP = 15.9, 7.70 Hz, 1H) , 3.99 (s, 2H) , 3.98 (d, J = 12.2 Hz, 1H) , 3.79 (d, J = 12.2 Hz, 1H) , 2.31 (ddd, J = 8.61, 7.70, 6.80 Hz, 1H) , 1.58 (dd, J = 8.61, 4.53 Hz, 1H), 1.08 (dd, J = 6.80, 4.53 Hz, 1H) ; 13C-NMR (CD3OD, 100 MHz) δ: 176.2, 172.0, 140.6, 134.6, 132.9, 132.6, 130.5, 128.7, 123.0, 120.1, 112.3, 62.2, 42.3, 33.5, 30.0, 19.3; HR-MS (ESI) calcd for Ci6H1604 3 314.1146 [ (M + H)+] , found 314.1150
[0202]
Corapound-I-01-036
2- ( (E) -2- (lH-indazol-5-yl) vinyl) -N- (cyclohexylmethyl) -1- (hydroxymethyl) cyclopropanecarboxamide
mp 174 °'C (a colorless prism from EtOH); 1H-NMR (CD3OD, 400 MHz)
i
δ: 8.79 (s, 1H) , 7.93 (d, J = 9.06 Hz, 1H) , 7.86 (s, 1H) , 7.67 (d, J = 9.06 Hz, 1H) , 6.69 (d, J = 15.9 Hz, 1H) , 6.29 (dd, J = 15.9, 8.16 Hz, 1H) , 3.93 (d, J = 12.2 Hz, 1H) , 3.74 (d, J = 12.2 Hz, lH), 3.07 (dd, J = 6.80, 3.62 Hz, 2.H) , 2.25 (ddd, J = 8.61, 8.16, 6.34 Hz, 1H) , 1.70-0.90 (m, 11H) , 1.53 (dd, J = 8.61, .53 Hz, 1H) , 1.04 (dd, J = 6.34, 4.53 Hz, 1H) ; 13C-NMR (CD3OD, 100 MHz) δ: 175.7, 140.3, 135.7, .132.2, 132.2, 131.7, 129.9, 122.3, 120.4, 112.7, 62.5, 47.2, 39.1, 33.6, 31.9, 29.5, 27.5, 27.0, 19.0, 7.83; HR-MS (ESI) calcd for C2iH2702 3 a 376.1996 [ (M+Na) +] , found 376.1994
[0203] Compound-1-01-04
2- ( (E) -2- (lH-indazol-5-yl) inyl) -1- (hydroxymethyl) -N- (3- methoxybenzyl) cyclopropanecarboxamide
a yellow oil; 1H- MR (CD30D, 400 MHz) δ: 8.75 (s, 1H) , 7.89 (d, J 5 = 8.98 Hz, 1H) , 7~.84 (s,. 1H) , 7.65 (d, J = 8.98 Hz, 1H) , 7.17
(dd, J = 7.63, 7.63 Hz, 1H) , 6.84 (d, J = 7.63 Hz, 1H) , 6.83 (s, 1H) , 6.73 (d, J = 7.63 Hz, 1H) , 6.68. (d, J = 15.7 Hz, .1H) , 6.29 (d, J = 15.7, 8.08 Hz, 1H) , 4.39 (s, 2H) , 3.96 (d, J = 12.1 Hz, 1H) , 3.79 (d, J = 12.1 Hz, 1H) , 3.72 (s, 3H) , 2.29 (ddd, J = 10 8.79, 8.08, 6.56 Hz, 1H) , 1.57 (dd, J = 8.79, 4.75 Hz, 1H) , 1.07 (dd, J = 6.56, 4.75 Hz, 1H) ; 13C-NMR (CD3OD, 100 MHz) δ: 175.6, 161.3, 141.6, 140.3, 135.6, 132.3, 132.1, 131.7, 130.6, 129.9,
122.3, 120.5, 120.4, 113.8, 113.5, 112.7, 62.3, 55.6, 44.4, 33.8, 29.7, 19.2; HR-MS (ESI) calcd for C22H2303N3Na 400.1632 [(M+Na)+],
15 found 400.1629
[0204]
Compound-I-01-052
2- ( (E) -2- (lH-indazol-5-yl) vinyl) -1- (hydroxymethyl) -N- isopropylcyclopropanecarboxamide
20 mp 83-87 °C (a colorless prism from EtOH) ; ¾-NMR (CD3OD, 400 MHz) δ: 8.71 (s, 1H) , 7.88 (d, J = 8.98 Hz, 1H) , 7.84 (d, J = 8.98 Hz, 1H), 7.64 (d, J = 8.98 Hz, 1H) , 6.68 (d, J = 15.7 Hz, 1H) , 6.26 .(dd, J = 15.7, 8.08 Hz, 1H) , 4.01-3.93 (m, 1H) , 3.90 (d, J = 12.1 Hz, 1H) , 3.71 (d, J = 12.1 Hz, 1H) , 2.23 (ddd, J = 8.08,
25 6.51, 6.51 Hz, 1H), 1.51 (dd, J = 6.51, 4.71 Hz, 1H) , 1.16 (d, J = 6.73 Hz, 3H), 1.14 (d, J = 6.73 Hz, 3H) , 1.00 (dd, J = 6.51, 4.71 Hz, 1H) ; 13C-NMR (CD3OD, 125 MHz) δ: 174.7, 140.4, 135.4,
132.4, 131.9, 131.8, 129.7, 122.5, 120.3, 112.6, 62.4, 43.0, 33.6, 29.5, 22.7, 22.6, 19.0; HR-MS (ESI) calcd for C17H2i02N3Na
30 322.1526 [(M+Na)+], found 322.1524
[0205] '
Compound-I-01-060
2- ( (E) -2- (lH-indazol-5-yl) vinyl) -1- (hydroxymethyl) -N- (piperidin-
3-yl) cyclopropanecarboxamide
35 a yellow oil; 1H-NMR (CD3OD, 500 MHz) δ: 8.74 (s, 1H) , 7.89 (d, J = 9.20 Hz, lH), 7.85 (s, 1H) , 7.66 (d, J = 9.20 Hz, 1H) , 6.69 (d, J = 15.5 Hz, 1H) , 6.35-6.25 (m, 1H) , 4.11-4.08 (m, 1H) , 4.00- 3.74 (m, 2H) , 3.39-3,36 (m, 1H) , 3.25-3.24 (m,. 1H), 3.00-2.95 (m, 2H) , 2.29-2.25 (m, 1H) , 1.99-1.05 (m, 6H) ; 13C-NMR (CD3OD, 100 MHz) δ: 175.5, 140.6, 134.6, 132.9, 132.6, 130.5, 128.7, 123.0, 120.2, 112.4, 62.1, 47.7, 45.3, 44.7, 33.7, 30.1, 28.9, 22.0, 19.4; HR-MS (ESI) calcd'for C19H25O2 4 341.1972 [ (M + H)+], found 341.1972
[0206]
Conrpound-I-01-068
2- ( (E) -2- (lH-indazol-5-yl) vinyl) -1- (hydroxymethyl) -N- phenylcyclopropanecarboxamide - mp 186-191°C (a colorless prism. from EtOH) ; XH-NMR (CD3OD, 500 MHz) 'δ: 7.8.2 (s, 1H) , 7.52 (s, 1H) , 7.38 (dd, J = 8.59, 1.15. Hz, 1H) , 7.35 (dd, J = 8.59, 1.15 Hz, 1H) , 7.34 (d, J = 8.59 Hz, 1H) , 7.29 (d, J = 8.59 Hz, 1H) , 7.14 (dd, J = 8.59, 7.45 Hz, 2H) , 6.92 (dd, J = 7.45, 7.45 Hz, 1H) , 6.54 (d, J = 16.0 Hz, 1H) , 6.05 (dd, J = 16.0, 8.02 Hz, 1H) , 3.87 (d, J = 12.0 Hz, 1H) , 3.69.(d, J = 12.0 Hz, 1H) , 2.19 (ddd, J = 8.59, 8.02, 6.31 Hz, 1H) , 1.49 (dd, J = 8.59, 4.58 Hz, 1H) , 0.92 (dd, J = 6.31, 4.58 Hz, 1H) ; 13C-NMR (CD3OD, 125 MHz) δ: 174.1, 139.7, 134.3, 132.0, 129.9, 126.2, 126.0, 125.2, 124.6, 121.5, 119.6, 111.3, 62.3, 33.9, 30.4, 19.1; HR-MS (ESI) calcd for
Figure imgf000087_0001
356.1370
[(M+Na)+], found 356.1370
[0207]
Each compound (I) was dissolved in DMSO and diluted with assay buffer (20 rtiM HEPES, 0.01 % Triton X-100, 2 mM DTT, pH
7.5) and diluted to 10 μΜ concentration with substrate/ATP/Mg or. ■ Mn solution. Test sample solution was incubated for 1 or 5 h. Termination buffer solution (Quickscout Screening Assist MSA) was added to quench the reaction and checked inhibition %.
Compound-1-.09-033 for Flt-3 and TrkA was . inhibited at 10 μΜ concentrations. The results are shown in Table 1. Table 1
Kinase Inhibition (%) at 10 uM concentrations
Flt-3 56.7
TrkA 49.4
[0208]
Formulation Compound-I -01-004 (production of capsule)
1) Compound-I-01-004 .30 mg .
2) fine powder cellulose 10 mg
3) lactose » 19 mg
4) magnesium stearate 1 mg
total 60 mg
1), 2), 3) and 4) are mixed and filled in a gelatin capsule. Industrial
Figure imgf000088_0001
[0209]
Compound (I) has a tyrosine kinase inhibitory action on Trk receptors such as TrkA, TrkB, TrkC or other tyrosine kinase receptors such as Flt-3, and is useful for the prophylaxis or treatment of proliferative diseases such as tumor or cancer, fibrotic diseases, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, tuberous sclerosis complex, hair loss, and Alzheimer's disease.
[0210]
It will be appreciated that, although specific embodiments of the invention have been described herein for the purposes of illustration, various modifications may be made without
departing from the spirit and scope of the invention.
Accordingly, the invention is not limited . except by the appended claims.
[0211]
All of the above U.S. patents, . U . S . patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference. From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the . appended claims .
[0212]
This application is based on patent application No.
61/810,951 filed in USA, the contents of which are hereby incorporated by reference.

Claims

CLAIMS com ound represented by the formula
Figure imgf000090_0001
wherein
R1 and R2 are each independently hydrogen, an optionally
substituted hydrocarbon group or an optionally substituted heterocyclic group, or
R1 and R2 in combination form, together with the adjacent nitrogen atom, optionally substituted 4- to 7-membered ring, and R3 is -W1-R30,
wherein
W21 is bond, -0-, -S(0)p- (wherein p is an integer of 0 to 2) or -NRa- (wherein Ra is hydrogen, an optionally
substituted hydrocarbon group or an optionally substituted heterocyclic group) ; and
R30 is hydrogen, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
R4 is an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted carbocyclyl-alkyl group or an optionally substituted
heterocyclyl-alkyl group;
the carbon atom marked with * is an asymmetric carbon atom, and the carbon atom marked with ** is an asymmetric carbon atom, or a salt thereof.
2. The compound or salt of claim 1, wherein R1 is optionally substituted Ci_6 alkyl, optionally substituted C3-8 cycloalkyl-Ci_3 alkyl, optionally substituted C7-13 aralkyl, optionally .
substituted C6-10 aryl or an optionally substituted 5- or 6- membered non-aromatic heterocyclic group, and R2 is hydrogen.
3. The compound or salt of claim 1, wherein R3 is -W21-R30, wherein
W21 is -0-; and
R30 is hydrogen or optionally substituted Ci-io alkyl.
4. The compound or salt of claim 1, wherein R4 is " optionally substituted Οε-ιο aryl or an optionally substituted aromatic heterocyclic group.
5. The compound or salt of claim 1, wherein
R1 is optionally substituted Ci_6 alkyl, optionally substituted C3- 8 cycloalkyl-Ci-3 alkyl, optionally substituted C7_i3 aralkyl, optionally substituted C6-io aryl or an optionally substituted 5- or 6-membered non-aromatic heterocyclic group, and R2 is
hydrogen;
R3 is - 21-R30, wherein
21 is -0-; and
R30 is hydrogen or optionally substituted Ci-10 alkyl; and R4 is optionally substituted C6-10 aryl or an optionally
substituted aromatic heterocyclic group.
"
6. A pharmaceutical composition comprising the compound or salt of claim 1, and a pharmaceutically acceptable carrier.
7. The composition of claim 6, which is an agent for the
prophylaxis or treatment of proliferative disease.
8. The composition of claim 6, which is tyrosine kinase
inhibitor.
9. A method for the prophylaxis or treatment of proliferative disease in a mammal, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal.
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